Solid-phase synthesis of skeletally diverse benzofused sultams via palladium-catalyzed cyclization

Article abstract of DOI:10.1016/j.tetlet.2011.01.055

The solid-phase synthesis of sultams from resin-bound amino acids is described. The sulfonylation of the resin-bound primary amines afforded the requisite secondary amines, after which the intramolecular Buchwald-Hartwig-type coupling forms the C-S bond.

Full text of DOI:10.1016/j.tetlet.2011.01.055

Tetrahedron Letters 52 (2011) 1456–1458
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Tetrahedron Letters
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Solid-phase synthesis of skeletally diverse benzofused sultams
via palladium-catalyzed cyclization
Wenteng Chen a, Zhi Li a, Lili Ou a, Marc A. Giulianott b, Richard A. Houghten b, Yongping Yu a,b,
⇑
a Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
b Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The solid-phase synthesis of sultams from resin-bound amino acids is described. The sulfonylation of the
resin-bound primary amines afforded the requisite secondary amines, after which the intramolecular
Buchwald–Hartwig-type coupling forms the C–S bond. A final alkylation on the sulfonamides followed
by cleavage provided the corresponding seven-membered sultams.
Received 22 November 2010
Revised 2 January 2011
Accepted 14 January 2011
Available online 20 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Sultams (cyclic sulfonamides) are one of the most important
heterocyclic skeletons in organic chemistry. Due to their diverse
biological properties, sultams have emerged as privileged struc-
tures in drug discovery.1 Most recently, the significance of sul-
tams has reached new frontiers, due in part to the discovery
of promising bioactive sultams in areas such as, antiviral,2 anti-
cancer,3 antimicrobial,4 antimalarial,5 and antileukemic thera-
peutics.6 As part of the efforts toward utilizing solid-phase
synthesis as a powerful methodology for the synthesis of a com-
pound library for discovering biologically relevant compounds,7
herein, we report on the development of a solid-phase synthetic
strategy for the generation of seven-membered sultams. We uti-
lized a Buchwald–Hartwig-type reaction8 between a thiol group
Pd(PPh3)4 (0.2 equiv), and ( )-BINAP (0.4 equiv) in anhydrous
DMF at 100 °C for 20 h. Further treatment with K2CO3 and a
variety of electrophilic reagents, such as alkyl halides, benzyl ha-
lides, and phenylacyl bromide introduced the R3 diversity ele-
ment seen in the corresponding resin 7. The desired products
were obtained following cleavage from the resin using HF for
1.5 h at 0 °C. To illustrate the versatility of this chemistry, a li-
brary of 15 compounds (8a–8o) were prepared (Table 1). The
product was characterized by electrospray LC–MS, 1H, and 13C
NMR.12
In summary, we have demonstrated a feasible approach to facil-
itate the rapid parallel multistep synthesis of seven-membered
sultams from amino acids and short peptides on the solid-phase
via a palladium-catalyzed intramolecular cyclization reaction. This
methodology is of value for the formation of a C–S bond. Further-
more, the reaction utilizes chiral amino acids, which in turn pro-
duces chiral sultams.
and
a-haloarylsulfonamides, in part because a-haloarylsulfona-
mide represents an attractive building block for the production
of benzofused sultams.9
As outlined in Scheme 1, we began our investigation on the
solid-phase using the ‘tea-bag’ methodology.10 Starting from p-
methylbenzhydrylamine (MBHA) resin, a variety of Boc-
acids (Boc- -AA-OH) were coupled to the resin. The Boc group
was removed by 55% TFA in DCM. The resulting primary amine
was then coupled with Fmoc- -Cys(Trt)-OH to provide the dipep-
L
-amino
Acknowledgments
L
We thank the National Natural Science Foundation of China
(No. 30772652 and 90813026) and National key Tech project for
Major Creation of New Drugs (No. 2009ZX09501-010).
L
tide 3, which following a standard Fmoc deprotection afforded
the primary amine. Subsequent sulfonylation of the resin-bound
primary amine with 2-bromoarylsulfonyl chloride gave the resin-
bound sulfonamide 4. The palladium-catalyzed intramolecular
coupling of aryl halides with the thiol group proved to be an
efficient method to form the C–S bond. This C–S bond is a com-
mon functionality found in numerous pharmaceutically active
compounds.11 After optimization of the reaction conditions, we
found that the resin-bound seven-membered sultams could be
obtained efficiently by treatment of 5 with Cs2CO3 (10 equiv),
References and notes
1. Levy, L. Drugs Future 1992, 17, 451–454.
2. Di Santo, R.; Costi, R.; Artico, M.; Massa, S.; Marongiu, M. E.; Loi, A. G.; De
Montis, A.; La Colla, P. Antiviral Chem. Chemother. 1998, 9, 127–137.
3. Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr. Med. Chem. 2003,
10, 925–953.
4. Zia-ur-Rehman, M.; Choudary, J. A.; Ahmad, S.; Siddiqui, H. L. Chem. Pharm. Bull.
2006, 54, 1175–1178.
5. Valente, C.; Guedes, R. C.; Moreira, R.; Iley, J.; Gut, J.; Rosenthal, P. J. Bioorg. Med.
Chem. Lett. 2006, 16, 4115–4119.
6. (a) Silvestri, R.; Marfe, G.; Artico, M.; La Regina, G.; Lavecchia, A.; Novellino, E.;
Morgante, M.; Di Stefano, C.; Catalano, G.; Filomeni, G.; Abruzzese, E.; Ciriolo,
M. R.; Russo, M. A.; Amadori, S.; Cirilli, R.; La Torre, F.; Sinibaldi Salimei, P. J.
⇑
Corresponding author. Tel./fax: +86 571 88208452.
E-mail address: yyu@zju.edu.cn (Y. Yu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.055

W. Chen et al. / Tetrahedron Letters 52 (2011) 1456–1458
1457
Trt
S
O
O
H
N
H
N
b
a
.
NH2
HCl
Fmoc
N
H
Boc
N
H
N
H
R1
O
R1
O
3
1
2
Trt
HS
S
O
O
O
O
O
S
d
O
c
H
N
H
S
R2
N
R2
N
H
N
N
H
N
H
H
R1
O
S
R1
O
Br
Br
5
4
R2
S
R2
O
g
H
N
e
H
N
S
H2N
S
O
N
H
N
H
N
H
O
O
R1
O
O
R1
O
8a-8k
6
f
S
R2
O
S
N
g
R2
H
N
O
H
S
O
H2N
N
N
O
S
O
R1
O
R3
N
H
O
R1
O
R3
8l-8o
7
Scheme 1. Reagents and conditions: (a) (i) prewash with 5% DIEA/DCM; (ii) Boc-L-AA-OH, DIC, HOBT, DMF, rt, 2 h; (b) (i) 55% TFA/DCM; (ii) Fmoc-L-Cys(Trt)-OH, DIC, HOBT,
DMF, rt, 2 h; (c) (i) 20% piperidine/DMF; (ii) R2SO2Cl, DIEA, DCM, rt, overnight; (d) 5% TFA/5% triisopropylsilane/90% DCM; (e) Pd(PPh3)4, ( )-BINAP, Cs2CO3, 100 °C, 20 h;
(f) R3X, K2CO3, DMF, 48 h; or R3X, DIEA, DMF, 48 h; (g) HF, 0 °C, 1.5 h.
Table 1
Individual sultams of 8
Entry
R1
R2
R3
Yielda (%)
Purityb (%)
MWc
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
H
H
CH3–
CH3–
(CH3)2CHCH2–
–(CH2)3–d
–(CH2)3–d
CH3SO(CH2)2–
CH3SO(CH2)2–
HOCH2–
HOCH2–
(CH3)2CH–
H
H
CF3–
H
CF3–
H
H
CF3–
H
CF3–
H
CF3–
H
H
H
H
H
H
H
H
H
H
88
76
85
59
52
98
75
67
61
54
67
69
84
63
40
98
99
98
87
94
85
98
91
89
92
97
83
70
62
91
315.9 ([M+H]+)
383.9 ([M+H]+)
329.9 ([M+H]+)
397.9 ([M+H]+)
372.0 ([M+H]+)
356.0 ([M+H]+)
446.0 ([M+Na]+)
405.9 ([M+H]+)
474.0 ([M+H]+)
345.9 ([M+H]+)
435.9 ([M+Na]+)
408.0 ([M+Na]+)
450.9 ([M+H]+)
478.0 ([M+Na]+)
498.1 ([M+Na]+)
H
H
H
CH3CH2–
4-NO2PhCH2–
2,4-Di-FPhCH2–
PhCOCH2–
CH3–
(CH3)2CH–
H
H
a
b
c
Yields (in %) are based on the weight of crude material and are relative to the initial loading of the resin.
The purity of the crude material was estimated by the peak area from analytical HPLC traces at k = 254 nm.
Confirmed by mass spectra (ESI).
–(CH2)3–:
d
N
Med. Chem. 2006, 49, 5840–5844; (b) Lebegue, N.; Gallet, S.; Flouquet, N.;
Carato, P.; Pfeiffer, B.; Renard, P.; Leonce, S.; Pierre, A.; Chavatte, P.; Berthelot, P.
J. Med. Chem. 2005, 48, 7363–7373.
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Nandy, J. P.; Prakesch, M.; Khadem, S.; Reddy, P. T.; Sharma, U.; Arya, P. Chem.
Rev. 2009, 109, 1999–2060; (e) Lindell, S. D.; Pattenden, L. C.; Shannon, J. Bioorg.
Med. Chem. 2009, 17, 4035–4046; (f) Dolle, R. E.; Le Bourdonnec, B.;
Goodman, A. J.; Morales, G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem. 2009,
11, 739–790.
7. (a) Kappe, C. O.; Matloobi, M. Comb. Chem. High Throughput Screening 2007, 10,
735–750; (b) Kennedy, J. P.; Williams, L.; Bridges, T. M.; Daniels, R. N.; Weaver,
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1458
W. Chen et al. / Tetrahedron Letters 52 (2011) 1456–1458
8. (a) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973–986; (b) Hill, L. L.;
Moore, L. R.; Huang, R.; Craciun, R.; Vincent, A. J.; Dixon, D. A.; Chou, J.;
Woltermann, C. J.; Shaughnessy, K. H. J. Org. Chem. 2006, 71,
5117–5125; (c) Reddy, C. V.; Kingston, J. V.; Verkade, J. G. J. Org. Chem. 2008,
73, 3047–3062.
9. For the use of a-halo arylsulfonamides in synthesis of sultams, for Heck
reactions, see: (a) Grigg, R.; York, M. Tetrahedron Lett. 2000, 41, 7255–7258; (b)
Evans, P.; McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7, 44–46; (c)
Vasudevan, A.; Tseng, P. S.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 8591–8593;
(d) Paquette, L. A.; Dura, R.; Fosnaugh, N.; Stephanian, M. J. Org. Chem. 2006, 71,
8438–8445; For radical cyclization: (e) Bressy, C.; Menant, C.; Piva, O. Synlett
2005, 577–582; For alkyne 6-endo cyclizations: (f) Barange, D. K.; Nishad, T. C.;
Swamy, K.; Bandameedi, V.; Kumar, D.; Bukkapattanam, R. S.; Vyas, K.; Pal, M. J.
Org. Chem. 2007, 72, 8547–8550; For SNAr cyclization, see: (g) Cleator, E.;
Baxter, C. A.; O’Hagan, M.; O’Riordan, T. J. C.; Sheen, F. J.; Stewart, G. W.
Tetrahedron Lett. 2010, 51, 1079–1082; (h) Rolfe, A.; Samarakoon, T. B.; Hanson,
P. R. Org. Lett. 2010, 12, 1216–1219.
10. Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A 1985, 82, 5131–5135.
11. (a) Liu, L.; Stelmach, J. E.; Natarajan, S. R.; Chen, M.-H.; Singh, S. B.; Schwartz, C.
D.; Fitzgerald, C. E.; O’Keefe, S. J.; Zaller, D. M.; Schmatz, D. M.; Doherty, J. B.
Bioorg. Med. Chem. Lett. 2003, 13, 3979–3982; (b) Kaldor, S. W.; Kalish, V. J.;
Davies, J. F., II; Shetty, B. V.; Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K.
M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.;
Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K.
S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979–3985.
resin was washed with DCM (2 times), neutralized with a solution of 5% DIEA
in DCM. The resin-bound amine was then coupled with Fmoc- -Cys(Trt)-
L
OH(6.0 equiv, 0.1 M), HOBT (6.0 equiv, 0.1 M) and DIC (6.0 equiv, 0.1 M) in
DMF for 2 h. Deprotection of the Fmoc group with 20% piperidine in DMF
(10 min  2 times), the resin was washed with DMF (2 times), DCM (2 times)
and lyophilized. To the dried resin, DIEA (10.0 equiv) was added into the
solution of anhydrous DCM. The reaction mixture was then gently stirred for
5 min before the addition of the corresponding benzenesulfonyl chloride. The
resulting mixture was then stirred at room temperature overnight. After that,
the resin was washed with DMF (2 times), DCM (2 times), and methanol
(2 times). Deprotection of the Trt group with 5% TFA/5% triisopropylsilane/90%
DCM for 15 min (3 times), the resin was washed with DCM (6 times) and
lyophilized overnight. The palladium-catalyzed cyclization reaction was
performed under nitrogen. To each tube was added the resin, Cs2CO3
(10.0 equiv), Pd(PPh3)4 (0.2 equiv) and ( )-BINAP (0.4 equiv), followed by
10 ml of anhydrous DMF. The reaction mixture was heated at 100 °C for 20 h.
The resin was then washed with DMF (2 times), DCM (2 times) and methanol
(2 times). Diverse alkyl or benzyl halides were tethered to the resin-bound
sultams in the presence of K2CO3 or DIEA in the DMF at room temperature for
48 h. After the alkylation, the resin was washed with DMF (2 times), DCM
(2 times) and methanol (2 times). The final product was cleaved with HF at 0 °C
for 1.5 h. The desired product was extracted with acetic acid/water (95:5) and
lyophilized. The product was characterized by LC–MS under ESI conditions, 1
H
and 13C NMR. ESI-MS (m/z) of 8g: 446.0 (M+Na)+; 1H NMR of 8g: (500 MHz,
DMSO-d6): 1.85–1.91 (1H, m), 1.93–1.95 (2H, m), 2.07–2.11 (1H, m), 2.91 (1H,
dd, J1 = 10.0 Hz, J2 = 15.0 Hz), 3.42–3.48 (1H, m), 3.70–3.75 (2H, m), 4.19 (1H,
dd, J1 = 3.0 Hz, J2 = 9.0 Hz), 4.73 (1H. dd. J1 = 2.0 Hz, J2 = 10.0 Hz), 6.99 (1H, s),
7.31 (1H, s), 7.91 (1H, dd, J1 = 2.0 Hz, J2 = 8.5 Hz), 7.96 (1H, d, J = 8.0 Hz), 8.09
(1H, d, J = 2.0 Hz); 13C NMR of 8g: (125 MHz, DMSO-d6): 24.1, 29.4, 34.9, 46.6,
58.1, 60.0, 123.3 (q, J = 271 Hz), 125.2, 128.3 (q, J = 33 Hz), 128.7, 135.6, 137.0,
146.7, 166.4, 173.2.
12. General produce for the synthesis of sultams: 100 mg of MBHA resin was
contained in a polypropylene mesh packet. Following neutralization with 5%
diisopropylethylamine (DIEA), the resin was then coupled with Boc-
acid, hydroxybenzotriazole (HOBt, 6.0 equiv, 0.1 M)
L
-amino
and
diisopropylcarbodiimide (DIC, 6.0 equiv, 0.1 M) in DMF at room temperature
for 2 h. Upon removal of the Boc group with 55% TFA in DCM (30 min), the