Ring-closing metathesis strategies to cyclic sulfamide peptidomimetics

Article abstract of DOI:10.1016/S0040-4020(00)00885-1

Ring-closing metathesis (RCM) strategies toward the synthesis of a number of constrained sulfamides are discussed. This approach exploits the inherent chemistry of sulfamides and sulfonyl carbamates to generate both symmetric and unsymmetric cyclic sulfamides. Two strategies are revealed, one centers on the RCM reaction of allylated sulfamides 9a-e to generate the C₂-symmetric cyclic sulfamides 4a-e in high yields. A second RCM strategy utilizes the known sulfonyl carbamate 15 to prepare unsymmetric cyclic sulfamides 16 and 6 in two four-step sequences. Overall, the routes described are applicable to the synthesis of a variety of constrained dipeptidal sulfamides representing novel peptidomimetic scaffolds. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00885-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9781±9790
Ring-Closing Metathesis Strategies to Cyclic
Sulfamide Peptidomimetics
Joseph M. Dougherty,a Donald A. Probst,a Randall E. Robinson,b Joel D. Moore,a
Thomas A. Klein,a Kelley A. Snelgrovea and Paul R. Hansona,
*
aDepartment of Chemistry, Malott Hall, University of Kansas, Lawrence, KS 66045-2506, USA
bDepartment of Chemistry, Luther College, Decorah, IA 52101, USA
Received 27 April 2000; accepted 4 August 2000
AbstractÐRing-closing metathesis (RCM) strategies toward the synthesis of a number of constrained sulfamides are discussed. This
approach exploits the inherent chemistry of sulfamides and sulfonyl carbamates to generate both symmetric and unsymmetric cyclic
sulfamides. Two strategies are revealed, one centers on the RCM reaction of allylated sulfamides 9a±e to generate the C2-symmetric cyclic
sulfamides 4a±e in high yields. A second RCM strategy utilizes the known sulfonyl carbamate 15 to prepare unsymmetric cyclic sulfamides
16 and 6 in two four-step sequences. Overall, the routes described are applicable to the synthesis of a variety of constrained dipeptidal
sulfamides representing novel peptidomimetic scaffolds. q 2000 Published by Elsevier Science Ltd.
Introduction
are being developed as novel pharmaceutical agents.6
Unfortunately, even small peptides suffer from proteolytic
instability which limits their use as drug candidates.
Recently, peptide mimics have been developed that utilize
the urea moiety as a non-hydrolyzable linker and/or a hydro-
gen bond acceptor.7 Further modi®cation to cyclic ureas has
led to the generation of a new sub-class of biologically
active compounds.8 Led by DuPont±Merck, a number of
cyclic HIV protease inhibitors have been developed that
incorporate ureas,9 sulfamides,10 and other urea surrogates11
as the central lynch pin. In these cases, it has been shown
that the H-bonding urea moieties may serve to replace the
water molecule unique to the active site of HIV protease.9a,9d
The RCM reaction has become a powerful strategy for the
construction of a number of important heterocycles1 and
constrained peptides.2 Recently, we and others have
shown that the RCM reaction catalyzed by the Grubbs
ruthenium catalyst 3 is an effective method for the construc-
tion of P-heterocycles3 and complex cyclic sulfonamides.4
We have now extended this approach to report the ®rst
examples of the RCM reaction on sulfamide templates
(Scheme 1). This strategy couples the RCM reaction with
the unique chemistry inherent to sulfamides and sulfonyl
carbamates to synthesize diverse amino acid-derived cyclic
sulfamides.
Sulfamides have also served as nonhydrolyzable peptidomi-
metics and have been shown to be potent and selective
matrix metalloprotease inhibitors,12 serine protease inhibi-
tors,13 and constrained di- and tripeptides.14,15 Our approach
generates an array of constrained dipeptidal sulfamides with
structures such as 2 (Scheme 1). The strategies we describe
are highly ¯exible and applicable to the synthesis of an array
of peptidomimetic scaffolds.
Small peptides are excellent starting points for drug design
due to their potential to overcome the pharmacokinetic
shortcomings of larger peptides, yet retain the desirable
quality of molecular recognition.5 A number of dipeptides
Two separate 3-component coupling protocols are used,
followed by allylation and RCM, to yield symmetric sulfa-
mides 4 and 5, as well as unsymmetric sulfamide 6 (Scheme
2). With respect to the development of HIV protease
inhibitors, our strategy allows for the incorporation of
amino acid side chains into both the P1/P10 and P2/P20
regions of 4±6. Functionalization of the internal P1/P10
positions16 and external P2/P20 positions17 in other cyclic
ureas and sulfamides has been shown to in¯uence the activ-
ity of HIV protease inhibitors. The routes to the symmetric
Scheme 1.
Keywords: metathesis; peptidomimetics; cyclic sulfamides; sulfur hetero-
cycles.
* Corresponding author. Tel. 11-785-864-3094; fax: 11-785-864-5396;
e-mail: phanson@ukans.edu
0040±4020/00/$ - see front matter q 2000 Published by Elsevier Science Ltd.
PII: S0040-4020(00)00885-1

9782
J. M. Dougherty et al. / Tetrahedron 56 (2000) 9781±9790
Scheme 2.
Scheme 3.
sulfamides 4 and 5 center on the coupling of two equivalents
of an amine with sulfuryl chloride (SO2Cl2).18 Routes to
unsymmetric sulfamide 6 feature the sequential coupling
of an alcohol, then an amine to chlorosulfonyl isocyanate
(OCNSO2Cl) followed by a Mitsunobu reaction.
and 4 should be applicable to a host of other non-racemic
amines and will prove useful for the synthesis of various
cyclic sulfamide compounds.
Another attractive feature of the sulfamide group is its toler-
ance to various reaction conditions. In order to highlight its
versatile nature, we have carried out a number of transfor-
mations on dipeptides 4a±d as outlined in Scheme 5. A two-
step protocol involving reduction and benzylation yields the
sulfamide 10c (80% yield). Exposure to CH3NH2/CH3OH
at room temperature gives suitable yields of the bis-
carboxamide 11c. Finally, dihydroxylation of cyclic sulfa-
mides 4a±d yields diols 12a±d in excellent yields.
The route to the amino acid-derived C2-symmetric sulfa-
mides 4a±d is outlined in Scheme 3. Condensation of a
slight excess of amino esters 7a±d with SO2Cl2 produces
the sulfamides 8a±d in excellent yields.18 Subsequent
diallylation to sulfamides 9a±d proceeds quantitatively.
Ring-closing metathesis using the Grubbs benzylidene cata-
lyst 3, gives excellent yields of the C2-symmetric cyclic
sulfamides 4a±d. Attempts to derive unsymmetric sulfa-
mides in this manner resulted in unacceptably low yields.
In addition, attempts to directly couple secondary amines
(allylated amino esters) to SO2Cl2 were not successful. We
therefore adopted an alternative procedure employing the
Mitsunobu reaction of sulfonyl carbamates, vide infra.
Direct coupling does, however, work nicely with other
non-racemic amines such as (R)-(2)-a-methyl benzylamine
(7e) to derive non-racemic C2-symmetric sulfamides such as
4e (Scheme 4). Overall, the method outlined in Schemes 3
A concise route to the C2-symmetric cyclic sulfamide 5
incorporating the valine side chain into the internal positions
(P1/P10) of sulfamide 2 is outlined in Scheme 6. As a proof of
concept, we have initially developed a route to sulfamides
such as 5 starting from the valine-derived non-racemic allylic
amine 13.19 Amine 13 can be coupled with sulfuryl chloride,
as described above, to yield sulfamide 14 (71%). Subse-
quent RCM, although sluggish, occurred over a two-day
period to produce sulfamide 5 in 69% yield.
Scheme 4.

J. M. Dougherty et al. / Tetrahedron 56 (2000) 9781±9790
9783
Scheme 5.
Scheme 6.
Unsymmetric cyclic sulfamides have also been shown to be
potent HIV protease inhibitors.20 We have developed a ¯ex-
ible strategy to unsymmetric sulfamides 16 and 6 as outlined
in Scheme 7. This strategy utilizes inherent features of the
sulfonyl carbamate 15 to differentiate its two nucleophilic
N±H sites.21 In the ®rst route, after diallyation/RCM, the
carbamate protecting group is unmasked and alkylated to
derive the unsymmetric sulfamide 16. In the second route,
we utilize the pKa difference of the sulfonyl carbamate N±H
and sulfamide N±H in a selective Mitsunobu/deprotection
sequence ®rst developed by Montero21 and later exploited
by Groutas.22 Thus, sulfonyl carbamate 15b is utilized in a
regioselective Mitsunobu reaction to generate, after depro-
tection, the unsymmetric dipeptidal scaffold 17 in excellent
yield. Subsequent diallylation (81%), and RCM (99%)
produces the unsymmetric cyclic sulfamide 6. These high
yielding four-step routes are amenable to a number of
variations which are currently being pursued.
Scheme 7.

9784
J. M. Dougherty et al. / Tetrahedron 56 (2000) 9781±9790
In conclusion, we have established the strategies described
herein as effective methods for the synthesis of a variety of
symmetric and unsymmetric cyclic sulfamides. Current
efforts are aimed at the synthesis of a diverse array of
sulfur-based peptidomimetics. These compounds are
currently being evaluated for biological activity and the
results of those investigations will be reported in due course.
(neat) 3273, 1734, 1457, 1378, 1353, 1137 cm21; HRMS
(M1H)1 calcd for C8H17N2O6S 269.0807, found 269.0791.
N,N0-Sulfonyl bis-l-leucine dimethyl ester (8c) and N,N0-
Sulfonyl bis-l-phenylalanine dimethyl ester (8d) were
prepared according to literature procedure, see Ref. 18.
N,N0-Sulfonyl bis[(R)-1-phenyl-ethylamine] (8e). Coupling
and ¯ash chromatography (3:1 Hexanes/EtOAc) produced
356 mg (63%) of sulfamide 8e as a white solid. Mpˆ96±
978C; TLC Rfˆ0.37 (3:1 Hexanes/EtOAc); [a]2D5ˆ231.2
Experimental
1
(cˆ1.02, CHCl3); H NMR (CDCl3, 400 MHz) d 7.27±
General methods
7.21 (m, 6H), 7.17±7.14 (m, 4H), 4.74 (s, 2H), 4.43 (dq,
Jˆ12.2. 6.2 Hz, 2H), 1.46 (d, Jˆ6.8 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) d 142.7, 128.6, 127.5, 126.1, 53.7,
23.6; FTIR (neat) 3312, 3032, 2992, 2944, 1603, 1493,
1454, 1381, 1320, 1149, 751, 701 cm21; HRMS (M1H)1
calcd for C16H21N2O2S 305.1324, found 305.1322.
