Stereocontrolled synthesis of the AB rings of samaderine C

Article abstract of DOI:10.1021/ol303385a

A concise synthesis of the AB rings of samaderine C (12 steps, 8 isolation steps, 7.8% overall yield), a quassinoid with antifeedant and insecticidal activity, is described. The development of the first general approach to the trans-1,2-diol A-ring motif

Full text of DOI:10.1021/ol303385a

ORGANIC
LETTERS
2013
Vol. 15, No. 2
394–397
Stereocontrolled Synthesis of the AB
Rings of Samaderine C
David J. Burns,† Stefan Mommer,† Peter O’Brien,*,† Richard J. K. Taylor,†
Adrian C. Whitwood,† and Shuji Hachisu‡
Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K., and
Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire,
RG42 6EY, U.K.
peter.obrien@york.ac.uk
Received December 11, 2012
ABSTRACT
A concise synthesis of the AB rings of samaderine C (12 steps, 8 isolation steps, 7.8% overall yield), a quassinoid with antifeedant and insecticidal
activity, is described. The development of the first general approach to the trans-1,2-diol A-ring motif in samaderine C and other quassinoids is a
key feature. The trans-1,2-diol is crafted via stereoselective R-hydroxylation (of a silyl enol ether) and reduction, a strategy that has much potential
for quassinoid synthesis.
Samaderine C (Scheme 1) is a highly oxygenated, poly-
cyclicquassinoid isolatedfrom the bark and seedkernels of
Scheme 1. Samaderine C and 1, an AB Ring Analogue
the samadera indica plant found primarily in Madagascar
and southeast Asia.1,2 One of eight isolated samaderines,
our interest in samaderine C was initiated by its re-
ported antifeedant and insecticidal properties.3 To date,
there have been rather limited synthetic efforts on the
samaderines, with only two reported total syntheses. In
1994, Grieco et al. disclosed a racemic total synthesis
(>30 steps) of samaderine B.4 More, recently, Shing and
co-workers reported a 21-step synthesis of (ꢀ)-samaderine
Y starting from (þ)-carvone.5
we sought a general strategy for constructing the trans-1,2-
diol A-ring motif present in samaderine C and other
quassinoids. Indeed, we could find no previous syntheses
of such trans-1,2-diols in the quassinoid literature. Diol 1
was chosen as a suitable AB ring analogue of samaderine C,
and herein we describe a concise, stereocontrolled synthesis
starting from the known6 bicyclic enone 2 (Scheme 1).
Our retrosynthetic analysis of diol 1 is summarized in
Scheme 2. Our long-term plan had protected enone 3
serving as an advanced intermediate from which the CDE
rings of samaderine C would be elaborated. Enone 3 would
As there have been no previous synthetic studies on
samaderine C, and to explore possible agrochemical struc-
tureꢀactivity relationships, we focused on the synthesis of
analogues of the AB rings of samaderine C. In particular,
† University of York.
‡ Syngenta.
(1) Zylber, J.; Polonsky, J. Bull. Chim. Soc. Fr. 1964, 2016.
(2) Malathi, R.; Rajan, S. S.; Suresh, G.; Krishnakumari, G. N.;
Gopalakrishnan, G. Acta Crystallogr. 2003, C59, 416.
(3) Govindachari, T. R.; Krishnakumari, G. N.; Gopalakrishnan,
G.; Suresh, G.; Wesley, S. D.; Sreelatha, T. Fitoterapia 2001, 72, 568.
(4) Grieco, P. A.; Pineiro-Nunez, M. M. J. Am. Chem. Soc. 1994, 116,
7606.
(5) Shing, T. K. M.; Yeung, Y. Y. Angew. Chem., Int. Ed. 2005, 44,
7981.
(6) Ziegler, F. E.; Hwang, K.-J.; Kadow, J. F.; Klein, S. I.; Pati,
U. K.; Wang, T.-F. J. Org. Chem. 1986, 51, 4573.
r
10.1021/ol303385a
Published on Web 01/09/2013
2013 American Chemical Society

