Reduction of a,p-acetylenic ketones

Conjugate reductions. This combination (usually 1 3 ratio) effects conjugate reduction of a,p-acetylenic ketones or esters to a, 3-enones or unsaturated esters at -50° with moderate (E)-selectivity. The HMPT is believed to function as a ligand to aluminum and thus to promote hydroalumination to give a vinylaluminum intermediate, which can be trapped by an allylic bromide (equation I).1 The re-... 

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. 

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). 

The reduction of a,p-acetylenic ketones is accomplished in 24-48 h at room temperature by using twofold excess of NB-Enantrane and running the reaction without solvent. Both chemical and enantiomeric yields are high (Table 26.14) and provide (S)-propargyl alcohols. The reduction fits the steric model proposed for Alpine-Borane reduction [3]. Nopol benzyl ether liberated after the reduction maybe easily isolated during purification of the product and recycled. 

Table 26.14 Reduction of a,p-acetylenic ketones with NB-Enantrane [1] ...

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. 

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. 

In summary, a number of effective chiral reducing agents have been developed based on the modification of LAH. Excellent results have been obtained with aryl alkyl ketones and a,p-acetylenic ketones. However, dialkyl ketones are reduced in much lower enantiomeric excess. This clearly indicates that steric effects alone do not control stereoselectivity in these reductions. Systematic studies have been carried out with the objective of designing improved reagents. A better understanding of the mechanisms and knowledge of the active species is required in order to provide more accurate models of the transition states of the key reduction steps. 

Reduction of a,p-ynones. a,/J-Acetylenic ketones are reduced by 1 to (S> propargyl alcohols in 86-96% enantioselective purity. It is thus comparable to B-3-pinanyl-9-BBN in enantiomeric yields, although the reductions require 1-2 days and an excess of neat reagent for complete reaction. 

The selective reduction of the a,p-acetylenic ketones such as 4.12 to a,p-ethylenic ketones is accomplished by reaction with DIBAH in THF-HMPA [TY2]. In the presence of a catalytic quantity of MeCu, the reduction is faster and the stereoselectivity is modified (Figure 4.4). Nevertheless, the stereoselectivity is never very high [TY2]. The reagent does not reduce the isolated triple bond of 4.13 (Figure 4.4). 

Regioselective conjugate reduction and reductive silylation of a,p-unsaturated ketones, esters, and aldehydes, also of acetylenes using a stable copper (I) hydride cluster ((Ph3P)CuH]6 (see 1st edition). 

Based on this strategy, Garcia et al. have used oxazaborolidine, (R)-2, and effectively reduced several a,p-acetylenic ketones. The e.e. value of the products was in the range 90 to 97%. To improve the results further, the monobranched ketones were complexed with hexacarbonyl dicobalt complexes and snbjected to reduction. Unfortunately, the reactions were sluggish and under forced conditions or modifications of oxazaborolidine resnlled only in low yields and enantioselectives (Table 21.3). 

In a totally different approach, Noyori et al. have used binaphthol-modifled aluminum hydride reagent for enatioselective reduction of alkynyl ketones. Suitably modified boranes can be used for stereoselective reduction of ketones. Along these same lines. Midland" has developed Alpine borane (1, Scheme 21.5), which is excellent for several acetylenic ketones but has been found inefficient for hindered ot,p-acetylenic ketones. To overcome this problem, Brown et al." have introduced P-chlorodiisopinocamphenyl borane 2(-)-DIP-Cl (2, (Scheme 21.5), which reacts well with hindered ketones to provide the corresponding propargyl alcohols in 96 to 99% e.e. 

Table 26.12 Reduction of prochiral a,p-acetylenic (from 92% (+)-a-pinene) at 25 °C [3] ketones with 40% excess of neat Alpine-Borane ...

The reduction is considered to proceed through a six-membered transition state30 (Scheme 4.3aa). In the hydride-bridged six-membered transition state A, the acetylenic unit positions itself away from the isopinocampheyl skeleton. The hydrogen P to the boron is then transferred to the carbonyl group from the bottom face of the ketone. Computational analysis on the proposed transition state of the Midland reduction has not, however, been reported.32... 

The rate of reduction with B- -octyl-9-BBN ofp-substituted benzaldehydes correlates with (p + 1.03) [12]. Relative rates ofp-substituted benzaldehydes with B-3-pinanyl-9-BBN gave a of + 0.49. Electron-withdrawing groups increase the rate of reduction of substituted benzaldehydes. This effect is presumably also important for alkynyl ketones [7], where the small steric size of the acetylene and its negative inductive effect can combine to make the reduction possible. 

The tethered catalyst 24a proved to be superior over its untethered version 26 in the reduction of functionalised acetylenic ketones 27 with FA-TEA as hydrogen donor (Fig. 8) [59]. High enantioselectivity and substituent tolerance of these ketones indicate that the alkyne group has a dominating stereo-controlling effect through C-Wn interaction. Additionally, an efficient dynamic kinetic resolution was observed with substrates 27 favouring the syn products. The table in Fig. 8 shows selected examples of the reduction of acetylenic p-keto esters. 

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