Transfer hydrogenation of cyclopamine analogs

Abstract

Provided herein is a process for the transfer-hydrogenation of ketone analogs of members of the jervine type of Veratrum alkaloids, such as cyclopamine. Also provided herein are novel ruthenium transfer-hydrogenation catalysts.

Claims

1. A process for preparing a compound of formula (II): ##STR00235## or a pharmaceutically acceptable form thereof; from a compound of formula (I): ##STR00236## or a pharmaceutically acceptable form thereof; wherein: R.sup.1 is alkyl, alkenyl, alkynyl, aralkyl, C(O)R.sup.16, CO.sub.2R.sup.16, SO.sub.2R.sup.16, [C(R.sup.23).sub.2].sub.qR.sup.23, [(W)N(R.sup.17)C(O)].sub.qR.sup.16, [(W)C(O)N(R.sup.17)].sub.qR.sup.17, or [(W)N(R.sup.17)].sub.qR.sup.16, W is (CH.sub.2).sub.q and each q is independently 1, 2, 3, 4, 5, or 6; R.sup.5 and R.sup.6 are each H, or R.sup.5 and R.sup.6 taken together with the carbon to which they are bonded form CO; R.sup.11 and R.sup.12 are each H, or R.sup.11 and R.sup.12 taken together form a double bond; X is a bond or the group CH.sub.2; R.sup.16 is alkyl, alkenyl, alkynyl, aralkyl, alkoxy, arylalkoxy, or heteroaralkyl; R.sup.17 is H, alkyl, alkenyl, or alkynyl; and R.sup.23 is H, alkyl, alkenyl, alkynyl, amido, or amino; the process comprising reducing a compound of formula (I) or a pharmaceutically acceptable form thereof in the presence of a ruthenium transfer hydrogenation catalyst and a hydrogen donor to thereby preferentially generate a stereoisomer of a compound of formula (II) or a pharmaceutically acceptable form thereof, wherein the ruthenium transfer hydrogenation catalyst comprises one or more of (iii-a), (iii-i), and (iii-k): ##STR00237## wherein R.sup.a and R.sup.b are each the same group selected from hydrogen and alkyl; R.sup.c is selected from hydrogen and alkyl; X.sub.a is selected from iodo (I.sup.), bromo (Br.sup.), chloro (Cl.sup.) and fluoro (F); and each of R.sup.h, R.sup.i, R.sup.k, R.sup.l, and R.sup.m is independently selected from hydrogen and alkyl.

2. The process of claim 1, wherein the compound of formula (I) is a compound of formula (I-AA): ##STR00238## or a pharmaceutically acceptable form thereof, and the compound of formula (II) is a compound of formula (II-AA): ##STR00239## or a pharmaceutically acceptable form thereof, wherein X is (CH.sub.2); R.sup.1 is benzyl or CO.sub.2R.sup.16, and R.sup.16 is benzyl; R.sup.2 and R.sup.3 are taken together to form a double bond; R.sup.5 and R.sup.6 are each hydrogen or R.sup.5 and R.sup.6 taken together with the carbon to which they are bonded form CO; and R.sup.10, R.sup.11 and R.sup.12 are each hydrogen, or R.sup.11 and R.sup.12 taken together, form a double bond.

3. The process of claim 2 wherein the ring carbon atom that is directly attached to the hydroxyl group on the compound of formula (II-AA) has an (S) stereochemical configuration and R.sup.11 is hydrogen in the -position.

4. The process of claim 1, wherein R.sup.a and R.sup.b are both CH.sub.3 and R.sup.c is CH.sub.2CH.sub.3.

5. The process according to claim 1, wherein the benzene ligand with R.sup.h-R.sup.m is selected from benzene, mesitylene, p-cymene, and hexamethylbenzene.

6. The process according to claim 5, wherein the ruthenium transfer-hydrogenation catalyst is generated from (hexamethylbenzene)ruthenium chloride dimer and an achiral amino alcohol.

7. The process according to claim 1, wherein the ruthenium transfer-hydrogenation catalyst is of formula (iii-a): ##STR00240## wherein: each R.sup.a and R.sup.b are the same group selected from hydrogen and alkyl, R.sup.c is selected from hydrogen and alkyl; and each of R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m is independently selected from hydrogen and alkyl.

8. The process according to claim 7, wherein the ruthenium transfer-hydrogenation catalyst is of the formula (iii-g): ##STR00241##

9. The process of claim 1, wherein R.sup.a and R.sup.b are each methyl, R.sup.c is ethyl, each of R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m is methyl, and X.sub.a is Cl.sup..

10. The process of claim 1, wherein the hydrogen donor is an organic alcohol.

11. The process of claim 10, wherein the reducing is carried out in an ether solvent.

12. The process of claim 11, wherein the reducing is carried out at a temperature of about 10 C. to about 40 C.

13. The process of claim 11, wherein the reducing is carried out in the presence of base.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 depicts the chemical synthesis of IPI-926 (V-a) from cis-decalone starting material (I-a) as described in Tremblay et al., Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926) J. Med. Chem. (2009) 52:4400-4418. Step 1 of the depicted synthesis, the K-selectride reduction, provided the reduced product (S)-(II-a) in >96:4 to selectivity.

(2) FIG. 2 depicts the ruthenium-catalyzed transfer-hydrogenation of (I-a). Transfer-hydrogenation of (I-a) using 1 mol % of the achiral ruthenium transfer-hydrogenation catalyst (iii-g) provided the reduced product (S)-(II-a) in >98.7:1.3 : selectivity.

DETAILED DESCRIPTION

(3) For example, in one aspect, provided herein is a process for preparing a compound of formula (II):

(4) ##STR00030##

(5) or its pharmaceutically acceptable forms thereof;

(6) from a compound of formula (I):

(7) ##STR00031##

(8) or its pharmaceutically acceptable forms thereof;

(9) wherein:

(10) R.sup.1 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, OR.sup.16, C(O)R.sup.16, CO.sub.2R.sup.16, SO.sub.2R.sup.16, C(O)N(R.sup.17)(R.sup.17), [C(R.sup.16).sub.2]q-R.sup.16, [(W)N(R.sup.17)C(O)].sub.qR.sup.16, [(W)C(O)].sub.qR.sup.16, [(W)C(O)O].sub.qR.sup.16, [(W)OC(O)].sub.q, R.sup.16, [(W)SO.sub.2].sub.qR.sup.16, [(W)N(R.sup.17)SO.sub.2].sub.qR.sup.16, [(W)C(O)N(R.sup.17)].sub.qR.sup.17, [(W)O].sub.qR.sup.16, [(W)N(R.sup.17)].sub.qR.sup.16, or [(W)S].sub.qR.sup.16; wherein W is a diradical and q is 1, 2, 3, 4, 5, or 6;

(11) each R.sup.2 and R.sup.3 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, halo, OR.sup.16, OR.sup.16, N(R.sup.17).sub.2, or SR.sup.16, or R.sup.2 and R.sup.3 taken together form a double bond or form a group:

(12) ##STR00032##
wherein Z is NR.sup.17, O, or C(R.sup.18).sub.2;

(13) R.sup.4 is independently H, halo, OR.sup.16, N(R.sup.17).sub.2, or SR.sup.16;

(14) each R.sup.5 and R.sup.6, is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, OR.sup.16, N(R.sup.17).sub.2, or SR.sup.16; or R.sup.5 and R.sup.6 taken together with the carbon to which they are bonded form CO, CS, CNOR.sup.17, CNR.sup.17, CNN(R.sup.17).sub.2, or form an optionally substituted 3-8 membered ring;

(15) each R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, OR.sup.16, N(R.sup.17).sub.2, or SR.sup.16;

(16) or R.sup.11 and R.sup.12 taken together, form a double bond;

(17) or R.sup.10 and R.sup.11 taken together, or R.sup.11 and R.sup.12 taken together, form a group:

(18) ##STR00033##
wherein Z is NR.sup.17, O, or C(R.sup.18).sub.2;

(19) each R.sup.14 and R.sup.15 is, independently, H, halo, OR.sup.16, N(R.sup.17).sub.2, or SR.sup.16; or R.sup.14 and R.sup.15 taken together with the carbon to which they are bonded form CO or CS;

(20) X is a bond or the group C(R.sup.19).sub.2, wherein each R.sup.19 is, independently, H, alkyl, aralkyl, halo, CN, OR.sup.16, or N(R.sup.17).sub.2;

(21) R.sup.16 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or [C(R.sup.20).sub.2].sub.pR.sup.21 wherein p is 0-6; or any two occurrences of R.sup.16 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;

(22) R.sup.17 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, C(O)R.sup.20, C(O)OR.sup.20, SO.sub.2R.sup.20, C(O)N(R.sup.20).sub.2, or [C(R.sup.20).sub.2].sub.pR.sup.21 wherein p is 0-6; or any two occurrences of R.sup.17 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;

(23) R.sup.18 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, CN, OR.sup.20, OSi(R.sup.20).sub.3, C(O)R.sup.20, C(O)OR.sup.20, SO.sub.2R.sup.20 or C(O)N(R.sup.20).sub.2;

(24) R.sup.20 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R.sup.20 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;

(25) R.sup.21 is OR.sup.22, N(R.sup.22)C(O)R.sup.22, N(R.sup.22)C(O)OR.sup.22, N(R.sup.22)SO.sub.2(R.sup.22), C(O)R.sup.22N(R.sup.22).sub.2, OC(O)R.sup.22N(R.sup.22(R.sup.22), SO.sub.2N(R.sup.22)(R.sup.22), N(R.sup.22)(R.sup.22), C(O)OR.sup.22, C(O)N(OH)(R.sup.22), OS(O).sub.2OR.sup.22, S(O).sub.2OR.sup.22, OP(O)(OR.sup.22)(OR.sup.22), N(R.sup.22)P(O)(OR.sup.22)(OR.sup.22), or P(O)(OR.sup.22)(OR.sup.22); and

(26) R.sup.22 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl; or any two occurrences of R.sup.22 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;

(27) the process comprising reacting a compound of formula (I) or its pharmaceutically acceptable forms thereof with a transfer-hydrogenation catalyst in order to provide a compound of formula (II) or its pharmaceutically acceptable forms thereof.

(28) For example, in one aspect, provided herein is a process for preparing a compound of formula (II):

(29) ##STR00034##
or its pharmaceutically acceptable forms thereof;
from a compound of formula (I):

(30) ##STR00035##
or its pharmaceutically acceptable forms thereof;
wherein:

(31) R.sup.1 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, heteroalkyl, C(O)R.sup.16, CO.sub.2R.sup.16, SO.sub.2R.sup.16, C(O)N(R.sup.17)(R.sup.17), [C(R.sup.23).sub.2].sub.qR.sup.23, [(W)N(R.sup.7)C(O)]R.sup.16, [(W)C(O)N(R.sup.17)].sub.qR.sup.17, [(W)N(R.sup.17)].sub.qR.sup.16, or [(W)S].sub.qR.sup.16; wherein W is (CH.sub.2).sub.q and each q is independently 1, 2, 3, 4, 5, or 6;

(32) each R.sup.2 and R.sup.3 is, independently, H, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, haloalkyl, heteroalkyl, CN, NO.sub.2, halo, OR.sup.16, N(R.sup.17).sub.2, or SR.sup.16, or R.sup.2 and R.sup.3 taken together form a double bond or form a group:

(33) ##STR00036##

(34) wherein Z is NR.sup.17, O, or C(R.sup.18).sub.2;

(35) R.sup.4 is H, halo, OR.sup.16, N(R.sup.17).sub.2, or SR.sup.16;

(36) each R.sup.5 and R.sup.6, is, independently, H, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, heteroalkyl; or R.sup.5 and R.sup.6 taken together with the carbon to which they are bonded form CO or CS;

(37) each R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 is, independently, H, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, heteroalkyl, halo, or OR.sup.16, or R.sup.11 and R.sup.12 taken together, form a double bond;

(38) each R.sup.14 and R.sup.15 is, independently, H, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, heteroalkyl, halo, OR.sup.16, N(R.sup.17).sub.2, or SR.sup.16; or R.sup.14 and R.sup.15 taken together with the carbon to which they are bonded form CO or CS;

(39) X is a bond or the group C(R.sup.19).sub.2, wherein each R.sup.19 is, independently, H, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, heteroalkyl, halo, CN, NO.sub.2, OR.sup.16, or N(R.sup.17).sub.2;

(40) R.sup.16 is alkyl, alkenyl, alkynyl, alkoxy, arylalkoxy, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R.sup.16 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;

(41) R.sup.17 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, C(O)R.sup.20, C(O)OR.sup.20, SO.sub.2R.sup.20, or C(O)N(R.sup.20).sub.2; or any two occurrences of R.sup.17 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;

(42) R.sup.18 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl, halo, CN, OR.sup.20, OSi(R.sup.20).sub.3, N(R.sup.17).sub.2, C(O)R.sup.20, C(O)OR.sup.20, SO.sub.2R.sup.20 or C(O)N(R.sup.20).sub.2;

(43) R.sup.20 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R.sup.20 on the same substituent are taken together to form a 4-8 membered optionally substituted ring; and

(44) R.sup.23 is H, alkyl, alkenyl, alkynyl, amido, or amino;

(45) the process comprising reacting a compound of formula (I) or its pharmaceutically acceptable forms thereof with a transfer-hydrogenation catalyst in order to provide a compound of formula (II) or its pharmaceutically acceptable forms thereof.

