and Enantioselective Hydride Reductions of Ketone Phosphinyl

Chapter 8

Diastereo- and Enantioselective Hydride Reductions of Ketone Phosphinyl Imines to Phosphinyl Amines Synthesis of Protected Amines and Amino Acids 1

Downloaded by UNIV OF MONTANA on January 26, 2016 | http://pubs.acs.org Publication Date: August 13, 1996 | doi: 10.1021/bk-1996-0641.ch008

Robert O. Hutchins, Qi-Cong Zhu, Jeffrey Adams , Samala J. Rao, Enis Oskay, Ahmed F. Abdel-Magid, and MaryGail K. Hutchins Department of Chemistry, Drexel University, Philadelphia, PA 19104 Three protocols involving asymmetric reductions of ketone phosphinyl imines (1) to enantiomeric or diastereomeric phosphinyl amines (2), (which represent protected versions of primary amines), are presented, including the use of substrates containing diastereotopic faces to stereoselectively generate diastereomers, employment of chiral reagents for enantioselective reductions, and the utility of chiral auxiliary attachments for diastereoselective reductions followed by release of enantiomeric amines. R"R'C=N-P(O)R 1

2

R"R'CH-NH-P(O)R 2

2

Recent investigations (1-4) have demonstrated that reductions of Ndiphenylphosphinyl imines (1) with hydride reagents to the corresponding Ndiphenylphosphinyl amines (2) provide attractive and effective entrances to protected versions of primary amines. Thus, derivatives 1 are easily prepared, often stable, but highly reactive intermediates which are readily reduced by most hydride reagents (including very bulky examples), from which the free primary amines can be released by mild acid hydrolysis. Of particular importance in this area are reductive protocols which afford stereoisomeric amine derivatives using processes that afford high stereoselection for particular diastereomers or enantiomers. This report presents three diversified applications directed toward describing the utility of intermediates 1 as reductive precursors to enantiomeric and diastereomeric amine stereoisomers. These are: • Reduction of cyclic derivatives bearing diastereotopic faces with bulky trialkylborohydrides to provide highly diastereoselective production of cyclic amine diastereomers. • Enantioselective reductions of α-iminoester derivatives with chiral hydride reagents to afford protected α-amino acids in high enantiomeric excesses. • Use of a chiral auxiliary group residing in the phosphinyl group (derived from a camphoryl exo-àiol) to induce asymmetry via reduction with achiral reagents and subsequent removal of the auxiliary group to afford chiral amines. Each of these approaches will be addressed separately below. 1

Current address: B I O M O L Research Laboratories, Inc., 5100 Campus Drive, Plymouth Meeting, P A 19462 0097-6156/96/0641-0127$15.00/0 © 1996 American Chemical Society

In Reductions in Organic Synthesis; Abdel-Magid, Ahmed F.; ACS Symposium Series; American Chemical Society: Washington, DC, 1996.

128

REDUCTIONS IN ORGANIC SYNTHESIS

Results and Discussion


Diastereoselective Reductions of Cyclic AT-Diphenylphosphinyl Imines. Although considerable effort has been devoted to uncovering synthetically useful and stereo controllable reductions of cyclic ketones to diastereomeric alcohols (see 4 for cited references), relatively few investigations have focused on developing processes for the corresponding stereoselective reductions of cyclic imines to amines (5, 6\ Particularly sparse are studies directed toward securing primary amines via reductive protocols with hydride reagents (3-5). In this regard, cyclic N-diphenylphosphinyl imines (4) were considered attractive intermediates for explorations aimed at developing successful stereoselective conversions to imine diastereomers. The requisite imines (4) were prepared from corresponding oximes (3) as outlined below.

ft

4

3

Considerable experimentation revealed that while "small" unhindered reagents (e.g. amine boranes) provided very poor stereoselection, the very bulky reagent lithium trwec-butylborohydride afforded excellent diastereo selectivity for production of axial amines (with cyclohexyl systems), resulting from equatorial approach. This parallels results obtained with analogous ketones (7) and imines (5) and prompted a thorough study of the scope and generality of such highly stereoselective reductions using a variety of substituted ring systems. In all cases, P N M R was utilized to determine diastereomer ratios. For comparison (and to insure that both diastereomers gave separate P signals), the corresponding reductions were also conducted using NaBKU. The results and data are presented in Tables I-IV for variously substituted cyclohexyl, cyclopentyl and bicyclo ring derivatives.

