Enantioselective total synthesis of the Melodinus alkaloid (+)-meloscine

Article abstract of DOI:10.1002/anie.200800693

(Chemical Equation Presented) Enantioselective synthesis in a new light: The template-controlled [2+2] photocycloaddition leading to product 1 is the first example of this type of reaction in natural product synthesis. In addition, a retrobenzilic acid rearrangement (→2), a Claisen rearrangement (→3), and a ring-closing metathesis played decisive roles in the synthesis of the alkaloid (+)-meloscine (4).

Full text of DOI:10.1002/anie.200800693

Communications
DOI: 10.1002/anie.200800693
Natural Product Synthesis
Enantioselective Total Synthesis of the Melodinus Alkaloid
(+)-Meloscine**
Philipp Selig and Thorsten Bach*
Dedicated to Professor Gernot Boche on the occasion of his 70th birthday
Melodinus alkaloids, also known as meloquinolines, represent
a group of monoterpenoid indole alkaloids. Their pentacyclic
carbon skeleton A is closely related to the general structure B
of aspidoperma alkaloids of the aspidospermidine type.[1]
Melodinus alkaloids were isolated from certain Apocynacea
species, for example, from Melodinus scandens Forst.[2] and
from Melodinus hemsleyanus Diels.,[3] which play a role in
Scheme 1. Retrosynthetic analysis of (+)-meloscine. Boc=tert-
traditional Chinese folk medicine. A proposed biosynthetic
pathway B!A proceeding by skeletal rearrangement
appears to be likely as it has been realized in small yields by
laboratory syntheses.[4]
butyloxycarbonyl, Bn=benzyl.
Retrosynthetic disconnection of the natural product led us
from intermediate 2, which had already been used in racemic
form by Overman et al., to the tetracyclic ester 3, which
offered a variety of possibilities for the construction of the
quaternary stereogenic center at C5.[10] The plan to construct
the stereogentic center at C19 by reductive amination and to
introduce the exocyclic double bond by a carbonyl olefination
resulted in the hypothetical 1,2-diketone 4 as a formal
intermediate, which was to be derived from a [2+2] photo-
cycloaddition product of the known quinolone 5.[11] In fact, an
enantioselective [2+2] photocycloaddition in the presence of
the chiral complexing agent 6[12] was considered as the pivotal
step for the generation of the stereogenic centers at positions
C3 and C12.
Ring expansion from the four- to the five-membered ring,
however, was not trivial, and numerous attempts to construct
a cyclopentane ring by a classical Wagner–Meerwein rear-
rangement of an iminium ion[13] were futile. Considering these
difficulties, the two-step sequence depicted in Scheme 2 was a
decisive breakthrough, as it allowed for the rapid synthesis of
an equivalent of aminodiketone 4 in a surprisingly easy
fashion. The rearrangement of cyclobutane 7 into the a-
hydroxycyclopentenone 9 can be explained as a retro-benzilic
ester rearrangement[14] (step b), which effectively takes
advantage of a captodative electronic situation in the
electron-rich alkoxide 8. The silyl enol ether[15] derived from
methyl pyruvate was employed for the first time in a [2+2]
photocycloaddition and gave the cycloaddition product 7
(step a) with perfect regio- and diastereoselectivity.
The prototype of all Melodinus alkaloids is (+)-meloscine
(Scheme 1), the constitution and absolute configuration of
which were elucidated already in 1969 by Bernauer et al.[5]
and Oberhänsli.[6] From a synthetic point of view, the
construction of the central, highly substituted cyclopentane
ring with four stereogenic centers, two of which are quater-
nary, represents the main challenge, which only Overman
et al. have successfully mastered so far.[7] Starting from ethyl-
2-oxocyclopentylacetic acid, they achieved the synthesis of
racemic (ꢀ )-meloscine in 25 steps with an overall yield of
2%. However, neither the synthesis of enantiopure (+)-
meloscine nor an enantiospecific entry into the meloquinoline
skeleton has yet been described.[8] We report herein on the
first enantioselective total synthesis of (+)-meloscine, which
employs a template-controlled [2+2] photocycloaddition as
one of the key steps.[9]
[*] P. Selig, Prof. Dr. T. Bach
Department of Chemistry
Technische Universität München
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax: (+49)89-2891-3315
E-mail: thorsten.bach@ch.tum.de
[**] This project was supported by the Deutsche Forschungsgemein-
schaft as part of the Schwerpunktprogramm Organokatalyse (Ba
1372-10), by the Studienstiftung des Deutschen Volkes (doctoral
fellowship to P.S.), and by the Fonds der Chemischen Industrie.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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pyrrolidine 11, was obtained after reprotection of the basic
amine nitrogen atom in an overall yield of 78% over three
steps starting from enol acetate 10.
Pyrrolidine 11 was then converted into the Michael
acceptor 3 (Scheme 1) by saponification of the acetate,
oxidation of the secondary alcohol to the ketone with o-
iodoxybenzoic acid (IBX),[17] and subsequent Wittig reaction.
Unfortunately, all attempts to achieve a nucleophilic attack at