(46) For example, in one aspect, provided herein is a process for preparing a compound of formula (II):

(47) ##STR00037##

(48) or its pharmaceutically acceptable forms thereof;

(49) from a compound of formula (I):

(50) ##STR00038##

(51) or its pharmaceutically acceptable forms thereof;

(52) wherein:

(53) R.sup.1 is alkyl, alkenyl, alkynyl, aralkyl, C(O)R.sup.16, CO.sub.2R.sup.6, SO.sub.2R.sup.16, [C(R.sup.23).sub.2].sub.qR.sup.23, [(W)N(R.sup.17)C(O)].sub.qR.sup.16, [(W)C(O)N(R.sup.17)].sub.qR.sup.17, or [(W)N(R.sup.17)].sub.qR.sup.16, W is (CH.sub.2).sub.q and each q is independently 1, 2, 3, 4, 5, or 6;

(54) R.sup.5 and R.sup.6 are each H, or R.sup.5 and R.sup.6 taken together with the carbon to which they are bonded form CO;

(55) R.sup.11 and R.sup.12 are each H, or R.sup.11 and R.sup.12 taken together form a double bond;

(56) X is a bond or the group CH.sub.2;

(57) R.sup.16 is alkyl, alkenyl, alkynyl, aralkyl, alkoxy, arylalkoxy, or heteroaralkyl;

(58) R.sup.17 is H, alkyl, alkenyl, or alkynyl; and

(59) R.sup.23 is H, alkyl, alkenyl, alkynyl, amido, or amino; the process comprising reacting a compound of formula (I) or its pharmaceutically acceptable forms thereof with a transfer-hydrogenation catalyst in order to provide a compound of formula (II) or its pharmaceutically acceptable forms thereof.

(60) In certain embodiments, R.sup.1 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, C(O)R.sup.16, CO.sub.2R.sup.6, SO.sub.2R.sup.16, C(O)N(R.sup.17)(R.sup.17), or [C(R.sup.6).sub.2].sub.qR.sup.16. In certain embodiments, R.sup.1 is H, aralkyl, C(O)R.sup.16, CO.sub.2R.sup.16, SO.sub.2R.sup.16 or C(O)N(R.sup.17)(R.sup.17). In certain embodiments, R.sup.1 is H, aralkyl or CO.sub.2R.sup.16

(61) In certain embodiments, R.sup.1 is H.

(62) In certain embodiments, R.sup.1 is aralkyl (e.g., benzyl).

(63) In certain embodiments, R.sup.1 is CO.sub.2R.sup.16. In certain embodiments, R.sup.1 is CO.sub.2R.sup.16 and R.sup.16 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl. In certain embodiments, R.sup.1 is a -Boc group (e.g., wherein R.sup.1 is CO.sub.2R.sup.16 and R.sup.16 is t-butyl). In certain embodiments, R.sup.1 is a -Cbz group (e.g., wherein R.sup.1 is CO.sub.2R.sup.16 and R.sup.16 is benzyl).

(64) In certain embodiments, R.sup.2 and R.sup.3 are taken together form a double bond.

(65) In certain embodiments, R.sup.2 and R.sup.3 form a group:

(66) ##STR00039##

(67) wherein Z is NR.sup.17, O, or C(R.sup.18).sub.2. In certain embodiments, Z is C(R.sup.18).sub.2. In certain embodiments, Z is CH.sub.2.

(68) In certain embodiments, X is a bond. For example, in certain embodiments, wherein R.sup.2 and R.sup.3 are taken together form a double bond, or wherein R.sup.2 and R.sup.3 form a group:

(69) ##STR00040##

(70) and Z is NR.sup.17, O, or C(R.sup.18).sub.2, then X is a bond.

(71) In certain embodiments, X is the group C(R.sup.19).sub.2. In certain embodiments, R.sup.19 is H, e.g., wherein X is CH.sub.2.

(72) In certain embodiments, wherein R.sup.2 and R.sup.3 are taken together form a double bond, then X is the group C(R.sup.19).sub.2. In certain embodiments, wherein R.sup.2 and R.sup.3 are taken together form a double bond, then X is the group CH.sub.2.

(73) In certain embodiments, R.sup.4 is H.

(74) In certain embodiments, each R.sup.5 and R.sup.6, is, independently, H, or R.sup.5 and R.sup.6 taken together, along with the carbon to which they are bonded, form CO. In certain embodiments, each of R.sup.5 and R.sup.6 is independently H. In certain embodiments, R.sup.5 and R.sup.6 taken together with the carbon to which they are bonded form CO.

(75) In certain embodiments, R.sup.7 and R.sup.8 are each H.

(76) In certain embodiments, R.sup.9 and R.sup.10 are each H.

(77) In certain embodiments, R.sup.1 is a H.

(78) In certain embodiments, R.sup.12 and R.sup.13 are each H.

(79) In certain embodiments, R.sup.14 and R.sup.15 are each H.

(80) In certain embodiments, each of R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 is H.

(81) In certain embodiments, R.sup.13 is H, and R.sup.11 and R.sup.12 taken together form a double bond.

(82) In certain embodiments, the compound of formula (I) is a compound of the formula (I-AA):

(83) ##STR00041##

(84) or its pharmaceutically acceptable forms thereof,

(85) and the compound of formula (II) is a compound of the formula (II-AA):

(86) ##STR00042##

(87) or its pharmaceutically acceptable forms thereof,

(88) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.10, R.sup.11, R.sup.12 and X are as defined herein.

(89) In certain embodiments, the compound of formula (I) is a compound of the formula (I-AA):

(90) ##STR00043##

(91) or its pharmaceutically acceptable forms thereof,

(92) and the compound of formula (II) is a compound of the formula (II-AA):

(93) ##STR00044##

(94) or its pharmaceutically acceptable forms thereof,

(95) wherein X is (CH.sub.2);

(96) R.sup.1 is benzyl, or CO.sub.2R.sup.16 and R.sup.16 is benzyl;

(97) R.sup.2 and R.sup.3 are taken together to form a double bond;

(98) R.sup.5 and R.sup.6 are each hydrogen or R.sup.5 and R.sup.6 taken together with the carbon to which they are bonded form CO; and

(99) R.sup.10, R.sup.11 and R.sup.12 are each hydrogen, or R.sup.11 and R.sup.12 taken together, form a double bond.

(100) In certain embodiments, the compound of formula (I) is a compound of the formula (I-BB):

(101) ##STR00045##

(102) or its pharmaceutically acceptable forms thereof,

(103) and the compound of formula (II) is a compound of the formula (II-BB):

(104) ##STR00046##

(105) or its pharmaceutically acceptable forms thereof,

(106) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6 and X are as defined herein.

(107) In certain embodiments, the compound of formula (I) is a compound of the formula (I-CC):

(108) ##STR00047##

(109) or its pharmaceutically acceptable forms thereof,

(110) and the compound of formula (II) is a compound of the formula (II-CC):

(111) ##STR00048##

(112) or its pharmaceutically acceptable forms thereof,

(113) wherein R.sup.1 and X are as defined herein.

(114) Exemplary compounds of formula (I), and subgenera thereof, are provided in U.S. Pat. No. 7,812,164 and U.S. Publication No. 20090012109, each of which is incorporated herein by reference in their entirety.

(115) In some embodiments, the compound of formula (I) or its pharmaceutically acceptable forms thereof include, but are not limited to the following:

(116) ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053##
or its pharmaceutically acceptable forms thereof.

(117) Suitable compounds of Formula (I) for use in the processes disclosed herein can be accessed from members of the Liliaceae natural product family through synthetic methods within the knowledge scope of the skilled artisan. (See., e.g., Li, H.-J. et al., Chemistry, bioactivity and geographical diversity of steroidal alkaloids from the Liliaceae family Nat. Prod. Rep. (2006) 23:735-752, incorporated herein by reference in its entirety). Compounds of Formula (I) can result from the appropriate transformation of the following non-limiting examples of known Veratrum-type natural products, including jervine, jervinone, O-acetyljervine, methyljervine-N-3-propanoate, 1-hydroxy-5,6-dihydrojervine, pseudojervine, verdine, verapatuline, cycloposine, hupehenisine, songbeisine, kuroyurinidine, 23-isokuroyurinidine, yibeissine, tortifolisine, peimicine, and ebeiensine.

(118) In certain embodiments, the compound of formula (I) or its pharmaceutically acceptable forms thereof, and a compound of formula (II) or its pharmaceutically acceptable forms thereof, are selected from the set of compounds, or their pharmaceutically acceptable forms thereof, provided in Tables 1, 2, and 3, and wherein R.sup.1 is as defined above and herein:

(119) TABLE-US-00001 TABLE 1 Compound of formula (I) Compound of formula (II) 0

(120) TABLE-US-00002 TABLE 2 Compound of formula (I) Compound of formula (II)

(121) TABLE-US-00003 TABLE 3 Compound of formula (I) Compound of formula (II) 0

(122) In certain embodiments, R.sup.1 is H.

(123) In certain embodiments, R.sup.1 is aralkyl (e.g., benzyl).

(124) In certain embodiments, R.sup.1 is CO.sub.2R.sup.16. In certain embodiments, R.sup.1 is CO.sub.2R.sup.16 and R.sup.16 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl. In certain embodiments, R.sup.1 is a -Boc group (e.g., wherein R.sup.1 is CO.sub.2R.sup.16 and R.sup.16 is t-butyl). In certain embodiments, R.sup.1 is a -Cbz group (e.g., wherein R.sup.1 is CO.sub.2R.sup.16 and R.sup.16 is benzyl).

(125) As used herein, the term preferentially generates refers to the production of one stereoisomer of a compound of formula (II) in excess over the other stereoisomer. In certain embodiments, the process preferentially generates a compound of formula (II), or its pharmaceutically acceptable forms thereof, wherein the carbon atom that is directly attached to the newly-formed hydroxyl group has the (R) or (S) configuration, in greater than 40% diastereomeric excess (de), greater than 50% de, greater than 60% de, greater than 70% de, greater than 75% de, greater than 80% de, greater than 85% de, greater than 90% de, greater than 95% de, greater than 98% de, or greater than 99% de, as determined by HPLC or other analytical methods known to the skilled artisan.

(126) In certain embodiments, the process preferentially generates a compound of formula (II), or its pharmaceutically acceptable forms thereof, from a compound of formula (I), or its pharmaceutically acceptable forms thereof, wherein the carbon atom that is directly attached to the newly-formed hydroxyl group provided in formula (II) has the (R) or (S) configuration.

(127) For example, in certain embodiments, the process preferentially generates a compound of formula (II), or its pharmaceutically acceptable forms thereof, from a compound of formula (I), or its pharmaceutically acceptable forms thereof, wherein the newly-formed hydroxyl group has the a (alpha) orientation; or the carbon atom that is directly attached to the newly-formed hydroxyl group has the (R) configuration; or the newly-formed hydroxyl group has the a (alpha) orientation, and the carbon atom that is directly attached to the newly-formed hydroxyl group has the (R) configuration; e.g., a compound of the formula (R)-(II):

(128) ##STR00078##

(129) or its pharmaceutically acceptable forms thereof,

(130) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and X are as defined herein.

(131) In certain embodiments, the process preferentially generates a compound of formula (II), or its pharmaceutically acceptable forms thereof, from a compound of formula (I), or its pharmaceutically acceptable forms thereof, wherein the newly-formed hydroxyl group has the (beta) orientation; or the carbon atom that is directly attached to the newly-formed hydroxyl group has the (S) configuration; or the newly-formed hydroxyl group has the P (beta) orientation, and the carbon atom that is directly attached to the newly-formed hydroxyl group has the (S) configuration; e.g., a compound of the formula (S)-(II):

(132) ##STR00079##

(133) or its pharmaceutically acceptable forms thereof,

(134) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and X are as defined herein.

(135) In one embodiment, the process preferentially generates a compound of formula (II), or its pharmaceutically acceptable forms thereof, wherein the carbon atom that is directly attached to the newly-formed hydroxyl group has the (S) configuration.

(136) In certain embodiments, the compound of formula (I) is a compound of the formula (I-AA):

(137) ##STR00080##

(138) or its pharmaceutically acceptable forms thereof,

(139) and the compound of formula (II) is a compound of the formula (S)-(II-AA):

(140) ##STR00081##

(141) or its pharmaceutically acceptable forms thereof,

(142) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.10, R.sup.11, R.sup.12 and X are as defined herein.

(143) In certain embodiments, the compound of formula (I) is a compound of the formula (I-BB):

(144) ##STR00082##

(145) or its pharmaceutically acceptable forms thereof,

(146) and the compound of formula (II) is a compound of the formula (S)-(II-BB):

(147) ##STR00083##

(148) or its pharmaceutically acceptable forms thereof,

(149) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6 and X are as defined herein.

(150) In certain embodiments, the compound of formula (I) is a compound of the formula (I-CC):

(151) ##STR00084##

(152) or its pharmaceutically acceptable forms thereof,

(153) and the compound of formula (II) is a compound of the formula (II-CC):

(154) ##STR00085##

(155) or its pharmaceutically acceptable forms thereof,

(156) wherein R.sup.1 and X are as defined herein.

