Benzothiazines in synthesis. A formal total synthesis of pseudopteroxazole

Article abstract of DOI:10.1021/jo9009112

(Chemical Equation Presented) A formal total synthesis of the antitubercular natural product was accomplished. This work was undertaken to address certain stereochemical problems in our initial synthesis. By using an ester group as a surrogate for a methy

Full text of DOI:10.1021/jo9009112

pubs.acs.org/joc
Benzothiazines in Synthesis. A Formal Total Synthesis of
Pseudopteroxazole
Michael Harmata,* Zhengxin Cai, and Yugang Chen
Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211
harmatam@missouri.edu
Received May 1, 2009
A formal total synthesis of the antitubercular natural product was accomplished. This work was
undertaken to address certain stereochemical problems in our initial synthesis. By using an ester
group as a surrogate for a methyl group, we were able to intercept a key intermediate in our first
synthesis with better selectivity and greater convergence than had previously been the case.
Introduction
natural products with antitubercular properties have been
identified.2
The problem of tuberculosis has accompanied mankind
for millennia.1 At present, approximately one-third of the
world’s population is infected with the causative organism,
Mycobacterium tuberculosis. Of this group, 5-10% proceed
to active disease. Over two million people a year die world-
wide due to tuberculosis.
Though still a disease that can be treated, tuberculosis often
requires chemotherapy on the order of months or years to
achieve a cure. This long course often results in noncompliance
on the part of patients and this has led to the emergence of
moderately drug resistant (MDR) and extensively drug resis-
tant (XDR) strains of the disease. The latter are resistant to the
typical first line of drugs used for the treatment of TB as well as
at least two drugs comprising the second line of defense.
The persistence of this disease and in particular the rise of
exceptionally resistant strains of the TB microorganism have
made the discovery of new chemotherapies a priority. As
is often the case, natural products can provide lead com-
pounds for the development of new drugs, and a number of
One such compound is pseudopteroxazole (1), which was
isolated from the sea whip Pseudopterogorgia elisabethae
by Rodriguez and co-workers.3 This compound displayed
significant activity against M. tuberculosis H37Rv and thus is
a potential lead for the development of antitubercular
agents. Corey corrected the stereochemical assignment ori-
ginally given to 1 and also produced the first total synthesis
of the compound.4 We published a synthesis of 1 as well,5
further demonstrating the synthetic utility of enantiomeri-
cally pure benzothiazines in synthesis.
However, our first synthesis was not without some pro-
blems. A key step involved the intramolecular conjugate
addition of the sulfoximine carbanion derived from 2 to
(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) Handbook of tuberculosis; molecular biology
and biochemistry; Kaufmann, S. H. E., Rubin, E., Eds.; Wiley-VCH:
Weinheim, Germany, 2008. (d) Handbook of tuberculosis; immunology
and cell biology; Kaufmann, S. H. E., Britton, W. J., Eds.;
Wiley-VCH: Weinheim, Germany, 2008. (e) Handbook of tuberculosis;
clinics, diagnostics, therapy and epidemiology; Kaufmann, S. H. E.,
van Helden, P., Eds.; Wiley-VCH: Weinheim, Germany, 2008.
(3) Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Gonzalez, E. Org.
Lett. 1999, 1, 527–530.
(4) (a) Johnson, T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 123, 4475–
4479. (b) Davidson, J. P.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 13486–
13489.
(2) (a) Gutierrez-Lugo, M.-T.; Bewley, C. A. J. Med. Chem. 2008, 51,
2606–2612. (b) Copp, B. R.; Pearce, A. N. Nat. Prod. Rep. 2007, 24, 278–297.
(5) (a) Harmata, M.; Hong, X. Org. Lett. 2004, 6, 2201–2203. (b)
Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3583–3583.
DOI: 10.1021/jo9009112
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Published on Web 06/18/2009
J. Org. Chem. 2009, 74, 5559–5561 5559
2009 American Chemical Society

Harmata et al.
