Benzothiazines in synthesis. Formal synthesis of erogorgiaene

Article abstract of DOI:10.1016/j.tetlet.2005.03.184

A benzothiazine, readily available in enantiomerically pure form via a completely selective, intramolecular addition of a sulfoximine-stabilized carbanion to an α,β-unsaturated ester, could be converted to a precursor to erogorgiaene in good overall yield

Full text of DOI:10.1016/j.tetlet.2005.03.184

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3847–3849
Benzothiazines in synthesis. Formal synthesis of erogorgiaene
Michael Harmata* and Xuechuan Hong
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Received 5 March 2005; revised 24 March 2005; accepted 28 March 2005
Available online 11 April 2005
Abstract—A benzothiazine, readily available in enantiomerically pure form via a completely selective, intramolecular addition of a
sulfoximine-stabilized carbanion to an a,b-unsaturated ester, could be converted to a precursor to erogorgiaene in good overall
yield.
Ó 2005 Elsevier Ltd. All rights reserved.
Introducing a stereogenic center at the benzylic position
is very important in asymmetric synthesis. A very large
number of natural and man-made structures are known
that bear such a stereogenic center.1,2 Such compounds
exhibit a diversity of biological activities including
anti-viral, analgesic, anti-inflammatory, and anti-myco-
bacterial properties.3 Their importance in medicinal
chemistry and limited availability has brought enormous
attention to their synthesis in the recent past.
sis of new anti-tubercular agents. Since its reported iso-
lation, only two syntheses of erogorgiaene have
appeared in the literature.
The first, by Hoveyda and co-workers, utilized catalytic,
asymmetric conjugate addition chemistry to install a ste-
reogenic center.5a The second, by Davies and co-work-
ers, made use of an elegant carbene insertion/Cope
rearrangement strategy to rapidly establish all of the ste-
reocenters of the natural product.5b
Me Me
Recently, we reported a completely stereoselective,
intramolecular Michael addition of sulfoximine carba-
nions to a,b-unsaturated esters as exemplified in Scheme
1.1b Based on the methodology introduced by Bolm and
Me
H
Me
CO2Me
Me
5% Pd(OAc)2, 7.5% BINAP
1.4 eq. Cs2CO3, 1.2eq. (R)-3
1: erogorgiaene
toluene, reflux, 44h
91%
Br
Erogorgiaene (1) is a new type of anti-mycobacterial
serrulatane diterpene, which was first isolated from the
sea whip, the West Indian gorgonian octocoral, Pseudo-
pterogorgia elisabethae Bayer, as part of a bioassay-
guided evaluation of extracts of this organism by
Rodriguez and co-workers in 2001.4 Biological evalua-
tion of erogorgiaene 1 showed that it can inhibit 96%
of Mycobacterium tuberculosis H37Rv growth at
12.5 ug/mL, making it of interest as a lead in the synthe-
2
CO2Me
CO2Me
2.0 eq. LDA,THF
Me
S
-78oC to -20oC
1h, 92%
O
S
Ph
O
N
N
Ph
4
5
Me
O
S
HN
Ph
Keywords: Benzothiazine; Sulfoximine; Anti-tubercular; Stereoselec-
tive; Erogorgiaene.
3
*
Corresponding author. Tel.: +1 573 882 1097; fax: +1 573 882
2754; e-mail: harmatam@missouri.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.184