(157) In another embodiment, the compounds of formulae (I) and (II) are selected from the set of compounds, or their pharmaceutically acceptable forms thereof, provided in Table 1.

(158) In certain embodiments, the process preferentially generates a compound of formula (II) of Table 1, or its pharmaceutically acceptable forms thereof, wherein the carbon atom that is directly attached to the newly-formed hydroxyl group has the (S) configuration.

(159) For example, in certain embodiments, the compounds of formulae (I) and (II) are selected from a set of compounds, or their pharmaceutically acceptable forms thereof, provided in Table 4, wherein the carbon atom that is directly attached to the newly-formed hydroxyl group of the compound of formula (II) has the (S) configuration:

(160) TABLE-US-00004 TABLE 4 Compound of formula (I) Compound of formula (II) 0

(161) In certain embodiments, the compound of formula (I) is a compound of formula (I-a)

(162) ##STR00094##

(163) or its pharmaceutically acceptable forms thereof,

(164) and the compound of formula (II) is a compound of formula (S)-(II-a):

(165) ##STR00095##

(166) or its pharmaceutically acceptable forms thereof,

(167) wherein R.sup.1 is as defined herein, (see, e.g., FIG. 2).

(168) In certain embodiments, R.sup.1 is H.

(169) In certain embodiments, R.sup.1 is aralkyl (e.g., benzyl).

(170) In certain embodiments, R.sup.1 is CO.sub.2R.sup.16. In certain embodiments, R.sup.1 is CO.sub.2R.sup.16 and R.sup.16 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl. In certain embodiments, R.sup.1 is a -Boc group (e.g., wherein R.sup.1 is C.sub.2R.sup.16 and R.sup.16 is t-butyl). In certain embodiments, R.sup.1 is a -Cbz group (e.g., wherein R.sup.1 is CO.sub.2R.sup.16 and R.sup.16 is benzyl).

(171) Ruthenium TransferHydrogenation Catalysts

(172) As generally defined above, provided herein is a process of preparing a compound of formula (II), or its pharmaceutically acceptable forms thereof, from a compound of formula (I), or its pharmaceutically acceptable forms thereof, the process comprising reacting a compound of formula (I), or its pharmaceutically acceptable forms thereof, with a transfer-hydrogenation catalyst in order to provide a compound of formula (II), or its pharmaceutically acceptable forms thereof.

(173) Exemplary transfer-hydrogenation catalysts include, for example, iridium transfer-hydrogenation catalysts, ruthenium transfer-hydrogenation catalysts and rhodium transfer-hydrogenation catalysts, e.g., as described in Zassinovich and Mestroni, Chem. Rev. (1992) 92:1051-1069, the entirety of which is incorporated herein by reference.

(174) In certain embodiments, the transfer-hydrogenation catalyst is a ruthenium transfer-hydrogenation catalyst. Ruthenium transfer-hydrogenation catalysts are described in, for example, U.S. Pat. No. 6,184,381, U.S. Pat. No. 6,887,820, T. Ikariya et al., Org. Biomol. Chem. (2006) 4:393-406 and Hashiguchi et al., J. Am. Chem. Soc. (1995) 117:7562-7563 (Noyori ruthenium catalysts); U.S. Pat. No. 6,909,003; U.S. Pat. No. 6,545,188; U.S. Pat. No. 7,250,526; U.S. Pat. No. 6,372,931; U.S. Pat. No. 6,509,467; U.S. Pat. No. 7,112,690; U.S. Patent Application No. 2002/0193347 and Evaraere et al., Adv. Synth. Catal. (2003) 345:67-77 (Carpentier ruthenium catalysts); PCT application No. WO 2000/18708; PCT application No. WO 2001/09077; Reetz et al., J. Am. Chem. Soc. (2006) 1044-1045; Genov et al., Angew. Chem. (2004) 43:2816-2819; Sasson and Blum, Tet. Lett. (1971) 24:2167; Mao et al., Tet. Lett (2005) 46:7341-7344; H.-U. Blaser and H.-J. Federsel, Eds., Asymmetric Catalysis on Industrial Scale, 2.sup.nd edition, (2010) Wiley-VCH: A. J. Blacker, P. Thompson, Scale up Studies in Asymmetric Transfer Hydrogenation, pgs. 265-289, the entirety of each of which is incorporated herein by reference. Such references describe the preparation and use of chiral ruthenium transfer-hydrogenation catalysts.

(175) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is a chiral ruthenium transfer-hydrogenation catalyst selected from Cl.sub.3[((R)-tol-BINAP)RuCl].sub.2 Me.sub.2NH.sub.2.sup.+, Cl.sub.3[((S)-tol-BINAP)RuCl].sub.2.sup. Me.sub.2NH.sub.2.sup.+, ((R)-DIFLUORPHOS)RuCl.sub.2(DMF).sub.n, ((S)-DIFLUORPHOS)RuCl.sub.2(DMF).sub.n, ((R)-DTBM-SEGPHOS)RuCl.sub.2(p-cymene), ((S)-DTBM-SEGPHOS)RuCl.sub.2(p-cymene), Cl.sub.3[((R)-xylyl-SEGPHOS)RuCl].sub.2Me.sub.2NH.sub.2+, Cl.sub.3[((S)-xylyl-SEGPHOS)RuCl.sub.2].sup.Me.sub.2NH.sub.2.sup.+, ((R)-xylyl-SEGPHOS)RuCl.sub.2(R,R)DPEN, ((S)-xylyl-SEGPHOS)RuCl.sub.2(S,S)DPEN, (Ph.sub.3P)RuCl.sub.2((+)-(R)Fe-oxazoline), (Ph.sub.3P)RuCl.sub.2(()-(S)Fe-oxazoline), ((S,R)JOSIPHOS)RuCl.sub.2(DMF).sub.n, ((R,S)JOSIPHOS)RuCl.sub.2(DMF).sub.n, (11bS,11bS)-4,4-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis-dinaphtho[2,1-d:1,2-f][1,3,2]dioxaphosphepine and its enantiomer, (S,S)TsDPEN-RuCl(p-cymene), (S,S)TsDPEN-RuCl(hexamethylbenzene), (S,S)TsCyDN-RuCl(hexamethylbenzene), RuHCl(mesitylene)[(1S,2R)-ephedrine], RuHCl(hexamethylbenzene)[(1S,2R)-ephedrine], RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine], RuHCl(p-cymene)[(1S,2R)-ephedrine], RuHCl(p-cymene)[(1R,2S)-ephedrine], RuHCl(benzene)[(1S,2R)-ephedrine], RuHCl(mesitylene)[(1R,2S).sub.2-methylaminocyclohexanol], RuHCl(hexamethylbenzene) [(1R,2S).sub.2-methylaminocyclohexanol], RuHCl(hexamethylbenzene)[(1S,2S).sub.2-methylaminocyclohexanol], RuHCl(p-cymene)[(1R,2S).sub.2-methylaminocyclohexanol], and RuHCl(benzene)[(1R,2S).sub.2-methylaminocyclohexanol], RuHCl(hexamethylbenzene) [R-propranolol], RuHCl(hexamethylbenzene) [S-propranolol], RuHCl(hexamethylbenzene)[1R,2S-cis-1-amino-2-indanol], and RuHCl(hexamethylbenzene)[D-prolinol].

(176) ##STR00096##

(177) These ruthenium transfer-hydrogenation catalysts and others, both chiral and achiral, are further described below and herein.

(178) Ligands Coordinated to the Catalyst

(179) In certain embodiments, the ruthenium transfer-hydrogenation catalyst comprises one or more ligands.

(180) Ligands can be classified as anionic (e.g., monoanionic, dianionic) or charge-neutral (see Green, A new approach to the formal classification of covalent compounds of the elements Journal of Organometallic Chemistry (1995) 500:127-148, incorporated herein by reference in its entirety). Ligands can also be classified according to the denticity, i.e., to the number of times a ligand bonds to a metal through non-contiguous donor sites (represented by .sup.n wherein n indicates the number of sites by which a ligand attaches to a metal). For example, a monodentate ligand (.sup.1 ligand) refers to a ligand which bonds through one donor site, and a bidentate ligand (.sup.2 ligand) refers to a ligand which bonds through two non-contiguous donor sites. Ligands can further be classified according to the hapticity of the ligand, i.e., the number of contiguous atoms that comprise a donor site and attach to the metal center (represented by .sup.x wherein x indicates the number of contiguous atoms). For example, an aromatic 6-membered ring (e.g., a benzene ring) can exist as an .sup.2 ligand, .sup.4 ligand or .sup.6 ligand depending upon the number of pi () electrons used in forming the coordinate bond.

(181) Exemplary monoanionic monodentate ligands include, but are not limited to, iodo (I), bromo (Br.sup.), chloro (Cl.sup.), fluoro (F.sup.), hydroxyl (HO.sup.), cyano (CN.sup.), nitro (NO.sub.2.sup.), isothiocyanato (SCN.sup.) and S-thiocyanato (NCS.sup.). In some embodiments, the monoanionic monodentate ligand is chloro (Cl.sup.).

(182) Exemplary monodentate neutral ligands include, but are not limited to, water (H.sub.2O), acetonitrile (CH.sub.3CN), ammonia (NH.sub.3), carbon monoxide (CO), trimethylphosphine (PMe.sub.3), tricyclohexylphosphine (PCy.sub.3), triphenylphosphine (PPh.sub.3), tri(o-tolyl)phosphine (P(o-tolyl).sub.3) and pyridine (C.sub.5H.sub.5N). In some embodiments, the monodentate neutral ligand is selected from trimethylphosphine (PMe.sub.3), tricyclohexylphosphine (PCy.sub.3), and triphenylphosphine (PPh.sub.3).

(183) Exemplary bidentate neutral ligands include, but are not limited to, 2,2bipyridine, 1,10-phenanthroline, bisphosphino ligands (e.g., 1,2-bis(diphenylphophino)ethane, 1,2-bis(diphenylphophino)methane), diamine ligands (e.g., ethylenediamine) and amino alcohol ligands.

(184) Exemplary .sup.x neutral ligands include, but are not limited to, optionally substituted benzene ligands, e.g., benzene (C.sub.6H.sub.6), toluene (C.sub.6H.sub.5CH.sub.3), xylene (e.g., o-xylene, m-xylene, p-xyelene), cymene (e.g., o-cymene, m-cymene, p-cymene), mesitylene and hexamethylbenzene. In some embodiments, the .sup.x neutral ligand is selected from optionally substituted benzene (C.sub.6H.sub.6), p-cymene, mesitylene, and hexamethylbenzene.

(185) In certain embodiments, the ruthenium transfer-hydrogenation catalyst comprises at least one ligand selected from an amino alcohol ligand, a monoanionic monodentate ligand and an optionally substituted benzene ligand. Such ligands will be further described below and herein.

(186) Monodentate and Bidentate Neutral Ligands

(187) In certain embodiments, the ruthenium transfer-hydrogenation catalyst comprises one or more monodentate or bidentate ligands. In some embodiments, these ligands can render chirality to the ruthenium transfer-hydrogenation catalyst. In other embodiments, these ligands generate an achiral ruthenium transfer-hydrogenation catalyst.

(188) Exemplary monodentate phosphine ligands include, but are not limited to, trimethylphosphine (PMe.sub.3), tricyclohexylphosphine (PCy.sub.3), triphenylphosphine (PPh.sub.3), tri(o-tolyl)phosphine (P(o-tolyl).sub.3), (S)Fe-oxazoline, and (R)Fe-oxazoline. Non-limiting examples of bidentate bisphosphino ligands include 1,2-bis(diphenylphophino)ethane, 1,2-bis(diphenylphophino)methane, (R)-tol-BINAP, (S)-tol-BINAP, (R)-DIFLUORPHOS), (S)-DIFLUORPHOS, (R)-DTBM-SEGPHOS, (S)-DTBM-SEGPHOS, (S,R)JOSIPHOS), (R,S)JOSIPHOS), 4,4-(9,9-dimethyl-9H-xanthene-4,5-diyl)didinaphtho[2,1-d:1,2-f][1,3,2]dioxaphosphepine, and (1 bS,11bS)-4,4-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis-dinaphtho[2,1-d:1,2-f][1,3,2]dioxaphosphepine and its enantiomer.

(189) In addition to the monodentate neutral ligand NH.sub.3, other such monodentate amino ligands include, but are not limited to, unsubstituted or substituted alkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl amines. Exemplary alkyl amines include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, and n-hexyl amine, or substituted variants thereof. Unsubstituted or substituted cycloalkyl amines include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl amines. Unsubstituted or substituted aryl amines and heteroaromatics include, but are not limited to, aniline, pyridine, pyrimidine.

(190) Exemplary bidentate amino ligands include, but are not limited to, unsubstituted or substituted 2,2bipyridine, ethylenediamine, propylenediamine, o-cyclopentyldiamine, o-cyclohexyldiamine, (R,R)-TsDPEN, (R,S)-TsDPEN, (S,R)-TsDPEN, (S,S)-TsDPEN, (R,R)-MsDPEN, (R,S)-MsDPEN, (S,R)-MsDPEN, and (S,S)-MsDPEN.