JOCArticle
SCHEME 1. Summary of Our First Synthesis of Pseudopter-
oxazole
SCHEME 2. Preparation of Phosphonate 8
SCHEME 3. Formal Synthesis of Pseudopteroxazole
afford 3 (Scheme 1). This proceeded in high yield and
diastereoselectivity. Unfortunately, the diastereoselection
was in a direction opposite to that desired and ultimately
the stereochemistry at the methyl-bearing carbon atom, the
one that would be carbon 3 of pseudopteroxazole, had to be
corrected. Once this was done, the synthesis of diene 4
proved to be straightforward, as did the conversion of the
latter to pseudopteroxazole. We thus set out to prepare 4 via
a modified route, and this report details the results of our
efforts.
Results and Discussion
Our plan was to bring in all of the elements needed to
construct 4 at a very early stage of the synthesis and use the
inherent diastereoselectivity of the benzothiazine formation
to our advantage. First, we made phosphonate 8 from
commercially available 3-methyl-2-butenal 5 and trimethyl
phosphonoacetate 6 in 4 steps (Scheme 2).6 This reagent
was then coupled with 2-bromo-3-methoxy-5-methylbenzal-
dehyde 97 to give 10 with high stereoselectivity, using Ba-
(OH)2 as base (Scheme 3).8
A key step was the Buchwald-Hartwig coupling of triene
10 with sulfoximine (R)-11.9 We were pleased to find that
the coupling product 12 could be obtained in 81% yield,
with minimal complications due to Heck reactions, a side
reaction that we feared might dash our hopes of using this
strategy.10
The next critical step was the intramolecular Michael
addition.11 Treatment of 12 with LiHMDS followed by
quenching with HCl in cold methanol afforded 13 with
a diastereoselectivity that was as high as 10:1.12 The stereo-
chemical outcome of the reaction could be rationalized on
the basis of a model we presented earlier4 and, in fact, was the
same stereochemical outcome observed for the formation of
3. However, the key difference is that we planned to convert
the ester group in 13 to a methyl group en route to 4.
Thus treatment of 13 with DIBAL afforded the corre-
sponding alcohol 14 in 88% yield. Mesylation afforded the
corresponding mesylate 15. Attempted reduction of this
mesylate with various reducing agents did not proceed very
successfully. After numerous attempts at reduction of this
and related sulfonates, we ultimately used a procedure that
presumably resulted in the in situ formation of the corre-
sponding iodide with concomitant reduction. Thus, treat-
ment of 15 with excess lithium iodide and excess lithium
(6) Minami, T.; Tokumasu, S.; Mimasu, R.; Hirao, I. Chem. Lett. 1985,
1099–1102.
(7) Koyama, H.; Kamikawa, T. J. Chem. Soc., Perkin Trans. 1 1998, 1,
203-209.
(8) Nicolaou, K. C.; Nold, A. L.; Milburn, R. R.; Schindler, C. S.; Cole,
K. P.; Yamaguchi, J. J. Am. Chem. Soc. 2007, 129, 1760–1780.
(9) (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.
(c) Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000, 65, 169–175.
(10) Only trace amounts of a compound assigned as an intramolecular
Heck reaction product were isolated whenever this reaction was performed.
This product 16 was characterized and details on it are reported in the
Supporting Information. The enantiopurity of 12 is considered to be the same
as that of (R)-11, which was established by both optical rotation and HPLC
to be 100%, within experimental error.
(11) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754–5756.
(12) Diastereomeric ratios were determined based on proton NMR
analysis of crude reaction mixtures. The diastereoselectivity varied from 7
to 10:1. The minor isomer was not characterized but could be separated from
the desired diastereomer by column chromatography.
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triethylborohydride at -30 °C for 26 h resulted in the
formation of 4 in 79% yield, thereby completing a formal
total synthesis of 1.
was washed with 3 Â 50 mL CH2Cl2, and concentrated in vacuo.
