Communication

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Total Synthesis of (−)-Calyciphylline N

Artem Shvartsbart and Amos B. Smith, III*
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United States
*
S Supporting Information

bridgehead, a fused A ring dihydropyrrole, and a DEF

ABSTRACT: The total synthesis of the architecturally decahydrocyclopentazulene ring system surrounding a central
complex Daphniphyllum alkaloid (−)-calyciphylline N has bicyclo[2.2.2]octane BC core.
been achieved. Highlights of the synthesis include a Retrosynthetically (Figure 2), we envisioned that the
Et2AlCl-promoted, highly stereoselective, susbtrate-con- dihydropyrrole A ring could arise via condensation of a primary
trolled intramolecular Diels−Alder reaction, a transannular
enolate alkylation, an effective Stille carbonylation/
Nazarov cyclization sequence, and a high-risk diastereo-
selective hydrogenation of a fully substituted conjugated
diene ester.

T he Daphniphyllum alkaloids comprise a large family of

complex natural products including more than 180 known
members,1 many with diverse biological activities, that have
proven challenging as targets for total synthesis.2 We in
particular became interested in the calyciphylline alkaloids,
largely due to their unique frameworks and at the time, limited
synthetic studies.3,4 Calyciphylline N [(−)-1, Figure 1], isolated
Figure 2. Retrosynthetic analysis.
in 2008 by Kobayashi and co-workers,5 was chosen as our initial
target.
amine with the carbonyl group in ring B, while the
stereochemistry of the EF ring system could be installed by a
challenging/critical late-stage α,β-reduction of an exceptionally
hindered diene ester (2). The secondary hydroxyl in ring C
could in turn be generated via a Tamao−Kumada7 oxidation of
the siloxane ring, while construction of ring F would entail an
aldol condensation, simplifying the structure to 3, the latter
accessible from 4 via a cyclopentenone annulation involving a
Stille carbonylation8/Nazarov cyclization9 sequence. Continu-
ing with this analysis, tetracycle 4 could be accessed through
elaboration of bicyclic ester 5, anticipated to be the product of
an intramolecular Diels−Alder (IMDA) reaction.10 The
requisite IMDA triene, in turn, would arise via union of
enantiomerically pure homoallylic alcohol 6 and known silyl
acrylate 7.11
The synthesis of (−)-calyciphylline N (1) began with alcohol
(−)-8 (Scheme 1), prepared in three steps from commercially
available p-tolylacetic acid.12 Birch reduction13 readily furnished
the desired cyclohexadiene; olefin isomerization with KOt-Bu
in DMSO14 then provided an inseparable mixture (3.5:1) of the
Figure 1. (−)-Calyciphylline N and related congeners.6 1,3- and 1,4-dienes 6 and (−)-9, respectively, in excellent yield.
Silyl acrylate 7, obtained via oxidative hydrosilylation of ethyl
While the biological activity of (−)-calyciphylline N (1) has acrylate with phenyldimethylsilane,11 was subsequently ap-
not been investigated, we reasoned that a synthetic effort pended, employing a method introduced by Sieburth.15 To this
toward this alkaloid would not only unveil a wealth of end, treatment of 7 with TfOH at 0 °C, followed by sequential
interesting reactivity but also permit access to other congeners
of the family. Notable structural features of 1 include six Received: November 12, 2013
contiguous stereogenic centers, three of which are quaternary

© XXXX American Chemical Society A dx.doi.org/10.1021/ja411539w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Journal of the American Chemical Society Communication