(191) Exemplary methods for preparing ruthenium transfer-hydrogenation catalysts employing these phosphino and amino neutral ligands can be found, e.g., in the references detailed above.

(192) Amino Alcohol Ligands

(193) In certain embodiments, the ruthenium transfer-hydrogenation catalyst comprises an amino alcohol ligand.

(194) In certain embodiments, the amino alcohol ligand is of the formula (i-a):

(195) ##STR00097##

(196) or its pharmaceutically acceptable forms thereof,

(197) wherein each R.sup.a and R.sup.b are independently selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, or R.sup.a and R.sup.b are joined to form a 3-8 membered carbocyclic or heterocyclic ring system;

(198) and R.sup.c is selected from alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.

(199) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is an achiral ruthenium transfer-hydrogenation catalyst.

(200) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is an achiral ruthenium transfer-hydrogenation catalyst comprising an amino alcohol ligand of the formula (i-a) where R.sup.a and R.sup.b are the same group. For example, in certain embodiments, R.sup.a and R.sup.b are the same group selected from C.sub.1-6 alkyl and C.sub.1-6 perhaloalkyl. In certain embodiments, R.sup.a and R.sup.b are the same group selected from C.sub.1-6 alkyl. In certain embodiments, R.sup.a and R.sup.b are both CH.sub.3.

(201) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is a chiral ruthenium transfer-hydrogenation catalyst.

(202) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is a chiral ruthenium transfer-hydrogenation catalyst comprising an amino alcohol ligand of the formula (i-a). For example, in certain embodiments, R.sup.a is hydrogen and R.sup.b is C.sub.1-6 alkyl, or R.sup.b is hydrogen and R.sup.a is C.sub.1-6 alkyl. In certain embodiments, R.sup.a is hydrogen and R.sup.b is C.sub.1-6 alkyl, or R.sup.b is hydrogen and R.sup.a is C.sub.1-6 alkyl.

(203) In certain embodiments, R.sup.a is selected from alkyl and perhaloalkyl. In certain embodiments, R.sup.a is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.a is C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, R.sup.a is C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R is methyl (CH.sub.3) or perfluoromethyl (CF.sub.3). In certain embodiments, R.sup.a is methyl (CH.sub.3). In certain embodiments, R.sup.a is perfluoromethyl (CF.sub.3).

(204) For example, in certain embodiments, wherein R.sup.a is methyl, the amino alcohol ligand is of the formula (i-b):

(205) ##STR00098##
wherein R.sup.b and R.sup.c are as defined above and herein.

(206) In certain embodiments, R.sup.b is selected from alkyl and perhaloalkyl. In certain embodiments, R.sup.b is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.b is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, R.sup.b is selected from C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.b is methyl (CH.sub.3) or perfluoromethyl (CF.sub.3). In certain embodiments, R.sup.b is methyl (CH.sub.3). In certain embodiments, R.sup.b is perfluoromethyl (CF.sub.3).

(207) For example, in certain embodiments, wherein R.sup.b is methyl, the amino alcohol ligand is of the formula (i-c):

(208) ##STR00099##
wherein R.sup.a and R.sup.c are as defined above and herein.

(209) In certain embodiments, R.sup.c is alkyl. In certain embodiments, R.sup.c is C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, R.sup.c is C.sub.1-3 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl). In certain embodiments, R.sup.c is ethyl (CH.sub.2CH.sub.3).

(210) For example, in certain embodiments, wherein R.sup.c is ethyl, the amino alcohol ligand is of the formula (i-d):

(211) ##STR00100##
wherein R.sup.a and R.sup.b are as defined above and herein.

(212) In certain embodiments, wherein R.sup.a is methyl and R.sup.c is ethyl, the amino alcohol ligand is of the formula (i-e):

(213) ##STR00101##
wherein R.sup.b is as defined above and herein.

(214) In certain embodiments, wherein R.sup.b is methyl and R.sup.c is ethyl, the amino alcohol ligand is of the formula (i-f):

(215) ##STR00102##
wherein R.sup.a is as defined above and herein.

(216) In certain embodiments, the amino alcohol of formula (i-a) is a chiral amino alcohol, which contains at least one asymmetric center). For example, in certain embodiments, R.sup.a and R.sup.b are different groups or at least one of R.sup.a, R.sup.b or R.sup.c contains at least one asymmetric center. In certain embodiments, wherein the amino alcohol of formula (i-a) is a chiral amino alcohol, the ruthenium transfer-hydrogenation catalyst is also a chiral ruthenium transfer-hydrogenation catalyst.

(217) In certain embodiments, wherein the amino alcohol of formula (i-a) is a chiral amino alcohol, R.sup.a and R.sup.b are different groups. For example, in certain embodiments, R.sup.a is hydrogen and R.sup.b is alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. In certain embodiments, R.sup.a is hydrogen and R.sup.b is C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) or C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.a is hydrogen and R.sup.b is C.sub.1-6 alkyl. In certain embodiments, R.sup.a is hydrogen and R.sup.b is methyl (CH.sub.3).

(218) For example, in certain embodiments, wherein R.sup.a is hydrogen and R.sup.b is methyl, the amino alcohol ligand is of the formula (i-g):

(219) ##STR00103##
wherein R.sup.c is as defined above and herein.

(220) In other embodiments, wherein the amino alcohol of formula (i-a) is a chiral amino alcohol, R.sup.b is hydrogen and R.sup.a is alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. In certain embodiments, R.sup.b is hydrogen and R.sup.a is C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) or C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.b is hydrogen and R.sup.a is C.sub.1-6 alkyl. In certain embodiments, R.sup.b is hydrogen and R.sup.a is methyl (CH.sub.3).

(221) For example, in certain embodiments, wherein R.sup.a is methyl and R.sup.b is hydrogen, the amino alcohol ligand is of the formula (i-h):

(222) ##STR00104##
wherein R.sup.c is as defined above and herein.

(223) However, in certain embodiments, the amino alcohol of formula (i-a) is an achiral amino alcohol, which does not contain an asymmetric center). For example, in certain embodiments, both R.sup.a and R.sup.b are the same group selected from alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, or R.sup.a and R.sup.b are joined to form a 3-8 membered carbocyclic or heterocyclic ring system provided that R.sup.a and R.sup.b or the joined ring do not contain an asymmetric center. In certain embodiments, wherein the amino alcohol of formula (i-a) is an achiral amino alcohol, the ruthenium transfer-hydrogenation catalyst is an achiral ruthenium transfer-hydrogenation catalyst.

(224) In certain embodiments wherein the amino alcohol of formula (i-a) is an achiral amino alcohol, both R.sup.a and R.sup.b are the same group selected from alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In certain embodiments, both R.sup.a and R.sup.b are the same group selected from alkyl and perhaloalkyl. In certain embodiments, both R.sup.a and R.sup.b are the same group selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, both R.sup.a and R.sup.b are the same group selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, both R.sup.a and R.sup.b are the same group selected from C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, both R.sup.a and R.sup.b are the same group selected from methyl (CH.sub.3) and perfluoromethyl (CF.sub.3). In certain embodiments, both R.sup.a and R.sup.b are methyl (CH.sub.3). In certain embodiments, both R.sup.a and R.sup.b are perfluoromethyl (CF.sub.3).

(225) For example, in certain embodiments, wherein both R.sup.a and R.sup.b are methyl, the amino alcohol ligand is of the formula (i-i):

(226) ##STR00105##
wherein R.sup.c is as defined above and herein.

(227) In some embodiments, R.sup.c is hydrogen. In some embodiments, R.sup.c is C.sub.1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl). In some embodiments, R.sup.c is methyl. In some embodiments, R.sup.c is ethyl. In some embodiments, R.sup.c is propyl. In some embodiments, R.sup.c is isopropyl.

(228) For example, in certain embodiments, the amino alcohol is of the formula (i-j):

(229) ##STR00106##

(230) In certain embodiments wherein the amino alcohol of formula (i-a) is an achiral amino alcohol, R.sup.a and R.sup.b are joined to form a 3-8 membered carbocyclic or heterocyclic ring system provided that the joined ring does not contain an asymmetric center.

(231) For example, in certain embodiments, R.sup.a and R.sup.b are joined to form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring system provided that the joined ring does not contain an asymmetric center. In certain embodiments, R.sup.a and R.sup.b are joined to form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring system selected from:

(232) ##STR00107##
wherein R.sup.c is as defined above and herein.

(233) In certain embodiments, R.sup.a and R.sup.b are joined to form a 4-, 6- or 8-membered heterocyclic ring system provided that the joined ring does not contain an asymmetric center. In certain embodiments, R.sup.a and R.sup.b are joined to form a 4-, 6- or 8-membered heterocyclic ring system selected from:

(234) ##STR00108##

(235) wherein R.sup.c is as defined above and herein,

(236) R.sup.e is a group selected from H, alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, and

(237) both R.sup.f and R.sup.g are the same group selected from alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl,

(238) provided that the groups R.sup.e, R.sup.f and R.sup.g do not contain an asymmetric center.

(239) In some embodiments, R.sup.a and R.sup.b are joined to form a 4-, 6- or 8-membered heterocyclic ring system where the joined ring does contain an asymmetric center. In certain embodiments, R.sup.a and R.sup.b are joined to form a 4-, 6- or 8-membered heterocyclic ring system selected from:

(240) ##STR00109##

(241) wherein R.sup.c is as defined above and herein, and

(242) R.sup.e is a group selected from H, alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.

(243) In certain embodiments, both R.sup.f and R.sup.g are the same group selected from alkyl and perhaloalkyl. In certain embodiments, both R.sup.f and R.sup.g are the same group selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, both R.sup.f and R.sup.g are the same group selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, both R.sup.f and R.sup.g are the same group selected from C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, both R.sup.f and R.sup.g are the same group selected from methyl (CH.sub.3) and perfluoromethyl (CF.sub.3). In certain embodiments, both R.sup.f and R.sup.g are methyl (CH.sub.3). In certain embodiments, both R.sup.f and R.sup.g are perfluoromethyl (CF.sub.3).

(244) In some embodiments, the amino alcohol ligand is of Formula (i-z):

(245) ##STR00110##
or its pharmaceutically acceptable forms thereof,

(246) wherein each R.sup.a and R.sup.b are independently selected from hydrogen, alkyl, perhaloalkyl, aryloxyalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, or R.sup.a and R.sup.b are joined to form a 3-10 membered carbocyclic or heterocyclic ring system;

(247) each R.sup.n and R.sup.o are independently selected from hydrogen, alkyl, aryloxyalkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, or R.sup.n and R.sup.o are joined to form a 3-10 membered carbocyclic or heterocyclic ring system; or

(248) R.sup.a and R.sup.n are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.b and R.sup.o are each hydrogen; or

(249) R.sup.a and R.sup.o are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.b and R.sup.n are each hydrogen; or

(250) R.sup.b and R.sup.o are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.a and R.sup.n are each hydrogen; or

(251) R.sup.b and R.sup.n are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.a and R.sup.o are each hydrogen; and

(252) R.sup.c i selected from alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; or

(253) R.sup.a and R.sup.c are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.b is hydrogen; or

(254) R.sup.b and R.sup.c are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.a is hydrogen.

(255) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is a chiral ruthenium transfer-hydrogenation catalyst comprising an amino alcohol ligand of the formula (i-z). For example, in certain embodiments, R.sup.a is hydrogen and R.sup.b is C.sub.1-6 alkyl, or R.sup.b is hydrogen and R.sup.a is C.sub.1-6 alkyl. In certain embodiments, R.sup.a is hydrogen and R.sup.b is Me, or R.sup.b is hydrogen and R.sup.a is Me. In certain embodiments, R.sup.n is aryl and R.sup.o is hydrogen, or R.sup.o is hydrogen and R.sup.n is aryl. In certain embodiments, R.sup.n is phenyl and R.sup.o is hydrogen, or R.sup.o is hydrogen and R.sup.n is phenyl.

(256) In certain embodiments, R.sup.a is selected from alkyl and perhaloalkyl. In certain embodiments, R.sup.a is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.a is C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, R.sup.a is C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.a is methyl (CH.sub.3) or perfluoromethyl (CF.sub.3). In certain embodiments, R.sup.a is methyl (CH.sub.3). In certain embodiments, R.sup.a is perfluoromethyl (CF.sub.3).

(257) In certain embodiments, R.sup.b is selected from alkyl and perhaloalkyl. In certain embodiments, R.sup.b is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.b is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, R.sup.b is selected from C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.b is methyl (CH.sub.3) or perfluoromethyl (CF.sub.3). In certain embodiments, R.sup.b is methyl (CH.sub.3). In certain embodiments, R.sup.b is perfluoromethyl (CF.sub.3).

(258) In certain embodiments, R.sup.n is selected from alkyl and perhaloalkyl. In certain embodiments, R.sup.n is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.n is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, R.sup.n is selected from C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.o is methyl (CH.sub.3) or perfluoromethyl (CF.sub.3). In certain embodiments, R.sup.n is methyl (CH.sub.3). In certain embodiments, R.sup.n is perfluoromethyl (CF.sub.3).

(259) In certain embodiments, R.sup.o is selected from alkyl and perhaloalkyl. In certain embodiments, R.sup.o is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.o is selected from C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, R.sup.o is selected from C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.o is methyl (CH.sub.3) or perfluoromethyl (CF.sub.3). In certain embodiments, R.sup.o is methyl (CH.sub.3). In certain embodiments, R.sup.o is perfluoromethyl (CF.sub.3).

