New strategies to symmetric and unsymmetric cyclic sulfamide analogs of DMP 323: A 'sulfur linchpin'/RCM approach

Article abstract of DOI:10.1016/j.tet.2003.04.001

The synthesis of 7-membered cyclic sulfamides utilizing the RCM reaction is described herein. Two major synthetic strategies that expand the scope and utility of our previously reported sulfamide and sulfamoyl carbamate chemistry are employed. Both Mitsun

Full text of DOI:10.1016/j.tet.2003.04.001

Tetrahedron 59 (2003) 8901–8912
New strategies to symmetric and unsymmetric cyclic sulfamide
analogs of DMP 323: a ‘sulfur linchpin’/RCM approach
*
´ ´
Jung Ho Jun, Joseph M. Dougherty, Marıa del Sol Jimenez and Paul R. Hanson
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
Received 31 March 2003; accepted 14 April 2003
Abstract—The synthesis of 7-membered cyclic sulfamides utilizing the RCM reaction is described herein. Two major synthetic strategies
that expand the scope and utility of our previously reported sulfamide and sulfamoyl carbamate chemistry are employed. Both Mitsunobu
alkylation and simple alkylation0 of core sulfamides and sulfamoyl carbamates coupled with RCM are used to efficiently install lipophilic
groups into the P1/P10 and P2/P2 periphery of the cyclic sulfamides. Overall, the routes described are applicable to the synthesis of a variety
of cyclic 7-membered sulfamides.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Cyclic ureas DMP 323 and DMP 450 are the most
prominent members of a class of highly potent HIV protease
inhibitors initially developed at DuPont Merck Labora-
tories.1 Since the discovery of DMP 323, a large number of
derivatives have been synthesized and screened.2 Extensive
SAR studies have been carried out to elucidate the effects of
varying P1/P10/P2/P20 residues,3 as well as the absolute and
relative stereochemistry at the P1/P10 and hydroxyl-bearing
stereogenic centers4 (Fig. 1). It was found that each of these
factors significantly influenced inhibitor potency by accent-
uating hydrophobic (P1/P10), hydrogen bonding (P2/P20),
and catalytic aspartate (diol functionality) interactions with
Figure 1.
the enzyme. While cyclic ureas have been the most widely
examined, independent studies by DuPont Merck,5 Hallberg
6
7
´
and co-workers, and Karlen and co-workers have shown
that sulfamide analogs of DMP 323 also display high
inhibitory activity (Fig. 2). In addition, unsymmetric DMP
323 derivatives are of particular interest due to their
potential to exhibit different solubility and inhibitory
profiles relative to their C2-symmetric counterparts.8
Our interest in this area has led us to previously develop
ring-closing metathesis9 (RCM) strategies to the synthesis
of a number of C2-symmetric and unsymmetric analogs of
DMP 323, including cyclic phosphonamides,10,11 sulfa-
mides,12 and ureas.11 In the course of this work we have
developed an efficient P-tether/RCM approach11a to
assemble highly functionalized 1,4-diamines that can be
Keywords: DMP 323; cyclic sulfamides; sulfur heterocycles; RCM;
metathesis.
*
Corresponding author. Tel.: þ1-785-864-3094; fax: þ1-785-864-5396;
Figure 2.
e-mail: phanson@ku.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.04.001

8902
J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
effectively converted into an array of 7-membered hetero-
cycles related to DMP 323.11b In addition, we have reported a
concise RCM strategy to symmetric and unsymmetric cyclic
sulfamides.12 This approach utilized the sulfur coupling
reagents sulfuryl chloride (SO2Cl2) and chlorosulfonyl
isocyanate (CSI) to produce sulfamide and sulfamoyl
carbamate building blocks that could easily be functionalized
via Mitsunobu and simple alkylation procedures.
2. Discussion and results
The strategy we now report exploits the robust nature of
both sulfamide and sulfamoyl carbamate moieties coupled
with the power of RCM to synthesize both symmetric and
unsymmetric sulfamides. Thus far, we have employed a
two-fold strategy utilizing the symmetric and unsymmetric
reagents, sulfuryl chloride (SO2Cl2, Scheme 1) and
chlorosulfonyl isocyanate (ClSO2NCO, Scheme 2). Overall,
the strengths of these approaches lie in the ability to (i)
exploit the versatility of both sulfamide and sulfamoyl
carbamate groups to effectively serve as ‘robust S-linchpins’
to allow a number of simple, yet powerful transformations
to occur on each respective template; (ii) implement simple
ester groups in 1 as latent olefins for subsequent RCM
(Scheme 1); and (iii) use the power of the Mitsunobu
reaction and simple alkylation to efficiently install side-
chain groups into the P1/P10 and P2/P20 periphery of the
cyclic sulfamides (Scheme 2).
Scheme 2.
The central focus of this strategy is the development of
concise synthetic pathways that allow for judicious place-
ment of side-chain groups in each of the P1/P10/P2/P20
regions of the cyclic sulfamide core, with the ultimate goal
of occupying the active site of HIV protease. Furthermore,
these strategies will allow for the generation of cyclic
sulfamides containing differentiated P1/P10/P2/P20 regions.
This goal will be accomplished by exploiting the versatility
of the core S-linchpins coupled with the non-racemic chiral
building blocks 6 and 7 (Scheme 2).
We have previously reported a synthetic route to C2-
symmetric cyclic sulfamides such as 3 that involved
bis-coupling of an amino ester with SO2Cl2 to yield C2-
symmetric sulfamides such as 1 (Scheme 1).12 These
sulfamides can be readily allylated, subjected to RCM,
and dihydroxylated to cleanly afford sulfamide diols such as
3 bearing hydrophobic side-chains in the P2/P20 regions. In
an analogous fashion, more elaborate allylic amines could
be coupled with SO2Cl2 to construct 2; subsequent RCM,
benzylation, and dihydroxylation cleanly provided sulfa-
mide diols such as 4 bearing hydrophobic side-chains in the
P1/P10 regions. While the synthesis of sulfamide 4 was
concise, the production of allylic amines salts required four
steps.13 A new more efficient route has been designed to
generate C2-symmetric sulfamides bearing hydrophobic
side-chains in the P1/P10 regions as outlined in Scheme 3.
Our new route employs two-directional chain synthesis14 on
the leucine-derived, C2-symmetric sulfamide 11. Dialkyl-
ation of 11 with benzyl bromide under standard conditions
gave the corresponding bis-benzylated sulfamide 12 in 99%
yield. Next, a three-step protocol was employed on each of
the homotopic ester moieties to convert the diester moiety in
11 to the diene moiety in 14. Thus, reduction of the esters
with LiAlH4 (100%) cleanly produced diol 13. Swern
oxidation (99%), followed by bis-Wittig olefination with
PPh3CH2Br (87%), yielded the diene sulfamide 14. The
efficiency of this three-step pathway further exemplifies the
robust nature of the sulfamide group as it withstood a variety
of reaction conditions to cleanly afford sulfamide 14.
Metathesis with 5 mol% of (ImesH2)(PCy3)(Cl)2-
RuvCHPh15,16 generated cyclic sulfamide 15 in 69%
Scheme 1.

J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
8903
Scheme 3. Conditions: (a) BnBr, K2CO3, MeCN, 708C, 99%; (b) LAH,
THF, 100%; (c) DMSO, (COCl)2, Et3N, CH2Cl2, 99%; (d) Ph3PCH2Br,
BuLi, THF, 87%; (e) 5 mol% (ImesH2)(PCy3)–(Cl)2RuvCHPh, CH2Cl2,
458C, 69%; (f) OsO4, NMO, 3:1 acetone/H2O, 99%; (g) m-CPBA, CH2Cl2,
52%.
yield. Dihydroxylation of the C2-symmetric sulfamide 15
bearing homotopic olefinic faces using OsO4 proceeded
smoothly to produce the cyclic sulfamide diol 16 in 99%
yield. Alternatively, epoxidation was utilized to give the
epoxy sulfamide 17 in modest yield (52%, unoptimized).
Our synthesis of a cyclic sulfamide bearing stereogenic
centers in both the P1/P10 and P2/P20 positions is outlined in
Scheme 4. Initially, a three-component coupling reaction of
tert-butyl alcohol, chlorosulfonyl isocyanate (CSI), and the
valine-derived allylic amine salt 1813 gave the correspond-
ing sulfamoyl carbamate 5a in 71% yield (Scheme 4).
This building block, first developed by Montero and
co-workers,17 contains two nucleophilic NH sites of
differing pKa that can be exploited in sequential
alkylations.18 Thus, sulfamoyl carbamate 5a was first
alkylated under Mitsunobu conditions (PPh3, THF,
DEAD) with either ethyl lactate (6a, R1¼Me, R2¼Et) or
2-hydroxy-4-methylpentanoic acid methyl ester (6b, R1¼
CH2CHMe2, R2¼Me) to produce 19a,b in good yields.
Methylation of the remaining sulfamide NH, followed by
Boc-deprotection and allylation generated the metathesis
precursor 22a,b. Final RCM with 6 mol% of the first
generation Grubbs catalyst [(PCy3)2(Cl)2RuvCHPh]19
afforded the differentiated cyclic sulfamides 8a,b in excellent
yields. Surprisingly, dihydroxylation of sulfamide 8a,b
occurred with little stereoselectivity to yield an approximate
1.3:1 mixture of diols 23a,b and 24a,b, respectively.
Scheme 4. Conditions: (a) t-BuOH, Et3N, CH2Cl2, 08C, 71%; (b) PPh3,
DEAD, THF, 84–87%; (c) MeI, K2CO3, MeCN, 458C, 96–100%; (d) TFA,
CH2Cl2, 88–100%; (e) allyl-Br, K2CO3, MeCN, 708C, 91–95%; (f) 6 mol%
(PCy3)2(Cl)2RuvCHPh, CH2Cl2, 458C, 97%; (g) OsO4, NMO, 3:1
acetone/H2O 97% (dr,1.3:1.0).
that the nature of the R group adjacent to the isopropyl side-
chain influenced the diastereoselectivity where the
selectivity was diminished in dihydroxylation of the benzyl
substituted sulfamide B [A, R¼H, dr¼11:1 vs. B, R¼Bn,
dr¼5.9:1]. When taken collectively, it appears that
N-substitution on the sulfamide has a substantial effect on
the selectivity of the dihydroxylation. We are currently
Recent work in our group has shown that dihydroxylation of
sulfamide systems11b that are similar in structures to
sulfamide 8b, occurred with good diastereofacial selectivity
(dr¼5.9–11:1, Fig. 3). In this previous study, it was found
Figure 3. Dihydroxylation of sulfamides derived from P-tether approach.
Conditions: 3 mol% OsO4 (4 wt% solution in H2O), 1.2 equiv. NMO·H2O,
acetone/H2O [Ref. 11b].

