Benzothiazines in synthesis. A total synthesis of pseudopteroxazole

Article abstract of DOI:10.1021/ol0515412

(Chemical Equation Presented) An enantioselective total synthesis of the naturally occurring antitubercular agent pseudopteroxazole is described. The synthesis is organized around the use of a stereoselective, intramolecular addition of a sulfoximine carbanion to an αβ-unsaturated ester to form an enantiomerically pure benzothiazine. Other important processes include a completely stereoselective intramolecular Friedel-Crafts alkylation and a stereoselective and regioselective hydrogenation.

Full text of DOI:10.1021/ol0515412

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3581-3583
Benzothiazines in Synthesis. A Total
Synthesis of Pseudopteroxazole
Michael Harmata* and Xuechuan Hong
Department of Chemistry, UniVersity of Missouri-Columbia,
Columbia, Missouri 65211
harmatam@missouri.edu
Received June 30, 2005
ABSTRACT
An enantioselective total synthesis of the naturally occurring antitubercular agent pseudopteroxazole is described. The synthesis is organized
around the use of a stereoselective, intramolecular addition of a sulfoximine carbanion to an -unsaturated ester to form an enantiomerically
Crafts alkylation and a stereoselective
r,â
pure benzothiazine. Other important processes include a completely stereoselective intramolecular Friedel
−
and regioselective hydrogenation.
Pseudopteroxazole (1) is an amphilectane diterpene recently
isolated from the marine soft coral Pseudopterogorgia
Scheme 1
elisabethae as part of a bioassay-guided evaluation of extracts
of this organism.1 It is one of a series of compounds isolated
from this organism that shows activity against Mycobacte-
rium tuberculosis H37Rv. The structure of 1 was initially
elucidated by extensive NMR studies and comparisons with
known amphilectane models. Subsequently, the structure was
reassigned by Corey and co-workers through the total
synthesis of 1.2,3 The promising biological activity of
pseudoteroxazole and related compounds has stimulated
considerable interest in their synthesis.2-4 However, since
its reported isolation, only one synthesis of 1 has appeared.3
Recently, we have established a novel way to introduce
benzylic stereocenters with high selectivity through a com-
pletely stereoselective, intramolecular Michael addition of
sulfoximine carbanions to R,â-unsaturated esters.5 The
benzothiazines thus formed can serve as templates around
which various functional groups and structural features can
be stereoselectively introduced. We have applied this meth-
odology to the formal total syntheses of (+)-curcuphenol,
(+)-curcumene, and erogorgiaene.6,7 We have also published
an approach to the synthesis of pseudopteroxazole that
culminated with the stereoselective synthesis of 5 (Scheme
1).8 We now wish to report that we have successfully
converted this compound to pseudopteroxazole.
(1) Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Gonzalez, E. Org.
Lett. 1999, 1, 527.
(2) Johnson, T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 123, 4475.
(3) Davidson, J. P.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 13486.
(4) Heckrodt, T. J.; Mulzer, J. Top. Curr. Chem. 2005, 244, 1.
(5) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754.
10.1021/ol0515412 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/15/2005

