Optically active trans-4-(tert-butyldimethylsiloxymethyl)-5-(tert- butyldimethylsiloxy)-2-cyclohexenone as a useful chiral building block for preparation of substituted cyclohexane rings: Synthesis and its highly stereoselective reaction with RCu(CN)Li

Article abstract of DOI:10.1016/S0040-4039(00)00239-2

Optically active trans-4-(tert-butyldimethylsiloxymethyl)-5-(tert- butyldimethylsiloxy)-2-cyclohexenone (2) has been synthesized in 25% overall yield starting from easily available 1,4-bis(benzyloxy)-2,3-epoxy butane (3). The enone 2 reacts with excellent stereoselectivity with RCu(CN)Li thus working as an efficient chiral building block for preparation of substituted cyclohexane compounds. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00239-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2659–2662
Optically active trans-4-(tert-butyldimethylsiloxymethyl)-
5-(tert-butyldimethylsiloxy)-2-cyclohexenone as a useful chiral
building block for preparation of substituted cyclohexane rings:
synthesis and its highly stereoselective reaction with RCu(CN)Li
Takeshi Hanazawa, Masakazu Koiwa, Georges P.-J. Hareau and Fumie Sato ∗
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8501, Japan
Received 17 January 2000; revised 3 February 2000; accepted 4 February 2000
Abstract
Optically active trans-4-(tert-butyldimethylsiloxymethyl)-5-(tert-butyldimethylsiloxy)-2-cyclohexenone (2) has
been synthesized in 25% overall yield starting from easily available 1,4-bis(benzyloxy)-2,3-epoxy butane (3). The
enone 2 reacts with excellent stereoselectivity with RCu(CN)Li thus working as an efficient chiral building block
for preparation of substituted cyclohexane compounds. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; copper; copper compounds; cyclohexenones; cyclohexanes.
Many biologically important compounds have a chiral cyclohexane ring in their structure as the main
or a subunit. One attractive method to synthesize these skeletons involves the use of naturally occurring
or man-made non-racemic 2-cyclohexenone compounds as the starting material, taking advantage of
their versatile reactivity. Recently, we have developed an efficient and practical method for preparation
of optically active 5-(tert-butyldimethylsiloxy)-2-cyclohexenone (1) and have shown that it can be
effectively used as a chiral building block for synthesizing a variety of substituted 2-cyclohexenone and
cyclohexanone derivatives.1
However, it is not an easy task to prepare 2-cyclohexenone or cyclohexanone derivatives ha-
ving a substituent at the 4-position starting from 1. Optically active 5-(tert-butyldimethylsiloxy)-2-
cyclohexenone having a siloxymethyl group at the 4-position seems to be an attractive chiral building
block for the preparation of a variety of these types of compounds, since the siloxymethyl group can
be potentially used as a handle for further functionalization. We report here the synthesis of 4-(tert-
butyldimethylsiloxymethyl)-5-(tert-butyldimethylsiloxy)-2-cyclohexenone with trans configuration, 2,
starting from 1,4-bis(benzyloxy)-2,3-epoxy butane (3), both enantiomers of which can be readily pre-
∗
Corresponding author. Tel: +0081 45 924 5787; fax: +0081 45 924 5826; e-mail: fsato@bio.titech.ac.jp (F. Sato)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00239-2
tetl 16519

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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

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(1)
Table 1
1,4-Addition of lower-order and higher-order cyanocuprates onto 2
At this point, we were interested in the diastereoselectivity of the reaction of organocopper com-
pounds with 4-(tert-butyldimethylsiloxymethyl)-5-(tert-butyldimethylsiloxy)-2-cyclohexenone having
cis configuration, 10, i.e., the diastereomer of 2. We assumed that the reaction with R2Cu(CN)Li2
would proceed highly selectively to introduce the R group at the trans position to both the tert-
butyldimethylsiloxymethyl and tert-butyldimethylsiloxy groups, while the reaction with RCu(CN)Li
might occur with low stereoselectivity. Our assumption turned out to be valid: thus, as shown in Eq.
(2), the reaction of rac-10 with Me2Cu(CN)Li2 or Bu2Cu(CN)Li2 provided the 1,4-addition product with
the expected stereochemistry almost exclusivly(<5:>95), but the reaction with BuCu(CN)Li afforded a
mixture of the two possible adducts in a ratio of 56:44. Thus, it may safely be said that the 1,4-addition
reaction of organocopper compounds to 5-(tert-butyldimethylsiloxy)-2-cyclohexenone having a substi-
tuent at the 4-position can be carried out with excellent selectivity irrespective of the stereochemistry of
the enone by using either RCu(CN)Li or R2Cu(CN)Li2.
(2)
Further synthetic utility of 2 and 8 (obtained from 2 and RCu(CN)Li) in organic syntheses is currently
under study in our laboratory. We have so far found that the osmylation of 2 proceeds in a stereoselective
way to afford the diol 11 exclusively.8 The treatment of 8 (R=Me) with TBAF resulted in β-elimination
to give 12. The relative configuration of 12 was confirmed by converting to trans-3-methyl-4-(tert-
butyldimethylsiloxymethyl)-cyclohexanone9 by hydrogenation of the double bond of 12.

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Acknowledgements
G.H. thanks the Japan Society for the Promotion of Science for financial support.
References
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