Total synthesis of (-)-lycoposerramine-S

Article abstract of DOI:10.1002/anie.201206863

To the core: The first total synthesis of (-)-lycoposerramine-S has been accomplished in 14 steps. The synthesis features the facile construction of the tetracyclic core through an intramolecular 1,3-dipolar cycloaddition of an azomethine ylide, with unex

Full text of DOI:10.1002/anie.201206863

.
Angewandte
Communications
DOI: 10.1002/anie.201206863
Natural Product Synthesis
Total Synthesis of (À)-Lycoposerramine-S**
Naoaki Shimada, Yuzo Abe, Satoshi Yokoshima, and Tohru Fukuyama*
Lycopodium alkaloids have attracted the attention of syn-
thetic chemists because of their intriguing structural features
and the remarkable bioactivities.[1] Among them is (À)-
lycoposerramine-S (1; Figure 1), which was isolated from
Lycopodium serratum by Takayama
achieved by alkylation of a nosyl amide and radical cycliza-
tion, respectively. The requisite precursor 2 would be derived
from the ketoester 3. The bicyclic system of 3 could in turn be
constructed by an intramolecular cycloaddition of the azo-
methine ylide 4.[4]
Our synthesis commenced with preparation of the pre-
cursor of the azomethine ylide (Scheme 2). Reaction of the
alkyl iodide 5[5] with an anion derived from the terminal
and co-workers in 2002[2] and has
a unique structure including a highly
fused tetracyclic skeleton with two
nitrogen atoms and one quaternary
carbon center. Although synthetic
studies of (À)-lycoposerramine-S
were reported by Elliott and co-work-
Figure 1. Structure of
lycoposerramine-S.
ers,[3] its total synthesis has not been
reported to date. Although the bio-
logical activity of this molecule has
not yet been determined, we were interested in exploring this
unique molecule and its derivatives for drug discovery.
Herein, we report the first total synthesis of (À)-lycoposerr-
amine-S (1). Key to the straightforward construction of the
tetracyclic skeleton was the unexpected stereoselectivity in
the intramolecular cycloaddition of an azomethine ylide.
Our retrosynthesis is shown in Scheme 1. Formation of the
nine-membered ring and the cyclopentane ring could be
Scheme 2. Preparation of a precursor for the azomethine ylide.
a) nBuLi, HCC(CH2)3OTBS (6), THF/DMPU, À788C to RT, 87%;
b) [Cp2ZrCl2], DIBAL, THF, 08C to RT; I2, À788C, 87%; c) nBuLi, Et2O,
À788C; 9, À788C, 66%; d) TPAP, NMO, 4ꢀ M.S., CH2Cl2, RT, 75%.
Cp=cyclopentadienyl, DIBAL=diisobutylaluminum hydride,
DMPU=N,N’-dimethylpropyleneurea, M.S.=molecular sieves,
NMO=N-methylmorpholine N-oxide, TBS=tert-butyldimethylsilyl,
TPAP=tetrapropylammonium perruthenate.
alkyne 6 afforded the alkyne 7, which was subjected to
hydrozirconation and subsequent addition of iodine to give
the alkenyl iodide 8.[6] Halogen–lithium exchange of 8
generated the corresponding alkenyllithium species, which
was reacted with the known lactone 9[7] to afford 10.
Subsequent oxidation of the hydroxy group in 10 furnished
the ketoaldehyde 11, which was used for the cycloaddition of
the azomethine ylide.
Treatment of 11 with N-benzylglycine ethyl ester in
refluxing toluene formed an azomethine ylide, which under-
went cycloaddition to afford the product as a 4:3 mixture of
two diastereomers which differed in the relative configuration
at C15. This result indicated that the distant methyl group on
C15 did not control the facial selectivity of the cycloaddition.
Therefore we decided to employ chiral amino esters as
reagents for the cycloaddition. Using (5S,6R)-5,6-diphenyl-
morpholin-2-one,[8] the cycloaddition proceeded stereoselec-
tively, albeit in low yield. After intensive screening of chiral
amino esters, we found that the morpholinone 12 gave the
best selectivity and yield.[9] Thus, heating 11 with 12 in toluene
furnished the adduct 13 in 86% yield as a single isomer
Scheme 1. Retrosynthesis.
