Synthetic studies on daphnicyclidin A: enantiocontrolled construction of the BCD ring system

Article abstract of DOI:10.1021/ol9003405

An enantiocontrolled entry to the tricyclic core of daphnicyclidin A with five chlral centers Including an all-carbon quaternary center Is reported. The synthesis features a highly dlastereoselectlve conjugate addition of nltromethane, an Ireland- Clalsen rearrangement, and a tandem acyliminium/ Mannich- type reaction.

Full text of DOI:10.1021/ol9003405

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1833-1836
Synthetic Studies on Daphnicyclidin A:
Enantiocontrolled Construction of the
BCD Ring System
Shuhei Ikeda, Masatoshi Shibuya, Naoki Kanoh, and Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aoba, Sendai 980-8578, Japan
iwabuchi@mail.pharm.tohoku.ac.jp
Received February 16, 2009
ABSTRACT
An enantiocontrolled entry to the tricyclic core of daphnicyclidin A with five chiral centers including an all-carbon quaternary center is reported.
The synthesis features a highly diastereoselective conjugate addition of nitromethane, an Ireland-Claisen rearrangement, and a tandem
acyliminium/Mannich-type reaction.
In 2001, Kobayashi and co-workers reported the isolation
of a novel class of Daphniphyllum alkaloids, daphnicyclidins
A-H, from the stems of D. humile and D. Teijsmanni.1
Extensive spectroscopic analyses including X-ray crystal-
lography and CD analysis unambiguously revealed their
unprecedented fused penta- or hexacyclic skeletons including
their absolute stereochemistries. As a unique common
structure, members of this class of Daphniphyllum alkaloids
possess the reactive fulvene moiety. These alkaloids are
cytotoxic against murine lymphoma L1210 and human
epidermoid carcinoma KB cells with IC50 values ranging
from 0.1 to 10 µg/mL. Owing to the interesting biological
activities coupled with highly complex structural features,
daphnicyclidins have attracted our attention as targets for
total synthesis. In this paper, we describe an enantiocontrolled
entry to the tricyclic intermediate corresponding to the BCD
portion (6-5-7) of daphnicyclidin A (1), which represents
the first publication on the synthesis of these natural
products.2
Our retrosynthetic analysis of daphnicyclidin A (1) is
depicted in Scheme 1. We ranked 2 as an important synthetic
platform in this research, because tricyclic intermediate 2
sets all of the chiral centers of 1. In particular, the structural
feature of 2 having three contiguous chiral centers (C4-5-
6), one of which is an all-carbon quaternary center, poses
significant challenges for stereoselective construction. For
efficient synthesis of the BCD ring system, we envisioned a
tandem acyliminium/Mannich-type reaction of chiral amide
3. Demonstration of this strategy was also expected to be of
value for broadening the scope of the Mannich reaction, since
to the best of our knowledge there are no examples3 in which
such a tactic has been applied to the construction of an all-
carbon quaternary center using a seven-membered ketone
as a nucleophile. Chiral amide 3 was dissected into two
fragments, 4 and 5. Chiral amine 4 could potentially be
prepared from enoate 6 with an appropriate chiral auxiliary
(1) Kobayashi, J.; Inaba, Y.; Shiro, M.; Yoshida, N.; Morita, H. J. Am.
Chem. Soc. 2001, 123, 11402.
(2) In the structural analogy to 1, racemic synthesis of the tricyclic core
of calyciphylline A, one of the Daphniphyllum alkaloids, was reported: Sole´,
D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7, 5461.
(3) (a) Earley, W. G.; Oh, T.; Overman, L. E. Tetrahedron Lett. 1988,
29, 3785. (b) Uchida, K.; Yokoshima, S.; Kan, T.; Fukuyama, T. Org. Lett.
2006, 8, 5311. (c) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367. (d) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(e) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff,
C. A. Chem. ReV. 2004, 104, 1431.
10.1021/ol9003405 CCC: $40.75
Published on Web 03/25/2009
2009 American Chemical Society

