Preparation of (S)‐2‐Methylbutyl and (S)‐sec‐Butyl Ketones from Optically Active 2‐Methyl‐1‐butanol by the Dithiane Method

Abstract

(10) + (2) (11) + ( 2 ) (3). R = Li, + Cyclohexene epoxide (94 + (2) ( 3 ) , R = Li. + (CH+,SiCI (7), R = Li, + CHsI (7). R = Li, + n-CsH11ISince optical resolution of aldehydes and ketones is difficult, optically active members of these series are usually prepared from other optically active compounds. Thus the carbonyl compounds ( 4 ) can be prepared from fermentation alcohol (2-methyl-1-butanol) (1) by way of (2) and its metal derivatives [yield (2) +(4) < 50 73 "1.The dithiane method121 offers a suitable means for replacement of the halogen atom in (2) by an acyl group. For example, with 2-lithio-1.3-dithiane (9a) the iodide (2) givesa 65 "i, yield of compound (3a) (b.p. 74 OC/O.3 torr) and thence by hydrolysis the aldehyde (4a). The optically active ketones (4b)-(4e) can be obtained similarly. The lithio derivatives (10) and (11) were also used as "masked" acyl anions. the dithianes). Further, (S)-2-methylbutyraldehyde, which is readily prepared from the alcohol ( 1 ) , is converted by 1,3-propanedithiol into the dithiane (61, whence hydrolysis [5bl regenerates the aldehyde with only 20% loss of activity (an average of 10% in each step).The aldehyde (5) can thus be converted by way of (6) and its Li derivative into the dithianes (7) and thence into ( S ) -ketones such as (86) and (Sf). Since compounds ( 6 ) and (7) cannot racemize, danger of racemization is confined to preparation of (6) and the hydrolysis (7) +(8). From the experiments outlined it can be concluded that the loss of activity in passing from the aldehyde to the ketones (8) is probably less than 20%.Owing to the manifold reactivity of the readily accessible Li derivatives of (3a) and ( 6 ) the dithiane method is superior to the methods previously customary for synthesis of compounds of type ( 4 ) and (8) [cl Calculated on optically pure starting material ( I ) , (21, (6). or (8), R=OH; cf. experimental section.[dl Hydrolysis affords first the dimethyl acetal of (4a) in 80 % yield; b.p. 72 "C/SO torr, n'," = 1.4073. [alh' = +4.3 ( c = 1 I , ether). This was hydrolyzed to the free aldehyde.[el In CHCI,.and distilled to yield 14-17 g of ( 6 ) , b.p. 67-7OoC/0.6 torr,Optically active ketones of type (8) containing acidic hydrogen a t the center of asymmetry racemize readily through the en01 form. Since acidic or basic conditions cannot be avoided in the methods conventionally used for synthesis and resolution, preparation of such ketones presents particular problems. We have found that (Sf) 131 and even (8d) [Id, 31, which has an enolizable H atom only on the asymmetric C atom, lose less than 5 % of their optical activity when their aqueousmethanolic solutions are boiled for one to three hours with 2 molecular equivalents of HgC12 and one of HgOC21 or CdC03 141 (these being conditions for neutral hydrolysis of n'," = 1.5387; [a]g = -0.50 (c = 15, ether). Alkylation of (6) to give 2-(l-methylpropyl)-2-pentyl-l,3-dithiane (7f): 3.85 g of (6) is metalated in 70 ml of THF with a 5 % excess of butyllithiumc2al. After addition of 3.6 ml of 1-i...