Synthesis of cyclic sulfamoyl carbamates and ureas via ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2005.03.140

Synthetic routes to a diverse set of cyclic sulfamoyl carbamates and ureas are reported. These routes utilize 3-component coupling, Mitsunobu alkylation, and ring-closing metathesis using the second-generation Grubbs catalyst to achieve the synthesis of t

Full text of DOI:10.1016/j.tet.2005.03.140

Tetrahedron 61 (2005) 6218–6230
Synthesis of cyclic sulfamoyl carbamates and ureas via
ring-closing metathesis
Joseph M. Dougherty,a,b Marıa Jimeneza,b and Paul R. Hansona,b,
*
´
´
aDepartment of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
bThe KU Chemical Methodologies and Library Development Center of Excellence, University of Kansas, 1501 Wakarusa Drive,
Lawrence, KS 66047, USA
Received 14 December 2004; revised 26 January 2005; accepted 4 March 2005
Available online 12 May 2005
Abstract—Synthetic routes to a diverse set of cyclic sulfamoyl carbamates and ureas are reported. These routes utilize 3-component
coupling, Mitsunobu alkylation, and ring-closing metathesis using the second-generation Grubbs catalyst to achieve the synthesis of the
target S-heterocyclic compounds. Cyclic S-heterocycles ranging from 9- to 11-membered rings have been obtained.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The recent growth of high-throughput screening for
biologically active agents has increased the demand for
diverse libraries of synthetic compounds.1 A growing area
in combinatorial chemistry2 is the generation of novel
structural scaffolds that are inherently advantageous from
both a chemical and a biological standpoint.3 The ability of
the sulfonamide moiety, and related analogs, to serve as
non-hydrolyzable amide surrogates has opened the door for
their use as key functional groups in the development of new
scaffolds. A number of compounds based on this premise
have been developed including, biologically active sulfona-
Figure 1.
mides,4 sulfamides,5 sulfamoyl carbamates,6 sulfahydan-
of synthesis utilizing the 3-component coupling with
toins,7 and sulfamoyl ureas.8 Recently, novel libraries based
chlorosulfonyl isocyanate (CSI), and facile derivatization
by standard alkylation and Mitsunobu alkylation.17 The
result has been the production of linear sulfamoyl
carbamates,18,19 sulfahydantoins,16 and linear16,20 and
cyclic sulfamides.13a,15 Sulfamoyl carbamates have been
studied as acyl-CoA:cholesterol O-acyl-transferase (ACAT)
inhibitors21 in conjunction with sulfamoyl ureas, vide infra.
While examples of acyclic sulfamoyl carbamates are
prevalent in the literature, reports of cyclic sulfamoyl
carbamates are limited, with only two cases reported to date
(compounds 6 and 7, Fig. 2).22 Furthermore, no examples of
on sulfonamide,9 sulfamoyl urea,10 sulfahydantoin,11 and
sulfamide12 scaffolds have been reported. Our interest in the
development of new routes to both phosphorus and sulfur-
containing heterocycles (P- and S-heterocycles)13 leads us
to herein report a ring-closing metathesis (RCM) route13,14
to a diverse set of cyclic sulfamoyl carbamates (4) and
sulfamoyl ureas (5). These compounds represent novel
scaffolds possessing multiple points of diversity from which
to produce combinatorial libraries.
Sulfamoyl carbamates of structure 2 (Fig. 1) have been
primarily used as important synthetic intermediates in the
generation of unsymmetric sulfamides13a,15 and sulfa-
hydantoins.16 Their popularity originates from their ease
Keywords: Cyclic sulfamoyl carbamate; Cyclic sulfamoyl urea; Sulfur
heterocycles; RCM; Metathesis.
*
Corresponding author. Tel.: C1 785 864 3094; fax: C1 785 864 5396;
e-mail: phanson@ku.edu
Figure 2.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.140

J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
6219
cyclic sulfamoyl carbamates of general structure 8 have
been reported.
Sulfamoyl ureas have been shown to be active as
hypoglycemic agents,23 ACAT inhibitors,21 and herbi-
cides.24 Large libraries of linear sulfamoyl ureas have
been synthesized from the 3-component coupling of two
amine nucleophiles and CSI. The chemical features of the
sulfamoyl urea group are different from that of a sulfamoyl
carbamate. The higher pKa of the urea N–H, compared to
the carbamate N–H, has hindered efforts to alkylate the urea
N–H using the Mitsunobu reaction. Thus, derivatization of
these compounds has previously fallen solely to base
alkylation. Cyclic sulfamoyl ureas have been largely
unexplored. To date, a single report has appeared detailing
the synthesis of cyclic sulfamoyl ureas 9 and 10 (Fig. 3).25
Figure 4.
The emergence of ring-closing olefin metathesis (RCM)26,27
over the last decade has fundamentally changed the method
of generating both carbocyclic and heterocyclic targets.27
Specifically, RCM has become a routine transformation for
the facile construction of small-, medium-, and large ring-
containing systems.27,28 When coupled with the versatile
nature of both titled compounds, several factors provided
impetus for this investigation, including: (i) the ease of
synthesis and analog generation in both sulfamoyl carba-
mate and urea classes, (ii) the convenience of using RCM to
generate cyclic structures, (iii) the ability of both sulfamoyl
carbamate and urea moieties to serve as surrogates for
sulfamide or urea groups present in known biologically
active systems, and (iv) the correlation to the known
biological activities of linear sulfamoyl carbamates and
ureas.
Figure 5.
nitrogen; and (iv) generate novel cyclic sulfamoyl carba-
mates and sulfamoyl ureas utilizing RCM.
Our initial efforts began with the 3-component coupling of
allyl alcohol, CSI, and N-allyl (L)-valine methyl ester (13a)
to produce the corresponding sulfamoyl carbamate 14a
(Scheme 1). Optimization of the reaction conditions led to
the use of 1.2 equiv of Et3N to efficiently facilitate the
formation of sulfamoyl carbamate 14a in 79% yield.
Sulfahydantoin formation via intramolecular cyclization
between the carbamate nitrogen and the ester group was
thwarted under these conditions. Next, it was synthetically
desirable to functionalize the carbamate nitrogen in 14a.
Though alkylation of sulfamoyl carbamates with K2CO3
was a viable option, the Mitsunobu reaction was employed
because of its versatility and to reduce possible hydantoin
formation. Subjection of 14a to Mitsunobu conditions gave
sulfamoyl carbamate 15a in excellent yield (89–92%).
Figure 3.
2. Results and discussion
Previously, we have utilized sulfamoyl carbamate building
blocks as synthetically valuable starting materials to
generate a variety of unsymmetic cyclic sulfamides related
to the potent HIV protease inhibitors DMP-323 and DMP-
450.15 Our new route utilizes this functional group as the
central ‘linchpin’ in an RCM methodology. The strength of
this approach lies in the wide variety of 9–11-membered
cyclic sulfamoyl carbamates (4) (Fig. 4) and sulfamoyl
ureas (5) (Fig. 5) that can be accessed from the correspond-
ing dienes of general structure 11 and 12, respectively.
The focal points of this method include the ability to: (i) use
3-component coupling of CSI, allylic alcohols and allylic
amines to synthesize sulfamoyl carbamates and sulfamoyl
ureas with asymmetry in peripheral areas of the molecules;
(ii) functionalize the sulfamoyl carbamate nitrogen via a
Mitsunobu reaction; (iii) utilize base-promoted alkylation or
the Mitsunobu reaction to functionalize the sulfamoyl urea
Scheme 1.
The initial attempts to cyclize diene 15a using (PCy3)2-
(Cl)2Ru]CHPh (cat-A)29 resulted in formation of 9-mem-
bered cyclic sulfamoyl carbamate 16a in only 33% yield,
with a major byproduct tentatively assigned as the dimer
arising from cross-metathesis (X-MET).30 RCM using
the more active (IMesH2)(PCy3)(Cl)2Ru]CHPh catalyst
(cat-B)31 resulted in the formation of desired 9-membered

6220
J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
Table 1
these yields were marginal, no X-MET dimer was observed,
prompting us to further optimize the RCM reaction.
Entry
3-Component
coupling yield
Mitsunobu
yield
Product
RCM yield
In the second route shown in Scheme 2, 3-component
coupling was carried out with various olefinic alcohols, CSI,
and (L)-phenylalanine methyl ester to produce corresponding
sulfamoyl carbamates 17a–c in good yields (56–86%). The
Mitsunobu reaction was employed to regioselectively install
the PMB moiety at the carbamate position (N–R2 position) in
sulfamoyl carbamates 18a–c (79–97%). Allylation under
standard conditions produced RCM precursors 19a–c (90–
99%). Subjection to RCM conditions using cat-B in refluxing
DCE gave corresponding 9-, 10-, and 11-membered cyclic
sulfamoyl carbamates 20a–c in good yields (65–87%).
1
2
3
14b (90%)
14c (85%)
14d (86%)
15b (92%)
15c (87%)
15d (81%)
16b (40%)
16c (51%)
16d (52%)
The initial examples outlined in Schemes 1 and 2 utilized
simple Mitsunobu benzylation to install diversity at the
sulfamoyl carbamate N–R2 position. Installation of side
chains bearing stereogenic centers, as previously shown
in the synthesis of unsymmetric sulfamides,15 were next
pursued as outlined in Scheme 3. Thus, alkylation of 21 with
naturally occurring (S)-ethyl lactate under Mitsunobu
conditions, generated 22 in 65% yield. Simple allylation,
followed by RCM in DCE afforded cyclic sulfamoyl
carbamate 24 in good yield (70%) containing both valine
and alanine side chains at the periphery.
cyclic sulfamoyl carbamate 16a in 69% overall yield, with
no observable dimer formation via X-MET. This newly
formed sulfamoyl carbamate represents the first example of
RCM on this class of compounds and highlights the
potential for library production utilizing more elaborate
alcohols at the stage of both initial coupling and Mitsunobu
alkylation steps.
With a general route to cyclic sulfamoyl carbamates in
hand, analogous cyclic sulfamoyl carbamates were synthe-
sized using benzylamine and other (L)-amino esters as
represented in Table 1. Coupling with CSI and allyl alcohol
afforded sulfamoyl carbamates 14b–d in good yields
(85–90%). Benzylation via the Mitsunobu reaction afforded
metathesis precursors 15b–d in 81–92% yields. RCM with
6 mol% of cat-B gave cyclic sulfamoyl carbamates 16b–d
in modest yields of 40–52%. The Georg RCM purification
procedure,32 employing DMSO, was utilized to purify
compounds throughout this study. Surprisingly, although
Scheme 3.
Subsequent efforts were focused toward the exploration of a
similar three-step protocol to generate 9-membered cyclic
sulfamoyl ureas (Scheme 4). Benzylamine was chosen as
the initial test substrate, due to potential problems with
sulfahydantoin formation from the use of amino esters, vide
infra. Coupling of 2 equiv of benzylamine with CSI gave 25
in 90% yield (Scheme 4). As with the sulfamoyl carbamates,
functionalization of the urea nitrogen with a benzyl group
was desirable. Unfortunately, sulfamoyl ureas were unable
to undergo Mitsunobu benzylations under standard DEAD
Scheme 2.
Scheme 4.

J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
6221
or DIAD conditions. Initial attempts at benzylation using
DBU and NaH were found to be surprisingly ineffective
despite literature precedent,21 yielding no noticeable
benzylated product. Utilizing our previous method to
alkylate sulfamides (K2CO3, BnBr) resulted in the forma-
tion of benzylated sulfamoyl carbamate 26, albeit in a
modest 58% yield. RCM of 26 proved to be efficient as
6 mol% cat-B afforded 9-membered cyclic sulfamoyl urea
27 in 74% yield. Importantly, no product from X-MET was
observed. This result represents the first known example of
RCM on a sulfamoyl urea template, and opens opportunities
to diversification strategies.
(43–65%). Surprisingly, these conditions produced only
minor amounts of the sulfahydantoin despite elevated
temperatures, with no single entry yielding more than 5%
of hydantoin byproduct.
Metathesis of the amino ester-derived sulfamoyl ureas met
with consistent results as treatment of 30a–c with 6 mol% of
cat-B afforded the desired cyclic sulfamoyl ureas 31a–c
in good yields (71–81%). Importantly, no byproducts via
X-MET were observed during the RCM.
