Total Synthesis of (±)-Herbertenolide by Stereospecific Formation of Vicinal Quaternary Centers in a Crystalline Ketone

Article abstract of DOI:10.1021/ol0499250

(Matrix presented) The sesquiterpene (±)-herbertenolide was synthesized in seven steps from commercial 2-bromo-4-methylanisole. In the key step, two adjacent stereogenic quaternary centers were controlled by a highly chemoselective and stereospecific phot

Full text of DOI:10.1021/ol0499250

ORGANIC
LETTERS
2004
Vol. 6, No. 4
645-647
Total Synthesis of (±)-Herbertenolide by
Stereospecific Formation of Vicinal
Quaternary Centers in a Crystalline
Ketone
Danny Ng, Zhe Yang, and Miguel A. Garcia-Garibay*
Department of Chemistry and Biochemistry, UniVersity of California-Los Angeles,
Los Angeles, California 90095-1569
mgg@chem.ucla.edu
Received January 13, 2004
ABSTRACT
The sesquiterpene (±)-herbertenolide was synthesized in seven steps from commercial 2-bromo-4-methylanisole. In the key step, two adjacent
stereogenic quaternary centers were controlled by a highly chemoselective and stereospecific photodecarbonylation reaction of crystalline
methyl-trans-3-(2-methyl-5-methoxyphenyl)-1,3-dimethyl-2-oxocyclohexancarboxylate (3). An efficient generation of radical pairs and the
stereochemical control exerted by the solid state suggest that this reaction may become a useful synthetic method.
Strongly motivated by the potential of solvent-free proce-
dures and the development of “green chemistry”1 for the
Scheme 1
synthesis of structurally challenging natural products and
specialty chemicals, we have recently shown that photode-
carbonylation of crystalline ketones may be a reliable and
efficient method for generating biradicals and radical pairs
in the solid state.2-4 We have also observed that radicals
formed in such a constrained environment recombine with
chemoselectivities and stereospecificities that frequently rival
those observed in enzymatic processes (Scheme 1).
A critical requirement for a successful solid-state photo-
decarbonylation is the presence of radical stabilizing groups
(1) (a) Poliakoff, M.; Fitzpatrick, J. M.; Farren, T. R. A.; Anastas, P. T.
at the two R-carbons of the ketone. Therefore, in the past
Science 2002, 297, 807-810. (b) Anastas, P. T.; Warner, J. C. Green
few years we have directed our efforts to the systematic
exploration of suitable substituents for this purpose. We have
reported that combinations of phenyl,2 carbonyl,3 alkoxy,4
and cyano groups5 allow efficient solid-state photodecarbo-
nylation to occur. We recently disclosed the use of this
Chemistry: Theory and Practice; Oxford University Press: Oxford, 1998.
(2) (a) Choi, T.; Peterfy, K.; Khan S. I.; Garcia-Garibay, M. A. J. Am.
Chem. Soc. 1996, 119, 12477-12478. (b) Peterfy, K.; Garcia-Garibay, M.
A. J. Am. Chem. Soc. 1998, 120, 4540-4541.
(3) (a) Yang, Z.; Garcia-Garibay, M. A. Org. Lett. 2000, 2, 1963-1965.
(b) Yang, Z.; Ng, D.; Garcia-Garibay, M. A. J. Org. Chem. 2001, 66, 4468-
4475. (c) Campos, L. M.; Ng, D.; Yang, Z.; Dang, H.; Martinez, H. L.;
Garcia-Garibay, M. A. J. Org. Chem. 2002, 67, 3749-3754.
(4) Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Tetrahedron Lett. 2002,
43, 7063-7066.
(5) Ellison, M. E. M.S. Thesis, University of California-Los Angeles,
Los Angeles, 2003.
10.1021/ol0499250 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/28/2004