[*] N. Shimada, Dr. Y. Abe, Dr. S. Yokoshima,[+] Prof. T. Fukuyama
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: fukuyama@mol.f.u-tokyo.ac.jp
[+] Current address: Graduate School of Pharmaceutical Sciences,
Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601 (Japan)
[**] We thank Prof. Hiromitsu Takayama at Chiba University for helpful
discussions. This work was financially supported by Grants-in-Aid
for Scientific Research (20002004, 22590002) from the Japan
Society for the Promotion of Science (JSPS), the Research
Foundation for Pharmaceutical Sciences, the Mochida Memorial
Foundation for Medical and Pharmaceutical Research, and the
Uehara Memorial Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206863.
11824
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 11824 –11826

Angewandte
Chemie
is expected to have the conformations as shown in Figure 2. In
the case of the E ylide, the substituents on the double bond
and the azomethine ylide (shown as dots) would be oriented
anti to each other. As a result, the four-atom linkage between
these moieties would be too short to provide good overlap of
the orbitals for the cycloaddition. In contrast, in the case of
the Z ylide these two moieties can be connected with the
linkage without any constraints. The reaction, therefore,
proceeds through the latter transition state with the Z ylide,
giving the adduct 13 which has the correct stereochemistry
required for the synthesis of (À)-lycoposerramine-S.
Scheme 3. Stereoselective intramolecular cycloaddition of azomethine
ylide.
Having constructed the bicyclic skeleton with complete
stereoselectivity, we turned our attention to forming the
cyclopentane ring of the natural product by radical cycliza-
tion. Reduction of 13 with Red-Al afforded a triol, which was
subjected to hydrogenolysis in the presence of Boc2O to
afford 14 as a single diastereomer (Scheme 5).[14] Selective
dehydration of the secondary alcohol in the diol 14 was
efficiently achieved in a one-pot procedure, involving acyla-
tion of the primary alcohol with methoxyacetyl chloride,
activation of the secondary alcohol with chloromethanesul-
(Scheme 3). The stereochemistry of 13 was determined by
a NOESY experiment.[10]
The intermolecular cycloaddition reactions of azomethine
ylides, derived from 5-substituted or 5,6-disubstituted mor-
pholin-2-one with aldehydes, have been reported to give
a mixture of 2,5-trans- and 2,5-cis-disubstituted pyrrolidines
via the E and Z ylides, respectively (Scheme 4). However, the
analogous cycloadditions with ylides derived from sterically
Scheme 4. Stereochemical outcome of cycloaddition of azomethine
ylides.
demanding aldehydes preferentially proceed via E ylides to
furnish the 2,5-trans isomers.[8,11] As shown in Scheme 3, the
reaction of 11 with 12 unexpectedly afforded a 2,5-cis-
disubstituted pyrrolidine via the Z-ylide intermediate.[12,13]
The unexpected stereoselectivity can be rationalized by
considering the possible transition states for the cycloaddition
(Figure 2). In the cycloaddition, the double bond would
approach the azomethine ylide from the convex face. To
minimize steric repulsion between the two siloxypropyl chains
on the double bond and the indane moiety, the transition state
Scheme 5. Completion of the synthesis. a) Red-Al, toluene, 08C to RT,
81%; b) H2, Pd(OH)2/C, Boc2O, EtOAc, RT, 98%; c) methoxyacetyl
chloride, TMEDA, toluene, RT; ClCH2SO2Cl, TMEDA, RT; K2CO3,
MeOH, reflux, 75%; d) phenyl chlorothionoformate, DMAP, MeCN,
508C; e) V-70, (Me3Si)3SiH, toluene, 508C; CSA, MeOH, RT, 69% (2
steps); f) MsCl, TMEDA, CH2Cl2, RT, 91%; g) pNsNH2, Cs2CO3, TBAI,
DMF, 508C, 48%; h) PhSH, Cs2CO3, MeCN, 508C; aq HCHO, NaBH-
(OAc)3, RT, 88%; i) TFA, CH2Cl2, RT, 91%. Boc=tert-butoxycarbonyl,
CSA=10-camphorsulfonic acid, DMAP=4-(dimethylamino)pyridine,
DMF=N,N-dimethylformamide, Ms=methanesulfonyl, Ns=nitroben-
zenesulfonyl, Red-Al=sodium bis(2-methoxyethoxy)aluminium hy-
dride, TBAI=tetra-n-butylammonium iodide, TFA=trifluoroacetic acid,
TMEDA=N,N,N’,N’-tetramethylethylenediamine, V-70=2,2’-azobis(4-
methoxy-2.4-dimethylvaleronitrile).