After flash chromatography (25% ethyl acetate in hexanes), 491 mg
(81%) of 12 was obtained as a pale yellow semisolid. IR (film) 3064,
2974, 2925, 1703, 1560, 1454, 1336, 1270, 1233, 1094, 735 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 8.00 (dd, 2H, J=1.5, 10.0 Hz),
7.77(s,1H),7.56-7.50 (m, 3H), 7.20 (dd, 1H, J=11.0, 15.5 Hz), 6.80
(s, 1H), 6.60 (s, 1H), 6.40 (d, 1H, J=15.5 Hz), 5.87 (d, 1H, J=11.0
Hz), 5.21 (m, 1H, J = 6.0 Hz), 3.59 (s, 3H), 3.10 (s, 3H), 2.28 (s, 3H),
1.81 (s, 6H), 1.36 (s, 3H), 1.34 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 167.6, 152.2, 142.4, 137.2, 136.9, 132.3, 132.0, 131.6,
130.7, 130.2, 129.8, 128.9, 127.5, 126.6, 123.4, 113.1, 67.8, 55.6, 46.0,
26.2, 22.0, 21.2, 18.6; HRMS calcd for C27H33NO4SNa [M+Na]+
490.2022, found 490.2016; [R]2D5 77.975 (c 0.79, CHCl3).
Conclusion
This approach to 4 required 6 steps from aldehyde 9
(conversion of 12 to 13 shows the workup as step 2). The
old procedure (Scheme 1) required 7 steps from the same
aldehyde, but suffered from the need to separate a significant
amount of undesired stereoisomer en route to the synthesis of
4. Further, in this new approach, we have demonstrated that
the palladium-catalyzed coupling of a sulfoximine to a highly
unsaturated compound is possible in high yield, without loss
of material due to other palladium-catalyzed processes. The
reaction time for the coupling is significantly shorter than
what has been typically reported and only a slight excess of 11
was needed to produce a very high yield of 12.
Isopropyl
(2S,3E)-6-Methyl-2-[(2R,4R)-2-methyl-2-oxido-
3,4-dihydro-2λ4,1-benzothiazin-4-yl]hepta-3,5-dienoate (13). A
100 mL round-bottomed flask was charged with bromo ester
(1.58 g, 3.38 mmol) in 40 mL of THF. LiHMDS (6 mL, 1 M in
toluene, 6 mmol) was added dropwise to the mixture at -78 °C.
After 10 min at -78 °C, the reaction was quenched with 1 N HCl
in methanol at -78 °C, then poured into water, extracted with
3 Â 20 mL of CH2Cl2, dried with MgSO4, and concentrated in
vacuo. After flash chromatography (30% ethyl acetate in hex-
anes), 1.28 g (81%) of 13 was obtained as the main isomer.
This work further establishes that benzothiazines are
easily prepared templates that are useful for total synthesis.
Further studies of their synthesis and applications will be
reported in due course.
1
IR (film) 2970, 2921, 2868, 1720, 1462, 1245, 1102 cm-1; H
NMR (CDCl3, 500 MHz) δ 8.10-8.12 (m, 2H), 7.62-7.66 (m,
1H), 7.54-7.57 (m, 2H), 6.68 (s, 1H), 6.64 (s, 1H), 6.26 (dd, 1H,
J = 11.0, 15.0 Hz), 5.77 (d, 1H, J = 11.0 Hz), 5.49 (dd, 1H, J =
7.5, 15.0 Hz), 4.89 (septet, 1H, J = 6.0 Hz), 3.96 (t, 1H, J =
7.0 Hz), 3.88 (s, 3H), 3.60-3.64 (m, 1H), 3.52-3.56 (m, 2H),
2.30 (s, 3H), 1.75 (s, 3H), 1.69 (s, 3H), 1.15 (d, 3H, J = 6.5 Hz),
1.05 (d, 3H, J = 6.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 172.3,
152.6, 139.4, 136.8, 133.8, 132.1, 131.1, 129.9, 129.5, 129.4,
124.9, 124.9, 124.3, 119.4, 111.9, 68.4, 56.2, 51.1, 49.2, 38.4,
26.2, 21.8, 21.6, 18.6; HRMS calcd for C27H33NO4SNa [M+
Na]+ 490.2022, found 490.2012; [R]D25 -60.48 (c 1.66, CHCl3).
