Enantioselective modular synthesis of cyclohexenones: Total syntheses of (+)-crypto-and (+)-infectocaryone

Article abstract of DOI:10.1021/ol101588j

A modular synthesis of cyclohexenones is described and applied to the first enantioselective total syntheses of (+)-crypto-and (+)-infectocaryone. Key steps in the synthesis of cyclohexenones are an iridium-catalyzed allylic alkylation, nucleophilic allyl

Full text of DOI:10.1021/ol101588j

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3886-3889
Enantioselective Modular Synthesis of
Cyclohexenones: Total Syntheses of
(+)-Crypto- and (+)-Infectocaryone
Ge´raldine Franck, Kerstin Bro¨dner, and Gu¨nter Helmchen*
Organisch-Chemisches Institut der Ruprecht-Karls-UniVersita¨t Heidelberg,
Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
g.helmchen@oci.uni-heidelberg.de
Received July 9, 2010
ABSTRACT
A modular synthesis of cyclohexenones is described and applied to the first enantioselective total syntheses of (+)-crypto- and (+)-infectocaryone.
Key steps in the synthesis of cyclohexenones are an iridium-catalyzed allylic alkylation, nucleophilic allylation, and ring-closing metathesis.
On the way to (+)-cryptocaryone, a catch and release strategy involving an iodolactonization/elimination and a regioselective C-acylation were used.
Enantiomerically pure cyclohexenones are versatile building
blocks for the synthesis of natural products.1 Their EPC
(enantiomerically pure compound) synthesis has been carried
out by ex-chiral pool approaches,1,2 using terpenes such as
pulegone or carvone as starting materials, and by asymmetric
synthesis.3 We herein present a novel modular synthesis
of cyclohexenones and its application in the first enanti-
oselective total syntheses of (+)-infecto- (1) and (+)-
cryptocaryone (2).
Our method comprises an iridium-catalyzed allylic alkyl-
ation as the enantiodiscriminating step, expected to proceed
with ee of >96%,4 decarboxylation, reduction to an aldehyde,
nucleophilic allylation, and ring-closing metathesis (RCM)
to give a cyclohex-3-enone (Figure 1).5 The ee of the product
can be considerably improved if an asymmetric allylation,
e.g., Brown allylation,6 is employed. Cyclohex-3-enones are
valuable because addition reactions at the double bond, for
(1) For reviews see: (a) Ho, T.-L. EnantioselectiVe Synthesis: Natural
Products Synthesis from Chiral Terpenes; Wiley: New York, 1992. (b)
Klunder, A. J. H.; Zhu, J.; Zwanenburg, B. Chem. ReV. 1999, 99, 1163–
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E. A. Tetrahedron Lett. 2004, 45, 5039–5041. (c) Lakshmi, R.; Bateman,
(4) Reviews: (a) Helmchen, G. In Iridium Complexes in Organic
Synthesis; Oro, A., Claver, C., Eds.; Wiley-VCH: Weinheim, 2009; pp
211-250. (b) Helmchen, G.; Dahnz, A.; Du¨bon, P.; Schelwies, M.;
Weihofen, R. Chem. Commun. 2007, 675–691. (c) Miyabe, H.; Takemoto,
Y. Synlett 2005, 1641–1655. (d) Takeuchi, R. Synlett 2002, 1954–1965.
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2466–2469. (b) Du¨bon, P.; Schelwies, M.; Helmchen, G. Chem.sEur. J.
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10.1021/ol101588j  2010 American Chemical Society
Published on Web 08/02/2010

