Benzothiazines in organic synthesis. An approach to floresolide B

Article abstract of DOI:10.1016/j.tetlet.2011.05.091

The intramolecular conjugate addition of a sulfoximine carbanion to an α,β-unsaturated ester results in the formation of a benzothiaine bearing a benzylic stereocenter with extremely high fidelity. We have used this methodology to complete a formal total

Full text of DOI:10.1016/j.tetlet.2011.05.091

Tetrahedron Letters 52 (2011) 4069–4071
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Tetrahedron Letters
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Benzothiazines in organic synthesis. An approach to floresolide B
⇑
Yugang Chen, Michael Harmata
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The intramolecular conjugate addition of a sulfoximine carbanion to an a,b-unsaturated ester results in
Received 2 May 2011
Revised 18 May 2011
Accepted 19 May 2011
Available online 6 June 2011
the formation of a benzothiaine bearing a benzylic stereocenter with extremely high fidelity. We have
used this methodology to complete a formal total synthesis of the antitumor agent (+)-floresolide B.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Floresolide B
Benzothiazine
Sulfoximine
Michael addition
Diastereoselectivity
In the course of our work on antitubercular agents like pseu-
dopteroxazole,1 we became interested in another compound that
appeared to be amenable to asymmetric synthesis using the meth-
odology we had developed in the context of pseudopteroxazole
and related natural products. This was the cytotoxic agent (+)-flo-
resolide B (1) (Fig. 1).
the SN2’ reaction arose out of our discovery that related Michael
additions proceeded with exquisite transfer of stereochemical
information. For example, the reactions of (E)-6 and (Z)-6 with base
produced high yields of single, diastereomerically pure cyclization
Me
Floresolide B (1) was isolated from a sea squirt (Aplidium sp.)
along with two analogues, one of which could be assigned absolute
stereochemistry by means of X-ray analysis.2 This allowed the
assignment of stereochemistry to 1. The unusual metacyclophane
structure of 1 combined with some evidence of cytotoxicity against
KB cells has attracted some interest from the synthetic community.
Dudley and co-workers reported a synthesis of the hydroquinone
lactone substructure of 1 using a ring closing metathesis. Nicolaou
and Xu reported a total synthesis of racemic 1 that involved a ring
closing metathesis3 as a key step in the formation of the macrocy-
clic lactone portion of the natural product.4
Our goal in pursuing a total synthesis of 1 was based on our
interest in discovering if we could effect the process shown in
Scheme 1: a highly stereoselective SN2’ reaction of 2 that would
set the appropriate benzylic stereochemistry and create an isopro-
penyl group in one step, affording 4. This would then be followed
by the conversion of 4 into 5. The latter has been converted into
racemic floresolide B in 10 steps.4
(S)
HO
10
Me
(E)
O
6
1
O
(Z)
1, (+)-floresolide B
Figure 1. Structure of (+)-floresolide B.
X
X
Me
Me
MOMO
LiHMDS
MOMO
Me
CH2
S
Ph
S
Ph
O
N
O
N
2
TIPSO
3
TIPSO
Me
In the event, it has not yet proved possible to effect the desired
SN2’ reaction, though various congeners of 2 have been prepared
and treated with base. We thus decided to proceed to our objective
via means that we had firmly established as successful. The idea for
Me
MOMO
MOMO
Ph
Me
S
OMOM
N
O
5
4
TIPSO
TIPSO
⇑
Corresponding author. Tel.: +1 573 882 1097; fax: +1 573 882 2754.
E-mail address: harmatam@missouri.edu (M. Harmata).
Scheme 1. Outline of initial synthetic plan.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.091

