A short total synthesis of (±)-epimeloscine and (±)-meloscine enabled by a cascade radical annulation of a divinylcyclopropane

Article abstract of DOI:10.1021/ja2042854

The first stereoselective synthesis of epimeloscine has been accomplished in 13 total steps with a longest linear sequence of 10 steps. The core of the synthesis takes only five steps, the key ones being acylation, stereoselective tandem radical cyclization of a divinylcyclopropane to make two rings, and group-selective ring-closing metathesis of the resulting divinylcyclopentane to make the last ring.

Full text of DOI:10.1021/ja2042854

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A Short Total Synthesis of (()-Epimeloscine and (()-Meloscine
Enabled by a Cascade Radical Annulation of a Divinylcyclopropane
Hanmo Zhang and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S Supporting Information
b
ABSTRACT: The first stereoselective synthesis of epime-
loscine has been accomplished in 13 total steps with a longest
linear sequence of 10 steps. The core of the synthesis takes only
five steps, the key ones being acylation, stereoselective tandem
radical cyclization of a divinylcyclopropane to make two rings,
and group-selective ring-closing metathesis of the resulting
divinylcyclopentane to make the last ring.
eloscine (1) is the parent of a small but important group of
M
Melodinus alkaloids (Figure 1).1 It is thought that in nature,
1 and its less stable epimer epimeloscine (2) arise from scandine
(3) by hydrolysis and decarboxylation. In turn, scandine arises
from 18,19-dehydrotabersonine (4) by expansion of the B ring
and contraction of the C ring.2
Figure 1. Structures of meloscine alkaloids and key synthetic inter-
mediates of Bach and Mukai.
The highly functionalized C ring of meloscine with its four stereo-
centers (two of which are quaternary) presents a significant synthetic
challenge. Overman met this challenge in 1989 with a 22-step syn-
thesis featuring a classic example of the aza-Cope Mannich reaction.3
Appealing syntheses of meloscine have been reported by Bach in
20084 and very recently by Mukai.5 Bach made (þ)-meloscine
through key intermediate 5a, which was made by [2 þ 2] cycloaddi-
tion and ring expansion to construct rings B and C. Mukai made
intermediate 5b by a PausonꢀKhand cyclization. Both Bach and
Mukai ultimately made the E ring of meloscine by a ring-closing
metathesis (RCM) reaction, but the sequences from 5a and 5b to the
natural product took 10ꢀ11 steps.
The elegant syntheses of Bach and Mukai illustrate the challenge of
late introduction of the E ring with its C5 quaternary stereocenter.
Herein we report an exceptionally short synthesis of the meloscines in
which the B and C rings of an ABCD-ring product are constructed
in a single step by a cascade radical annulation of a divinylcyclo-
propane. The subsequent synthesis of the E ring is then expedited
by the presence of the two vinyl groups that are essential for the
radical cascade. As a bonus, the sequence produces exclusively
(()-epimeloscine, which is readily epimerized to (()-meloscine.1a
Figure 2 shows our retrosynthetic analysis. Meloscine (1) and
epimeloscine (2) should be readily available from 6 by an RCM
end game ꢀa la Bach and Mukai but in just a few short steps
(removal of the protecting group, N-allylation, RCM). Divinylcy-
clopentane 6 is the direct product of the cascade radical annulation
of divinylcyclopropane 7. In turn, 7 is formed by acylation of
aniline 8 by acid 9. Our recent work on radical cyclizations and o-
alkenyl anilides6 and the early studies of radical annulations of
monovinylcyclopropanes by several groups7,8 supported the fea-
sibility of this retrosynthetic analysis.
Figure 2. Retrosynthetic analysis of meloscines based on RCM, a
radical cascade, and acylation.
Divinylcyclopropanecarboxylic acid 9 was readily prepared in
five steps, as summarized in Scheme 1. Rhodium(II)-catalyzed
cyclopropanation of bisbenzyl ether 10 provided trisubstituted
cyclopropane 11 in 66% yield. Hydrogenation of 11 with Pearl-
man’s catalyst followed by TEMPO oxidation of the resulting
crude diol afforded dialdehyde 12 in 86% yield. Double Wittig
reaction of 12 followed by hydrolysis of the crude product
produced acid 9 in 60% yield over two steps.
The completion of the synthesis is shown in Scheme 2. We