the cyclohexene 9 as key intermediate (Figure 2). Infecto-
caryone (1) has not yet been synthesized; for (+)-crypto-
Figure 1. Modular enantioselective synthesis of cyclohexenones.
example, epoxidation or aziridination, are expected to
proceed with high degrees of diastereoselectivity, and
subsequent treatment with base yields γ-substituted R,ꢀ-
unsaturated ketones. This catch and release strategy was
employed in the synthesis of (+)-cryptocaryone (2).
In the first stage of this project, we have prepared the
cyclohexenones 8a-8d from the allylic alkylation products
3a-d (Scheme 1). Synthesis of the latter with ee of g96%
Figure 2. Retrosynthetic analysis.
Scheme 1. Modular Synthesis of Cyclohexenones
caryone (2) a chiral auxiliary based synthesis has recently
been reported.8 (+)-Cryptocaryone was first isolated from
the roots of Cryptocarya bourdilloni in 1972, and its structure
was established in 1985.9,10 (+)-Infectocaryone was isolated
from the trunk bark of Cryptocarya infectoria in 2001.11a
Both compounds display activity against KB cell lines,11 with
IC50 values of 1.7 µM for 1 and 1.8 µM for 2. In addition,
2 was found to be cytotoxic against erythroleukemic K562
and doxorubicin-resistant K562 cells at an IC50 value of 2
µM.11a
The synthesis of the key intermediate 9 with ee of >99%
started with an iridium-catalyzed allylic alkylation of the
allylic carbonate 10. Substrates with alkoxyalkyl or silyl-
oxyalkyl substituents can give rise to relatively low levels
of regioselectivity upon use of the standard catalysts derived
from [Ir(cod)Cl]2.12 With our new catalyst system based on
[Ir(dbcot)Cl]2, improved regioselectivities are generally
obtained.7a The branched product 11 was formed with
excellent regioselectivity of b/l ) 97:3 (Scheme 2), while
the cod complex induced a regioselectivity of only b/l )
84:16.
by iridium-catalyzed allylic alkylation has previously been
described.7 All of the cyclohexenones were prepared in high
enantiomeric excess and excellent overall yield on a multi-
gram scale. The route is advantageous, particularly for the
synthesis of cyclohexenones with substituents in the
3-position.2b The ketone 8d, also known as celery ketone,
is used in its racemic form as a synthetic fragrance with
typical lovage and celery character. We have prepared the
(S)- as well as the (R)-enantiomer. These compounds have
recently been characterized with respect to olfactory
properties.3e
Subsequent saponification/decarboxylation, O-deprotec-
tion, and Dess-Martin oxidation gave the aldehyde 13 in
(8) Fujioka, H.; Nakahara, K.; Oki, T.; Hirano, K.; Hayashi, T.; Kita,
Y. Tetrahedron Lett. 2010, 51, 1945–1946.
(9) Govindachari, T. R.; Parthasarathy, P. C. Tetrahedron Lett. 1972,
13, 3419–3420
.
(10) Parthasarathy, P. C. Tetrahedron Lett. 1985, 26, 5491–5492
.
(11) (a) Dumontet, V.; Gaspard, C.; Van Hung, N.; Fahy, J.; Tchertanov,
L.; Se´venet, T.; Gue´ritte, F. Tetrahedron 2001, 57, 6189–6196. (b)
Meragelman, T. L.; Scudiero, D. A.; Davis, R. E.; Staudt, L. M.; McCloud,
T. G.; Cardellina, J. H., II; Shoemaker, R. H. J. Nat. Prod. 2009, 72, 336–
339.
Next, we focused on asymmetric total syntheses of
infectocaryone (1) and the related cryptocaryone (2) using
(12) Streiff, S.; Welter, C.; Schelwies, M.; Lipowsky, G.; Miller, N.;
Helmchen, G. Chem. Commun. 2005, 2957–2959.
(7) For 3a-c see: (a) Spiess, S.; Welter, C.; Franck, G.; Taquet, J.-P.;
Helmchen, G. Angew 2008, 47, 7652–7655. For 3d see: (b) Alexakis, A.;
Polet, D. Org. Lett. 2004, 6, 3529–3532.
(13) The corresponding allylation with allyl magnesium chloride was
not chemoselective.
Org. Lett., Vol. 12, No. 17, 2010
3887