reaction as a simple and efficient method for the enantiospe-
cific preparation of compounds with vicinal tertiary and
quaternary stereocenters.6 In this communication, we extend
the method for the synthesis of compounds with adjacent
quaternary stereocenters, a common structural feature of
many natural products and one of the most demanding
challenges in organic synthesis.7 As a test case, we report a
diastereospecific total synthesis of the sesquiterpene her-
bertenolide (1), in which the bond connecting the vicinal
quaternary centers is formed in the solid state. This synthesis
represents the first time that a solid-state reaction is used
as a key step in the total synthesis of a natural product.
trapped in the crystal lattice of its precursor, the two radical
centers remain configurationally trapped until they can spin
flip to the singlet state (ISC′) to form the desired bond.
Even though a priori predictions of the crystallinity and
melting point of 3 are impossible, the presence of the ester
functional group should allow one to modify the physical
properties of the precursor by changing the nature of the
alkoxy substituent. The requisite trans configuration of 3
should arise from the diastereoselective acylation of the cor-
responding ketone precursor, prepared from 4. The synthesis
of (()-herbertenolide began with the commercially available
2-bromo-4-methylanisole (4) (Scheme 3). Lithiation of 4 with
Herbertenolide (1, Scheme 2) was first isolated and char-
acterized by Matsuo et al. from the leafy liverwort Herberta
Scheme 3 a
Scheme 2
a Conditions: (a) BuLi, cyclohexene oxide, BF3‚OEt2, THF, -78
°C; (b) DMSO, (COCl)2, Et3N, CH2Cl2, -78 °C; (c) NaH, MeI,
glyme, reflux; (d) LDA, MeI, THF, -0 °C to rt; (e) LDA,
CNCO2Me, ether.
adunca, the extract of which has been shown to exhibit a
remarkable growth suppression of certain plant pathogenic
fungi.8 To date, there have been only two reported syntheses
of this natural product.9 The two vicinal quaternary centers
in its structure present an ideal platform for testing our
proposed methodology. The retrosynthetic analysis outlined
in Scheme 2 suggests that formation of the lactone ring
should proceed spontaneously after hydrolysis of the ester
and deprotection of the ether group in 2. The preparation of
ester 2, which contains the target vicinal quaternary centers,
may be accomplished via the stereospecific solid-state pho-
todecarbonylation of the cyclohexanone precursor 3. As indi-
cated in Scheme 1, the reaction starts by electronic excitation
and proceeds by intersystem crossing to the triplet excited
state (ISC). We have shown that a substitution pattern such
as that of ester 3 can lower the bond dissociation energies
of the two R-bonds, thus facilitating sequential R-cleavage
and decarbonylation reactions within the lifetime of the trip-
let. As the 1,5-biradical formed in this manner is structurally
butyllithium followed by treatment with cyclohexene oxide
and BF3‚Et2O resulted in the acid-catalyzed epoxide opening
to give trans-cyclohexanol 5. Oxidation of 5 under Swern
conditions10 proceeded smoothly to give the desired 2-aryl-
cyclohexanone 6 with an overall yield of 96% over two steps.
After several low-yielding attempts at one-pot double-
methylation of 6, a sequential two-step procedure using
sodium hydride/MeI followed by LDA/MeI was found to
give the best yield of 7 (60%, two steps).
Acylation of 7 was then carried out using a modification
of Mander’s procedure11 with commercially available methyl
cyanoformate (Scheme 3). Satisfyingly, the resulting methyl
ester 3 was obtained in 72% yield with an excellent diastereo-
selectivity (>98:2). The ketoester 3 turned out to be a highly
crystalline material with a mp ) 96-97 °C. The desired
trans stereochemistry was unambiguously established by
X-ray crystallographic analysis (Figure 1), which revealed
a chair conformation with the aromatic group adopting an
equatorial position.12
(6) Ellison, M. E.; Ng, D.; Dang, H.; Garcia-Garibay, M. A. Org. Lett.
2003, 5, 2531-2534.
(7) (a) Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc.
1999, 121, 7702-7703. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388-401. (c) Fuji, K. Chem. ReV. 1993, 93, 2037-
2066.
(8) (a) Matsuo, A.; Yuki, S.; Nakayama, M. Chem. Lett. 1983, 7, 1041-
1042. (b) Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc., Perkin Trans.
1 1986, 4, 701-710.
(9) (a) Eicher, T.; Servet, F.; Speicher, A. Synthesis 1996, 7, 863-870.
(b) Fukuyama, Y.; Yuasa, H.; Tonoi, Y.; Harada, K.; Wada, M.; Asakawa,
Y.; Hashimoto, T. Tetrahedron 2001, 57, 9299-9307.
(10) Mancuso, A. J.; Swern, D. Synthesis 1981, 3, 165-185.
(11) Crabtree, S. R.; Chu, W. L. A.; Mander, L. N. Synlett 1990, 3, 169-
170.
(12) Selected crystal data: C18H24O4, colorless prisms, FW ) 304.37
amu, space group P21/c, a ) 8.7539(13) Å, b ) 14.491(2) Å, c ) 13.0722-
(19) Å, â ) 95.806(3)°, Z ) 4, Fcalcd ) 1.225 Mg/m3, F(000) ) 656, λ )
0.71073 Å, T ) 100(2) K, crystal size ) 0.20 × 0.30 × 0.30 mm3. Of the
7269 reflections collected (2.10° e θ e 27.55°), 2915 [R(int) ) 0.0208]
were independent reflections; max/min residual electron density 273 and
-188 e/nm3, R1 ) 0.0352, wR2 ) 0.0907 (all data).
646
Org. Lett., Vol. 6, No. 4, 2004

