Toward the total synthesis of elisapterosin B: A Hg(OTf) 2-promoted diastereoselective intramolecular Friedel-Crafts alkylation reaction

Article abstract of DOI:10.1016/j.tetlet.2010.10.109

As part of an approach to the synthesis of the antitubercular agent elisapterosin B, we prepared two different chiral, non-racemic olefinic substrates and examined their diastereoselective ring closure using mercury salts. The effort yielded potential pre

Full text of DOI:10.1016/j.tetlet.2010.10.109

Tetrahedron Letters 52 (2011) 177–180
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Toward the total synthesis of elisapterosin B: a Hg(OTf)2-promoted
diastereoselective intramolecular Friedel–Crafts alkylation reaction
⇑
Weijiang Ying, Charles L. Barnes, Michael Harmata
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
As part of an approach to the synthesis of the antitubercular agent elisapterosin B, we prepared two dif-
ferent chiral, non-racemic olefinic substrates and examined their diastereoselective ring closure using
mercury salts. The effort yielded potential precursors to elisapterosin B in good yield with good to excel-
lent diastereocontrol.
Received 17 September 2010
Revised 15 October 2010
Accepted 21 October 2010
Available online 5 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Benzothiazine
Elisapterosin B
Friedel–Crafts
Mercuric acetate
Tuberculosis
1. Introduction
terpenes that also showed various degrees of activity against
tuberculosis. Another example is the amphilectane diterpene,
Tuberculosis is a major worldwide health problem, with as
many as one third of the planet’s population infected with the
causative organism. Approximately 10% of those infected proceed
to active disease and between one and two million people die
annually as a result. Current chemotherapies against TB are often
effective, but require months of treatment, during which time
compliance with dosing regimens can be compromised. This and
other factors have given rise to the emergence of multidrug resis-
tant (MDR) and extremely (extensively) drug resistant (XDR)
strains of tuberculosis.1 These require new, more aggressive thera-
pies to effect cures. There is thus a need for new chemotherapeutic
agents that are more potent and efficacious that those currently in
clinical use, both to combat resistant strains of TB and to shorten
the time necessary for treatment of all forms of TB, so that treat-
ment can be effected in a conveniently timely fashion, mitigating
problems of noncompliance with long-term chemotherapies.
There is therefore much current interest in exploring new leads
for the treatment of TB. One approach involves the discovery of
natural products that have antitubercular activity.2 For example,
elisapterosin B (1) was isolated from the gorgonian coral Pseudo-
pterogorgia elisabethae and found to have antitubercular activity,
inhibiting the growth of Mycobacterium tuberculosis H37Rv to the
pseudopteroxazole.4
Me
Me
Me
HO
O
Me
Me
H
Me
O
C
H
N
Me
Me
O
Me
1, elisapterosin B
2, pseudopteroxazole
Our interest in this area was stimulated both by the serious
nature of the medical problem and the fact that we had developed
benzothiazine chemistry that we thought applicable to the syn-
thetic challenges of compounds like 1 and 2. In fact, we reported
that our completely stereoselective approach to benzothiazines5
was a powerful approach to the synthesis of pseudopteroxazole.6
Further, we used the chemistry to synthesize related molecules
such as curcumene, curcuphenol, and erogorgiaene in enantiomerically
pure form;7,8 and used it in an approach to seco-pseudopteroxazole.9
Our approach to elisapterosin B is presently centered on a for-
mal total synthesis that intersects the Rychnovsky route10,11 to 1
at 3, which can be converted into 1 via a Lewis acid-mediated
(5+2)-cycloaddition (Scheme 1). It is anticipated that 3 can be ob-
tained from 4 and that the stereoselective formation of 4 can be
accomplished by an intramolecular Friedel–Crafts alkylation (IFCA)
extent of 79% at 1.5 l
g/mL.3 This is but one of a family of related
⇑
Corresponding author. Tel.: +1 573 882 1097; fax: +1 573 882 2754.
E-mail address: harmatam@missouri.edu (M. Harmata).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.109