An alternate route of benzylation was sought in order to
circumvent problems associated with generating benzylated
sulfamoyl ureas. We felt that if a Mitsunobu reaction could
be initiated at the sulfamoyl urea nitrogen, the potential
for derivatization would greatly improve. The difficulty is
encountered in the inability of the DEAD/PPh3 complex to
deprotonate the sulfamoyl ureas containing a less acidic
N–H moiety. Mitsunobu reactions with higher pKa nucleo-
philes have been realized with the advent of 1,10-(azo-
dicarbonyl)dipiperidine-tributylphosphine (ADDP)33 as a
more powerful DEAD equivalent. To test the efficacy of this
method, benzylamine-derived sulfamoyl urea 25 was
subjected to modified conditions with ADDP, to afford
benzylated sulfamoyl urea 26 in 52% yield (Scheme 7).
To our knowledge, this is the first example of a Mitsunobu
reaction using a sulfamoyl urea as the nucleophile. Though
the yield was less than that obtained via standard alkylation
conditions, these results are encouraging. In addition to
nitrogen protection, utilization of more elaborate non-
racemic secondary alcohols will provide an excellent
pathway for diversification of these sulfamoyl ureas.
With a method for the generation of cyclic sulfamoyl ureas
in hand, the synthesis of sulfamoyl ureas utilizing allylated
aminoesters was explored. Sulfahydantoin formation,
arising from attack of the sulfamoyl urea nitrogen into the
sulfamide amino ester forming hydantoin 29, was of major
concern (Scheme 5). Thus, our initial use of excess base in
the 3-component coupling reaction generated sulfahydan-
toins as a significant byproduct. In addition, the sulfamoyl
ureas were found to form the sulfahydantoin at rt, over time,
and in small amounts during column chromatography.
Scheme 5.
Despite these concerns, our initial 3-component coupling
reaction with allylated amino ester 13a–c and CSI produced
sulfamoyl ureas 28a–c in good overall yields (Scheme 6).
Furthermore, optimal results were obtained with 1.2 equiv
of Et3N and 2.2 equiv of the amino ester. Use of lesser
equivalents of the amino ester gave a complex mixture of
product, sulfahydantoin and sulfamoyl chloride. For stab-
ility reasons, benzylation was therefore utilized as a means
of both protection and functionalization. The standard
K2CO3 promoted benzylation of 28a–c resulted in moderate
yields of benzyl-protected RCM precursors 30a–c
Scheme 7.
3. Conclusion
In conclusion, we have described the first synthesis of both
cyclic sulfamoyl carbamates and ureas utilizing RCM. This
method represents an extension of our recent sulfamide
research and a new direction in the synthesis of novel
S-heterocycles. Further research on sulfamoyl carbamates
will focus on functionalization of the sulfamoyl carbamate
nitrogen utilizing secondary allylic alcohols and amines in the
3-component coupling reaction to generate a variety of novel
sulfamoyl carbamates and sulfamoyl ureas. In addition, the
Mitsunbou reaction will be optimized and exploited as an
important means to functionalize the sulfamoyl ureas.
Biological screening and further refinement of these com-
pounds is underway and will be reported in due course.
4. Experimental
4.1. General
All reactions were carried out in flame-dried glassware
Scheme 6.

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J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
under argon. Toluene, THF, Et2O, and CH2Cl2 were purified
by passage through a purification system (Solv-Tek)
employing activated Al2O3.34 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
FTIR (neat) 3620, 3600, 3260, 3087, 3031, 2928, 1747,
1647, 1606, 1455, 1352, 1150, 778, 700 cmK1; HRMS
(MCH)C calcd for C14H19N2O4S 311.1066, found
311.1050.
4.1.3. N-[[[(2-Propenyloxy)carbonyl]amino]sulfonyl]-N-
(2-propenyl)-(S)-leucine methyl ester (14c). In a pro-
cedure similar to the preparation of sulfamoyl carbamate
14a, coupling and flash chromatography (SiO2, hexanes/
EtOAc) yielded 727 mg (85%) of the sulfamoyl carbamate
14c as a clear yellow oil. TLC RfZ0.28 (3:1 hexanes/
EtOAc); [a]2D5 K88 (c 1.5, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.70 (bs, 1H), 6.00–5.87 (m, 1H), 6.00–5.87 (m,
1H), 5.35 (dd, JZ17.2, 1.4 Hz, 1H), 5.26 (dd, JZ10.5,
1.2 Hz, 1H), 5.20 (dd, JZ17.2, 1.2 Hz, 1H), 5.13 (dd, JZ
10.1, 1.1 Hz, 1H), 4.63–4.60 (m, 2H), 4.63–4.60 (m, 1H),
4.20 (dd, JZ16.7, 5.4 Hz, 1H), 3.92 (dd, JZ16.5, 7.3 Hz,
1H), 3.71 (s, 3H), 1.78–1.63 (m, 2H), 1.78–1.63 (m, 1H),
0.96 (d, JZ6.2 Hz, 3H), 0.91 (d, JZ6.2 Hz, 3H); 13C
(CDCl3, 100 MHz) d 172.1, 150.9, 134.9, 131.4, 119.1,
117.6, 67.5, 59.5, 52.2, 49.6, 38.9, 24.3, 22.5, 21.3; FTIR
(neat) 3620, 3600, 3033, 2954, 1747, 1647, 1606, 1455,
1
purchased from Advanced Chem Tech. H and 13C spectra
were recorded in CDCl3 on either a Bruker DRX-400 or a
Bruker AM-500 spectrometer operating at 400/100 MHz
and 500/125 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 a Nicolet 320 Fourier
Transform Infrared Spectrophotometers. Melting points
were obtained on a Thomas Hoover capillary melting
point apparatus. Optical rotations were carried out on a
Rudolph Automatic Polarimeter (AUTOPOL IV).
4.1.1. N-[[[(2-Propenyloxy)carbonyl]amino]sulfonyl]-N-
(2-propenyl)-(S)-valine methyl ester (14a). To a stirring
solution of chlorosulfonyl isocyanate (CSI) (0.61 mL,
7.01 mmol) and CH2Cl2 (25 mL) at 0 8C was added allyl
alcohol (0.40 mL, 7.01 mmol) in CH2Cl2 (3 mL) and stirred
10 min. The mixture was then transferred, via cannula, to
a stirring solution of allylvaline methyl ester (1.23 g,
7.71 mmol) and Et3N (1.17 mL, 8.41 mmol) in CH2Cl2
(35 mL) at 0 8C. The resulting mixture was stirred for 12 h.
The solvent was removed and EtOAc (80 mL) was added.
The solution was washed with 10% NaHSO4 (60 mL),
NaHCO3 (2!50 mL), brine (60 mL), dried with MgSO4,
filtered, and the solvent removed. Flash chromatography
(SiO2, hexanes/EtOAc) afforded 1.86 g (79%) of 14a as a
yellow solid. TLC RfZ0.28 (3:1 hexanes/EtOAc). Mp
72 8C; [a]2D5 K67.7 (c 1.5, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.50 (s, 1H), 5.97 (dddd, JZ17.5, 10.1, 7.7,
5.4 Hz, 1H), 5.89 (dddd, JZ16.2, 11.6, 5.8, 5.8 Hz, 1H),
5.33 (dd, JZ17.1, 1.4 Hz, 1H), 5.25 (dd, JZ10.5, 1.2 Hz,
1H), 5.22 (dd, JZ17.2, 1.4 Hz, 1H), 5.13 (dd, JZ10.1,
1.1 Hz, 1H), 4.62–4.59 (m, 2H), 4.24 (ddd, JZ16.4, 5.4,
1.4 Hz, 1H), 4.12–4.06 (m, 1H), 4.12–4.06 (m, 1H), 3.69 (s,
3H), 2.21–2.15 (m, 1H), 1.02 (d, JZ6.6 Hz, 3H), 0.94 (d,
JZ6.6 Hz, 3H); 13C (CDCl3, 100 MHz) d 170.9, 150.6,
134.8, 131.3, 119.2, 117.8, 67.1, 66.8, 51.7, 49.6, 28.7, 19.6,
1379, 1147 cmK1
;
C14H25N2O6S 349.1433, found 349.1421.
HRMS (MCH)C calcd for
4.1.4. N-[[[(2-Propenyloxy)carbonyl]amino]sulfonyl]-N-
(2-propenyl)-(S)-phenylalanine methyl ester (14d). In a
procedure similar to the preparation of sulfamoyl carbamate
14a, coupling and flash chromatography (SiO2, hexanes/
EtOAc) yielded 1.36 g (86%) of 14d as a yellow oil. TLC
RfZ0.21 (3:1 hexanes/EtOAc); [a]2D5 K29.3 (c 1.5, CHCl3);
1H NMR (CDCl3, 400 MHz) d 7.53 (bs, 1H), 7.31–7.21 (m,
5H), 5.95–5.80 (m, 1H), 5.95–5.80 (m, 1H), 5.35 (dd, JZ
17.2 Hz, 1.4 Hz, 1H), 5.26 (dd, JZ10.4, 1.1 Hz, 1H), 5.24
(dd, JZ18.1, 1.2 Hz, 1H), 5.16 (dd, JZ10.2, 1.1 Hz, 1H),
4.79 (dd, JZ7.5, 7.5 Hz, 1H), 4.62 (dd, JZ5.7, 1.1 Hz, 1H),
4.15 (ddd, JZ16.4, 6.0, 1.0 Hz, 1H), 4.01 (ddd, JZ16.3,
6.4 Hz, 1H), 3.67 (s, 3H), 3.32 (dd, JZ14.0, 7.8 Hz, 1H),
3.32 (dd, JZ14.0, 7.8 Hz, 1H), 3.11 (dd, JZ14.1, 7.5 Hz,
1H); 13C (CDCl3,100 MHz) 170.9, 150.6, 136.5, 134.2,
131.3, 129.2, 128.5, 127.0, 119.2, 118.4, 67.1, 62.2, 52.3,
50.2, 36.8; FTIR (neat) 3620, 3600, 3262, 3029, 2953, 1747,
1648, 1605, 1496, 1455, 1367, 1159, 750, 700 cmK1
;
(HRMS (MCH)C calcd for C17H23N2O6S 383.1277, found
383.1275.
19.4; FTIR (neat) 3260, 2967, 1747, 1456, 1370, 1142 cmK1
;
HRMS (MCH)C calcd for C13H23N2O6S 335.1277, found
335.1283.
4.1.5. N-[[[(2-Propenyloxy)carbonyl]-N0-(benzyl)amino]-
sulfonyl]-N-(2-propenyl)-(S)-valine methyl ester (15a).
