Total synthesis of (-)-chamobtusin A

Article abstract of DOI:10.1021/ol302880x

The first asymmetric total synthesis of a structurally unique alkaloid, chamobtusin A (1), is described. The route features a novel aziridine formation from the 1,2-oxazine derivative and a palladium-mediated annulation of the vinylaziridine intermediate.

Full text of DOI:10.1021/ol302880x

ORGANIC
LETTERS
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Vol. XX, No. XX
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Total Synthesis of (ꢀ)-Chamobtusin A
Hikaru Suzuki and Sakae Aoyagi*
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi,
Hachioji, Tokyo 192-0392, Japan
aoyagis@toyaku.ac.jp
Received October 19, 2012
ABSTRACT
The first asymmetric total synthesis of a structurally unique alkaloid, chamobtusin A (1), is described. The route features a novel aziridine
formation from the 1,2-oxazine derivative and a palladium-mediated annulation of the vinylaziridine intermediate.
Chamobtusin A (1), isolated by Tan and co-workers
from Chamaecyparis obtusa cv. tetragon in 2007, is the first
alkaloid from the order Pinales, as well as the first diter-
pene alkaloid from the family Cupressacea. Its structure
was established mainly on the basis of 2D NMR techni-
ques (Figure 1) and was confirmed by single-crystal X-ray
diffraction analysis, but the absolute configuration has not
been assigned.1 To date, two syntheses of racemic chamob-
tusin A have been reported independently by Watanabe’s
group2 and our group3 using an approach that featured an
intramolecular aza-Michael reaction to construct the key
nitrogen-bearing quaternary center. We now report the first
enantioselective total synthesis of (ꢀ)-chamobtusin A (1).
Our retrosynthetic analysis for chamobtusin A is shown
in Scheme 1. Chamobtusin A (1) would be derived from
perhydrobenzoindole 2 by manipulation of the keto alco-
hol side chain and the 2H-pyrrole moiety. The key C-8
stereocenter of 2 could be introduced through a stereo-
selective allylation of tricyclic 1,2-oxazine 3 bearing the
siloxy group at C-9, which could be derived from octahy-
dronaphthalenone 4.
Figure 1. Structure of chamobtusin A (1).
form from (S)-(þ)-WielandꢀMiescher ketone6 in seven
steps, following the publishedprocedure.7 Oxidation of the
obtained 5 with DessꢀMartin periodinane and treatment
of the resulting diketone with LHMDS followed by TBSCl
trapping of the enolate gave the corresponding tert-butyl-
dimethylsilyl enol ether 6, which was successively treated
with vinyl Grignard reagent and tetrabutylammonium
fluoride (TBAF) in THF to produce the desired vinyl
alcohol 7 as a single diastereomer in 77% yield over four
steps from 5. Having successfully constructed the requisite
C-9 stereocenter, we set out to synthesize the tricyclic 1,
2-oxazine 3. Thus, 7 was subjected to hydroboration with
dicyclohexylborane (Chx2BH)8 followed by oxidation of
the alkylborane intermediatetoaffordprimary alcohol 8 in
As depicted in Scheme 2, our synthesis commenced with
the preparation of the known R-hydroxy ketone 54 from
the known ketone 4,5 which was obtained in optically pure
(1) Zhang, Y.-M.; Tan, N.-H.; Lu, Y.; Chang, Y.; Jia, R.-R. Org.
Lett. 2007, 9, 4579–4581.
€
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(2) Kuzuya, K.; Mori, N.; Watanabe, H. Org. Lett. 2010, 12, 4709–4711.
(3) Suzuki, H.; Aoyagi, S. Chem. Commun. 2011, 47, 7878–7879.
(4) Ihara, M.; Toyota, M.; Fukumoto, K. J. Chem. Soc., Perkin
Trans. 1 1986, 2151–2161.
(5) Hatzellis, K.; Pagona, G.; Spyros, A.; Demetzos, C.; Katerinopoulos,
H. E. J. Nat. Prod. 2004, 67, 1996–2001.
Wiley: New York, 1990; Collect. Vol. VII, pp 368ꢀ372.
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1997, 38, 5455–5458.
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10.1021/ol302880x
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Scheme 1. Retrosynthetic Analysis for Chamobtusin A (1)
Scheme 3. Formation of Vinylaziridine Derivative 12
65% yield.9 Treatment of 8 with N-hydroxyphthalimide
under Mitsunobu conditions gave 9 in quantitive yield.
Deprotection of the phthalimide group of 9 by treating
with hydrazine monohydrate, heating of the formed hemi-
aminalwithaceticacid inEtOH, and exposure toTMSOTf
and 2,6-lutidine resulted in an 84% yield of the oxime ether 3.
Scheme 2. Preparation of 1,2-Oxazine 3
reaction with allylmagnesium chloride (4 equiv) in THF at
0 °C. To our surprise, however, this reaction provided the
unexpected spiro aziridine 11 in 58% yield, presumably via
initial abstraction of an allylic hydrogen by an appropri-
ately oriented proximal allyl component on the nitrogen of