initially pursued a traditional strategy with a protecting group on
the anilide nitrogen. Aniline 13b (R = H) is a known compound that
Received: May 10, 2011
Published: June 13, 2011
r
2011 American Chemical Society
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Scheme 1. Five-Step Synthesis of Divinylcyclopropanecar-
boxylic Acid 9
and finally RCM with the second-generation GrubbsꢀHoveyda
catalyst. As expected on the basis of ring strain,5 only one of the two
diastereotopic vinyl groups was engaged to provide pentacycle 18a
in 94% yield. The synthesis then hit a minor roadblock when several
pilot reactions to make epimeloscine by debenzylation of 18a were
unsuccessful.
Faced with the apparent choice of scaling up to make more 18a
for renewed tries of debenzylation or changing the N-protecting
group to something easier to remove, we decided to do neither.
Instead, we attempted to remove the N-protecting group entirely.
This cut two steps from the synthesis, but there was uncertainty
because anilide 15b has a Z ground-state geometry,11 so its derived
radical would not be predisposed for cyclization.12 We elected this
option since it was easy to prepare 15b.
Indeed, acylation of aniline 13b using acid 9 and Ghosez’s
reagent as before provided 15b in 77% yield. Syringe pump
addition of tin hydride to 15b under the conditions optimized for
15a provided ABCD tetracycle 16b in 38% yield after careful
purification. Removal of the Boc group and N-allylation provided
17b in 73% yield. RCM as described above then directly provided
the natural product (()-epimeloscine (2) in 89% yield.1a,c
Overman produced epimeloscine in his classic synthesis,3 but it
came from a minor stereoisomer (<10%) of a mixture on the way
to meloscine. Thus, this is the first stereoselective synthesis of
epimeloscine. Epimerization of 2 with KOtBu provided (()-
meloscine (1) in 83% yield.
Scheme 2. Five- and Six-Step Syntheses of (()-Epimeloscine
and (() Meloscine from Acid 9 and Aniline 13b
In summary, we have achieved the first stereoselective synthesis of
(()-epimeloscine (2) with a longest linear sequence of just 10 steps
in ∼6% overall yield. (()-Meloscine (1) is readily produced from 2
by epimerization. The core part of the synthesis, which involves
coupling of two simple precursors (13b and 9) followed by rapid
formation of rings B and C (in tandem) and then ring E (Scheme 2),
takes just five steps and proceeds in almost 20% overall yield. There is
room for improvement because the yield of the radical cyclization
(38%) was unoptimized. This core sequence features no oxidations,
no reductions, no functional-group transformations, and only one
deprotection (removal of the N-Boc group). The use of a divinylcy-
clopropane in the cascade radical annulation to make the B and C
rings paves the way for immediate construction of ring E to complete
the synthesis.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental details
b
and copies of NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
was prepared in three steps9 (see the Supporting Information) and
then benzylated under standard conditions to provide 13a (R = Bn)
in 73% yield. Acid chloride 14 was prepared in situ from 9 with
Ghosez reagent [Me2CdC(Cl)NMe2],10 after which aniline 13a
was added to provide 15a in 83% yield. Importantly, this key
precursor was expected to exist predominantly as the shown E
rotamer,11 predisposing it to undergo the first radical cyclization.12
Syringe pump addition of tributyltin hydride (2 equiv) and
AIBN to a refluxing solution of 15a in toluene provided 16a in
55% yield after purification to remove the tin residues. This sole
stereoisomer has the epimeloscine configuration at C3.
Corresponding Author
curran@pitt.edu
’ ACKNOWLEDGMENT
We thank the National Institutes of Health (NIGMS P50-
GM067082) and the National Science Foundation for funding of
this work. This paper is dedicated to Professor Barry M. Trost on
the occasion of his 70th Birthday.
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the N-Boc group with TFA, subsequent N-allylation to provide 17a,
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’ NOTE ADDED AFTER ASAP PUBLICATION
This article was published ASAP on June 16, 2011. Figure 1
was updated and a dedication was added to the Acknowledg-
ment. The corrected version was posted on June 20, 2011.
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