Scheme 1
.
Retrosynthetic Analysis
Scheme 2. Synthesis of Chiral Amine Fragment 16
As shown in Scheme 2, the synthesis of the amine
fragment commenced from commercially available cyclo-
heptanone (8). Installation of the methoxycarbonyl group to
8 followed by transesterification7 with (-)-8-phenylmenthol
gave ꢀ-ketoester 9. Regioselective one-pot dehydrogenation
of 9 using Mukaiyama-Matsuo reagent 108 furnished enoate
11. Upon treatment of 11 with the lithium salt of ni-
tromethane in THF at -78 °C, the expected conjugate
addition reaction took place presumably through the s-trans
(CdC/CdO) conformation 12 to give a transient enolate,
which was trapped by TIPSOTf to afford silyl enol ether 13
and ꢀ-ketoester 14. Reduction of 13 with DIBAL-H gave
nitro alcohol 15 along with recovered (-)-8-phenylmenthol
(90%). At this stage, the optical purity was determined to
be 96% ee by chiral HPLC analysis.9 Finally, reduction of
nitro alcohol 15 using Fe-NH4Cl furnished chiral amine 16.10
by means of a diastereoselective conjugate addition of
nitromethane. On the other hand, chiral acid 5, bearing two
contiguous chiral centers (C2-C18), could be obtained via
an Ireland-Claisen rearrangement of chiral allyl ester 7.
In launching this strategy, we selected (-)-8-phenylmen-
thol as the chiral auxiliary for the crucial conjugate addition
to enoate 6 because of its reliable utility and availability.4
According to the empirical rule developed by Oppolzer and
co-workers,5 the configuration at the C6 chiral center installed
by the reaction was expected to be R, which is opposite to
that of the natural product, (+)-daphnicyclidin A (1). In this
context, we decided to synthesize the acid fragment from
an antipode of 7 to tentatively establish the enantiocontrolled
synthetic route for 1.6
(4) (-)-8-Phenylmenthol is now commercially available: (a) Corey, E. J.;
Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908. (b) Ort, O. Organic
Synthesis; Wiley: New York, 1993; Collect. Vol. VIII, p 522.
(5) (a) Oppolzer, W.; Lo¨her, H. HelV. Chim. Acta 1981, 64, 2808. (b)
Oppolzer, W.; Moretti, R.; Godel, T.; Meunier, A.; Lo¨her, H. Tetrahedron
Lett. 1983, 24, 4971.
(9) The absolute stereochemistry at C6 was confirmed at a later stage
(Scheme 4). As far as we know, since the conjugate addition of nucleophiles
to chiral enoates has been reported exclusively for acyclic systems, our
result is expected to provide an attractive methodology for the asymmetric
functionalization of cyclic compounds: (a) Rossiter, B. E.; Swingle, N. M.
Chem. ReV. 1992, 92, 771. (b) Whitesell, J. K. Chem. ReV. 1992, 92, 953.
(10) 16 was used in the next step without further purification as a CH2Cl2
solution including pyridine because of the instability to acid and concentra-
tion.
(6) To obtain the S configuration at C6, we can choose (-)-camphor
derived alcohol as a chiral auxiliary, which is prepared from (-)-camphor
over 6 steps. See: (a) Oppolzer, W.; Chapuis, C.; Dupuis, D.; Guo, M.
HelV. Chim. Acta 1985, 68, 2100. (b) Fabris, F.; Zambrini, L.; Rosso, E.;
De Lucchi, O. Eur. J. Org. Chem. 2004, 3313.
(11) Banerjee, S.; Ghosh, S.; Sinha, S.; Ghosh, S. J. Org. Chem. 2005,
70, 4199.
(7) Taber, D. F.; Amedio, J. C., Jr.; Patel, Y. K. J. Org. Chem. 1985,
50, 3618.
(12) Soldermann, N.; Velker, J.; Neels, A.; Stoeckli-Evans, H.; Neier,
R. Synthesis 2007, 2379.
(8) Matsuo, J.; Aizawa, Y. Tetrahedron Lett. 2005, 46, 407.
1834
Org. Lett., Vol. 11, No. 8, 2009