To a stirring solution of sulfamoyl carbamate 14a (1.00 g,
3.4 mmol) and DEAD (0.562 mL, 3.57 mmol) in THF
(1 mL) under argon, was added a mixture of BnOH
(0.370 mL, 3.57 mmol) and PPh3 (936 mg, 3.57 mmol) in
THF (1 mL) via dropwise addition from a syringe. The
solution was stirred for 6 h, the solvent removed, and
purified by flash chromatography to yield 1.20 g (92%)
of 15a as a clear oil. TLC RfZ0.45 (3:1 hexanes/EtOAc);
[a]2D5 K65.9 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d
7.41 (d, JZ7.9 Hz, 2H), 732–7.23 (m, 3H), 5.97 (dddd, JZ
18.0, 13.0, 7.8, 5.2 Hz, 1H), 5.88 (dddd, JZ16.3, 10.5, 5.8,
5.8 Hz, 1H), 5.30, (dd, JZ17.2, 1.4 Hz, 1H), 5.24 (dd, JZ
10.5, 1.1 Hz, 1H), 5.20 (dd, JZ18.3, 1.1 Hz, 1H), 5.11 (dd,
JZ10.1, 1.0 Hz, 1H), 4.90 (s, 2H), 4.63 (dd, JZ5.8, 1.2 Hz,
2H), 4.25 (ddd, JZ16.4, 5.1, 1.4 Hz, 1H), 4.10 (dd, JZ16.4,
4.1.2. N-[[[(2-Propenyloxy)carbonyl]amino]sulfonyl]-N-
(2-propenyl)-benzylamine (14b). In a procedure similar to
the preparation of sulfamoyl carbamate 14a, allyl alcohol
(0.48 mL, 7.08 mmol) and allylbenzylamine (1.25 g,
8.48 mmol) were subjected to 3-component coupling
conditions. Flash chromatography (SiO2, hexanes/EtOAc)
yielded 1.98 g (90%) of 14b as a clear liquid. TLC RfZ0.27
1
(3:1 hexanes/EtOAc); H NMR (CDCl3, 400 MHz) d 7.65
(bs, 1H), 7.35–7.8 (m, 5H), 5.90 (dddd, JZ16.4, 1.5, 5.8,
5.8 Hz, 1H), 5.78 (dddd, JZ16.8, 12.9, 6.5, 6.5 Hz, 1H),
5.36 (dd, JZ17.2, 1.2 Hz, 1H), 5.28 (dd, JZ10.4, 1.0 Hz,
1H), 5.19 (d, JZ8.9 Hz, 1H), 5.16 (dd, JZ16.7, 1.1 Hz,
1H), 4.64 (d, JZ5.8 Hz, 2H), 4.55 (s, 2H), 3.91 (d, JZ
6.4 Hz, 2H); 13C (CDCl3, 100 MHz) d 150.9, 135.7, 132.1,
131.2, 128.6, 128.4, 127.9, 119.4, 119.3, 67.1, 51.9, 50.6;

J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
6223
7.9 Hz, 1H), 3.89 (d, JZ10.4 Hz, 1H), 3.66 (s, 3H), 2.19–
2.09 (m, 1H), 1.02 (d, JZ6.6 Hz, 3H), 0.88 (d, JZ6.6 Hz,
3H); 13C (CDCl3, 100 MHz) d 170.7, 152.5, 137.1, 135.3,
131.3, 128.3, 128.1, 127.6, 119.2, 117.2, 67.6, 66.3, 52.3,
51.4, 49.7, 28.7, 19.6, 19.2; FTIR (neat) 3033, 2967, 1739,
16.6, 6.7 Hz, 1H), 3.61 (s, 3H), 3.26 (dd, JZ13.8, 9.0 Hz,
1H), 3.04 (dd, JZ13.8, 9.0 Hz, 1H); 13C (CDCl3,100 MHz)
170.4, 152.6, 137.1, 136.5, 135.1, 131.4, 129.2, 128.5,
128.4, 128.2, 127.7, 126.9, 119.2, 117.6, 67.7, 61.6, 52.2,
51.9, 50.1, 37.1; FTIR 3031, 2952, 1732, 1649, 1605, 1496,
1454, 1384, 1170, 750, 700 cmK1; HRMS (neat) (MCH)C
calcd for C24H29N2O6S 473.1746, found 473.1744.
1649, 1607, 1497, 1435, 1370, 1142, 701, 768 cmK1
;
HRMS (MCH)C calcd for C20H29N2O6S 425.1746, found
425.1729.
4.1.9. (2S)-2-(3-Benzyl-2,4,4-trioxo-3,4,6,9-tetrahydro-
2H-4l6-[1,4,3,5]oxathiadiazonin-5-yl)-3-methyl-butyric
acid methyl ester (16a). Sulfamoyl carbamate 15a
(200 mg, 0.471 mmol), and CH2Cl2 (50 mL) were placed
in a 100 mL round-bottomed flask and degassed with argon
gas for 15 min. Catalyst B (12 mg, 0.014 mmol) was added,
the flask was quickly fitted with a condenser under argon
balloon, and the solution heated to reflux for 12 h. Another
equivalent of catalyst was added (12 mg, 0.014 mmol) and
the solution stirred for 6 h. The solution was cooled to rt,
DMSO (0.2 mL) added, and the solution stirred for 12 h.
The solvent was removed under reduced pressure and the
material was subjected to flash chromatography (SiO2,
hexanes/EtOAc) to yield 128 mg (69%) of 16a as a white
solid. TLC RfZ0.23 (3:1 hexanes/EtOAc). Mp 97–98 8C
[a]2D5 K27.3 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d
7.44 (d, JZ7.2 Hz, 2H), 7.34–7.25 (m, 3H), 5.73 (dddd, JZ
11.4, 3.6, 1.6, 1.6 Hz, 1H), 5.60–5.53 (m, 1H), 5.30 (d, JZ
16.0 Hz, 1H), 5.00 (d, JZ15.5 Hz, 1H), 4.90 (d, JZ
15.5 Hz, 1H), 4.82–4.77 (m, 1H), 4.67 (d, JZ16.5 Hz, 1H),
3.92 (d, JZ11.0 Hz, 1H), 3.60–3.50 (m, 1H), 3.54 (s, 3H),
2.35–2.26 (m, 1H), 1.02 (d, JZ6.3 Hz, 3H), 0.99 (d, JZ
6.7 Hz, 3H); 13C (CDCl3, 100 MHz) d 170.7, 153.1, 136.8,
131.3, 128.4, 128.2, 127.7, 125.4, 64.5, 63.7, 52.2, 51.5,
43.3, 25.8, 20.9, 18.6; FTIR (neat) 3023, 2967, 1741, 1600,
1507, 1386, 1136, 767, 701 cmK1; HRMS (MCH)C calcd
for C18H25N2O6S 397.1433, found 397.1429.
4.1.6. N-[[[(2-Propenyloxy)carbonyl]-N0-(benzyl)amino]-
sulfonyl]-N-(2-propenyl)-benzylamine (15b). In a pro-
cedure similar to the preparation of sulfamoyl carbamate
15a, Mitsunobu reaction and flash chromatography (SiO2,
hexanes/EtOAc) afforded 1.19 g (92%) of 15b as a clear
liquid. TLC RfZ0.51 (3:1 hexanes/EtOAc); 1H NMR
(CDCl3, 400 MHz) d 7.45 (d, JZ8.5 Hz, 2H), 7.35–7.24
(m, 8H), 5.92 (dddd, JZ16.4, 11.7, 5.9, 5.9 Hz, 1H), 5.65
(dddd, JZ16.8, 10.5, 6.5, 6.5 Hz, 1H), 5.35 (dd, JZ17.4,
1.2 Hz, 1H), 5.28 (d, JZ10.4 Hz, 1H), 5.14 (d, JZ10.2 Hz,
1H), 5.06 (dd, JZ17.2, 1.2 Hz, 1H), 4.94 (s, 2H), 4.70
(d, JZ5.8 Hz, 2H), 4.46 (s, 2H), 3.77 (d, JZ6.4 Hz, 2H);
13C (CDCl3, 100 MHz) d 152.8, 137.2, 136.0, 132.0, 131.4,
128.5, 128.4, 128.3, 128.2, 127.7, 127.7, 119.4, 119.0, 67.6,
52.0, 51.8, 50.3; FTIR (neat) 3086, 3033, 2983, 1732, 1650,
1606, 1496, 1455, 1372, 1158, 750, 700 cmK1; HRMS
(MCH)C calcd for C21H25N2O4S 401.1535, found
401.1517.
4.1.7. N-[[[(2-Propenyloxy)carbonyl]-N0-(benzyl)amino]-
sulfonyl]-N-(2-propenyl)-(S)-leucine methyl ester (15c).
In a procedure similar to the preparation of sulfamoyl
carbamate 15a, Mitsunobu reaction and flash chromatog-
raphy (SiO2, hexanes/EtOAc) afforded 721 mg (87%) of
15c as a clear yellow liquid. TLC RfZ0.49 (3:1 hexanes/
EtOAc); [a]2D5 K81.5 (c 5.0, CHCl3); H NMR (CDCl3,
1
400 MHz) d 7.41 (d, JZ7.1 Hz, 2H), 7.33–7.23 (m, 3H),
5.99–5.86 (m, 1H), 5.99–5.86 (m, 1H), 5.33 (dd, JZ17.2,
1.3 Hz, 1H), 5.26 (dd, JZ10.4, 1.0 Hz, 1H), 5.16 (dd, JZ
17.2, 1.2 Hz, 1H), 5.10 (dd, JZ10.2, 1.0 Hz, 1H), 4.93
(d, JZ15.7 Hz, 1H), 4.75 (d, JZ15.6 Hz, 1H), 4.67 (d, JZ
5.7 Hz, 2H), 4.40 (dd, JZ8.6, 6.0 Hz, 1H), 4.17 (d, JZ16.7,
5.3 Hz, 1H), 3.91 (dd, JZ16.7, 7.4 Hz, 1H), 3.65 (s, 3H),
1.71–1.56 (m, 2H), 1.71–1.56 (m, 1H), 0.93 (d, JZ6.2 Hz,
3H), 0.88 (d, JZ6.4 Hz, 3H); 13C (CDCl3,100 MHz) d
171.9, 153.1, 137.6, 136.0, 131.8, 128.7, 128.6, 128.0,
119.5, 117.4, 68.6, 59.3, 52.6, 52.2, 50.1, 39.8, 24.7, 22.7,
21.8; FTIR (neat) 3033, 2955, 1747, 1649, 1607, 1497,
1455, 1380, 1147, 770, 700 cmK1; HRMS (MCH)C calcd
for C21H31N2O6S 439.1903, found 439.1904.
4.1.10. 2,9-Dibenzyl-1,1-dioxo-1,2,4,5,8,9-hexahydro-
1l6-[1,4,2,9]thiaoxdiazonin-3-one (16b). In a procedure
similar to that used for the preparation of 16a, sulfamoyl
carbamate 15b (200 mg, 0.50 mmol) and cat-B (13 mg,
0.015 mmol) in CH2Cl2 (50 mL) were subjected to RCM.
Flash chromatography (SiO2, 3:1 hexane/EtOAc) afforded
74 mg (40%) of 16b as a brown oil. TLC RfZ0.40 (3:1
1
hexanes/EtOAc); H NMR (CDCl3, 400 MHz) d 7.48 (d,
JZ7.2 Hz, 2H), 7.37–7.26 (m, 8H), 5.93 (dt, JZ11.5,
3.2 Hz, 1H), 5.58–5.50 (m, 1H), 5.50 (bs, 2H), 4.92 (s, 2H),
4.14–3.86 (m, 2H), 3.96 (bs, 2H); 13C (CDCl3, 100 MHz) d
153.5, 137.7, 134.6, 132.9, 128.8, 128.6, 128.5, 128.3,
128.2, 127.9, 125.8, 64.6, 51.4, 48.7, 44.3; FTIR (neat)
3220, 3030, 2980, 1729, 1508, 1370, 1167, 753, 699 cmK1
;
HRMS (MCH)C calcd for C19H21N2O4S 373.1222, found
373.1220.
4.1.8. N-[[[(2-Propenyloxy)carbonyl]-N0-(benzyl)amino]-
sulfonyl]-N-(2-propenyl)-(S)-phenylalanine methyl ester
(15d). In a procedure similar to the preparation of sulfamoyl
carbamate 15a, Mitsunobu and flash chromatography (SiO2,
hexanes/EtOAc) afforded 1.24 (81%) of 15d as a clear oil.
TLC RfZ0.40 (3:1 hexanes/EtOAc); [a]2D5 K27.3 (c 1.5,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.42 (d, JZ7.1 Hz,
2H), 7.33–7.23 (m, 6H), 7.17 (d, JZ6.9 Hz, 2H), 5.98–5.86
(m, 1H), 5.98–5.86 (m, 1H), 5.33 (dd, JZ17.2, 1.2 Hz, 1H),
5.27 (dd, JZ10.4, 1.3 Hz, 1H), 5.26 (dd, JZ16.7, 1.3 Hz,
1H), 5.17 (dd, JZ10.2, 1.1 Hz, 1H), 4.94 (d, JZ15.6 Hz,
1H), 4.86 (d, JZ15.7 Hz, 1H), 4.69–4.65 (m, 2H), 4.69–
4.65 (m, 1H), 4.21 (dd, JZ16.7, 5.8 Hz, 1H), 4.06 (dd, JZ
4.1.11. (2S)-2-(3-Benzyl-2,4,4-trioxo-3,4,6,9-tetrahydro-
2H-4l6-[1,4,3,5]oxathiadiazonin-5-yl)-4-methyl-penta-
noic acid methyl ester (16c). In a procedure similar to that
used for the preparation of 16a, sulfamoyl carbamate 15c
(121 mg, 0.28 mmol) and cat-B (17 mg, 0.020 mmol) in
CH2Cl2 (56 mL) were subjected to RCM. Flash chroma-
tography (SiO2, 10:1 heptane/EtOAc) afforded 58 mg (51%)
of 16c as a white solid. TLC RfZ0.26 (3:1 hexanes/EtOAc).
