chlorohydrin, which was then cyclized with DBU.10 The
diastereomeric epoxides 7 and 8 were obtained as a mixture
in a 3:5 ratio. Further purification allowed small amounts of
each epoxide to be obtained separately, allowing full
characterization. Thus the major product was confirmed as
Scheme 1. Previous Routes to Key Epoxydiynes
1
1
trans due to its smaller coupling constant.
The stereochemical outcome is consistent with the major
stereoisomer being generated from a transition state minimiz-
ing the steric interaction between the alkyne and the chlorine
9
atom (Scheme 3).
this strategy we require the attachment of the C-8 carbon
to the alkyne component prior to the union of the two
fragments. This strategy requires that we find a general route
to unsymmetrical epoxydiynes and despite considerable work
we have been unable to extend any of the methods previously
utilized for the synthesis of NCS chromophore and related
structures. The purpose of this letter is to describe a new
approach to unsymmetrical epoxydiynes that is not based
on utilizing a Sharpless asymmetric epoxidation approach.
It has recently been reported that allenyl zinc bromide 4
can be added to a number of aldehydes and ketones to give
halohydrins, which are subsequently cyclized to give prop-
Scheme 3. Proposed Transition State Model for Selectivity
9
argylic epoxides. Inspired by this work, we conceived of
an approach to the desired epoxydiynes by addition of an
allenyl zinc bromide to a propargyl ketone. Preliminary
studies directed toward assessing the feasibility of this
approach and in particular the stereochemical outcome were
initiated. Treatment of propargyl chloride 5 with 2 equiv of
zinc bromide followed by 2 equiv of LDA at low temperature
led to the formation of an organozinc reagent, which we
assumed to be 4 (Scheme 2). Addition of 2-octynal to this
It was then considered that according to this transition state
model, propargylic ketones including a bulky substituent in
the R position would preferentially form the epoxide with
the alkynes in a cis configuration. With NCS chromophore
in mind the ketone 9 was synthesized from the D-mannitol
derivative 3 via periodate cleavage of the diol, followed by
the addition of TMS-acetylide and finally oxidation with
pyridinium dichromate (Scheme 4).
Scheme 2. Preparation of the Allenyl Zinc Bromide and the
Scheme 4. Synthesis of Chiral Ketone 9
Synthesis of Simple Epoxydiynes
There was also literature precedent to presume that the
chiral center at the R-position of 9 would guide the addition
of the allenyl zinc species to the ketone to favor the resultant
1
2
alcohol with the desired R-stereochemistry. This can be
rationalized by proceeding via the transition state shown in
Scheme 5, following a nonchelation Felkin-Anh model or
alternatively a â-chelation effect.
(
9) (a) Chemla, F.; Bernard, N.; Ferreira, F.; Normant, J. F. Eur. J. Org.
Chem. 2001, 3295-3300. (b) Chemla, F.; Ferreira, F. Curr. Org. Chem.
002, 6, 539-570.
10) Working up the desilylated intermediate and stirring it with a 10%
2
(
mixture led to the formation of two new products, proposed
to be the diastereomers of chlorohydrin 6. The crude mixture
was treated with KF in DMF to afford the desilylated
NaOH solution led to an incomplete reaction after one week. This was also
the case if the reaction was left stirring in DMF.
3
3
(
(
11) Jcis > Jtrans. Mortimer, F. S. J. Mol. Spectrosc. 1960, 5, 199-205.
12) (a) Kobayashi, S.; Das, P.; Wang, G. X.; Mita, T.; Lear, M. J.;
Hirama, M. Chem. Lett. 2002, 300-301. (b) Das, P.; Mita, T.; Lear, M. J.;
Hirama, M. Chem. Commun. 2002, 2624-2625. (c) Jurczak, J.; Pikul, S.;
Bauer, T. Tetrahedron 1986, 42, 447-488.
(
8) Caddick, S.; Delisser, V. M.; Doyle, V. E.; Khan, S.; Avent, A. G.;
Vile, S. Tetrahedron 1999, 55, 2737-2754.
46
Org. Lett., Vol. 9, No. 1, 2007