UAIH4, N a B H , N a B H C N , 4

3

3 1

3 1

Reductions of 2, 3, 4 andJor 5-Substituted Cyclohexyl Derivatives. The results demonstrate that reductions of 3,4 andJor 5-substituted cyclohexyl derivatives 5 with tri-.sgc-butylborohydride (Table I) in all cases provide excellent stereoselection (>97%) for the corresponding axial phosphinyl amine derivatives 6. Likewise, 2substituted derivatives 7 gave equally superior (>97%) diastereoselection for the axial derivatives 8 (Table II). As seen in Tables I and II, reductions with borohydride were, in general, relatively non-stereoselective and led to mixtures of diastereomers. Further discussions of the trends observed with this reagent are beyond the scope of this chapter but may be found in reference 4. A notable exception involves the 2-r-butyl derivative 7e (Table II) in which borohydride afforded the same high cis diastereoselectivity (>97J3) as obtained with tri-sec-butylborohydride. This probably arises because of unusual conformational situations created by the proximity of the 2-r-butyl group to the phosphinyl imine. Thus, with the phosphinyl analog 7e, both chair conformations experience severe destabilizing steric interactions (in the axial r-butyl conformer) or severe allylic strain repulsions (5, 8) (in the equatorial r-butyl conformer) The likely result is that the 2 -


8. HUTCHINS ET AL.

Hydride Reductions of Ketone Phosphinyl Imines129

r-butyl phosphinyl imine 7e resides predominantly in non-chair conformations such as 9 ("boat") andJor 10 ("twist") both of which are concave and present incoming reagents with bowl-like conformations. Table I. Reduction of 3 and ^Substituted Cyclohexylidene NDiphenylphosphinyl Imines


NP(0)Ph

NHP(0)Ph

2

R

2

^£^T~NHP(0)Ph

2

6 Entry

5

R

LiBH(s-Bu) NaBH ratio of equatorialJaxial attack of 3

4

(% Yield)* (% Yield) 1 26J74 a 4-f-Bu >97J3 (64) (65) 2 b 4-j-Pr >97J3 32J68 (58) (60) 3 c 4-Et >97J3 34J66 (64) (65) 4 d 4-Me >97J3 41J59 (72) (72) 5 e 4-Ph 95J5 52J48 (59) (55) 6 f r-3,4-diMe 37J63 >97J3 (69) (73) 7 c-3,5>97J3 40J60 g diMe (57) (70) 8 h 3,3.5-triMe >97J3 94J6 (66) (71) 9 i 3-Me >97J3 42J58 (79) (63) yields are for isolated, purified products calculated from oxime. 8

a

Thus, attack by both large and small hydride reagents suffers severe steric interactions in approach toward the inside the "bowl" (leading to the trans diastereomer) while attack from outside the "bowl" (which provides the cis isomer) is relatively un-encumbered and leads almost exclusively to the cis product as observed (>97% equatorial attack). The "twist" conformation 10 is probably preferred because it minimizes eclipsing interactions between the f-butyl group and the vicinal hydrogen (both in the "gunwale" position).


130

REDUCTIONS IN ORGANIC SYNTHESIS

Table II. Reduction of 2-Substituted Cyclohexylidene jV-Diphenylphosphinyl Imines NHP(0)Ph

2

+ ^^-^^NHP(0)Ph

2


8 Entry T "

R

NaBH LiBH(5-M ratio of equatorialJaxial attack of "i (% Yield)* (% Yield) 1 a 2-Me 50J50 >97J3 (63) (64) 2 b 2-Et >97J3 58J42 (63) (67) 3 c rra>w -2-J-Pr-5-Me >97J3 60J40 (60) (60) 4 d 2-Ph >97J3 40J60 (57) (63) 5 e 2-r-Bu >97J3 >97J3 (79) (57) 6 f 2-MeO >97J3 75J25 (71) (71) - yields are for isolated, purified products calculated from oxime. 4

3

8

"ii,

Reduction of Substituted Cyclopentyl and Other Cyclic Derivatives. The highly stereoselective reduction results obtained with cyclohexyl phosphinyl imines prompted an extension to cyclopentyl and bicyclic analogs. Table i n presents results obtained for substituted cyclopentyl derivatives. As evident, reduction of 2substituted derivatives with tri-stfc-butylborohydride (entries 1 and 2) afforded highly stereoselective discrimination to produce the cis diastereoisomers in analogy to similar results with 2-alkyl cyclopentanones (7). Here again, allylic strain may force a normally pseudo equatorial group to adopt a pseudo axial orientation (11a), thus


8. HUTCHINS ET AL.

Hydride Reductions of Ketone Phosphinyl Imines131

favoring approach of the bulky reagent from the face opposite the alkyl group. Reductions of 3-substituted derivatives with tri-5-butylborohydride (and NaBHJO gave poor stereoselectivities (entries 3 and 4). This was not unexpected since preferred half-chair conformation of cyclopentyl systems provides essentially no bias for attack at either face (C2 symmetry axis), unlike the situation in cyclohexyl systems. The 3-alkyl substituents probably reside in pseudo equatorial positions and thus offer no steric resistance to an incoming reagent (See lib).


Table in. Reduction of Cyclopentylidene JV-Diphenylphosphinyl Imines

NHP(0)Ph 9 Entry

10 9

R

LiBH(s-Bu) NaBH % cis attack of 9> (% Yield) (% Yield) 1 a 2-Me

and Enantioselective Hydride Reductions of Ketone Phosphinyl

Recommend Documents