crystalline 3 with a medium-pressure Hanovia mercury lamp
at 0 °C for 6-12 h of irradiation occurred with remarkably
1
high chemo- and stereoselectivity. H NMR and GC-MS
analysis revealed the formation of the desired cyclopentane
2 in ca. 76% yield with no traces of the cis diastereomer
after 20% conversion. Treatment of 2 with excess BBr3 in
CH2Cl2 resulted in tandem hydrolysis, ether deprotection,
and lactonization to give herbertenolide (1) in 60% yield.
The spectral data of the product obtained in this manner were
identical to that reported for the natural product.8
The exceptional simplicity, chemoselectivity, and ste-
reospecificity of the solid-state reaction, combined with well-
developed alkylation chemistry of aliphatic ketones, make
it a powerful combination for the preparation of natural and
nonnatural compounds containing vicinal quaternary centers.
The synthesis reported in this manuscript was completed in
seven steps with an overall yield of ca. 19%. Although the
key step (3 f 2) was only carried out to 20-35% conversion
due to subsequent melting of the methyl ester and formation
of small amounts of undesirable solution phase products,
higher conversions can be achieved by recycling unreacted
starting material or by using lower photolysis temperatures.
However, nearly quantitative solid-to-solid reactions at am-
bient temperatures should be possible by acylation of 7 with
other alkyl cyanoformates to prepare higher melting ana-
logues of 3. Studies involving the preparation of such com-
pounds, the enantiospecific construction of herbertenolide,
and the synthesis of other compounds in the herbertane
family are currently in progress.
Figure 1. ORTEP diagram of ketone 3.12
Photochemical irradiation of 3 in 0.1 M, argon-sparged
benzene solutions produced a complex mixture, later shown
not to contain cyclopentane 2 (Scheme 4). The H NMR
1
Scheme 4 a
Acknowledgment. Financial support by the National
Science Foundation is gratefully acknowledged.
a Conditions: (a) hν (solid), 310 nm filter, 0 C; (b)BBr3, CH2Cl2.
Supporting Information Available: Synthetic details and
characterization of compounds 1-3 and 5-7 and crystal-
lographic data (CIF) for compound 3. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
spectrum of the crude reaction mixture contained several
vinylic hydrogen signals, suggesting disproportionation of
the biradical intermediate as the dominant solution pathway.
In contrast, the photolysis of finely powdered samples of
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