protocol,16 removal of the TIPS group by TBAF in a one-
pot process led to the successive elimination of tosylate
to provide enone 27. Hydrogenation of the exo olefin in the
presence of Pd-C/NaHCO3 furnished chiral amide 28.
Having succeeded in the synthesis of chiral amide 28, then
we extensively investigated the key tandem acyliminium/
Mannich-type reaction, which has the potential for the one-
step construction of the B-C ring system bearing a quaternary
methyl carbon. After considerable experimentation, the
intended tandem cyclizations were accomplished by exposure
of 28 to refluxing isopropanol with the evolution of hydrogen
chloride in situ. It was found that the undesired tricycle 30
(56%)17 predominated over the desired tricycle 31 (31%).
The stereochemistries of 30 and 31 were verified by X-ray
crystallographic analysis and NOESY correlations, respec-
tively. These assignments unambiguously confirmed the
configuration of the three preformed chiral centers (C4-5-6)
as expected, one of which was installed by the diastereose-
lective conjugate addition of nitromethane, whereas the others
were introduced by the Ireland-Claisen rearrangement.
Considering the fact that the products do not interconvert
under the reaction conditions, the stereochemical outcome
may be rationalized by transition state models exo-A and
endo-B, where the steric hindrance of endo-B (pivaloy-
loxymethyl vs six-membered ring) overrides that of exo-A
(methyl vs six-membered ring). Two additional experiments
with alternative substrates 29 and 33,18 which offer the
reduction of steric factors, afforded the enhanced preferences
in endo-selectivity (36:32 for 29; 61:22 for 33), supporting
the validity of the working model to allow further improve-
ment.
Scheme 3. Synthesis of Chiral Acid Fragment 25
Finally, we have focused on the functionalization at C9,
which will serve for construction of the remaining AEF ring
system. Upon treatment of 31 with KHMDS at -50 °C
followed by the addition of allyl iodide, the allylation at
R-position was realized in 60% yield. The stereochemistry
of 32 was assigned from NOESY correlations.
Scheme 3 shows the synthesis of the acid fragment from
the known chiral allyl alcohol 17 prepared from D-mannitol.11
Allyl alcohol 17 was converted to allyl ester 19 via a four-
step sequence. With the requisite allyl ester 19 in hand, our
attention was then focused on the Ireland-Claisen rear-
rangement. After several attempts, we found that treatment
of allyl ester 19 with LHMDS (THF solution) in the presence
of TBSCl and HMPA in 2-Me-THF12 gave carboxylic acid
20 in good yield. The diastereoselectivity in this reaction
In conclusion, we have developed an enantiocontrolled
route to the BCD ring system having all the chiral centers
(16) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183.
1
(17) The exo-tricycle 30 was accompanied by another minor diastereomer
(10:1) after silica gel column chromatography. Thus, the yield of 30 was
determined from the 1H NMR spectrum. The minor tricycle may arise from
a small amount of the C18 epimer of 28 originating from the Ireland-Claisen
rearrangement.
was estimated to be 9:1 based on the H NMR analysis of
allyl carbonate 22.13 Upon sequential protection of the
carboxyl group as a benzyl ester,14 deprotection of the TBS
group, and carbonate formation with ClCO2Me in pyridine,
20 afforded 22. The successful palladium-catalyzed formate
reduction15 of 22 furnished terminal alkene 23. Finally, the
desired acid 25 was obtained by ozonolysis, dimethyl acetal
formation, and hydrogenolysis of benzyl ester 24.
(18) In our model studies of the tandem cyclization, treatment of racemic
amide 33 with methanolic hydrogen chloride provided the desired endo-
tricycle 34 predominantly. Details and further consideration of this reaction
are shown in Supporting Information.
As illustrated in Scheme 4, condensation of 16 and 25 in
the presence of EDCI-DMAP proceeded smoothly to give
amide 26. After conversion of 26 to tosylate by Tanabe’s
(13) Ultimately, a small amount of minor diastereomeric compound
originating from the rearrangement was separated during the conversion of
28 to 30 and 31 (Scheme 4); see ref 17.
(14) Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. AdV.
Synth. Catal. 2003, 345, 1209.
(15) Tsuji, J.; Yamakawa, T. Tetrahedron Lett. 1979, 613.
Org. Lett., Vol. 11, No. 8, 2009
1835

Scheme 4. Construction of the BCD Ring System of Daphnicyclidin A (1)
of daphnicyclidin A (1). The synthesis features (1) the highly
diastereoseletive conjugate addition of nitromethane to chiral
enoate 11, (2) the Ireland-Claisen rearrangement of chiral
allyl ester 19, and (3) the tandem acyliminium/Mannich-type
reaction of chiral amide 28. In addition, we have succeeded
in functionalizing the D-ring of the desired 31 for construc-
tion of the remaining AEF ring framework. Synthetic efforts
toward ent-(-)-daphnicyclidin A (1) including improvement
of the stereoselectivity of the tandem cyclization are now
underway.
Acknowledgment. This work was financially supported,
in part, by Grobal COE program for International Center of
Research & Education for Molecular Complex Chemistry,
Tohoku University.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9003405
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