Benzothiazines in synthesis. Toward the synthesis of pseudopteroxazole

Article abstract of DOI:10.1021/ol049334+

The tricyclic benzothiazine 15 was prepared in a straightforward fashion via a completely stereoselective intramolecular Friedel-Crafts alkylation. This compound represents a potential precursor to the antitubercular agent, pseudopteroxazole. Its synthesi

Full text of DOI:10.1021/ol049334+

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2201-2203
Benzothiazines in Synthesis. Toward the
Synthesis of Pseudopteroxazole
Michael Harmata,* Xuechuan Hong, and Charles L. Barnes
Department of Chemistry, UniVersity of Missouri-Columbia,
Columbia, Missouri 65211
harmatam@missouri.edu
Received April 12, 2004
ABSTRACT
The tricyclic benzothiazine 15 was prepared in a straightforward fashion via a completely stereoselective intramolecular Friedel−Crafts alkylation.
This compound represents a potential precursor to the antitubercular agent, pseudopteroxazole. Its synthesis proceeded via a completely
selective, intramolecular addition of a sulfoximine-stabilized carbanion to an r,â-unsaturated ester, followed by functional group manipulations.
Tuberculosis is a disease whose history and present status
suggest an insidious and significant threat to human health
on a global scale. It is estimated that as many as 2 billion
people are currently infected with Mycobacterium tubercu-
losis, the microorganism responsible for the disease. Many
of these individuals will remain asymptomatic, but a
significant portion will develop tuberculosis. Eight million
new cases of TB appear annually. Three million people die
from the disease each year. This number exceeds that caused
by any other infectious agent, including the malarial parasite.1
Despite this picture, tuberculosis is generally highly
curable and it is likely that progress made on the scientific
front will not result in the realization of diminution of the
disease without effective public policy. Current treatment
for TB involves a “short course” of antibiotic treatment that
can last for 10 months or more. Treating drug resistant
variants can require two years of treatment. The cost and
general difficulty of effectively maintaining such treatment
regimens is one motivation for the continued search for new
and more effective treatments for TB.
A current problem associated with tuberculosis is the
appearance of multidrug resistant variants. Up to 50 million
people are infected with resistant forms of M. tuberculosis.
This problem is exacerbated by the presence of the HIV
pandemic. Individuals with HIV are significantly more
susceptible to TB infection than the general population. Other
factors associated with a compromised immune system as
well as public health factors, including crowding, drug use,
poor nutrition, and even aging, create increased risks for
contracting the disease. This can occur either through new
infection or transformation of latent disease into active TB.
There is therefore high general interest in the pursuit of
new chemotherapeutics for tuberculosis. As with other
diseases, leads to effective drugs can often be found among
natural products.2 One such natural product is the amphi-
lectane diterpene, pseudopteroxazole.
(1) See: (a) Mitscher, L. A.; Baker, W. Med. Res. ReV. 1998, 18, 363-
374. (b) Tuberculosis: Current Concepts and Treatment; Friedman, L. N.,
Ed.; CRC: Boca Raton, FL, 2001. (c) The Tuberculosis Antimicro-
bial Acquisition and Coordinating Facility (TAACF) website. http://
www.taacf.org/.
Pseudopteroxazole (1) was isolated from the sea whip
Pseudopterogorgia elisabethae as part of a bioassay-guided
10.1021/ol049334+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/27/2004

