Expedient enantioselective synthesis of cermizine D

Article abstract of DOI:10.1021/ol300342n

An efficient enantioselective synthesis of cermizine D has been developed that exploits the use of a common intermediate to access over 85% of the carbon backbone. Key steps include an organocatalyzed heteroatom Michael addition, a diastereoselective alky

Full text of DOI:10.1021/ol300342n

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1596–1599
Expedient Enantioselective Synthesis of
Cermizine D
Nagarathanam Veerasamy, Erik C. Carlson, and Rich G. Carter*
Department of Chemistry, 153 Gilbert Hall, Oregon State University, Corvallis,
Oregon 97331, United States
rich.carter@oregonstate.edu
Received February 11, 2012
ABSTRACT
An efficient enantioselective synthesis of cermizine D has been developed that exploits the use of a common intermediate to access over 85% of
the carbon backbone. Key steps include an organocatalyzed heteroatom Michael addition, a diastereoselective alkylation with R-iodomethyl
phenyl sulfide, a conjugate addition to a vinyl sulfone species, and a sulfone coupling/desulfurization sequence to join the two major subunits.
Cermizine D (1) was isolated in 2004 by Kobayashi and
co-workers from the club moss Lycopodium cernuum and
displaced modest cytotoxicity aginst murin lymphoma
L1210 cells (7.5 μg/mL).1 Related cermizine alkaloids have
attracted the attention of several laboratories.2 To date,
one elegant 18-step total synthesis of 1 has been reported
by Takayama and co-workers.3 Herein, we report an
efficient, enantioselective synthesis of cermizine D, which
exploits the use of a common intermediate strategy to
access two of the three piperidine rings.
Our retrosynthetic strategy is shown in Scheme 1. We
envision that the C7ÀN bond could be formed through an
intramolecular SN2-type cyclization of alcohol 2. Alcohol
2 would in turn be accessible from a sulfoneÀaldehyde
coupling/desulfurization sequence using sulfone 3 and
common intermediate 4. Sulfone 3 would be accessible
from the same common intermediate 4.
The synthesis commenced with the commercially avail-
able amine 5 (Scheme 2). The amine can also be conveni-
ently prepared from 1-bromo-5-hexene through a two-step
sequence.4 Subsequent Boc protection gave the known
alkene 6.5 After cross-metathesis using crotonaldehyde,
intramolecular heteroatom Michael addition (under a
(1) Morita, H.; Hirasawa, Y.; Shinato, T.; Kobayashi, J. Tetrahedron
2004, 60, 7015–7023.
(2) (a) Snider, B. B.; Grabowski, J. F. J. Org. Chem. 2007, 72, 1039–
1042. (b) Cui, L.; Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394–
8395. (c) Beng, T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010, 132, 12216–
12217. (d) Cheng, G.; Wang, X.; Su, D.; Liu, H.; Liu, F.; Hu, Y. J. Org.
Chem. 2010, 75, 1911–1916. (e) Taber, D. F.; Guo, P.; Pirnot, M. T.
J. Org. Chem. 2010, 75, 5737–5739. (f) Chou, S.-S. P.; Chung, Y.-C.;
Chen, P.-A.; Chiang, S.-L.; Wu, C.-J. J. Org. Chem. 2011, 76, 692–695.
(3) (a) Nishikawa, Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 10,
1987–1990. (b) Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H.
Tetrahedron 2009, 65, 1608–1617.
(4) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.; Carter,
R. G. J. Org. Chem. 2008, 73, 5155–5158.
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Org. Lett. 2007, 9, 5283–5286. (b) Gerasyuto, A. I.; Hsung, R. P.;
Sydorenko, N.; Slafer, B. J. Org. Chem. 2005, 70, 4248–4256.
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Yue, T. Y.; Liu, P.; Zhou, J. Org. Lett. 2009, 11, 1999–2002.
r
10.1021/ol300342n
Published on Web 02/28/2012
2012 American Chemical Society

