Chiral benzyl centers through asymmetric catalysis. A three-step synthesis of (R)-(-)-α-curcumene via asymmetric hydrovinylation

Article abstract of DOI:10.1021/ol048790v

(Chemical Equation Presented) A three-step, two-pot procedure involving asymmetric hydrovinylation followed by Suzuki-Miyaura reaction represents by far the shortest synthesis of this popular bisabolane. Other applications for the synthesis of similar com

Full text of DOI:10.1021/ol048790v

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3159-3161
Chiral Benzyl Centers through
Asymmetric Catalysis. A Three-Step
Synthesis of (R)-(−)-r-Curcumene via
Asymmetric Hydrovinylation
Aibin Zhang and T. V. RajanBabu*
Department of Chemistry, 100 West 18th AVenue, The Ohio State UniVersity,
Columbus, Ohio 43210
rajanbabu.1@osu.edu
Received June 24, 2004
ABSTRACT
A three-step, two-pot procedure involving asymmetric hydrovinylation followed by Suzuki−Miyaura reaction represents by far the shortest
synthesis of this popular bisabolane. Other applications for the synthesis of similar compounds with chiral benzyl centers can be easily
envisioned.
Several important classes of natural products, among them,
bisabolanes, heliannanes, serrulatanes, and pseudopterosins
(Figure 1), are characterized by a benzylic chiral center, often
carrying a methyl group at this position.1 Diverse biological
activities2 exhibited by these compounds include antiinflam-
matory, antiviral, and antimycobacterial properties, and they
have attracted considerable attention from synthetic chemists.
No less than 12 nonracemic syntheses of the simplest
member of this class of compounds, (R)-(-)-R-curcumene,
are known. (R)-(-)-R-Curcumene and related (R)-(-)-ar-
turmerone are the consitutents of a large number of essential
oils, and it has been amply demonstrated that intermediates
for their synthesis could in principle be used for a number
of other bisabolane and other related terpenes.1a
Despite their rather simple structures, the stereocenter at
the benzylic position3 poses a significant challenge in the
asymmetric synthesis of even the simplest of these molecules.
Judged by the number of publications (vide infra) dealing
(2) (a) Bohlman, F.; Lonitz, M. Chem. Ber. 1978, 111, 843. (b) McEnroe,
F. J.; Fenical, W. Tetrahedron 1978, 34, 1661. (c) Fusetani, N.; Sugano,
M.; Matsunaga, S.; Hashimoto, K. Experientia 1987, 43, 1234. (d) Wright,
A. E.; Pomponi, S. A.; McConnell, O. J.; Kohmoto, S.; McCarthy, P. J. J.
Nat. Prod. 1987, 50, 976. (e) Ohno, M.; Todoriki, R.; Yamamoto, Y.; Akita,
H. Chem. Pharm. Bull. 1994, 42, 1590. (f) Asaoka, M.; Shima, K.; Fujii,
N.; Takei, H. Tetrahedron 1988, 44, 4757. (g) Rucker, G.; Breitmaier, E.;
Manns, D.; Maier, W.; Marek, A.; Heinzmann, B.; Heiden, K.; Seggewies,
S. Arch. Pharm. 1997, 330, 12. (h) Mayer, A. M. S.; Jacobson, P. B.;
Fenical, W.; Jacobs, R. S.; Glaser, K. B. Life Sci. 1998, 62, 401.
(3) For a recent approach in which an asymmetric Cu-catalyzed conjugate
addition of Me2Zn was used in synthesis of the serrulatane diterpene
erogorgiaene, see: Cesati, R. R.; de Armas, J.; Hoveyda, A. H. J. Am. Chem.
Soc. 2004, 126, 96.
(1) For recent references, see the following and others cited therein. (a)
Bisabolanes: Hagiwara, H.; Okabe, T.; Ono, H.; Kamat, V. P.; Hoshi, T.;
Suzuki, T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 2002, 895. Vyvyan,
J. R.; Loitz, C.; Looper, R. E.; Mattingly, C. S.; Peterson, E. A.; Staben, S.
T. J. Org. Chem. 2004, 69, 2461. (b) Heliannanes: Kishuku, H.; Shindo,
M.; Shishido, K. Chem. Commun. 2003, 350. (c) Pseudopterosins: Look,
S. A.; Fenical, W.; Jacobs, R. S.; Clardy, J. Proc. Natl. Acad. Sci. 1986,
83, 6238. Johnson, T. W.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 13486.
Harrowven, D. C.; Tyte, M. J. Tetrahedron Lett. 2004, 45, 2089. (d)
Serrulatanes: Rodriguez, A.; Ramirez, C. J. Nat. Prod. 2001, 64, 100.
Dehmel, F.; Lex, J.; Schmalz, H.-G. Org. Lett. 2002, 4, 3915.
10.1021/ol048790v CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/03/2004

