Angewandte
Chemie
Aggarwal, E. Alonso, M. Ferrara, S. E. Spey, J. Org. Chem. 2002,
the alkene bond in the dimeric compound (R,R)-5h was also
achieved under mild conditions (1 atm H2, 5 mol% Pd on C,
RT) to give the saturated analogue 8 in 99% yield. This result
further highlights the utility of the dimerization methodology,
and demonstrates efficient access to saturated protected
enantiopure C2-symmetric 1,4-diamines.
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ˇ
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In summary, we have developed a dimerization pathway
of terminal aziridines by lithiation to give N-protected 2-ene-
1,4-diamines with complete E-olefin selectivity when starting
with enantiopure substrates. The dimerization proved highly
efficient for a range of alkyl-substituted and functionalized
aziridines, by using the same straightforward reaction con-
ditions in each case. The usefulness of the method was
demonstrated by the efficient and selective synthesis of
diaminodiol (R,S,S,R)-7, the core unit of a number of
extremely potent HIV protease inhibitors.
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[9] Enantiopure aziridines were prepared in a straightforward
manner and in excellent yield from the corresponding epoxides
of opposite configuration (available commercially or according
to: S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B.
Hansen, A. E. Gould, M. E. Furrow, E. N. Jacobsen, J. Am.
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a) tBuSO2NH2, BnEt3NCl, K2CO3; b) (MeSO2)2O, 4-dimethyla-
minopyridine, pyridine; c) K2CO3 (see Ref. [3] and also: D. M.
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Experimental Section
Representative procedure for dimerization of terminal aziridine 4:
nBuLi (1.6m in hexanes, 1.88 mL, 3.0 mmol) was added dropwise to a
solution of 2,2,6,6-tetramethylpiperidine (0.51 mL, 3.0 mmol) in THF
(0.4 mL) at À788C. The mixture was warmed to 08C over 15 min,
then cooled to À788C before dropwise addition of the aziridine 4
(1.0 mmol) in THF (0.8 mL). The mixture was stirred at À788C for
20 min, then at 08C for 1 h, before the addition of MeOH (0.8 mL),
saturated aqueous NH4Cl (8 mL), and Et2O (16 mL). The layers were
separated, and the aqueous phase was extracted with Et2O (16 mL).
The combined organic phase was dried (MgSO4) and concentrated
under reduced pressure. Flash chromatography of the residue (SiO2,
petroleum ether/diethyl ether) gave the protected 2-ene-1,4-diamine
5.
[10] In studies with substrate 4a, the use of fewer equivalents of
LTMP or extended reaction times at À788C led to incomplete
reaction.
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Received: September 16, 2005
Published online: December 27, 2005
Keywords: aziridines · lithiation · small ring systems ·
.
synthetic methods
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[14] Conversely, when 2,3-epoxypropylbenzene was subjected to
dimerization conditions (see Experimental Section) the major
product was cinnamyl alcohol (arising from benzylic deproto-
nation and eliminative rearrangement), and no significant 2-ene-
1,4-diol was observed.
[15] Similar dihydroxylation of the analogous N-Boc-protected 2-
ene-1,4-diamine displayed poor diastereoselectivity (2:3) and
favored the opposite (less desirable for HIV protease inhibition)
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