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vacuum. In this manner, yields between 60-80% were generally obtained. Using this protocol,
unnatural aromatic amino acids were utilized to prepare p-methoxyphenyl (58e), p-fluorophenyl
(58f), 2-thienyl (58g) and an N-Boc-indolyl (58h) derivatized allenes in yields ranging from 64
to 83%. The rearrangement of the N-Boc-indolyl derivative 56h required heating to 50 °C to
proceed which is attributed to the bulkiness of this group.
A serine derived allene 58i was also synthesized following the route outlined in Scheme
2.5. Esterification of acid 59 with 3-butyn-2-ol in 73% yield was followed by removal of the Boc
protecting group in 60 with TFA and coupling of the primary amine with benzoyl chloride to
afford amido-ester 61 in 60% yield for the two steps. Claisen rearrangement of 61 afforded
allene 58i in 87% yield as a ~2 : 1 mixture of diastereomers (determined by integration of the
allenic methyl group resonances in the 1 H NMR spectrum).
Scheme 2.5 Synthesis of serine derived allene 58i.
TBSO
Boc
NH
OH
DCC, DMAP
COOH
CH2Cl2, 73%
TBSO
Boc
NH
O
O
1. TFA, CH2Cl2, rt
2. BzCl, Et3N, CHCl3 60% (2 steps)
TBSO
Bz
NH
O
O
1. PPh3, CCl4, Et3N, MeCN
2. MeOH, HCl, rt.
87%
dr = 2 : 1
MeO2C •
NHBz
OTBS
59 60 61 58i
2.2.1.2 Ester-enolate Claisen Rearrangement
The ester-enolate version of the Claisen rearrangement was first introduced by Ireland 60 in 1976
and has since become a widely used method for acyclic stereocontrol. 61 Extension of the scope of
the reaction to α-hydroxy and α-amino ester derivatives was reported by Bartlett and coworkers
in 1982. 62 Subsequently, Kazmaier reported an ester-enolate Claisen rearrangement of α-amino
acid propargylic esters to form α-allenyl amino acids with diastereoselectivity ranging between
93-98%. 57 Control of the enolate geometry was accomplished by using an equimolar amount of
20
H