All reactions were carried out in ¯ame-dried glassware
under argon. Toluene, THF, Et2O, and CH2Cl2 were puri®ed
by passage through the Solv-Tek puri®cation system
employing activated Al2O3.23 Et3N was distilled from
CaH2. Flash column chromatography was performed with
Merck silica gel (EM-9385-9, 230±400 mesh). Thin layer
chromatography was performed on silica gel 60F254 plates
(EM-5715-7, Merck). All amino acid precursors were
N,N0-Bis(2-propenyl)-N,N0-sulfonyl bis-l-valine dimethyl
ester (9b). To a stirring solution of sulfamide 8b (500 mg,
1.54 mmol) in CH3CN (35 mL) in a 100 mL round-bottom
¯ask was added K2CO3 (1.06 g, 7.70 mmol) and allyl
bromide (1.12 g, 9.24 mmol). The ¯ask was ®tted with a
condenser, and the mixture was heated to 708C for 14 h.
The resulting yellow orange mixture was ®ltered by suction,
and the solvent removed under reduced pressure to give a
yellow oil. Flash chromatography (10:1 Hexanes/EtOAc)
afforded 619 mg (98.7%) of sulfamide 9b as a clear oil.
TLC Rfˆ0.31 (10:1 Hexanes/EtOAc); [a]2D5ˆ289.3
(cˆ1.00, CHCl3); 1H NMR (CDCl3, 400 MHz) d 5.92
(dddd, Jˆ15.9, 10.2, 7.5, 5.7 Hz, 2H), 5.14 (dd, Jˆ16,
1.3 Hz, 2H), 5.05 (dd, Jˆ10.2, 1.2 Hz, 2H), 3.99±3.90 (m,
6H), 3.68 (s, 6H), 2.16±2.08 (m, 2H), 0.97 (d, Jˆ6.7 Hz,
6H), 0.86 (d, Jˆ6.6, 6H); 13C NMR (CDCl3, 100 MHz) d
171.6, 135.2, 117.3, 66.3, 51.5, 47.7, 28.4, 19.6, 19.5; FTIR
(neat) 3080, 1745, 1640, 1436, 1351, 1137 cm21; HRMS
(M1H)1 calcd for C18H33N2O6S 405.2059, found 405.2031.
1
purchased from Advanced ChemTech. H and 13C spectra
were recorded in CDCl3 on a Bruker DRX-400 spectrometer
operating at 400 MHz and 100 MHz respectively. High
resolution mass spectrometry (HRMS) and FAB spectra
were obtained on a VG Instrument ZAB double-focusing
mass spectrometer. Infrared data was obtained on an ATI-
Mattson Genesis Series FTIR or a Nicolet Impact 410 FTIR.
Melting points were obtained on a Thomas Hoover capillary
melting point apparatus.
N,N0-Sulfonyl bis-l-valine dimethyl ester (8b). H-Val-
OMe´HCl (7b) (2.61 g, 15.56 mmol) and CH2Cl2 (85 mL)
were added sequentially to a 250 mL round-bottom ¯ask.
The solution was cooled to 08C, Et3N (4.50 g, 44.5 mmol)
added slowly, and the resulting solution was stirred for
15 min. SO2Cl2 (595 mL, 1.00 g, 7.41 mmol) was added
slowly over 45 min and the resulting yellow solution was
then warmed to rt over 3 h. The solvent was concentrated to
15 mL under reduced pressure, EtOAc (225 mL) was added,
and the solution was washed with 10% NaHSO4 (2£),
aqueous NaHCO3, brine, and dried (MgSO4). The solution
was ®ltered, concentrated under reduced pressure to leave a
crude oil. Flash chromatography (2:1. 1:1, Hexanes/EtOAc)
afforded 1.98 g (82.6%) of sulfamide 8b as a white solid.
Mpˆ76±778C; TLC Rfˆ0.58 (2:1 Hexanes/EtOAc);
[a]2D5ˆ114.2 (cˆ1.02, CHCl3); 1H NMR (CDCl3,
400 MHz) d 5.01 (d, Jˆ9.6 Hz, 2H), 3.88 (dd, Jˆ9.6,
4.4 Hz, 2H), 3.77 (s, 6H), 2.18±2.10 (m, 2H), 1.00
(d, Jˆ6.9 Hz, 6H), 0.88 (d, Jˆ6.9 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) d 172.9, 61.1, 52.4, 31.5, 18.8, 17.4;
FTIR (neat) 3317, 3266, 1737, 1466, 1355, 1327,
1137 cm21; HRMS (M1H)1 calcd for C12H25N2O6S
325.1437, found 325.1432.
N,N0-Bis(2-propenyl)-N,N0-sulfonyl bis-l-alanine dimethyl
ester (9a). Bis-allylation and ¯ash chromatography (10:1,
Hexanes/EtOAc) produced 596 mg (92%) of 9a as a yellow
oil. TLC Rfˆ0.53 (3:1 Hexanes/EtOAc); [a]2D5ˆ220.3
1
(cˆ1.004, CHCl3); H NMR (CDCl3, 400 MHz) d 5.87
(dddd, Jˆ16.8, 10.5, 6.5, 6.3 Hz, 2H), 5.24 (dd, Jˆ15.9,
1.4 Hz, 2H), 5.16 (dd, Jˆ10.2, 1.2 Hz, 2H), 4.37
(q, Jˆ7.2 Hz, 2H), 3.98 (dddd, Jˆ16.1, 6.1, 1.1, 1.1 Hz,
2H), 3.77 (dddd, Jˆ16.1, 6.7, 1.1, 1.1 Hz, 2H) 3.72
(s, 6H), 1.47 (d, Jˆ4.2 Hz, 6H); 13C NMR (CDCl3,
100 MHz) d 172.0, 134.4, 118.0, 55.0, 52.0, 48.8, 15.3;
FTIR (neat) 1743, 1645, 1333, 1226 cm21; HRMS
(M1H)1 calcd for C14H25N2O6S 349.1433, found 349.1436.
N,N0-Bis(2-propenyl)-N,N0-sulfonyl bis-l-leucine dimethyl
ester (9c). Bis-allylation and ¯ash chromatography (2:1
Hexanes/EtOAc) produced 2.22 g (87%) of 9c as a yellow
oil. TLC Rfˆ0.64 (2:1 Hexanes/EtOAc); [a]2D5ˆ242.5
(cˆ0.51, CDCl3); 1H NMR (CDCl3, 400 MHz) d 5.90
(dddd, Jˆ17.2, 10.2, 6.8, 6.1 Hz, 2H), 5.20 (dd, Jˆ17.2,
1.3 Hz, 2H), 5.13 (dd, Jˆ10.2, 1.1 Hz, 2H) 4.38 (dd,
Jˆ8.2, 6.0 Hz, 2H), 3.96 (dd, Jˆ16.2, 6.0 Hz, 2H), 3.86
(dd, Jˆ16.2, 7.0 Hz, 2H) 3.72 (s, 6H), 1.81±1.66 (m, 6H),
0.96 (d, Jˆ6.1 Hz, 6H), 0.91 (d, Jˆ6.2 Hz, 6H) 13C NMR
N,N0-Sulfonyl bis-l-alanine dimethyl ester (8a). Coupling
and ¯ash chromatography (2:1, 1:1 Hexanes/EtOAc)
produced 617 mg (31%) of sulfamide 8a as a white solid.
Mpˆ91±928C; TLC Rfˆ0.40 in (2:1 Hexanes/EtOAc);
[a]2D5ˆ275.8 (cˆ1.003, CHCl3); 1H NMR (CDCl3,
400 MHz) d 5.24 (d, Jˆ8.0 Hz, 2H), 4.09 (dq, Jˆ7.3,
7.3 Hz, 2H), 3.75 (s, 6H), 1.43 (d, Jˆ7.2 Hz, 6H); 13C
NMR (CDCl3, 100 MHz) d 173.7, 52.7, 51.8, 19.2; FTIR

J. M. Dougherty et al. / Tetrahedron 56 (2000) 9781±9790
9785
(CDCl3, 100 MHz) d 172.4, 134.9, 117.8, 58.1, 52.0, 48.7,
38.7, 24.4, 22.4, 21.8; FTIR (neat) 3074, 1746, 1641, 1344,
1169 cm21; HRMS (M1H)1 calcd for C20H37N2O6S
433.2372, found 433.2397.
2,20-(2S,20S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-1,1-
dioxido-2,7-diyl)]bis-propionic acid dimethyl ester (4a).
RCM and ¯ash chromatography (3:1 Hexanes/EtOAc)
produced 223 mg (97%) of cyclic sulfamide 4a as a brown
oil. TLC Rfˆ0.19 (3:1 Hexanes/EtOAc); [a]2D5ˆ262.6
(cˆ0.942, CHCl3); 1H NMR (CDCl3, 400 MHz) d 5.68
(t, Jˆ1.5 Hz, 2H), 4.76 (q, Jˆ7.3 Hz, 2H), 4.09
(d, Jˆ17.2 Hz, 2H), 3.73 (s, 6H), 3.68 (ddd, Jˆ20.1, 3.2,
3.2 Hz, 2H) 1.41 (d, Jˆ7.3 Hz, 6H); 13C NMR (CDCl3,
100 MHz) d 172.0, 127.8, 55.3, 52.3, 42.1, 16.1; FTIR
(neat) 2989, 1741, 1457, 1313, 1174 cm21; HRMS (M1H)1
calcd for C12H21N2O6S 321.1120, found 321.1103.
N,N0-Bis(2-propenyl)-N,N0-sulfonyl bis-l-phenyl alanine
dimethyl ester (9d). Bis-allylation and ¯ash chroma-
tography (10:1, 5:1 Hexanes/EtOAc) produced 560 mg
(95%) of 9d as a yellow oil. TLC Rfˆ0.15 (10:1 Hexanes/
EtOAc); [a]2D5ˆ247.9 (cˆ1.012, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.28±7.25 (m, 8H), 7.22±7.19 (m, 2H), 5.77
(dddd, Jˆ16.8, 10.5, 6.5, 6.5 Hz, 2H), 5.17±5.13 (nfom,
4H), 4.51 (dd, Jˆ7.3, 7.3 Hz, 2H), 3.71 (dd, Jˆ15.9,
6.3 Hz, 2H), 3.66 (s, 6H), 3.58 (dd, Jˆ15.9, 6.9 Hz, 2H),
3.40 (dd, Jˆ14.1, 7.6 Hz, 2H), 3.07 (dd, Jˆ14.1, 7.1 Hz,
2H); 13C NMR (CDCl3, 100 MHz) d 171.0, 137.3, 134.0,
129.2, 128.3, 126.7, 118.6, 61.0, 52.0, 48.8, 35.9; FTIR
(neat) 3064, 3029, 1742, 1653, 1559, 1497, 1456, 1436,
1339, 1149, 743, 700 cm21; HRMS (M1H)1 calcd for
C26H33N2O6S 501.2059, found 501.2043.
