Angewandte
Chemie
stage, we were unable to determine the relative configuration
of the major product, presumably owing to conformational
equilibria of the cycloheptanone ring; we note that for
a straightforward synthesis, we required annulation onto the
same face of the cycloheptenone as the resident C7-ester. In
two simple steps, the silyl ether was converted into tosylate
ester 19, which was subjected to base-mediated ring closure to
cis-bicyclo[5.3.0]decane 20. Even in this bicyclic setting, the
relative stereochemical relationship of the ring junction
centers to C7 could not be defined with certainty by NMR
spectroscopy. This enolate alkylation reaction was generally
not run to complete conversion; rather, we typically isolated
the desired product in 25–40% yield and recovered close to
30% of the starting material. In so doing, we avoided
problematic C1 epimerization that was observed in the
course of longer reaction times. Efforts to improve this
reaction using halide and mesylate leaving groups, and with
different bases, solvents, and temperatures, never led to
a particularly efficient ring closure. Nonetheless, gram
quantities of bicycle 20 could be easily obtained through
this short route, especially with recycling of recovered 19.
Wittig reaction of the ketone moiety of 20 followed by
ester reduction afforded a single diastereomer of aldehyde 21.
Alkynylation with the Ohira–Bestmann reagent (22)[12] led to
a 4.5:1 ratio of diastereomeric alkyne products. Subjection of
aldehyde 21 to the reaction conditions without phosphonate
reagent 22 (K2CO3, MeOH, 08C) led to diastereomeric
aldehydes in a 4:1 ratio, the minor component of which was
the starting stereoisomer. This control experiment provided
circumstantial evidence to support epimerization as the major
outcome of the Ohira–Bestmann reaction. Lithiation and
methoxymethylation (with MOMCl) of the diastereomeric
mixture of alkynes (23) led to 12 in high yield.
unexpected side product 26. The synthesis of echinopine B
was complete in only 13 steps.[14]
Although the cycloisomerization reaction smoothly deliv-
ered the echinopine architecture from the much simpler
guaiane-like bicycle 12, this sequence required a terminal
oxidation step. Furthermore, the efficiency of these last two
steps was compromised by the generation of undesired side
products 25 and 26. We considered that cycloisomerization of
a substrate at a higher oxidation state might directly generate
one of the echinopines while potentially avoiding unwanted
reaction pathways. To test this hypothesis, we transformed
terminal alkyne 23 directly into dimethyl acetal 27
(Scheme 5). We anticipated the use of a similar PtII-catalyzed
Scheme 5. Cycloisomerization of ene-propargylic acetal 27 directly
affords echinopine B and unexpected epoxide 28.
cycloisomerization, because the acetal should confer similar
ꢀ
or greater hydride character to the acetal C H bond. Under
In the initial cycloisomerization experiment, subjection of
crude ene-propargylic ether 12 to the conditions prescribed
by Michelet and co-workers provided the desired cyclo-
isomerization product 24 as a 2:1 mixture of Z/E enol-ether
isomers (38% yield over two steps from the diastereomeric
mixture; the minor diastereomer of the starting material
could be observed unchanged in the NMR spectrum of the
crude reaction mixture). Successful reaction would only be
possible if the C7 configuration were such that the alkyne was
projected into the concave face of the cis-fused bicyclic ring
system; therefore, we hypothesize that the conjugate addition
of 17 to 14 generated 18 as predominantly the undesired
stereoisomer. The fortuitous epimerization in the course of
the alkynylation reaction largely corrected the C7 config-
uration and enabled the desired cycloisomerization. In later
experiments, cycloisomerization was conducted on diastereo-
merically pure substrate, resulting in a yield of 56% (46%
over two steps when 12 is not purified), along with quantities
of a cyclopropane-containing side product, which was tenta-
tively assigned as 25. Although formation of 24 completes
a formal synthesis of both echinopines according to the
synthesis of Nicolaou, Chen, and co-workers,[3] we opted to
generate echinopine B in only one step by enol-ether
oxidation as prescribed by Piancatelli et al.[13] Thus, treatment
of 24 with PCC provided echinopine B (2), along with
the standard reaction conditions that were reported by
Michelet and co-workers,[7a] we did indeed observe the
formation of echinopine B in moderate yield (up to 20%
yield, isolated in about 90% purity), presumably formed via
the intermediacy of a hydrolytically unstable ketene acetal.
Although ultimately less efficient in terms of overall yield,
this process was one step shorter and is, to our knowledge, the
first example of the cycloisomerization of an ene-propargylic
acetal. From this reaction, yet another major unanticipated
side product, the structure of which we have assigned as
tetracyclic epoxide 28, was generated in approximately 40%
yield.
Possible mechanistic pathways for the formation of each
of the three unexpected side products, 25, 26, and 28, are
shown in Schemes 6, 7, and 8, respectively. In the reports of
echinopine syntheses by other research groups,[2–5] there were
no mentions of rearrangements of the tetracyclic core; our
work demonstrates both the delicate balance of different
cycloisomerization reaction manifolds in complex systems
and the propensity for the strained echinopine ring system to
undergo rearrangement. Only small quantities of each side
product were isolated, and their structures were proposed on
the basis of extensive NMR experiments coupled with
plausible mechanistic hypotheses for the generation of each
structure (see below). Our attempts to further validate the
proposed structures led us to compare observed and calcu-
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
These are not the final page numbers!
Michels, Theo D.
