Synthesis of non-racemic unsymmetrical tetrasubstituted vinylallenes

Article abstract of DOI:10.1016/S0040-4039(00)01406-4

Tetrasubstituted chiral vinylallenes are constructed from the enantioselective epoxidation of an enyne followed by an S(N)2' addition of a cuprate. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01406-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8033–8036
Synthesis of non-racemic unsymmetrical tetrasubstituted
vinylallenes
Claude Spino* and Sylvie Fre´chette
Universite´ de Sherbrooke, De´partement de Chimie, Sherbrooke, Que´bec, J1K 2R1, Canada
Received 19 July 2000; revised 7 August 2000; accepted 14 August 2000
Abstract
Tetrasubstituted chiral vinylallenes are constructed from the enantioselective epoxidation of an enyne
followed by an SN2% addition of a cuprate. © 2000 Elsevier Science Ltd. All rights reserved.
We recently disclosed the use of tetrasubstituted vinylallenes to construct tetrasubstituted
exocyclic double bonds.1 The vinylallenes underwent Diels–Alder cycloadditions under mild
conditions even when highly strained alkenes were produced in this way. Vinylallenes have been
used in synthesis, mostly as dienes in [4+2]-cycloadditions,2–11 but tetrasubstituted vinylallenes
were used only rarely. We report herein the synthesis of chiral tetrasubstituted vinylallenes that
were used as models in our synthetic efforts toward the cytotoxic quassinoids.
Pentanal 1 was reacted with ethynylmagnesium bromide and the resulting alcohol 2 was
protected as its methoxymethyl ether (Scheme 1).† Initially, we performed Sonogashira’s
Scheme 1.
* Corresponding author.
†
All new compounds gave satisfactory IR, NMR and Mass spectral data.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01406-4

8034
cross-coupling of alkyne 3 with 2-bromo-2-propen-1-ol (Pd+2, CuI, Et3N) and obtained substan-
tial amounts of by-product 4b resulting from the homocoupling of alkyne 3 along with the
desired enyne 4a. Rossi’s modifications proved superior and under those conditions the ratio of
cross versus homocoupling products was >9:1.12 The allylic alcohol 4a was epoxidized stereose-
lectively using Shi’s catalyst system and 5 was obtained in 72% yield as a ca 4:1 mixture of 5a–b
and 5c–d (55% ee).13–16 The lack of substituent at position 2 on the alkene may be responsible
for the lower enantioselectivity.16
The Sharpless asymmetric epoxidation conditions produced 5 in 69% ee but in lower yield. At
this stage, the diastereomeric epoxides appear and behave like pairs of enantiomers. The
acetylenic unit between the two chiral carbons isolate them so effectively that the two pairs of
diastereomers were undifferentiable by proton and 13C NMR. Thus 5 appeared as a single
compound by spectroscopy. The (S)-(−)-Mosher esters of 5 were prepared and it was found to
consist of a ca 4:1 mixture of two epoxides (i.e. [5a+5b]:[5c+5d]).‡
The epoxide mixture 5 was submitted to the action of methylcopper in THF to yield 72% of
two separable diastereomeric allenic alcohols 6 in a 1:1 ratio each being 54% ee (Scheme 2). The
enantiomeric excesses were again checked by making the Mosher esters of each pair of
enantiomeric allenyl alcohols. This implies a highly anti selective addition of methylcopper on
epoxide 5, a result consistent with what is known on cross-coupling reactions of cuprates with
allylic and propargylic epoxides.17–20
Scheme 2.
While the epoxidation of enyne 4a proceeded with moderate enantioselectivity, the chiral
center on 4a (bearing the MOM ether) serves to increase substantially the enantiomeric purity
of the major allene 6a obtained. Propargyl alcohol 2 has been prepared in 85% ee.21 If the
sequence of epoxidation–cuprate addition is performed on this material, the enantiomeric ratio
6a:6d becomes 48:1 (ca 98% ee), after separation of the diastereomeric mixture on a normal
silica gel column (note that the ratio 6b:6c is ca 1:3).
‡ Compounds 5a and 5b (or 5c and 5d) could not be separated by GC or HPLC and the NMR spectra of their
Mosher esters were identical.

8035
To complete the sequence, allene 6a (54% ee) was oxidized with perruthenate and converted
to the desired vinylallene 7 using a Wadsworth–Emmons reaction (Scheme 3). The diisobutyl-
aluminium hydride reduction product of vinylallene 7 underwent a Diels–Alder cycloaddition
with tetracyanoethylene at room temperature to give 8 possessing an exocyclic tetrasubstituted
double bond and in which the hydroxyl group had cyclized internally to give an iminoester. As
expected, the major adduct corresponded to an approach of the dienophile from the least
hindered face of the vinylallene.1 Confirmation of the stereochemistry of the major Diels–Alder
adduct, and thus of the vinylallene precursor, was obtained from a single crystal X-ray analysis
of an unusual methanolic adduct 9 which occurred when 8 was crystallized from methanol.
Scheme 3.
The pseudo-symmetrical nature of allene 6a also permitted us to construct the vinylallene with
the opposite configuration (Scheme 4). Protection of the alcohol in 6a as a pivalate ester and
deprotection of the silyl ether using ultrasound gave 10 which was submitted to the oxidation/
olefination sequence to give 11. Careful and prompt handling of the allenic alcohols is desirable
since they slowly epimerize over time. We have determined that two different mechanisms are
responsible for the epimerization depending on the circumstance. First, daylight induces slow
epimerization of some allenes presumably via a diradical. We irradiated the aldehyde obtained
from 6a (see Scheme 3) under a 275 W sunlamp and obtained the equilibrium mixture (ca 1:1)
of this aldehyde and its epimer (aldehyde corresponding to 6c) in 1 hour. Second, several basic
reaction conditions promote the migration of some protecting groups between the alcohol
Scheme 4.

8036
functions. For example, during an attempt to protect the hydroxyl group in 6a, deprotonation
with NaH led to a 1:1 mixture of 6a and 6c instantaneously, probably from a migration of the
silyl group. Fortunately, the final vinylallenes 7 and 11 are stable to epimerization.
Acknowledgements
We thank the National Sciences and Engineering Research Council of Canada and the
University of Sherbrooke for financial support.
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