evaluation of extracts of this organism.3 It was assigned as
a member of the amphilectane class of diterpenes, and the
appearance of the benzoxazole functionality was highlighted
as particularly noteworthy, due to its rare occurrence in
natural products. Biological evaluation of 1 demonstrated
potent inhibitory activity (97% at 12.5 µg/mL) against M.
tuberculosis H37Rv.
Scheme 2
Recent synthetic studies by Corey and co-workers have
established that the original structure assigned to 1 is
incorrect.4 The originally assigned structure had the incorrect
configuration at C-7. It is the structure proposed by Corey
that is shown in 1. Recently, Corey and co-workers con-
firmed their assignment through the total synthesis of 1.5
We considered pseudopteroxazole to be a target particu-
larly suited to methodology we had developed involving the
stereoselective, intramolecular addition of sulfoximine car-
banions to R,â-unsaturated esters.6 In this Letter, we report
on our progress toward pseudopteroxazole and present a very
highly selective intramolecular Friedel-Crafts alkylation
reaction.
benzothiazine formation to protonation of the intermediate
enolate on its less-hindered face.9 As shown in 6, models
suggest that the enolate intermediate will adopt a conforma-
tion in which one face of the enolate is significantly more
congested than the other. This model explains the stereo-
chemistry of the major product of the reaction. Unfortunately,
5 has the wrong stereochemistry at the methyl-bearing
carbon, at least with respect to a projected pseudopteroxazole
synthesis. We nevertheless pushed this material forward in
order to evaluate the viability of subsequent steps.
We began our study with the ester 2,7 whose coupling with
sulfoximine 3 proceeded uneventfully (Scheme 1) to afford
We therefore addressed this problem through reduction,
oxidation, and epimerization. Thus, reduction and a “long”
Swern oxidation of 5 afforded aldehydes 10 and 11 in a 1.6:1
ratio (Scheme 3). We simply allowed the basic reaction
mixture to stir after the oxidation was complete to effect
epimerization. Without separation, these compounds were
treated with the Wittig reagent derived from 12 to give 13
and 14 in 52 and 33% yields, respectively, as single
stereoisomers. These compounds were separable. Each was
treated individually with methanesulfonic acid.5 The results
are intriguing. Diene 13 afforded 15 as a single diastereomer
in 88% yield. The structure of this compound was confirmed
by X-ray analysis. When 14 was treated under the same
reaction conditions, 16 was formed in 81% yield as a 3.6:1
ratio of diastereomers.
Scheme 1
This last result is very significant. Related cyclizations
reported in the literature are often not selective or selective
in the opposite stereochemical sense.4,5,9,10 One exception to
this generalization was reported by Corey and co-workers,
who demonstrated a stereochemical divergence in the reac-
tion of 17a and 17b with methanesulfonic acid.10d While
compound 17a afforded 20 and 21 with a diastereoselectivity
of 25:1, 17b afforded the corresponding compounds in a ratio
of 1:8.
This result was rationalized on the basis of the different
directing effects of the substituents on the aromatic ring of
4.8 Interestingly, we had reported that ester 7 reacted with
sulfoximine 3 to afford both sulfoximine and benzothiazine
products 8 and 9 under our standard coupling conditions
(Scheme 2).6 Apparently, the presence of the methyl group
on 2 was sufficient to prevent benzothiazine formation.
Treatment of 4 with LDA followed by protic quench afforded
the benzothiazine 5 as a 10:1 mixture of diastereomers in
88% yield. We attribute the selectivity observed in the
(4) Johnson, T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 123, 4475-
4479.
(5) Davidson, J. P.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 13486-
13489.
(6) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754-5756.
(7) See Supporting Information.
(8) (a) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419-
2422. (b) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731-
5734.
(2) Newton S. M.; Lau, C.; Wright, C. W. Phytother. Res. 2000, 14,
303-322.
(3) Rodr´ıguez, A. D.; Ram´ırez, C.; Rodr´ıguez, I. I.; Gonza´lez, E. Org.
Lett. 1999, 1, 527-530.
(9) A very similar transition state model has been proposed to rationalize
the stereochemical outcome of the reaction of a related enolate. See: Chow,
R.; Kocienski, P. J.; Kuhl, A.; LeBrazidec, J.-Y.; Muir, K.; Fish, P. J. Chem.
Soc., Perkin Trans. 1 2001, 2344-2355.
2202
Org. Lett., Vol. 6, No. 13, 2004

Scheme 3
Scheme 4
In summary, we have developed a succinct route to a
potential precursor to pseudopteroxazole, including a
completely stereoselective intramolecular Friedel-Crafts
allylation. Tasks at hand include the development of a better
route to 10, firmly establishing the basis for selectivity in
the formation of 15 and converting 15 to pseudopteroxazole.
Progress in these areas will be reported in due course.
17a and 17b. In the case of 17a, the benzyloxy group served
to direct the cyclization, and minimization of untoward steric
interactions favored an approach of the allylic cation to the
benzene ring as illustrated in 18. In the case of 17b, the
-OTBS groups served to direct the regiochemistry of allylic
cation attack as shown in 19.
Acknowledgment. This work was funded by the Petro-
leum Research Fund, administered by the American Chemi-
cal Society, to whom we are grateful. Some of the lithium
reagents used in this work were a gift from FMC Lithium.
Supporting Information Available: X-ray structure data
for 15 and the alcohol derived from 5 and detailed experi-
1
mental procedures, copies of H and 13C NMR, and other
characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL049334+
Applying these and related concepts to 13 and assuming
the methoxy group is a better directing group than the
sulfoximine group, we can formulate two possible approaches
of the allylic cation to the benzene ring, as shown in 22 and
23. The former suffers from steric interactions between the
allylic cation and the sulfoximine phenyl substituent. The
latter approach should thus be preferred, and this in fact leads
to 15.
(10) (a) Harrowven, M. C.; Tyte, M. J. Tetrahedron Lett. 2004, 45, 2089-
2091. (b) Kocienski, P. J.; Pontiroli, A.; Qun, L. J. Chem. Soc., Perkin
Trans. 1 2001, 2356-2366. (c) Lazerwith, S. E.; Johnson, T. W.; Corey,
E. J. Org. Lett. 2000, 2, 2389-2392. (d) Corey, E. J.; Lazerwith, S. E. J.
Am. Chem. Soc. 1998, 120, 12777-12782. (e) LeBrazidec, J.; Kocienski,
P. J.; C., Joseph D.; Muir, K. W. J. Chem. Soc., Perkin Trans. 1 1998,
2475-2478. (f) Majdalani, A., Schmalz, H. Synlett 1997, 1303-1305. (g)
Gill, S.; Kocienski, P.; Kohler, A.; Pontiroli, A.; Qun, L. J. Chem. Soc.,
Chem. Commun.1996, 1743-1744.
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