8904
J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
investigating the origin of this result and will report our
findings at a later time.
The methods outlined in Schemes 3 and 4 were exploited
further in the synthesis of0 an unsymmetric sulfamide
bearing differentiated P1/P1 /P2/P20 regions as outlined in
Scheme 5. Thus, benzylation of our previously reported
unsymmetric sulfamoyl carbamate 2512 (94%) followed by
Boc-deprotection with TFA (97%) proceeded without
incident to generate sulfamide 27 in excellent yield.
Protection of the remaining sulfamide nitrogen with
p-methoxybenzyl chloride yielded sulfamide 28 (77%).
Sulfamide 28 was next subjected to two-directional chain
synthesis employing the aforementioned three-step trans-
formation of both ester groups into the corresponding
olefinic groups primed for RCM. Thus, reduction with LAH
(38%), Swern oxidation (99%), and Wittig olefination
(69%) produced the metathesis precursor 30. RCM with
5 mol% (ImesH2)(PCy3)(Cl)2RuvCHPh proceeded
smoothly to yield the unsymmetric sulfamide 9 bearing
differentiated lipophilic side-chains that occupy the P1
(Me), P10 (iPr), P2 (p-MeOBn), and P20 (Bn) positions. Final
dihydroxylation afforded the sulfamide diol 31 in excellent
yield, but with only modest stereoselectivity (dr¼3.9:1).
Scheme 6. Conditions: (a) PPh3, DIAD, THF, 67%; (b) allyl-Br,
K2CO3, MeCN, 708C, 92%; (c) 5 mol% (ImesH2)(PCy3)–(Cl)2RuvCHPh,
CH2CH2, 458C, 96%; (d) TFA, 96%; (e) BnBr, K2CO3, MeCN, 708C, 89%;
(f) OsO4, NMO, 3:1 acetone/H2O 70% (dr¼16.0:1).
rather than the competing SN20 route. The solvent system
chosen for this transformation had minor influence upon the
ratio of the two observed products as seen in the following
examples: THF (9.3:1 32:SN20), CH2Cl2 (8:1, 32:SN20) and
benzene (.10:1, 32:SN20). Currently, further investigations
into this transformation are underway and will be reported
in due course. Standard allylation conditions yielded
sulfamide diene 33. RCM with 5 mol% of (ImesH2)-
(PCy3)–(Cl)2RuvCHPh produced the cyclic sulfamides
34 in excellent yields. Boc-deprotection with TFA, and
benzylation gave the desired cyclic sulfamide 36 in
excellent yield. Finally, dihydroxylation with OsO4 afforded
the differentiated sulfamide diol 37 in good yield (70%) and
with high diastereoselectivity (dr¼16:1), with the major
product tentatively assigned as the diastereomer resulting
from dihydroxylation on the olefinic face opposite the
benzyloxymethyl group of the adjacent stereocenter.
In conclusion, we have synthesized a variety of symmetric
and unsymmetric cyclic sulfamides with varied substitution
in their P1/P10 and P2/P20 periphery. These methods have
been accomplished using ‘robust S-linchpins’ in combi-
nation with Mitsunobu alkylations, simple alkylations,
RCM, and diastereoselective dihydroxylations. Biological
evaluation of these novel sulfamides is currently in progress
and will be reported in due course.
Scheme 5. Conditions: (a) BnBr, K2CO3, MeCN, 708C, 94%; (b) TFA,
97%; (c) PMBCl, K2CO3, MeCN, 708C, 77%; (d) LAH, THF, 38%;
(e) DMSO, (COCl)2, Et3N, CH2Cl2, 99%; (f) Ph3PCH2Br, BuLi, THF,
69%; (g) 5 mol% (ImesH2)(PCy3)(Cl)2RuvCHPh, CH2Cl2, 408C, 69%;
(h) OsO4, NMO, 3:1 acetone/H2O, 91% (dr¼3.9:1.0).
The final approach that we investigated is outlined in
Scheme 6. This new strategy employs the Mitsunobu
reaction to install the stereogenic center occupying the P1
position. Mitsunobu alkylation of sulfamide 5b12 with the
readily prepared nonracemic secondary allylic alcohol 7,
derived from the condensation of trimethyl sulfonium ylide
with (R)-benzyl protected glycidol,20 generates sulfamide
32 in good yield. It is important to note that the Mitsunobu
product primarily originated from the desired SN2 pathway
3. Experimental
3.1. General methods
All reactions were carried out in flame-dried glassware

J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
8905
under argon. Toluene, THF, Et2O, and CH2Cl2 were purified
by passage through a purification system (Solv-Tek)
employing activated Al2O3.21 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
128.5, 127.5, 62.5, 58.8, 49.2, 39.5, 25.1, 23.1, 21.7; FTIR
(neat) 3386, 3029, 2956, 1604, 1496, 1455, 1323, 1143, 758,
698 cm21; HRMS calcd for C26H41N2O4S (MþH)þ
required 477.2787, found 477.2808.
3.1.3. N, N0-Bis-benzyl-N-N0-bis-[(1S)-1-(2-methyl-
propyl)-2-propenyl]-sulfamide (14). To a stirring solution
of oxalyl chloride (0.30 mL, 3.44 mmol) in 1 mL CH2Cl2 at
2788C under an argon atmosphere was added DMSO
(30 mL, 4.23 mmol) in CH2Cl2 (1 mL) over 20 min. After
40 min, the sulfamide diol 13 (477 mg, 1.00 mmol) in
CH2Cl2 (10 mL) was added over 30 min with an addition
funnel, and the funnel was rinsed with CH2Cl2 (10 mL). The
mixture was stirred at 2788C for 5 h and monitored by TLC.
Et3N (1.5 mL, 10.76 mmol) was added over 15 min and
stirred at 2788C for 2 h. THF (4 mL, 1:1 H2O/THF) was
added at 2788C for 5 min, and the mixture stirred at 08C for
3 h. The reaction mixture was extracted with CH2Cl2
(50 mL), washed with 2M HCl, dried over MgSO4, filtered,
and concentrated under reduced pressure to afford 507 mg
(99%) of the desired dialdehyde sulfamide as a white solid
that was carried on immediately without further purification.
TLC Rf¼0.91 (1:1 hexanes/EtOAc).
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).
3.1.1. N, N0-Bis-benzyl-N-N0-bis-[(1S)-1-(2-methyl-
propyl)-2-methoxycarbonyl]-sulfamide (12). To a stirring
solution of the leucine-derived sulfamide 11 (500 mg,
1.43 mmol) in CH3CN (20 mL) at rt under an argon
atmosphere was added K2CO3 (430 mg, 3.13 mmol) and
benzyl bromide (0.37 mL, 3.11 mmol). The reaction
mixture was heated to reflux for 24 h, filtered, and
concentrated under reduced pressure. The filtrate was
extracted with EtOAc (50 mL£2). The combined organic
extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The resulting oil was purified by
column chromatography (10:1 hexanes/EtOAc) to afford
750 mg (99%) of the desired dibenzyl sulfamide 12 as a
clear oil. TLC Rf¼0.28 (10:1 hexanes/EtOAc);
[a]2D5¼235.9 (c¼1.00, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.41 (d, J¼7.4 Hz, 4H), 7.30–7.23 (m, 6H),
4.71 (d, J¼15.8 Hz, 2H), 4.44 (d, J¼15.8 Hz, 2H), 4.26 (t,
J¼6.5 Hz, 2H), 3.64 (s, 6H), 1.82–1.77 (m, 2H), 1.58–1.49
(m, 4H), 0.85 (d, J¼6.2 Hz, 6H), 0.59 (d, J¼6.2 Hz, 6H);
13C NMR (CDCl3, 100 MHz) d 172.2, 137.1, 128.5, 128.4,
127.6, 58.1, 52.1, 50.3, 39.0 24.9, 22.2, 22.0; FTIR (neat)
To a stirring solution of CH3PPh3Br (2.69 g, 7.53 mmol) in
THF (25 mL) at 08C under an argon atmosphere was slowly
added a solution of BuLi (3.75 mL, 6.0 mmol, 1.6 M in
hexanes) over 3 min. After 3 h, the yellow ylide solution
was cooled to 2788C and a solution of dial sulfamide
(474 mg, 1.00 mmol) in THF (25 mL) at 2788C was added
via cannula. After 24 h, 30 mL acetone was added to quench
the reaction. The reaction mixture was concentrated under
reduced pressure and extracted with EtOAc (50 mL£2). The
combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. Flash chromato-
graphy (10:1 hexanes/EtOAc) gave 418 mg (89%) of the
desired sulfamide diene 14 as white solid. Mp 868C; TLC
Rf¼0.66 (10:1 hexanes/EtOAc); [a]2D5¼218.5 (c¼1.00,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.38 (d,
J¼7.2 Hz, 4H), 7.34–7.22 (m, 6H), 5.86 (ddd, J¼17.5,
10.3, 7.8 Hz, 2H), 5.19 (d, J¼10.3 Hz, 2H), 5.11 (d,
J¼17.2 Hz, 2H), 4.34 (d, J¼15.6 Hz, 2H), 4.22 (d,
J¼15.6 Hz, 2H), 4.02 (dd, J¼13.6, 7.8 Hz, 2H), 1.52–
1.34 (m, 6H), 0.79 (d, J¼6.1 Hz, 6H), 0.64 (d, J¼6.2 Hz,
6H); 13C NMR (CDCl3, 100 MHz) d 138.1, 136.8, 128.6,
128.4, 127.4, 118.2, 59.8, 49.3, 41.5, 24.6, 23.1, 21.5; FTIR
(neat) 3033, 2956, 2930, 1496, 1455, 1332, 1147, 700,
744 cm21; HRMS calcd for C28H41N2O2S (MþH)þ
required 469.2889, found 469.2875.
3031, 2956, 1747, 1497, 1455, 1338, 1147, 755, 698 cm21
;
HRMS calcd for C28H41N2O6S (MþH)þ required 533.2685,
found 533.2672.
3.1.2. N, N0-Bis-benzyl-N-N0-bis-[(1S)-2-hydroxy-1-(2-
methylpropyl)ethyl]-sulfamide (13). To a stirring solution
of 12 (110 mg, 0.22 mmol) in 30 mL of THF at 08C under an
argon atmosphere was added LAH (160 mg, 4.29 mmol).
After 1 h, a 15% NaOH aqueous solution was added to
quench the reaction, and the reaction mixture was filtered
under reduced pressure. The filtrate was concentrated under
reduced pressure, and extracted with EtOAc (50 mL£2).
The combined organic extracts were dried over MgSO4,
filtered, concentrated under reduced pressure, and purified
by column chromatography (1:1 hexanes/EtOAc) to afford
100 mg (100%) of the desired sulfamide diol 13 as a clear
oil. TLC Rf¼0.51 (1:1 hexanes/EtOAc); [a]2D5¼þ15.6
3.1.4. (3S,6S)-2,7-Dibenzyl-3,6-diisobutyl-2,3,6,7-tetra-
hydro-1,2,7-thiadiazepine-1,1-dioxide
(15).
To
a
degassed solution of 14 (320 mg, 0.68 mmol) in benzene
(25 mL) was added (ImesH2)(PCy3)(Cl)2RuvCHPh
(20 mg, 0.030 mmol) at rt. After 24 h, DMSO (1.0 mL)
and silica gel were added to remove the catalyst. After 24 h,
the reaction mixture was filtered, and concentrated under
reduced pressure. Flash chromatography (5:1 hexanes/
EtOAc) afforded 210 mg (69%) of the desired cyclic
sulfamide 15 as white solid. Mp 1088C; TLC Rf¼0.79
1
(c¼1.00, CHCl3); H NMR (CDCl3, 400 MHz) d 7.41 (d,
J¼7.1 Hz, 4H), 7.26–7.16 (m, 6H), 4.49 (d, J¼15.8 Hz,
2H), 4.45 (d, J¼15.8 Hz, 2H), 3.83–3.75 (m, 2H), 3.63–
3.56 (m, 4H), 2.60 (bs, 2H), 1.54–1.44 (m, 2H), 1.44–1.37
(m, 2H), 1.19–1.12 (m, 2H), 0.79 (d, J¼6.5 Hz, 6H), 0.73
(d, J¼6.5 Hz, 6H); 13C NMR (CDCl3, 100 MHz) d 138.5,
1
(5:1 hexanes/EtOAc); [a]2D5¼255.1 (c¼1.00, CHCl3); H
NMR (CDCl3, 400 MHz) d 7.39 (d, J¼10.3 Hz, 4H), 7.33–
7.22 (m, 6H), 5.52 (s, 2H), 4.86 (d, J¼16.0 Hz, 2H), 4.23