Mp 78–80 8C; [a]D25 K54.3 (c 1.1, CHCl3); 1H NMR
(CDCl3, 400 MHz) d 7.45 (d, JZ7.0 Hz, 2H), 7.33–7.23

6224
J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
(m, 3H), 5.73 (dddd, JZ11.7, 3.7, 1.8, 1.8 Hz, 1H), 5.56–
5.51 (m, 1H), 5.28 (dd, JZ16.7, 3.7 Hz, 1H), 4.96 (d, JZ
15.4, Hz, 1H), 4.89 (d, JZ15.4 Hz, 1H), 4.79 (dd, JZ15.2,
7.1 Hz, 1H), 4.71 (d, JZ16.7 Hz, 1H), 4.45 (dd, JZ9.2,
5.6 Hz. 1H), 3.69–3.63 (m, 1H), 3.56 (s, 3H), 1.83 (ddd, JZ
14.5, 8.8, 5.7 Hz, 1H), 1.69 (ddd, JZ14.2, 9.4, 4.7 Hz, 1H),
1.69–1.59 (m, 1H), 0.97 (d, JZ6.5 Hz, 3H), 0.97 (JZ
6.5 Hz, 3H); 13C (CDCl3,100 MHz) d 171.6, 153.4, 137.0,
131.9, 128.4, 128.4, 127.7, 124.9, 64.9, 56.9, 52.3, 51.4,
43.3, 37.0, 24.3, 22.9, 21.6; FTIR (neat) 3033, 2954, 1739,
1505, 1450, 1385, 1272, 1157, 772, 701 cmK1; HRMS
(MCH)C calcd for C19H27N2O6S 411.1590, found
411.1583.
(1.21 mL, 13.9 mmol), 3-buten-1-ol (1.2 mL, 13.9 mmol),
and (L)-phenylalanine methyl ester hydrochloride (3.0 g,
13.9 mmol) and Et3N (3.87 mL, 27.8 mmol) were subjected
to 3-component coupling conditions. Flash chromatography
(SiO2, 2:1 heptane/EtOAc) afforded 3.60 g (73%) of the
desired carbamate 17b as a white solid. TLC RfZ0.38 (1:1
heptane/EtOAc). Mp 95–97 8C [a]2D5 C38.3 (c 1.05,
1
CHCl3); H NMR (CDCl3, 500 MHz) d 7.32–7.25 (m, 3H
and N–H), 7.15 (d, JZ6.8 Hz, 2H), 5.75 (dddd, JZ17.0,
10.2, 6.7, 6.7 Hz, 1H), 5.11 (d, JZ17.1 Hz, 1H), 5.07 (d,
JZ10.3 Hz, 1H), 4.51 (t, JZ5.8 Hz, 1H), 4.18 (t, JZ
6.6 Hz, 2H), 3.72 (s, 3H), 3.13 (d, JZ5.8 Hz, 2H), 2.39 (dd,
JZ13.1, 6.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) d 171.0,
150.8, 134.7, 133.3, 129.4, 128.8, 127.5, 117.8, 65.9, 57.6,
52.7, 38.8, 32.8; FTIR (neat) 3273, 2955, 1744, 1642 cmK1
HRMS (MCH)C calcd for C15H21N2O6S 357.1120, found
357.1099.
4.1.12. (2S)-2-(3-Benzyl-2,4,4-trioxo-3,4,6,9-tetrahydro-
2H-4l6-[1,4,3,5]oxathiadiazonin-5-yl)-3-phenyl-propi-
onic acid methyl ester (16d). In a procedure similar to that
used for the preparation of 16a, RCM and flash chroma-
tography (SiO2, hexanes/EtOAc) yielded 122 mg (52%) of
16d as a brown solid. TLC RfZ0.26 (3:1 hexanes/EtOAc).
4.1.15. N-[[[(2-Pentenyloxy)carbonyl]amino]sulfonyl]-
(S)-phenylalanine methyl ester (17c). In a procedure
similar to the preparation of sulfamoyl carbamate 17a,
CSI (1.21 mL, 13.9 mmol), 4-penten-1-ol (1.44 mL,
13.9 mmol), (L)-phenyl alanine methyl ester hydrochloride
(3.0 g, 13.9 mmol) and Et3N (3.87 mL, 27.8 mmol) were
subjected to 3-component coupling conditions. Flash
chromatography (SiO2, 3:1 heptane/EtOAc) afforded
3.17 g (62%) of the desired carbamate 17c as white solid.
TLC RfZ0.21 (2:1 heptane/EtOAc). Mp 101–103 8C [a]D25
Mp 83 8C; [a]2D5 K45 (c 0.5, CHCl3); H NMR (CDCl3,
1
400 MHz) d 7.45 (d, JZ7.1 Hz, 2H), 7.33–7.23 (m, 8H),
5.75 (ddd, JZ11.5, 1.9, 1.9 Hz, 1H), 5.66–5.59 (m, 1H),
5.22 (d, JZ16.2 Hz, 1H), 4.94 (d, JZ15.5 Hz, 1H), 4.89
(d, JZ15.5 Hz, 1H), 4.73 (d, JZ16.8 Hz, 1H), 4.67 (d,
JZ7.5 Hz, 1H), 4.65 (d, JZ7.5 Hz, 1H), 3.89–3.81 (m, 1H),
3.58 (s, 3H), 3.43 (dd, JZ14.4, 7.5 Hz, 1H), 3.02 (dd, JZ
14.4, 7.5 Hz, 1H); 13C (CDCl3,100 MHz) 170.6, 153.2,
136.9, 136.9, 131.9, 129.1, 128.6, 128.4, 128.4, 127.7,
127.0, 125.0, 65.0, 59.9, 52.4, 51.4, 44.1, 35.2; FTIR (neat)
1
C35.0 (c 1.03, CHCl3); H NMR (CDCl3, 500 MHz) d
7.35–7.25 (m, 3H), 7.16 (d, JZ7.1 Hz, 2H), 5.77 (dddd,
JZ16.9, 10.2, 6.6, 6.6 Hz, 1H), 5.58 (dd, JZ12.6, 8.5 Hz,
1H), 5.04 (dd, JZ17.2, 1.0 Hz, 1H), 5.00 (dd, JZ10.2,
1.1 Hz, 1H), 4.52 (dd, JZ14.3, 5.9 Hz, 1H), 4.14 (t, JZ
6.6 Hz, 2H), 3.72 (s, 3H), 3.13 (d, JZ5.9 Hz, 2H), 2.08 (q,
JZ7.1 Hz, 2H), 1.73 (quintet, JZ7.1 Hz, 2H); 13C NMR
(CDCl3, 125 MHz) d 171.0, 150.9, 137.0 134.7, 129.4
128.7, 127.4, 115.7, 66.5, 57.7, 52.7, 39.0, 29.7, 27.6; FTIR
(neat) 3271, 1744, 1641 cmK1; HRMS (MCH)C calcd for
C16H23N2O6S 371.1277, found 371.1280.
3030, 2950, 1740, 1498, 1386, 1168, 753, 699 cmK1
;
HRMS (MCH)C calcd for C22H25N2O6S 445.1433, found
445.1433.
4.1.13. N-[[[(2-Propenyloxy)carbonyl]amino]sulfonyl]-
(S)-phenylalanine methyl ester (17a). To a stirring
solution of CSI (1.97 g, 13.9 mmol) in CH2Cl2, (10 mL) at
0 8C was added allyl alcohol (0.95 mL, 13.9 mmol) via
syringe and the reaction was stirred for 1 h. This solution
was transferred via cannula to a stirring solution of
phenylalanine ester hydrochloride (3.0 g, 13.9 mmol) and
Et3N (3.87 mL, 27.8 mmol) in CH2Cl2 (25 mL) at 0 8C. The
resulting mixture was stirred under Ar for 12 h. The product
of the reaction was dissolved in 100 mL of H2O and
extracted with CH2Cl2 (4!50 mL), dried with Na2SO4,
filtered and concentrated under reduced pressure. The
product was purified by flash chromatography (SiO2, 3:1
heptane/EtOAc) to afford 2.65 g (56%) of carbamate 17a as
white solid. TLC RfZ0.38 (1:1 heptane/EtOAc). Mp 101–
4.1.16. N-[[[(2-Propenyloxy)carbonyl]-N0-(4-methoxy-
benzyl)-amino]sulfonyl]-(S)-phenylalanine methyl ester
(18a). To a stirring solution of Ph3P (1.85 g, 7.04 mmol) in
THF (4 mL) at rt was added PMBOH (973 mg, 7.04 mmol)
via syringe and the solution stirred for 30 min. This mixture
was transferred via cannula to a stirring solution of
sulfamoyl carbamate 17a (2.41 g, 7.04 mmol) and DIAD
(1.42 g, 7.04 mmol) in THF (5 mL) and the reaction was
stirred for 3 h and concentrated under reduced pressure.
Flash chromatography (SiO2, 4:1 heptane/EtOAc) afforded
3.17 g (97%) of the desired alkylated sulfamoyl carbamate
18a as a yellow oil. TLC RfZ0.49 (1:1 heptane/EtOAc).
[a]2D5 C2.9 (c 1.02, CHCl3); 1H NMR (CDCl3, 500 MHz) d
7.35 (d, JZ8.6 Hz, 2H), 7.31–7.28 (m, 3H), 7.07 (d, JZ
6.3 Hz, 2H), 6.87 (d, JZ8.5 Hz, 2H), 5.90 (dddd, JZ16.6,
11.2, 5.8, 5.4 Hz, 1H), 5.74 (d, JZ8.2 Hz, 1H), 5.36 (d, JZ
17.2 Hz, 1H), 5.28 (d, JZ10.4 Hz, 1H), 4.85 (d, JZ
15.3 Hz, 1H), 4.73 (d, JZ15.3 Hz, 1H), 4.71–4.74 (m, 2H),
4.06 (dd, JZ14.0, 5.9 Hz, 1H), 3.82 (s, 3H), 3.61 (s, 3H),
3.03 (d, JZ9.4 Hz, 2H), 13C NMR (CDCl3, 125 MHz) d
170.6, 159.4, 152.6, 136.2, 134.8, 131.0, 130.1, 129.3,
128.6, 127.3, 119.4, 113.9, 67.4, 57.0, 55.2, 52.4, 50.3, 38.9;
FTIR (neat) 3304, 2979, 1736, 1728, 1612, 1514 cmK1
1
102.5 8C [a]2D5 C32.9 (c 0.99, CHCl3); H NMR (CDCl3,
500 MHz) d 7.33–7.27 (m, 3H and N–H), 7.16 (d, JZ
7.0 Hz, 2H), 5.88 (dddd, JZ16.6, 11.3, 5.8, 5.6 Hz, 1H),
5.58 (d, JZ8.5 Hz, 1H), 5.34 (d, JZ17.1 Hz, 1H), 5.27 (d,
JZ10.4 Hz, 1H), 4.61, (d, JZ5.8 Hz, 2H), 4.55–4.51 (m,
1H), 3.72, (s, 3H), 3.13 (d, JZ5.9 Hz, 2H), 13C NMR
(CDCl3, 125 MHz) d 171.0, 150.6, 134.7, 130.9, 129.4,
128.7, 127.5, 119.5, 67.4, 57.7, 52.7, 39.0; FTIR (neat)
3271, 1740, 1732, 1647 cmK1; HRMS (MCH)C calcd for
C14H19N2O6S 343.0964, found 343.0957.
4.1.14. N-[[[(2-Butenyloxy)carbonyl]amino]sulfonyl]-
(S)-phenylalanine methyl ester (17b). In a procedure
similar to the preparation of sulfamoyl carbamate 17a, CSI

J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
6225
HRMS (MCH)C calcd for C22H27N2O7S 463.1539, found
463.1566.
17.6 Hz, 1H), 5.17 (d, JZ10.2 Hz, 1H), 4.87 (d, JZ
15.4 Hz, 1H), 4.77 (d, JZ15.4 Hz, 1H), 4.65 (d, JZ5.9 Hz,
2H), 4.55 (dd, JZ8.9, 6.2 Hz, 1H), 4.17 (dd, JZ16.7,
5.7 Hz, 1H), 4.00 (dd, JZ16.7, 6.8 Hz, 1H), 3.77 (s, 3H),
3.59 (s, 3H), 3.22 (dd, JZ13.7, 9.0 Hz, 1H), 2.97 (dd, JZ
13.7, 6.2 Hz, 1H), 13C NMR (CDCl3, 100 MHz) d 170.3,
159.1, 152.5, 136.2, 134.9, 131.2, 129.9, 129.1, 129.0,
128.4, 126.8, 119.4, 117.6, 113.6, 67.7, 61.1, 55.1, 52.0,
51.4, 50.0, 36.8; FTIR (neat) 3350, 2982, 1732, 1649,
1612, 1585, 1514 cmK1; HRMS (MCH)C calcd for
C25H31N2O7S 503.1852, found 503.1863.