(260) In certain embodiments, R.sup.a is hydrogen and R.sup.b is C.sub.1-6 alkyl or R.sup.b is hydrogen and R.sup.a is C.sub.1-6 alkyl, and R.sup.n and R.sup.o are each hydrogen.

(261) In certain embodiments, R.sup.c is alkyl. In certain embodiments, R.sup.c is C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, R.sup.c is C.sub.1-3 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl). In certain embodiments, R.sup.c is ethyl (CH.sub.2CH.sub.3).

(262) In certain embodiments, the amino alcohol of formula (i-z) is a chiral amino alcohol (i.e., the amino alcohol contains at least one asymmetric center). For example, in certain embodiments, R.sup.a and R.sup.b are different groups, R.sup.n and R.sup.o are different groups, or at least one of R.sup.a, R.sup.b, R.sup.n, R.sup.o or R.sup.c contains at least one asymmetric center. In certain embodiments, wherein the amino alcohol of formula (i-z) is a chiral amino alcohol, the ruthenium transfer-hydrogenation catalyst is also a chiral ruthenium transfer-hydrogenation catalyst.

(263) In certain embodiments, wherein the amino alcohol of formula (i-z) is a chiral amino alcohol, R.sup.a and R.sup.b are different groups. In certain embodiments, wherein the amino alcohol of formula (i-z) is a chiral amino alcohol, R.sup.a and R.sup.b are different groups. For example, in certain embodiments, R.sup.a is hydrogen and R.sup.b is alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. In certain embodiments, R.sup.a is hydrogen and R.sup.b is C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) or C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.a is hydrogen and R.sup.b is C.sub.1-6 alkyl. In certain embodiments, R.sup.a is hydrogen and R.sup.b is methyl (CH.sub.3).

(264) In certain embodiments, R.sup.b is hydrogen and R.sup.a is alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. In certain embodiments, R.sup.b is hydrogen and R.sup.a is C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) or C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.b is hydrogen and R.sup.a is C.sub.1-6 alkyl. In certain embodiments, R.sup.b is hydrogen and R.sup.a is methyl (CH.sub.3).

(265) In other embodiments, R.sup.n is hydrogen and R.sup.o is alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. In certain embodiments, R.sup.o is hydrogen and R.sup.n is C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) or C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, R.sup.n is hydrogen and R.sup.o is C.sub.1-6 alkyl. In certain embodiments, R.sup.n is hydrogen and R.sup.o is methyl (CH.sub.3). In certain embodiments, R.sup.o is hydrogen and R.sup.n is C.sub.1-6alkyl. In certain embodiments, R.sup.o is hydrogen and R.sup.n is methyl (CH.sub.3).

(266) In certain embodiments, R.sup.a, R.sup.b and R.sup.n are each hydrogen, R.sup.c is alkyl (e.g., isopropyl), and R.sup.o is substituted alkyl, such as, but not limited to, aryloxyalkyl (e.g., naphthyloxymethyl). In other embodiments, R.sup.a, R.sup.b and R.sup.o are each hydrogen, R.sup.c is alkyl (e.g., isopropyl), and R.sup.n is substituted alkyl, such as, but not limited to, aryloxyalkyl (e.g., naphthyloxymethyl).

(267) In some embodiments, the amino alcohol ligand of Formula (i-z) is (+)-(1S,2R)ephedrine, ()-(1R,2S)ephedrine, (+)-(1S,2S)pseudoephedrine, or ()-(1R,2R) pseudoephedrine. In some embodiments, the amino alcohol ligand is (+)-(1S,2R)ephedrine. In some embodiments, the amino alcohol ligand is ()-(1R,2S)ephedrine.

(268) In some embodiments, R.sup.a and R.sup.n are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.b and R.sup.o are each hydrogen. In some embodiments, R.sup.a and R.sup.o are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.b and R.sup.n are each hydrogen. In other embodiments, R.sup.b and R.sup.o are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.a and R.sup.n are each hydrogen. In certain embodiments, R.sup.b and R.sup.n are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.a and R.sup.o are each hydrogen. Exemplary 3-10 monocyclic carbocyclic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl and cyclooctyl rings. Exemplary 3-10 bicyclic carbocyclic ring systems include bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, octahydro-1H-indenyl, decahydronaphthalenyl, and spiro[4.5]decanyl.

(269) In one embodiment, R.sup.a and R.sup.o are joined together to form a cyclohexyl ring system, R.sup.b and R.sup.n are each hydrogen, and R.sup.c is C.sub.1-6alkyl (e.g., Me). In another embodiment, R.sup.b and R.sup.n are joined together to form a cyclohexyl ring system, R.sup.a and R.sup.o are each hydrogen, and R.sup.c is C.sub.1-6alkyl (e.g., Me). In another embodiment, R.sup.a and R.sup.n are joined together to form a cyclohexyl ring system, R.sup.b and R.sup.o are each hydrogen, and R.sup.o is C.sub.1-6alkyl (e.g., Me). In another embodiment, R.sup.b and R.sup.o are joined together to form a cyclohexyl ring system, R.sup.a and R.sup.n are each hydrogen, and R.sup.c is C.sub.1-6alkyl (e.g., Me). In another embodiment, R.sup.a and R.sup.n are joined together to form a octahydro-1H-indenyl ring system, R.sup.b and R.sup.o are each hydrogen, and R.sup.c is hydrogen. In another embodiment, R.sup.b and R.sup.o are joined together to form a octahydro-1H-indenyl ring system, R.sup.a and R.sup.n are each hydrogen, and R.sup.c is hydrogen. In some embodiments, R.sup.a and R.sup.e are joined together to form a 3-10 membered carbocyclic ring system (e.g., cyclopentyl) and R.sup.b, R.sup.n and R.sup.o are each hydrogen. In some embodiments, R.sup.b and R.sup.c are joined together to form a 3-10 membered carbocyclic ring system (e.g., cyclopentyl) and R.sup.a, R.sup.n and R.sup.o are each hydrogen.

(270) Optionally Substituted Benzene Ligands

(271) In certain embodiments, the ruthenium transfer-hydrogenation catalyst comprises an optionally substituted benzene ligand.

(272) In certain embodiments, the optionally substituted benzene ligand is of the formula (ii-a):

(273) ##STR00111##

(274) wherein each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl.

(275) In certain embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, alkyl and perhaloalkyl. In certain embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen and C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certain embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, methyl (CH.sub.3) and perfluoromethyl (CF.sub.3). In certain embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen and methyl (CH.sub.3). In certain embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen and perfluoromethyl (CF.sub.3).

(276) For example, in certain embodiments, wherein each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen and C.sub.1-6 alkyl, the optionally substituted benzene ligand is selected from any one of the following ligands:

(277) ##STR00112## ##STR00113##

(278) In some embodiments, the optionally substituted benzene ligand is selected from any one of the following ligands:

(279) ##STR00114##

(280) In certain embodiments, the hapticity of the optionally substituted benzene ligand is .sup.2. In certain embodiments, the hapticity of the optionally substituted benzene ligand is .sup.4. In certain embodiments, the hapticity of the optionally substituted benzene ligand hapticity is .sup.6.

(281) In certain embodiments, the optionally substituted benzene ligand is .sup.6-hexamethylbenzene.

(282) Monoanionic Monodentate Ligands

(283) In certain embodiments, the ruthenium transfer-hydrogenation catalyst includes a monoanionic monodentate ligand. Exemplary monoanionic monodentate ligands include, but are not limited to, halo (e.g., iodo (I.sup.), bromo (Br.sup.), chloro (Cl.sup.) and fluoro (F.sup.)), hydroxyl (HO.sup.), cyano (CN.sup.), nitro (NO.sub.2.sup.), isothiocyanato (SCN.sup.) and S-thiocyanato (NCS.sup.) ligands.

(284) For example, in certain embodiments, the ruthenium transfer-hydrogenation catalyst comprises a halo ligand. In certain embodiments, the halo ligand is iodo (I.sup.), bromo (Br.sup.), or chloro (Cl.sup.). In certain embodiments, the halo ligand is chloro (Cl.sup.).

(285) Ruthenium Transfer-Hydrogenation Catalyst

(286) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is a chiral ruthenium transfer-hydrogenation catalyst. In some embodiments, the ruthenium transfer-hydrogenation catalyst is selected from (S,S)TsDPEN-RuCl(p-cymene), ((S,R)JOSIPHOS)RuCl2(DMF)n, ((R,S)JOSIPHOS)RuCl2(DMF)n, (11bS,11bS)-4,4-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis-dinaphtho[2,1-d:1,2-f][1,3,2]dioxaphosphepine and its enantiomer, RuHCl(mesitylene)[(1S,2R)-ephedrine], RuHCl(hexamethylbenzene)[(1S,2R)-ephedrine], RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine], RuHCl(p-cymene)[(1R,2S).sub.2-methylaminocyclohexanol], RuHCl(hexamethylbenzene) [R-propranolol], RuHCl(hexamethylbenzene) [1R,2S-cis-1-amino-2-indanol], RuHCl(hexamethylbenzene) [(1R,2S)2-methylaminocyclohexanol], RuHCl(hexamethylbenzene) [(1S,2S)2-methylaminocyclohexanol], RuHCl(hexamethylbenzene)[R-propranolol], RuHCl(hexamethylbenzene)[S-propranolol], and (S,S)TsDPEN-RuCl(hexamethylbenzene).

(287) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is an achiral ruthenium transfer-hydrogenation catalyst.

(288) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is of the formula (iii-a):

(289) ##STR00115##

(290) wherein R.sup.a, R.sup.b, R.sup.c, R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are as defined above and herein.

(291) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is of the formula (iii-a):

(292) ##STR00116##

(293) wherein R.sup.a and R.sup.b are the same group selected from C.sub.1-6 alkyl and C.sub.1-6 perhaloalkyl, or R.sup.a and R.sup.b are joined to form a 3-8 membered carbocyclic or heterocyclic ring system;

(294) R.sup.c is selected from C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, aralkyl, heteroaralkyl, aryl and heteroaryl; and

(295) each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

(296) In certain embodiments, wherein R.sup.a is methyl, the ruthenium transfer-hydrogenation catalyst is of the formula (iii-b):

(297) ##STR00117##

(298) wherein R.sup.b, R.sup.c, R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are as defined above and herein

(299) In certain embodiments, wherein R.sup.b is methyl, the ruthenium transfer-hydrogenation catalyst is of the formula (iii-c):

(300) ##STR00118##

(301) wherein R.sup.a, R.sup.c, R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are as defined above and herein.

(302) In certain embodiments, wherein R.sup.c is ethyl, the ruthenium transfer-hydrogenation catalyst is of the formula (iii-d):

(303) ##STR00119##

(304) wherein R.sup.a, R.sup.b, R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are as defined above and herein.

(305) In certain embodiments, wherein both R.sup.a and R.sup.b are methyl, the ruthenium transfer-hydrogenation catalyst is of the formula (iii-e):

(306) ##STR00120##

(307) wherein R.sup.c, R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are as defined above and herein.

(308) In certain embodiments, wherein both R.sup.a and R.sup.b are methyl and R.sup.c is ethyl, the ruthenium transfer-hydrogenation catalyst is of the formula (iii-f):

(309) ##STR00121##
wherein R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are as defined above and herein.

(310) For example, in certain embodiments, the ruthenium transfer-hydrogenation catalyst is an achiral catalyst of the formula (iii-g):

(311) ##STR00122##

(312) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is of the formula (iii-h):

(313) ##STR00123##

(314) wherein each R.sup.a, R.sup.b, R.sup.n and R.sup.o are independently selected from hydrogen, alkyl, aryloxyalkyl, aryl, and perhaloalkyl, or

(315) R.sup.a and R.sup.n are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.b and R.sup.o are each hydrogen; or

(316) R.sup.a and R.sup.o are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.b and R.sup.n are each hydrogen; or

(317) R.sup.b and R.sup.o are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.a and R.sup.n are each hydrogen; or

(318) R.sup.b and R.sup.n are joined together to form a 3-10 membered carbocyclic or heterocyclic ring system and R.sup.a and R.sup.o are each hydrogen; and

(319) R.sup.c is selected from C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, aralkyl, heteroaralkyl, aryl and heteroaryl; and

(320) each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

(321) In some embodiments, to form the ruthenium transfer hydrogenation catalyst, the Ru starting material is an (arene)Ru(X.sub.a) dimer, such as (v-a):

(322) ##STR00124##

(323) wherein R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are as defined above and herein, and

(324) X.sup.a is selected from halo (e.g., iodo (I.sup.), bromo (Br.sup.), chloro (Cl.sup.) and fluoro (F.sup.)).