8906
J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
(dd, J¼9.1, 5.2 Hz, 2H), 4.20 (d, J¼16.0 Hz, 2H), 1.61–
1.53 (m, 2H), 1.39–1.33 (m, 2H), 1.18–1.11 (m, 2H), 0.80
(d, J¼6.5 Hz, 6H), 0.48 (d, J¼6.7 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) d 139.0, 132.1, 128.3, 127.7, 127.2,
53.4, 50.9, 42.6, 24.2, 22.3, 21.4; FTIR (neat) 3064, 3028,
2957, 1606, 1496, 1338, 1147 cm21; HRMS calcd for
C26H37N2O2S (MþH)þ required 441.2576, found 441.2584.
methylethyl)-2-propenyl]-sulfamide (5a). To a stirring
solution of chlorosulfonyl isocyanate (610 mL, 7.0 mmol)
and CH2Cl2 (35 mL) at 08C in a 100 mL round-bottomed
flask was added tert-butyl alcohol (0.67 mL, 7.0 mmol) in
CH2Cl2 (2 mL) over 5 min and stirred for an additional
10 min. The mixture was then transferred, via cannula, to a
stirring solution of valine-derived allylic amine salt 18
(1.00 g, 7.37 mmol) and Et3N (3.91 mL, 22.1 mmol) in
CH2Cl2 (50 mL) at 08C in a 250 mL round-bottomed flask
over 10 min. The resulting mixture was stirred for 10 h
while slowly being raised to rt. CH2Cl2 (50 mL) was added,
the solution washed with 10% NaHSO4 (3£60 mL),
NaHCO3 (3£50 mL), brine (60 mL), dried (MgSO4),
filtered, and the solvent removed under reduced pressure.
Flash chromatography (SiO2, hexanes/EtOAc) afforded
1.40 g (71%) of the sulfamoyl carbamate 5a as a white
solid. Mp 1518C; TLC Rf¼0.48 (2:1 hexanes/EtOAc);
[a]2D5¼226.0 (c¼1.05, CH3C(O)CH3); 1H NMR (CD3-
C(O)CD3, 400 MHz) d 5.78 (ddd, J¼17.3, 10.3, 8.1 Hz,
1H), 5.25 (dd, J¼17.2, 1.0 Hz, 1H), 5.15 (d, J¼10.4 Hz,
1H), 3.56 (dd, J¼7.4, 7.4 Hz, 1H), 1.88–1.79 (m, 1H), 1.44
(s, 9H), 0.97 (d, J¼6.8 Hz, 3H), 0.92 (d, J¼6.8 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) d 151.4, 137.2, 117.5, 82.2, 64.1,
33.4, 28.3, 19.2, 19.1; FTIR (neat) 3283, 3282, 2967, 1701,
1445, 1371, 1354, 1140 cm21; HRMS (MþH)þ calcd for
C11H23N2O4S 279.1379, found 279.1383.
3.1.5. (3S,4R,5S,6S)-2,7-Dibenzyl-3,6-diisobutyl-2,3,6,7-
tetra-hydro-4,5-dihydroxy-1,2,7-thiadiazepine-1,1-
dioxide (16). To a stirring solution of cyclic sulfamide 15
(40 mg, 0.10 mmol) in acetone (630 mL) and water
(200 mL) was added NMO (15 mg, 0.12 mmol) and OsO4
(18 mL, 2.8 mmol, 4 wt% solution in water). After 3 days,
the reaction mixture was washed with saturated Na2SO3,
dried over MgSO4, filtered, and concentrated under reduced
pressure. Flash chromatography (5:1 hexanes/EtOAc)
afforded 50 mg (99%) of the desired sulfamide diol 16 as
a white solid. Mp 1748C; TLC Rf¼0.28 (5:1 hexanes/
EtOAc); [a]2D5¼265.1 (c¼1.00, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.49–7.45 (m, 4H), 7.35–7.26 (m, 6H), 4.92
(d, J¼16.8 Hz, 1H), 4.62 (d, J¼16.8 Hz, 1H), 4.52 (d,
J¼16.0 Hz, 1H), 4.46 (d, J¼16.0 Hz, 1H), 3.81 (ddd, J¼9.6,
9.6, 4.4 Hz, 1H), 3.75 (dd, J¼4.0, 4.0 Hz, 1H), 3.67 (dd,
J¼6.9, 6.9 Hz, 1H), 3.48 (ddd, J¼10, 5, 5 Hz, 1H), 2.27 (d,
J¼5.0 Hz, 1H), 2.12 (d, J¼7.2 Hz, 1H), 1.79 (ddd, J¼13.7,
8.3, 5.4 Hz, 1H), 1.67–1.47 (m, 3H), 1.46–1.36 (m, 1H),
1.31–1.17 (m, 1H), 0.90 (d, J¼6.0 Hz, 3H), 0.83 (d,
J¼6.4 Hz, 3H), 0.69 (d, J¼6.6 Hz, 3H), 0.67 (d, J¼6.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz) d 139.3, 138.3, 128.6,
128.5, 128.4, 127.6, 127.5, 127.2, 73.9, 71.3, 55.4, 54.4, 51.5,
49.0, 39.8, 36.9, 24.8, 24.1, 23.1, 22.3, 22.1, 21.3; FTIR (neat)
3483, 2956, 1454, 1309, 1144 cm21; HRMS calcd for
C26H39N2O4S (MþH)þ required 475.2631, found 475.2609.
3.1.8. N-[(1,1-Dimethylethoxy)carbonyl]-N-[(1R)-1-
methyl-2-ethoxycarbonyl]-N0-[(1S)-1-(1-methylethyl)-2-
propenyl]-sulfamide (19a). To as stirring solution of 5a
(1.00 g, 3.60 mmol) and DEAD (656 mL, 3.77 mmol) in
THF (1 mL) under argon in a 50 mL round-bottomed flask
was added a mixture of (S)-ethyl lactate (6a) (423 mL,
3.77 mmol) and PPh3 (989 mg, 3.77 mmol) in THF (1 mL)
via drop-wise addition from a syringe. The solution was
stirred for 6 h and the solvent concentrated under reduced
pressure. Flash chromatography (hexanes/EtOAc) afforded
1.14 g (84%) of the sulfamoyl carbamate 19a as a clear
yellow oil. TLC Rf¼0.59 (2:1 hexanes/EtOAc); [a]2D5¼þ4.0
(c¼2.24, CHCl3); 1H NMR (CDCl3, 500 MHz) d 5.72 (ddd,
J¼17.3, 10.5, 6.8 Hz, 1H), 5.72 (d, J¼6.7 Hz, 1H), 5.28 (d,
J¼17.2, 1H), 5.19 (d, J¼10.5 Hz, 1H) 4.87 (q, J¼7.0 Hz, 1H),
4.20 (dq, J¼10.8, 7.1 Hz, 1H), 4.15 (dq, J¼10.8, 7.1 Hz, 1H),
3.78 (q, J¼6.7 Hz, 1H), 1.95–1.86 (m, 1H), 1.54 (d,
J¼7.0 Hz, 3H), 1.45 (s, 9H), 1.26 (dd, J¼7.2, 7.2 Hz, 3H),
0.91 (d, J¼6.8 Hz, 3H), 0.89 (d, J¼6.9 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d 170.1, 150.9, 134.7, 117.5, 84.5, 62.2,
61.4, 55.5, 32.3, 27.9, 18.2, 17.5, 16.4, 14.1; FTIR (neat) 3313,
2978, 2876, 1744, 1721, 1456, 1369, 1151 cm21; HRMS
(MþH)þ calcd for C16H31N2O6S 379.1903, found 379.1895.
3.1.6. (1S,2R,6S,7S)-3,5-Dibenzyl-2,6-diisobutyl-8-oxa-4-
thia-3,5-diaza-bicyclo[5.1.0]octane 4,4-dioxide (17). To a
stirring solution of 15 (250 mg, 0.56 mmol) in CH2Cl2
(5.0 mL) at 08C was added M-CPBA (390 mg, 2.27 mmol).
After 48 h, the reaction was filtered, and the filtrate was
extracted with CH2Cl2 (50 mL£2), and washed with
NaHCO3 (saturated aq). The combined organic extracts
were dried over MgSO4, filtered, and concentrated under
reduced pressure. Flash chromatography (5:1 hexanes/
EtOAc) afforded 140 mg (52%) of the desired epoxysulfa-
mide 17 as a clear oil. [a]2D5¼233.9 (c¼1.00, CHCl3); TLC
Rf¼0.41 (5:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d 7.27–7.05 (m, 10H), 4.83 (d, J¼17.1 Hz, 1H), 4.63 (d,
J¼15.5 Hz, 1H), 4.53 (d, J¼15.5 Hz, 1H), 4.42 (d,
J¼17.1 Hz, 1H), 4.05 (dd, J¼9.0, 4.8 Hz, 1H), 3.71 (ddd,
J¼10, 4.5, 4.5 Hz, 1H), 2.92 (dd, J¼4.2, 4.2 Hz, 1H), 2.84
(d, J¼4.2 Hz, 1H), 1.85 (ddd, J¼14.1, 9.4, 4.9 Hz, 1H),
1.73–1.65 (m, 1H), 1.65–1.55 (m, 1H) 1.45 (ddd, J¼14.2,
8.4, 6.2 Hz, 1H), 1.34–1.25 (m, 2H), 0.82 (d, J¼5.8 Hz,
3H), 0.76 (d, J¼5.8 Hz, 3H), 0.75 (d, J¼6.0 Hz, 3H), 0.51
(d, J¼6.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 139.4,
138.0, 128.5, 128.4, 128.3, 127.7, 127.1, 126.9, 59.8, 58.4,
54.0, 52.0, 51.8, 51.4, 41.3, 41.1, 24.7, 24.4, 22.5, 22.0,
21.8, 21.5; FTIR (neat) 3031, 2958, 1605, 1496, 1338,
1150 cm21; HRMS calcd for C26H37N2O3S (MþH)þ
required 457.2525, found 457.2534.
3.1.9. N-[(1,1-Dimethylethoxy)carbonyl]-N-[(1R)-1-
methyl-2-ethoxycarbonyl]-N0-methyl-N0-[(1S)-1-(1-
methylethyl)-2-propenyl]-sulfamide (20a). Sulfamoyl
carbamate 19a (500 mg, 1.32 mmol), CH3CN (30 mL),
K2CO3 (910 mg, 6.60 mmol), and methyl iodide (0.826 mL,
13.2 mmol) were added sequentially to a 100 mL round-
bottomed flask. The flask was fitted with a condenser, and
the mixture heated to 458C for 12 h. The resulting yellow-
orange mixture was filtered by suction, and the solvent
removed under reduced pressure. Flash chromatography
(10:1 hexanes/EtOAc) yielded 521 mg (100%) of sulfamide
20a as a clear oil. TLC Rf¼0.35 (10:1 hexanes/EtOAc);
3.1.7. N-[(1,1-Dimethylethoxy)carbonyl]-N0-[(1S)-1-(1-