2,20-(2S,20S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-1,1-
dioxido-2,7-diyl)]-4,40-dimethyl bis-pentanoic acid dimethyl
ester (4c). RCM and ¯ash chromatography (2:1 Hexanes/
EtOAc) produced 1.05 g (56%) of cyclic sulfamide 4c as a
white solid. Mpˆ89±908C; TLC Rfˆ0.48 (2:1 Hexanes/
EtOAc); [a]2D5ˆ267.3 (cˆ1.06, CHCl3); 1H NMR
(CDCl3, 400 MHz): 5.61 (m, 2H), 4.66 (dd, Jˆ7.9,
6.8 Hz, 2H), 3.96±3.82 (m, 4H), 3.68 (s, 6H), 1.68±1.57
(m, 6H), 0.95 (d, Jˆ6.1 Hz, 6H), 0.91 (d, Jˆ6.3 Hz, 6H);
13C NMR (CDCl3, 100 MHz): 171.8, 127.4, 57.4, 52.1, 41.7,
38.9, 24.6, 22.9, 21.6; FTIR (neat) 3039, 2959, 2871, 1741,
1437, 1373, 1181 cm21; HRMS (M1H)1 calcd for
C18H33N2O6S 405.2059, found 405.2033.
N,N0-Bis(2-propenyl)-N,N0-sulfonyl bis[(R)-1-phenyl-
ethylamine] (9e). Bis-allylation and ¯ash chromatography
(10:1 Hexanes/EtOAc) produced 313 mg (99%) of 9e as a
colorless oil. TLC Rfˆ0.59 (10:1 Hexanes/EtOAc);
[a]2D5ˆ177.5 (cˆ1.00, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.46 (d, Jˆ7.4 Hz, 4H), 7.39±7.35 (m, 4H),
7.32±7.30 (m, 2H), 5.79 (dddd, Jˆ15.7, 9.7, 7.1, 5.8 Hz,
2H), 5.19 (q, Jˆ7.1 Hz, 2H), 5.03 (dd, Jˆ6.1, 1.3 Hz, 2H),
5.01±4.99 (m, 2H), 3.77 (dd with small allylic coupling,
Jˆ16.3, 5.8 Hz, 2H), 3.55 (dd, Jˆ16.3, 7.2 Hz, 2H), 1.67
(d, Jˆ7.1 Hz, 6H); 13C NMR (CDCl3, 100 MHz) d 140.1,
135.9, 128.2, 127.9, 127.5, 116.9, 56.5, 47.3, 17.9; FTIR
(neat) 3064, 3030, 2980, 2937, 1640, 1603, 1496, 1452,
1378, 1323, 1161, 784, 699 cm21; HRMS (M1H)1 calcd
for C22H29N2O2S 385.1950, found 385.1958.
2,20-(2S,20S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-1,1-
dioxido-2,7-diyl)] 3,30-diphenyl bis-propionic acid dimethyl
ester (4d). RCM and ¯ash chromatography (3:1, 2:1
Hexanes/EtOAc) produced 181 mg (96%) of cyclic sulfa-
mide 4d as a brown oil. TLC Rfˆ0.39 (3:1 Hexanes/
EtOAc); [a]2D5ˆ255.2 (cˆ1.098, CHCl3); 1H NMR
(CDCl3, 400 MHz) d 7.29±7.19 (m, 10H), 5.46 (t, Jˆ
1.8 Hz, 2H), 4.91 (dd, Jˆ7.8, 7.8 Hz, 2H), 3.65±3.63
(m, 10H), 3.21 (dd, Jˆ14.2, 7.4 Hz, 2H), 2.89 (dd,
Jˆ14.2, 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) d
170.7, 136.0, 129.2, 128.2, 127.3, 126.8, 60.3, 52.1, 41.9,
36.4; FTIR (neat) 3030, 1739, 1653, 1604, 1497, 1356,
2,20-(2S,20S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-1,1-
dioxido-2,7-diyl)]-3,30-dimethyl bis-butyric acid dimethyl
ester (4b). A stirring solution of the allylated sulfamide 9b
(200 mg, 0.494 mmol) in CH2Cl2 (50 mL) in a 100 mL
round-bottom ¯ask was degassed by bubbling argon gas
through the solution for 15 min. The Grubbs methathesis
catalyst 3 (12 mg, 0.015 mmol, 3 mol%) was added, the
¯ask was quickly ®tted with a condenser containing an
argon balloon, and the solution was heated to re¯ux for
1.5 h. The solution was cooled to rt and the ¯ask opened
up to the air. CH2Cl2 (40 mL) and Celitew (5.0 g) were
added, and the solution was stirred for 18 h. The solvent
was removed under reduced pressure, EtOAc (100 mL)
was added, and the solution was ®ltered through a plug of
silica. The solvent was again removed under reduced
pressure to leave a crude solid. Flash chromatography
(10:1, 5:1 Hexanes/EtOAc) gave 181 mg (97%) of the
cyclic sulfamide 4b as a white solid. Mpˆ57±588C; TLC
Rfˆ0.11 (10:1 Hexanes/EtOAc); [a]2D5ˆ2114.7 (cˆ1.00,
1170, 744, 700 cm21
;
C24H29N2O6S 473.1746, found 473.1751.
HRMS (M1H)1 calcd for
1,10-(1R,10R)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-1,1-
dioxido-2,7-diyl)]-1,10-diphenyl ethane (4e). RCM and
¯ash chromatography (10:1 Hexanes/EtOAc) produced
887 mg (94%) of cyclic sulfamide 4e as a white solid.
Mpˆ90±928C; TLC Rfˆ0.41 (10:1 Hexanes/EtOAc);
[a]2D5ˆ294.3 (cˆ0.70, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.45 (d, Jˆ7.4 Hz, 4H), 7.39±7.35 (m, 4H),
7.30±7.27 (m, 2H), 5.51 (t, Jˆ1.3 Hz, 2H), 5.44
(q, Jˆ7.0 Hz, 2H), 3.84 (d, Jˆ17 Hz, 2H), 3.54 (dd,
Jˆ17.5, 2.8 Hz, 2H), 1.57 (d, Jˆ7.1 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) d 140.5, 128.4, 128.0, 127.4, 127.3,
56.1, 40.8, 17.7; FTIR (neat) 3029, 2978, 2931, 1602,
1496, 1451, 1382, 1300, 1177, 785, 698 cm21; HRMS
(M1H)1 calcd for C20H25N2O2S 357.1637, found 357.1616.
1
CHCl3); H NMR (CDCl3, 400 MHz) d 5.49 (t, Jˆ2.1 Hz,
2H), 4.17±4.12 (m, 4H), 3.65 (s, 6H), 3.65±3.60 (m, 2H),
2.17±2.11 (m, 2H), 1.02 (d, Jˆ6.8 Hz, 6H), 0.91
(d, Jˆ6.5 Hz, 6H); 13C NMR (CDCl3, 100 MHz) d 170.7,
126.7, 65.1, 51.8, 40.4. 27.3, 19.1, 18.8; FTIR (neat) 3031,
1741, 1436, 1391, 1370, 1321, 1137, cm21; HRMS
(M1H)1 calcd for C16H29N2O6S 377.1746, found 377.1748.
2,20-(2S,20S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-1,1-
dioxido-2,7-diyl)]-4,40-dimethyl bis-pentanol. To a stir-
ring solution of cyclic sulfamide 4c (50 mg, 0.124 mmol)
in THF (8 mL) in a 25 mL round-bottom ¯ask ®tted with
argon balloon at 08C was added lithium aluminum hydride
(11 mg, 0.273 mmol). The reaction was stirred for 4 h with

9786
J. M. Dougherty et al. / Tetrahedron 56 (2000) 9781±9790
the addition of another equivalent of lithium aluminum
hydride. Na2SO4´10H2O and several drops of distilled H2O
were added until the stirred solid turned white. The mixture
was ®ltered and the solvent was removed under reduced
pressure to gave a clear oil. Puri®cation by ¯ash chroma-
tography (3:1, 1:1, 1:2 Hexanes/EtOAc) gave 42 mg (98%)
of the leucinol cyclic sulfamide as clear oil. TLC Rfˆ0.34
1300, 1179 cm21; HRMS (M1H)1 calcd for C18H35N4O4S
403.2379, found 403.2406.
2,20-(2S,20S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-(4R),
(5S)-dihydroxy-1,1-dioxido-2,7-diyl)]-4,40-dimethyl bis-
pentanoic acid dimethyl ester (12c). To a stirring solution
of cyclic sulfamide 4c (50 mg, 0.123 mmol) in a mixture of
acetone (3 mL) and distilled water (1 mL) was added
N-methyl morpholine N-oxide (32 mg, 0.248 mmol) and
the mixture was stirred for 15 min. A 0.5 M aqueous solu-
tion of OsO4 (1 mg, 4 mmol) was then added. After 19 h,
Na2SO3 (50 mg, 0.31 mmol) was added to destroy the OsO4.
The mixture was ®ltered and concentrated to 1.5 mL under
reduced pressure. Flash chromatography (1:2 Hexanes/
EtOAc) gave 50 mg (92%) of 12c as a clear oil. TLC
Rfˆ0.58 (1:2 Hexanes/EtOAc); [a]2D5ˆ221.9 (cˆ0.64,
1
(1:2 Hexanes/EtOAc); [a]2D5ˆ26.8 (cˆ0.78, CHCl3); H
NMR (CDCl3, 400 MHz) d 5.75 (t, Jˆ1.8 Hz, 2H), 4.15±
4.08 (m, 2H), 3.86 (d, Jˆ17.9 Hz, 2H), 3.70 (d, Jˆ17.9 Hz,
2H), 3.58±3.49 (m, 4H), 2.37 (s, 2H), 1.68±1.59 (m, 2H),
1.38 (ddd, Jˆ14.3, 9.5, 4.8 Hz, 2H), 1.14 (ddd, Jˆ14.3, 9.2,
5.0 Hz, 2H), 0.94 (d, Jˆ6.5 Hz, 6H), 0.89 (d, Jˆ6.7 Hz,
2H); 13C NMR (CDCl3, 100 MHz) d 128.8, 64.3, 59.5,
40.9, 38.8, 25.2, 23.7, 22.4; FTIR (neat) 3463, 2955,
2870, 1468, 1379, 1290, 1176 cm21; HRMS (M1H)1
calcd for C16H33N2O4S 349.2161, found 349.2170.