178
W. Ying et al. / Tetrahedron Letters 52 (2011) 177–180
Me
HO
2. Preparation of benzothiazine 6
O
Me
Me
Me
O
C
The synthesis of benzothiazine 6 began with the known alde-
hyde 7.13 A Horner–Wadsworth–Emmons (HWE) reaction afforded
the ortho-bromocinnamate 10 in quantitative yield. A Buchwald–
Hartwig coupling reaction14 between 10 and enantiomerically
pure (+)-sulfoximine (S)-11 gave an N-arylated sulfoximine inter-
mediate, which was converted with complete diastereocontrol into
benzothiazine 6 via intramolecular Michael addition8 by using
LiHMDS as base (Scheme 2).5
MeO
Me
Me
OMe
H
Me
Me
1
3
OMe
Me
Hg(OTf)2
Me
HO
MeO
Me
Me
OMe
MeO
Me
Me
OMe
3. Preparation of 5a and 5b
OMe
5
OMe
OMe
4
CO2Et
In considering a study of the cyclization process and its diaste-
reoselectivity, we chose to synthesize both 5a and its desmethyl
analog 5b. Thus, benzothiazine 6 was reduced with LAH and desul-
furized with Na/Hg to give aniline 12 in excellent yield. Oxidation
of 12 with CAN afforded quinone 13 in 76% yield,15 which was re-
duced and methylated to give alcohol 14 in one pot. Compound 14
was oxidized to the aldehyde, which was homologated to 15. A
HWE reaction using Roush conditions16 and reduction with DIBAL
afforded 5a and 5b in good yield (Scheme 3).
MeO
Me
CHO
Br
MeO
Me
Ph
S
N
O
OMe
7
6
Scheme 1. Retrosynthesis for elisapterosin B.
CO2Et
MeO
Me
CHO
MeO
Me
(EtO)2P(O)CH2CO2Et
n-BuLi, THF
>99%
4. The mercury-catalyzed cyclization of 5a
Br
Br
In an effort to optimize the preparation of 4, particularly in the
context of stereocontrol, conditions were sought for the mercury-
catalyzed cyclization of 5a that would be optimal. The results of
the study are shown in Table 1. Using catalytic amounts of
Hg(OTf)2, the reaction was performed at different temperatures
in toluene. Beginning the process at a relatively high temperature
was better than beginning at ambient temperature followed by
warming (entries 1–4). However, when the initial temperature
was increased to 110 °C, both the conversion and diastereoselectiv-
ity decreased (entry 5). Under these reaction conditions, the
reaction was not clean. Side reactions such as double bond migra-
tion may have occurred due to presence of triflic acid produced in
the reaction. In order to suppress these side reactions, 2,6-tert-
butylpyridine was added; however, no reaction was observed even
at 110 °C (entry 6). Further, solvent effects were studied (entries
7–10). The reaction did not proceed in acetonitrile. Interestingly,
when dichloromethane was the solvent, the diastereoselectivity
was high (entry 8); and with 1,2-dichloroethane was the solvent,
the diastereoselectivity was even higher, up to 15:1 (entry 9).
However, both reactions gave low yields due to unwanted side
reactions. When Hg(SO3C4F9)2 was the catalyst, the reaction was
very poor (entry 10).
OMe
7
OMe
10
CO2Et
Me
1. Pd(OAc)2, BINAP
Cs2CO3, (S)-11
2. LHMDS
MeO
Me
Ph
S
HN
11
Ph
O
S
N
O
OMe
6
85%
Scheme 2. Synthesis of benzothiazine 6.
of 5. Finally, 5 would be available using our benzothiazine synthe-
sis, leading retrosynthetically to 6 and 7 (Scheme 1).
The intramolecular cyclization, the subject of this Letter, was
anticipated to be successful based on a report by the Nishizawa
group, who reported a mercury-catalyzed arylene cyclization (Eq.
1).12 Allylic alcohol 8 was cyclized to 9 in good yield. However,
the critical factor for us was the diastereocontrol available in such
a process.
HO
Hg(OTf)2
65%
ð1Þ
The structural assignment of the products was carried out using
proton and carbon NMR. The stereochemical assignment was
based on the fact that the alkene methylene protons of the major
8
9
CH2OH
CO2Et
HO
O
Na2S2O4, KOH
Me2SO4
MeO
Me
CAN
76%
MeO
Me
1. LAH
2. Na/Hg
82%
Me
Me
NH2
Ph
S
Me
O
OMe
13
N
83%
O
OMe
OMe
OMe
6
12
R
CH2OH
Me
HO
O
P
O
OHC
EtO
1. Swern
1.
OEt
MeO
Me
MeO
Me
EtO
MeO
Me
Me
OMe
R
Me
OMe
2. MeOCH=PPh3
(acidic work up)
84%
OMe
LiCl, DBU
2. DIBAL
OMe
OMe
5a, R = Me, 83%
5b, R = H, 79%
15
14
Scheme 3. Synthesis of alcohols 5a and 5b.