Figure 2. Ligands for asymmetric hydrovinylation.
isolated from many natural sources in both enantiomerically
pure forms, where as ar-turmerone (2), isolated from the
rhizomes of Curcuma longa Linn exists only in the (S)-(+)-
form. Since biological activities of the two bisabolane
enantiomers vary considerably,2a-c any practical synthesis
should deliver both enantiomers in high stereochemical
purity. We recently achieved12 significant improvements in
the Ni-catalyzed asymmetric hydrovinylation of various
vinylarene derivatives, and in this note we document an
application of this reaction for a three-step enantioselective
synthesis of (R)-(-)-R-curcumene starting from commer-
cially available 4-methylstyrene and ethylene. The intermedi-
ates generated for this synthesis can also be used for a
number of bisabolane sesquiterpenes. As an example, a new
five-step synthesis (26% yield from 4-methylstyrene, [R]D
) -58) of (R)-(-)-ar-turmerone is presented. The current
best synthesis of this compound uses a low-yielding baker’s
yeast reduction to install the asymmetric center and involves
six steps (11% yield, [R]D ) +62).4b Bisacumol, which
carries an additional chiral center at C9, can also be prepared
by this route from ar-tumerone by using already established
reduction protocols.13 Synthesis of R-curcumene starts with
Figure 1. Prototypical natural products with chiral benzyl centers.
with the synthesis of curcumene, this molecule has evolved
as a test target for demonstrating new asymmetric processes.
The nonenzymatic methods4 employed include stoichiometric
chirality transfer via diastereoselective synthesis starting from
a t-leucinol-derived oxazoline (8 steps, 31% yield),5 cit-
ronellal (6 steps, 28% yield),6 and (-)-phenyl methyl
sufoximine (>9 steps, ∼13% yield).7 More practical catalytic
procedures to install the asymmetric center have used
Itsuno-Corey ketone reduction (∼6 steps, 14% yield),8
Sharpless asymmetric epoxidation (8 steps, 7% yield),9 and
Ni-catalyzed cross-coupling of benzyl Grignard reagents (5
steps, 34% yield).10 Selectivity in the key step11 and ease of
synthesis vary considerably among these methods, and most
involve chromatographic separations. For example, the ee
of the final product from the cross-coupling approach is only
66%, whereas it approaches ∼100% in the t-leucine-derived
material. Arguably the “shortest (incidentally, also the most
recent) route” starts with citronellal and involves six steps
and multiple chromatographic separations to produce cur-
cumene in 28% overall yield.6 R-Curcumene (1) has been
(4) Enzymatic or microbial methods: (a) Fuganti, C.; Serra, S. Synlett
1998, 1252. (b) Fuganti, C.; Serra, S.; Dulio, A. J. Chem. Soc., Perkin Trans.
1 1999, 279.
(5) Meyers, A. I.; Stoianova, D. J. Org. Chem. 1997, 62, 5219.
(6) Hagiwara, H.; Okabe, T.; Ono, H.; Kamat, V. P.; Hoshi, T.; Suzuki,
T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 2002, 895.
(7) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003, 44,
7261.
(8) Schmalz, H.-G.; de Koning, C. B.; Bernicke, D.; Siegel, S.;
Pfletschinger, A. Angew. Chem., Int. Ed. 1999, 38, 1620.
(9) Takano, S.; Yanase, M.; Sugihara, T.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1988, 1538.
hydrovinylation of 4-methylstyrene. In the racemic series,
the hydrovinylation of 4-methylstyrene can be achieved in
(10) Tamao, K.; Hayashi, T.; Matsumoto, H.; Yamamato, H.; Kumada,
M. Tetrahedron Lett. 1979, 20, 2155.
(12) (a) RajanBabu, T. V. Chem. ReV. 2003, 103, 2845. (b) Nandi, M.;
Jin, J.; RajanBabu, T. V. J. Am. Chem. Soc. 1999, 121, 9899. (c) Park, H.;
RajanBabu, T. V. J. Am. Chem. Soc. 2002, 124, 734. (d) Zhang, A.;
RajanBabu, T. V. Org. Lett. 2004, 6, 1515. (e) For review of classical work
on hydrovinylation, see also: Jolly, P. W.; Wilke, G. In Applied Homo-
geneous Catalysis with Organometallic Compounds; Cornils, B., Herrmann,
W. A., Eds.; VCH: New York, 1996; Vol. 2, p. 1024.
(11) Since optical rotation ([R]D) was primarily used in estimating
enantioselectivities, the values reported in many of the publications are prone
to error. For example: Uhde, G.; Ohloff, G. HelV. Chim. Acta 1972, 55,
262 reports [R]D values between 34.3 and 37.7. Schmalz reports8 a specific
rotation of +31 (c 0.9, CHCl3) for material of 90% ee as determined by
HPLC. For a compilation of various values, see ref 7. In this paper we
report values based on HPLC of key intermediates, which are further
corroborated by optical rotations.
(13) Li, A.; Yue, G.; Li, Y.; Pan, X.; Yang, T.-K. Tetrahedron:
Asymmetry 2003, 14, 75.
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Org. Lett., Vol. 6, No. 18, 2004