J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
8907
[a]2D5¼þ23.9 (c¼1.80, CHCl3); 1H NMR (CDCl3,
500 MHz) d 5.78 (ddd, J¼17.5, 10.4, 7.3 Hz, 1H), 5.33 (d,
J¼17.4 Hz, 1H), 5.26 (d, J¼10.6 Hz, 1H), 4.91 (q,
J¼6.8 Hz, 1H), 4.29–4.13 (m, 2H), 3.86 (dd, J¼9.3,
9.3 Hz, 1H), 2.89 (s, 3H), 1.91–1.84 (m, 1H), 1.56 (d,
J¼6.9 Hz, 3H), 1.45 (s, 9H), 1.28 (dd, J¼7.1, 7.1 Hz, 3H),
1.00 (d, J¼6.6 Hz, 3H), 0.94 (d, J¼6.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d 170.4, 150.6, 133.5, 119.0, 83.9, 65.6,
61.4, 56.7, 31.1, 28.9, 28.0, 20.1, 19.5, 16.5, 14.2; FTIR
3.1.12. 2-(2R)-[6-(6S)-Isopropyl-7-methyl-1,1-dioxo-
2,3,6,7-tetrahydro-1,2,7-thiadiazepin-2-yl]-propionic
acid ethyl ester (8a). To a 50 mL round-bottomed flask
were added 22a (50 mg, 0.15 mmol), and CH2Cl2 (15 mL)
and the mixture degassed with argon for 15 min. (PCy3)2-
(Cl)2RuvCHPh (4 mg, 0.005 mmol) was added, the flask
fitted with a condenser containing an argon balloon, and the
solution was heated to reflux for 10 h. The solution was
cooled to rt and the flask opened up to air. The solvent was
removed under reduced pressure, and flash chromatography
(hexanes/EtOAc) afforded 44 mg (97%) of cyclic sulfamide
8a as a clear oil. TLC Rf¼0.35 (3:1 hexanes/EtOAc);
[a]2D5¼28.7 (c¼2.10, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 5.88 (dddd, J¼11.5, 5.9, 5.1, 2.2 Hz, 1H), 5.65 (ddd,
J¼10.8, 4.3, 1.3 Hz, 1H), 4.62 (q, J¼7.3 Hz, 1H), 4.21–
4.10 (m, 2H), 3.97 (d, J¼14.0 Hz, 1H), 3.81 (dd, J¼17.5,
6.1 Hz, 1H), 3.56 (dd, J¼17.6, 5.7 Hz, 1H), 2.54 (s, 3H),
1.79–1.71 (m, 1H), 1.39 (d, J¼7.3 Hz, 3H), 1.26 (t,
J¼7.2 Hz, 3H), 1.01 (d, J¼6.5 Hz, 3H), 0.97 (d,
J¼6.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) d 171.6,
132.5, 129.5, 61.6, 61.3, 55.7, 41.1, 29.7, 29.6, 19.9, 19.4,
16.5, 14.1; FTIR (neat) 2979, 2876, 1736, 1467, 1366, 1327,
1164 cm21; HRMS (MþH)þ calcd for C13H25N2O4S
305.1535, found 305.1513.
(neat) 2989, 2940, 2876, 1739, 1467, 1369, 1141 cm21
;
HRMS (MþH)þ calcd for C17H33N2O6S 393.2059, found
393.2041.
3.1.10. N-[(1R)-1-Methyl-2-ethoxycarbonyl]-N0-methyl-
N0-[(1S)-1-(1-methylethyl)-2-propenyl]-sulfamide (21a).
Sulfamide 20a (150 mg, 0.382 mmol), CH2Cl2 (380 mL),
and trifluoroacetic acid (440 mL, 5.70 mmol) were added
sequentially to a 10 mL round-bottomed flask and stirred for
2 h. The mixture was diluted with CH2Cl2 (30 mL), washed
with NaHCO3 (2£20 mL), brine (20 mL), dried (MgSO4),
filtered and the solvent removed under reduced pressure.
Flash chromatography (hexanes/EtOAc) yielded 111 mg
(100%) of sulfamide 21a as a yellow liquid. TLC Rf¼0.52
1
(2:1 hexanes/EtOAc); [a]2D5¼þ35.6 (c¼1.35, CHCl3); H
NMR (CDCl3, 500 MHz) d 5.78 (ddd, J¼17.3, 9.9, 9.9 Hz,
1H), 5.27 (d, J¼16.2 Hz, 1H), 5.24 (d, J¼10.2 Hz, 1H), 4.87
(d, J¼6.7 Hz, 1H), 4.22–4.14 (m, 2H), 3.95–3.89 (m, 1H),
3.80 (dd, J¼9.8, 9.8 Hz, 1H), 2.68 (s, 3H), 1.80–1.70 (m,
1H), 1.38 (d, J¼7.2 Hz, 3H), 1.27, (t, J¼7.1 Hz, 3H), 0.97
(d, J¼6.6 Hz, 3H), 0.87 (d, J¼6.6 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d 173.0, 134.8, 119.3, 67.4, 61.6, 51.2,
29.0, 29.0, 20.0, 19.7, 19.6, 14.0; FTIR (neat) 3295, 2978,
2939, 2875, 1737, 1467, 1453, 1367, 1134 cm21; HRMS
(MþH)þ calcd for C12H25N2O4S 293.1535, found
293.1539.
3.1.13. 2-(2R)-[(4R,5S,6S)-4,5-Dihydroxy-6-isopropyl-7-
methyl-1,1-dioxo-2,3,6,7-tetrahydro-1,2,7-thiadiazepan-
2-yl]-propionic acid ethyl ester (23a) and 2-(2R)-
[(4S,5R,6S)-4,5-dihydroxy-6-isopropyl-7-methyl-1,1-
dioxo-2,3,6,7-tetrahydro-1,2,7-thiadiazepan-2-yl]-pro-
pionic acid ethyl ester (24a). In a procedure similar to the
preparation of 16, sulfamide 8a (38 mg, 0.125 mmol) was
subjected to dihydroxylation conditions (OsO4, NMO, citric
acid, 3:1 acetone/H2O). Flash chromatography (hexanes/
EtOAc) yielded 43 mg (99%) of the sulfamide diols 23a and
24a as an inseparable mixture as a clear oil. TLC Rf¼0.13
(1:1 hexanes/EtOAc); C13H27N2O6S 339.1590, found
339.1570.
3.1.11. N-[(1R)-1-Methyl-2-ethoxycarbonyl]-N-2-pro-
penyl-N0-methyl-N0-[(1S)-1-(1-methylethyl)-2-propenyl]-
sulfamide (22a). Sulfamide 21a (103 mg, 0.352 mmol),
CH3CN (20 mL), K2CO3 (243 mg, 1.76 mmol), and methyl
iodide (152 mL, 13.2 mmol) were added sequentially to a
100 mL round-bottomed flask. The flask was fitted with a
condenser, and the mixture was heated to 558C for 12 h. The
resulting yellow orange mixture was filtered by suction, and
the solvent removed under reduced pressure. Flash
chromatography (hexanes/EtOAc) gave 106 mg (91%) of
the desired diallyl sulfamide 22a as a clear liquid. TLC
Rf¼0.19 (10:1 hexanes/EtOAc); [a]2D5¼þ18.3 (c¼1.20,
CHCl3); 1H NMR (CDCl3, 500 MHz) d 5.86 (dddd,
J¼16.5, 10.2, 6.2, 6.2 Hz, 1H), 5.78 (ddd, J¼17.1, 10.3,
8.1 Hz, 1H), 5.24 (dd, J¼17.1, 1.0 Hz, 1H), 5.22 (dd,
J¼10.1, 1.0 Hz, 1H), 5.21 (dd, J¼17.2, 1.4 Hz, 1H), 5.12
(dd, J¼10.2, 1.3 Hz, 1H), 4.23 (q, J¼7.2 Hz, 1H), 4.17 (dd,
J¼14.3, 3.0 Hz, 1H), 4.15 (dd, J¼14.3, 3.0 Hz, 1H), 3.88
(dd, J¼9.8, 9.8 Hz, 1H), 3.85 (dd, J¼16.4, 6.2 Hz, 1H), 3.75
(dd, J¼16.2, 6.4 Hz, 1H), 2.68 (s, 3H), 1.83–1.73 (m, 1H),
1.46 (d, J¼7.2 Hz, 3H), 1.27 (t, J¼7.1 Hz, 3H), 0.99 (d,
J¼6.6 Hz, 3H), 0.89 (d, J¼6.6 Hz, 3H); 13C NMR (CDCl3,
125 MHz) d 171.8, 134.9, 134.8, 118.9, 117.6, 67.5, 61.1,
55.2, 48.7, 29.2, 28.6, 20.1, 19.7, 15.6, 14.1; FTIR (neat)
3.1.14. N-[(1,1-Dimethylethoxy)carbonyl]-N-[(1R)-1-(2-
methylpropyl)-2-methoxycarbonyl]-N0-[(1S)-1-(1-
methylethyl)-2-propenyl]-sulfamide (19b). In a procedure
similar to the preparation of sulfamoyl carbamate 19a,
sulfamoyl carbamate 5a (454 mg, 1.63 mmol) and
2-hydroxy-4-methyl pentanoic acid methyl ester (6b)
(253 mg, 1.71 mmol) were subjected to Mitsunobu reaction
conditions (DEAD, PPh3, THF). Flash chromatography
(hexanes/EtOAc) yielded 574 mg (87%) of sulfamoyl
carbamate 19b as a white solid. Mp 97–998C; TLC
Rf¼0.59 (2:1 hexanes/EtOAc); [a]2D5¼þ79.5 (c¼1.00,
CHCl3); 1H NMR (CDCl3, 500 MHz) d 5.73 (ddd,
J¼17.2, 10.6, 6.5 Hz, 1H), 5.41 (d, J¼6.9 Hz, 1H), 5.28
(d, J¼17.3 Hz, 1H), 5.20 (d, J¼10.6 Hz, 1H), 4.87
(dd, J¼8.8, 5.2 Hz, 1H), 3.90 (dd, J¼11.8, 6.5 Hz, 1H),
3.77 (s, 3H), 1.98–1.90 (m, 2H) 1.86–1.78 (m, 1H),
1.78–1.72 (m, 1H), 1.45 (s, 9H), 0.96 (d, J¼6.5 Hz,
3H), 0.94 (d, J¼6.5 Hz, 3H), 0.93 (d, J¼6.2 Hz, 3H),
0.90 (d, J¼6.9 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 170.9, 151.0, 134.8, 117.1, 84.4, 61.8, 58.4, 52.2, 39.8,
32.5, 28.0, 24.7, 23.2, 21.7, 18.1, 17.5; FTIR (neat) 3308,
2960, 2873, 1748, 1717, 1436, 1369, 1151 cm21; HRMS
(MþH)þ calcd for C18H35N2O6S 407.2216, found
407.2195.
2977, 2870, 1740, 1642, 1467, 1327, 1159, 1136 cm21
;
HRMS (MþH)þ calcd for C15H29N2O4S 333.1848, found
333.1831.

