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pared from diethyl D- or L-tartrate, respectively, according to the protocol of Nicolaou et al.,2 and its
highly diastereoselective conjugate addition reaction with an organocopper compound.
The preparation of 2 from 3 was carried out according to the procedure shown in Scheme 1. Reaction
of (R,R)-3 with vinylmagnesium bromide in the presence of CuI gave the vinylalcohol 4 (94% yield),3
which in turn was converted to the triol 5 under the Birch reduction conditions (88% yield). From 5,
epoxide 6 was prepared via a four-step sequence according to the procedure developed by Sharpless in
64% overall yield.4 Compound 6 was then converted to the ester 7 in 62% overall yield by conventional
reaction sequences which involve ring opening with the CN anion using Et2AlCN, protection of the
resulting hydroxy group as a TBS-ether, and the following conversion of the CN moiety to a methylester
group. The ester 7 could then be converted to the expected 2 in 72% overall yield according to the
procedure used previously for the synthesis of 1, i.e., the intramolecular nucleophilic acyl substitution
reaction mediated by a Ti(O-i-Pr)4/2i-PrMgCl reagent5 and FeCl3-induced ring enlargement reaction.6
In conclusion, the enone 2 was prepared from 3 in 25% overall yield.
Scheme 1. (a) CuI, CH2_CHMgBr, Et2O; (b) Li/NH3, THF; (c) (i) MeC(OMe)3, cat. PPTS, CH2Cl2, (ii) CH3COBr, CH2Cl2,
(iii) K2CO3, MeOH, (iv) TBSCl, imidazole, DMF; (d) (i) Et2AlCN, THF, (ii) TBSCl, imidazole, DMF, (iii) DIBAL-H, C6H14,
(iv) NaClO2, NaH2PO4·2H2O, H2O, tBuOH, 2-methyl-2-butene, (v) MeI, K2CO3, acetone; (e) (i) Ti(O-i-Pr)4/2i-PrMgCl, Et2O,
(ii) FeCl3, pyr, DMF, (iii) AcONa, MeOH
With 2 in hand, our next concern was the diastereoselectivity of the conjugated addition of organo-
copper compounds to it. It had been reported that 1,4-addition of organocopper compounds to 4- or
5-substituted 2-cyclohexenones proceeds highly selectively via an anti-addition pathway, respectively.
Thus, at first glance, it seemed difficult to get high diastereoselectivity for the reaction of 2 with
organocopper compounds. However, we had previously found that, while the reaction of 1 with the
Gillman cuprates R2CuLi or higher-order cyanocuprates R2Cu(CN)Li2 proceeded via an anti-addition
pathway, the reaction with lower-order cyanocuprates RCu(CN)Li, exceptionally, afforded syn-addition
products highly selectively owing to the ligating effect of the alkoxy group.1a,b We, therefore, expected
that this syn-addition tendency by the reaction with RCu(CN)Li might be applicable to the reaction with
2 irrespective of the presence of the tert-butyldimethylsiloxymethyl substituent at the C-4 position, thus
affording highly selectively the 1,4-addition product 8 having the structure where the R group introduced
is cis to the tert-butyldimethylsiloxy group and trans to the tert-butyldimethylsiloxymethyl group. As
expected, the reaction of RCu(CN)Li where R is a methyl and primary-, secondary-, and tertiary-alkyl
group afforded the 1,4-addition product 8 with the anticipated structure almost exclusively. The phenyl
derivative, however, proceeded with lower selectivity and lower yield; this observation is in accord with
our earlier result observed for the reaction with 1.1b We also confirmed that the reaction of 2 with
R2Cu(CN)Li2 provided the mixture of two possible diastereomers, 8 and 9, in a variable ratio dependent
on the R group (Table 1); it is noteworthy, however, that the reaction with Ph2Cu(CN)Li2 proceeded with
exceptionally high selectivity to afford the corresponding 8 exclusively.7
Hanazawa, Takeshi