Scheme 1 Scheme 3

addition of pyridine and the mixture of the alcohols 6 and

(−)-9 at −78 °C, led to the requisite triene 10 for the IMDA
reaction. However, due to the instability of 10 toward silica gel
chromatography, the mixture was carried forward without
purification. Interestingly, while the thermal Diels−Alder
reaction led to a mixture of all possible diastereomers (as
determined by 1H NMR), we were pleased to discover that the
Et2AlCl-promoted cyclization provided a 9:1 mixture of
diastereomers in favor of the desired cycloadduct (−)-5. hydroxy ketone, provided diketone (+)-18 in 91% yield for the
One-carbon homologation of (−)-5 to alcohol (−)-13 two steps.18 Introduction of the allyl group via the Tsuji−Trost
(Scheme 2) was next achieved by LiAlH4 reduction and allylation19 then furnished (−)-19 as a single diastereomer
(95%), which upon exposure to catalytic p-TsOH in MeOH
Scheme 2 cleanly led to the corresponding alcohol (−)-20; the latter
converted to primary iodide (−)-21 in 97% yield. Pleasingly,
transannular cyclization utilizing LDA delivered tetracycle
(+)-4 as a crystalline solid (mp 123−125 °C), completing
the construction of ring D. Interestingly, use of NaHMDS led
only to elimination of the iodide. Single-crystal X-ray analysis of
(+)-4 confirmed the structure, as well as the relative and
absolute configurations.
Before turning to elaboration of the eastern hemisphere, we
investigated the proposed Tamao−Kumada7 oxidation of the
siloxane ring in (+)-4. Unfortunately, the siloxane was found to
be completely inert to the oxidation. Standard conditions
(various fluoride sources, H2O2, and bicarbonate salts)7,20 led
only to the recovery of starting material, while strongly basic
conditions21 resulted in decomposition. Curiously, the use of
TBAF (with or without oxidant) resulted in desilylation rather
than oxidation.22 Attempts to transform the siloxane to a more
reactive silane (e.g., silyl halide or hydride)23 prior to oxidation
conversion to the corresponding iodide (−)-11, followed by also proved unrewarding. Earlier studies, however, had
cyanide displacement and a two-step reduction of the resulting demonstrated that a similar siloxane was a substrate for
nitrile. The overall yield for the five steps was 65%. Epoxidation nucleophilic ring-opening at the Si−O bond upon treatment
of the olefin in (−)-13 with m-CPBA then led to (−)-14 as a with aryllithium reagents. Such reactivity was recently
single diastereomer in 70% yield. Installation of the C1 ketone employed for the development of siloxanes as recoverable
was next achieved in two steps and 67% yield via an acid- transfer agents in Pd-catalyzed cross-coupling reactions.24 We
promoted epoxide opening and oxidation of the resulting surmised that an arylsilane could be converted to the
secondary alcohol, employing Dess−Martin periodinane corresponding alcohol via the Fleming modification26 of the
(DMP),16 to deliver (+)-15. Reductive cleavage of the Tamao−Kumada oxidation.
tetrahydropyran ring with SmI2 in a mixture of THF/MeOH With these earlier observations in mind, attempted siloxane
then led to hydroxy ketone (+)-16 in 82% yield,17 the primary opening in (+)-4 resulted in partial isomerization of the
alcohol of which was protected as the TBS ether terminal alkene (not shown). We therefore functionalized the
(TBSCl/imidazole in DMF) to provide (+)-17. allyl group before moving forward (Scheme 4). Brown
Elaboration of the requisite side chain for eventual hydroboration (9-BBN) and oxidation (NaOH and H2O2)25
construction of ring D called for introduction of disubstitution delivered the expected primary alcohol in 71% yield. Protection
α to the carbonyl in ketone (+)-17 (Scheme 3). Initially, of the alcohol with TBSCl then furnished (+)-22 in 94% yield.
(+)-17 proved unreactive toward standard acylating agents Pleasingly, the siloxane could now be converted to arylsilane
(EtOAc, Ac2O, 1-acetyl-imidazole, etc.) employing the lithium, (+)-23 in excellent yield by treatment with 4-methoxyphenyl-
potassium, or sodium enolates, with the exception of AcCl, lithium at room temperature. Selection of the methoxyphenyl
which led to complex mixtures of C- and O-acylated products. substituent was in anticipation of greater reactivity toward the
However, an LDA-mediated aldol reaction with acetaldehyde, protodesilylation step of the Fleming−Tamao oxidation.26
followed without purification by DMP oxidation of the β- Notably, both hindered carbonyls in (+)-22 remained
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Journal of the American Chemical Society Communication

Scheme 4 Next, oxidative removal of the TES ether with IBX (Scheme
6) directly provided aldehyde (+)-31 in excellent yield.28 The

Scheme 6

requisite aldol condensation to prepare (+)-32 was then

achieved employing the conditions reported by Weiss and
Carreira (Bn2NH2O2CCF3, PhH, 50 °C) in their synthesis of
(+)−daphmanidin E.3
completely inert to nucleophilic addition. Moving forward,
Turning to the critical 1,4-reduction of the conjugated diene
rather than protect the newly generated primary alcohol, we
in (+)-32, extensive experimentation on a less advanced
introduced the requisite nitrogen with protection via treatment
aldehyde revealed a set of conditions involving the combination
of (+)-23 with phthalimide under Mitsunobu conditions27 to
of ZnCl2, Ph2SiH2, and catalytic Pd(PPh3)429 as uniquely
provide (+)-24 in 99% yield.
effective (see Supporting Information). Unfortunately, when
Turning to construction of ring E via the proposed Stille
applied to (+)-32, this reduction protocol resulted only in
carbonylation8/Nazarov9 cyclization sequence, exposure of
decomposition. Undeterred, aldehyde (+)-32 was oxidized to
(+)-24 to KHMDS in the presence of PhN(Tf)2 at −78 °C
methyl ester (+)-2 (AcOH, NaCN, MeOH, then MnO2) via
furnished vinyl triflate (+)-25, which underwent a highly
the method of Corey.30 A screen of cationic hydrogenation
efficient Stille carbonylation in DMF at 90 °C, employing only
catalysts was next explored with the intent of directing the
1 atm. of CO, to provide dienone (+)-26 in 97% yield. Given
hydrogenation to the α,β-olefinic bond. Pleasingly, the BArF
that both Nazarov cyclizations and protodesilylations can be
analogue of the Crabtree catalyst,31 developed by Wuestenberg
achieved with protic acid,9,26 we reasoned that both trans-
and Pfaltz,32 employing 900 psi of H2 pressure, proved effective
formations could be accomplished in the same flask. Indeed,
in reducing (+)-2 to furnish a mixture (4:1) of diastereomers in
treatment of (+)-26 with HBF4·OEt2 at ambient temperature
84% yield (Scheme 7). Detailed 2D NMR analysis revealed the
directly furnished silyl fluoride (+)-27 in 82% overall yield
(Scheme 5). Under these conditions, the primary TBS group
Scheme 7
Scheme 5