8908
J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
3.1.15. N-[(1,1-Dimethylethoxy)carbonyl]-N-[(1R)-1-(2-
methylpropyl)-2-methoxycarbonyl]-N0-methyl-N0-[(1S)-
1-(1-methylethyl)-2-propenyl]-sulfamide (20b). In a pro-
cedure similar to the preparation of 20a, 19b (300 mg,
0.740 mmol) was subjected to methylation conditions (MeI,
K2CO3, CH3CN, 558C). Flash chromatography (hexanes/
EtOAc) afforded 298 mg (96%) of sulfamide 20b as a clear
oil. TLC Rf¼0.59 (3:1 hexanes/EtOAc); [a]2D5¼þ23.6
(c¼3.40, CHCl3); 1H NMR (CDCl3, 500 MHz) d 5.77
(ddd, J¼17.6, 10.6, 7.2 Hz, 1H), 5.32 (d, J¼17.4 Hz, 1H),
5.24 (d, J¼10.6 Hz, 1H), 4.90 (dd, J¼8.1, 5.5 Hz, 1H), 3.93
(dd, J¼9.9, 7.4 Hz, 1H), 3.72 (s, 3H), 2.92 (s, 3H), 2.01–
1.95 (m, 1H), 1.92–1.84 (m, 1H), 1.82–1.75 (m, 2H), 1.43
(s, 9H), 1.00 (d, J¼6.6 Hz, 3H), 0.97 (d, J¼6.3 Hz, 3H),
0.95 (d, J¼6.5 Hz, 3H), 0.95 (d, J¼6.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d 170.4, 150.6, 133.5, 119.0, 83.9, 65.6,
61.4, 56.7, 31.1, 29.7, 28.8, 28.2, 28.0, 20.1, 19.5, 16.4,
14.1; FTIR (neat) 2959, 2873, 1735, 1469, 1368, 1337,
1154, 1140 cm21; HRMS (MþH)þ calcd for C19H37N2O6S
421.2372, found 421.2367.
3.1.18. 2-(2R)-[6-(6S)-Isopropyl-7-methyl-1,1-dioxo-
2,3,6,7-tetrahydro-1,2,7-thiadiazepin-2-yl]-4-methyl-
pentanoic acid methyl ester (8b). In a procedure similar to
that used for the preparation of 8a, sulfamide 22a (50 mg,
0.139 mmol) was subjected to standard RCM conditions
(refluxing CH2Cl2, 3 mol% (PCy3)2(Cl)2RuvCHPh, 4 h).
Flash chromatography (hexanes/EtOAc) afforded 45 mg
(97%) of cyclic sulfamide 8b as a clear oil. TLC Rf¼0.44
(3:1 hexanes/EtOAc); [a]2D5¼þ4.6 (c¼2.05, CHCl3); 1H
NMR (CDCl3, 500 MHz) d 5.87 (dddd, J¼12.3, 6.1, 4.4,
2.2 Hz, 1H), 5.67 (ddd, J¼10.7, 4.4, 1.3 Hz, 1H), 4.60 (dd,
J¼7.9, 7.9 Hz, 1H), 3.96 (d, J¼11.1 Hz, 1H), 3.78 (dd,
J¼17.4, 6.0 Hz, 1H), 3.70 (s, 3H), 3.59 (dd, J¼17.5, 6.1 Hz,
1H), 2.55 (s, 3H), 1.79–1.73 (m, 1H), 1.73–1.66 (m, 1H),
1.63 (d, J¼7.7 Hz, 1H), 1.62 (dd, J¼7.9, 2.6 Hz, 1H), 1.01
(d, J¼6.5 Hz, 3H), 0.97 (d, J¼6.5 Hz, 3H), 0.93 (d,
J¼6.5 Hz, 3H), 0.93 (d, J¼6.5 Hz, 3H); 13C NMR (CDCl3,
125 MHz) d 172.0, 133.0, 129.3, 61.5, 57.8, 52.0, 40.4, 39.1,
29.7, 29.6, 24.4, 22.9, 21.5, 20.0, 19.4; FTIR (neat) 2959,
2872, 1741, 1467, 1367, 1336, 1164 cm21; HRMS (MþH)þ
calcd for C15H29N2O4S 333.1848, found 333.1824.
3.1.16. N-[(1R)-1-(2-Methylpropyl)-2-methoxycar-
bonyl]-N0-methyl-N0-[(1S)-1-(1-methylethyl)-2-pro-
penyl]-sulfamide (21b). In a procedure similar to the
preparation of 21a, 20b (208 mg, 0.495 mmol) was
subjected to BOC-deprotection conditions (TFA, CH2Cl2).
Flash chromatography (hexanes/EtOAc) yielded 142 mg
(88%) of the deprotected sulfamide 21b as a clear oil. TLC
Rf¼0.50 (2:1 hexanes/EtOAc); [a]2D5¼þ25.5 (c¼1.65,
CHCl3); 1H NMR (CDCl3, 500 MHz) d 5.77 (ddd,
J¼17.2, 10, 9.2 Hz, 1H), 5.28 (d, J¼17.3 Hz, 1H), 5.25
(d, J¼10.8 Hz, 1H), 4.768 (d, J¼9.8 Hz, 1H), 3.89 (ddd,
J¼9.2, 9.2, 5.9 Hz, 1H), 3.82 (dd, J¼9.6, 9.6 Hz, 1H), 3.73
(s, 3H), 2.68 (s, 3H), 1.82–1.72 (m, 2H), 1.56–1.45 (m,
2H), 0.99 (d, J¼6.6 Hz, 3H), 0.94 (d, J¼6.6 Hz, 3H), 0.91
(d, J¼6.7 Hz, 3H), 0.87 (d, J¼6.6 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d 173.8, 134.8, 119.4, 67.6, 54.1, 52.3,
42.5, 29.0, 29.0, 24.4, 22.6, 21.8, 20.0, 19.6; FTIR (neat) 3289,
2959, 2873, 1742, 1467, 1367, 1335, 1157 cm21; HRMS
(MþH)þ calcd for C14H29N2O4S 321.1848, found 321.1834.
3.1.19. 2-(2R)-[(4R,5S,6S)-4,5-Dihydroxy-6-isopropyl-7-
methyl-1,1-dioxo-2,3,6,7-tetrahydro-1,2,7-thiadiazepan-
2-yl]-4-methyl-pentanoic acid methyl ester (23b) and 2-
(2R)-[(4S,5R,6S)-4,5-dihydroxy-6-Isopropyl-7-methyl-
1,1-dioxo-2,3,6,7-tetrahydro-1,2,7-thiadiazepan-2-yl]-4-
methyl-pentanoic acid methyl ester (24b). In a procedure
similar to the preparation of 16, 8b (44 mg, 0.132 mmol)
was subjected to dihydroxylation conditions (OsO4, NMO,
citric acid, 3:1 acetone/H2O). Flash chromatography
(hexanes/EtOAc) yielded 47 mg (97%) of the sulfamide
diols 23b and 24b as an inseparable mixture of a clear oil.
TLC Rf¼0.13 (1:1 hexanes/EtOAc); HRMS (MþH)þ calcd
for C14H31N2O6S 367.1903, found 367.1905.
3.1.20. N-[(1,1-Dimethylethoxy)carbonyl]-N-[(1R)-1-
methyl-2-ethoxycarbonyl]-N0-[(1S)-1-(1-methylethyl)-2-
methoxycarbonyl]-sulfamide (25). To a stirring solution of
5b (3.34 g, 10.77 mmol) and DIAD (2.4 mL, 12.19 mmol)
in THF (20 mL) at rt, was added the solution of (L)-(2)-
ethyl lactate (1.4 mL, 12.35 mmol) and Ph3P (2.40 g,
9.13 mmol) in THF (20 mL). After 24 h, the reaction
mixture was concentrated under reduced pressure, and
purified by column chromatography (4:1 hexanes/EtOAc) to
afford 3.14 g (85%) of the desired sulfamide 25 as a clear
oil. TLC Rf¼0.42 (4:1 hexanes/EtOAc) [For characteriz-
ation data, see, reference 12].
3.1.17. N-[(1R)-1-(2-Methylpropyl)-2-methoxycar-
bonyl]-N-2-propenyl-N0-methyl-N0-[(1S)-1-(1-methyl-
ethyl)-2-propenyl]-sulfamide (22b). In a procedure similar
to the preparation of 22a, sulfamide 21b (100 mg,
0.312 mmol) was subjected to allylation conditions (allyl
bromide, K2CO3, CH3CN, 708C). Flash chromatography
(hexanes/EtOAc) afforded 107 mg (95%) of diallyl
sulfamide 22b as a clear oil. TLC Rf¼0.55 (3:1 hexanes/
EtOAc); [a]2D5¼þ34.6 (c¼1.55, CHCl3); 1H NMR (CDCl3,
500 MHz) d 5.88 (dddd, J¼17.1, 10.2, 6.5, 6.5 Hz, 1H),
5.77 (ddd, J¼17.2, 10.0, 8.8 Hz, 1H), 5.24 (d, J¼17.2 Hz,
1H), 5.22 (d, J¼10.3 Hz, 1H), 5.16 (d, J¼17.2, 1.5 Hz, 1H),
5.09 (dd, J¼10.1, 1.0 Hz, 1H), 4.30 (dd, J¼8.2, 8.2 Hz, 1H),
3.90 (dd, J¼16.9, 6.0 Hz, 1H), 3.90–3.82 (m, 1H), 3.87 (dd,
J¼16.4, 7.0 Hz, 1H), 3.69 (s, 3H), 2.65 (s, 3H), 1.80–1.64
(m, 4H), 1.00 (d, J¼6.6 Hz, 3H), 0.95 (d, J¼5.9 Hz, 3H),
0.90 (d, J¼6.4 Hz, 3H), 0.88 (d, J¼6.8 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d 172.5, 135.2, 134.7, 118.9, 117.3,
67.8, 57.9, 51.9, 48.6, 38.8, 29.2, 28.6, 24.5, 22.5, 21.8,
20.1, 19.7; FTIR (neat) 2958, 2872, 1744, 1469, 1329, 1160,
1135 cm21; HRMS (MþH)þ calcd for C17H33N2O4S
361.2161, found 361.2176.
3.1.21. N-[(1,1-Dimethylethoxy)carbonyl]-N-[(1R)-1-
methyl-2-ethoxycarbonyl]-N0-benzyl-N0-[(1S)-1-(1-
methylethyl)-2-methoxycarbonyl]-sulfamide (26). In a
procedure similar for the preparation of sulfamide 12;
sulfamide 25 (2.03 g, 4.95 mmol) in CH3CN (50 mL) was
reacted with benzyl bromide (0.75 mL, 6.52 mmol) and
K2CO3 (1.55 g, 11.22 mmol) and refluxed at 828C for 24 h.
The reaction mixture was extracted with EtOAc (3£50 mL),
and the combined organic extracts were dried over MgSO4,
filtered, concentrated under reduced pressure. Flash chro-
matography (3:1 hexanes/EtOAc) afforded 2.11 g (94%) of
the desired ester 26 as a clear oil. TLC Rf¼0.62 (3:1
hexanes/EtOAc); [a]D25¼213.7 (c¼1.00, CHCl3); 1H NMR
(CDCl3, 400 MHz) d 7.47–7.23 (m, 5H), 4.89 (d,