Figure 2. Possible transition states for the cycloaddition.
Angew. Chem. Int. Ed. 2012, 51, 11824 –11826
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11825

.
Angewandte
Communications
fonyl chloride[15] and TMEDA,[16] and methanolysis/elimina-
tion with K2CO3 in refluxing methanol, to give the olefin 15 in
75% yield. Conversion of 15 into the thionocarbonate 16 with
phenyl chlorothionoformate and subsequent subjection to
radical reaction conditions[17] led to a smooth 5-exo-trig
cyclization to give, after acidic treatment, the tricyclic
compound 17.
[7] L. Poppe, L. Novꢀk, P. Kolonits, ꢁ. Bata, C. Szꢀntay, Tetrahedron
1988, 44, 1477 – 1487.
[8] R. M. Williams, W. X. Zhai, D. J. Aldous, S. C. Aldous, J. Org.
Chem. 1992, 57, 6527 – 6532.
[9] The morpholinone 12 was readily prepared from (1S,2R)-1-
amino-2-indanol by treatment with phenyl bromoacetate in the
presence of N,N-diisopropylethylamine. For details, see the
Supporting information.
After mesylation of the two hydroxy groups, the nine-
membered ring was constructed by alkylation with 4-nitro-
benzenesulfonamide to furnish 18.[18] Finally, cleavage of the
p-Ns group, reductive methylation, and removal of the Boc
group under acidic conditions furnished (À)-lycoposerra-
mine-S (1).[19]
[10] Reaction of 11 with ent-12 gave 13’ as a single isomer in 82%
yield. The product 13’ was an epimer of ent-13 at C15. This result
clearly suggested that the stereoselectivity of the cycloaddition
was
completely
controlled
by
the
morpholinone.
In summary, the total synthesis of (À)-lycoposerramine-S
has been accomplished in 14 steps from the known alkyl
iodide 5. Key steps of our synthesis involved facile construc-
tion of the tetracyclic system through an intramolecular 1,3-
dipolar cycloaddition of an azomethine ylide with unexpected
stereoselectivity, a 5-exo-trig radical cyclization, and alkyla-
tion of a nosyl amide.
[11] a) A. S. Anslow, L. M. Harwood, H. Phillips, D. Watkin, L. F.
Wong, Tetrahedron: Asymmetry 1991, 2, 1343 – 1358; b) P. R.
Sebahar, R. M. Williams, J. Am. Chem. Soc. 2000, 122, 5666 –
5667.
Received: August 24, 2012
Published online: October 15, 2012
Keywords: alkaloids · azomethine ylide · cycloaddition ·
radical reactions · stereoselectivity
[12] Harwood and Lilley reported that the reaction of 5-phenyl-
morpholin-2-one with 6-heptenal resulted in an intramolecular
cycloaddition of an azomethine ylide and proceeded via the
E ylide to give the 2,5-trans-disubstituted pyrrolidine derivative.
L. M. Harwood, I. A. Lilley, Tetrahedron Lett. 1993, 34, 537 –
540.
[13] For examples of 2,5-cis products by cycloadditions of azome-
thine ylides derived from 2,2-disubstituted 6-heptenals and N-
alkyl glycine esters, see: I. Coldham, K. M. Crapnell, J. D.