(325) In certain embodiments, X.sup.a is selected from iodo (I.sup.), bromo (Br.sup.), and chloro (Cl.sup.). In certain embodiments, X.sup.a is chloro (Cl.sup.). In some embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. In certain embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, C.sub.1-6 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C.sub.1-6 perhaloalkyl (e.g., CF.sub.3, CCl.sub.3, CBr.sub.3, CF.sub.2CF.sub.3, etc). In certain embodiments, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen and methyl (CH.sub.3). In some embodiments, the optionally substituted arene ring is selected from benzene, toluene, o-xylene, m-xylene, p-xylene, mesitylene, hexamethylbenzene, o-cymene, m-cymene, and p-cymene. In some embodiments, the optionally substituted arene ring is selected from benzene, mesitylene, hexamethylbenzene, and p-cymene. In certain embodiments, the optionally substituted benzene ligand is .sup.6-hexamethylbenzene.

(326) The ruthenium transfer-hydrogenation catalyst can be prepared by a variety of known methods for complexation (see, e.g., T. Ikariya et al., Org. Biomol. Chem. (2006) 4:393-406). In some embodiments, the ruthenium transition metal catalyst is synthesized from an (arene)Ru(X.sub.a).sub.2 dimer and an amino alcohol ligand in the presence of a base (e.g., an alkoxide base or an amine base) and alcoholic solvent (e.g., isopropanol). First, a catalyst precursor, such as (iii-i) or (iii-j), is formed having the monodentate anionic ligand X.sub.a bound to Ru:

(327) ##STR00125##

(328) wherein R.sup.a, R.sup.b, R.sup.c, R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, R.sup.m, R.sup.n, R.sup.o and X.sub.a are as defined above and herein.

(329) Upon addition of base, such as, but not limited to, an amine base (e.g., triethylamine) or an alkoxide base (e.g., KOiPr, NaOiPr, KOtBu, NaOtBu), the catalyst precursor can convert to the active hydrido catalyst (iii-a) or (iii-h) with concommitant formation of acetone:

(330) ##STR00126##

(331) wherein R.sup.a, R.sup.b, R.sup.c, R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, R.sup.m, R.sup.n, R.sup.o and X.sub.a are as defined above and herein.

(332) During the transfer-hydrogenation reaction of a compound of formula (I) to form a compound of formula (II), in some embodiments, the active catalyst can cycle between the hydrido catalyst (iii-a) or (iii-h) and the free aminoalkoxy species (iii-k) or (iii-l), respectively:

(333) ##STR00127##

(334) wherein R.sup.a, R.sup.b, R.sup.c, R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, R.sup.m, R.sup.n, and R.sup.o are as defined above and herein.

(335) Thus, the term ruthenium transfer-hydrogenation catalyst as used herein refers to any and all ruthenium complexes of the formulas (iii-a), (iii-h), (iii-i), (iii-j), (iii-k), and (iii-l) and their mixtures, and all subgenuses thereof. In some embodiments, the ruthenium transfer-hydrogenation catalyst is a mixture of any or all of (iii-i), (iii-a), and (iii-k). In certain embodiments, the ruthenium transfer-hydrogenation catalyst is a mixture of any or all of (iii-j), (iii-h), and (iii-l).

(336) In certain embodiments of formula (iii-i), R.sup.a and R.sup.b are the same group selected from C.sub.1-6 alkyl and C.sub.1-6 perhaloalkyl, or R.sup.a and R.sup.b are joined to form a 3-8 membered carbocyclic or heterocyclic ring system; R.sup.c is selected from C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, aralkyl, heteroaralkyl, aryl and heteroaryl; each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl; and X.sup.a is selected from halo (e.g., iodo (I.sup.), bromo (Br.sup.), chloro (Cl.sup.) and fluoro (F.sup.)). In certain embodiments of formula (iii-i), R.sup.a and R.sup.b are the same group selected from C.sub.1-6 alkyl; R.sup.c is selected from C.sub.1-6 alkyl; each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen and C.sub.1-6 alkyl; and X.sub.a is Cl. In some embodiments of formula (iii-i), R.sup.a and R.sup.b are each Me, R.sup.c is Et, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m is Me, and X.sub.a is Cl.

(337) In certain embodiments of formula (iii-k), R.sup.a and R.sup.b are the same group selected from C.sub.1-6 alkyl and C.sub.1-6 perhaloalkyl, or R.sup.a and R.sup.b are joined to form a 3-8 membered carbocyclic or heterocyclic ring system; R.sup.c is selected from C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, aralkyl, heteroaralkyl, aryl and heteroaryl; and each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl. In certain embodiments of formula (iii-k), R.sup.a and R.sup.b are the same group selected from C.sub.1-6 alkyl; R.sup.c is selected from C.sub.1-6 alkyl; and each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen and C.sub.1-6 alkyl. In some embodiments of formula (iii-k), R.sup.a and R.sup.b are each Me, R.sup.c is Et, and each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m is Me.

(338) Provided herein is an achiral catalyst comprising one or more complexes of formulas (iii-a) and (iii-k):

(339) ##STR00128##

(340) wherein, independently for each of formulas (iii-a) and (iii-k):

(341) each R.sup.a and R.sup.b are the same group selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl, or R.sup.a and R.sup.b are joined to form a 3-8 membered carbocyclic or heterocyclic ring system;

(342) R.sup.c is selected from alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

(343) each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

(344) In some embodiments, for both formulas (iii-a) and (iii-k), R.sup.a and R.sup.b are each Me, R.sup.c is Et, and each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m is Me.

(345) Provided herein is an achiral catalyst of formula (iii-i):

(346) ##STR00129##

(347) wherein:

(348) each R.sup.a and R.sup.b are the same group selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl, or R.sup.a and R.sup.b are joined to form a 3-8 membered carbocyclic or heterocyclic ring system;

(349) R.sup.c is selected from alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

(350) each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m are independently selected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

(351) X.sub.a is selected from iodo (I.sup.), bromo (Br.sup.), chloro (Cl.sup.) and fluoro (F).

(352) In some embodiments, R.sup.a and R.sup.b are each Me, R.sup.c is Et, each R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.l, and R.sup.m is Me, and X.sub.a is Cl.sup..

(353) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is generated by heating (hexamethylbenzene)RuCl.sub.2 dimer and an amino alcohol in isopropanol and triethylamine. In other embodiments, the ruthenium transfer-hydrogenation catalyst is generated by heating (hexamethylbenzene)RuCl.sub.2 dimer and an amino alcohol in isopropanol and an alkoxide base (e.g., KOiPr, NaOiPr, KOtBu, NaOtBu). In some embodiments, KOiPr is employed in the complexation reaction.

(354) In certain embodiments, the ruthenium transfer-hydrogenation catalyst is generated from hexamethylbenzene ruthenium chloride dimer and an amino alcohol. In certain embodiments, the ruthenium transfer-hydrogenation catalyst is generated from hexamethylbenzene ruthenium chloride dimer and a chiral amino alcohol. In certain embodiments, the ruthenium transfer-hydrogenation catalyst is generated from hexamethylbenzene ruthenium chloride dimer and an achiral amino alcohol.

(355) In certain embodiments, the ruthenium transition metal catalyst is prepared using about 0.1% to about 1 mol %, or about 0.25% to about 0.5% of a ruthenium halide dimer. In some embodiments, the ruthenium halide dimer is an (arene)ruthenium halide dimer, such as (hexamethylbenzene)RuCl.sub.2 dimer. In some embodiments of the complexation reaction, the amino alcohol ligand is present in about 0.5 mol % to about 5 mol %, about 1 mol % to about 3 mol %, or about 1 mol % to about 2 mol %. In certain embodiments, the amino alcohol ligand is present in about 3 mol %. In some embodiments, the amino alcohol ligand is of Formula (i-a), such as (i-j). In certain embodiments, the amount of base used in the complexation reaction is about 0.25 mol % to about 10 mol %, about 0.5 mol % to about 5 mol %, or about 0.5 mol % to about 1 mol %. In some embodiments, the amount of base used in the complexation reaction is about 5 mol %. In some embodiments, the reaction is performed at about 25 C. to about 100 C., about 40 C. to about 80 C., or about 50 C. to 75 C. In certain embodiments, the reaction is performed at about 50 C. In other embodiments, the reaction is performed at about 80 C. In some embodiments, the reaction is performed for 1 hour or 2 hours.

(356) Several exemplary non-limiting sets of reaction parameters for the synthesis of the ruthenium transition metal catalyst are given below in Table 5.

(357) TABLE-US-00005 TABLE 5 Amino iPrOH Alcohol (vol. Parameter (Hexamethylbenzene) Ligand (i-j) KOiPr relative to Temp Time Set RuCl.sub.2 Dimer (mol %) (mol %) (mol %) Ru dimer) ( C.) (h) 1 0.5 1.5 1.5 160 ~80 2 2 0.5 2 1 100 ~50 1 3 0.25 1 0.5 100 ~50 1
Other Reaction Conditions

(358) In one aspect, provided herein is a process for preparing a compound of formula (II) or its pharmaceutically acceptable forms thereof from a compound of formula (I) or its pharmaceutically acceptable forms thereof, the process comprising reacting a compound of formula (I) or its pharmaceutically acceptable forms thereof with a transfer-hydrogenation catalyst in order to provide a compound of formula (II) or its pharmaceutically acceptable forms thereof.

(359) In certain embodiments, the process further comprises a base. Exemplary bases include, but are not limited to, alkoxides (e.g., KOiPr, NaOiPr, KOtBu, NaOtBu), hydroxides (e.g., KOH, NaOH) and tertiary amines (e.g., NEt.sub.3). In certain embodiments, the base is an alkoxide. In certain embodiments, the base is KOiPr. In certain embodiments, the base is KOtBu. In other embodiments, the base is NaOiPr. In certain embodiments, the base is NaOtBu. In some embodiments, the base is NEt.sub.3.

(360) In certain embodiments, the process provides about 5 mol % to about 30 mol %, about 5 mol % to about 20 mol %, about 5 mol % to about 15 mol %, or about 5 mol % to about 10 mol % of base (calculated from the molar amount of compound (I)). In certain embodiments, the process provides about 10 mol % of base. In certain embodiments, the process provides about 20 mol % of base. In other embodiments, the process provides about 5% weight/volume of base. In some embodiments, the process provides about 0.1 to about 0.2 (e.g., 0.2) equivalents of base based upon the amount of compound (I).

(361) In certain embodiments, the process further comprises a hydrogen donor. Exemplary hydrogen donors include, but are not limited to, organic alcohols (e.g., methanol (MeOH), ethanol (EtOH), isopropanol (iPrOH), t-butanol (tBuOH), benzyl alcohol) and formic acid or salts thereof (e.g., amonium formate, and alkyl ammonium formates such as triethylammoniumformate (TEAF)). In certain embodiments, the organic alcohol is isopropanol. In other embodiments, the organic alcohol is methanol. In some embodiments, the organic alcohol is t-butanol.

(362) In some embodiments, the process comprises a mixture of a base (e.g., an alkoxide base as described herein) and a hydrogen donor (e.g., an organic alcohol as described herein). In certain embodiments, the ratio of base to hydrogen donor is 0.4 equivalents base/2 vol. hydrogen donor. In other embodiments, the ratio of base to hydrogen donor is 0.1 equivalents base/10 vol. hydrogen donor. In some embodiment, the base is KOiPr and the hydrogen donor is iPrOH.

(363) In certain embodiments, the process further comprises a solvent. Exemplary solvents include, but are not limited to, ethers (e.g., dimethyl ether, diethyl ether, diisopropyl ether, methyltert-butyl ether, tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me-THF), 1,3-dioxolane, 1,4-dioxane), hydrocarbons (e.g., benzene, toluene, xylene, mesitylene, hexanes, heptanes, cyclohexane, methylcyclohexane, acetonitrile, acetone), polar aprotic solvents (e.g., dimethylformamide, dimethylsulfoxide), halogenated solvents (e.g., dichloromethane, chloroform) or combinations thereof. In certain embodiments, the solvent is an ether. In certain embodiments, the solvent is 2-methyl tetrahydrofuran (2-Me-THF). In some embodiments, the solvent is selected from acetonitrile, 2-methyl tetrahydrofuran (2-Me-THF), acetone, and mesitylene. In some embodiments, the solvent is mesitylene.

(364) In certain embodiments, the process further comprises a hydrogen donor and a solvent, as described above and herein. For example, in certain embodiments, the process further comprises an organic alcohol and a solvent. In certain embodiments, the process further comprises a hydrogen donor and an ether solvent. In certain embodiments, the process further comprises isopropanol and 2-methyltetrahydrofuran. In certain embodiments, the process further comprises isopropanol and mesitylene. In some embodiments, the process further comprises a hydrogen donor, a base, and a solvent. For example, the process can further comprise formic acid, triethylamine and DMF.

(365) In certain embodiments, the process further comprises a hydrogen donor and a solvent, as described above and herein, wherein the mixture comprises about 10% to about 80%, about 20% to about 75% or about 30% to about 70% hydrogen donor in solvent. In certain embodiments, the mixture comprises about 40% hydrogen donor in solvent (i.e., a ratio of about 2:5 hydrogen donor:solvent). In certain embodiments, the mixture comprises about 66% hydrogen donor in solvent (i.e., a ratio of about 2:1 hydrogen donor:solvent).