J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
8909
J¼16.8 Hz, 1H), 4.86 (q, J¼7.0 Hz, 1H), 4.77 (d,
J¼16.1 Hz, 1H), 4.25 (d, J¼10.5 Hz, 1H), 4.26–4.10 (m,
2H), 3.67 (s, 3H), 1.99 (m, 1H), 1.48 (s, 9H), 1.33 (d,
J¼7.0 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H), 0.86 (d, J¼6.6 Hz,
3H), 0.84 (d, J¼6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 171.0, 170.3, 150.7, 137.4, 128.7, 128.2, 127.5, 84.3, 66.7,
61.5, 56.6, 51.5, 50.3, 29.1, 28.0, 19.6, 19.5, 15.8, 14.1;
FTIR (neat) 2979, 1732 (br, 3CO), 1455, 1372, 1147, 756,
695 cm21; HRMS calcd for C23H37N2O8S (MþH)þ
required 501.2271, found 501.2287.
28 (1.59 g, 3.05 mmol) in THF (50 mL) was treated with
LAH (0.77 g, 20.4 mmol) at 08C for 1 h. Flash chromato-
graphy (1:1 hexanes/EtOAc) afforded 430 mg (38%) of the
desired sulfamide diol 29 as a clear oil. TLC Rf¼0.38 (1:1
hexanes/EtOAc); [a]D25¼229.1 (c¼1.00, CHCl3); 1H NMR
(CDCl3, 400 MHz) d 7.48 (d, J¼6.8 Hz, 2H), 7.38–7.27 (m,
5H), 6.84 (d, J¼6.8 Hz, 2H), 4.43 (d, J¼15.6 Hz, 1H), 4.38
(d, J¼15.7 Hz, 1H), 4.31 (d, J¼15.7 Hz, 1H), 4.24 (d,
J¼15.6 Hz, 1H), 4.05–3.98 (m, 1H), 3.85 (dd, J¼12.1,
3.8 Hz, 1H), 3.78 (s, 3H), 3.75 (dd, J¼9.5, 4.7 Hz, 1H), 3.56
(dt, J¼9.8, 3.9 Hz, 1H), 3.49 (dd, J¼11.6, 9.8 Hz, 1H), 3.39
(dd, J¼11.6, 4.8 Hz, 1H), 2.43 (bs, 2H), 1.58–1.49 (m, 1H),
1.02 (d, J¼6.9 Hz, 3H), 0.92 (d, J¼6.7 Hz, 3H), 0.80 (d,
J¼6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 158.9,
137.6, 130.5, 129.6, 129.1, 128.3, 127.7, 113.7, 67.8, 63.9,
61.2, 56.0, 55.1, 48.6, 47.6, 29.2, 21.0, 20.2, 15.8; FTIR
(neat) 3444, 3029, 2963, 1612, 1513, 1496, 1456, 1325,
1140, 746, 700 cm21; HRMS calcd for C23H35N2O5S
(MþH)þ required 451.2267, found 451.2256.
3.1.22. N-[(1R)-1-Methyl-2-ethoxycarbonyl]-N0-benzyl-
N0-[(1S)-1-(1-methylethyl)-2-methoxycarbonyl]-sulfa-
mide (27). To a stirring solution of sulfamide 26 (2.00 g,
4.00 mmol) in CH2Cl2 (10 mL) at room temperature was
added TFA (10 mL, 129.8 mmol) in CH2Cl2 (10 mL). The
reaction was stirred for 24 h and extracted with EtOAc
(40 mL£2). The combined organic layers were washed with
aqueous NaHCO3 (40 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. Flash chromatography
(3:1 hexanes/EtOAc) yielded 1.52 g (97%) of the desired
sulfamide 27 as a clear oil. TLC Rf¼0.47 (3:1 hexanes/
EtOAc); [a]2D5¼247.0 (c¼1.00, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.41–7.38 (m, 2H), 7.33–7.25 (m, 3H), 4.99
(d, J¼7.5 Hz, 1H), 4.52 (d, J¼15.6 Hz, 1H), 4.47 (d,
J¼15.6 Hz, 1H), 4.18 (q, J¼7.1, 7.1 Hz, 2H), 3.97 (d,
J¼10.6 Hz, 1H), 4.00 (dq, J¼7.2, 7.2 Hz, 1H), 3.72 (s, 3H),
2.11 (m, 1H), 1.38 (d, J¼7.1 Hz, 3H), 1.27 (t, J¼7.1 Hz,
3H), 0.87 (d, J¼6.6 Hz, 3H), 0.82 (d, J¼6.6 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) d 172.6, 171.7, 136.9, 128.9,
128.3, 127.7, 67.2, 61.7, 51.8, 51.6, 49.7, 28.3, 19.8, 19.6,
19.5, 14.0; FTIR (neat) 3293, 2968, 1738 (br, CO), 1455,
1346, 1139, 752, 700 cm21; HRMS calcd for C18H29N2O6S
(MþH)þ required 401.1746, found 401.1723.
3.1.25. N-[(1R)-1-Methyl-2-propenyl]-N-(4-methoxy)-
benzyl-N0-benzyl-N0-[(1S)-(1-methylethyl)-2-propenyl]-
sulfamide (30). To a stirring solution of oxalyl chloride
(0.44 mL, 5.04 mmol) in CH2Cl2 (1 mL) at 2788C under an
argon atmosphere was added DMSO (430 mL, 6.06 mmol)
in CH2Cl2 (1 mL) over 20 min. After 40 min, the sulfamide
diol 29 (820 mg, 1.82 mmol) in CH2Cl2 (10 mL) was added
over 30 min, and the dropping funnel was rinsed with
CH2Cl2 (4 mL). The mixture was stirred at 2788C for 5 h
and monitored by TLC. Et3N (2.1 mL, 15.1 mmol) was
added over 15 min and the reaction was stirred at 2788C for
2 h. THF (4 mL, 1:1 H2O/THF) was added at 2788C and
after 5 min, the reaction was warmed to 08C and stirred for
30 min. The reaction mixture was extracted with CH2Cl2,
(50 mL) washed with 2M HCl, dried over MgSO4, filtered,
and concentrated under reduced pressure to give 0.81 g
(99%) of the desired dialdehyde sulfamide that was used
immediately without further purification. TLC Rf¼0.91 (1:1
hexanes/EtOAc).
3.1.23. N-[(1R)-1-Methyl-2-ethoxycarbonyl]-N-(4-meth-
oxy)benzyl)-N0-benzyl-N0-[(1S)-1-(1-methylethyl)-2-
methoxycarbonyl]-sulfamide (28). In
a benzylation
procedure similar for the preparation of sulfamide 12,
sulfamide 27 (70 mg, 0.17 mmol) in CH3CN (5 mL) was
reacted with 4-methoxybenzyl chloride (0.1 mL,
0.74 mmol) and K2CO3 (0.12 g, 0.83 mmol) and refluxed
for 24 h. Flash chromatography (3:1 hexanes/EtOAc)
yielded 80 mg (77%) of the desired sulfamide 28 as a
clear oil. TLC Rf¼0.50 (3:1 hexanes/EtOAc); [a]2D5¼218.3
To a solution of methyltriphenylphosphonium bromide
(4.59 g, 12.85 mmol) in THF (25 mL) was added BuLi
(6.4 mL, 10.24 mmol, 1.6 M in hexane) at 08C, the mixture
stirred for 2 h, and cooled down to 2788C. A solution of
dialdehyde sulfamide (0.76 g, 1.71 mmol) in THF (25 mL)
at 2788C was added via cannula. After 24 h, the reaction
mixture was extracted with EtOAc (50 mL£3), dried over
MgSO4, filtered and concentrated under reduced pressure.
Flash chromatography (5:1 hexanes/EtOAc) afforded
520 mg (69%) of the desired sulfamide diene 30 as a clear
oil. TLC Rf¼0.49 (5:1 hexanes/EtOAc); [a]2D5¼þ36.8
1
(c¼1.00, CHCl3); H NMR (CDCl3, 400 MHz) d 7.42 (d,
J¼6.6 Hz, 2H), 7.26–7.18 (m, 5H), 6.77 (d, J¼8.7 Hz, 2H),
4.86 (d, J¼15.9 Hz, 1H), 4.49 (dd, J¼15.5, 4.3 Hz, 1H) 4.40
(d, J¼15.6 Hz, 1H), 4.26–4.20 (m, 1H), 4.16–3.89 (m, 3H),
3.79 (s, 3H), 3.79–3.72 (m, 1H), 3.58 (s, 3H), 1.94–1.85
(m, 1H), 1.39 (d, J¼7.1 Hz, 3H), 1.20 (t, J¼7.2 Hz, 3H),
0.79 (d, J¼6.5 Hz, 3H), 0.77 (d, J¼6.6 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 171.4, 171.1, 159.1, 137.4, 129.7,
129.2, 128.8, 128.2, 127.6, 113.7, 67.2, 61.2, 55.5, 55.2,
51.6, 49.5, 49.0, 28.6, 19.7, 19.4, 14.8, 13.9; FTIR (neat)
1
(c¼1.00, CHCl3); H NMR (CDCl3, 400 MHz) d 7.38 (d,
J¼7.0 Hz, 2H), 7.33–7.26 (m, 5H), 6.81 (d, J¼8.6 Hz, 2H),
5.87 (m, 1H), 5.86 (dd, J¼16.6, 9.7 Hz, 1H), 5.23 (dd,
J¼1.5, 10.2 Hz, 1H), 5.13 (d, J¼10.6 Hz, 1H), 5.08 (dd,
J¼6.8, 6.5 Hz, 2H), 4.30–4.14 (m, 2H), 4.31 (d, J¼15.6 Hz,
1H), 4.21 (d, J¼7.4 Hz, 1H), 4.16 (d, J¼15.7 Hz, 1H), 3.78
(s, 3H), 3.50 (t, J¼9.9 Hz, 1H), 1.87–1.80 (m, 1H), 1.19 (d,
J¼6.9 Hz, 3H), 0.90 (d, J¼6.6 Hz, 3H), 0.69 (d, J¼6.7 Hz,
3H); 13C NMR (CDCl3. 100 MHz) d 158.8, 138.7, 137.3,
135.9, 130.6, 129.8, 129.0, 128.3, 127.6, 119.2, 116.4,
113.5, 69.8, 55.2, 55.1, 49.7, 47.9, 30.1, 20.6, 20.4, 17.4;
FTIR (neat) 3068, 2962, 1612, 1513, 1456, 1331,
2966, 1738, 1612, 1513, 1456, 1338, 1154, 750, 701 cm21
;
HRMS calcd for C26H37N2O7S (MþH)þ required 521.2321,
found 521.2325.
3.1.24. N-[(1R)-2-Hydroxy-1-methylethyl]-N-(4-meth-
oxy)benzyl-N0-benzyl-N0-[(1S)-2-hydroxy-1-(1-methyl-
ethyl)ethyl]-sulfamide (29). In a reduction procedure
similar for the preparation of sulfamide diol 13, sulfamide

