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effected after liberation of the phosphane by decomplexation
with 1,4-diazabicyclo[2.2.2]octane (dabco; 2–5 equiv) at
708C. The unfunctionalized 7–9-membered lactams 5a–c
were isolated in yields of 84, 59, and 80%, respectively. It
was calculated by 1H NMR spectroscopic analysis of the
reaction mixtures that the cyclizations to 5b and 5c occurred
essentially quantitatively. aZ-lysine (1d) also cyclized effi-
ciently to give 5d in 80% yield. The cyclization of precursors
4e and 4 f, which have a conformationally unbiased tertiary
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ꢀ
N CO bond, gave bislactams 5e and 5 f in yields of 80 and
60%, respectively. Finally, we turned our attention to the
highly challenging target 3-benzyl-[1,4]diazepane-2,5-dione
(5g). Gratifyingly, both 4g and 4h reacted to give 5g in
isolated yields of 35 and 29%, respectively, as 1g and 1h can
not be lactamized directly by using traditional methodolo-
gies.[7b] The higher yields in the reactions of 4e and 4g in
comparison to those of 4 f and 4h suggests that the cyclization
is sensitive to steric congestion in the C-terminal fragment.
This is a phenomenon that has been observed in peptide
cyclizations previously by us and others.[7b,17]
In conclusion, the results described herein show that
medium-sized lactams that are inaccessible or can only be
prepared with great difficulty by methods that rely on the
direct carboxy activation of w-amino acids can be prepared by
using this intramolecular Staudinger ligation method. Work is
currently in progress to expand the intramolecular Staudinger
ligation approach to the synthesis of small cyclopeptides.
[17] X.-M. Gao, Y.-H. Ye, M. Bernd, B. Kutscher, J. Pept. Sci. 2002, 8,
418 – 430.
Received: May 20, 2003 [Z51930]
Keywords: cyclization · lactams · medium-ring compounds ·
.
ring contraction · synthetic methods
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