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ation of two stereogenic centers, leading directly to the
enantiopure tricyclic lactam 3 in 35% yield. Cyclohexenone 4
(22%) and hydroquinolone 5 (25% yield; nearly equimolec-
ular mixture of stereoisomers) were also isolated. Formation
of 3 can be rationalized by considering that, after an initial
aldol cyclization from the symmetrical starting diketone 2, the
resulting d oxoester 4 undergoes a phenylglycinol-promoted
cyclocondensation reaction in a process that mimics the
proposed biosynthetic pathway depicted in Scheme 1. In
accordance with this interpretation, 2 was first cyclized to
cyclohexenone 4 in excellent yield (90%) by treatment with
aqueous LiOH (1 molLÀ1) followed by reesterification, and
then converted into lactam 3 (60% yield) by reaction with
(R)-phenylglycinol in refluxing C6H6 containing a catalytic
amount of AcOH.[12] On the other hand, the formation of 5 in
the direct reaction of 2 with (R)-phenylglycinol is a conse-
quence of the initial generation of an oxazolidine, which then
undergoes two successive cyclizations, as depicted in
Scheme 3.
Scheme 4. Biomimetic synthesis of decahydroquinoline cis-195A.
TFA=trifluoroacetic acid, TMS=trimethylsilyl, Boc=tert-butyloxycar-
bonyl. See the Supporting Information for further details.
Scheme 3. Plausible mechanism for the formation of 5.
(BrCH2CO2Me, CHCl3; then (MeO)3P, Et3N, CHCl3, reflux)
to give b enamino ester 10 in 50% overall yield.
At this point, the complete relative stereochemistry of the
target alkaloid cis-195A (pumiliotoxin C) was installed by
hydrogenation of 10 in the presence of PtO2 under acidic
conditions, which brought about both the stereoselective
reduction of the vinylogous urethane double bond and
By choosing the appropriate 1,5-polycarbonyl derivative,
the biomimetic double cyclocondensation can be adapted to
the enantioselective synthesis of a variety of 2,5-disubstituted
decahydroquinoline derivatives, as exemplified by the syn-
thesis of the decahydroquinoline alkaloid cis-195A outlined
in Scheme 4. The required diketoester 6 was prepared in 65%
yield by the palladium-catalyzed coupling of 5-oxohexanoyl
chloride with the functionalized organozinc derivative 1 and
stereoselectively converted as in the above series into a
tricyclic hydroquinolone lactam (8) in excellent overall yield.
Thus, the initial aldol cyclocondensation took place in 85%
yield, whereas cyclocondensation of the resulting cyclohex-
enone 7 with R-phenylglycinol led to lactam 8 in 70% yield in
a process which again involved the generation of two
stereogenic centers from an achiral precursor.[12] In this
series, the configuration of the stereogenic ring-fusion carbon
atoms generated in this step was unambiguously established
by X-ray crystallographic analysis[13] of perhydroquinoline 9,
which was stereoselectively obtained in nearly quantitative
yield by catalytic hydrogenation of 8. The X-ray structure of 9
also made evident the trans relationship between the hydro-
gen atoms at the 4a and 5 positions of the quinoline ring.
The lactam carbonyl present in tricyclic lactam 9 allows
the introduction of substituents at the 2-position of the
hydroquinoline ring, ultimately leading to enantiopure 2,5-
disubstituted cis-perhydroquinolines. Thus, 9 was converted
into the corresponding thioamide, which was then subjected
À
cleavage of the oxazolidine C O bond. A subsequent
debenzylation with hydrogen and Pd(OH)2 in the presence
of Boc2O led to the protected cis-perhydroquinoline 11.
Finally, the conversion of ester 11 into pumiliotoxin C was
accomplished in satisfactory overall yield by reduction to
alcohol 12, followed by methylenation of the corresponding
aldehyde, subsequent catalytic hydrogenation of the resulting
N-Boc-2-allylperhydroquinoline, and finally deprotection of
the piperidine nitrogen. The NMR spectroscopy data and
[a]2D2 value (À15.3, c = 0.5 in MeOH) of cis-195A (pumilio-
toxin C) hydrochloride were consistent with those values
reported in the literature.[11]
The above results significantly expand the scope and
potential of phenylglycinol-derived oxazolopiperidone lac-
tams as chiral building blocks for the enantioselective syn-
thesis of complex piperidine-containing derivatives.[15] These
lactams are easily accessible by a cyclocondensation reaction
of a d oxoacid derivative with phenylglycinol. The use of
diketo(di)esters 2 and 6 as the d-oxoester partners in the
cyclocondensation reactions reported herein allows the
straightforward construction of the hydroquinoline ring
system. These 1,5-polycarbonyl derivatives mimic the bioge-
netic intermediates A (Scheme 1) by undergoing a biomim-
etic double cyclization that reproduces the key step of the
to
Eschenmoser
sulfide
contraction[14]
conditions
3350
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 3348 –3351
Amat, Mercedes
