Acetylenic ketones, asymmetric reduction

Brown and coworkers [1] have found that NB-Enantrane is effective only for the reduction of a,(3-acetylenic ketones. The reduction of other ketones is too slow to be of any practical use. The retarded rate is attributed to the steric bulk at the 2 position since no internal coordination has been detected by "B NMR (6 86 ppm) [2]. On the other hand, Alpine-Borane has proven to be versatile reagent for the asymmetric reduction of variety of ketones. Consequently, two reagents B-(iso-2-ethylapopinocampheyl)-9-borabicyclo[3.3.1]nonane (Eapine-Borane) and B-(iso-2- -propylapopinocampheyl)-9-BBN (Prapine-Borane) having increasing steric requirement at the 2 position, are prepared by the hydroboration [3] of 2-ethyl- and 2-n-propylapopinene. 

LBADH also catalyzed the asymmetric reduction of a broad variety of differently substituted acetylenic ketones, including aromatic alkynones and a number of aliphatic derivatives [71]. For example, methyl alkynones bearing an aromatic unit attached to the triple bond were reduced to the corresponding (7 )-propargylic alcohols with >99% ee. Similarly, alkylsilyl-substituted... 

The reagent 78 was found to be highly effective in the asymmetric reduction of a-acetylenic ketones (89). Acetylenic carbinols were prepared in 75 to 90%... 

Asymmetric Reduction of Acetylenic Ketones with Amino Alcohol-LAH Reagents... 

The Darvon alcohol-LAH complex was used in the reduction of the acetylenic ketone (93) in one step of an asymmetric total synthesis of lla-hydroxypro-gesterone (97), a key intermediate in the production of hydrocortisone acetate... 

Asymmetric reduction of a,f -acetylenic ketones. This borane can be used to reduce 1-deulerio aldehydes to chiral (S)-l-deulerio primary alcohols in 90% optical yields. It also reduces a,/ -acctylcnic ketones to (R)-propargylic alcohols with enantiomeric purity of 73-100%. The ee value is increased by an increase in the size of the group attached to the carbonyl group. The value is also higher in reductions of terminal ynones. Alcohols of the opposite configuration can be obtained with the reagent prepared from (— )-a-pinene. 

Asymmetric reduction of a, -acetylenic ketones 2 Detailed directions for reduction of l-octyne-3-one to (R)-l-octyne-3-ol with this reagent are available. This method has been used to reduce 10 other acetylenic ketones in >70% ee. 

M. Mark Midland and Richard S. Graham 57 ASYMMETRIC REDUCTION OF a,8-ACETYLENIC KETONES WITH B-3-PINANYL-9-BORABICYCLO-[3.3.1DN0NANE (R)-(+)-1-0CTYN-3-0L... 

Acetylenic ketones are important synthetic intermediates in the synthesis of a variety of natural products. Optically active propargyl alcohols of either configuration are readily available in high optical purity by asymmetric reduction of propargyl ketones with B-3-pinanyl-9-borabicyclo(3.3.1)nonane761 (Eq. 31). 

Asymmetric reduction. The complex of L1A1H4, N-methylephedrine, and 3,5-dimethylphenol (1 1 2) reduces aryl alkyl ketones and a-acetylenic ketones to optically active alcohols with a purity of 75-90%. The optical yields are comparable to those observed with the structurally related darvon alcohol (8, 184-186). The reduction of benzoylacetylene, G HsCOC CH, results in a racemic alcohol. ... 

This time there are so many possibilities that we don t want to push any one solution. We hi mind the asymmetric reduction of an acetylenic ketone by CBS or some other asymmetric red-.-m agent and then using the alkyne to make the tram alkene. You also have to consider at what stac -introduce the ester group. This open-ended problem cannot have a more defined solution. 

Midland, M. M., McDowell, D. C., Hatch, R. L., Tramontane, A. Reduction of a,P-acetylenic ketones with B-3-pinanyl-9-borabicyclo[3.3.1]nonane. High asymmetric induction in aliphatic systems. J. Am. Chem. Soc. 1980,102, 867-869. 

Asymmetric reductions. HofFmann-LaRoche chemists1 have examined in detail the asymmetric reduction of a,/(-acetylenic ketones with Darvon alcohol (1) and related alcohols. Use of the enantiomer of 1 resulted predominately in reduction to the enantiomer (S) of the (R)-carbinols obtained with 1. Several optically pure 1,3-... 

Conjugate addition of the complete allylic alcohol fragment is possible with the mixed cuprate reagents 33 prepared by asymmetric reduction (chapter 26) of acetylenic ketones 29 to give the alcohols 30, protection as a silyl ether 31 and hydroboration-iodination. Lithiation and reaction with hexynyl copper (I) gives the mixed cuprate 33 from which the less stable anion is transferred selectively to an enone.3 This approach has been widely used in the synthesis of prostaglandins. 