1
CHCl3); H NMR (CDCl3, 400 MHz) d 4.28 (dd, Jˆ9.3,
5.8 Hz, 1H), 4.21 (dd, Jˆ10.6, 4.6 Hz, 1H), 3.92 (t, Jˆ
4.6, 1H), 3.83±3.73 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H),
3.65 (dd, Jˆ15.5, 8.9 Hz, 1H), 3.40, (d, Jˆ12.4 Hz, 1H),
3.35 (dd, Jˆ15.6, 6.9 Hz, 1H), 1.97, (ddd, Jˆ13.8, 10.3,
3.3 Hz, 1H), 1.83±1.72 (m, 5H), 0.97 (d, Jˆ6.3 Hz, 3H),
0.97 (d, Jˆ6.6 Hz, 3H), 0.96 (d, Jˆ6.2 Hz, 3H), 0.94
(d, Jˆ6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 174.2,
173.8, 69.4, 69.0, 61.6, 59.2, 53.1, 52.8, 48.8, 46.1, 39.2,
38.8, 24.7, 24.7, 23.2, 22.9, 21.6, 21.5; FTIR (neat) 3432,
1740, 1457, 1437, 1380, 1311, 1168 cm21; HRMS (M1H)1
calcd for C18H35N2O8S 439.2114, found 439.2132.
1,10-Bis(benzyloxy)-2,20-(2S,20S)-[(2,3,6,7-tetrahydro-1,2,7-
thiadiazepine-1,1-dioxido-2,7-diyl)]-4,40-dimethyl bis-
pentane (10c). To a stirring solution of the leucinol sulfa-
mide (39 mg, 0.112 mmol) in THF (10 mL) at 08C was
added sodium hydride (8 mg, 0.336 mmol). The mixture
stirred for 45 min and benzyl bromide (57 mg,
0.336 mmol) was added. After stirring for 12 h at rt,
EtOAc (20mL) was added and the mixture was washed
with 10% NaHSO4, NaHCO3, brine, and dried (MgSO4).
The solution was ®ltered and the solvent removed under
reduced pressure. Puri®cation by ¯ash chromatography
(Hexanes, 20:1, 10:1 Hexanes/EtOAc) gave 48 mg (81%)
of sulfamide 10c as a clear oil. TLC Rfˆ0.78 (1:2 Hexanes/
EtOAc); [a]2D5ˆ211.5 (cˆ0.66, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.36±7.27 (m, 10H), 5.57 (s, 2H), 4.51
(d, Jˆ11.9 Hz, 2H), 4.44 (d, Jˆ11.9 Hz, 2H), 4.31
(m, 2H), 4.07 (d, Jˆ17.3 Hz, 2H), 3.59 (dd, Jˆ19.2,
2.1 Hz, 2H), 3.46 (d, Jˆ5.4 Hz, 4H), 1.73±1.65 (m, 2H),
1.50 (ddd, Jˆ14.3, 10.0, 4.6 Hz, 2H), 1.27 (dd, Jˆ14.2, 9.3,
5.0 Hz, 2H), 0.98 (d, Jˆ6.5 Hz, 6H), 0.93 (d, Jˆ6.7 Hz,
6H); 13C NMR (CDCl3, 100 MHz) d 138.1, 128.3, 127.9,
127.6, 127.5, 72.9, 72.5, 55.5, 40.4, 38.5, 24.6, 23.4, 21.9;
FTIR (neat) 3033, 2955, 2867, 1496, 1453, 1386,1366,
1301, 1183, 734, 698 cm21; HRMS (M1H)1 calcd for
C30H45N2O4S 529.3100, found 529.3082.
2,20-(2S,20S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-(4R),
(5S)-dihydroxy-1,1-dioxido-2,7-diyl)] bis-propionic acid
dimethyl ester (12a). Dihydroxylation and ¯ash chroma-
tography (1:2 Hexanes/EtOAc) produced 75 mg (53%) of
12a as a colorless oil. TLC Rfˆ0.09 (1:2 Hexanes/EtOAc);
[a]2D5ˆ25.52 (cˆ1.36, CHCl3); 1H NMR (CDCl3,
400 MHz) d 4.35 (q, Jˆ7.3 Hz, 1H), 4.23(q, Jˆ7.3 Hz,
1H), 3.88 (t, Jˆ4.6 Hz, 1H), 3.80±3.72 (m, 2H), 3.77
(s, 3H), 3.75 (s, 3H), 3.66 (dd, Jˆ15.6, 8.9 Hz, 1H), 3.37
(d, Jˆ15.6 Hz, 1H), 3.35 (dd, Jˆ15.6, 3.1 Hz, 1H), 1.56
(d, Jˆ7.3 Hz, 3H), 1.53 (d, Jˆ7.4 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 173.9, 173.6, 69.4, 68.9, 58.8, 56.5,
53.0, 52.8, 48.3, 45.8, 16.3, 15.8; FTIR (neat) 3489, 3400,
2998, 1743, 1457, 1382, 1307, 1171 cm21; HRMS (M1H)1
calcd for C12H23N2O8S 355.1175, found 355.1161.
N,N0-Dimethyl-[2,20-(2S,20S)-[(2,3,6,7-tetrahydro-1,2,7-
thiadiazepine-1,1-dioxido-2,7-diyl)]]-4,40-dimethyl bis-
pentanamide (11c). A 10 mL round-bottom ¯ask was
charged with the leucine derived cyclic sulfamide (25 mg,
0.062 mmol) and MeNH2 (39 mg, 1.24 mmol) in MeOH.
The mixture was stirred under argon balloon for 5 days
with the addition of two more equivalents of MeNH2. The
solvent was removed and the crude oil was puri®ed by ¯ash
chromatography (2:1 Hexanes/EtOAc) to give 21 mg (84%)
of 11c as a clear oil. TLC Rfˆ0.23 (1:2 Hexanes/EtOAc);
[a]2D5ˆ2158.5 (cˆ0.26, CHCl3); 1H NMR (CDCl3,
400 MHz) d 6.41 (d, Jˆ3.8 Hz, 2H), 5.69±5.68 (m, 2H),
4.41 (dd, Jˆ9.1, 5.4 Hz, 2H), 4.05 (d, Jˆ16.8 Hz, 2H), 3.61
(ddd, Jˆ17.0, 4.5, 1.1 Hz, 2H), 2.82 (d, Jˆ4.8 Hz, 6H), 1.84
(ddd, Jˆ14.2, 8.8, 5.4 Hz, 2H), 1.66±1.57 (m, 2H) 1.48
(ddd, Jˆ14.1, 9.1, 4.9 Hz, 2H), 0.95 (d, Jˆ6.5 Hz, 6H),
0.91 (d, Jˆ6.6 Hz, 6H); 13C NMR (CDCl3, 100 MHz) d
170.8, 127.4, 59.2, 42.4, 38.2, 26.6, 24.8, 23.0, 21.7; FTIR
(neat) 3381, 3317, 2958, 2870, 1662, 1544, 1456, 1368,
2,20-(2S,20S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-(4R),
(5S)-dihydroxy-1,1-dioxido-2,7-diyl)]-3,30-dimethyl bis-
butyric acid dimethyl ester (12b). Dihydroxylation and
¯ash chromatography (1:2 Hexanes/EtOAc) produced
69 mg (96%) of 12b as a white solid. TLC Rfˆ0.33 (1:2
Hexanes/EtOAc); [a]D25ˆ232.7 (cˆ0.92, CHCl3); 1H NMR
(CDCl3, 400 MHz) d 3.94 (d, Jˆ10.1 Hz, 1H), 3.92±3.83
(m, 2H), 3.86 (d, Jˆ10.6 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H),
3.59±3.36 (m, 4H), 2.31±2.23 (m, 1H), 2.23±2.14 (m, 1H)
1.04 (d, Jˆ6.6 Hz, 6H), 0.97 (d, Jˆ6.4 Hz, 3H), 0.97
(d, Jˆ6.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 173.1,
172.6, 70.0, 69.5, 67.9, 66.0, 52.5, 52.3, 47.4, 45.3, 28.5,
28.3, 20.0, 20.0, 19.6, 19.5; FTIR (neat) 3457, 1740, 1436,
1380, 1311, 1158 cm21; HRMS (M1H)1 calcd for
C16H31N2O8S 411.1801, found 411.1809.
2,20-(2S,20S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-
(4R),(5S)-dihydroxy-1,1-dioxido-2,7-diyl)]-3,30-diphenyl

J. M. Dougherty et al. / Tetrahedron 56 (2000) 9781±9790
9787
bis-propionic acid dimethyl ester (12d). Dihydroxylation
and ¯ash chromatography (1:1 Hexanes/EtOAc) produced
110 mg (97.2%) of 12d as a white solid. Mpˆ153±1548C;
TLC Rfˆ0.20 (1:1 Hexanes/EtOAc); [a]2D5ˆ2131.8
(400 MHz, CDCl3) d 7.08 (s, 1H), 5.54 (d, Jˆ9.2 Hz,
1H), 4.04 (dd, Jˆ9.2, 4.9 Hz, 1H), 3.76 (s, 3H), 2.18±2.10
(m, 1H), 1.49 (s, 9H), 1.18 (d, Jˆ6.9 Hz, 3H), 0.91
(d, Jˆ6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
171.85, 149.86, 83.75, 62.07, 52.44, 31.44, 27.89, 18.89,
17.25 ppm; FTIR (neat) 3268, 1742, 1451, 1400, 1371,
1146 cm21. HRMS (M1H)1 calcd for C11H23N2O6S
311.1277, found 311.1266.