results,14 while reactions with lithium enolates (LDA or
LiHMDS) were poorly reproducible. Subsequent Dess-Martin
oxidation gave enone 15 in 64% yield. Preparation of 15 by
direct acylation of 14 with a cinnamoyl derivative was also
achieved (see below). Finally, ester cleavage with TFA and
reesterification with diazomethane furnished analytically pure
(+)-infectocaryone (1) in 91% yield; its spectral data were
in agreement with those reported for the natural product.11a
The completion of the total synthesis of (+)-cryptocaryone
(2) was straightforward in the first part, but more challenging
than anticipated in the final stage (Scheme 4). According to
Scheme 2. Iridium-Catalyzed Allylic Alkylation
Scheme 4
.
Synthesis of (+)-Cryptocaryone (2) via a Catch and
Release Strategy
a b/l ) branched product/linear product.
good yield (Scheme 3). Brown allylation13 followed by ring-
closing metathesis (RCM) furnished the cyclohexene 9 as a
Scheme 3. Synthesis of (+)-Infectocaryone (1)
the catch and release strategy, the ester 9 was saponified and
the resulting carboxylic acid was subjected to an iodolac-
tonization reaction to give the lactone 16. Swern oxidation
effected both generation of the carbonyl group and elimina-
tion of HI to give the crystalline enone 17 in good overall
yield.15
Next a selective C-acylation of 17 had to be realized to
yield (+)-cryptocaryone (2). Attempts to perform an aldol
reaction with cinnamaldehyde followed by oxidation, as in
the synthesis of 1, did not lead to the desired product. We
decided to explore a direct acylation of an enolate of 17. A
screening with respect to both bases for enolate generation
as well as acylating agents was performed (Table 1).
As acylating agents, activated acyl derivatives were tested
that had been used in C-acylation reactions of enolates
before: cinnamoyl chloride,16 cinnamoyl cyanide,17 N-
(cinnamoyl)-imidazole,18 and N-(cinnamoyl)-benzotriazole19
(Table 1). Enolate formation required close attention, because
the enolates of 17 were found to be unstable if deprotonation
times exceeding 30 min at -78 °C were employed. Eventu-
ally, LiHMDS was identified as suitable base. Trials were
mixture of the cis- and the trans-diastereoisomers in a ratio
of 94:6. The minor trans-diastereoisomer was separated off
by column chromatography. The ester cis-9 was obtained
with very high ee of >99% (HPLC) because of double
diastereoselection in the two asymmetric syntheses leading
to it.
(+)-Infectocaryone (1) was synthesized from 9 in five
steps as follows. Oxidation of 9 to the ketone and isomer-
ization of the double bond with base gave the R,ꢀ-unsaturated
ketone 14 in excellent yield. The second side chain was
introduced by an aldol reaction with trans-cinnamaldehyde.
The enolate produced with n-Bu2BOTf gave excellent
(14) (a) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1–200. (b)
Kurasaki, H.; Okamoto, I.; Morita, N.; Tamura, O. Chem.sEur. J. 2009,
15, 12754–12763.
(15) The lactone 17 was characterized by crystal structure analysis. The
data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif. CCDC 776574
contains the supplementary crystallographic data.
(16) Casey, M.; Donnelly, J. A.; Ryan, J. C.; Ushioda, S. AkriVoc 2003,
Vii, 310–327.
3888
Org. Lett., Vol. 12, No. 17, 2010

The acylation procedure was also effective in the synthesis
of (+)-infectocaryone (1); using conditions according to entry
7 of Table 1, the reaction of ketone 14 with cinnamoyl
cyanide produced the enone 15 in 76% yield.
Table 1. Reagent Screening for C-Acylation of 17
In summary, we are reporting a modular asymmetric
synthesis of substituted cyclohexenones, which was applied
in the first enantioselective total syntheses of (+)-crypto-
caryone (2) and (+)-infectocaryone (1) (total yields of 26%
and 32%, respectively). Key steps are iridium-catalyzed
allylic alkylations with an improved catalyst based on dbcot
as dienylic ligand, iodolactonization/elimination reactions in
catch and release fashion, and a chemoselective C-acylation.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 623) and the Fonds
der Chemischen Industrie. We thank the following members
of our institute: Marcel Brill, Alina Muschko, Reida Rutte,
and Christopher Brauch for experimental assistance and Dr.
F. Rominger for X-ray crystal structure analyses. We are
also grateful for continued supply of phenethylamines by
Prof. Ditrich of BASF SE, Ludwigshafen.
Supporting Information Available: Experimental details
including spectral and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL101588J
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also performed with LDA, NaHMDS (decomposition), KOt-
Bu, and Schwesinger base (phosphazene base P1-t-Bu)20 (no
reaction). The combination of enolate formation with LiH-
MDS and reaction of the enolate with cinnamoyl cyanide at
-100 °C gave (+)-cryptocaryone (2) in a yield of 74%.
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