the prostereogenic b-carbon atom were unsuccessful, both as
intra- and as intermolecular variants. Two of the most
promising options explored, radical addition reactions[18]
and the addition of soft nucleophiles,[19] did not give any
useful products. A solution was eventually found by conduct-
ing a Claisen rearrangement[20] of allylic alcohol 12, which was
easily accessible from ester 3 by reduction. The rearrange-
ment was performed as the Johnson variant[21] employing
trimethyl orthoacetate as the reagent. The rearrangement
product was obtained as an inseparable mixture of diastereo-
isomers in a diastereomeric ratio (d.r.) of 70:30, with the
major diastereoisomer possessing the desired relative config-
uration. After N-deprotection and basic workup the minor
diastereoisomer spontaneously cyclized to a pentacyclic
lactam which could be removed easily. N-allylation of the
major diastereomer resulted in the diastereomerically pure
compound 13 in 65% yield. Ring-closing metathesis[22] of 13
with a commercially available 2nd generation Grubbs cata-
lyst[23] gave rise to the final tetrahydropyridine ring (95%
yield), thus completing the construction of the pentacyclic
meloquinoline skeleton. Reduction of the ester side chain was
best achieved in two steps via the corresponding aldehyde and
resulted in alcohol 2, already
Scheme 2. Synthesis of the tricyclic intermediate 9 by a sequence of
enantioselective [2+2] photocycloaddition and rearrangement: a) hn
(370 nm), 6 (2.5 equiv), silyl enol ether (5.0 equiv), toluene, ꢁ608C,
4 h, 76%; b) K2CO3, MeOH, 208C, 2 h, 98%.
Successful further conversion of a-hydroxycyclopente-
none 9 required chemical fixation in its enol form, which was
achieved by conversion to its O-acetyl derivative 10
(Scheme 3). After cleavage of the Boc group, heterogeneous
reduction with Pearlmanꢀs catalyst Pd(OH)2/C and hydrogen
initiated a domino reaction,[16] in the course of which the C C
=
bond was diastereoselectively hydrogenated, the N-benzyl
protecting group was cleaved, and the resulting free primary
amine was involved in an intramolecular, diastereoselective
reductive amination. As no isolation of the intermediates was
necessary, the final product of this reductive sequence, N-Boc
known in racemic form. The sub-
sequent elimination was con-
ducted
following
essentially
Overmanꢀs procedure.[7] In con-
trast to this precedence, however,
the successful oxidative elimina-
tion of the intermediate sele-
nide[24] was possible only after
quantitative protonation of the
basic tertiary amine by a slight
excess of acid. Direct oxidation
with meta-chloroperoxybenzoic
acid (mCPBA) gave either no
significant conversion or resulted
in an unspecific decomposition if
an excess of more than two equiv-
alents of mCPBA was employed.
(+)-Meloscine obtained after suc-
cessful elimination was in every
respect identical to the natural
product.[4b,5,25]
Scheme 3. Completion of the total synthesis of (+)-meloscine (1) starting from tricyclic ketone 9:
a) AcCl (1.1 equiv), NEt3 (1.5 equiv), THF, 08C, 15 min, 95%; b) TFA (10 vol%), CH2Cl2, 208C, 1 h;
c) H2 (1 atm), 15% Pd(OH)2/C (20 mol%), MeOH, 08C!208C, 18 h; d) addition of NEt3 to pH 8–10,
Boc2O (1.3 equiv), CH2Cl2, 208C, 1 h, 78% over 3 steps; e) K2CO3, MeOH, 208C, 3.5 h, 94%; f) IBX
(3.0 equiv), DMSO, 208C, 18 h, 94%; g) Ph3PCHCOOEt (1.4 equiv), THF, reflux, 22 h, 84%; h) DIBAL-
H (3.75 equiv), CH2Cl2, ꢁ458C, 30 min, 81%; i) MeC(OMe)3 (3 equiv), hydroquinone (0.66 equiv),
1358C, 16 h, 85% (d.r. 70:30); j) TFA (10 vol%), CH2Cl2, 208C, 1 h; k) allylbromide (0.8 equiv), K2CO3
(1.0 equiv), MeCN, 208C, 20 h, 65% over 2 steps; l) GrubbsII (15 mol%), toluene, 658C, 18 h, 95%;
m) DIBAL-H (2.1 equiv), CH2Cl2, ꢁ788C, 30 min; n) NaBH4 (1.2 equiv), EtOH, 08C, 20 min, 70% over
2 steps; o) TsCl (10 equiv), NEt3 (20 equiv), CH2Cl2, 208C, 18 h, 72%; p) 2-nitrophenylselenocyanate
(21 equiv), NaBH4 (20 equiv), EtOH, 208C, 80 h, 98%; q) TFA (1.5 equiv), 75% mCPBA (1.0 equiv),
CH2Cl2, ꢁ788C to 208C, 4 h, 86%. AcCl=acetyl chloride, TFA=trifluoroacetic acid, DIBAL-H=diisobu-
tylaluminum hydride, GrubbsII=benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]di-
chloro(tricyclohexylphosphine)ruthenium, TsCl=p-toluenesulfonyl chloride.
In conclusion, the synthesis of
enantiopure (+)-meloscine (1)
was realized starting from quino-
lone 5 in 15 steps and 7% overall
yield. The scale of the enantiose-
lective synthesis is still somewhat
limited owing to the restricted
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availability of the chiral complexing agent 6. Generally,
however, the yields of the photochemical key step are high
and suitable for use on a larger scale, as could be shown in a
parallel synthesis of racemic (ꢀ )-meloscine. Further conver-
sion of the racemic photoproduct with the established
methods gave access to the complete meloquinoline skeleton
in multigram amounts.
Received: February 12, 2008
Published online: May 27, 2008
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Keywords: asymmetric synthesis · natural products ·
photochemistry · rearrangement · total synthesis
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