1
(cˆ0.22, CHCl3); H NMR (CDCl3, 400 MHz) d 7.38±
7.21 (m, 10H), 4.36 (dd, Jˆ10.3, 5 Hz, 1H), 4.13 (dd,
Jˆ10.6, 4.1 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.62±3.53
(nfom, 4H), 3.45 (dd, Jˆ14.7, 5 Hz, 1H), 3.39 (dd, Jˆ14.4,
4.1 Hz, 1H), 3.23 (dd, Jˆ14.4, 10.6 Hz, 1H), 3.12 (dd,
Jˆ14.7, 10.4 Hz, 1H), 2.62 (d, Jˆ12.7 Hz, 1H), 2.52 (dd,
Jˆ16.0, 4.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 173.7,
171.0, 137.0, 136.5, 129.5, 129.2, 128.6, 128.5, 127.0,
126.9, 69.8, 68.3, 68.0, 63.7, 53.6, 52.6, 51.4, 47.0, 36.9,
36.6; FTIR (neat) 3502, 3382, 3029, 1741, 1716, 1604,
1559, 1497, 1312, 1153, 753, 702 cm21; HRMS (M1H)1
calcd for C24H31N2O8S 507.1801, found 507.1806.
N,N0-Bis(2-propenyl)-N-(tert-butoxycarbonylsulfonyl) l-
phenylalanine methyl ester. To a stirring solution of 15d
(0.500 g,1.40 mmol) in dry acetone (14 mL) in a 50 mL
round-bottom ¯ask was added anhydrous K2CO3 (0.771 g,
5.58 mmol) and allyl bromide (0.507 mL, 0.709 g,
5.86 mmol). The mixture was heated to re¯ux under argon
for 12 h. The solution was then cooled, suction ®ltered, and
the solvent removed under reduced pressure to give a pale
yellow oil. Flash chromatography (4:1 Hexane:EtOAc)
yielded 504 mg (82%) of a clear, colorless oil. TLC
Rfˆ0.35 (4:1 Hexanes/EtOAc); [a]2D5ˆ227.2 (cˆ1.00,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.31±7.21 (m,
5H), 5.98±5.82 (m, 2H), 5.28 (ddd, Jˆ15.8, 3.6, 1.5 Hz,
2H), 5.17 (ddd, Jˆ10.3, 5.1, 1.3 Hz, 2H), 4.83 (dd, Jˆ9.0,
6.2 Hz, 1H), 5.28 (ddd, Jˆ15.8, 3.5, 1.5 Hz, 2H), 5.17 (ddd,
Jˆ9.2, 5.1, 1.3 Hz, 2H), 4.32 (dd, Jˆ9.0, 6.2 Hz, 1H), 4.22
(m, 3H), 4.12 (dd, Jˆ16.6, 6.8 Hz, 1H), 3.62 (s, 3H), 3.26
(dd, Jˆ13.6, 9.0 Hz, 1H), 3.05 (dd, Jˆ13.6, 6.2 Hz, 1H),
1.51 (s, 9H); 13C NMR (CDCl3, 100 MHz) d 171.3, 151.6,
136.9, 135.5, 133.6, 129.7, 128.9, 127.3, 118.0, 117.9, 84.0,
62.1, 52.4, 51.6, 50.0, 37.5, 28.5; FTIR (neat) 3082, 2980,
1731, 1644, 1605, 1494, 1442, 1371, 1319, 1249, 1149,
1036 cm21; HRMS (M1H)1 calcd for C21H30N2O6S
439.1903, found 439.1882.
N,N0-Sulfonyl-(3S,30S)-bis(4-methyl-1-penten-3-amine) (14).
Dihydroxylation and ¯ash chromatography (3:1 Hexanes/
EtOAc) produced 128 mg (56%) of 14 as a white solid.
Mpˆ51±528C; TLC Rfˆ0.48 (3:1 Hexanes/EtOAc);
1
[a]2D5ˆ85.9 (cˆ0.51, CHCl3); H NMR (CDCl3, 400 MHz)
d 5.70 (ddd, Jˆ17.7, 10.3, 7.8 Hz, 2H), 5.25 (dd, Jˆ17,
0.9 Hz, 2H), 5.21 (d, Jˆ10.2 Hz, 2H), 4.29 (d, Jˆ7.7 Hz,
2H), 3.65 (dd, Jˆ7.8, 5.4 Hz, 2H), 1.84 (m, 2H), 0.92
(d, Jˆ6.9 Hz, 6H), 0.89 (d, Jˆ6.8 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) d 136.5, 117.5, 62.3, 32.4, 18.6, 17.8;
FTIR (neat) 3290, 2962, 2939, 2875, 1652, 1568, 1456,
1436, 1369, 1316, 1157 cm21; HRMS (M1H)1 calcd for
C12H25N2O2S 261.1637, found 261.1646.
(3S,6S)-[(2,3,6,7-Tetrahydro-3,6-bis(methylethyl)-1,2,7-
thiadiazepine-1,1-dioxide (5). RCM and ¯ash chroma-
tography (3:1 Hexanes/EtOAc) produced 31 mg (69%) of
5 as a white solid. Mpˆ152±1538C; TLC Rfˆ0.35 (3:1
2-(2S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-1,1-dioxido-
7-tert-butyloxycarbonyl-2-yl)] 3-phenyl-propionic acid
methyl ester. Bis-allylation and ¯ash chromatography
(4:1 Hexanes/EtOAc) produced 78 mg (84%) of cyclic
sulfamide as a clear, colorless oil. TLC Rfˆ0.22 (4:1
Hexanes/EtOAc); [a]2D5ˆ237.7 (cˆ1.00, CHCl3); 1H
NMR (CDCl3, 400 MHz) d 7.32±7.24 (m, 5H), 5.81 (ddd,
Jˆ11.2, 5.5, 5.5 Hz, 1H), 5.67 (ddd Jˆ11.3, 3.7, 3.7 Hz,
1H), 5.09 (t, Jˆ7.8 Hz, 1H), 4.15 (dd, Jˆ16.9, 5.7 Hz,
2H), 4.08 (m, 2H), 3.86 (ddd, Jˆ16.9, 5.1, 1.3 Hz, 1H),
3.68 (s, 3H), 3.29 (dd, Jˆ14.0, 7.6 Hz, 1H), 2.99 (dd,
Jˆ14.0, 7.9 Hz, 1H), 1.50 (s, 9H); 13C NMR (CDCl3,
100 MHz) d 170.4, 151.3, 135.7, 129.2, 128.6, 128.3,
127.3, 127.1, 83.8, 61.6, 52.3, 43.8, 43.5, 37.0, 27.8; FTIR
(neat) 3031, 2981, 2259, 1732, 1604, 1496, 1445, 1367,
1
Hexanes/EtOAc); [a]D25ˆ50.0 (cˆ0.18, CHCl3); H NMR
(CDCl3, 400 MHz) d 5.59 (s, 2H), 4.94 (d, Jˆ10.7 Hz,
2H), 3.98 (dd, Jˆ8.2, 4.0 Hz, 2H), 1.92±1.87 (m, 2H),
0.99 (d, Jˆ6.7 Hz, 6H), 0.92 (d, Jˆ6.9 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) d 133.1, 56.3, 32.6, 18.7, 17.1; FTIR
(neat) 3303, 3257, 2959, 2931, 2875, 1653, 1559, 1321,
1161 cm21; HRMS (M1H)1 calcd for C10H21N2O2S
233.1324, found 233.1321.
(tert-Butoxycarbonylsulfonyl) l-phenylalanine methyl
ester (15d). Was prepared using literature procedure, see
Groutas Ref. 17.
(tert-Butoxycarbonylsulfonyl) l-valine methyl ester (15b).
To a stirring solution of chlorosulfonyl isocyanate (1.23 mL,
14.1 mmol) and CH2Cl2 (40 mL) at 08C in a 250 mL round-
bottom ¯ask was added a solution of t-BuOH (1.0 M,
1.35 mL, 14.1 mmol) in CH2Cl2 dropwise over a period of
10 min. The resulting solution was transferred via cannula
to a mixture of H-Val-OMe´HCl (2.37 g, 14.1 mmol) and
Et3N (3.94 mL, 28.3 mmol) in CH2Cl2 (40 mL) at 08C. The
slurry was allowed to warm to rt and stirred for an additional
2.5 h. The salts were ®ltered, the organic portion was
washed with H2O (2£), brine (2£), and dried (Na2SO4).
The mixture was ®ltered and concentrated under reduced
pressure to yield 4.19 g (96.0%) of sulfamide 15 as a pure
white solid. Mpˆ128±1298C; TLC Rfˆ0.42 (2:1 Hexanes/
EtOAc); [a]2D5ˆ140.6 (cˆ1.00, CHCl3); 1H NMR
1327, 1265, 1151, 1093, 1037, 918 cm21
; HRMS
(M1H)1 calcd for C19H26N2O6S 411.1590 found 411.1582.
2-(2S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-1,1-dioxido-
2-yl)]-3-phenyl-propionic acid methyl ester. The
Boc-protected cyclic sulfamide prepared in the previous
experimental (50 mg, 0.122 mmol) was added to a 5 mL
round-bottom ¯ask, followed by tri¯uoroacetic acid
(194 mg, 0.131 mL, 1.71 mmol). The solution was stirred
at ambient temperature for 36 h. CH2Cl2 (4 mL) was added
and the resulting solution washed with saturated NaHCO3
(3£). The aqueous solution was back-extracted with
methylene chloride (2£) and the combined organic solutions
washed with water (2£), brine (2£), and dried (Na2SO4).

9788
J. M. Dougherty et al. / Tetrahedron 56 (2000) 9781±9790
The solution was suction ®ltered and the solvent removed
under reduced pressure. Flash chromatography (2:1
Hexanes/EtOAc) yielded 31.2 mg (83%) of a white crystal-
line solid. Mpˆ62±648C; TLC Rfˆ0.20 (2:1 Hexanes/
EtOAc); [a]2D5ˆ259.85 (cˆ1.00, CHCl3); 1H NMR
(CDCl3, 400 MHz) d 7.31±7.21 (m, 5H), 5.73±5.65 (m,
1H), 5.64±5.57 (m, 1H), 4.97 (dd, Jˆ8.0, 5.7 Hz, 1H),
4.86(dd, Jˆ8.9, 6.8 Hz, 1H), 4.04 (ddd, Jˆ8.9, 2.3,
1.7 Hz, 1H), 3.81 (ddd, Jˆ18.5, 5.1, 1.0 Hz, 1H), 3.69 (s,
3H), 3.47 (ddd, Jˆ18.0, 4.6, 1.0 Hz, 1H), 3.44±3.34 (m,
1H), 3.29 (dd, Jˆ26.1, 6.8 Hz, 1H), 2.96 (dd, Jˆ14.3,
8.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 171.0, 136.2,
129.7, 129.5, 129.2, 128.4, 128.2, 128.0, 126.9, 126.7, 61.0,
52.2, 41.9, 40.7, 36.3; FTIR (neat) 3297, 3030, 2952, 2861,
1737, 1603, 1496, 1437, 1348, 1318, 1238, 1161, 1095, 983,
917, 887 cm21; HRMS (M1H)1 calcd for C14H18N2O4S
311.1066 found 311.1060.
