Benzothiazines in synthesis. Formal syntheses of (+)-curcumene and (+)-curcuphenol

Article abstract of DOI:10.1016/S0040-4039(03)01882-3

A benzothiazine readily available in enantiomerically pure form via a stereoselective, intramolecular Michael addition reaction could be converted to a precursor to (+)-curcuphenol and to (+)-curcumene.

Full text of DOI:10.1016/S0040-4039(03)01882-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7261–7264
Benzothiazines in synthesis. Formal syntheses of (+)-curcumene
and (+)-curcuphenol
Michael Harmata,* Xuechuan Hong and Charles L. Barnes
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Received 11 July 2003; revised 29 July 2003; accepted 4 August 2003
Abstract—A benzothiazine readily available in enantiomerically pure form via a stereoselective, intramolecular Michael addition
reaction could be converted to a precursor to (+)-curcuphenol and to (+)-curcumene.
© 2003 Elsevier Ltd. All rights reserved.
We recently reported the completely stereoselective,
intramolecular Michael addition of sulfoximine carban-
ions to a,b-unsaturated esters as exemplified in Scheme
1.1 Preparation of sulfoximine 3 was conducted via the
methodology introduced by Bolm and co-workers.2
Subsequent treatment of sulfoximine 3 with LDA
afforded 4 as a single stereoisomer in high yield. The
reaction is stereospecific, and offers a way of establish-
ing benzylic stereocenters with high fidelity and as such
should be applicable to many synthetic problems.
the rhizomes of Curcuma aromatica Salisb.4 (+)-Cur-
cuphenol was isolated from a marine sponge (Epipolasis
and Didiscus flavus) and is an inhibitor of gastric
H,K-ATPase and has antitumor and antifungal acitiv-
ity.5,6 Interestingly, its enantiomer, which has been iso-
lated from the gorgonian coral Pseduopterogorgia rigida
and the plant Lasianthaea podocephata, exhibits
antibacterial activity against Staphylococcus aureus.6,7
Our initial efforts in developing applications for the
chemistry have focused on relatively simple bisabolane
sesquiterpenes, represented by (+)-curcumene (5) and
(+)-curcuphenol (6). These compounds, and a large
number of other terpenoids of related structure have
often been targeted as a means of demonstrating a
particular methodology.3 Curcumene was isolated from
Our approach to these compounds began with the
commercially available aniline 7. This was converted
via a known procedure to the ortho-bromobenzalde-
hyde 88 (Scheme 2). The reaction of 8 with the anion of
the phosphonate 9 afforded the ester 10 in 82% yield.
Use of the corresponding Wittig reagent gave 10 in a
72% yield. This ester was then coupled with (S)-2 under
our standard reaction conditions1 for this coupling to
afford the sulfoximine 11 in excellent yield. Ring clo-
sure to afford the corresponding benzothiazine resulted
in the formation of 12 as a single stereoisomer. The
structure of 11 and 12 were unequivocally established
by X-ray analysis.9 Treatment of 12 with lithium alu-
minium hydride smoothly led to benzothiazine 13, the
precursor to both 5 and 6.
Scheme 1.
The conversion of 13 to a known precursor to (+)-cur-
cumene began with the reductive desulfurization of 13
with sodium/amalgam to afford 14 in 85% yield10
* Corresponding author. Tel.: +1-573-882-1097; fax: +1-573-882-2754;
e-mail: harmatam@missouri.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01882-3

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M. Harmata et al. / Tetrahedron Letters 44 (2003) 7261–7264
Scheme 2.
Scheme 3.
inating anilines.14 In our particular case, the product we
isolated was one of formal hydrolysis of the diazonium
ion derived from the aniline. This compound was
obtained in 50% yield. No effort has been made to
determine the origin of the phenolic hydroxy group in
22. However, it should be noted that we were able to
perform reductive deaminations on simple anilines
using the same procedure without observing the forma-
tion of phenols.15 Removal of the THP group in 22
afforded 23, which has been converted to curcuphe-
(Scheme 3). Reductive deamination using a protocol
introduced by Corey and co-workers11 afforded the
alcohol 15, but only in 36% yield. We hoped that
protection of the hydroxy group in 13 would improve
the yield in this reaction. Thus, 13 was reacted with
sodium hydride and benzyl bromide to give 16 in good
yield. Desulfurization afforded the aniline 17 in 92%
yield. Reductive deamination of 17 afforded the ether
18 in 61% yield. Finally, deprotection of the hydroxy
group afforded 15. Spectral and rotation data for 15
corresponded to that reported in the literature.12
Compound 15 has been converted to curcumene via a
sequence shown in Scheme 4.3j Bromination afforded
the bromide 19 in 96% yield. Displacement of the
bromide with the appropriate organolithium led to
(+)-curcumene in excellent yield.13
The formal synthesis of (+)-cucurphenol involved a
similar approach to that of (+)-curcumene and was the
result of serendipity. Thus, the hydroxy group of ben-
zothiazine 13 was protected as a THP ether to give 20
in nearly quantitative yield (Scheme 5). Desulfurization
then afforded the aniline 21 in 85% yield. This aniline
was then treated with isoamyl nitrite in DMF and
heated for 10 minutes. This protocol was published by
Doyle and co-workers as a means of reductively deam-
Scheme 4.