W. Ying et al. / Tetrahedron Letters 52 (2011) 177–180
179
Table 1
Mercury-catalyzed IFCA reaction of 5a
Me
Me
Me
HO
HgX2
various
MeO
MeO
Me
MeO
Me
Me
OMe
+
Me
OMe
Me
OMe
Me
conditions
OMe
5a
OMe
trans-4
OMe
cis-4
Entry
HgX2, (equiv)
Conditions
PhMe, rt, 1.5 h; 48 °C, 25 h
PhMe, rt, 20 min; 60 °C, 25 h
PhMe, 45 °C, 4 h
Yielda (%), (trans/cis)b
1
2
3
4
5
6
7
8
9
Hg(OTf)2, (0.005)
Hg(OTf)2, (0.005)
Hg(OTf)2, (0.005)
Hg(OTf)2, (0.005)
Hg(OTf)2, (0.005)
Hg(OTf)2, (0.01)c
Hg(OTf)2, (0.005)
Hg(OTf)2, (0.005)
Hg(OTf)2, (0.005)
40%,d 12.5:1
54%,d 8:1
54%, 9:1
50%, 9:1
34%, <9:1
0
PhMe, 55 °C, 4 h
PhMe, 110 °C, 10 min
PhMe, 60 °C, 30 min; 110 °C, 12 hc
MeCN, rt, 20 min; 70–80 °C, 19 h
CH2Cl2, rt, 35 min; 90 °C, 5 h
0
13%,d 12.5:1
27%,d 15:1
e
ClCH2CH2Cl, rt, 35 min; 90 °C, 5 h
PhMe, rt, 24 h; 80 °C, 15 min
10
Hg(SO3C4F9)2, (0.005)
a
b
c
Yields are for isolated products unless otherwise stated.
The diastereomeric ratio was determined by analysis of the 1H NMR spectrum of the crude reaction mixture.
2,6-Di-tert-butylpyridine was added.
Crude yield.
A complex mixture was formed.
d
e
Table 2
IFCA reaction of allylic alcohol 5b
HO
HgX2
various
MeO
MeO
Me
MeO
Me
Me
OMe
+
Me
OMe
Me
OMe
Me
conditions
OMe
5b
OMe
OMe
cis-16
trans-16
Entry
HgX2, (equiv)
Conditions
Yield %a(dr = trans/cis)b
1
2
3
4
5
6
7
8
0.02 equiv Hg(SO3C4F9)2
0.02 equiv Hg(SO3C4F9)2
0.02 equiv Hg(OTf)2
0.02 equiv Hg(OTf)2
0.005 equiv Hg(OTf)2
0.02 equiv Hg(OTf)2
0.005 equiv Hg(OTf)2
0.005 equiv Hg(OTf)2
Benzene, rt, 2d
Benzene, rt, 4d
Benzene, rt, 1 h, 70 °C, 30 min
Benzene, 70 °C, 15 min
Benzene, rt, 35 min, 80 °C, 1.5 h
PhMe, 70 °C, 15 min
trace
50%, dr >10:1
73%, dr = 6.3:1
73%, dr = 6.3:1
73%, dr = 5.9:1
72%, dr = 6.3:1
73%, dr = 5.6:1
58%, dr = 5.6:1
PhMe, 110 °C, 5 min
PhMe, 110 °C, 20 min
a
Yields are for isolated products.
b
The diastereomeric ratio was determined by analysis of the 1H NMR spectrum of the crude reaction mixture.
trans isomer were upfield from those of the minor isomer, which
was assigned as cis.17 A similar phenomenon was observed for
the isomers of cyclization products derived from 5b, and the ste-
reochemistry of the major product was established by an X-ray
analysis in that case. Furthermore, a report by Schmalz on the
cyclization of a compound related to 5a (and which did not work
with 5a) indicated that same basic pattern in chemical shifts, the
methylene protons of the trans cyclization products resonated up-
field from those of the corresponding cis isomer.18
>10:1, entries 1 and 2), but the reaction was slow. At higher tem-
peratures, the yield improved but the selectivity dropped some-
what and remained relatively constant over a temperature range
of 70–110 °C. This suggests kinetic control in the cyclization pro-
cess, as one would expect an increase in the amount of trans-16
at higher temperatures if the reaction were reversible.19 Overall,
the best reaction conditions appeared to be heating at 70 °C in ben-
zene or toluene for 15 min (Table 2, entries 3 and 6).
In order to verify the structure of 16, an attempt was made to
produce a crystalline derivative. Hydroboration of alkene 16 with
BH3ꢀTHF, followed by oxidation gave 17 in 71% isolated yield. Reac-
tion of 17 with TsCl furnished 18 in 84% isolated yield. Treatment
of 18 with thiophenol and potassium carbonate in DMSO, followed
by oxidation of intermediate sulfide with m-CPBA, furnished the
sulfone 19 in 63% yield over two steps (Scheme 4). The major iso-
mer of 19 was separable by recrystallization from MeOH/CH2Cl2.
The X-ray crystal structure20 confirmed the stereochemistry of
5. The mercury-catalyzed cyclization of 5b
The mercury-catalyzed IFCA reaction of the allylic alcohol 5b
was also investigated. The results of this reaction are tabulated in
Table 2. Using benzene as solvent and Hg(SO3C4F9)2 as catalyst,
at room temperature, the cyclized product 16 was obtained in
50% isolated yield with good selectivity (Table 2, dr = trans/cis