1.01 (d, Jˆ6.8 Hz, 3H), 0.89 (d, Jˆ6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 171.15, 170.10, 150.34, 128.22, 84.82,
61.52, 61.48, 56.11, 52.29, 32.01, 27.73, 18.62, 17.14,
16.45, 14.03; FTIR (neat) 3297, 1742, 1458, 1429, 1371,
1299, 1277, 1262, 1219, 1153 cm21; HRMS (M1H)1 calcd
for C16H31N2O8S 411.1801, found 411.1784.
N-[[(1R)-1-Ethoxycarbonyl-ethylamino]sulfonyl]-l-valine
methyl ester (17). To a stirring solution of the Boc-
protected sulfamide prepared in the previous experimental
(500 mg, 1.22 mmol) in CH2Cl2 (1.0 mL) was added TFA
(1.41 mL, 18.3 mmol). After 1.5 h, the reaction mixture was
diluted with CH2Cl2 (15 mL) and washed with NaHCO3
(2£), H2O (2£), brine (2£), and dried (Na2SO4). The organic
layer was concentrated under reduced pressure. Flash
chromatography (1:1 Hexanes/EtOAc) yielded 380 mg
(100%) of sulfamide 17 as a light yellow solid. Mpˆ79±
818C; TLC Rfˆ0.55 (1:1 Hexanes/EtOAc); [a]2D5ˆ2129.2
(cˆ0.5, CDCl3); 1H NMR (400 MHz, CDCl3) d 4.98
(t, Jˆ10.1, 8.9 Hz, 2H), 4.22 (q, Jˆ7.1 Hz, 2H), 4.01
(m, 1H), 3.80 (dd, Jˆ10.2, 4.9 Hz, 1H), 3.77 (s, 3H), 2.08
(m, 1H), 1.37 (d, Jˆ7.1 Hz, 3H), 1.26 (t, Jˆ7.1 Hz, 3H),
0.98 (d, Jˆ6.8 Hz, 3H), 0.88 (d, Jˆ6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 173.01, 172.87, 61.73, 61.09, 52.36,
51.66, 31.16, 19.20, 18.88, 17.45, 14.02; FTIR (neat) 3282,
1742, 1451, 1437, 1349, 1299, 1270, 1139 cm21; HRMS
(M1H)1 calcd for C11H23N2O6S 311.1277, found 311.1262.
2-(2S)-[(2,3,6,7-Tetrahydro-1,2,7-thiadiazepine-1,1-dioxido-
7-benzyl-2-yl)]-3-phenyl-propionic acid methyl ester. To
a stirring solution of the cyclic sulfamide prepared in the
previous experimental (49 mg, 0.159 mmol) and dry
CH3CN (1.5 mL), in a 5 mL round-bottom ¯ask, were
added anhydrous K2CO3 (44 mg, 0.318 mmol) and benzyl
bromide (40 mL, 0.057g, 0.334 mmol). The solution was
heated to 558C and stirred for 36 h, cooled to rt, and diluted
with CH2Cl2 (3 mL). The solution was ®ltered, and the
solvent removed under reduced pressure. Flash chroma-
tography (4:1 Hexanes/EtOAc) yielded 62 mg (96%) of
sulfamide 16 as a white crystalline solid. Mpˆ56±588C;
TLC Rfˆ0.26 (4:1 Hexanes/EtOAc); [a]2D5ˆ236.8
N,N0-Bis(2-propenyl)-N-[[(1R)-1-ethoxycarbonyl-ethyl-
amino]sulfonyl]-l-valine methyl ester. Bis-allylation and
¯ash chromatography (1:1 Hexanes/EtOAc) produced
152 mg (81%) of sulfamide as clear oil. TLC Rfˆ0.56
1
(cˆ1.00, CHCl3); H NMR (CDCl3, 400 MHz) d 7.33±
1
(2:1 Hexanes/EtOAc); [a]2D5ˆ230.2 (cˆ1.00, CHCl3); H
7.20 (m, 10H), 5.83 (ddd, Jˆ10.9, 4.4, 1.3 Hz, 1H), 5.45
(ddd, Jˆ9.8, 5.3, 4.4 Hz, 1H), 4.97 (dd, Jˆ9.3, 6.4 Hz, 1H),
4.03 (s, 2H), 3.98 (ddd, Jˆ18.2, 4.0, 2.0 Hz, 1H), 3.76 (dd,
Jˆ18.2, 5.8 Hz, 1H), 3.73 (s, 3H), 3.53 (dd, Jˆ17.8, 3.9 Hz,
1H), 3.38 (d, 2.4 Hz, 1H), 3.32 (dd Jˆ14.3, 6.4 Hz, 1H),
2.95 (dd, Jˆ18.2, 8.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d 171.2, 136.4, 136.1, 129.5, 128.8, 128.5, 128.4, 128.1,
127.7, 127.3, 126.9, 61.4, 52.3, 51.1, 43.5, 41.6, 36.6;
FTIR (neat) 3065, 3026, 2951, 1740, 1603, 1498, 1451,
1439, 1354, 1320, 1160, 1099, 926, 753 cm21; HRMS
(M1H)1 calcd for C21H24N2O4S 401.1535 found 401.1556.
NMR (400 MHz, CDCl3) d 5.93 (m, 2H), 5.21 (m, 2H), 5.15
(dd, Jˆ10.2, 1.2 Hz, 1H), 5.11 (dd, Jˆ10.1, 1.1 Hz, 1H),
4.19 (m, 3H), 4.07 (d, Jˆ10.6 Hz, 1H), 3.99 (m 2H), 3.90
(dd, Jˆ16.2, 6.16 Hz, 1H), 3.78 (dd, 16.1, 6.6 Hz, 1H), 3.70
(s, 3H), 2.20 (m, 1H), 1.48 (d, Jˆ7.2 Hz, 3H), 1.28 (t, Jˆ
7.1 Hz, 3H), 1.02 (d, Jˆ6.6 Hz, 3H), 0.92 (d, Jˆ6.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 171.62, 171.52,
135.12, 134.67, 118.08, 117.60, 66.25, 61.29, 55.49,
51.69, 49.02, 47.84, 28.23, 19.62, 19.56, 15.45, 14.05
ppm; FTIR (neat) 1741, 1643, 1441, 1380, 1336, 1205,
1134 cm21; HRMS (M1H)1 calcd for C17H31N2O6S
391.1903, found 391.1879.
N-tert-butyloxycarbonyl-N0-[[(1R)-1-ethoxycarbonyl-ethyl-
amino]sulfonyl]-l-valine methyl ester. To a stirring solution
of sulfamide 15b (1.00 g, 3.23 mmol) in THF (2 mL) was
slowly added DEAD (508 mL, 3.23 mmol) via dropwise
addition. A solution consisting of (l)-(2)-Ethyl lactate
(366 mL, 3.23 mmol) and PPh3 (847 mg, 3.23 mmol) in
THF (3 mL), was slowly transferred via cannula into the
sulfamide solution. After 3 h, the reaction mixture was
concentrated and dissolved in ether to precipitate Ph3PO.
The solution was ®ltered, and concentrated under reduced
pressure to leave a crude oil. Flash chromatography (5:1
Hexanes/EtOAc) yielded 1.07 g (81%) of Boc-protected
sulfamide as a yellow oil. TLC Rfˆ0.63 (2:1 Hexanes/
EtOAc); [a]2D5ˆ168.8 (cˆ1.00, CHCl3); 1H NMR
(400 MHz, CDCl3) d 6.13 (d, Jˆ7.6 Hz, 1H), 4.89 (q,
Jˆ6.9 Hz, 1H), 4.19 (q, Jˆ7.1 Hz, 2H), 4.09 (dd, Jˆ7.6,
4.0 Hz, 1H), 3.77 (s, 3H), 2.18±2.15 (m, 1H), 1.57
(d, Jˆ6.9 Hz, 3H), 1.50 (s, 9H), 1.27 (t, Jˆ7.1 Hz, 3H),
2-(2S)-[(7-[(10R)-10-Ethoxycarbonyl-ethyl]-2,3,6,7-tetra-
hydro-1,2,7-thiadiazepine-1,1-dioxido-2-yl)] 3-phenyl
propionic acid methyl ester (6). RCM and ¯ash chroma-
tography (2:1 Hexanes/EtOAc) produced 31.6 mg (67%) of
the cyclic sulfamide 6 as pure brown oil. TLC Rfˆ0.37 (2:1
Hexanes/EtOAc); [a]D25ˆ224.0 (cˆ0.25, CDCl3); 1H NMR
(400 MHz, CDCl3) d 5.58 (m, 2H), 4.71 (q, Jˆ7.3, 1H),
4.18 (q, Jˆ7.1 Hz, 2H), 4.11 (m, 3H), 3.72 (dd, Jˆ18.8,
4.9 Hz, 1H), 3.66 (s, 3H), 3.61 (dd, Jˆ18.3, 4.5 Hz, 1H),
2.14 (m, 1H), 1.39 (d, Jˆ7.3 Hz, 3H), 1.28 (t, Jˆ7.2 Hz,
3H), 1.01 (d, Jˆ6.7 Hz, 3H), 0.91 (d, Jˆ6.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 171.52, 170.87, 127.51, 127.21,
64.87, 61.43, 55.65, 51.80, 41.67, 41.02, 27.47, 19.13,
18.90, 16.29, 14.10; FTIR (neat) 1742, 1589, 1458, 1437,
1361, 1357, 1320, 1190, 1161 cm21; HRMS (M1H)1 calcd
for C15H27N2O6S 363.1590, found 363.1575.

J. M. Dougherty et al. / Tetrahedron 56 (2000) 9781±9790
9789
S. M. J. Am. Chem. Soc. 1999, 121, 8126±8127. (c) Long, D. D.;
Termin, A. P. Tetrahedron Lett. 2000, 41, 6743±6747.
Acknowledgements
5. (a) Horwell, D. C.; Howson, W.; Ratcliffe, G. S.; Rees, D. C.
Bioorg. Med. Chem. Lett. 1993, 3, 799±802. (b) Boden, P.; Eden,
J. M.; Hodgson, J.; Horwell, D. C.; Howson, W.; Hughes, J.;
McKnight, A. T.; Meecham, K.; Pritchard, M. C.; Raphy, J.;
Ratcliffe, G. S.; Suman-Chauhan, N.; Woodruff, G. N. Bioorg.