4.1.17. N-[[[(2-Butenyloxy)carbonyl]-N0-(4-methoxybenz-
yl)-amino]sulfonyl]-(S)-phenylalanine methyl ester
(18b). In a procedure similar to the preparation of sulfamoyl
carbamate 18a, compound 17b (3.56 g, 9.99 mmol), DIAD
(1.97 mL, 9.99 mmol), Ph3P (2.62 g, 9.99 mmol) and
PMBOH (1.25 mL g, 9.99 mmol) were utilized in the
Mitsunobu reaction. Flash chromatography (SiO2, 5:1
heptane/EtOAc) afforded 3.94 g (83%) of the desired
alkylated product 18b as a yellow oil. TLC RfZ0.55 (1:1
1
heptane/EtOAc). [a]2D5 C3.0 (c 1.00, CHCl3); H NMR
4.1.20. N-(2-Propenyl)-N-[[[(2-butenyloxy)carbonyl]-N0-
(4-methoxybenzyl)amino]sulfonyl]-(S)-phenylalanine
methyl ester (19b). In a procedure similar to the preparation
of sulfamoyl carbamate 19a, 18b (1.58 g, 3.3 mmol),
K2CO3 (912 mg, 6.6 mmol), and allyl bromide (0.29 mL,
3.30 mmol) was subjected to the allylation procedure. Flash
chromatography (SiO2, 100% EtOAc) afforded 1.68 g
(98%) of 19b as a yellow oil. TLC RfZ0.60 (1:1 heptane/
(CDCl3, 500 MHz) d 7.33 (d, JZ8.5 Hz, 2H), 7.27–7.24
(m, 3H), 7.05 (d, JZ7.0 Hz, 2H), 6.84 (d, JZ8.5 Hz, 2H),
5.75–5.69 (m, 1H and N–H), 5.10 (d, JZ17.2 Hz, 1H), 5.00
(d, JZ10.2 Hz, 1H), 4.82 (d, JZ15.2 Hz, 1H), 4.68 (d, JZ
15.2 Hz, 1H), 4.24 (t, JZ6.5 Hz, 2H), 4.02 (dd, JZ14.2,
5.9 Hz, 1H), 3.80 (s, 3H), 3.59 (s, 3H), 2.98 (d, JZ5.9 Hz,
2H), 2.40 (dd, JZ12.8, 6.4 Hz, 2H), 13C NMR (CDCl3,
125 MHz) d 170.6, 159.3, 152.8, 134.8, 134.0, 130.2, 129.4,
129.2, 128.6, 127.3, 117.8, 113.8, 66.4, 56.9, 55.3, 52.4,
50.2, 39.0, 32.9; FTIR (neat) 3319, 3055, 2926, 1744,
1728, 1612, 1514 cmK1 HRMS (MCNH4)C calcd for
C23H32N3O7S 494.1961, found 494.1953.
1
EtOAc). [a]2D5 K19.8 (c 0.98, CHCl3); H NMR (CDCl3,
500 MHz) d 7.35 (d, JZ8.6 Hz, 2H), 7.29–7.22 (m, 3H),
7.13 d, JZ7.0 Hz, 2H), 6.81 (d, JZ11.5 Hz, 2H), 5.91
(dddd, JZ16.9, 10.2, 6.3, 6.1 Hz, 1H), 5.75 (dddd, JZ17.0,
10.3, 6.7, 6.7 Hz, 1H), 5.25 (dd, JZ17.2, 1.1 Hz, 1H), 5.16
(dd, JZ10.3, 1.0 Hz, 1H), 5.12 (dd, JZ17.2, 1.5 Hz, 1H),
5.10 (dd, JZ9.3, 1.3 Hz, 1H), 4.83 (d, JZ15.5 Hz, 1H),
4.74 (d, JZ15.5 Hz, 1H), 4.58 (dd, JZ8.9, 6.2 Hz, 1H),
4.20 (t, JZ6.3 Hz, 2H), 4.17 (d, JZ5.7 Hz, 1H)), 4.02 (dd,
JZ16.6, 6.7 Hz, 1H), 3.77 (s, 3H), 3.59 (s, 3H), 3.22 (dd,
JZ13.7, 9.0 Hz, 1H), 2.97 (dd, JZ13.7, 6.1 Hz, 1H), 2.42
(dd, JZ13.5, 6.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz) d
170.4, 159.3, 152.7, 136.3, 135.0, 133.3, 129.9, 129.2,
129.1, 128.4, 126.8, 117.8, 117.7, 113.7, 66.3, 61.2, 55.2,
52.0, 51.4, 49.9, 36.9, 33.0; FTIR (neat) 2955, 1728, 1612,
1514 cmK1; HRMS (MCNa)C calcd for C26H32N2O7SNa
539.1828, found 539.1834.
4.1.18. N-[[[(2-Pentenyloxy)carbonyl]-N0-(4-methoxy-
benzyl)-amino]sulfonyl]-(S)-phenylalanine methyl ester
(18c). In a procedure similar to the preparation of sulfamoyl
carbamate 18a, compound 17c (3.0 g, 8.1 mmol), DIAD
(1.59 mL, 8.1 mmol), Ph3P (2.12 g, 8.1 mmol) and PMBOH
(1.0 mL, 8.1 mmol) were utilized in the Mitsunobu reaction.
Flash chromatography (SiO2, 4:1 heptane/EtOAc) afforded
3.08 g (78%) of the desired alkylated product 18c as a
yellow oil. TLC RfZ0.54 (1:1 heptane/EtOAc). [a]2D5 C3.3
(c 1.01, CHCl3);1H (CDCl3, 500 MHz) d 7.34 (d, JZ8.6 Hz,
2H), 7.31–7.27 (m, 3H), 7.08 (d, JZ6.5 Hz, 2H), 6.87
(d, JZ8.6 Hz, 2H), 5.78 (dddd, JZ16.9, 10.2, 6.6, 6.6 Hz,
1H), 5.73 (d, JZ5.5 Hz, 1H), 5.03 (dd, JZ16.9, 1.5 Hz,
1H), 5.00 (d, JZ9.0 Hz, 1H), 4.85 (d, JZ15.3 Hz, 1H), 4.72
(d, JZ15.3, 1H), 4.24–4.17 (m, 2H), 4.06 (dd, JZ13.9,
5.9 Hz, 1H), 3.82 (s, 3H), 3.62 (s, 3H), 3.01 (d, JZ5.8 Hz,
2H), 2.08 (dt, JZ7.4, 7.1 Hz, 2H), 1.75 (quintet, JZ7.1 Hz,
2H); 13C (CDCl3, 125 MHz) d 170.6, 159.3, 152.8, 137.0,
134.8, 129.9, 129.3, 129.1, 128.6, 127.3, 115.6, 113.8, 67.0,
57.0, 55.2, 52.4, 50.2, 38.9, 29.7, 27.6; FTIR (neat) 3296,
1728, 1612, 1514 cmK1; HRMS (MCNH4)C calcd for
C24H34N3O7S 508.2117, found 508.2094.
4.1.21. N-(2-Propenyl)-N-[[[(2-pentenyloxy)carbonyl]-
N0-(4-methoxybenzyl)amino]sulfonyl]-(S)-phenylalanine
methyl ester (19c). In a procedure similar to the preparation
of sulfamoyl carbamate 19a, 18c (513 mg, 3.3 mmol),
K2CO3 (1.45 g, 10.5 mmol), allyl bromide (0.45 mL,
5.23 mmol) in CH3CN (20 mL) was subjected to the
allylation procedure. Flash chromatography (SiO2, 4:1
heptane/EtOAc) afforded 506 mg (91%) of 19c as a yellow
oil. TLC RfZ0.67 (1:1 heptane/EtOAc). [a]2D5 K20.2
(c 0.92, CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.38
(d, JZ8.7 Hz, 2H), 7.33–7.25 (m, 3H), 7.17 (d, JZ6.8 Hz,
2H), 6.86 (d, JZ8.7 Hz, 2H), 5.95 (dddd, JZ16.9, 10.2, 6.5,
5.9 Hz. 1H), 5.80 (dddd, JZ16.9, 10.2, 6.6, 6.6 Hz, 1H),
5.29 (dd, JZ17.2, 1.2 Hz, 1H), 5.20 (dd, JZ10.2, 1.1 Hz,
1H), 5.05 (dd, JZ17.1, 1.6 Hz, 1H), 5.04 (d, JZ10.0,
1.5 Hz, 1H), 4.89 (d, JZ15.5 Hz, 1H), 4.79 (d, JZ15.5 Hz,
1H), 4.61 (dd, JZ8.9, 6.2 Hz, 1H), 4.22 (dd, JZ16.3,
5.7 Hz, 1H), 4.19 (t, JZ7.0 Hz, 2H), 4.07 (dd, JZ16.6,
6.7 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 3.26 (dd, JZ13.7,
8.9 Hz, 1H), 3.01 (dd, JZ13.7, 6.2 Hz, 1H), 2.11 (q, JZ
7.1 Hz, 2H), 1.79 (quintet, JZ7.0 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) d 170.3, 159.1, 152.7, 136.9, 136.2,
134.9, 129.6, 129.1, 129.0, 128.3, 126.8, 117.6, 115.5,
113.6, 66.5, 61.1, 55.1, 52.0, 51.4, 49.9, 36.8, 29.6, 27.6;
4.1.19. N-(2-Propenyl)-N-[[[(2-propenyloxy)carbonyl]-
N0-(4-methoxybenzyl)-amino]sulfonyl]-(S)-phenylala-
nine methyl ester (19a). To a stirring solution of 18a
(3.06 g, 6.62 mmol) in CH3CN (25 mL) was added K2CO3
(9.15 g, 66.2 mmol), and allyl bromide (2.86 mL,
33.1 mmol). The reaction was stirred under reflux for
24 h. The product was filtered and purified by flash
chromatography (SiO2, 5:1 heptane/EtOAc) to afford
2.01 g (60%) of the pure product 19a as a yellow oil. TLC
RfZ0.51 (1:1 heptane/EtOAc). [a]2D5 K15.1 (c 1.09,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.37 (d, JZ
8.6 Hz, 2H), 7.30–7.21 (m, 3H), 7.12 (d, JZ6.9 Hz, 2H),
6.82 (d, JZ8.6 Hz, 2H), 5.97–5.85 (m, 2H), 5.35 (d, JZ
17.1 Hz, 1H), 5.28 (d, JZ10.4 Hz, 1H), 5.25 (d, JZ

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J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
FTIR (neat) 1728, 1612, 1514 cmK1; HRMS (MCNH4)C
calcd for C27H38N3O7S 548.2430, found 540.2431.
for C25H34N3O7S 520.2117, found 520.2091. A portion of
this compound was immediately subjected to the following
hydrogenation protocol: Cyclic sulfamoyl carbamate 20c
(57 mg, 0.11 mmol) was weighed into a round-bottomed
flask followed by the addition of 5% Pd/C (29 mg) and
EtOAc (10 mL). The flask was evacuated using suction
followed by the insertion of two H2 balloons. The reaction
was stirred at rt for 2 h. The crude product was filtered
through celite and concentrated under reduced pressure to
afford 54 mg (95%) of a white solid. TLC RfZ0.49 (1:1
heptanes/EtOAc). Mp 99–102 8C; [a]2D5 K9.7 (c 0.82,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.44 (d, JZ
8.5 Hz, 2H), 7.24–7.17 (m, 3H), 6.91 (d, JZ6.0 Hz, 2H),
6.76 (d, JZ8.5 Hz, 2H), 5.03 (d, JZ15.0 Hz, 1H), 4.81 (d,
JZ15.0 Hz, 1H), 4.22 (m, 1H), 4.10 (t, JZ10.1 Hz, 1H),
3.90 (dd, JZ9.8, 3.7 Hz, 1H), 3.73 (s, 3H), 3.68–3.51 (m,
2H), 3.58 (s, 3H), 3.17 (t, JZ10.5 Hz, 1H), 2.87 (dd, JZ
13.3, 4.2 Hz, 1H), 2.05–1.92 (m, 2H), 1.78–1.66 (m, 2H),
1.56–1.51 (m, 2H), 1.32–1.28 (m, 2H); 13C (CDCl3,
100 MHz) d 169.9, 159.2, 152.9, 136.0, 130.5, 129.1,
129.0, 128.4, 126.7, 113.6, 69.2, 60.6, 55.1, 52.0, 51.5,
46.9, 34.9, 25.8, 23.4, 23.3, 22.1; FTIR (neat) 2953, 1743,
1726, 1612, 1514 cmK1; HRMS (MCNa)C calcd for
C25H32N2O7SNa 527.1828, found 527.1820.