allylated intermediate complex 10, followed by simulta-
neous aziridine ring formation/NꢀO bond cleavage.10 The
stereostructure of 11 was confirmed by X-ray crystallo-
graphic analysis of the N,O-dinosyl derivative 12, derived
in 85% yield from 11.
Our next task was toelaborate the tricyclic frameworkof
chamobtusin A. For this, we envisioned use of a palladium-
mediated ring-expansion,11 in which a π-allylpalladium
intermediate 13 derived from vinylaziridine derivative 12
by palladium-catalyzed hydrogenolysis,12 would serve as
a precursor for an intramolecular SN2-like amination
(Scheme 4). Thus, when 12 was subjected to the standard
conditions for palladium-catalyzed hydrogenolysis
(Pd2(dba)3CHCl3, PBu3, formic acid, Et3N), the cascade
reaction occurred to generate the desired perhydroben-
zoindole 2, albeit in low yield (21%). The use of PPh3 as a
ligand, however, greatly increased the yield of 2 to 92%.
Subsequent transformation of the C-8 allyl moiety into
the 3-hydroxy-3-methyl-2-butanone sidechain was accom-
plished by means of our previously developed sequence
(10) For related examples of the preparation of aziridines from
oximes, see: (a) Kotera, K.; Takano, Y.; Matsuura, A.; Kitahonoki,
K. Tetrahedron 1970, 26, 539–556. (b) Freeman, J. P. Chem. Rev. 1973,
73, 283–292.
(11) For related palladium-mediated annulation of vinylaziridines,
see: Lowe, M. A.; Ostovar, M.; Ferrini, S.; Chen, C. C.; Lawrence, P. G.;
Fontana, F.; Calabrese, A. A.; Aggarwal, V. K. Angew. Chem., Int. Ed.
2011, 50, 6370–6374.
With the desired oxime ether 3 in hand, we next focused
on stereoselective construction of the pyrrolidine moiety
and elaboration of the necessary side chain of perhydro-
benzoindole 2 (Scheme 3). Thus, in order to stereoselec-
tively introduce the allyl group at C-8, 3 was subjected to
(12) (a) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis 1986, 623–627.
(b) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. J. Org. Chem.
1992, 57, 1326–1327. (c) Tsuji, J.; Mandai, T. Synthesis 1996, 1–24.
(9) Treatment of 7 with borane reagents such as 9-BBN, disiamyl-
borane, or thexylborane gave low yields or complex mixtures.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 4. Synthesis of Perhydrobenzoindole 2
Scheme 5. Synthesis of (ꢀ)-Chamobtusin A
(Scheme 5). Dihydroxylation of 2 with OsO4 and NMO,
followed by NaIO4 cleavage of the resulting diol, provided
aldehyde 14 in 80% yield. Wittig reaction gave alkene 15 in
86% yield. At this stage, the silyl protecting group of 15
was removed, and the resulting tertiary alcohol was treated
with Burgess’ reagent13 in THF at reflux to cleanly afford
dihydropyrrole 16 in 92% yield for these two steps.
Regioselective dihydroxylation of the side chain of 16, in
preference to the ring double bond with OsO4, followed by
TPAP oxidation of the resulting diol gave keto alcohol 17
in 72% yield over two steps. Finally, the nosyl group was
removed using Fukuyama’s conditions,14 and the result-
ing secondary amine was oxidized with iodosobenzene15 in
CH2Cl2 at room temperature, furnishing (ꢀ)-chamobtusin
A (1) in 78% yield over two steps. The spectroscopic data
of (ꢀ)-chamobtusin A. The key features of this synthesis
include a novel aziridine formation from the correspond-
ing 1,2-oxazine derivative and a palladium-mediated an-
nulation of the vinylaziridine derivative.
(1H and 13C NMR, and IR) and optical rotation [[R]25
D
ꢀ233.2 (c 0.14, MeOH) (lit.1 [R]24D ꢀ220.1 (c 0.24, MeOH))]
of synthetic 1 were in accord with those reported for the
natural product.
Acknowledgment. We thank Mr. Haruhiko Fukaya of
our department for carrying out the X-ray structural ana-
lysis and Tokyo University of Pharmacy and Life Sciences
for financial support.
In summary, we have completed the first asymmetric
synthesis and determined the absolute configuration
(13) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744–
4745.
Supporting Information Available. Experimental pro-
cedures and compound characterization data including
X-ray data (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) (a) Kurosawa, W.; Kan, T.; Fukuyama, T. Org. Synth. 2002, 79,
186–195. (b) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353–359.
(15) (a) Muller, P.; Gilabert, D. M. Tetrahedron 1988, 44, 7171–7175.
(b) Larsen, J.; Jorgensen, K. A. J. Chem. Soc., Perkin Trans. 2 1992,
1213–1217. (c) Han, G.; LaPorte, M. G.; Folmer, J. J.; Werner, K. M.;
Weinreb, S. M. J. Org. Chem. 2000, 65, 6293–6306.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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