M. Yu et al. / Tetrahedron Letters 45 (2004) 2879–2881
2881
C. Boucher (Boehringer Ingelheim Canada) for ee
measurements. M.Y. holds a province of Alberta
Graduate Fellowship.
MOMO
O
MOMO
O
N
N
N
ii
AcO
XO
iv
iii
29a,b X = H
30a,b X = Ms
i
27a,b
26
vi
MOMO
O
MOMO
O
4
N
References and notes
v
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28
31
Scheme 2. Reagents and conditions: (i) Bu3SnH (addition over 10 h),
AIBN, PhH, 80 °C, reflux 3 h more, less polar isomer of 26 gave 27a in
20% yield, and 28 in 67% yield, more polar isomer of 26 gave 27b in
33% yield and 28 in 46% yield; (ii) MeONa, MeOH, 4 h, 91% for less
polar acetate, 92% for more polar acetate; (iii) MeSO2Cl, Et3N, THF;
(iv) DBU, PhMe, reflux, 48 h, 69% over two steps for less polar alco-
hol; 64% for more polar alcohol; (v) Me2CuLi, Me3SiCl, Et3N, THF,
ꢀ78 °C, 2 h, then 25 °C for ca. 1 h, 81%; (vi) Me3OBF4, 2,6-di-t-bu-
tylpyridine, CH2Cl2, 4.5 h, aqueous Na2CO3, 71%.
resulting alcohols were mesylated in the usual way. The
crude mesylates were treated with DBU in refluxing
PhMe to produce 28 (69% for less polar alcohol, 64% for
more polar alcohol). Introduction of the required
methyl group in the correct stereochemical sense was
now easily achieved by using Me2CuLi in the presence of
Me3SiCl,14 lactam 31 being produced in 81% yield. Ini-
tially, opening of the lactam proved very troublesome
because semireduction with a variety of reagents was
unsuccessful, but we eventually found that treatment of
31 with Meerweinꢀs reagent,15 followed by basic aqueous
workup gave 4 in 71% yield.
Compound 4 represents the aza spiro system of
halichlorine with the correct relative stereochemistry at
each of the asymmetric centers, and the sidechain methyl
group is in a configurationally stable location, since it is
b to the ester carbonyl. The route to 4 illustrates two
synthetically useful characteristics of a phenylseleno
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trigger that is far less sensitive to basic conditions than
bromine. At several points in this work steric or con-
formational factors led to unusual results; in particular
we note the selective pivaloylation of the C(6) hydroxy-
methyl group of 8, in preference to that at C(2). Lactam
31 has unusual properties: it is very easily reduced to the
corresponding tertiary amine, and semireduction was
not possible, even with LiH2NBH3, which is nor-
mally6m;16;17 an effective reagent for this purpose. Our
attempts to hydrolyze 31 (as well as lactam 22) under
standard basic or acidic conditions were unsuccessful,
but the indirect procedure, via O-alkylation with
Meerweinꢀs reagent, worked well, and the resulting
amino ester 4 showed little tendency to recyclize.
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Acknowledgements
We thank the Natural Sciences and Engineering
Research Council of Canada for financial support, and