Angewandte
Chemie
involving aldehyde 12 (Scheme 2). In one experi-
ment, we noted that 12 could be isolated with great
care as a mixture of diastereomers (5:1), before it
rapidly undergoes epimerization. If the formation
of 16 occurs with high facial selectivity in the
protonation step, subsequent reduction of the
iminium group would produce an amine that is no
longer susceptible to epimerization at the C3 posi-
tion. Consequently, the coupling of the two reac-
tions in a cascading sequence provides a shunt
mechanism that precludes the loss of stereochem-
ical information.
Having constructed the carbocyclic core, com-
pletion of the synthesis required the installation of
the pyrrolidine. We reasoned that this oxidation
sequence could be best accomplished by bromina-
tion at the Ca position of the ketone, followed by
nucleophilic displacement by the pendant amine
(Scheme 4). PHT proved to be a highly regioselec-
tive bromination agent at C10.[25] We speculate that
the selectivity arises by the kinetic generation of N-
bromoamine 17, which leads to directed, regiose-
lective ketone bromination to give 18. This was
followed by ring closure in the same pot, albeit to
a maximum of 50% conversion. We then observed
that addition of DMAP after bromination led to
complete conversion into 19 in 63% yield. We
hypothesize that DMAP might not merely act as
a base, but that it could also induce epimerization
ꢀ
Scheme 2. Reagents and conditions: a) LiAlH4, THF, 08C, 95%; b) PhCOCl, DMAP,
NEt3, CH2Cl2, 08C to RT; c) AcOH, H2O, 508C; d) tBuMe2SiCl, DMAP, imidazole,
CH2Cl2, 08C to RT, 77% over three steps; e) HF·pyridine, THF, 08C to RT, 84%;
f) (COCl)2, Me2SO, NEt3, ꢀ788C to RT, 98%; g) 9, 08C; EtMgBr, 81%, d.r. (anti/
syn)=2.2:1; h) TEMPO, PhI(OAc)2, CH2Cl2, 08C to RT, 88%; i) iPr2NLi, Me3SiCl,
THF, ꢀ788C to RT; toluene, 1108C; j) Me3SiCHN2, C6H6, MeOH, 68C to RT, 95%
over two steps; k) HF·pyridine, THF, 08C to RT, 88%; l) PCC, celite, CH2Cl2, RT,
76%; m) C5H9N, C6H6, 4 ꢁ molecular sieves, 808C, 65%, d.r.=2:1. TBS=tert-
butyldimethylsilyl; TBDPS=tert-butyldiphenylsilyl; TEMPO=2,2,6,6-tetramethyl-
piperidine-1-oxyl; PCC=pyridinium chlorochromate; DMAP=4-dimethylamino-
pyridine.
Thus, treatment of 10 with N-methylbenzylamine followed by
exposure to H2/Pd led to the selective formation of 3 in high
diastereoselectivity (Scheme 3).[23] Overall, this
at the C10 position, such that the C Br bond is correctly
aligned for SN2 displacement. Furthermore, DMAP may also
sequence not only allowed the diastereoselective
ꢀ
formation of the crucial C3 C11 bond, but also for
the elegant introduction of the desired pendant
amine in 68% yield.[24]
The mechanistic possibilities for the sequence
that may lead to the selective formation of 3 are
shown in Scheme 3. In the first possibility (path-
way A), the direct formation of 3 with complete
control at the C3 and C11 positions, in principle,
could occur during the cyclization. However, this
would require that the enamine side chain be
oriented endo during the course of the cyclization.
As an alternative, following cyclization of 13, the
first-formed iminium cation undergoes proton loss
to give enamine 14. Nonselective protonation
furnishes diastereomeric intermediates 15 and 16
(pathways B or D: concave versus convex proto-
nation) followed by preferential and rapid reduc-
tion of 16. In effect, the sequence affording 3
would correspond to a dynamic kinetic resolution
process. As a third mechanistic option (path-
=
way C), reduction of C C in 14 from the convex
face would directly and stereoselectively produce
3. We favor the fourth option (pathway D) in
which stereoselective protonation of 14 gives 16,
which then undergoes reduction to amine 3. This is
consistent with an observation that we have made
Scheme 3. Cascade sequence to construct the core structure of (ꢀ)-dendrobine (1).
Angew. Chem. Int. Ed. 2012, 51, 3436 –3439
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3437