in turn be prepared from diol 1 by diol protection, ketal
deprotection, 1,3-carbonyl transposition, enone formation,
and enone R-functionalization. It was our intention that the
bridgehead axial methyl group would control the config-
uration of the diol functionality in 1: reduction of hydroxy
ketone 4 (f 1) and R-hydroxylation of silyl enol ether
5 (f 4) should both occur on the face opposite to the
axial methyl group to deliver the requisite trans-1,2-diol
motif. Silyl enol ether 5 would be derived from enone 6
(by γ-enolization), itself obtained from enone 7 via a 1,3-
carbonyl transposition (Wharton rearrangement of an
epoxy ketone7 was envisaged). Previously, Grieco had
developed an approach for the R-hydroxylation of enones
such as 6,8 and the preparation of enone 7 from bicyclic
enone 2 has been described.9
(catalytic Pd(OAc)2/oxygen), none of 7 was formed and a
Nicolaou-style12 IBX-mediated oxidation of ketone 9 gave
only a 14% yield of enone 7.
Scheme 3. Synthesis of Bicyclic Enone 7
Scheme 2. Detailed Retrosynthetic Analysis of Diol 1
Next, we needed to carry out a 1,3-carbonyl transposi-
tion on enone 7 to place the ketone adjacent to the bridge-
head methyl group (as in 6). For this, a nucleophilic
epoxidation of enone 7 and a Wharton rearrangementꢀ
oxidation were planned. However, all attempts at directly
epoxidizing 7 (e.g., H2O2 and NaOH or Triton B) met
with failure, presumably due to steric hindrance from the
neighboring methyl and ketal groups. Instead, we resorted
to a three-step reduction, m-CPBA epoxidation, and oxi-
dationwhich, althoughitinvolvedmoresteps, was efficient
and was ultimately telescoped successfully.
Multigram quantities of racemic enone 7 were prepared
as outlined in Scheme 3. First, 2-methyl-1,3-cyclohexa-
dione and ethyl vinyl ketone were reacted in a DABCO-
mediated Robinson annelation6 to give, after elimination,
bicyclic enone 2 in 78% yield. Ketal formation to give 8
(81% yield) was accomplished using ethylene glycol and
catalytic p-TsOH under DeanꢀStark conditions. Next,
stereoselective reduction of enone 8 using lithium in
ammonia (in the presence of 1 equiv of H2O) gave ketone
9 in 61% yield. Over-reduction to the secondary alcohol
was a complicating factor although the alcohol could be
isolated and oxidized to give additional quantities of 9.
Finally, the enone in 7 was constructed using a stoichio-
metric Pd(OAc)2-mediated oxidation10 of an intermediate
silyl enol ether (formed by regioselective deprotona-
tion of ketone 9 using LDA), as developed by Saegusa.9
This delivered a single diastereomer of enone 7 in 82% yield.
Using the Larock modification11 of the Saegusa oxidation
Initially, the steps were separately explored (Scheme 4).
Luche reduction (NaBH4/CeCl3 7H2O) of enone 7 gave
3
a 94:6 mixture of diastereomeric alcohols from which an
89% yield of alcohol 1013 was isolated. Then, m-CPBA
epoxidation of allylic alcohol 10 gave an inseparable 88:12
mixture of epoxides 11 in 79% yield. The relative stereo-
chemistry of epoxides 11 is of no consequence (vide infra)
and remains unassigned.14 Oxidation with Dess-Martin
periodinane (DMP) delivered an 88:12 mixture of epoxy-
ketones 12 (70% yield). A more efficient synthesis of 12
was achieved by telescoping these three reactions. By
working-up the first two reactions and carrying the crude
products forward withoutpurification, an85:15 mixture of
epoxy-ketones 12 was obtained after chromatography
(73% yield from 7) (Scheme 4).
Treatment of the 85:15 mixture of diastereomeric epoxy-
ketones12withhydrazine hydrate (50% aqueous solution)
and acetic acid led to the allylic alcohols 13 (characterized
(13) The relative configuration of alcohol 10 was assigned as shown
due to the presence of a characteristic trans-diaxial 3J coupling between
the CHOH and CHMe protons in the 1H NMR spectrum (3J = 8.5 Hz).
(14) It is tempting to assign the major epoxide as being trans to the
axial methyl group in a sterically controlled epoxidation of 10. However,
there is also the potential of hydrogen-bonded directed epoxidation cis
to the hydroxyl group (and hence cis to the methyl group), and this
should not be ruled out given the enhanced cis-directing potential of an
equatorial hydroxyl group. See: (a) Chamberlain, P.; Roberts, M. L;
Whitham, G. G. J. Chem. Soc. (B) 1970, 1374. (b) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
(7) Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615.
(8) (a) Spohn, R. F.; Grieco, P. A.; Nargund, R. P. Tetrahedron Lett.
1987, 28, 2491. (b) Grieco, P. A.; Collins, J. L.; Moher, E. D.; Fleck, T. J.;
Gross, R. S. J. Am. Chem. Soc. 1993, 115, 6078.
(9) Poigny, S.; Guyot, M.; Samadi, M. J. Org. Chem. 1998, 63, 5890.
(10) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(11) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng,
D. Tetrahedron Lett. 1995, 36, 2423.
(12) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122, 7596.
Org. Lett., Vol. 15, No. 2, 2013
395