8910
J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
1147 cm21; HRMS calcd for C25H35N2O3S (MþH)þ
drop-wise addition of DIAD (256 mL, 1.3 mmol). The
solution was stirred for 8 h and the solvent removed under
reduced pressure. Flash chromatography (20:1, heptanes/
EtOAc) afforded 403 mg (67%, ,6:1 mixture of regio-
isomers) of the sulfamoyl carbamate 32 as a clear yellow
oil. TLC Rf¼0.30 (3:1 heptane/EtOAc); [a]2D5¼þ33.4
required 443.2368, found 443.2346.
3.1.26. 2-(3S,6R)-Benzyl-3-isopropyl-7-(4-methoxy-ben-
zyl)-6-methyl-2,3,6,7-tetrahydro-1,2,7-thiadiazepine 1,1-
dioxide (9). To a refluxing solution of 30 (0.38 g,
0.86 mmol) in degassed benzene (10 mL) was added
(ImesH2)(PCy3)-(Cl)2RuvCHPh (0.03 g, 0.04 mmol) and
stirred for 1 h. The reaction mixture was cooled down to rt,
and silica gel and DMSO (5 drops) were added, and the
solution was stirred overnight. The reaction mixture was
filtered, concentrated under reduced pressure and purified
by column chromatography (5:1 hexanes/EtOAc) to yield
320 mg (89%) of the desired sulfamide 9 as a clear oil. TLC
Rf¼0.27 (5:1 hexanes/EtOAc); [a]2D5¼þ0.44 (c¼1.00,
1
(c¼1.246, CHCl3); H NMR (CDCl3, 400 MHz) d 7.39–
7.28 (m, 5H), 6.00–5.93 (m, 2H), 5.28 (dd, J¼17.4, 1.0 Hz,
1H), 5.21 (dd, J¼10.4, 1.0 Hz, 1H), 5.10 (dd, J¼14.4,
7.1 Hz, 1H), 4.61 (d, J¼12.0 Hz, 1H), 4.57 (d, J¼12.0 Hz,
1H), 4.03 (dd, J¼8.3, 4.4 Hz, 1H), 3.93 (dd, J¼10.0, 8.8 Hz,
1H), 3.67 (s, 3H), 3.65 (dd, J¼10.0, 6.0 Hz, 1H), 2.14–2.06
(m, 1H), 1.52 (s, 9H), 0.99 (d, J¼6.8 Hz, 3H), 0.83 (d,
J¼6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 171.4,
151.2, 137.9, 134.0, 128.3, 127.7, 127.6, 118.4, 84.4, 72.8,
70.1, 61.8, 60.4, 52.1, 31.8, 27.9, 18.8, 17.1; FTIR (neat)
3321, 3064, 1741, 1724, 1643, 1605, 1495, 1369,
1151 cm21;; HRMS (MþH)þ calcd for C22H35N2O7S
471.2165, found 471.2155.
CHCl3); 1H NMR (CDCl3, 400 MHz)
d 7.41 (d,
J¼7.3 Hz, 2H), 7.32–7.22 (m, 5H), 6.85 (d, J¼8.6 Hz,
2H), 6.02 (ddd, J¼10.1, 6.1, 1.3 Hz, 1H), 5.88 (ddd, J¼10.5,
5.8, 1.5 Hz, 1H), 4.75 (d, J¼15.9 Hz, 1H), 4.60 (d,
J¼15.6 Hz, 1H), 4.57 (m, 1H), 4.04 (d, J¼15.9 Hz, 1H),
3.96 (d, J¼15.6 Hz, 1H), 3.93 (m, 1H), 3.79 (s, 3H), 1.78–
1.72 (m, 1H), 1.17 (d, J¼7.2 Hz, 3H), 0.87 (d, J¼6.6 Hz,
3H), 0.71 (d, J¼6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 158.5, 138.1, 136.2, 134.6, 131.5, 128.2, 128.2, 128.1,
127.1, 113.6, 63.7, 55.1, 51.4, 49.9, 49.1, 30.2, 20.1, 20.0,
19.9; FTIR (neat) 3028, 2963, 1613, 1513, 1496, 1456,
1352, 1147, 826, 750, 700 cm21; HRMS calcd for
C23H31N2O3S (MþH)þ required 415.2055, found 415.2046.
3.1.29. N-[(1S)-1-(1-Benzyloxy)methyl-2-propenyl]-N-
[(1,1-dimethylethoxy)carbonyl]-N0-[(1S)-1-(1-methyl-
ethyl)-2-methoxycarbonyl]-N0-2-propenyl-sulfamide
(33). To a stirring solution of 32 (119 mg, 0.25 mmol) in
CH3CN (3 mL) in a pressure tube was added K2CO3
(173 mg, 1.25 mmol) and allyl bromide (216 mL,
2.5 mmol). The pressure tube was heated to 708C for 12 h.
The resulting yellow-orange mixture was filtered by suction,
and the solvent removed under reduced pressure. Flash
chromatography (8:1 heptanes/EtOAc) afforded 120 mg
(92%) of 33 as a clear yellow oil. TLC Rf¼0.41 (3:1
3.1.27. 2-(3S,4S,5R,6R)-Benzyl-4,5-dihydroxy-3-iso-
propyl-7-(4-methoxy-benzyl)-6-methyl-2,3,6,7-tetra-
hydro-1,2,7-thiadiazepane 1,1-dioxide (31). To a stirring
solution of 9 (25 mg, 0.06 mmol) in acetone (230 mL,
3.13 mmol) and water (100 mL, 5.55 mmol) were added
NMO (21 mg, 0.15 mmol), OsO4 (50 mL, 0.0082 mmol,
4 wt% solution in water), and citric acid monohydrate
(30 mg, 0.14 mmol). After 72 h, the reaction mixture was
washed with NaHSO3 (30 mL), extracted with EtOAc
(30 mL£2), dried over MgSO4, filtered, and concentrated
under reduced pressure. Flash chromatography (2:1
hexanes/EtOAc) gave 25 mg (91%) of the desired sulfamide
31 as a white solid. TLC Rf¼0.35 (2:1 hexanes/EtOAc);
[a]2D5¼28.6 (c¼0.22, CHCl3); 1H NMR (CDCl3, 400 MHz)
d 7.44 (d, J¼7.1 Hz, 2H), 7.39–7.33 (m, 5H), 6.88 (d,
J¼8.6 Hz, 2H), 4.59 (d, J¼14.3 Hz, 1H), 4.57 (d, J¼
13.8 Hz, 1H), 4.50 (d, J¼13.8 Hz, 1H), 4.47 (d, J¼14.7 Hz,
1H), 4.24 (d, J¼3.5 Hz, 1H), 3.93 (d, J¼8.5 Hz, 1H), 3.81
(s, 3H), 3.29 (m, 1H), 2.91 (dd, J¼10.6, 4.4 Hz, 1H), 2.15–
2.13 (m, 1H), 2.13 (d, J¼5.7 Hz, 1H), 2.00 (d, J¼5.7 Hz,
1H), 1.14 (d, J¼6.7 Hz, 3H), 0.87 (d, J¼6.6 Hz, 3H), 0.70
(d, J¼6.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 159.1,
137.3, 129.7, 129.6, 128.6, 128.0, 113.9, 68.6, 56.6, 55.2,
55.1, 53.0, 29.4, 21.2, 21.0, 18.0; FTIR (neat) 3448, 3028,
1
heptane/EtOAc); [a]D25¼237.9 (c¼0.98, CHCl3); H NMR
(CDCl3, 400 MHz) d 7.34–7.27 (m, 5H), 6.03 (dddd,
J¼17.4, 10.1, 5.3, 5.3 Hz, 1H), 5.97 (ddd, J¼17.0, 10.5,
6.1 Hz, 1H), 5.29 (d, J¼17.4 Hz, 1H), 5.20 (d, J¼10.5 Hz,
1H), 5.15 (dd, J¼11.5, 1.0 Hz, 1H), 5.10–5.03 (m, 1H),
5.04 (dd, J¼10.0, 1.0 Hz, 1H), 4.57 (d, J¼12.2 Hz, 1H) 4.54
(d, J¼12.0 Hz, 1H), 4.30 (dd, J¼16.8, 7.7 Hz, 1H), 4.24 (dd,
J¼16.9, 5.2 Hz, 1H), 4.14 (d, J¼10.5 Hz, 1H), 3.89 (dd,
J¼9.7, 7.7 Hz, 1H), 3.68 (s, 3H), 3.67 (dd, J¼9.9, 6.8 Hz,
1H), 2.16–2.04 (m, 1H), 1.42 (s, 9H), 1.02 (d, J¼6.6 Hz,
3H), 0.88 (d, J¼6.7 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 171.4, 151.1, 137.8, 135.8, 134.5, 128.2, 127.6, 127.5,
117.6, 116.6, 83.6, 72.7, 70.6, 66.2, 60.8, 51.2, 48.8, 28.8,
27.9, 19.6, 19.2; FTIR (neat) 3081, 1726, 1640, 1367,
1140 cm21; HRMS (MþH)þ calcd for C25H39N2O7S
511.2478, found 511.2460.
3.1.30. 2-(2S)-[(6S)-(6-Benzyloxymethyl-7-(1,1-dimethyl-
ethoxy)carbonyl-1,1-dioxo-1,3,6,7-tetrahydro-1,2,7-thia-
diazepin-2-yl)]-3-methyl-butyric acid methyl ester (34).
To a stirring solution of allylated sulfamide 33 (115 mg,
0.22 mmol) in degassed CH2Cl2 (3 mL) in a pressure tube
was added (ImesH2)(PCy3)(Cl)2RuvCHPh (9 mg,
0.011 mmol, 5 mol%). The solution was stirred at reflux
for 3 h and opened up to air. DMSO (40 mL) was added the
mixture stirred for 12 h, and the solvent concentrated. Flash
chromatography (10:1 heptanes/EtOAc) yielded 104 mg
(96%) of cyclic sulfamide 34 as a clear yellow oil. TLC
Rf¼0.32 (3:1 heptanes/EtOAc); [a]2D5¼259.8 (c¼0.88,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.35–7.27 (m,
5H), 5.78–5.72 (m, 1H), 5.55–5.50 (m, 1H), 5.04 (bs, 1H),
4.57 (s, 2H), 4.28 (d, J¼10.4 Hz, 1H), 4.15–4.10 (m, 1H),
2916, 1610, 1511, 1458, 1329, 1137, 823, 753, 700 cm21
;
HRMS calcd for C23H33N2O5S (MþH)þ required 449.2110,
found 449.2110.
3.1.28. N-[(1S)-1-(1-Benzyloxy)methyl-2-propenyl]-N-
[(1,1-dimethylethoxy)carbonyl]-N0-[(1S)-1-(1-methyl-
ethyl)-2-methoxycarbonyl]-sulfamide (32). To a stirring
solution of sulfamoyl carbamate 5b (400 mg, 1.30 mmol) in
THF (1.0 mL) at rt under argon was added PPh3 (341 mg,
1.3 mmol) and alcohol 7 (231 mg, 1.30 mmol) followed by