Med. Chem. Lett. 1994, 4, 1679±1684. (c) Chatterjee, S.; Ator,
M. A.; Bozyczko-Coyne, D.; Josef, K.; Wells, G.; Tripathy, R.;
Iqbal, M.; Bihovsky, R.; Senadhi, S. E.; Mallya, S.; O'Kane, T. M.;
McKenna, B. A.; Siman, R.; Mallamo, J. P. J. Med. Chem. 1997,
40, 3820±3828.
This investigation was generously supported by partial
funds provided by the Petroleum Research Fund (PRF-
AC, administered by the ACS) and the National Institutes
of Health (National Institute of General Medical Sciences
RO1-GM58103). The authors also thank Dr Martha Morton
and Dr David Vander Velde for their assistance with NMR
measurements, and Dr Todd Williams for HRMS analysis.
6. (a) Higaki, J. N.; Chakravarty, S.; Bryant, C. M.; Cowart, L. R.;
Harden, P.; Scardina, J. M.; Mavunkel, B.; Luedtke, G. R.; Cordell,
B. J. Med. Chem. 1999, 42, 3889±3898. (b) Blackburn, C.; Pingali,
A.; Kehoe, T.; Herman, L. W.; Wang, H.; Kates, S. A. Bioorg.
Med. Chem. Lett. 1997, 7, 823±826. (c) Ramsland, P. A.;
Movafagh, B. F.; Reichlin, M.; Edmundson, A. B. J. Mol. Rec.
1999, 12, 249±257. (d) Schullek, J. R.; Butler, J. H.; Ni, Z.-J.;
Chen, D.; Yuan, Z. Anal. Biochem. 1997, 246, 20±29. (e) Dorner,
B.; Ostresh, J. M.; Dooley, C. T.; Eichler, J.; Houghten, R. A. PCT
Int. Appl. WO 97 33,174, 1997; Chem. Abstr. 1997, 127, 263064.
(f) Huang, H.; Martasek, P.; Roman, L. J.; Masters, B. S. S.;
Silverman, R. B. J. Med. Chem. 1999, 42, 3147±3153. (g) Long,
R. D.; Moeller, K. D. J. Am. Chem. Soc. 1997, 119, 12394±12395.
(h) Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J.
Tetrahedron Lett. 1992, 33, 6389±6392.
References
1. (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856±9857. (b) Grubbs, R. H.; Miller, S. J.; Fu, G. C.
Acc. Chem. Res. 1995, 28, 446±452. (c) Fuerstner, A.; Langemann,
K. J. Am. Chem. Soc. 1997, 119, 9130±9136. (d) Blechert, S.;
Schuster, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037±2056.
(e) Randall, M. L.; Snapper, M. L. J. Mol. Catal. A: Chem. 1998,
133, 29±40. (f) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413±4450. (g) La, D. S.; Alexander, J. B.; Cefalo, D. R.; Graf, D.
D.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120,
9720±9721. (h) Zhu, S. S.; Cefalo, D. R.; La, D. S.; Jamieson, J. Y.;
Davis, W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc.
1999, 121, 8251±8259. (i) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371±388. (j) Fu, G. C.; Grubbs, R. H. J. Am. Chem.
Soc. 1992, 114, 5426±5427. (k) Fu, G. C.; Grubbs, R. H. J. Am.
Chem. Soc. 1992, 114, 7324±7325. (l) Crimmins, M. T.; Choy,
A. L. J. Am. Chem. Soc. 1999, 121, 5653±5660. (m) Martin,
S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Patzel, M.; Ramser,
M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251±7264.
(n) Martin, S. F.; Liao, Y.; Chen, H.-J.; Paetzel, M.; Ramser,
M. N. Tetrahedron Lett. 1994, 35, 6005±6008. (o) Schuster, M.;
Stragies, R.; Blechert, S. Targets Heterocycl. Syst. 1998, 2, 193±
206.
7. (a) Zhang, X.; Rodrigues, J.; Evans, L.; Hinkle, B.; Ballantyne,
L.; Pena, M. J. Org. Chem. 1997, 62, 6420±6423. (b) Burgess, K.;
Ibarzo, J.; Linthicum, D. S.; Shin, H.; Shitangkoon, A.; Totani, R.;
Zhang, A. J. J. Am. Chem. Soc. 1997, 119, 1556±1564. (c)
Burgess, K.; Linthicum, D. S.; Shin, H. Angew. Chem., Int. Ed.
Engl. 1995, 34, 907±909. (d) Boeijen, A.; Liskamp, R. M. J. Eur. J.
Org. Chem. 1999, 2127±2135. (e) Hamuro, Y.; Marshall, W. J.;
Scialdone, M. A. J. Comb. Chem. 1999, 1, 163±172. (f) Nefzi, A.;
Dooley, C.; Ostresh, J. M.; Houghten, R. A. Bioorg. Med. Chem.
Lett. 1998, 8, 2273±2278. (g) Anbazhagan, M.; Rakeeb, A.;
Deshmukh, A. S.; Rajappa, S. Tetrahedron Lett. 1998, 39, 3609±
3612.
2. (a) Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117,
5855±5856. (b) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am.
Chem. Soc. 1996, 118, 9606±9614. (c) Hammer, K.; Undheim, K.
Tetrahedron 1997, 53, 5925±5936. (d) Blackwell, H. E.; Grubbs,
R. H. Angew. Chem., Int. Ed. 1998, 37, 3281±3284. (e) Boger,
D. L.; Chai, W. Tetrahedron 1998, 54, 3955±3970. (f) Campagne,
J.-M.; Ghosez, L. Tetrahedron Lett. 1998, 39, 6175±6178. (g) Fink,
B. E.; Kym, P. R.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1998,
120, 4334±4344. (h) O'Leary, D. J.; Miller, S. J.; Grubbs, R. H.
Tetrahedron Lett. 1998, 39, 1689±1690. (i) Ripka, A. S.; Bohacek,
R. S.; Rich, D. H. Bio. Med. Chem. Lett. 1998, 8, 357±360. (j) Fujii,
N.; Hirohashi, M.; Oishi, S.; Akaji, M.; Omagari, A.; Otaka, A.;
Ibuka, T. Pept. Sci. 1999, 36, 193±194.
8. (a) Chou, Y. L.; Guilford, W. J.; Koovakkat, S.; Mohan, R.; Wu,
S. C.; Liang, A.; Trinh, L.; Morrissey, M. M. Book of Abstracts,
215th ACS National Meeting, Dallas, March 29±April 2, 1998,
MEDI-130. (b) Cui, J.; Alkassoum, S.; Zhou, Y.; Wanna, L.;
Crich, D.; Johnson, M. E. Book of Abstracts, 217th ACS National
Meeting, Anaheim, Calif., March 21±25, 1999, MEDI-086.
(c) Galemmo Jr., R. A.; Maduskuie, T. P.; Dominguez, C.;
Rossi, K. A.; Knabb, R. M.; Wexler, R. R.; Stouten, P. F. W.
Bioorg. Med. Chem. Lett. 1998, 8, 2705±2710. (d) Galemmo Jr.,
R. A.; Wells, B. L.; Rossi, K. A.; Alexander, R. S.; Dominguez, C.;
Maduskuie, T. P.; Stouten, P. F. W.; Wright, M. R.; Aungst, B. J.;
Wong, P. C.; Knabb, R. M.; Wexler, R. R. Bioorg. Med. Chem.
Lett. 2000, 10, 301±304. (e) Himmelsbach, F.; Austel, V.; Linz, G.;
Pieper, H.; Guth, B.; Mueller, T.; Weisenberger, J. Eur. Pat.
Appl. EP 587,134, 1994; Chem. Abstr. 1995, 122, 81372.
(f) Himmelsbach, F.; Pieper, H.; Austel, V.; Linz, G.; Mueller,
T.; Weisenberger, J.; Eisert, W. Eur. Pat. Appl. EP 503,548,
1992; Chem. Abstr. 1992, 118, 101980. (g) Himmelsbach, F.;
Pieper, H.; Austel, V.; Linz, G.; Weisenberger, J.; Eisert, W.;
Mueller, T. US Patent 92-849557, 1998; Chem. Abstr. 1999, 130,
66504. (h) Liu, P. S.; Marquez, V. E.; Driscoll, J. S.; Fuller, R. W.;
McCormack, J. J. J. Med. Chem. 1981, 24, 662±666. (i) Mohan, R.;
Morrissey, M. M. PCT Int. Appl. WO 96 38,421, 1996; Chem.
Abstr. 1996, 126, 104087. (j) Boots, S. G.; Boots, M. R.; Moreland,
3. (a) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1998, 39,
3939±3942. (b) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett.
1999, 40, 3297±3300. (c) Bujard, M.; Gouverneur, V.;
Mioskowski, C. J. Org. Chem. 1999, 64, 2119±2123. (d) Trevitt,
M.; Gouverneur, V. Tetrahedron Lett. 1999, 40, 7333±7336.
(e) Hetherington, L.; Greedy, B.; Gouverneur, V. Tetrahedron
2000, 56, 2053±2060. (f) Stoianova, D. S.; Hanson, P. R. Org.
Lett. 2000, 2, 1769±1772. (g) Sprott, K. T.; Hanson, P. R. J. Org.
Chem. 2000, 65, 4721±4728. (h) Sprott, K. T.; Hanson, P. R.
J. Org. Chem. 2000, in press. (i) Sprott, K. T.; McReynolds,
M. D.; Hanson, P. R. Synthesis 2000, in press.
4. (a) Hanson, P. R.; Probst, D. A.; Robinson, R. E.; Yau, M.
Tetrahedron Lett. 1999, 40, 4761±4764. For other examples of
RCM on sulfonamide templates see: (b) Paquette, L. A.; Leit,

9790
J. M. Dougherty et al. / Tetrahedron 56 (2000) 9781±9790
D. E. J. Med. Chem. 1972, 15, 330±332. (k) Nieuwenhuijzen, J. W.;
Conti, P. G. M.; Ottenheijm, H. C. J.; Linders, J. T. M. Tetrahedron
Lett. 1998, 39, 7811±7814. (l) Nefzi, A.; Ostresh, J. M.; Meyer,
J.-P.; Houghten, R. A. Tetrahedron Lett. 1997, 38, 931±934.