Asymmetric transfer hydrogenation of a,p-acetylenic ketones with a pre-existing stereogenic center affords diastereomeric propargylic alcohols [128]. For example, reduction of a chiral amino ketone (S)-48 with R,R)-42 in 2-propanol gives (3S,4S)-49 predominantly (Scheme 42), whereas reaction using (S,S)-42 affords the 3R,4S stereoisomer in >97% yield. The sense of diastereoface selection is mostly dependent on the chirality of the Ru catalyst. 

In accord with this model, groups larger than methyl generally provide lower asymmetric induction. In the case of acetylenic ketones, the acetylene also occupies the equatorial position. Thus, the reagent does not appear to discriminate by purely steric factors. In fact, it is proposed that there is an unfavorable h/tt interaction between the axial oxygen of the 1, l -bi-2-naphthalenol moiety and an unsaturated system if it is in the axial position. One exception to this generalization is in the reduction of 4-cyclopentene-l,3-dione in which the alkene portion presumably occupies the axial position. In this case there is said to be a favorable n/tr interaction. 

Reduction of acetylenic ketones, RC=CCR. Alpine-Borane can effect this reduction in high cnantioselcctivity, but this borane is very sensitive to steric effects. Thus it fails to reduce a carbonyl group adjacent to a /-butyl group. In contrast, asymmetric reduction of alkyl aryl ketones with I is increased by a hindered alkyl group. The same effect obtains in reduction of actylenic ketones (2). Thus as the steric bulk of R increases, the enantioselcctivity also increases. 

Brinkmeyer and Kapoor have now found that acetylenic ketones, RC= CCOR, are reduced by LiAlH4 and 1 at — 78° with the highest enantiomeric selectivity observed to date. Thus CH3Ce CCOCH2CH(CH3)2 is reduced to the corresponding (R)-alcohol with an enantiomeric excess of 827 . Similar asymmetric reductions were observed with seven other ketones of this type. Propargylic ketones are readily available by reaction of lithium acetylides with aldehydes followed by Jones oxidation of the propargylic alcohols. 

ASYMMETRIC REDUCTION OF a,B-ACETYLENIC KETONES WITH B-3-PINANYL-9-B0RABICYCL0-... 

Prior to this work, Mosner and Yamaguchi" reported similar reduction with an LAH-quinine combination however, no example of acetylenic ketone was attempted. In a later study, Midland et al. developed a-pinene-9-Borabicyclo [3.3.1] nonane complex as an excellent reagent for the reduction of a,P-acetylenic ketones and observed high asymmetric induction in aliphatic systems (Table 21.1). 

Other Nitrogen-containing Metabolites. - A method for the asymmetric reduction of o<-acetylenic ketones to optically active propargyl alcohols has... 

Using neat (S)-Alpine-Borane the reaction is 67% complete in 92 h, and 22-(S)- is obtained in a 7 1 ratio. It is thus apparent that for (R)-Alpine-Borane the double asymmetric inductions are working together, whereas in (S)-Alpine-Bo-rane they are working in opposite direction. A similar change in selectivities is observed in the asymmetric reduction of these acetylenic ketones using (+)-and (-)-A-methylephedrine/LAH [18]. The faster rate of reduction with (R)-... 

The high asymmetric induction achieved with Eapine-Borane for the a,p-acetylenic ketones and a-ketoesters led an examination of the reduction of a series of a,p-acetylenic ketones (Eq. 26.16) and a-ketoesters (Eq. 26.17), and the comparative reduction data of Eapine-Borane with Alpine-Borane are summarized in Tables 26.16 and 26.17. It should be mentioned that Eapine-Borane offers no advantage for the reduction of aromatic a-ketoesters. Thus, Eapine-Borane is an efficient reagent for the chiral reduction of a,(3-acetylenic ketones (Table 26.16) [1] and of alkyl a-ketoesters (Table 26.17) [1], of appreciable steric difference between the two groups on both sides of the carbonyl group. 

R)-Propargylic alcohols have also been produced, this time in 73—100% e.e., by asymmetric reduction of a,/3-acetylenic ketones with the chiral borane prepared from (+)-a-pinene and 9-borabicyclo[3.3.1]nonane (9-BBN) (Scheme 10), a system already known to reduce aldehydes to chiral alcohols cf. 2,115). These results compare favourably with those from the LiAlH4- Darvon complex above, and the availability of both (+)-and (-)-o -pinene means that either (R)-or (5)-propargylic alcohols may be produced. 

Further examples of reagents and methods for asymmetric reduction are provided by the complexes obtained by partial decomposition of LiAlH4 by AT-methylephedrine(85) and either AT-ethylaniline" or 3,5-dimethylphenol. The first of these reduces open chain enones to allylic alcohols with enantiomeric excesses approaching 100%, whereas the second has been used to reduce conjugated acetylenic ketones to propargylic alcohols en route to optically pure y-lactones. Enantiomeric excesses of up to 90% are also obtained in the reduction of acetylenic ketones and acetophenones with LiAlH4 complexed with several optically active 1,3-amino-alcohols,and the chiral LiAlH4-derivatives (86) reduce ketones in up to 87% optical yield. ... 

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