Moseley, R. Rabot, J. Chem. Soc. Perkin Trans. 1 2001, 1758 –
1763.
[14] Using LiAlH4 instead of Red-Al gave a 3.3:1 mixture of 14 and
its epimer. The epimer of 14 did not undergo the subsequent
dehydration.
[15] T. Shimizu, S. Hiranuma, T. Nakata, Tetrahedron Lett. 1996, 37,
6145 – 6148.
[16] Y. Yoshida, K. Shimonishi, Y. Sakakura, S. Okada, N. Aso, Y.
Tanabe, Synthesis 1999, 1633 – 1636.
[17] Y. Kita, A. Sano, T. Yamaguchi, M. Oka, K. Gotanda, M.
Matsugi, Tetrahedron Lett. 1997, 38, 3549 – 3552.
[18] a) T. Kan, H. Kobayashi, T. Fukuyama, Synlett 2002, 697 – 699;
b) T. Kan, T. Fukuyama, Chem. Commun. 2004, 353 – 359; c) Y.
Kaburagi, H. Tokuyama, T. Fukuyama, J. Am. Chem. Soc. 2004,
126, 10246 – 10247. Pan and Williams carried out extensive
investigations on the inter- and intramolecular Mitsunobu
reaction of a diol with NsNH2 for construction of a nine-
membered ring in Lycopodium alkaloids: G. Pan, R. M.
Williams, J. Org. Chem. 2012, 77, 4801 – 4811.
.
[1] For reviews of the Lycopodium alkaloids, see: a) D. B. MacLean
in The Alkaloids, Vol. 10 (Ed.: R. H. F. Manske), Academic
Press, New York, 1968, pp. 305 – 382; b) D. B. MacLean in The
Alkaloids, Vol. 14 (Ed.: R. H. F. Manske), Academic Press, New
York, 1973, pp. 347 – 405; c) D. B. MacLean in The Alkaloids,
Vol. 26 (Ed.: A. Brossi), Academic Press, New York, 1985,
pp. 241 – 298; d) W. A. Ayer, Nat. Prod. Rep. 1991, 8, 455 – 463;
e) W. A. Ayer, L. S. Trifonov in The Alkaloids, Vol. 45 (Eds:
G. A. Cordell, A. Brossi), Academic Press, New York, 1994,
pp. 233 – 266; f) X. Ma, D. R. Gang, Nat. Prod. Rep. 2004, 21,
752 – 772; g) J. Kobayashi, H. Morita in The Alkaloids, Vol. 61
(Ed: G. A. Cordell), Academic Press, New York, 2005, pp. 1 – 57;
h) Y. Hirasawa, J. Kobayashi, H. Morita, Heterocycles 2009, 77,
679 – 729; i) H. Takayama, J. Synth. Org. Chem. Jpn. 2010, 68,
457 – 469.
[2] H. Takayama, K. Katakawa, M. Kitajima, K. Yamaguchi, N.
Aimi, Tetrahedron Lett. 2002, 43, 8307 – 8311. For a proposed
biogenetic route, see: K. Katakawa, M. Kitajima, N. Aimi, H.
Seki, K. Yamaguchi, K. Furihata, T. Harayama, H. Takayama, J.
Org. Chem. 2005, 70, 658 – 663.
[3] a) M. C. Elliott, N. N. E. El Sayed, J. S. Paine, Org. Biomol.
Chem. 2008, 6, 2611 – 2618; b) M. C. Elliott, J. S. Paine, Org.
Biomol. Chem. 2009, 7, 3455 – 3462.
[4] I. Coldham, R. Hufton, Chem. Rev. 2005, 105, 2765 – 2810.
[5] K. Miura, M. Tomita, J. Ichikawa, A. Hosomi, Org. Lett. 2008, 10,
133 – 136.
[19] Spectral data of the synthetic lycoposerramine-S were consistent
with the reported data (ref [2]).
[6] Z. Huang, E. Negishi, Org. Lett. 2006, 8, 3675 – 3678.
11826 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 11824 –11826