Stereoselective construction of the tetracyclic core of Cryptotrione

Article abstract of DOI:10.1039/c2ob25923k

An efficient stereoselective approach to the tetracyclic core of Cryptotrione, involving an asymmetric Michael addition, ring-closing metathesis, and subsequent cyclopropanation, is described.

Full text of DOI:10.1039/c2ob25923k

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Stereoselective construction of the tetracyclic core of Cryptotrione†
Song Chen,a Chao Rong,a Pengju Feng,a Songlei Lia and Yian Shi*a,b
Received 14th May 2012, Accepted 14th June 2012
DOI: 10.1039/c2ob25923k
An efficient stereoselective approach to the tetracyclic core of
Cryptotrione, involving an asymmetric Michael addition,
ring-closing metathesis, and subsequent cyclopropanation, is
described.
Cryptotrione (1) (Fig. 1), isolated by Kuo and coworkers in
2010 from the bark of Cryptomeria japonica, contains a unique
5-membered spirocycle fused with a cyclopropane and has been
shown to possess anticancer activity against KB cells (IC50
=
6.44 2.23 μM).1,2 The promising biological activity and inter-
esting structure of Cryptotrione make it an attractive synthetic
target. The left-hand 6-membered fused tricyclic structures are
present in a number of naturally occurring compounds, and their
syntheses have been reported.3 However, the right-hand 5-mem-
bered spirocycle fused with a cyclopropane is very rare in iso-
lated natural products. Herein we wish to report an asymmetric
approach to the right-hand tetracyclic core of Cryptotrione (2)
(Scheme 1).
Our retrosynthetic analysis of the tetracyclic fragment is illus-
trated in Scheme 1. Compound 2 was envisioned to form via
cyclopropanation of alkene 3, which could be constructed by
ring-closing metathesis of diene 4. Compound 4 could be pre-
pared from diester 5 via reduction, oxidation, and Wittig reac-
tion. The quaternary stereocenter of diester 5 could be formed by
asymmetric Michael addition of β-keto ester 6.4
Scheme 1 Retrosynthetic analysis of Cryptotrione core.
The synthesis of 5-membered spirocycle 3 is shown in
Scheme 2. The quaternary stereogenic center of compound 7
was constructed from β-keto ester 6 via an asymmetric Michael
addition with slight modification of the reported methods.5 After
various screenings, quinine derived catalyst 86 was found to be
the best choice, giving compound 7 with 72% yield and 90% ee
in CHCl3 at 25 °C with 10 mol% catalyst.7 The ketone in 7 was
reduced with (n-Bu)4NBH4 in the presence of CeCl3·7H2O in
EtOH at −78 °C,8 affording alcohol 9 in 72% yield and >10 : 1
dr. Addition of CeCl3·7H2O was found to be very important for
both reactivity and diastereoselectivity of the reduction. Diol 10
was obtained from 9 via protection with TBSCl and DIBAL-H
reduction.9 Then compound 10 could be converted to diene 4 by
Swern oxidation and Wittig olefination in 54% yield over two
steps.10 Spirocycle 3 was readily formed in 91% yield at rt via ring-
closing metathesis with the second-generation Grubbs catalyst.11 It
is worth mentioning that the initial reduction of the ketone in 7 and
TBS protection were important for the subsequent functional
groups manipulations. The ketalization of the ketone was unsuc-
cessful. When the ketone was protected as TBS enol ether, a messy
mixture was obtained during the subsequent Swern oxidation step.
As outlined in Scheme 3, the cyclopropanation of spirocycle 3
was achieved with ethyl diazoacetate, 2.5 mol% (CuOTf)2·PhH,
and 5.5 mol% ligand 12 in CH2Cl2 at 25 °C, giving compound
11 in 93% yield with >10 : 1 dr.12 It was found that slow addition
of ethyl diazoacetate via syringe pump was important for the
high yield. Compound 11 was finally converted to compound 2
by deprotection of the TBS group with TBAF (88% yield) and
methyl groups with BBr3 (79% yield).13
Fig. 1 Structure of Cryptotrione.
aBeijing National Laboratory of Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
bDepartment of Chemistry, Colorado State University, Fort Collins,
Colorado 80523, USA. E-mail: yian@lamar.colostate.edu;
Fax: +(1)-970-4911801; Tel: +(1)-970-4917424
†Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and X-ray structure of 15 along with
NMR spectra. CCDC 881889. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c2ob25923k
5518 | Org. Biomol. Chem., 2012, 10, 5518–5520
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Scheme 4 Synthesis of compound 15.
Scheme 2 Synthesis of compound 3.
Fig. 2 The X-ray structure of compound 15.
spirocycle, and copper-catalyzed stereoselective cyclopropana-
tion to construct the fused cyclopropane. The absolute configur-
ation of the core was determined by X-ray structure. The
application of this strategy to the total synthesis of Cryptotrione
and its derivatives as well as biological activity studies are cur-
rently under way.
Acknowledgements
The authors gratefully acknowledge the National Basic Research
Program of China (973 program, 2011CB808600) and the
Chinese Academy of Sciences for the financial support.
Scheme 3 Synthesis of compound 2.
After many attempts, the X-ray structure was finally obtained
for ammonium salt 15, derived from compound 11 and
(R)-(+)-N-benzyl-1-phenylethylamine (Scheme 4), which allows
the determination of the absolute configuration of the syn-
thesized spiro tetracyclic structure (Fig. 2).
Notes and references
1 C.-C. Chen, J.-H. Wu, N.-S. Yang, J.-Y. Chang, C.-C. Kuo, S.-Y. Wang
and Y.-H. Kuo, Org. Lett., 2010, 12, 2786.
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leaves of Cryptomeria japonica, see: W.-C. Su, J.-M. Fang and
Y.-S. Cheng, Phytochemistry, 1993, 34, 779.
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Conclusion
In summary, we have developed a stereoselective strategy to con-
struct the right-hand tetracyclic core of Cryptotrione. The key
steps involve an asymmetric Michael addition to form the
quaternary stereocenter, ring-closing metathesis to achieve the
4 The synthesis of compound 6 is described in the ESI.† For a similar
synthesis of β-keto ester, see: (a) U. K. Tambar, D. C. Ebner and
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