Scheme 4. Telescoped Synthesis of Epoxy-Ketone 12
Scheme 6. Stereoselective Synthesis and X-ray Crystal Structure
of trans-1,2-Diol 1
in a separate experiment) via a Wharton rearrangement
(Scheme 5).7 Workup and subjection of the crude allylic
alcohols 13 to Dess-Martin periodinane oxidation gave
enone 6 in 60% yield over the two steps. γ-Enolization of
enone 6 was achieved using Et3N and Me3SiOTf and gave
extended silyl enol ether 5. Based on Grieco’s precedent,8
in situ oxidation with purified m-CPBA followed by stir-
ring with TBAF generated R-hydroxy ketone 4 as a single
diastereomer in 70% yield. The stereochemistry of 4 was
confirmed by X-ray crystal structures of diols 1 and 14
(vide infra) which indicated that the oxidation had, as
expected, occurred opposite to the bridgehead axial methyl
group.
Scheme 7. Stereoselective Synthesis and X-ray Crystal Structure
of cis-1,2-Diol 14
Scheme 5. Synthesis of R-Hydroxy Ketone 4
In contrast, and somewhat surprisingly, reduction of
R-hydroxy ketone 4 using 3 equiv of DIBAL-H in THF at
ꢀ78 °C led to the preferred formation of cis-1,2-diol 14 which
was isolated in 73% yield. Structural proof was obtained
by X-ray crystallography (Scheme 7). There was no evidence
of the formation of trans-1,2-diol 1 in this reaction. Our con-
jecture is that, with DIBAL-H, an aluminum alkoxide forms
which, if it adopts an axial position, can coordinate to the
axial oxygen of the ketal group. This would lead to a confor-
mational change of the A-ring, exposing the other carbonyl
face to the excess DIBAL-H that is present. Notably, the
complementary diastereoselectivity produced with NaBH4
and DIBAL-H facilitates synthetic access to either trans-or
cis-1,2-diols in the quassinoid family of natural products.
In summary, a concise synthesis of the AB rings of
samaderine C has been developed (12 steps, 8 isolation
steps, 7.8% overall yield). In particular, we have successfully
implemented a strategy for the stereoselective synthesis of
the trans-1,2-diol motif present in samaderine C (and a range
Finally, the reduction of R-hydroxy ketone 4 was
explored. Using 4 equiv of NaBH4 in MeOH at 0 °C, an
82:18 mixture of alcohols 1 and 14 were generated. After
chromatography, trans-1,2-diol 1 was isolated in 80% yield
and cis-1,2-diol 14 in 13% yield. As predicted, steric
hindrance led to a preferred hydride attack on the face
opposite to the methyl group. Unequivocal proof of the
structure of trans-1,2-diol 1 was obtained by X-ray crystal-
lography (Scheme 6).
396
Org. Lett., Vol. 15, No. 2, 2013

of other quassinoids). Our approach includes a stereoselective
R-hydroxylation (of an extended silyl enol ether) and a
reduction. A complementary route to a cis-1,2-diol, a motif
that is present in other quassinoid natural products such as
castelanolide,15 has also been discovered. We believe that these
new aspects have great potential for quassinoid total synthesis.
Acknowledgment. We thank Syngenta and the Univer-
sity of York for funding.
Supporting Information Available. Full experimental
procedures, characterization data, and copies of 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Grieco, P. A.; Lis, R.; Ferrino, S.; Yan, J. J. Org, Chem. 1984, 49,
2342.
The authors declare no competing financial interest.
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