(366) In certain embodiments, the process is conducted at a temperature of 0 C. to about 90 C., of about 25 C. to about 80 C., of about 0 C. to about 50 C., of about 20 C. to about 45 C., of about 10 C. to about 40 C., of about 15 C. to about 30 C., or of about 5 C. to about 20 C. In certain embodiments, the process is conducted at about room temperature (e.g., at a temperature of about 23 C. or about 25 C.). In some embodiments, the process is conducted at about 80 C. In other embodiments, the process is conducted at about 45 C. In other embodiments, the process is conducted at about 40 C. In other embodiments, the process is conducted at about 0 C. In some embodiments, the process is conducted at about 5 C. to about 20 C.

(367) In certain embodiments, the process further comprises about 0.1 mol % to about 2.0 mol %, about 0.5 mol % to about 2.0 mol %, about 0.1 mol % to about 1.5 mol %, about 0.1 mol % to about 1.0 mol %, about 0.1 mol % to about 0.5 mol %, or about 0.2 mol % to about 0.5 mol % of the ruthenium transition metal catalyst (calculated from the molar amount of compound (I)). In certain embodiments, the process provides about 0.2 mol % of the ruthenium transition metal catalyst. In certain embodiments, the process provides about 0.25 mol % of the ruthenium transition metal catalyst. in other embodiments, the process provides about 0.5 mol % of the ruthenium transition metal catalyst. In certain embodiments, the process provides about 1 mol % of the ruthenium transition metal catalyst. In certain embodiments, the process provides about 1.5 mol % of the ruthenium transition metal catalyst.

(368) In certain embodiments, the process further comprises removing residual ruthenium from the reaction mixture once the compound of Formula (II) has formed using a scavenger. Exemplary scavengers include, but are not limited to, silica based products from Phosphonics (SEA, STA3, POH1, SEM22, SEM26, SPM36F, SPM32 and MTCf), SiliCycle (SiliaBond-DMT, Si-Imidazole, Si-TAAcOH, Si-Diamine, Si-Triamine, Si-DMT, Si-TAAcONa, Si-Thiol and Si-Thiourea), fiber based materials from Johnson-Matthey (S-301, Smopex 111pp, Smopex 112v and Smopex 234), activated carbon (Norit E-supra) and silica gel (EMD). In certain embodiments, the scavenger is SiliaBond-DMT. In other embodiments, the scavenger is SPM32. In some embodiments, the scavenger is Si-Thiol. In some embodiments, the scavenger is selected from SEM22, SPM32, Si-Thiol, Si-DMT, and STA3.

(369) ##STR00130##

(370) In some embodiments, the scavenger amount is about 20 wt % to about 100 wt % based on a theoretical 100% yield of the compound of Formula (II), such as about 30 to about 50 wt %. In other embodiments, the scavenger amount is about 100 wt %. In some embodiments, the scavenger amount is 40 wt % and the reaction mixture is stirred with the scavenger present for about 10 to about 25 hours (e.g., about 20 hours). In certain embodiments, the scavenger is SPM32 at 50 wt %, and the reaction mixture is stirred with the scavenger present at 50 C. for about 10 hours.

(371) In a non-limiting example, the synthesis of a compound of Formula (II) as described herein can be performed using about 0.25 mol % to about 2 mol % (e.g., about 1 mol %) ruthenium transition metal catalyst, about 2 vol. to about 20 vol. (e.g., about 10 vol.) hydrogen donor, about 0.02 mol % to about 0.1 mol % (e.g., about 0.05 mol %) base, at about 0 C. to about 20 C. (e.g., about 13 C.). In some embodiments, the synthesis of a compound of Formula (II) as described herein can be performed using about 0.5 mol % to about 2 mol % (e.g., about 0.5 mol % or about 1 mol %) ruthenium transition metal catalyst, such as (iii-g); about 2 vol. to about 20 vol. (e.g., about 2, 5, 6 or 10 vol.) hydrogen donor, such as iPrOH; about 0.05 equiv. to about 0.2 equiv. (e.g., about 0.1 or about 0.2 equiv.) base, such as KOiPr; about 3 vol. to about 10 vol. of organic solvent (e.g. about 5 vol.), such as 2-Me-THF; at about 5 C. to about 25 C. (e.g., about 20 C.). In some embodiments, the reaction proceeds for about 2 to about 10 hours (e.g., about 4 or about 7 hours).

Exemplification

(372) The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and/or techniques well known in the art.

(373) Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from 10 C. to 200 C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about 10 C. to about 110 C. over a period that is, for example, about 1 to about 24 hours; reactions left to run overnight in some embodiments can average a period of about 16 hours.

(374) The terms solvent, organic solvent, or inert solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (NMP), pyridine and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert organic solvents. Unless specified to the contrary, for each gram of the limiting reagent, one cc (or mL) of solvent constitutes a volume equivalent.

(375) Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures are given by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can also be used.

(376) When desired, the (R)- and (S)-isomers of the non-limiting exemplary compounds, if present, can be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

(377) The compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be optionally contacted with a pharmaceutically acceptable base to form the corresponding basic addition salts.

(378) In some embodiments, disclosed compounds can generally be synthesized by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, e.g., from Aldrich Chemical Company (Milwaukee, Wis.) or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.

(379) The discussion below is offered to illustrate certain of the diverse methods available for use in making the disclosed compounds and is not intended to limit the scope of reactions or reaction sequences that can be used in preparing the compounds provided herein.

(380) The present disclosure now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration and are not intended to limit the disclosure herein.

Example 1. Preparation of Ruthenium Transfer-Hydrogenation Catalyst (iii-g)

(381) A. Preparation of Amino Alcohol (i-j)

(382) ##STR00131##

(383) To a mixture of 2-amino-2-methyl-propan-1-ol (200 g, 2.2 mol, 1 equiv) and water (1 volume) was added bromoethane (489 g, 4.4 mol, 2 equiv). The mixture was stirred for 24-48 hours at 40 C., then cooled to RT. 50% aqueous NaOH (1 vol) was added and then the mixture was extracted with dichloromethane. Concentration of the organic layer in vacuo, followed by crystallization from MTBE (5 vol), afforded the amino alcohol (i-j).

(384) B. Preparation of Ru Amino Alcohol Catalyst (iii-g)

(385) ##STR00132##

(386) Into a three neck 3 L round bottom flask, equipped with Claisen adapter, temperature probe, gas inlet and outlet, condenser and heating mantle, were added (hexamethylbenzene)ruthenium chloride dimer (8.87 g, 13.27 mmol, 1 mole equiv) and 2-(N-ethylamino)-2-methyl-propan-1-ol (i-j) (6.22 g, 53.1 mmol, 4 mole equiv). The flask was evacuated and refilled with nitrogen for three times. 2-Propanol (1 L, 112 vol based on the Ru dimer), degassed by sparging with argon for 30 min, was added to the flask. To the stirred suspension, potassium isopropoxide (5.0% w/v in 2-PrOH, 52 ml, 27 mmol) was added at room temperature. The reaction mixture was heated to 50 C. and stirred at 50 C.5 C. for 80 min. The heating was turned off and the reaction was allowed to cool to room temperature with stirring. In this way, the catalyst [(2-N-ethylamino)-2-methyl-propan-1-ol](hexamethylbenzene)ruthenium hydride (iii-g) was prepared for use in transfer-hydrogenation of a compound of formula (I).

Example 2. Transfer Hydrogenation of a Compound of Formula (I-a)

(387) A. Preparation of a Compound of Formula (II-a)

(388) ##STR00133##

(389) A solution of the ketone (I-a) (1.825 kg, 3.54 mol) in 9.1 L 2-MeTHF was added to a 50 L jacketed reactor equipped with mechanical stirrer, 1000 mL addition funnel with PTFE connecting tube (with a shutoff valve in-between) to a 3 L catalyst vessel. The solution was diluted with 2-PrOH (11 L). Potassium isopropoxide (5% w/v in 2-PrOH, 354 mmol, 700 mL) was added. The mixture was sparged with argon for 60 min. The catalyst (iii-g) (0.5 mole %, 11.04 g, 26.5 mmol) was added via the addition funnel. The mixture was stirred for 90 min under argon atmosphere at room temperature. An HPLC sample was prepared by removing 10 l of the reaction mixture and diluting it into ACN (1 mL). The HPLC showed less than 1% of the starting material remained. PhosphonicS SPM32 resin (913.5 g, 50 wt % based on starting material) was added to the reaction mixture. The reactor was equipped with a reflux condenser, and the slurry was stirred for 18 h at 50 C. The mixture was cooled to room temperature (19 C.) and the scavenger was removed by filtration on a Buchner filter. The cake comprising (II-a) was washed with 2-MeTHF (2 volumes based on product 100% yield).

(390) In order to remove the 2-PrOH from the isolated cake, five solvent chases with 2-Me-THF were carried out prior to the crystallization. A 50 L jacketed reactor was equipped with mechanical stirrer, distillation apparatus and connected to Huber. The reactor was marked for 5 vol and 20 vol solution. The solution of (II-a) was charged to the reactor. Vacuum was applied and the solution was heated to begin the distillation (405 C.). The solution was concentrated to 5 vol (9 L based on II-a). 2-Me-THF (15 vol, 27.5 L) was added, and vacuum was applied before restarting the heating. The solution was concentrated to 5 vol (9 L) by vacuum distillation (405 OC). The charging of 2-Me-THF (15 vol, 27.5 L) and concentration to 5 volumes was performed as described above four more times. The solution (9 L in 2-Me-THF) was added to the reactor. Acetonitrile (11 L, 6 volumes) was charged at 205 C. with stirring. The mixture was stirred at 205 OC for 60 min to initiate the crystallization. Water was added over 60 min (22 L, 12 vol) at 205 C., and then the mixture was stirred for 2 hours. The product (II-a) was isolated by filtration on Buchner filter. The cake was washed with 2/1 water/ACN (2 vol, 60 mL). The cake was kept on the filter for 60 min. The product was dried in a vacuum oven at 70 C. to afford (S)-(II-a) as a 99:1 : ratio of diastereomers.

(391) B. Ru Scavenger Evaluation 1

(392) To the mixture attained after stirring the components for 90 minutes at room temperature, 1 wt equivalent of the following scavengers was added and the resulting mixture was stirred for 18 h at 50 C. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue evaluated for Ru content by ICP-OES as shown in Table 6.

(393) TABLE-US-00006 TABLE 6 Scavenger Residual Ru None 3211 ppm SEM26 16 ppm SPM32 19 ppm MTCf 53 ppm JM S-301 4195 ppm JM Smopex 111pp 2704 ppm JM Smopex 112v 1048 ppm JM Smopex 234 229 ppm Norit 570 ppm None 1654 ppm Si-Imidazole 357 ppm Si-Diamine 653 ppm SiliaBond DMT 8 ppm Si-TAAcONa 316 ppm Si-Thiol 7 ppm Si-Thiourea 75 ppm Si-Triamine 639 ppm SPM36f 22 ppm

(394) C. Ru Scavenger Evaluation 2

(395) To a mixture of 500 mg of (II-a) where R.sup.1=Bn, 1 wt equivalent of the following scavengers was added at 20 C. and the resulting mixture was stirred for 17 h at 50 C. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was evaluated for Ru content by ICP-MS as shown in Table 7.

(396) TABLE-US-00007 TABLE 7 Scavenger Residual Ru None 1500 ppm SEM22 5.2 ppm SPM32 4.1 ppm STA3 46.1 ppm Si-Thiol 2.4 ppm Si-DMT 4.1 ppm

(397) D. Ru Scavenger Evaluation 3

(398) Using the procedure of Example 2C, the following scavengers were evaluated for residual Ru at three time points as shown in Table 8.

(399) TABLE-US-00008 TABLE 8 Parameters Test D.1 Test D.2 Test D.3 Test D.4 Test D.5 Test D.6 Scale (g of 20 20 5 5 5 .sup.5 (II-a)) Scavenger SPM32 SPM32 SPM32 Si-Thiol Si-Thiol Si-Thiol Amt. 0.3 0.3 0.5 0.2 0.3 0.5 Scavenger (wt. equiv.) Temp. ( C.) 20 50 50 50 50 50 Residual Ru 43.0/5 37.5/2 8/4 33/4 15/4 .sup.9/4 (ppm)/time point 1 (h) Residual Ru 36.4/10 25.0/6 5/10 21/10 8/10 5/10 (ppm)/time point 2 (h) Residual Ru 30.6/19 17.8/16 4/18 15/18 6/18 4/18 (ppm)/time point 3 (h)

(400) E. Reaction Scale Evaluation

(401) The Example 2A procedure was performed using the following amounts of starting material (I-a) where R.sup.1 is Bn and allowed to react with the Ru catalyst (iii-g) for the given reaction times. The diastereoselectivity of the resulting compound (II-a) is shown in Table 9.

(402) TABLE-US-00009 TABLE 9 Reaction time Reaction scale with 1 mole % (II-a) (I-a) Ru catalyst / excess 37 g 60 min 99.3/0.7 60 g 90 min 99.3/0.7 50 g 420 min 99/1 39 g 90 min 99/1 183 g 150 min 98.7/1.3 1958 g 90 min 99/1

Example 3. Hydrogenation of a Compound of Formula (I-a) Using HCO2H:Et3N

(403) ##STR00134##

(404) A. General Reaction Conditions

(405) A Schlenk flask was charged with (I-a, R.sup.1=Bn) (0.5 g, 0.969 mmol) and (S,S)TsDPENRuCl.sub.2(p-cymene) (15.7 mg, 0.025 mmol). The flask was put under argon, and 16 mL triethylamine was added, followed by 4 mL of formic acid. This mixture was heated to 75 C. for 24 h. The reaction was then analyzed by HPLC after 24 h indicating a (S)-(II-a) / ratio of 80:20.