Scheme 1. Synthesis of R-Curcumene from 4-Methylstyrene
Scheme 2. Synthesis of (-)-(R)-ar-Turmerone
nearly quantitative yield and >99% selectivity for the desired
3-arylbutene using ethylene at 1 atm and catalytic amounts
of [(allyl)NiBr]2, Ph3P, and AgOTf (eq 1).14 Chiral ligands
such as MOP derivatives (1),15,14b sugar-derived diarylphos-
phinites (2),16 and binaphthol-derived phosphoramidites (3),17
which gave high ees for other styrene derivatives, gave
unacceptably low ees for 4-alkylstyrenes, and until recently,
practical levels of asymmetric induction were not feasible
for these substrates. We recently described a series of 1-aryl-
2,5-dialkylphospholane ligands (e.g., 4) which carry a
dioxolane moiety at the ortho position of the P-aryl group
that gave outstanding selectivity for a variety of styrene der-
ivatives.18 In the event, when hydrovinylation of 4-methyl-
styrene was carried out under our new protocol, 3-(4-methyl-
phenyl)but-1-ene was obtained in greater than 99% yield.19
Gas chromatographic analysis indicate >99% conversion and
>99% selectivity for the olefin isomer shown. No trace of
products of styrene dimerization or of isomerization of the
double bond was observed (Scheme 1). The enantiomers
undergo clean separation on a chiracel-OJ column, and the
enantiomeric ratio was estimated as 93:7 (R:S), which is
consistent with optical rotation data in the literature.20
The terminal olefin in 5 is ideally suited for further
elaboration of the curcumene side-chain.21 Thus, treatment
of compound 5 with 9-BBN in THF, followed by the addition
of Pd(PPh3)4 (5 mol %), K3PO4 (1.5 equiv), 2-methyl-1-
bromopropene (2 equiv), and dioxane and stirring at 60 °C
afforded (-)-R-curcumene 6 as a colorless oil {[R]D -38 (c
2.93, CHCl3; for literature value, see ref 11} in 55% overall
yield in three steps from 4-methylstyrene (Scheme 1).
Synthesis of (R)-(-)-ar-turmerone is accomplished starting
with the 3-arylbutene 5. The olefin 5 is subjected to
hydroboration with disiamylborane in THF, followed by
oxidation with hydrogen peroxide to give alcohol 7 {[R]D
-24 (c 4.11, CHCl3)} in 84% isolated yield in two steps
(Scheme 2). Swern oxidation of alcohol 7 gives aldehyde 8
{[R]D -31 (c 3.70, CHCl3)} in 90% yield. Treatment of
aldehyde 8 with 2-methyl-1-propenylmagnesium bromide in
THF at -78 °C to get a diastereomeric mixture (at C9 )
6:5) of alcohol(s) 9 in 78% isolated yield. Swern oxidation22
of alcohol 9 gave (R)-(-)-ar-turmerone 2 {[R]D -58 (c 0.84,
CHCl3); lit.4b 62 (c 1.25, hexane)} in 44% yield.
In summary, starting with commercially available 4-
methylstyrene, shortest asymmetric syntheses of bisabolanes
(R)-(-)-R-curcumene and (R)-(-)-ar-turmerone have been
completed in 52 and 26% yields, respectively. A highly
efficient Ni-catalyzed asymmetric hydrovinylation was used
as the key step to install the benzylic asymmetric center.
Depending on the configuration of the ligand employed,
either enantiomer of the product could be produced. Further
applications of this chemistry for the synthesis of more
complex, structurally related compounds listed in Figure 1
are under investigation.
Acknowledgment. Financial assistance for this research
by U.S. National Science Foundation (CHE-0308378) and
the donors of the Petroleum Research Fund, administered
by the American Chemical Society (36617-AC1), is grate-
fully acknowledged. We thank Dr. Jian Jin for some of the
early experiments.
(14) (a) Nomura, N.; Jin, J.; Park, H.; RajanBabu, T. V. J. Am. Chem.
Soc. 1998, 120, 459. (b) RajanBabu, T. V.; Nomura, N.; Jin, J.; Nandi, M.;
Park, H.; Sun, X. J. Org. Chem. 2003, 68, 8431.
(15) Nandi, M.; Jin, J.; RajanBabu, T. V. J. Am. Chem. Soc. 1999, 121,
9899.
(16) Park, H.; RajanBabu, T. V. J. Am. Chem. Soc. 2002, 124, 734.
(17) Francio´, G.; Faraone, F.; Leitner, W. J. Am. Chem. Soc. 2002, 124,
736.
Supporting Information Available: Full experimental
details spectroscopic and chromatographic data for charac-
terization of compounds listed. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 1515.
(19) See Supporting Information for procedures and chromatographic
and spectroscopic data.
(20) See ref 11.
(21) For another multistep procedure (hydroboration, tosylation, iodide
formation, Cu-catalyzed Grignard addition) for this conversion, see ref 4b.
Repeated attempts to do the SN2-diaplacement on the tosylate of 7 with
various copper reagents failed in our hands. The Cu-catalyzed reaction of
the corresponding iodide with 2-methyl-1-propenylmagnesium bromide was
also capricious.
OL048790V
(22) Several other oxidation procedures using PCC, MnO2, CrO3/H+/
acetone, Dess-Martin reagent gave unacceptable yields.
Org. Lett., Vol. 6, No. 18, 2004
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