Narasaka reduction

An excellent application of the Narasaka reduction is a diastereoselective synthesis by Merck scientists of 7, a structurally novel analog of the natural product compactin (8)7, which is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase8 (Scheme 4.1e). The key step in the construction of the P-hydroxy-8-lactone moiety in 7 is the highly diastereoselective reduction of the P-hydroxy ketone 9 using a triethyl borane/sodium borohydride system. The yyn-diol 10 was obtained in high yield and with a remarkably high level of diastereoselectivity. 

In the stereoselective synthesis of epothilone A (11), Carreira used a syn -reduction methodology in the synthesis of the key intermediate (14)9 (Scheme 4.If). Reduction of the isoxazoline 12 with samarium iodide at 0 C in THF gave the ketone 13. Narasaka reduction of the P-hydroxy ketone 13 using triethylb-orane/sodium borohydride afforded the. syn-diol 14 in high yield and with high diastereoselectivity. 

Paterson et al. [98] in their attempt used a similar disconnection for rhizopodin as described by Menche (fragments 144 and 149) (Scheme 2.151). However, unlike, Menche, they used silyl ketene acetal 16 in an asynunetric VMAR for the addition to ( )-iodoacrolein (142) to obtain dioxinone 143 in 94% ee. Methanolysis removed the aceto-nide, and the subsequent Narasaka reduction [99] provided the syn-diol 144 in 80% yield and a 10 1 selectivity for the desired isomer. The synthesis of segment 149 started with aldehyde 145, which was ultimately derived from Roche ester. Carbon chain extension was achieved through a chelation-controlled Mukaiyama aldol reaction with silyl ketene acetal 146, which installed the new chiral center with excellent stereocontrol (20 1 dr). For the installation of the third secondary alcohol, six-membered lactone 148 was obtained by treatment with K COj in methanol. Subsequent borane reduction provided stereospecifically the desired alcohol, which was then further transformed to the desired acid (149). 

In theory, the chiral center can be anywhere in the molecule, but in practice, reasonable diastereoselectivity is most often achieved when it is in the a position. For examples of high diastereoselectivity when the chiral center is further away, especially in reduction of P-hydroxy ketones, see Narasaka, K. Pai, F. Tetrahedron, 1984, 40, 2233 Hassine, B.B. Gorsane, M. Pecher, J. Martin, R.H. Bull. Soc. Chim. Belg., 1985, 94, 597 Bloch, R. Gilbert, L. Girard, C. Tetrahedron Lett., 1988, 53, 1021 Evans, D.A. Chapman, K.T. Carreira, E.M. J. Am. Chem. Soc., 1988, 110, 3560. 

Fig. 10.21. Diastereoselective reduction of /3-hydroxyketones to syn-configured 1,3-diols (Narasaka-Prasad reduction).

The second synthesis of lasubine II (6) by Narasaka et al. utilizes stereoselective reduction of a /3-hydroxy ketone O-benzyl oxime with lithium aluminum hydride, yielding the corresponding syn-/3-amino alcohol (Scheme 5) 17, 18). The 1,3-dithiane derivative 45 of 3,4-dimethoxybenzaldehyde was converted to 46 in 64% yield via alkylation with 2-bromo-l,l-dimethoxyethane followed by acid hydrolysis. Treatment of the aldol, obtained from condensation of 46 with the kinetic lithium enolate of 5-hexen-2-one, with O-benzylhydroxylamine hy-... 

To determine the effect of an a-substituent on the diastereoselectivity of the BBu3/NaBH4 system, Narasaka and Pai carried out the reduction of a-methyl-(3-hydroxy ketones1 (Scheme 4.1c). Whereas the o.,P-.vv -(i-hydroxy... 

Three years after Narasaka and Pai s disclosure, Prasad et al. developed a modified procedure to improve syn -diastereoselecti vi ty in the reduction of certain (3-hydroxy ketones6 (Scheme 4.Id). When methoxydiethylborane, in lieu of tributylborane, reacts with p-hydroxy ketones at —70 C in anhydrous methanol, the complex 5BEt2 is formed. Subsequent treatment of the complex with sodium borohydride and quenching the reaction mixture with acetic acid affords yyn-diols in excellent levels of diastereoselectivity regardless of the structure of p-hydroxy ketones. Another practical advantage of Prasad et al. s modification may be an enhanced safety feature, as methoxydiethylborane is generally less hazardous to handle than triethylborane.6... 

Deschenaux and Jacot-Guillarmod synthesised the Bartlett intermediate 124 with a chiral pool source and the Narasaka 1,3-diol synthesis for the C-6 to C-8 relationship (Scheme 16) (27). Methyl (-)-(3) )-3-hydroxybutanoate 115 (e.e. >99%) was converted to the p-ketoester 116. Reduction of the p-ketoalcohol using the Prasad version of the Narasaka method (23) with diethylmethoxyborane and sodium borohydride giving the diol 117. The acetonide 118 was homologated by way of the... 

Bromonaphthalene refluxed 3 hrs. with LiAlH4 and TiCl4 in tetrahydrofuran naphthalene. Y 98%. - The Lewis acid TiCl4 has a strong affinity toward halogen. F. e. and reductions s. T. Mukaiyama, M. Hayashi, and K. Narasaka, Chem. Lett. 1973, 291. 

A more general approach to get access to 1,3-syn-diols is the yn-selective Narasaka-Prasad reduction [77]. It utilizes the chelating capabilities of boron reagents and delivers the hydride externally, usually from NaBH (Scheme 2.144). Both a chair-like transition state and a boat transition state explain the observed yn-selective reduction. The mcommg... 

---