9. (a) Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.;
Ru, Y.; Bachelor, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.;
Wong, Y. N.; Chang, C.-H.; Weber, P. C.; Jackson, D. A.; Sharpe,
T. R.; Erickson-Vittanen, S. Science 1994, 263, 380±384.
(b) Patel, M.; Kaltenbach III, R. F.; Nugiel, D. A.; McHugh Jr.,
R. J.; Jadhay, P. K.; Bacheler, L. T.; Cordova, B. C.; Klabe, R. M.;
Erickson-Viitanen, S.; Garber, S.; Reid, C.; Seitz, S. P. Bioorg.
Med. Chem. Lett. 1998, 8, 1077±1082. (c) De Lucca, G. V.;
Kim, U. T.; Liang, J.; Cordova, B.; Klabe, R. M.; Garber, S.;
Bacheler, L. T.; Lam, G. N.; Wright, M. R.; Logue, K. A.;
Erickson-Viitanen, S.; Ko, S. S.; Trainor, G. L. J. Med. Chem.
1998, 41, 2411±2423. (d) De Lucca, G. V.; Lam, P. Y. S. Drugs
of the Future 1998, 23, 987±994. (e) Stone, B. R. P.; Harris, G. D.;
Cann, R. O.; Smyser, T. E.; Confalone, P. N. Tetrahedron Lett.
1998, 39, 6127±6130. (f) Dax, S. L.; Cook, S. C. Biorg. Med.
Chem. Lett. 1996, 6, 797±802. (g) Hodge, C. N.; Lam, P. Y. S.;
Eyermann, C. J.; Jadhav, P. K.; Ru, Y.; Fernandez, C. H.;
De Lucca, G. V.; Chang, C.-H.; Kaltenbach III, R. F.; Holler,
E. R.; Woerner, F.; Daneker, W. F.; Emmett, G.; Calabrese, J. C.;
Aldrich, P. E. J. Am. Chem. Soc. 1998, 120, 4570±4581.
been previously utilized in numerous systems to affect pharmaco-
logical properties: (a) Ripka, A. S.; Rich, D. H. Curr. Opin. Chem.
Â
Biol. 1998, 2, 441±452. (b) Aube, J. Adv. Amino Acid Mimetics
Peptidomimetics 1997, 1, 193±232. (c) Natchus, M. G.; Cheng, M.;
Wahl, C. T.; Pikul, S.; Almstead, N. G.; Bradley, R. S.; Taiwo,
Y. O.; Mieling, G. E.; Dunaway, C. M.; Snider, C. E.; McIver,
J. M.; Barnett, B. L.; McPhail, S. J.; Anastasio, M. B.; De, B.
Bioorg. Med. Chem. Lett. 1998, 8, 2077±2080. (d) Ghosh, A. K.;
Kincaid, J. F.; Cho, W.; Walters, D. E.; Krishnan, K.; Hussain,
K. A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J. Bioorg.
Med. Chem. Lett. 1998, 8, 687±690. (e) Janakiraman, M. N.;
Watenpaugh, K. D.; Tomich, P. K.; Chong, K.-T.; Turner, S. R.;
Tommasi, R. A.; Thaisrivongs, S.; Strohbach, J. W. Bioorg. Med.
Chem. Lett. 1998, 8, 1237±1242. (f) Choy, N.; Choi, H.; Jung, W.
H.; Kim, C. R.; Yoon, H.; Kim, S. C.; Lee, T. G.; Koh, J. S.
Bioorg. Med. Chem. Lett. 1997, 7, 2635±2638. (g) Freskos, J. N.;
McDonald, J. J.; Mischke, B. V.; Mullins, P. B.; Shieh, H.-S.;
Stegeman, R. A.; Stevens, A. M. Bioorg. Med. Chem. Lett. 1999,
9, 1757±1760. (h) See also Long Ref. 6g.
16. (a) See Refs. 9 and 10. (b) Nugiel, D. A.; Jacobs, K.; Worley,
T.; Patel, M.; Kaltenbach III, R. F.; Meyer, D. T.; Jadhav, P. K.;
De Lucca, G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.;
Rayner, M. M.; Seitz, S. P. J. Med. Chem. 1996, 39, 2156±2169.
(c) Han, W.; Pelletier, J. C.; Hodge, C. N. Bioorg. Med. Chem. Lett.
1998, 8, 3615±3620. (d) Patel, M.; Bachelor, L. T.; Rayner, M. M.;
Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.; Seitz, S. P.
Bioorg. Med. Chem. Lett. 1998, 8, 823±828. (e) Dax, S. L.; Cook,
S. C. Bioorg. Med. Chem. Lett. 1996, 6, 797±802.
10. (a) Jadhav, P. K.; Woerner, F. J. Tetrahedron Lett. 1995, 36,
6383±6386. (b) Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.;
Hodge, C. N.; De Lucca, G. V.; Rodgers, J. D. US Patent
Â
5,610,294, 1997; Chem. Abstr. 1997, 126, 293367. (c) Hulten, J.;
Bonham, N. M.; Nillroth, U.; Hansson, T.; Zuccarello, G.;
17. (a) See references 9 and 10. (b) Lam, P. Y. S.; Ru, Y.; Jadhav,
P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyermann, C. J.; Chang,
C.-H.; Emmett, G.; Holler, E. R.; Daneker, W. F.; Li, L.;
Confalone, P. N.; McHugh, R. J.; Han, Q.; Li, R.; Markwalder,
J. A.; Sietz, S. P.; Sharpe, T. R.; Bachelor, L. T.; Rayner, M. M.;
Klabe, R. M.; Shum, L.; Winslow, D. L.; Kornhauser, D. M.;
Jackson, D. A.; Erickson-Viitanen, S.; Hodge, C. N. J. Med.
Chem. 1996, 39, 3514±3525. (c) Han, Q.; Chang, C.-H.; Li, R.;
Ru, Y.; Jadhav, P. K.; Lam, P. Y. S. J. Med. Chem. 1998, 41, 2019±
2028. (d) Rodgers, J. D.; Johnson, B. L.; Wang, H.; Erickson-
Viitanen, S.; Klabe, R. M.; Bacheler, L.; Cordova, B. C.; Chang,
C.-H. Bioorg. Med. Chem. Lett. 1998, 8, 715±720.
Ê
Bouzide, A.; Aqvist, J.; Classon, B.; Danielson, U. H.; Karlen,
Â
È
A.; Kvarnstrom, I.; Samuelsson, B.; Hallberg, A. J. Med. Chem.
1997, 40, 885±897. (d) Baeckbro, K.; Loewgren, S.; Oesterlund,
K.; Atepo, J.; Unge, T.; Hulten, J.; Bonham, N. M.; Schaal, W.;
Â
Karlen, A.; Hallberg, A. J. Med. Chem. 1997, 40, 898±902.
Â
(e) Hulten, J.; Andersson, H. O.; Schaal, W.; Danielson, H. U.;
Â
È
Classon, B.; Kvarnstrom, I.; Karlen, A.; Unge, T.; Samuelsson, B.;
Hallberg, A. J. Med. Chem. 1999, 42, 4054±4061.
11. (a) Jadhav, P. K.; Woerner, F. J.; Lam, P. Y. S.; Hodge, C. N.;
Eyermann, C. J.; Man, H.-W.; Daneker, W. F.; Bacheler, L. T.;
Rayner, M. M.; Meek, J. L.; Erickson-Viitanen, S.; Jackson, D. A.;
Calabrese, J. C.; Schadt, M.; Chang, C.-H. J. Med. Chem. 1998, 41,
18. (a) Sowada, R. J. Prakt. Chem. 1963, 20, 310. (b) McDermott,
S. D.; Spillane, W. J.; Org. Prep. Proc. Int. 1984, 16, 49±77.
19. All non-racemic amines were synthesized by Wittig reaction
of Boc-protected a-aminoaldehydes: Fehrentz, J.-A.; Castro, B.
Synthesis 1983, 676±678.
Â
1446±1455. (b) Medou, M.; Priem, G.; Quelever, G.; Camplo, M.;
Kraus, J. L. Tetrahedron Lett. 1998, 39, 4021±4024.
12. (a) Chen, J. J.; Lin, X.; Browner, M. F. Book of Abstracts,
217th ACS National Meeting, Anaheim, Calif., March 21-25,
1999, MEDI-198.
20. (a) See Refs. 9f and 16b. (b) Patel, M.; Rodgers, J. D.;
McHugh Jr., R. J.; Johnson, B. L.; Cordova, B. C.; Klabe, R. M.;
Bacheler, L. T.; Erickson-Viitanen, S.; Ko, S. S. Bioorg. Med.
Chem. Lett. 1999, 9, 3217±3220. (c) Rodgers, J. D.; Sun, J. H.
US Patent 5,532,357, 1996; Chem Abstr. 1995, 125, 168034.
21. (a) Dewynter, G.; Montero, J. L. C. R. Acad. Sci., Ser. II 1992,
315, 1675±1682. (b) Dewynter, G.; Aouf, N.; Criton, M.; Montero,
J.-L. Tetrahedron 1993, 49, 65±76.
13. (a) Groutas, W. C.; Kuang, R.; Venkataraman, R. Epp, J. B.;
Ruan, S.; Prakash, O. Biochemistry 1997, 36, 4739±4750.
(b) Kuang, R.; Epp, J. B.; Ruan, S.; Yu, H.; Huang, P.; He, S.;
Tu, J.; Schechter, N. M.; Turbov, J.; Froelich, C. J.; Groutas, W. C.
J. Am. Chem. Soc. 1999, 121, 8128±8129. (c) Groutas, W. C.;
Kuang, R.; Ruan, S.; Epp, J. B.; Venkataraman, R.; Truong,
T. M. Bioorg. Med. Chem. 1998, 6, 661±671. (d) Groutas, W. C.;
Kuang, R. PCT Int. Appl. WO 99 9,977, 1999; Chem. Abstr. 1999,
130, 209985.
22. (a) Montero, J.-L.; Dewynter, G.-F.; Agoh, B.; Delaunay, B.;
Imbach, J.-L. Tetrahedron Lett. 1983, 24, 3091. (b) Lee, C.-H.;
Korp, J. D.; Kohn, H. J. Org. Chem. 1989, 54, 3077±3083.
(c) Groutas, W. C.; Kuang, R.; Venkataraman, R. Biochem.
Biophys. Res. Comm. 1994, 198, 341±349.
14. (a) Boudjabi, S.; Dewynter, G.; Voyer, N.; Toupet, L.;
Montero, J.-L. Eur. J. Org. Chem. 1999, 2275±2283. (b) Regainia,
Z.; Abdaoui, M.; Aouf, N.-E.; Dewynter, G.; Montero, J.-L.
Tetrahedron 2000, 56, 381±387.
23. Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics
1996, 15, 1518±1520.
15. Preorganization of binding conformations via constraint has