oxazolidinone 15 followed by conversion to the sulfide
and oxidation generated the sulfone 3.
Scheme 1. Retrosynthetic Analysis
Scheme 3. Synthesis of Sulfone Fragment
slight modification of our previously reported conditions4)
employing catalyst 96 cleanly generated the piperidine 4 in
85% yield and 96% ee as determined by chiral HPLC
analysis.5,7
Scheme 2. Synthesis of Common Intermediate
Our first generation approach for the conversion of the
common intermediate 4 into sulfone 3 is shown in Scheme 3.
Homogolation via Wittig olefination and enol ether clea-
vage revealed aldehyde 11. Pinnick oxidation followed by
coupling with Evans oxazolidinone 12 generated com-
pound 13. Diastereoselective alkylation8 was best achieved
using NaHMDS as base to provide a good yield of
methyl product 15 in modest diastereoselectivity (1.5:1 dr).
The absolute stereochemistry of alkylation product 15 was
determined by X-ray crystallographic analysis (Figure 1).
The poor level of diastereoselectivity appears to be a result
of a mismatched stereochemical array in 13; use of
the diastereomeric oxazolidinone series 14 generated
the alkylated product 17 in high levels of stereoselec-
tivity (20:1 dr). Subsequent reductive removal of the
Given poor diastereoselectivity in constructing the C15
stereogenic center, we sought an alternate approach
(Scheme 4). We were intrigued by the possibility of ex-
ploiting the matched stereochemistry showcased in the
alkylation with oxazolidinone 14; however, this strategy
would requirethe use of anR-halomethylphenylsulfone or
sulfide as the electrophile. Neither one of these electro-
philes have been extensively used in enolate alkylations.
We are aware of only one example (with PhSCH2I9) using
an oxazolidinone-derived enolate by Baker and co-workers
in their synthesis of milbemycin β3 in which they required
extended reaction times (5 d at À20 °C) to provide only
30% of the target compound.10,11 We had hoped that the
(9) Trost, B. M.; King, S. A. J. Am. Chem. Soc. 1990, 112, 408–422.
(10) (a) Baker, R.; O’Mahony, M. J.; Swain, C. J. Chem. Soc., Chem.
Commun. 1985, 1326–1328. (b) Baker, R.; O’Mahony, M. J.; Swain, C. J.
J. Chem. Soc., Perkin Trans 1 1987, 1623–1633.
(11) Three reports of thio-Michael addition/diastereoselective pro-
tonation to R,β-unsaturated acyl oxazolidinones have also been dis-
closed: (a) Tseng, T.-C.; Wu, M.-J. Tetrahedron: Asymmetry 1995, 6,
1633–1640. (b) Raghavan, S.; Tony, K. A. J. Org. Chem. 2003, 68, 5002–
5005. (c) Rana, N. K.; Singh, V. K. Org. Lett. 2011, 13, 6520–6523.
(7) Fustero and co-workers have also developed a related, organo-
ꢀ
ꢀ
catalyzed approach to compound 4. Fustero, S.; Moscardo, J.; Sanchez-
ꢀ
Rosello, M.; Flores, S.; Guerola, M.; del Pozo, C. Tetrahedron 2011, 67,
7412–7417.
(8) Jin, Y.; Liu, Y.; Wang, Z.; Kwong, S.; Xu, Z.; Ye, T. Org. Lett.
2010, 12, 1100–1103.
Org. Lett., Vol. 14, No. 6, 2012
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Scheme 4. Improved Routes to Sulfone Fragment
Figure 1. ORTEP representation of the X-ray crystallographic
data of compound 15.
matched nature of compound 14 might prove advanta-
geous to the reaction rate and chemical yield. We were
pleased to observe that the reaction proceeded smoothly
and in high levels of diastereoselectivity (1 h, 70% yield,
10:1 dr). Lithium borohydride reduction of 18 followed by
sulfide oxidation and deoxygenation provided the desired
coupling partner 3. We also investigated an alternate
route that provided more direct access to 3. HornerÀ
WadsworthÀEmmons olefination of aldehyde 4 generated
the unsaturated sulfone 21 in good yield. Subsequent
conjugate addition using Me2CuLi directly gave the
sulfone 3. While the diastereoselectivity in the cuprate
addition step was disappointing (approximately 1:1 dr),
the brevity of this cuprate route is highly attractive (just
two steps from aldehyde 4). It should also be noted that we
areaware of only limitedexamples ofconjugateaddition to
vinyl sulfones using cuprate or organolithium reagents.12
Recently, Feringa and co-workers have reported an
elegant catalytic, asymmetric protocol for addition to
R,β-unsaturated pyridyl sulfones using a monodentate
phosphoramidite ligand, copper triflate, and dialkylzincs;
however, they were unable to facilitate the addition of
dimethylzinc due to its reduced reactivity.13
Scheme 5. Completion of the Synthesis
The completion of the synthesis of cermizine D (1) is
shown in Scheme 5. Deprotonation of sulfone 3 using
LDA followed by addition of aldehyde 4 gave the hydroxy
sulfone as a mixture of diastereomers at both C7 and C8. It
was critical that the deprotonation step be conducted with
short reaction times (e.g., 1 min) as unwanted intramole-
cular addition to the neighboring Boc moiety was observed
with extended reaction times. The unwanted C7 diaster-
eomer 22 could be recycled via oxidation followed by
reduction with NaBH4 to regenerate a near equal (1.5:1)
ratio (22:2). It should be noted that we have not indepen-
dently confirmed the relative stereochemistry at C7 in
either compound 22 or 2. Next, direct desulfurization of
the hydroxy sulfone 2 was cleanly accomplished using
Raney Ni.14 This desulfurized product proved unstable
in our hands; attempts to purify by silica gel chromato-
graphy or derivatize as its Mosher ester (to establish the
absolute configuration at C7) led to decomposition. For-
tunately, deprotection of the crude product followed by
cyclization15 generated cermizine D (1) in reasonable yield
(60%, three steps). Comparison of our synthetic 1•TFA
material with the 1H/13C NMR and optical rotation data
(12) (a) De Chirico, G.; Fiandanese, V.; Marchese, G.; Naso, F.;
Sciacovelli, O. J. Chem. Soc., Chem. Commun. 1981, 523–524. (b)
Ichikawa, Y.; Isobe, M.; Masaki, H.; Kawai, T.; Goto, T. Tetrahedron
1987, 43, 4759–4766. (c) Dominguez, E.; Carretero, J. C. Tetrahedron
Lett. 1993, 34, 5803–5806.
(15) Comins, D. L.; Zheng, X.; Goehring, R. R. Org. Lett. 2002, 4,
1611–1613.
(16) While not stated in the original isolation data, the spectroscopic
data were also reported as the TFA salt of cermizine D (1). Hirasawa, Y.
Private communication.
ꢀ
ꢀ
ꢀ~
(13) Bos, P. H.; Macia, B.; Fernandez,-Ibanez; Minnard, A. J.;
Feringa, B. L. Org. Biomol. Chem. 2010, 8, 47–49.
(14) Truchot, C.; Wang, Q.; Sasaki, A. Eur. J. Org. Chem. 2005,
1765–1776.
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Org. Lett., Vol. 14, No. 6, 2012