(406) B. Reaction Solvent Evaluation

(407) A mixture of 140 mg of (I-a, R.sup.1=Cbz) and 3.2 mg (S,S)TsDPENRuCl.sub.2(p-cymene) was prepared in 1 mL 2-MeTHF and stirred until it became homogenous. To each of five vials was added 200 L of this solution, to give five vials total with 28 mg of (I-a, R.sup.1=Cbz) and 0.63 mg (S,S)TsDPENRuCl.sub.2(p-cymene) in 200 L 2-MeTHF. Then, to each vial was added 800 L of a solvent as shown in Table 10. 100 L of a 5:2 molar ratio solution of formic acid:triethylamine was added to each vial, and the mixture was stirred for 20 h at RT. The resulting / diastereomeric ratio of the product (II-a, R.sup.1=Cbz) was determined by HPLC.

(408) TABLE-US-00010 TABLE 10 (II-a, R.sup.1 = Cbz) Vial Solvent / ratio 1 2-MeTHF 91:9 2 DMF 95:5 3 MeOH 90:10 4 iPrOH 73:27 5 toluene 83:17

Example 4. Transfer-Hydrogenation of a Compound of Formula (I-g)

(409) ##STR00135##

(410) Using an analogous procedure to Example 2A, except ketone (I-g) was substituted for ketone (I-a), the Ru catalyzed transfer-hydrogenation afforded alcohol (R)-(II-g) as a 1:99 : ratio of diastereomers. LCMS: (M+H) 518.36.

Example 5. Transfer-Hydrogenation of a Compound of Formula (I-a) Using a Chiral Ru Catalyst

(411) Using an analogous procedure to Example 2A, except that 20 mol % NaOiPr in iPrOH was used in place of 5% KOiPr in iPrOH, the following Ru chiral transfer-hydrogenation catalysts 1-7 were evaluated for reduction of (I-a) to (II-a) as shown in Table 11. The -hydroxy isomer is (S)-(II-a) while the -hydroxy isomer is the diastereomeric (R)-(II-a).

(412) TABLE-US-00011 TABLE 11 Catalyst (II-a) : ratio 1. (S,S)TsDPEN-RuCl(p-cymene) (R.sup.1 = Cbz) 92:8 2. ((1R,2S)aminoindanol)RuCl(p-cymene) (R.sup.1 = Cbz) 63:27 3. ((1S,2R)aminoindanol)RuCl(p-cymene) (R.sup.1 = Cbz) 51:49 4. (Ph.sub.3P)RuCl.sub.2((+)-(R)-Fe-oxazoline) (R.sup.1 = Bn) 44:56 5. (Ph.sub.3P)RuCl.sub.2(()-(S)-Fe-oxazoline) (R.sup.1 = Bn) 52:48 6. ((S,R)JOSIPHOS)RuCl.sub.2(DMF).sub.n (R.sup.1 = Cbz) 4:96 7. ((R,S)JOSIPHOS)RuCl.sub.2(DMF).sub.n (R.sup.1 = Cbz) 4:96

Example 6. Transfer-Hydrogenation of a Compound of Formula (I-a) Using a Chiral Ru Bis-Phosphonite Catalyst

(413) ##STR00140##

(414) ##STR00141##

(415) Into a three-neck 500 ml round bottom flask, equipped with Claisen adapter, temperature probe, gas inlet and outlet, condenser and heating mantle, were added (p-cymene)ruthenium chloride dimer 43.3 mg, 0.071 mmol, 0.020 mole equiv) and (11bS,11bS)-4,4-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis-dinaphtho[2,1-d:1,2-f][1,3,2]dioxaphosphepin (302 mg, 0.36 mmol, 0.10 mole equiv). The flask was evacuated and refilled with nitrogen for three times. 2-Propanol (238 ml, 160 vol based on the Ru dimer), degassed by sparging with argon for 30 min, was added to the flask. The reaction mixture was heated to 80 C. To the stirred suspension, potassium t-butoxide (1 M in 2-PrOH, 3.6 ml, 3.6 mmol, 1 equiv) was added and the reaction was stirred at 40 C. for hours. A solution of the ketone (I-a) 1.83 g, 3.6 mmol, 1 equivalent) in 18 ml iPrOH was added and the mixture was stirred for 64 hours at 40 C. HPLC analysis of the reaction mixture indicated that the product (S)-(II-a) was a 97:3 : ratio of diastereomers.

(416) This procedure was repeated with 70 volumes of iPrOH based on the Ru dimer, affording (S)-(II-a) as a 95:5 : ratio of diastereomers, and 35 volumes of iPrOH based on the Ru dimer, affording (S)-(II-a) as an 82:18 : ratio of diastereomers.

Example 7. Transfer-Hydrogenation of a Compound of Formula (I-a) Using a Ru-Ephedrine Catalyst

(417) A. Exemplary Formation of Ru-Ephedrine Catalysts

(418) ##STR00142##

(419) To a mixture of (mesitylene)ruthenium chloride dimer (60.6 mg, 0.104 mmol, 0.5 mole equiv) and (1S,2R)-ephedrine HCl (62.7 mg, 0.311 mmol, 1.5 mole equiv) was added degassed iPrOH (14.8 ml). To the stirred suspension, Et.sub.3N (300 l, 2.15 mmol) was added to give a 4.01 mg Ru/ml solution. The reaction mixture was heated to 85 C. and stirred at 85 C. for two hours. The heating was turned off and the reaction allowed to cool to room temperature with stirring. In this way, the (mesitylene)RuCl-ephedrine catalyst (10) was prepared for use in the transfer-hydrogenation of a compound of formula (I). In addition, Ru chloride dimers having different arene ligands were used to prepare the following (arene)RuCl-ephedrine catalysts (11) to (17) in an analogous manner:

(420) ##STR00143##

(421) B. Transfer-Hydrogenation of a Compound of Formula (I-a) Using Ru Catalysts 11-17

(422) ##STR00144##

(423) To (I-a) (10.00 g, 19.4 mmol) was added iPrOH (100.0 mL, 10.0 vol) and the mixture was stirred. RuCl-ephedrine catalyst (10) (7.1 mL, 28.5 mg Ru, 0.0488 mmol, 0.25 mol % Ru dimer) was added, followed by 1.94 mL of 1M KOtBu in tBuOH (1.94 mmol, 10 mol %). The mixture was stirred for 45 min at room temperature. Then, EtOAc (135 mL) was added, followed by 20 mL of 5-6 N HCl in isopropanol, and the mixture was stirred for 16 h. After concentrating in vacuo to a net weight of 5 weights, filtering through a fritted funnel, and further concentration, (S)-(II-a) was isolated as its HCl salt with a : diastereoselectivity ratio of 98:2 by HPLC analysis.

(424) Using analogous procedures to Examples 7A and 7B, compounds of Formula (II-a) were prepared with Ru-ephedrine catalysts 10, 12-15, and 17 with the diastereoselctivity indicated in Table 12.

(425) TABLE-US-00012 TABLE 12 Catalyst: (II-a) : Catalyst: (II-a) : ratio with 1R,2S ratio with 1S,2R mol % Arene ephedrine ligand ephedrine ligand Ru used mesitylene (11): (10): 96.5:3.5 0.5% hexamethylbenzene .sup.(12): 96:4 (13): 98.8:1.2 1.5% p-cymene (14): 75:25 (15): 85:15 0.5% benzene (16): (17): 52:48 0.5%

(426) B.1 Effect of Temperature and Catalyst Loading on the Diastereoselectivity of a Compound of Formula (II-a)

(427) Using an analogous procedure to Example 7B, Ru-(1S,2R)-ephedrine transfer-hydrogenation catalysts having either mesitylene (10) or hexamethylbenzene (13) arene ligands were employed to determine the effect of temperature and catalyst loading (mol % based on amount of (I-a)) on diastereoselectivity in the transfer-hydrogenation of a compound of Formula (I-a) where R.sup.1 is Bn. The resulting diastereoselectivity of compounds of Formula (II-a) are summarized in Table 13.

(428) TABLE-US-00013 TABLE 13 Ru Catalyst Loading Temperature (II-a) Arene (mol %) ( C.) : ratio mesitylene (10) 0.5% 23 96.5:3.5 mesitylene (10) 0.5% 0 97:3 hexamethylbenzene (13) 0.2% 45 89:11 hexamethylbenzene (13) 0.5% 23 98.8:1.2 hexamethylbenzene (13) 0.5% 0

Example 8. Transfer-Hydrogenation of a Compound of Formula (I-a) Using a Chiral Ru Catalyst

(429) Using a procedure analogous to Example 7A, the following chiral Ru transfer-hydrogenation catalysts were prepared (Formulas 18 to 92) using the (arene)ruthenium chloride dimer and ligand given in Table 14. Using a procedure analogous to Example 7B, these Ru transfer-hydrogenation catalysts were used to reduce a ketone of Formula (I-a) where R.sup.1 is Bn. The diasteroselectivity of the resulting alcohol of Formula (II-a) is given in Table 14.

(430) TABLE-US-00014 TABLE 14 For- (II-a) mu- / la Arene Ligand ratio (18) benzene 45/55 (19) benzene 44/56 (20) benzene 39/61 (21) benzene 38/62 (22) benzene 38/62 (23) benzene 0 35/65 (24) benzene 28/72 (25) benzene 30/70 (26) benzene 43/57 (27) benzene 48/52 (28) benzene 54/46 (29) benzene 51/49 (30) benzene 45/55 (31) benzene 50/50 (32) benzene 44/56 (33) benzene 0 39/61 (34) benzene 43/57 (35) benzene 36/64 (36) p-cymene 65/35 (37) p-cymene 71/29 (38) p-cymene 46/54 (39) p-cymene 27/73 (40) p-cymene 64/36 (41) p-cymene 37/63 (42) p-cymene 58/42 (43) p-cymene 0 48/52 (44) p-cymene 70/30 (45) p-cymene 71/29 (46) p-cymene 48/52 (47) p-cymene 47/53 (48) p-cymene 50/50 (49) p-cymene 49/51 (50) p-cymene 64/36 (51) p-cymene 55/45 (52) p-cymene 80/20 (53) p-cymene 0 85/15 (54) p-cymene 71/29 (55) mesitylene 66/34 (56) mesitylene 68/32 (57) mesitylene 67/33 (58) mesitylene 67/33 (59) mesitylene 62/38 (60) mesitylene 79/21 (61) mesitylene 75/25 (62) mesitylene 84/16 (63) mesitylene 0 67/33 (64) mesitylene 93/7 (65) mesitylene 81/19 (66) mesitylene 80/20 (67) mesitylene 70/30 (68) mesitylene 69/31 (69) mesitylene 25/75 (70) mesitylene 57/43 (71) mesitylene 51/49 (72) mesitylene 63/37 (73) mesitylene 00 58/42 (74) hexamethylbenzene 01 89/11 (75) hexamethylbenzene 02 91/9 (76) hexamethylbenzene 03 83/17 (77) hexamethylbenzene 04 75/25 (78) hexamethylbenzene 05 86/14 (79) hexamethylbenzene 06 45/55 (80) hexamethylbenzene 07 91/9 (81) hexamethylbenzene 08 86/14 (82) hexamethylbenzene 09 95/5 (83) hexamethylbenzene 0 97/3 (84) hexamethylbenzene 68/32 (85) hexamethylbenzene 67/33 (86) hexamethylbenzene 92/8 (87) hexamethylbenzene 89/11 (88) hexamethylbenzene 88/12 (89) hexamethylbenzene 97/3 (90) hexamethylbenzene 81/19 (91) hexamethylbenzene 93/7 (92) hexamethylbenzene 89/11

Example 9. Transfer-Hydrogenation of a Compound of Formula (I-a) Using an Achiral Ru Catalyst

(431) Using an analogous procedure to Example 1B, the following achiral Ru transfer-hydrogenation catalysts (93, iii-g, iii-m-iii-y) were prepared using an achiral ligand and an (arene)dichlororuthenium dimer. The transfer-hydrogenation reactions of a compound of Formula (I-a) where R.sup.1 is Bn with these catalysts to afford a compound of Formula (II-a) were performed using an analogous procedure to Example 2A, except that the Ru catalyst loading was 1 mol % or 2 mol %. The diasteroselectivity of the resulting compounds of Formula (II-a) is given in Table 14.

(432) TABLE-US-00015 TABLE 14 Formula Arene Ligand (II-a) : ratio (93) mesitylene 0 75:25 iii-g hexamethylbenzene 99.1:0.9 iii-m mesitylene 59:41 iii-n mesitylene 90:10 iii-o mesitylene 55:45 iii-p mesitylene 56:44 iii-q mesitylene 40:60 iii-r mesitylene 60:40 iii-s hexamethylbenzene 96:4 iii-t hexamethylbenzene 94:6 iii-u hexamethylbenzene 0 52:48 iii-v hexamethylbenzene 98.7:1.3 iii-w hexamethylbenzene 91:9 iii-x p-cymene 82:18 iii-y benzene 37:63

EQUIVALENTS

(433) Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims.