Ring-closing metathesis to a divergent endocyclic sulfonamide template

Article abstract of DOI:10.1016/S0040-4039(00)01167-9

The efficient synthesis of a novel endocyclic sulfonamide template via a ring-closing metathesis methodology is reported. A solid-supported variant of the Grubbs catalyst is shown to be effective and the suitability of the template for both combinatorial derivatization and potential incorporation into peptidomimetics is demonstrated. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01167-9

Tetrahedron Letters 41 (2000) 6743±6747
Ring-closing metathesis to a divergent endocyclic
sulfonamide template
Daniel D. Long and Andreas P. Termin*
DuPont Pharmaceuticals Research Laboratories, Suite 400, 4570 Executive Drive, San Diego, CA 92121, USA
Received 7 June 2000; revised 11 July 2000; accepted 12 July 2000
Abstract
The ecient synthesis of a novel endocyclic sulfonamide template via a ring-closing metathesis methodology
is reported. A solid-supported variant of the Grubbs catalyst is shown to be e€ective and the suitability of
the template for both combinatorial derivatization and potential incorporation into peptidomimetics is
demonstrated. # 2000 Published by Elsevier Science Ltd.
The sulfonamide moiety is a common constituent of combinatorial small molecule libraries due
to its relative ease of derivatization and ubiquitous biological activity. The motif is a direct isostere
of the amide bond and it favorably displays signi®cantly di€erent physical characteristics.1 The
tetrahedral sulfonamide can provide a hydrolytically stable analogue of the transition state
adduct formed during the enzymatic hydrolysis of an amide linkage in a peptide.2 In addition, the
SO2NH junction may alter the conformation of a peptide.3 Cyclic, conformationally constrained
amino acids (i.e. proline,4 Freidinger lactams,5 sugar amino acids6) can alter or induce a short
peptide's speci®c secondary structure. The incorporation of a sulfonamide into novel peptidomimetics
has thus received attention7 and cyclic sulfonamide moieties may provide an area of further
interest.
As part of a program to develop highly functionalized templates for combinatorial derivatization
we report the synthesis of a novel, endocyclic sulfonamide template 1 via a ring-closing metathesis
(RCM) reaction.
The scope and functional group tolerance of the principal RCM catalysts developed by
Schrock and Grubbs has been extensively investigated and reviewed.8 However, there are few
* Corresponding author. E-mail: atermin@combichem.com
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01167-9

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examples for RCM of substrates bearing a sulfonamide.9 The Grubbs ruthenium catalyst 2 is
commercially available and particularly robust.y However, its use often requires repeated
chromatography of products to remove ruthenium residues and it is non-recyclable from the
reaction mixture. Recently, Barrett addressed these issues by developing a polystyrene bound
analogue 3.10 We chose to compare the e€ectiveness of the catalysts 2 and 3 for endocyclic
sulfonamide metathesis.
Scheme 1. (i) MeOH or PrOH, Et2O, 0ꢀC; (ii) 5b, allylamine, CH2Cl2, 0ꢀC; (iii) BOC2O, DMAP, Et3N, CH2Cl2;
i
(iv) allyl bromide, K2CO3, DMF; (v) TFA/CH2Cl2; (vi) 5 mol% 2 or 3, DCE, 80ꢀC; (vii) 5 mol% 2 or 3, DCE
The synthetic strategy towards template 1 necessitated both introduction of an allyl group a to
the carbonyl and formation of an N-allyl sulfonamide from the commercially available chloro-
sulfonylacetyl chloride 4 (Scheme 1). Reaction of the acid chloride 4 with 1 equivalent of methanol
or isopropyl alcohol in ether at 0ꢀC gave the esters 5a and 5b, respectively, in quantitative yield.
Treatment of the methyl ester 5a with a secondary or hindered amine a€orded selective reaction
with the sulfonyl chloride.11 However, reaction with allylamine yielded complex mixtures. In
contrast, the bulky isopropyl ester 5b reacted with allylamine to give the sulfonamide 6 (91%) in
excellent yield. The nitrogen of sulfonamide 6 was protected as its tert-butyloxycarbonyl (BOC)
derivative 7 (92%) upon treatment with BOC2O and triethylamine in the presence of
4,4-dimethylaminopyridine in dichloromethane. Subsequent mono-C-allylation a to the sulfone
motif of 7 was e€ected with allyl bromide in DMF in the presence of potassium carbonate to give
the racemic RCM substrate mixture 8 in 93% yield.
Exposure of the diole®n 8 to either ruthenium catalyst 2 or 312 in 1,2-dichloroethane (0.04 M)
at 80ꢀC for 24 h resulted in conversion to the seven-membered cyclic product 10 (79 and 84%,
respectively). The BOC group of 10 was easily removed upon treatment with TFA/dichloro-
methane to a€ord the endocyclic, divergent sulfonamide 11 (90%).13 Alternatively, removal of
the BOC protection from the acyclic substrate 8 prior to RCM using TFA/dichloromethane gave
the diole®n 9 in 97% yield. In this case, RCM of 9 mediated by either 2 or 312 in 1,2-dichloro-
ethane (0.04 M) was extremely ecient, proceeding at room temperature in 30 min to a€ord the
cyclic sulfonamide 11 in excellent yield (93 and 95%, respectively). This observation is in contrast
with reported RCM reactions which indicate that the eciency of the ole®n metathesis improves
with increased bulk at a developing endocyclic nitrogen center.14 Consideration of the use of
catalysts 2 and 3 showed that both were equally active in mediating endocyclic sulfonamide
y
Ruthenium catalyst 2 is available from Strem Chemicals, Inc. at $60.00/g.

6745
metathesis. However, the solid bound catalyst 3 was favorable since the crude metathesis
products obtained via its use required only a single silica gel chromatographic puri®cation to
completely remove the characteristic color of ruthenium residue impurities. The use of 2,
particularly on a large scale typically required two or three chromatographic puri®cations to
remove the brown ruthenium residue color. In addition, 3 could be regenerated for further use
from the reaction mixture by simple ®ltration. However, in contrast to the reports of Barrett the
recovered catalyst 3 was markedly less active.10 RCM of 8 and 9 in the presence of regenerated 3
gave the products 10 and 11 in lower yields (46 and 54%, respectively, 95 and 99% over recovered
starting material) than the reactions using fresh catalyst 3 (84 and 95%, respectively).
The diverse nature of the endocyclic sulfonamide template 11 and its suitability as a sca€old for
combinatorial library generation was demonstrated through matrix derivatization of two of the
three available functional groups (Scheme 2). Thus, mono-alkylation of the sulfonamide 11 with
a set of alkyl bromides in DMF in the presence of potassium carbonate proceeded in good yield
(83±95%) to a€ord the N-substituted derivatives 1215 (no C-alkylation was observed). Subsequent
hydrolysis of esters 12 with aqueous lithium hydroxide in a mixture of water/dioxane followed by
acidi®cation with hydrochloric acid gave crude acids, which were coupled with a set of amines
under standard peptide coupling conditions;16 EDCI, HOBt, DIPEA in DMF. All 16 products 13
were obtained in >95% purity after HPLC puri®cation.17
Scheme 2. RBr=tert-butyl bromoacetate; 4-bromobenzylbromide; cyclopentyl bromide; 4-bromomethylbiphenyl
R1R2NH=2-aminothiazole; piperidine; glycine methyl ester; N,N,N0-trimethyl-ethylenediamine
Of particular interest was the glycine methyl ester-derived compound 14.18 The orthogonally
protected ester groups of 14 should facilitate ready peptide formation at either C-terminus which
highlights the potential ease with which 14 and thus the parent sulfonamide template 1 could be
incorporated into a peptidomimetic.
In summary, we have e€ected the ecient synthesis of a highly functionalized endocyclic
sulfonamide template 11 via a RCM reaction and demonstrated its utility for both combinatorial
library generation and potential peptidomimetic incorporation. In addition, use of the solid-supported
ruthenium catalyst 3 was evaluated and shown to facilitate high yielding sulfonamide metathesis,
simple puri®cation of products and reasonable catalyst recovery. Application of this methodology
to eight-membered ring analogues and further combinatorial library generation including
automated approaches will be reported in due course.
Experimental procedure for compound 11: 1-Hexene (1.6 ml, 12.6 mmol) and catalyst 3 (90 mg, 5
mol%) were added to a stirred solution of compound 9 (66 mg, 0.25 mmol) in 1,2-dichloroethane
(6 ml). The reaction mixture was stirred at room temperature for 30 min. TLC (ethyl
acetate:hexane, 1:3) indicated complete conversion of the starting material (Rf 0.5) to a single

6746
product (Rf 0.3). The catalyst was recovered by ®ltration (dichloromethane eluant) and the ®ltrate
concentrated in vacuo. The slightly colored residue was puri®ed by ¯ash chromatography (ethyl
acetate:hexane, 1:3) to yield 11 (56 mg, 95%) as a white solid.13
Acknowledgements
The authors wish to thank Dr. Mark J. Suto for his support of this project and Xiaoli Wang
for HRMS analyses.
References
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2. (a) Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J. Tetrahedron Lett. 1991, 32, 409. (b) Calcagni, A.;
Gavuzzo, E.; Lucente, G.; Mazza, F.; Pinnen, F.; Pochetti, G.; Rossi, D. Int. J. Peptide Protein Res. 1991, 37, 167.
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2, 644. (b) Calcagni, A.; Rossi, D.; Paradisi, M. P.; Lucente, G.; Gavuzzo, E.; Mazza, F.; Pochetti, G.; Paci, M.
Biopolymers 1997, 41, 555.
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5. Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brook, J. R.; Saperstein, R. Science 1980, 210, 656.
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(b) Smith, M. D.; Long, D. D.; Marquess, D. G.; Claridge, T. D. W.; Fleet, G. W. J. J. Chem. Soc., Chem.
Commun. 1998, 2039. (c) Long, D. D.; Hungerford, N. L.; Smith, M. D.; Brittain, D. E. A.; Marquess, D. G.;
Claridge, T. D. W.; Fleet, G. W. J. Tetrahedron Lett. 1999, 40, 2195.
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(b) Pisabarro, M. T.; Oritz, A. R.; Palomer, A.; Cabre, F.; Garcia, L.; Wade, R. C.; Cago, F.; Mauleon, D.;
Carganico, G. J. Med. Chem. 1994, 37, 337. (c) Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J. J. Org.
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E. J. Am. Chem. Soc. 1998, 120, 10994. (e) van Ameijde, J.; Liskamp, R. M. J. Tetrahedron Lett. 2000, 41, 1103.
8. (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1997, 37, 2036. (c) Armstrong, S. K. J. Chem. Soc., Perkin 1 1998, 371. (d) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (e) Phillips, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75.
9. During the course of this work a paper appeared detailing the synthesis of similar endocyclic sulfonamides:
Hanson, P. R.; Probst, D. A.; Robinson, R. E.; Yau, M. Tetrahedron Lett. 1999, 40, 4761.
10. (a) Ahmed, M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.; Procopiou, P. A. Tetrahedron Lett. 1999, 40,
8657. (b) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S. Org. Lett. 1999, 1, 1083.
11. Paik, S.; White, E. H. Tetrahedron 1996, 52, 5303.
12. Compound 3 was prepared as reported and its use in RCM was accompanied by the addition of 1-hexene to the
reaction mixture to facilitate regeneration of the catalyst, as described in Ref. 10a. The loading of 3 was 1.4 mmol/
g and had an active site composition of 10 mol%.
13. Selected data for 11; ꢀH (CDCl3): 1.26±1.30 (6H, m, CH(CH3)2), 2.84 (2H, b-d, CH2CHSO2), 3.63±3.80 (2H, m,
NCH2), 4.06 (1H, m, CH2CHSO2), 4.90 (1H, b-s, NH), 5.08 (1H, sept, CH(CH3)2), 5.88, 6.03 (2H, 2Âm,
CHˆCH); dC (CDCl3): 21.8, 21.8 (2Âq, CH(CH2)2), 26.3 (t, CH2CHSO2), 40.9 (t, NCH2), 64.1 (d, CH2CHSO2),
70.5 (d, CH(CH3)2), 129.2, 132.8 (2Âd, CHˆCH), 166.0 (CˆO); m/z (TIC): 234.2 (M+H+), 251.0 (M+NH4 +);
HRMS+Na+: 256.0615. C9H15O4NS+Na requires: 256.0614.
14. Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38, 677.
15. In the case of the less reactive cyclopentyl bromide the reaction was heated to 75ꢀC to achieve completion. Selected
data for 12: (RBr=cyclopentyl bromide); ꢀH (CDCl3): 1.29 (6H, a-t, CH(CH3)2), 1.45±1.69 (6H, m,
CH2CH2CH2CH2), 1.83±1.96 (2H, m, CH2CH2CH2CH2), 2.58, 2.89 (2H, 2Âm, CH2CHSO2), 3.70±3.91 (3H, m,
NCH2CH, CH2CHSO2), 4.24 (1H, m, NCH), 5.09 (1H, sept, CH(CH3)2), 5.85±5.88 (2H, 2Âm, CHˆCH); ꢀC

6747
(CDCl3): 21.7, 21.8 (2Âq, CH(CH3)2), 23.1, 23.4, 30.4, 31.2 (4Ât, CH2CH2CH2CH2), 26.4 (t, CH2CHSO2), 41.3 (t,
NCH2), 59.4 (d, NCH), 67.8 (d, CH2CHSO2), 70.24 (d, CH(CH2)2), 128.4, 132.4 (2Âd, CHˆCH), 165.5 (s, CˆO);
m/z (TIC): 302.4 (M+H+); HRMS+Na+: 324.1239. C14H23O4NS+Na requires: 324.1240.
16. The acid labile tert-butyl acetate-derived hydrolysis mixture was not subjected to acidi®cation. The carboxylate
salt was used in subsequent amidation.
17. Isolated yields of the matrix compounds 13 ranged from 18±85% for the three-step procedure from 11.
18. Selected data for 14: dH (CD3OD): 1.48 (9H, s, C(CH3)3), 2.66, 2.80 (2H, 2Âm, CH2CHSO2), 3.73 (3H, s,
CO2CH3), 3.78±4.13 (7H, m, NCH2CH, CH2CHSO2, CH2CO2C(CH3)3, CH2CO2CH3), 5.98, 6.10 (2H, 2Âm,
CHˆCH); dC (CD3OD): 25.9 (t, CH2CHSO2), 27.1 (q, C(CH3)3), 41.0, 44.8, 49.5 (3Ât, NCH2, CH2CO2C(CH3)3,
CH2CO2CH3), 51.5 (t, CO2CH3), 65.4 (d, CH2CHSO2), 129.8, 132.1 (2Âd, CˆCH), 168.5, 170.2 (2Âs, 2ÂCˆO);
m/z (TIC): 321.2 (M+H+^C(CH3)3), 377.2 (M+H+); HRMS-C(CH3)3+Na+: 343.0582. C15H24O7N2S-C(CH3)3+Na
requires: 343.0570.