reported by Takayama and co-workers3,16 showed that
our synthesized material was in good agreement.
The National Science Foundation (CHE-0722319) and the
Murdock Charitable Trust (2005265) are acknowledged
fortheir supportof the NMR facility. Wethank Dr. LevN.
Zakharov (OSU and University of Oregon) for X-ray
crystallographic analysis of compound 15 as well as Pro-
In summary, a short, practical synthesis of cermizine
D has been developed. Key steps in this synthesis include
an organocatalyzed, heteroatom Michael addition to con-
struct the common intermediate 4 and a sulfoneÀaldehyde
coupling/desulfurization sequencetojointhe twosubunits.
The brevity of the outlined approach [9 steps with cuprate
addition strategy (via 21) or 16 steps using the PhSCH2I
alkylation approach (via 18)] compares favorably to
Takayama’s 18-step approach. In addition, the common
intermediate strategy provides access to over 85% of the
carbon skeleton (14 of 16 carbon atoms) and both nitrogen
atoms of cermizine D.
ꢀ
fessor Max Deinzer and Dr. Jeff Morre (OSU) for mass
spectra data. Finally, the authors are grateful to Pro-
fessor James D. White (OSU) and Dr. Roger Hanselmann
(Rib-X Pharmaceuticals) for their helpful discussions.
Supporting Information Available. Complete experimen-
tal procedures are provided, including 1H and 13C spectra,
of all new compounds. X-ray crystallographic data (CIF)
for compound 15 are also provided. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support was provided by
the National Institutes of Health (NIH) (GM63723).
The authors declare no competing financial interest.
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