4.1.22. (2S)-2-[3-(4-Methoxy)benzyl)-2,4,4-trioxo-3,4,
6,9-tetrahydro-2H-4l6-[1,4,3,5]oxathiadiazonin-5-yl]-3-
phenyl-propionic acid methyl ester (20a). Compound 19a
(202 mg, 0.40 mmol) was dissolved in DCE (80 mL, 0.005
M) and the solution was degassed with Ar for 15 min
followed by reflux for 30 min. Cat-B (75 mg, 22 mol%) was
added to the refluxing solution in three equal portions over a
period of 48 h. The reaction was cooled to rt, DCE was
removed under reduced pressure, followed the addition of
DMSO (0.32 mL, 50 equiv relative to catalyst) in CH2Cl2
(50 mL). The reaction was stirred at rt for 24 h and the
solvent was removed under reduced pressure. Flash
chromatography (SiO2, 4:1 heptane/EtOAc) afforded
124 mg (65%) of 19b as a yellow oil. TLC RfZ0.47 (1:1
heptane/EtOAc). [a]2D5 K60.6 (c 1.11, CHCl3); H NMR
1
(CDCl3, 400 MHz) d 7.39 (d, JZ8.9 Hz, 2H), 7.30 (d, JZ
7.4 Hz, 2H), 7.24–7.22 (m, 3H), 6.81 (d, JZ8.7 Hz, 2H),
5.74 (dd, JZ11.5 Hz, 1.7 Hz, 1H), 5.59 (dd, JZ9.2, 1.8 Hz,
1H), 5.24–5.14 (m, 1H), 4.83 (s, 2H), 4.71–4.67 (m, 1H),
4.61 (t, JZ7.3 Hz, 1H), 3.80–3.75 (m, 1H), 3.75 (s, 3H),
3.53 (s, 3H), 3.41 (dd, JZ14.4, 7.6 Hz, 1H), 2.98 (dd, JZ
14.4, 7.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz) d 170.8,
159.2, 153.1, 136.1, 132.0, 130.1, 129.0, 128.8, 128.6,
127.0, 124.5, 113.7, 64.9, 59.4, 55.2, 52.5, 50.7, 43.6, 34.8;
FTIR (neat) 2950, 1740, 1612, 1514 cmK1; HRMS (MC
NH4)C calcd for C23H29N3O7S 492.1804, found 492.1793.
4.1.25. N-[[[(2-Propenyloxy)carbonyl]amino]sulfonyl]-
(S)-valine methyl ester (21). CSI (29.8 mmol; 4.2 g) was
dissolved in CH2Cl2 (10 mL), the solution was cooled to
0 8C, and allyl alcohol (1.73 g, 29.8 mmol) was added via
syringe. In an adjacent round-bottomed flask, valine methyl
ester hydrochloride (5.0 g, 29.8 mmol) was dissolved in
CH2Cl2 (25 mL), cooled to 0 8C, and Et3N (6.03 g,
59.6 mmol) was added via syringe. Each solution was
stirred at 0 8C under Ar for approximately 1h. The CSI/
alcohol solution was cannulated into the amino acid solution
and the reaction was stirred for 12 h under Ar at 0 8C while
slowly warming to rt. The crude product was dissolved in
H2O (100 mL) and extracted with CH2Cl2 (4!50 mL),
dried (Na2SO4), filtered, and concentrated under reduced
pressure. Flash chromatography (SiO2, 4:1 heptane/EtOAc)
afforded 6.12 g (70%) of the desired carbamate 21 as white
solid. TLC RfZ0.35 (1:1 heptane/EtOAc). Mp 93–95 8C
[a]2D5 C43.6 (c 1.03, CHCl3); 1H NMR (CDCl3, 400 MHz) d
5.92 (dddd, JZ17.0, 10.4, 5.8, 5.8 Hz, 1H), 5.67 (d, JZ
9.4 Hz, 1H), 5.37 (dd, JZ17.2, 1.3 Hz, 1H), 5.29 (dd, JZ
10.4, 1.1 Hz, 1H), 4.66–4.63 (m, 2H), 4.07 (dd, JZ9.4,
5.0 Hz, 1H), 3.75 (s, 3H), 2.20–2.11 (m, 1H), 1.02 (d, JZ
6.8 Hz, 3H), 0.91 (d, JZ6.9 Hz, 3H), 13C NMR (CDCl3,
125 MHz) d 171.6, 150.7, 131.0, 119.4, 67.3, 62.2, 52.5,
31.4, 18.8, 17.2; FTIR (neat) 3276, 3205, 2966, 1744, 1720,
1651 cmK1; HRMS (MCH)C calcd for C10H19N2O6S
295.0964, found 295.0947.
4.1.23. (2S)-2-[3-(4-Methoxybenzyl)-2,4,4-trioxo-3,4,9,10
tetrahydro-2H,6H-4l6-[1,4,3,5]oxathiadiazonin-5-yl]-3-
phenyl-propionic acid methyl ester (20b). In a procedure
similar to the preparation of cyclic sulfamoyl carbamate
20a, 19b (209 mg, 0.40 mmol) and cat-B (34 mg, 10 mol%)
in DCE (80 mL) was subjected to the RCM procedure. Flash
chromatography (SiO2, 4:1 heptane/EtOAc) afforded
173 mg (87%) of 20b as an ivory-colored solid, MpZ43–
50 8C. TLC RfZ0.16 (2:1 heptane/EtOAc). [a]2D5 K97.5 (c
1
0.96, CHCl3); H NMR (CDCl3, 500 MHz) d 7.39 (d, JZ
8.6 Hz, 2H), 7.31 (d, JZ7.2 Hz, 2H), 7.27–7.24 (m, 3H).
6.78 (d, JZ8.6 Hz, 2H), 5.85 (dd, JZ16.6, 5.2 Hz, 1H),
5.62 (ddd, JZ11.0, 11.0, 5.5 Hz, 1H), 4.82 (d, JZ15.1 Hz,
1H), 4.76 (d, JZ15.1 Hz, 1H), 4.59 (bs,1H), 4.52 (t, JZ
7.4 Hz, 1H), 4.18–4.14 (m, 1H), 4.08 (dd, JZ11.3, 1.1 Hz,
1H), 3.74 (s, 4H), 3.52 (s, 3H), 3.45 (dd, JZ14.4, 7.0 Hz,
1H), 3.00 (dd, JZ14.4, 7.8 Hz, 1H), 2.74–2.68 (m, 1H),
2.25–2.21 (m, 1H); 13C NMR (CDCl3, 125 MHz) d 171.3,
159.2, 152.5, 136.5, 131.5, 130.3, 129.1, 129.1, 128.5,
126.9, 113.5, 65.6, 59.2, 55.2, 52.5, 50.8, 44.7, 35.0, 25.3;
FTIR (neat) 1732, 1612, 1514 cmK1; HRMS (MCNH4)C
calcd for C24H32N3O7S 506.1961, found 506.1955.
4.1.24. (2S)-2-[3-(4-Methoxybenzyl)-2,4,4-trioxo-1-oxa-
4l6-thia-3,5-diaza-cycloundec-7-en-5-yl]-3-phenyl-pro-
pionic acid methyl ester (20c) (hydrogenated for
characterization). In a procedure similar to the preparation
of cyclic sulfamoyl carbamate 20a, 19c (206 mg,
0.39 mmol) and cat-B (43 mg, 0.05 mmol) in DCE
(78 mL) was subjected to the RCM procedure. Flash
chromatography (SiO2, 5:1 heptane/EtOAc) afforded
170 mg (87%) of 20c (1.6:1 E:Z) as a yellow oil. TLC
RfZ0.50 (1:1 heptane/EtOAc); HRMS (MCNH4)C calcd
4.1.26. N-[[[[N0-(2-Propenyloxy)carbonyl]-N0-(1R)-1-
ethoxycarbonyl-ethyl]amino]sulfonyl]-(S)-valine methyl
ester (22). Compound 21 (2.66 g, 9.0 mmol) was dissolved
in THF (3 mL) followed by the addition of DIAD (1.82 g,
9.0 mmol) dropwise via syringe. In an adjacent round-
bottomed flask, Ph3P (2.37 g, 9.0 mmol) was dissolved in
THF (4 mL) followed by the addition of (S)-ethyl lactate
(1.02 mL, 9.0 mmol) via syringe. Each solution was stirred
under Ar atmosphere at rt for 1 h after which the Ph3P/
ethyl lactate solution was cannulated into the solution of

J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
6227
21/DIAD and the resulting reaction mixture stirred under at
rt for 24 h. The reaction was concentrated under reduced
pressure. Flash chromatography (SiO2, 9:1 heptane/EtOAc)
afforded 2.30 g (65%) of the desired alkylated product 22 as
1386 cmK1; HRMS (MCH)C calcd for C16H27N2O8S
407.1488, found 407.1497.
4.1.29. N-(Benzyl)-N-(2-propenyl)-N0-[[N00-(2-propenyl)-
N00-(benzyl)amino]sulfonyl]-urea (25). To a stirring solu-
tion of benzylallylamine (2.18 g, 14.8 mmol) and Et3N
(2.96 mL, 21.2 mmol) in CH2Cl2 (45 mL) at 0 8C under
argon was added CSI (615 mL, 2.40 mmol) in CH2Cl2
(3 mL) dropwise over 5 min. The solution was stirred for
12 h, and CH2Cl2 (130 mL) added. The solution was washed
with 10% NaHSO4 (50 mL), NaHCO3 (50 mL), brine
(50 mL), dried (MgSO4), and the solvent removed. Flash
chromatography (SiO2, hexanes/EtOAc) afforded 2.75 g of
25 (97%) as a white solid. TLC RfZ0.30 (2:1 hexanes/
EtOAc). Mp 54–58 8C; 1H NMR (CDCl3, 400 MHz) d 7.36–
7.26 (m, 10H), 5.87–5.71 (m, 1H), 5.87–5.71 (m, 1H), 5.25–
5.20 (m, 1H), 5.25–5.20 (m, 1H), 5.15–5.11 (m, 1H), 5.15–
5.11 (m, 1H), 4.57 (s, 2H), 4.50 (s, 2H), 3.91 (d, JZ5.6 Hz,
2H), 3.85 (d, JZ5.1 Hz, 2H); 13C (CDCl3,125 MHz) 152.8,
136.6, 132.8, 128.9, 128.9, 128.5, 128.5, 128.4, 127.9,
127.7, 127.6, 118.7, 118.0, 52.1, 50.6, 50.4, 49.7; FTIR
(neat) 3306, 3031, 2927, 1696, 1651, 1606, 1586, 1455,
1392, 1153, 740, 699 cmK1; HRMS (MCH)C calcd for
C21H26N3O3S 400.1695, found 400.1711.
a yellow oil. TLC RfZ0.53 (1:1 heptane/EtOAc). [a]D25
C
1
73.0 (c 1.18, CHCl3); H NMR (CDCl3, 500 MHz) d 6.08
(d, JZ7.4 Hz, 1H), 5.95 (dddd, JZ16.6, 11.1, 5.7, 5.4 Hz,
1H), 5.39 (d, JZ17.2 Hz, 1H), 5.30 (d, JZ10.5 Hz, 1H),
4.96 (q, JZ7.0 Hz, 1H), 4.71 (t, JZ5.6 Hz, 2H), 4.23–4.17
(m, 2H), 4.12 (dd, JZ7.0, 3.5 Hz, 1H), 3.77 (s, 3H), 2.22–
2.15 (m, 1H), 1.59 (d, JZ7.0 Hz, 3H), 1.27 (t, JZ7.1 Hz,
3H), 1.02 (d, JZ6.8 Hz, 3H), 0.86 (d, JZ6.9 Hz, 3H), 13C
NMR (CDCl3, 125 MHz) d 171.4, 170.0, 151.7, 131.0,
119.3, 68.1, 61.9, 61.8, 56.6, 52.5, 31.9, 18.8, 17.0, 16.5,
14.1; FTIR (neat) 3304, 2966, 1740, 1726, 1649 cmK1
;
HRMS (MCH)C calcd for C15H27N2O8S 395.1488, found
395.1472.