major diastereomer to be (−)-33. This transformation, possibly

directed by the C1 carbonyl in (+)-2, should prove useful in
accessing natural congeners bearing the same monounsaturated
DEF ring system (Figure 1).
was also removed. We were also pleased to discover that Exposure of (−)-33 to hydrazine in EtOH led cleanly to
treatment of (+)-27 with KF and m-CPBA in DMF resulted in removal of the phthalimide. Ring A construction involving
the successful Fleming−Tamao oxidation to diol (+)-28 in 74% imine formation was then readily achieved by heating the
yield. Differentiation of the alcohols was then realized via resulting amine with aqueous NH4Cl (sat.) in EtOH at 70 °C.3
chemoselective protection of the primary alcohol as the TES Completion of the total synthesis of (−)-calyciphylline N
ether, followed by MOM protection of the secondary alcohol to entailed treatment of (−)-34 with Ph2BBr33 to remove the
afford protected diol (+)-30. MOM acetal. Totally synthetic (−)-calyciphylline N displayed
C dx.doi.org/10.1021/ja411539w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Journal of the American Chemical Society Communication

spectral properties in excellent agreement with those derived (12) (a) Mori, K. Tetrahedron: Asymmetry 2005, 16, 1721. (b) Yadav,
from the natural product [i.e., 1H and 13C NMR (500 and 125 J. S.; Basak, A. K.; Srihari, P. Tetrahedron Lett. 2007, 48, 2841.
MHz, respectively), HRMS parent ion identification, and (13) Birch, A. J. J. Chem. Soc. 1944, 430.
chiroptic properties]. (14) Pearson, D. E.; Buehler, C. A. Chem. Rev. 1974, 74, 45.
(15) Sieburth, S. M.; Lang, J. J. Org. Chem. 1999, 64, 1780.
In summary, the first total synthesis of a member of the (16) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
calyciphylline alkaloids, (−)-calyciphylline N (1), has been (17) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
achieved with a longest linear sequence of 37 steps from known (18) Smith, A. B.; Levenberg, P. A. Synthesis 1981, 567.
alcohol (−)-8. Application of the strategies presented herein for (19) (a) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292.
the synthesis of other members of the Daphniphyllum alkaloids (b) Tsuji, J.; Takahash, H.; Morikawa, M. Tetrahedron Lett. 1965,
continues in our laboratory. 4387.

■
(20) Tamao, K. J. Syn. Org. Chem. Jpn. 1988, 46, 861.
ASSOCIATED CONTENT (21) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044.
(22) A similar observation was noted in a recent total synthesis of
*
S Supporting Information Maoecrystal V: Lu, P.; Gu, Z.; Zakarian, A. J. Am. Chem. Soc. 2013,
Experimental details, spectra, and X-ray crystallographic data 135, 14552.
(CIF). This material is available free of charge via the Internet (23) Tamao, K.; Yamauchi, T.; Ito, Y. Chem. Lett. 1987, 171.
at http://pubs.acs.org. (24) Smith, A. B.; Hoye, A. T.; Martinez-Solorio, D.; Kim, W. S.;

■
Tong, R. B. A. J. Am. Chem. Soc. 2012, 134, 4533.
(25) Brown, H. C.; Knights, E. F.; Scouten, C. G. J. Am. Chem. Soc.
AUTHOR INFORMATION
1974, 96, 7765.
Corresponding Author (26) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc. Chem. Commun.
smithab@sas.upenn.edu 1984, 29.
(27) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Mitsunobu, O.;
Notes Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
The authors declare no competing financial interest. (28) Wu, Y. K.; Huang, J. H.; Shen, X.; Hu, Q.; Tang, C. J.; Li, L. Org.

■ ACKNOWLEDGMENTS
Financial support was provided by the National Institutes of
Lett. 2002, 4, 2141.
(29) Keinan, E.; Greenspoon, N. J. Am. Chem. Soc. 1986, 108, 7314.
(30) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616.
Health (National Cancer Institute) through CA-19033. We also (31) Crabtree, R. Acc. Chem. Res. 1979, 12, 331.
thank Drs. George Furst, Rakesh Kohli, and Patrick Carroll for (32) Wuestenberg, B.; Pfaltz, A. Adv. Synth. Catal. 2008, 350, 174.
help in obtaining high-resolution NMR, mass spectral, and X- (33) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984, 49,
ray crystallographic data, respectively. 3912.

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