M. Harmata et al. / Tetrahedron Letters 44 (2003) 7261–7264
7263
Scheme 5.
nol.16 To further verify the stereochemistry of 23, it was
converted to the corresponding methyl ether 24, also a
known compound.17
3. For asymmetric syntheses of curcumene and curcuphe-
nol, see: (a) Hagiwara, H.; Okabe, T.; Ono, H.; Kamat,
V. P.; Hoshi, T.; Suzuki, T.; Ando, M. J. Chem. Soc.,
Perkin Trans. 1 2002, 7, 895; (b) Ono, M.; Ogura, Y.;
Hatogai, K.; Akita, H. Chem. Pharm. Bull. 2001, 49,
1581; (c) Kimachi, T.; Takemoto, Y. J. Org. Chem. 2001,
66, 2700; (d) Fuganti, C.; Serra, S. J. Chem. Soc., Perkin
Trans. 1 2000, 3758; (e) Fuganti, C.; Serra, S.; Dulio, A.
J. Chem. Soc., Perkin Trans. 1 1999, 279; (f) Tanaka, K.;
Nuruzzaman, M.; Yoshida, M.; Asakawa, N.; Yang, X.;
Tsubaki, K.; Fuji, K. Chem. Pharm. Bull. 1999, 47, 1053;
(g) Schmalz, H.; Koning, C. B.; Bernicke, D.; Siegel, S.;
Pfletschinger, A. Angew. Chem., Int. Ed. 1999, 38, 1620;
(h) Sugahara, T.; Ogasawara, K. Tetrahedron: Asymmetry
1998, 9, 2215–2217; (i) Fuganti, C.; Serra, S. Synlett 1998,
1252; (j) Meyers, A. I.; Stoianova, D. J. Org. Chem. 1997,
62, 5219; (k) Chavan, S. P.; Dhondge, V. J.; Patil, S. S.;
Rao, Y. T. S. Tetrahedron: Asymmetry 1997, 8, 2517; (l)
Ono, M.; Ogura, Y.; Hatogai, K.; Akita, H. Tetrahedron:
Asymmetry 1995, 6, 1829–1832; (m) Davisson, V. J.;
Poulter, C. D. J. Am. Chem. Soc. 1993, 115, 1245; (n)
Takano, S.; Yanase, M.; Sugihara, T.; Ogasawara, K. J.
Chem. Soc. Commun. 1988, 1538; (o) Asaoka, M.; Shima,
K.; Fuji, N.; Takei, H. Tetrahedron 1988, 4757–4766; (p)
Asaoka, M.; Shima, K.; Takei, H. Tetrahedron Lett.
1987, 5669; (q) Honda, Y.; Sasaki, M.; Tsuchihashi, G.
Chem. Lett. 1985, 1153; (r) Ghisalberti, E. L.; Jefferies, P.
R.; Stuart, A. D. Aust. J. Chem. 1979, 32, 1627.
Finally, several attempts were made to convert 14 to 23.
In the best case, diazotization of 14 followed by treat-
ment of the resulting diazonium ion with copper
nitrate/copper oxide according to a procedure intro-
duced by Boger and co-workers afforded 23 in 37%
yield (Eq. (1)).18
(1)
In summary, we have completed formal syntheses of
(+)-curcumene and (+)-curcuphenol. These applications
help to verify stereochemical assignments in the forma-
tion of benzothiazines via intramolecular Michael addi-
tions, which have heretofore been based largely on
analogy. Further, this work demonstrates that sulfox-
imines can serve as ammonia equivalents in the Buch-
wald–Hartwig reaction. The work also lays the
foundation for more complex applications. Details of
these studies will be the focus of future reports.
4. (a) Simonsen, S. J. The Terpenes; Cambridge University
Press, 1952; Vol. III, pp. 18, 202; (b) Honwad, V. K.;
Rao, A. S. Tetrahedron 1965, 21, 2593.
Acknowledgements
5. (a) Fusetani, N.; Sugano, M.; Matsunaga, S.; Hashimoto,
K. Experientia 1987, 43, 1234; (b) Wright, A. E.;
Pomponi, S. A.; McConnell, O. J.; Kohmoto, S.;
McCarthy, P. J. J. Nat. Prod. 1987, 50, 976.
This work was supported by the Petroleum Research
Fund, administered by the American Chemical Society,
to whom we are grateful.
6. McEnroe, F. J.; Fenical, W. Tetrahedron 1978, 34, 1661.
7. Bohlmann, F.; Lonitz, M. Chem. Ber. 1978, 111, 843.
8. Jolad, S. D.; Rajagopal, S. Org. Synth. 1966, 46, 13.
9. Crystallographic data (excluding structure factors) for the
structures in this paper (11 and 12), have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 215011 and
215012. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cam-
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M. Harmata et al. / Tetrahedron Letters 44 (2003) 7261–7264
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[h]2D5=−46.2°; Ref. 3q; (i) [h]2D5=+43.5°; Ref. 3i; (j)
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+33°; Honwad, V. K.; Rao, A. S. Tetrahedron 1964, 20,
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[h]2D5=+45.1°; Damodaran, N. P.; Dev, S. Tetrahedron
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(b) [h]2D5=+22.80°; Ref. 3d; (c) [h]2D5=+17.8°; Ref. 3i.
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