4070
Y. Chen, M. Harmata / Tetrahedron Letters 52 (2011) 4069–4071
CO2Me
with TIPSCl and a Swern oxidation gave aldehyde 11. This was fol-
lowed by a Wadsworth–Horner–Emmons homologation and the
key Buchwald–Hartwig coupling with (S)-136 and stereoselective
cyclization to give 14. The stereochemistry at the stereocenter
alpha to the ester was ignored, but prior work in our group has
shown that reasonable (ca. 10:1) diastereoselection at such centers
is possible.1b Reduction of the ester in 14 to the corresponding
alcohol and elimination of water afforded 4.7 Alkylation of the cor-
responding organolithium species and reductive desulfurization
gave 16. All attempts to convert 16 into 5 failed, a result we ulti-
mately attributed to the presence of the MOM protecting group.
To circumvent the problem, we pursued the synthesis using a
methyl protecting group on the phenolic oxygen. Thus, commer-
cially available 17 was brominated, protected, and oxidized to give
aldehyde 18 (Scheme 4). Chemistry already described led to the
aniline 22 efficiently. This compound, unlike its congener 16, could
be oxidized to quinone 23 using ceric ammonium nitrate (CAN) in
good yield.8 Reduction of the quinone with dithionite and protec-
tion of the resulting hydroquinone afforded 5 in excellent yield.
Its identity was confirmed by a comparison of 1H and 13C spectra
with those of authentic racemic material.
CO2Me
Me
2 equiv LDA, THF
-78 to -20 oC
92%
Ph
S
O
Ph
S
N
N
O
7a
(E)-6
CO2Me
MeO2C
2 equiv LDA, THF
-78 to -20 oC
92%
Me
Ph
S
O
O
N
S
N
Ph
7b
(Z)-6
Scheme 2. Stereospecific, intramolecular Michael addition.
O
MOMO
OH
HO
1. MOMCl, TEA
2. LAH
OMe
Br
3. NBS, MeCN
86%
HO
MeO
O
9
8
MOMO
In summary, we prepared an enantiomerically pure intermedi-
ate in a known racemic synthesis of floresolide B. Our route re-
quired 15 steps and proceeded in an overall yield of 11%. The
corresponding racemic material was prepared in 11 steps in
14.6% overall yield. Being able to circumvent certain transforma-
tions, such as the conversion of an ester into an alkene, would
increase the efficiency of our approach. Given the reliability of
OH
Swern
TIPSCl, TEA
CH2Cl2
Br
53% (2steps)
TIPSO
10
O
H
O
H
Me
OEt
LiHMDS, -78oC
O
MOMO
MOMO
EtO
P
CO2Et
Me
Br
EtO
Br
12
95%
TIPSO
O
MeO
CH2OH
TIPSO
O
11
1. NBS, MeCN
2. TIPSCl, TEA
3. Swern
MeO
H
Br
18
Me
CH2OH
OEt
Me
17
1. Buchwald-
Hartwig
1. LAH, THF
2. PhSO2Cl
79%
TIPSO
+
MOMO
Ph
S
HN
+
O
Ph
S
Me
CO2Et
H
N
2. LiHMDS
81%
(S)-13
O
_
LiHMDS, -78oC
MeO
TIPSO
1. Pdo, (S)-13
14
O
P
EtO
EtO
2. LiHMDS
CO2Et
Me
Br
Me
OSO2Ph
19
95%
MOMO
TIPSO
1. LAH
1. (PhSe)2, NaBH4
2. H2O2
+
N
Ph
Me
S
Me
CO2Et
O
_
66% (4 steps)
2. PhSO2Cl
3. NaSePh
4. H2O2
MeO
MeO
15
Me
TIPSO
+
S
O_
+
Ph
Ph
_
Me
S
O
Cl
N
N
Me
MOMO
Me
1. LiHMDS,
2. Na/Hg
TIPSO
21
71%
TIPSO
MOMO
20
+
Me
Ph
NH2
S
Me
N
78%
O_
MeO
Me
Cl
16
TIPSO
1. LiHMDS,
2. Na/Hg
4
TIPSO
NH2
Me
79%
22
TIPSO
Me
MOMO
Me
X
OMOM
CAN
MeCN, H2O
69%
1. NaS2O4
2. MOMCl, NaH
94%
O
5
TIPSO
Me
O
Scheme 3. First attempted synthesis of 5.
23
Me
TIPSO
products 7a and 7b (Scheme 2). This process is thus stereospecific,
and we continue to investigate the basis of the stereoselectivity
and use the reaction in synthesis.1,5
MOMO
Me
We thus set out to perform this reaction in the context of a syn-
thesis of 5. To that end, commercially available diester 8 was pro-
tected, exhaustively reduced, and regioselectively brominated with
NBS to afford 9 in 86% overall yield (Scheme 3). Mono-protection
OMOM
5
TIPSO
Scheme 4. Successful synthesis of 5.

Y. Chen, M. Harmata / Tetrahedron Letters 52 (2011) 4069–4071
4071
stereochemical information transfer that we have observed in the
References and notes
intramolecular Michael addition reaction, it seems quite reason-
able to continue to pursue this chemistry in an attempt to broaden
scope and increase efficiency in selected applications. Further re-
sults will be reported in due course.
1. (a) Harmata, M.; Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201; (b) Harmata, M.;
Hong, X. Org. Lett. 2005, 7, 3581; (c) Harmata, M.; Cai, Z.; Chen, Y. J. Org. Chem.
2009, 74, 5559.
2. Issa, H. H.; Tanaka, J.; Rachmat, R.; Higa, T. Tetrahedron Lett. 2003, 44, 1243.
3. Briggs, T. F.; Dudley, G. B. Tetrahedron Lett. 2005, 46, 7793.
4. Nicolaou, K. C.; Xu, H. Chem. Commun. 2006, 600.
Acknowledgments
5. (a) Harmata, M.; Zheng, P. Heterocycles 2009, 77, 279; (b) Harmata, M.; Rayanil,
K.-o.; Espejo, V. R.; Barnes, C. L. J. Org. Chem. 2009, 74, 3214; (c) Harmata, M.;
Hong, X.; Schreiner, P. R. J. Org. Chem. 2008, 73, 1290; (d) Harmata, M.; Ying, W.;
Hong, X.; Barnes, C. L. Synthesis 2008, 594; (e) Harmata, M.; Hong, X. Org. Lett.
2007, 9, 2701; (f) Harmata, M.; Hong, X. Tetrahedron Lett. 2005, 46, 3847; (g)
Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754.
This work was supported by the NIH (1R01-AI59000-01A1). We
thank Dr. Charles L. Barnes for the X-ray diffraction data and Dr.
K.C. Nicolaou for the spectroscopic data of compound 5.
6. (a) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909; (b) Bolm, C.;
Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731; (c) Sulfoximine 3 could be
prepared enantiomerically pure with detection limits of HPLC.
7. A procedure using o-nitrophenylselenocyanate worked, but the yield was not as
good as the procedure shown. See: Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org.
Chem. 1976, 41, 1485.
Supplementary data
Supplementary data (experimental procedures and character-
ization data) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.05.091.
8. Chen, Y.; Ying, W.; Harmata, M. Tetrahedron Lett. 2011, 52, 480.