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The requisite allenynes of general structure 112 were prepared as outlined in Scheme 3.15. The
mono-benzyl protected diol 116a was synthesized in >95% yield by addition of ethynyl-
magnesium bromide to commercially available aldehyde 115a. The corresponding mono-TBS
protected diol 116b was prepared by diprotection of 1,4-butanediol with TBSCl, followed by
ozonolysis and alkynylation of the resulting aldehyde. With alcohol 116b in hand, the
DCC/DMAP mediated coupling with Bz-phenylalanine was attempted under the standard
conditions (rt, in CH2Cl2). However, this reaction led only to formation of the oxazolone
intermediate 55a. It was reasoned that the sterically hindered nature of the secondary alcohol
prevents the facile opening of 55a under the reaction conditions. To solve this problem, 55a was
formed by separately treating benzoyl-phenylalanine with DCC and DMAP. Upon isolation, the
oxazolone was treated to neat alcohol 116a or 116b in presence of catalytic amount of Et3N.
Under these conditions formation of esters 120a and 120b was observed, albeit in relatively low
isolated yields (54% for the benzyl-protected and 32% for the TBS-protected alcohol). The lower
yield for the TBS-protected case is attributed to increased steric influence by the silyl group.
Next, the Claisen rearrangement of these propargyl esters 120a and 120b was attempted under
dehydrative conditions reported by Krantz. Reaction of the benzyl-protected 120a proceeded at
40 °C to give the desired allene 121a in >95% yield after treatment with MeOH. In contrast, the
reaction of the TBS-protected 120b required heating to 60 °C and afforded the product 121b in
lower yield (76%). Notably, formation of methyl ester was accomplished by using MeOH/Et3N
instead of the standard MeOH/HCl in order to avoid potential cleavage of the TBS-ether under
strong acidic conditions. As expected, allenes 121a and 121b were obtained as mixtures of
diastereomers in ~2 : 1 ratio determined by 1 H NMR.
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