4.1.27. N-(2-Propenyl)-N-[[[[N0-(2-propenyloxy)carbo-
nyl]-N0-(1R)-1-ethoxycarbonyl-ethyl]amino]sulfonyl]-
(S)-valine methyl ester (23). Compound 22 (1.10 g,
2.79 mmol) was weighed into a round-bottomed flask,
followed by the addition of K2CO3 (771 mg, 5.58 mmol),
allyl bromide (0.24 mL, 2.79 mmol) and CH3CN (25 mL).
The reaction was stirred under reflux at 85 8C for 6 h. The
product was filtered and concentrated under reduced
pressure. Flash chromatography (SiO2, 6:1 heptane/
EtOAc) afforded 825 mg (68%) of 23 as a yellow oil.
TLC RfZ0.38 (2:1 heptane/EtOAc). [a]2D5 K22.2 (c 1.05,
4.1.30. N-(Benzyl)-N-(2-propenyl)-N0-(benzyl)-N0-[[N00-
(2-propenyl)-N00(benzyl)amino]sulfonyl]-urea (26). Sul-
famoyl urea 25 (500 mg, 1.25 mmol), K2CO3 (863 mg,
6.25 mmol), CH3CN (40 mL) and BnBr (744 mL,
6.25 mmol) were added sequentially to a 100 mL round-
bottomed flask, a condenser was attached, and the mixture
stirred at 70 8C for 16 h. The solution was filtered, the
solvent removed under reduced pressure, and the crude
mixture was submitted to flash chromatography (SiO2,
hexanes/EtOAc) to yield 355 mg (58%) of 26 as a clear oil.
TLC RfZ0.44 (3:1 hexanes/EtOAc); 1H NMR (CDCl3,
400 MHz) d 7.38–7.17 (m, 15H), 5.91 (dddd, JZ16.9, 10.4,
6.5, 6.5 Hz, 1H), 5.77 (dddd, JZ16.3, 10.4, 5.9, 5.9, 1H),
5.48 (s, 2H), 5.19, (dd, JZ10.2, 1.0 Hz, 1H), 5.11 (dd, JZ
15.4, 1.1 Hz, 1H), 5.10 (dd, JZ8.6, 1.2 Hz, 1H), 5.09 (dd,
JZ18.3, 1.2 Hz, 1H), 4.56 (s, 2H), 4.30 (s, 2H), 3.96 (d, JZ
5.9 Hz, 2H), 3.75 (d, JZ6.5 Hz, 2H); 13C (CDCl3,
100 MHz) 157.1, 137.2, 136.3, 135.4, 133.8, 132.3, 129.1,
128.8, 128.7, 128.6, 128.5, 128.2, 127.7, 127.5, 127.3,
118.4, 118.0, 74.0, 51.5, 51.4, 51.0, 50.9; FTIR (neat) 3031,
1
CHCl3); H NMR (CDCl3, 500 MHz) d 6.02 (dddd, JZ
17.3, 10.2, 5.8, 5.8 Hz, 1H), 5.90 (dddd, JZ16.4, 10.6, 5.8,
5.8 Hz, 1H), 5.36 (dd, JZ17.2, 1.2 Hz, 1H), 5.29 (dd, JZ
10.2, 1.0 Hz, 1H), 5.22 (dd, JZ17.3, 1.2 Hz, 1H), 5.12 (dd,
JZ10.2, 1.1 Hz, 1H), 4.99 (q, JZ7.0 Hz, 1H), 4.64 (d, JZ
5.8 Hz, 2H), 4.23–4.21 (m, 2H), 4.19 (d, JZ7.1 Hz, 2H),
4.13 (d, JZ10.3 Hz, 1H), 3.70 (s, 3H), 2.22–2.14 (m, 1H),
1.61 (d, JZ7.0 Hz, 3H), 1.26 (t, JZ7.1 Hz, 3H), 1.03
(d, JZ6.6 Hz, 3H), 0.94 (d, JZ6.6 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d 171.0, 170.0, 151.9, 135.3, 131.0,
119.6, 117.5, 67.9, 66.2, 61.7, 56.8, 51.7, 49.5, 28.9, 19.7,
19.4, 16.1, 14.0; FTIR (neat) 2968, 1742, 1647 cmK1
;
HRMS (MCH)C calcd for C18H31N2O8S 435.1801, found
435.1778.
2925, 1743, 1566, 1496, 1454, 1313, 1153, 739, 699 cmK1
;
4.1.28. (2S)-2-((1R)-1-Ethoxycarbonyl-ethyl])-2,4,4-
trioxo-3,4,6,9-tetrahydro-2H-4l6-[1,4,3,5]oxathiadiazo-
nin-5-yl)-3-methyl-butyric acid methyl ester (24). In a
procedure similar to the preparation of cyclic sulfamoyl
carbamate 20a, 23 (24 mg, 0.055 mmol), cat-B (4 mg,
8 mol%) in DCE (11 mL) was subjected to the RCM
procedure. Flash chromatography (SiO2, 9:1 heptane/
EtOAc) afforded 15 mg (68%) of 24 as a yellow oil. TLC
RfZ0.45 (1:1 heptane/EtOAc). [a]2D5 K77.9 (c 1.00,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 5.72–5.69 (m,
1H), 5.54–5.51 (m, 1H), 5.33–5.29 (m, 1H), 4.95 (q, JZ
7.0 Hz, 1H), 4.89–4.85 (m, 1H), 4.73–4.69 (m, 1H), 4.33–
4.18 (m, 2H), 3.96 (d, JZ10.9 Hz, 1H), 3.57 (s, 3H), 3.57
(m, 1H), 2.37–2.27 (m, 1H), 1.62 (d, JZ7.0 Hz, 3H), 1.31
(t, JZ7.1 Hz, 3H), 1.04 (d, JZ6.3 Hz, 3H), 0.98 (d, JZ
6.8 Hz, 3H); 13C NMR (CDCl3, 125 MHz) d 170.7, 169.7,
152.6, 130.9, 124.6, 65.3, 61.8, 56.0, 51.8, 43.2, 29.7, 25.9,
20.5, 18.6, 15.6, 14.0; FTIR (neat) 2970, 1744, 1647, 1450,
HRMS (MCH)C calcd for C28H32N3O3S 490.2168, found
490.2158.
4.1.31. 2,4,9-Tribenzyl-1,1-dioxo-1,2,4,5,8,9-hexahydro-
1l6-[1,2,4,9]thiatriazonin-3-one (27). Sulfamoyl urea 26
(53 mg, 0.72 mmol), and CH2Cl2 (50 mL) were placed in a
100 mL round-bottomed flask and degassed with argon gas
for 10 min. Cat-B (3 mg, 0.023 mmol) was added, the flask
was quickly fitted with a condenser containing an argon
balloon, and the solution was heated to reflux for 10 h
during which another equivalent of cat-B was added. The
solution was cooled to rt, DMSO (0.1 mL) added, and the
solution stirred for 12 h. The solvent was removed and flash
chromatography (SiO2, hexanes/EtOAc) gave 41 mg (74%)
of 27 as a white solid. Mp 92 8C; TLC RfZ0.24 (3:1
1
hexanes/EtOAc); H NMR (CDCl3, 400 MHz) d 7.39–7.27
(m, 15H), 5.87 (dd, JZ15.4, 7.6 Hz, 1H), 5.45 (dd, JZ17.0,

6228
J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
8.4 Hz, 1H), 5.33 (s, 2H), 4.60 (s, 2H), 4.35 (s, 2H), 3.71 (s,
2H), 3.71 (s, 2H); 13C (CDCl3, 100 MHz) d 154.0, 136.6,
135.6, 135.2, 129.3, 128.8, 128.7, 128.6, 128.5, 128.5,
128.4, 128.1, 128.0, 127.9, 127.6, 71.1, 55.6, 50.7, 46.8,
40.6; FTIR (neat) 3030, 2956, 1741, 1680, 1508, 1455,
1365, 1163, 751, 699 cmK1; HRMS (MCH)C calcd for
C26H28N3O3S 462.1851, found 462.1861.
15.4, 7.2 Hz, 1H), 3.65 (s, 3H), 3.60 (s, 3H), 1.82–1.71
(m, 2H), 1.82–1.71 (m, 2H), 1.65–1.55 (m, 1H), 1.55–1.45
(m, 1H), 0.99 (d, JZ5.5 Hz, 3H), 0.94 (d, JZ6.0 Hz, 3H),
0.82 (d, JZ6.5 Hz, 3H), 0.82 (d, JZ6.5 Hz, 3H); 13C
(CDCl3,100 MHz) 172.1, 171.1, 155.4, 135.3, 135.3, 133.8,
129.8, 128.4, 128.1, 118.5, 117.6, 74.5, 59.1, 57.3, 52.0,
51.6, 51.5, 49.5, 39.5, 376, 24.6, 24.4, 22.8, 22.4, 21.9, 21.8;
FTIR (neat) 3347, 3080, 2958, 2870, 1732, 1681, 1642,
1548, 1455, 1368, 1168 cmK1; HRMS (MCH)C calcd for
C28H44N3O7S 566.2900, found 566.2875.
4.1.32. N-(2-Propenyl)-N-[[[N0-(2-propenyl)-N0-(1S)-1-
methoxycarbonyl-3-methyl-butyl]carbonyl]amino]-sul-
fonyl]-(S)-leucine methyl ester (28a). To a stirring solution
of N-allyl (L)-leucine methyl ester (975 mg, 5.26 mmol) and
Et3N (0.40 mL, 2.90 mmol) in CH2Cl2 at 0 8C under argon
was added CSI (0.21 mL, 2.40 mmol) in CH2Cl2 (3 mL)
slowly over 10 min. The solution was stirred for 12 h while
slowly being raised to rt. The solvent was removed under
reduced pressure and EtOAc (80 mL) added. The solution
was washed with 10% NaHSO4 (50 mL), NaHCO3 (50 mL),
brine (50 mL), dried with MgSO4, and the solvent removed.
Column chromatography (SiO2, hexanes/EtOAc) afforded
890 mg (78%) of 28a as a yellow oil. TLC RfZ0.20 (3:1
hexanes/EtOAc); [a]2D5 K131.6 (c 3.1, CHCl3); FTIR (neat)
3347, 2958, 2870, 1732, 1682, 1642, 1549, 1455, 1368,
1168 cmK1; HRMS (MCH)C calcd for C21H38N3O7S
476.2430, found 476.2433.
4.1.36. N-(2-Propenyl)-N-[[[N0-(2-propenyl)-N0-(1S)-1-
methoxycarbonyl-2-methyl-propyl]carbonyl]-N00-(benz-
yl)amino]-sulfonyl]-(S)-valine methyl ester (30b). In a
procedure similar to the preparation of 26, benzylation and
flash chromatography (SiO2, hexanes/EtOAc) gave 117 mg
(62%) of 30b as a clear oil. TLC RfZ0.43 (3:1 hexanes/
EtOAc); [a]2D5 K56.5 (c 0.6, CHCl3); H NMR (CDCl3,
1
500 MHz) d 7.34–7.25 (m, 5H), 6.06 (dddd, JZ17.2, 10.1,
6.1, 6.1 Hz, 1H), 5.50–5.38 (m, 1H), 5.21 (dd, JZ17.2,
1.1 Hz, 1H), 5.12 (dd, JZ10.1, 1.0 Hz, 1H), 5.04 (d, JZ
17.2 Hz, 1H), 4.97 (d, JZ10.1 Hz, 1H), 4.44 (s, 2H), 4.17
(d, JZ10.3 Hz, 1H), 4.16–4.11 (m, 2H), 4.07 (dd, JZ19.1,
5.8 Hz, 1H), 4.03–3.99 (m, 1H), 3.98–3.93 (m, 1H), 3.72 (s,
3H), 3.53 (s, 3H), 2.25–2.18 (m, 2H), 1.10 (d, JZ6.6 Hz,
3H), 0.95 (d, JZ6.6 Hz, 3H), 0.87 (d, JZ6.5 Hz, 3H), 0.48
(bs, 3H); 13C (CDCl3, 125 MHz) d 171.4, 170.5, 156.0,
135.2, 133.8, 129.9, 128.6, 128.5, 128.2, 118.0, 117.8, 67.1,
65.3, 51.6, 51.3, 48.8, 28.9, 28.2, 20.3, 19.9, 19.6, 18.9,
17.9, 17.8; FTIR (neat) 3080, 2966, 2877, 1742, 1676, 1456,
1436, 1364, 1161, 749, 700 cmK1; HRMS (MCH)C calcd
for C26H40N3O7S 538.2587, found 538.2571.