A retrosynthesis of pseudopteroxazole that leads to 5 is
shown in Scheme 2. Alkylation and reductive desulfurization
quently, upon treatment with diiodomethane in a sealed tube
at 80 °C for 20 h, triazene 10 was smoothly converted to
aryl iodide 11 in 75% yield.12
We then began to investigate possibilities to synthesize 7
directly from 11 by a Pd-catalyzed intramolecular Heck
coupling reaction. After a systematic literature evaluation,
we found that a catalytic system consisting of Pd(OAc)2,
tri(o-tol) phosphine, and triethylamine (TEA) would probably
lead to the desired product.13 In the event, exposure of 11 to
these reagents for 38 h at 120 °C in TEA afforded 7 in 62%
yield.14
Scheme 2
Our first attempt at the reduction of 7 consisted of
subjecting this compound to dissolving metal conditions (Li/
NH3 at -78 °C). This afforded two diastereoisomers in 77%
yield in a ratio of 1:1.15 The lack of stereoselectivity was a
problem, but we found a solution that turned out to be both
highly regio- and stereoselective.
In considering a solution, we were drawn to work by
Pfaltz, who showed that catalyst 12 was highly effective for
the enantioselective reduction of trisubstituted alkenes, with
facial selectivity commensurate with our goals.16 We thus
anticipated reduction of the styryl double bond in 7 to take
place from the top face. Further, we expected the conforma-
tion of the remaining trisubstituted double bond to be such
as to minimize 1,3-allylic strain.17 In this conformation, the
methyl group on the benzene ring blocks the face of the
olefin that should be preferred by 12 (Figure 1). This should
of 5 would give 8. Activation of the aniline nitrogen followed
by an intramolecular Heck reaction would afford 7. A
stereoselective reduction of the conjugated double bond and
installation of the oxazole ring would give 1.
Thus, the elaboration of 5 into pseudopteroxazole started
with deprotonation with LiHMDS followed by alkylation
with allyl bromide to deliver compound 9 as a single
diastereoisomer in quantitative yield.9 A reductive desulfu-
rization of 9 was then accomplished with Na/Hg to provide
aniline 8 in 92% yield (Scheme 3).10
Scheme 3
Figure 1.
inhibit reduction of this double bond and make the reaction
regioselective.
(6) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003, 44,
7261.
(7) Harmata, M.; Hong, X. Tetrahedron Lett. 2005, 46, 3847.
(8) Harmata, M.; Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201.
(9) Stereochemistry of this compound was not established rigorously but
is consistent with stereochemical outcomes for alkylations of other, related
benzothiazines.
Aniline 8 was converted to 1-aryl-3,3-diethyltriazene 10
in quantitative yield at 0-5 °C, in an Et2O/THF/CH3CN/
H2O solvent system, in the presence of K2CO3.11 Subse-
(10) Harmata, M.; Kahraman, M. Synthesis 1994, 142.
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Org. Lett., Vol. 7, No. 16, 2005

With 6 in hand, the last stage of the synthesis involved
establishing the benzoxazole ring. We followed the proce-
dures introduced by Corey in his synthesis of isomers of
pseudopteroxazole.2 First, 6 was demethylated by NaSEt in
DMF at reflux to give the phenol 13 in 87% yield.19
Subsequent nitration of 15 with concentrated HNO3 in
hexanes for 1.5 min produced the corresponding nitrophenol
14 in 84% yield. Finally, reduction of 14 with Zn dust,
followed by treatment with methyl orthoformate and a
catalytic amount of TsOH, completed the synthesis of
pseudopteroxazole (1) in 65% yield over the last two steps
(Scheme 4). The proton and carbon spectra of synthetic
pseudopteroxazole were identical in all aspects to those
reported previously by Rodriguez and Corey.1,3
Scheme 4
In conclusion, we have accomplished a total synthesis of
pseudopteroxazole that proceeds in nine steps from 5 in an
overall yield of 18%. Further studies of benzothiazine
chemistry are in progress, and results will be reported in due
course.
Acknowledgment. This work was supported by the NIH
(1R01-AI59000-01A1) and the donors of the Petroleum
Research Fund, sponsored by the American Chemical Society
(38288-AC1), to whom we are grateful. We thank Prof.
Andreas Pfaltz for the gift of catalyst 12. We thank Prof.
Abimael D. Rodriguez for the spectra of authentic pseudo-
pteroxazole. We thank Dr. Jeff Zablocki (CV Therapeutics)
for an informative conversation. We thank Mr. Nathan L.
Calkins for his assistance.
Supporting Information Available: Experimental pro-
cedures, as well as characterization and copies of proton and
carbon spectra for all previously unreported compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0515412
We conducted reductions of 7 with 3 mol % 12 in CH2-
Cl2 at 200 psi of hydrogen for 1 h and found that compound
6 was obtained with complete stereoselectivity in 90% yield,
along with only trace amounts of over-hydrogenated product
(Scheme 4).18
(13) Shi, L.; Narula, C. K.; Mak, K. T.; Kao, L.; Xu, Y.; Heck, R. F. J.
Org. Chem. 1983, 48, 3894.
(14) A 14% yield of the exocyclic alkene isomer of 7 was also produced.
This isomerized to 7 in 82% yield upon column chromatography.
(15) Cesati, R. R.; de Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc.
2004, 126, 96.
(16) Smidt, S. P.; Menges, F.; Pfaltz, A. Org. Lett. 2004, 6, 2023.
(17) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(18) Ratio was 158:1 by GC.
(19) Smith, A. B.; Schow, S. R.; Bloom, J. D.; Thompson, A. S.;
Winzenberg, K. N. J. Am. Chem. Soc. 1982, 104, 4015.
(11) Cary, J. M.; Moore, J. S.Org. Lett. 2002, 4, 4663.
(12) Moore, J. S.; Weinstein, E. J.; Wu, Z. Tetrahedron Lett. 1991, 32,
2465.
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