3848
M. Harmata, X. Hong / Tetrahedron Letters 46 (2005) 3847–3849
co-workers sulfoximines such as 4 were prepared
(Scheme 1).6 Subsequent treatment of sulfoximine 4 with
LDA (or LiHMDS) afforded 5 as a single stereoisomer
in high yield. The reaction is stereospecific and offers a
way to establish benzylic stereocenters with high selec-
tivity. We applied this methodology to the formal total
syntheses of (+)-curcuphenol, (+)-curcumene,2b and
are pursuing the synthesis of pseudopteroxazole.7
In an effort to expand the scope of this process, we
decided to explore the synthesis of erogorgiaene, using
our methodology to construct the benzylic stereocenter
of the target. With the appearance of the total synthesis
of erogorgiaene by Hoveyda, our short-term goal be-
came a formal total synthesis. A retrosynthesis based
on this approach is shown in Scheme 2.
The aniline (8) needed for this process was prepared as
shown in Scheme 3. We began with Horner–Wads-
worth–Emmons reaction of the commercially available
ortho-bromobenzaldehyde 10. This was then coupled
with (S)-methylphenylsulfoximine 3 using the Buch-
wald–Hartwig reaction as modified by Bolm and Hilde-
brand6b to give the sulfoximine 12 in 87% yield.
Treatment of the sulfoximine 12 with LDA resulted in
the formation of benzothiazine 9 with complete diastereo-
selectivity in 83% yield. The ester functional group was
reduced with lithium aluminum hydride to afford the
alcohol 13 in 89% yield. The alcohol 13 was then treated
with Na/Hg to provide the aniline 8 in 85% yield via a
reductive desulfurization.8
Scheme 3.
nitrite and HCl followed by reaction of the resulting dia-
zonium salt with diethylamine in the presence of K2CO3
led to triazene 14 in 90% yield.9 Subsequently, triazene
14 was directly converted to the key intermediate, iodide
7, by refluxing in a sealed tube at 130 °C for 30 min.9,10
This afforded 7 in 80% yield (Scheme 4).
Several attempts to do direct iodination of the diazo-
nium ion corresponding to 8 using KI were unsuccessful.
In order to introduce iodide into the aromatic ring, we
utilized triazene chemistry. Though direct iodination
of a diazonium species might save a step, the ease with
which triazenes are formed, as well as their stability,
were attractive. Diazotization of aniline 8 with sodium
Application of iodide 7 toward the formal synthesis of
erogorgiaene required a Sonogashira coupling reaction
to construct the alkyne 15. We found that treatment of
7 with (trimethylsilyl)acetylene in the presence of PdCl2,
PPh3, CuI, and triethylamine afforded compound 15 in
90% yield (Scheme 5).11 Swern oxidation of 15 gave alde-
hyde 16 in 96% yield. Finally, aldehyde 16 was converted
to compound 6 in 98% yield via a Wittig reaction.
Hoveyda and co-workers reported that this compound
could be converted to erogorgiaene in 12 steps. The
proton and carbon NMR data as well as rotation value
for compound 6 matched those reported by Hoveyda.12
Me
Me
Ref. 5
Me
H
Me
Me
TMS
6
Me Me
In conclusion, we have accomplished a formal synthesis
of the serrulatane diterpene, erogorgiaene (1), using our
benzothiazine synthesis as a key step. The 10-step
1
Me
I
Me
Me
OH
Me
NH2 OH
8
7
CO2CH3
S
O
Ph
Me
N
9
Scheme 2. Retrosynthesis of erogorgiaene.
Scheme 4.

M. Harmata, X. Hong / Tetrahedron Letters 46 (2005) 3847–3849
3849
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Scheme 5.
process proceeds in a 27% overall yield from the com-
mercially available benzaldehyde 10. HoveydaÕs route
required six steps from commercially available starting
materials and proceeded in an overall yield of 48%. This
means that both routes had essentially the same average
yield per step, but functional group manipulations
inherently required in our approach increase the number
of steps. Thus, it would behoove us to examine methods
to develop productive sulfoximine excision chemistry.
Future studies will include an independent approach
to erogorgiaene as well as the synthesis of pseudopterox-
azole and related compounds.13
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Chem. Soc. 2004, 126, 96; (b) Davies, H. M. L.; Walji, A.
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Acknowledgments
7. Harmata, M.; Hong, X. Org. Lett. 2004, 6, 2201.
8. Harmata, M.; Kahraman, M. Synthesis 1994, 142.
9. Cary, J. M.; Moore, J. S. Org. Lett. 2002, 4, 4663.
10. Moore, J. S.; Weinstein, E. J.; Wu, Z. Tetrahedron Lett.
1991, 32, 2465.
This work was supported by the NIH (1R01-AI59000-
01A1) and the Petroleum Research Fund, sponsored
by the American Chemical Society (38288-AC1), to
whom we are grateful. We thank FMC Lithium for a
gift of various alkyllithium reagents. We thank Mr.
Nathan L. Calkins for his assistance.
11. Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.;
Knochel, P. Tetrahedron 2003, 59, 1571.
1
12. Data for 6: colorless oil; H NMR (250 MHz, CDCl3): d
7.29–7.27 (m, 1H), 7.10–7.09 (m, 2H), 5.80–5.67 (m, 1H),
5.04–4.94 (m, 2H), 3.36 (dq, J = 14.3, 6.9 Hz, 1H), 2.46–
2.38 (m, 1H), 2.27 (s, 3H), 2.29–2.23 (m, 1H), 1.23 (d,
J = 7.0 Hz, 3H), 0.25 (s, 9H); 13C NMR (62.5 MHz,
CDCl3): d 146.2, 137.2, 135.0, 133.0, 129.6, 125.5, 122.0,
115.8, 104.2, 97.7, 41.8, 36.2, 20.6, 20.0, 0.00(3);
References and notes
1. (a) Paras, N. A.; Macmillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 7894; (b) Harmata, M.; Hong, X. J. Am. Chem.
Soc. 2003, 125, 5754.
2. For recent examples and references, see the following and
others cited therein (a) RajanBabu, T. V.; Zhang, A. Org.
Lett. 2004, 6, 3159; (b) Harmata, M.; Hong, X. Tetrahe-
dron Lett. 2003, 44, 7261; (c) Hagiwara, H.; Okabe, T.;
25
½aꢀD ꢁ60.6 (c 0.66, CHCl3). Reported rotation values for
25
16: ½aꢀD ꢁ60; Ref. 5.
1
13. All new compounds were characterized by H NMR, 13C
NMR and IR spectra as well as HRMS data.