4.1.33. N-(2-Propenyl)-N-[[[N0-(2-propenyl)-N0-(1S)-1-
methoxycarbonyl-2-methyl-propyl]carbonyl]amino]-
sulfonyl]-(S)-valine methyl ester (28b). In a procedure
similar to the preparation of 28a, 3-component coupling and
flash chromatography (SiO2, hexanes/EtOAc) yielded
921 mg (56%) of 28b as a clear oil, which was taken on
directly to the next step. TLC RfZ0.17 (3:1 hexanes/
EtOAc); [a]2D5 K87.3 (c 1.05, CHCl3); FTIR (neat) 3292,
4.1.37. N-(2-Propenyl)-N-[[[N0-(2-propenyl)-N0-(1S)-1-
methoxy-carbonyl-2-phenyl-ethyl]carbonyl]-N00-(benzyl)-
amino]-sulfonyl]-(S)-phenylalanine methyl ester (30c).
In a procedure similar to the preparation of sulfamoyl urea
26, benzylation and flash chromatography (SiO2, hexanes/
EtOAc) afforded 505 mg (65%) of 30c as a clear oil. TLC
RfZ0.36 (3:1 hexanes/EtOAc); [a]2D5 K104.9 (c 3.0,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.34–7.26
(m, 8H), 7.22–7.14 (m, 5H), 7.06–7.04 (m, 2H), 6.02
(dddd, JZ16.8, 10.2, 6.5, 6.5 Hz, 1H), 5.39–5.33 (m, 1H),
5.28 (dd, JZ17.2, 1.3 Hz, 1H), 5.22 (dd, JZ10.2, 1.1 Hz,
1H), 4.97 (dd, JZ10.1, 1.1 Hz, 1H), 4.94 (d, JZ17.2 Hz,
1H), 4.78 (dd, JZ7.9, 6.8 Hz, 1H), 4.29 (s, 2H), 4.14–4.02
(m, 2H), 4.14–4.02 (m, 2H), 3.70 (s, 3H), 3.52–3.44 (m,
1H), 3.50–3.40 (m, 1H), 3.46 (s, 3H), 3.43–3.37 (m, 1H),
3.18 (dd, JZ13.9, 6.7 Hz, 1H), 2.89 (dd, JZ14.2, 7.2 Hz,
1H); 13C (CDCl3,100 MHz) 170.9, 170.1, 155.4, 138.2,
137.1, 135.3, 134.6, 133.4, 129.5, 129.5, 129.4, 128.6,
128.5, 128.4, 128.1, 127.0, 126.5, 119.2, 118.7, 62.2, 61.4,
52.1, 51.9, 51.4, 49.4, 49.4, 36.8, 35.2; FTIR (neat) 3064,
3030, 2951, 1744, 1675, 1605, 1586, 1496, 1455, 1367,
1160, 749, 700 cmK1; HRMS (MCH)C calcd for
C34H40N3O7S 634.2587, found 634.2582.
3081, 2967, 1740, 1684, 1551, 1458, 1355, 1164 cmK1
;
HRMS (MCH)C calcd for C19H34N3O7S 448.2117, found
448.2118.
4.1.34. N-(2-Propenyl)-N-[[[N0-(2-propenyl)-N0-(1S)-1-
methoxycarbonyl-2-phenyl-ethyl]carbonyl]amino]-sul-
fonyl]-(S)-phenylalanine methyl ester (28c). In a pro-
cedure similar to the preparation of sulfamoyl urea 28a
coupling and flash chromatography (SiO2, hexanes/EtOAc)
yielded 1.01 g (90%) of 28c as a clear oil, which was taken
on directly to the next step. TLC RfZ0.28 (3:1 hexanes/
EtOAc); [a]2D5 K30.8 (c 1.1, CHCl3); FTIR (neat) 3306,
3032, 2964, 1738, 1556, 1455, 1327, 1155, 745, 699 cmK1
;
HRMS (MCH)C calcd for C27H34N3O7S 544.2117, found
544.2118.
4.1.35. N-(2-Propenyl)-N-[[[N0-(2-propenyl)-N0-(1S)-1-
methoxycarbonyl-3-methyl-butyl]carbonyl]-N00-(benzyl)-
amino]sulfonyl]-(S)-leucine methyl ester (30a). In a
procedure similar to the preparation of 26, benzylation
and flash chromatography (SiO2, hexanes/EtOAc) gave
140 mg (43%) of 30a as a white solid. TLC RfZ0.46 (3:1
hexanes/EtOAc). Mp 46–47 8C; [a]2D5 K47.3 (c 0.85,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.39–7.29 (m,
5H), 6.02 (dddd, JZ17.0, 10.2, 6.6, 6.6 Hz, 1H), 5.41 (dddd,
JZ16.9, 10.1, 6.7, 6.7 Hz, 1H), 5.22 (dd, JZ17.2, 1.0 Hz,
1H), 5.14 (d, JZ10.2 Hz, 1H), 5.04 (dd, JZ17.9, 1.2 Hz,
1H), 5.01 (d, JZ10.6, Hz, 1H), 4.52–4.49 (m, 1H), 4.50 (s,
2H), 4.17–4.01 (m, 2H), 4.17–4.01 (m, 2H), 3.85 (dd, JZ
4.1.38. (2S)-2-[2-Benzyl-4-[(1S)-1-methoxycarbonyl-3-
methyl-butyl]-1,1,3-trioxo-1,2,3,4,5,8-hexahydro-1l6-
[1,2,4,9] thiatriazonin-9-yl]-4-methyl-pentanoic acid
methyl ester (31a). In a procedure similar to that used for
the preparation of 27, RCM and flash chromatography
(SiO2, hexanes/EtOAc) afforded 35 mg (74%) of 31a as a

J. M. Dougherty et al. / Tetrahedron 61 (2005) 6218–6230
6229
white solid. Mp 86–87 8C; TLC RfZ0.31 (3:1 hexanes/
Acknowledgements
EtOAc); [a]2D5 K91.8 (c 0.65, CHCl3); H NMR (CDCl3,
1
400 MHz) d 7.41–7.37 (m, 2H), 7.40–7.26 (m, 3H), 5.78
(dd, JZ18.7, 8.7 Hz, 1H), 5.51 (dd, JZ18.8, 8.6, Hz, 1H),
4.90–4.86 (m, 1H), 4.80 (dd, JZ8.4, 5.6 Hz, 1H), 4.55 (d,
JZ13.2 Hz, 1H), 4.47 (d, JZ13.2 Hz, 1H), 4.09 (dd, JZ
15.0, 8.8 Hz, 1H), 3.95–3.78 (m, 2H), 3.95–3.78 (m, 1H),
3.77 (s, 3H), 3.62 (s, 3H), 1.86–1.77 (m, 2H), 1.76–1.61 (m,
2H), 1.57–1.48 (m, 2H), 1.02 (d, JZ6.0 Hz, 3H), 1.02 (d,
JZ6.0 Hz, 3H), 0.84 (d, JZ6.5 Hz, 3H), 0.84 (d, JZ
6.5 Hz, 3H); 13C (CDCl3,100 MHz) 172.3, 171.7, 154.7,
134.5, 130.7, 130.2, 128.2, 128.0, 127.8, 59.7, 58.3, 52.3,
51.9, 51.6, 42.0, 40.2, 39.7, 38.3, 24.9, 24.3, 23.1, 22.9,
21.7, 21.7; FTIR (neat) 3033, 2956, 1742, 1693, 1680, 1380,
1164, 752, 700 cmK1; HRMS (MCH)C calcd for
C26H40N3O7S 53.2587, found 538.2573.
This investigation was generously supported by partial
funds provided by the National Institutes of Health
(National Institute of General Medical Sciences RO1-
GM58103), and a Minority Supplement (RO1-GM58103,
M. J.), the National Institutes of Health (KU Chemical
Methodologies and Library Development Center of Excel-
lence, P50 GM069663), and a Minority Supplement (P50
GM069663, M. J.). The authors thank Dr. David Vander
Velde and Sarah Neuenswander for assistance with NMR
measurements, Dr. Todd Williams for HRMS analysis, and
Materia, Inc. for supplying ruthenium catalysts.
References and notes
4.1.39. (2S)-2-[2-Benzyl-4-[(1S)-1-methoxycarbonyl-2-
methyl-propyl)-1,1,3-trioxo-1,2,3,4,5,8-hexahydro-1l6-
[1,2,4,9] thiatriazonin-9-yl]-3-methyl-butyric acid
methyl ester (31b). In a procedure similar to that used for
the preparation of 27, RCM and flash chromatography
(SiO2, hexanes/EtOAc) afforded 75 mg (71%) of 31b as a
clear oil. TLC RfZ0.13 (3:1 hexanes/EtOAc); [a]2D5 K101.2
1. (a) Hill, D. C. Curr. Opin. Drug Dis. Dev. 1998, 1, 92–97.
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1
(c 0.75, CHCl3); H NMR (CDCl3, 400 MHz) d 7.38–7.29
(m, 5H), 5.95 (dd, JZ18.6, 8.6 Hz, 1H), 5.62 (dd, JZ18.0,
8.7 Hz, 1H), 5.45 (d, JZ12.2 Hz, 1H), 5.37 (d, JZ12.2 Hz,
1H), 4.48 (dd, JZ13.8, 9.3 Hz, 1H), 4.29–4.12 (m, 2H),
4.29–4.12 (m, 2H), 4.01 (dd, JZ15.3, 7.7 Hz, 1H), 3.71 (s,
3H), 3.68 (s, 3H), 2.23–2.13 (m, 1H), 2.15–2.05 (m, 1H),
1.07 (d, JZ6.7 Hz, 3H),) 0.95 (d, JZ6.5 Hz, 3H), 0.89
(d, JZ6.7 Hz, 3H), 0.88 (d, JZ6.7 Hz, 3H);); 13C
(CDCl3,100 MHz) 172.5, 170.4, 156.1, 135.1, 131.8,
128.6, 128.6128.5, 126.2, 72.4, 67.1, 65.9, 51.9, 51.4,
42.9, 40.0, 29.3, 28.7, 19.8, 19.5, 19.4, 19.3; FTIR (neat)
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3030, 2965, 1740, 1579, 1472, 1291, 1156, 753, 701 cmK1
;
HRMS (MCH)C calcd for C24H36N3O7S 510.2274, found
510.2273.
4.1.40. (2S)-2-[2-Benzyl-4-[(1S)-1-methoxycarbonyl-2-
phenyl-ethyl]-1,1,3-trioxo-1,2,3,4,5,8-hexahydro-1l6-
[1,2,4,9] thiatriazonin-9-yl]-3-phenyl-propionic acid
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chromatography (SiO2, hexanes/EtOAc) afforded 84 mg
(81%) of 31c as a clear oil. TLC RfZ0.20 (3:1 hexanes/
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EtOAc); [a]2D5 K110.3 (c 0.82, CHCl3); H NMR (CDCl3,
400 MHz) d 7.34–7.24 (m, 8H), 7.23–7.16 (m, 5H), 7.06–
7.02 (m, 2H), 5.69 (dd, JZ18.3, 7.7 Hz, 1H), 5.24 (dd, JZ
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8.9 Hz, 1H), 3.91 (dd, JZ15.6, 7.5 Hz, 1H), 3.73 (s, 3H),
3.64 (dd, JZ14.7, 8.1 Hz, 1H), 3.60 (s, 3H), 3.40 (dd, JZ
14.4, 7.1 Hz, 1H), 3.29 (dd, JZ14.3, 6.4 Hz, 1H), 3.07 (dd,
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130.5, 129.2, 129.2, 128.7, 128.4, 128.2, 128.2, 128.1,
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36.9, 35.4; FTIR (neat) 3032, 2958, 1742, 1649, 1545, 1455,
1365, 1164, 750, 700 cmK1; HRMS (MCH)C calcd for
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