(2R,4R)-4-[(1S,2E)-1,5-Dimethyl-2,4-hexadienyl]-3,4-dihydro-8-
methoxy-6-methyl-2-phenyl-2γ4-2,1-benzothiazine 2-Oxide (4). To
a solution of mesylate 15 (71 mg, 0.15 mmol) and LiI (201 mg,
1.5 mmol) in 7.5 mL of dry THF at -30 °C was added 1.5 mL of
1 M LiBHEt3 in THF slowly. After the reaction was kept at -30 °C
for 26 h, it was diluted with 15 mL of DCM and quenched with
10 mL of 10% NaOH and 5 mL of 30% H2O2. After the solution
was stirred for 30 min at rt, it was washed with 10 mL of saturated
Na2S2O3 solution, followed by 30 mL of brine. After drying with
Na2SO4, it was concentrated under vacuum. Chromatography
(20% ethyl acetate in hexanes) afforded 45 mg (79%) of 4 as a
colorless oil. The NMR data matched the published data.4
Experimental Section
(2E,3E)-Isopropyl 2-(2-Bromo-3-methoxy-5-methylbenzyli-
dene)-6-methylhepta-3,5-dienoate (10). To a solution of bromo
aldehyde 9 (2.22 g, 9.7 mmol) and phosphonoacetate 8 (3.43 g,
11.8 mmol) in 120 mL of THF and 6 mL of H2O was added Ba-
(OH)2 (7.35 g, 43 mmol) in portions with vigorous stirring at
40 °C. After 10 min, the reaction was allowed to reach rt and was
diluted with 200 mL of CH2Cl2. The solution was washed with
1Â100 mL of saturated NaHCO3 and 1Â100 mL of brine and
then dried with MgSO4, filtered through Celite, and concen-
trated in vacuo. After flash chromatography (1% TEA, 10%
ethyl acetate in hexane), 3.2 g (84%) of the brom oester
was obtained as a viscous oil. IR (neat) 2974, 2930, 1714,
1
1234, 1096 cm-1; H NMR (CDCl3, 300 MHz) δ 7.33(s, 1H),
7.16 (dd, 1H, J=11.0, 15.6), 6.79 (s, 1H), 6.67 (s, 1H), 6.22 (d,
1H, J=15.6 Hz), 5.82 (d, 1H, J=11.0 Hz), 5.22 (septet, 1H,
d=6.0 Hz), 3.90 (s, 3H), 2.33 (s, 3H), 1.79 (s, 6H), 1.38 (s, 3H),
1.36 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 167.0, 155.8, 138.3,
137.6, 137.4, 135.8, 132.2, 131.8, 126.2, 123.9, 122.2, 112.2,
110.1, 68.4, 56.2, 26.2, 21.8, 21.4, 18.6; HRMS calcd for
C20H25O3BrNa [M+Na]+ 415.0879, found 415.0875.
Isopropyl (2E,3E)-2-(2-{[R-methylphenyl(oxido)-λ6-sulfanyli-
dene]amino}benzylidene)-6-methylhepta-3,5-dienoate(12). A 100 mL
round-bottomed flask with condenser was charged with palladium
acetate (15 mg, 0.065 mmol) and rac-BINAP (60 mg, 0.1 mmol) in
35 mL of toluene. The mixture was stirred for 15 min at rt. The
bromoester 10 (510 mg, 0.5 mmol) and (R)-11 (220 mg, 0.77 mmol)
in 5 mL of toluene were added, followed by addition of Cs2CO3
(1.17 g, 2 mmol). The solution was refluxed at 110 °C for 12 h, then
diluted with 40 mL of CH2Cl2, filtered through Celite, which
Acknowledgment. This work was supported by the NIH
(1R01-AI59000-01A1) to whom we are grateful.
Supporting Information Available: Characterization data
for compound 16 and copies of proton and carbon spectra for
previously unreported compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 15, 2009 5561