Concise total synthesis of (+)-lyconadin A

Article abstract of DOI:10.1021/ja109516f

The total synthesis of lyconadin A from (R)-5-methylcyclohex-2-enone was accomplished. Our synthesis features the facile construction of a highly fused tetracyclic compound through a combination of an aza-Prins reaction and an electrocyclic ring opening.

Full text of DOI:10.1021/ja109516f

Published on Web 12/14/2010
Concise Total Synthesis of (+)-Lyconadin A
Takuya Nishimura, Aditya K. Unni, Satoshi Yokoshima, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received October 22, 2010; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
would form the basis of the unique tertiary amine moiety. Decaline
Abstract: The total synthesis of lyconadin A from (R)-5-methyl-
cyclohex-2-enone was accomplished. Our synthesis features the
facile construction of a highly fused tetracyclic compound through
a combination of an aza-Prins reaction and an electrocyclic ring
opening. Transformation of the bromoalkene moiety in the
tetracycle could be achieved by either a vinylogous Pummerer
rearrangement or the formation and subsequent isomerization of
the nitrosoalkene to furnish an R,ꢀ-unsaturated ketone, from
which the pyridone ring was constructed.
3 could in turn be prepared through a Diels-Alder reaction.
Our synthesis commenced with a Diels-Alder reaction between
isoprene and known enone 4,8 according to Overman’s conditions,9
to afford cis-octaline 6 (Scheme 2). After cleavage of the acetal,10
the resulting ketone was subjected to reductive amination with
benzylamine to furnish 7 with complete stereoselectivity. Upon
treatment with formalin under acidic conditions, 7 underwent an
aza-Prins reaction to give tricyclic compound 8.9,11 Replacement
of the benzyl group on the nitrogen atom with a Boc group by a
one-pot operation, followed by dibromocyclopropanation under
biphasic conditions, afforded 9.12 After cleavage of the Boc group
with trifluoroacetic acid (TFA), the resulting amine was heated
under reflux in pyridine to induce ring expansion and formation of
a C-N bond to furnish tetracyclic compound 11 in 96% yield in
two steps. This reaction might involve electrocyclic ring opening
of the dibromocyclopropane moiety with loss of a bromide ion to
generate allylic cation 10,13 which might be intramolecularly
intercepted by the secondary amine.
Lyconadin A (1) was isolated in 2001 by Kobayashi and co-
workers from the club moss Lycopodium complanatum.1,2 Lycona-
din A was shown to exhibit modest cytotoxicity against murine
lymphoma L1210 cells and human epidermoid carcinoma KB cells.
Closer examination revealed that lyconadin A enhanced mRNA
expression for nerve growth factor (NGF) in 1321N1 human
astrocytoma cells.3 In addition to these biological activities, the
unprecedented pentacyclic skeleton of lyconadin A has attracted
much attention as a challenging target for total synthesis,4 and two
total syntheses of the molecule have been reported to date.5 The
first total synthesis of (+)-lyconadin A was achieved in 2007 by
Beshore and Smith, who employed an intramolecular aldol/
conjugate addition cascade as well as an aminoiodination reaction
to construct the core tetracyclic structure. Shortly afterward, Sarpong
and co-workers accomplished total syntheses of (()- and then (+)-
lyconadin A, in which a unique oxidative C-N bond-forming
reaction was used to craft the pentacyclic skeleton.6 Herein, we
disclose a total synthesis of (+)-lyconadin A by means of a facile
construction of both the core structure and the pyridone ring.
Our retrosynthetic analysis of 1 is outlined in Scheme 1. The
pyridone moiety of 1 could be constructed from enone 2 according
to a procedure developed in our laboratory.7 We envisioned that
construction of the carbon framework of 2, bicyclo[5.4.0]undecane,
would be achieved via a ring expansion of the cis-decaline system
derived from 3. Both the carbonyl group and the double bond in 3
Scheme 2a
Scheme 1. Retrosynthetic Analysis
a Reagents and conditions: (a) TMSOCH2CH2OTMS, TMSOTf, isoprene,
CH2Cl2, -78 °C, 71%. (b) FeCl3/SiO2, acetone, rt, 91%. (c) BnNH2,
NaBH(OAc)3, ClCH2CH2Cl, 50 °C, 99%. (d) HCHO(aq), AcOH, SiO2, 60
°C, 81%. (e) H2, Pd(OH)2/C, MeOH; Boc2O, 94%. (f) CHBr3, BnNEt3Cl,
i-PrOH, NaOH(aq), CH2Cl2, 0 °C to rt, 61%. (g) TFA, CH2Cl2, rt. (h)
Pyridine, reflux, 96% (two steps).
Having achieved the efficient construction of the tetracyclic
skeleton, we next focused on the transformation of 11 into enone
2. Attempted oxidation of the double bond using a variety of
oxidants, including OsO4, m-chloroperoxybenzoic acid (mCPBA),
N-bromosuccinimide, and Br2 with or without acids, did not give
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418 J. AM. CHEM. SOC. 2011, 133, 418–419
10.1021/ja109516f  2011 American Chemical Society