180
W. Ying et al. / Tetrahedron Letters 52 (2011) 177–180
HO
Supplementary data
DMAP
BH3
NaOH, H2O2
71%
MeO
Me
OMe
trans-16
Supplementary data (experimental procedures, characteriza-
Et3N, TsCl
84%
tion data; 1H and 13C spectra for new compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.10.109.
Me
17
OMe
PhO2S
MeO
TsO
1. PhSH, K2CO3
2. m-CPBA
63%
MeO
Me
OMe
References and notes
Me
OMe
Me
19
Me
1. Haydel, S. E. Pharmaceuticals 2010, 3, 2268.
OMe
2. Gutierrez-Lugo, M.-T.; Bewley, C. A. J. Med. Chem. 2008, 51, 2606.
3. Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Barnes, C. L. J. Org. Chem. 2000, 65,
1390–1398.
4. Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Gonzalez, E. Org. Lett. 1999, 1,
527–530.
OMe
18
Scheme 4. Synthesis of a crystalline derivative of trans-16.
16. It should be noted that the terminal vinyl proton trans to the
internal vinyl proton resonated at 4.62 ppm for trans-16 but ap-
peared at 4.89 ppm in cis-16. This helped in assigning the stereo-
chemistry of the isomers of 4, as mentioned above.
The basis for the trans selectivity in these cyclization presum-
ably arises from a chair like six-membered transition state in
which the substituents are disposed in a pseudoequatorial orienta-
tion. How substitution patterns on the aromatic ring and the puta-
tive allylic cation intermediate affect this selectivity must be the
subject of future studies.
5. Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754.
6. (a) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581–3583; (b) Harmata, M.; Cai,
Z.; Chen, Y. J. Org. Chem. 2009, 74, 5559.
7. Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003, 44, 7261.
8. Harmata, M.; Hong, X.; Schreiner, P. R. J. Org. Chem. 2008, 73, 1290.
9. Harmata, M.; Zheng, P. Heterocycles 2009, 77, 279.
10. Kim, A. I.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2003, 42, 1267.
11. For other syntheses of elisapterosin B, see: (a) Waizumi, N.; Stankovic, A. R.;
Rawal, V. H. J. Am. Chem. Soc. 2003, 125, 13022; (b) Jarvo, E. R.; Lawrence, B. M.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6043; (c) Boezio, A. A.; Jarvo, E.
R.; Lawrence, B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6046; (d)
Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485.
12. Namba, K.; Yamamoto, H.; Sasaki, I.; Mori, K.; Imagawa, H.; Nishizawa, M. Org.
Lett. 2008, 10, 1767.
13. Harmata, M.; Ying, W.; Barnes, C. L. Tetrahedron Lett. 2009, 50, 2326.
14. Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419.
15. Further details of this oxidation will be reported elsewhere.
16. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush,
W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
17. 4.79 and 3.94 ppm for trans-4 and 4.81 and 4.43 ppm for cis-4.
18. Werle, S.; Fey, T.; Neudörfl, J. r. M.; Schmalz, H.-G. Org. Lett. 2007, 9, 3555–
3558.
19. Molecular mechanics calculations that the most stable conformation of trans-
16 was 5.9 kcal/mol more stable that the most stable conformation of cis-16.
20. Crystallographic data (excluding structure factors) for 19 has been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 734229. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44(1223)336033; Email: deposit@ccdc.ac.uk].
6. Conclusion
In summary, using benzothiazine chemistry and Hg(OTf)2-cata-
lyzed diastereoselective IFCA, we have synthesized the potential
precursors (4 and 16) to elisapterosin B. We are now targeting
the synthesis of diene 3 to finish this total synthesis. The results
of these studies will be reported in due course.
Acknowledgment
This work was supported by the NIH (1R01-AI59000-01A1) to
whom we are grateful.