that this result might be caused by the presence of another
reactive site, such as a ketone carbonyl function. Ketone 7
was, therefore, reduced with NaBH to give alcohol 8 as an
4
inseparable diastereoisomeric mixture (ca. 1:1).
After deprotection of the Boc group on treatment with
TFA, the resulting alcohol 9 was further converted to silyl
ether 10 in the usual manner (Scheme 1). Attempted
Scheme 1
Figure 2. Retrosynthetic route to (-)-adalinine.
The retrosynthetic route to (-)-adalinine is depicted in
Figure 2, in which we envisaged that a chiral quaternary
carbon center could be constructed with the desired stereo-
chemistry via Michael addition of a pentyl group to enami-
none A, readily accessible from (S)-(-)-pyroglutamic acid,
by the control of the stereochemistry of the ester function
on the pyrrolidine ring. Moreover, a ring enlargement of
pyrrolidine derivative B to δ-lactam would easily be achieved
by application of a samarium-promoted fragmentation reac-
4
tion, followed by recyclization of the resulting amino ester
C.
Thus, the requisite optically active pyrrolidine derivative
bearing a chiral quaternary carbon center was prepared as
follows. Treatment of thiolactam 3, derived from ethyl (S)-
6
(
-)-pyroglutamate 2 with phosphorus pentasulfide and
bromoacetone and subsequent desulfurization of thioether 4
7
with triphenylphosphine gave (Z)-enaminone 5. The stere-
ochemistry of the olefin was assumed to be Z by observation
-1
of an absorption at 1630 cm for an intramolecular hydrogen
bond between the enaminone carbonyl and NH groups in
its IR spectrum. This fact was already reported by Eschen-
moser. After protection of the amino group of 5 as a
carbamoyl group, (E)-Boc-enaminone 6 was subjected to
fragmentation reaction of 10 with 5 equiv of samarium iodide
in THF-HMPA (7:1) in the presence of pivalic acid as a
proton source brought about the carbon-nitrogen bond
cleavage smoothly, and simultaneous cyclization of the
7
Michael addition with pentylmagnesium bromide in the
8
presence of a copper sulfide-dimethyl sulfide complex to
resulting δ-amino ester to give the desired δ-lactam 11 in
provide the desired pyrrolidine 7 in 87% yield. Although
the stereochemistry of the newly generated chiral center could
not be determined at this stage, it was assumed that the major
product 7 should have the correct stereochemistry for natural
product synthesis, since Michael addition of a pentyl group
would be expected to take place from the less hindered side
of enaminone 6.
With the desired pyrrolidine derivative available, we first
investigated a samarium-promoted carbon-nitrogen bond
cleavage reaction for keto ester 7 or its de-Boc derivative;
however, the reactions were found to be sluggish. We thought
9
7
0% yield. In our previous study on this fragmentation
4
reaction, a cosolvent HMPA usually required only 5 equiv;
however, it was found that the use of a smaller amount of
HMPA or its absence in the conversion of 10 to 11 decreased
the yield, remarkably. The exact reason for this observation
is still obscure at the present time; however, the presence of
the disubstituents at the R-position to an amino group may
have some effect on this reaction.
Finally, desilylation of 11 on acid hydrolysis with hydro-
chloric acid, followed by oxidation of the resulting alcohol
1
2 with TPAP and NMO according to the reported proce-
2
dure (Scheme 2) gave (-)-adalinine 1, whose spectroscopic
(6) Peterson, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc. 1984, 106,
4
539.
(7) Roth, M.; Dubs, P.; G o¨ tschi, E.; Eschenmoser, A. HelV. Chim. Acta
(9) A small amount of uncyclized δ-amino ester could also be isolated
from this reaction; however, the uncyclized compound was easily trans-
formed to the cyclization product by heating in benzene or by standing at
room temperature for few days. The yield was demonstrated as the combined
yield.
1
971, 54, 710.
(
8) For Michael addition of Grignard reagent to enaminones, see:
Comins, D. L.; LaMunyon, D. H.; Chen, X. J. Org. Chem. 1997, 62,
182.
8
3926
Org. Lett., Vol. 2, No. 24, 2000