C O M M U N I C A T I O N S
the desired product. After extensive investigations, we found that
a halogen-lithium exchange of 11 could be carried out by reaction
with t-BuLi in THF at -78 °C, and two different routes from the
resulting alkenyllithium to enone 2 were established. Thus, treatment
of the resulting alkenyllithium with diphenyl disulfide furnished
sulfide 12 (Scheme 3). Oxidation of 12 with mCPBA and a
subsequent vinylogous Pummerer rearrangement gave 14,14 which
was subjected to acid hydrolysis in the presence of mercury(II)
sulfate to afford enone 2. On the other hand, treatment of the
alkenyllithium with isoamyl nitrite afforded oxime 16 (Scheme 4).
This reaction might proceed via formation and isomerization of
nitrosoalkene 15, and subsequent hydrolysis of oxime 16 under
acidic conditions afforded enone 2. While the yield remained
somewhat low because of the in situ formation of the acidic oxime,
the latter protocol enabled the more straightforward transformation
of 11 into enone 2 in only two steps. Further investigations of the
elaboration of 11 are currently underway and will be reported in
due course.
To complete the total synthesis, the pyridone ring was constructed
via a one-pot transformation. Thus, Michael addition of sulfinyla-
mide 17 to the enone moiety afforded a diastereomeric mixture of
adducts 18, which, upon treatment with hydrochloric acid in
methanol, underwent cyclization and desulfination to form the
pyridone ring, affording lyconadin A (1).
In summary, the total synthesis of lyconadin A was accomplished
in 11 steps (via the nitrosoalkene; 8.1% overall yield) or 13 steps
(via the sulfide; 11.6% overall yield) from known enone 4. Our
synthesis features the facile construction of the highly fused
tetracyclic compound 11 through a combination of an aza-Prins
reaction and an electrocyclic ring opening. Transformation of the
bromoalkene moiety in 11 via either a vinylogous Pummerer
rearrangement or the formation and subsequent isomerization of
the nitrosoalkene afforded enone 2, from which the pyridone ring
could be constructed.
Scheme 3a
Acknowledgment. We thank Prof. J. Kobayashi and Prof. T.
Kubota at Hokkaido University for providing a sample of natural
lyconadin A. This work was financially supported in part by Grants-
in-Aid (20002004 and 22590002) from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
Supporting Information Available: Experimental details and
spectroscopic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Scheme 4a
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a Reagents and conditions: (a) t-BuLi, THF, -78 °C; isoamyl nitrite,
37%. (b) HCl(aq), acetone, rt to 50 °C, 88%. (c) PhS(O)CH2CONH2 (17),
NaH, THF, 0 °C; HCl, MeOH, 40 °C, 87%.
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