J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
8911
3.86–3.79 (m, 3H), 3.64 (s, 3H), 2.20–2.11 (m, 1H), 1.49
(s, 9H), 1.00 (d, J¼6.8 Hz, 3H), 0.95 (d, J¼6.5 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) d 170.4, 151.1, 138.0, 128.5,
128.3, 127.6, 127.6, 125.4, 84.0, 72.8, 71.6, 65.5, 55.5, 52.0,
43.4, 28.3, 27.8, 19.2, 19.1; FTIR (neat) 3030, 1741, 1604,
1369, 1154 cm21; HRMS (MþH)þ calcd for C23H35N2O7S
483.2165, found 483.2156.
EtOAc) produced 70 mg (70%) of the sulfamide diol 37
obtain as a clear oil. TLC Rf¼0.49 (1:3 heptane/EtOAc);
[a]2D5¼237.5 (c¼0.995, CHCl3); 1H NMR (CDCl3,
500 MHz) d 7.39–7.09 (m, 10H), 4.58 (d, J¼14.2 Hz,
1H), 4.39 (d, J¼7.7 Hz, 1H), 4.35 (d, J¼10.3 Hz, 1H), 4.29
(d, J¼11.8 Hz, 1H), 4.25 (d, J¼11.8 Hz, 1H), 4.22–4.20
(m, 1H), 4.05 (d, J¼14.2 Hz, 1H), 3.88 (d, J¼1.3 Hz, 1H),
3.84 (dd, J¼10.2, 9.1 Hz, 1H), 3.78 (s, 3H), 3.69 (dd,
J¼14.5, 5.6 Hz, 1H), 3.42 (d, J¼14.3 Hz, 1H), 3.29–3.23
(m, 2H), 3.15 (dd, J¼9.0, 4.8 Hz, 1H), 2.21–2.13 (m, 1H),
1.05 (d, J¼6.7 Hz, 3H), 0.97 (d, J¼6.6 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d 172.9, 136.9, 136.6, 128.9, 128.5,
128.4, 127.9, 127.8, 127.4, 78.4, 74.1, 73.3, 73.2, 67.4, 59.2,
55.1, 52.1, 45.8, 28.9, 19.3, 19.2; FTIR (neat) 3468, 1739,
1345, 1140 cm21; HRMS (MþH)þ calcd for C25H35N2O7S
507.2165, found 507.2152.
3.1.31. 2-(2S)-[(6S)-(6-Benzyloxymethyl-1,1-dioxo-
1,3,6,7-tetrahydro-1,2,7-thiadiazepin-2-yl)]-3-methyl-
butyric acid methyl ester (35). The cyclic sulfamoyl
carbamate 34 was dissolved in TFA/CH2Cl2 (1:1). After
30 min the reaction was quenched with NaHCO3 (saturated
aq.) and extracted with CH2Cl2 (2£). The aqueous layer was
re-extracted with CH2Cl2, and the organic layers were
combined, dried (MgSO4), and concentrated under reduced
pressure to afford 49 mg (96%) of sulfamide 35 as a yellow
oil. TLC Rf¼0.21 (3:1 heptane/EtOAc); [a]2D5¼245.1
1
(c¼1.025, CHCl3); H NMR (CDCl3, 400 MHz) d 7.38–
Acknowledgements
7.30 (m, 5H), 5.64 (bs, 2H), 5.14 (d, J¼10.2 Hz, 1H), 4.57
(d, J¼12.0 Hz, 1H), 4.51 (d, J¼12.0 Hz, 1H), 4.20–4.15
(m, 2H), 4.11 (d, J¼11.0 Hz, 1H), 3.76–3.70 (m, 1H), 3.65
(s, 3H), 3.60–3.58 (m, 2H), 2.21–2.12 (m, 1H), 1.00 (d,
J¼6.7 Hz, 3H), 0.91 (d, J¼6.5 Hz, 3H); 13C NMR (CDCl3,
100 MHz) d 171.0, 137.4, 130.9, 128.6, 128.5, 128.0, 127.8,
73.5, 72.0, 66.1, 51.8, 50.9, 41.0, 27.4, 19.2, 19.0; FTIR
(neat) 3284, 3029, 1738, 1603, 1333, 1150 cm21; HRMS
(MþH)þ calcd for C18H27N2O5S 383.1641, found
383.1662.
This investigation was generously supported by partial
funds provided by the Petroleum Research Fund (PRF-AC,
administered by the ACS), the National Institutes of Health
(National Institute of General Medical Sciences RO1-
GM58103), and a minority supplement (RO1-GM58103-
S1, MdSJ). The authors thank Dr David Vander Velde and
Sarah Neuenswander for assistance with NMR measure-
ments, Dr Todd Williams for HRMS analysis, and Materia,
Inc. for supplying ruthenium catalysts. The authors also
kindly acknowledge Daiso Co., Ltd, Fine Chemical
Department for donating 100 g of each antipode of the
benzyl protected glycidols for use in the synthesis of allylic
alcohol 9 (e-mail: akkimura@daiso.co.jp).
3.1.32. 2-(2S)-[(6S)-(7-Benzyl-6-benzyloxymethyl-1,1-
dioxo-1,3,6,7-tetrahydro-1,2,7-thiadiazepin-2-yl)]-3-
methyl-butyric acid methyl ester (36). To a stirring
solution of cyclic sulfamide 35 (49 mg, 0.13 mmol) in
CH3CN (5 mL) in a pressure tube was added K2CO3
(90 mg, 0.65 mmol) and benzyl bromide (150 mL,
1.3 mmol). The reaction was heated to 708C for ,12 h,
filtered via suction filtration, and purified by column
chromatography (10:1 heptane/EtOAc) to afford 54 mg
(89%) of the benzylated sulfamide 36 as a yellow oil. TLC
Rf¼0.29 (3:1 heptanes/EtOAc); [a]2D5¼268.5 (c¼0.80,
CHCl3); 1H NMR (CDCl3, 500 MHz) d 7.41–7.18 (m,
10H), 5.82–5.78 (m, 1H), 5.75–5.72 (m, 1H), 4.66–4.63
(m, 2H), 4.31 (s, 1H), 4.28 (d, J¼3.7 Hz, 1H), 4.22 (d,
J¼11.9 Hz, 1H), 4.20 (d, J¼11.0 Hz, 1H), 3.99–3.94 (m,
1H), 3.82–3.76 (m, 1H), 3.72 (s, 3H), 3.54 (dd, J¼9.5,
6.0 Hz, 1H), 3.42 (dd, J¼9.5, 7.2 Hz, 1H), 2.22–2.14
(m, 1H), 1.06 (d, J¼6.7 Hz, 3H), 0.97 (d, J¼6.5 Hz,
3H); 13C NMR (CDCl3, 125 MHz) d 171.8, 138.3, 137.6,
128.8, 128.4, 128.3, 128.3, 128.2, 127.5, 127.1, 126.9, 72.9,
70.9, 65.8, 55.4, 51.8, 51.0, 40.6, 27.8, 19.2, 19.1; FTIR
(neat) 2962, 1740, 1496, 1454, 1334, 1150 cm21; HRMS
(MþH)þ calcd for C25H33N2O5S 473.2110, found
473.2110.
References
1. (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) De Lucca, G. V.; Lam, P. Y. S. Drugs Future
1998, 23, 987–994, and references cited therein.
2. (a) Nugiel, D. A.; Jacobs, K.; Worley, T.; Patel, M.;
Kaltenbach, R. F., III; 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. (b) Pierce, M. E.; Harris, G. D.; Islam, Q.;
Radesca, L. A.; Storace, L.; Waltermire, R. E.; Wat, E.;
Jadhav, P. K.; Emmett, G. C. J. Org. Chem. 1996, 61,
444–450. (c) Confalone, P. N.; Waltermire, R. E. In Process
Chemistry in the Pharmaceutical Industry; Gadamasetti, K. G.,
Ed.; Marcel Dekker: New York, 1999; pp 201–219.
3. For evalutation of P1/P10 substituents, see: (a) Nugiel, D. A.;
Jacobs, K.; Cornelius, L.; Chang, C.-H.; Jadhav, P. K.; Holler,
E. R.; Klabe, R. M.; Bacheler, L. T.; Cordova, B.; Garber, S.;
Reid, C.; Logue, K. A.; Gorey-Feret, L. J.; Lam, G. N.;
Erickson-Vittanen, S.; Seitz, S. P. J. Med. Chem. 1997, 40,
1465–1474. (b) Patel, M.; Bacheler, 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. For
evalutation of P2/P20 substituents, see: (c) Han, Q.; Chang,
3.1.33. 2-(2S)-[(4S,5R,6R)-(7-Benzyl-6-benzyloxymethyl-
4,5-dihydroxy-1,1-dioxo-1,3,6,7-tetrahydro-1,2,7-thia-
diazepin-2-yl)]-3-methyl-butyric acid methyl ester (37).
In a procedure similar to the preparation of the sulfamide
diol 16, sulfamide 36 (93 mg, 0.200 mmol) was subjected to
dihydroxylation conditions NMO·H2O (28 mg, 0.24 mmol),
citric acid (84 mg, 0.40 mmol) and OsO4 (75 mL,
0.012 mmol, 6 mol%). Flash chromatography (1:1 heptane/

8912
J. H. Jun et al. / Tetrahedron 59 (2003) 8901–8912
C.-H.; Li, R.; Ru, Y.; Jadhav, P. K.; Lam, P. Y. S. J. Med.
B. C.; Klabe, R. M.; Erickson-Viitanen, S.; Garber, S.; Reid,
C.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1998, 8, 1077–1082.
9. For recent reviews, see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413–4450. (b) Armstrong, S. K.
J. Chem. Soc., Perkin Trans. 1 1998, 371–388. (c) Fu¨rstner, A.
Angew. Chem. Int. Ed. 2000, 39, 3013–3043. (d) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29.
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.
4 DuPont Merck concluded that the optimal stereochemical
configuration of endocyclic substituted ureas is (4R,5S,6S,7R),
as demonstrated in DMP 323 (Fig. 2). However, a model study
(Ar¼Ph, Fig. 1) revealed that the analogous cis-diol (RSRR)
exhibited comparable HIV protease binding affinity
(Ki¼6.0 nM) relative to the trans-diol (RSSR, Ki¼3.6 nM),
see: Kaltenbach, R. F., III; Nugiel, D. A.; Lam, P. Y. S.; Klabe,
R. M.; Seitz, S. P. J. Med. Chem. 1998, 41, 5113–5117.
5. (a) Jadhav, P. K.; Woerner, F. J. Tetrahedron Lett. 1995, 36,
6383–6386. (b) De Lucca, G. V. J. Org. Chem. 1998, 63,
4755–4766. (c) Patel, M.; Rodgers, J. D.; McHugh, R. J., Jr.;
Johnson, B. L.; Cordova, B. C.; Klabe, R. M.; Bacheler, L. T.;
Erickson-Viitanen, S.; Ko, S. S. Bioorg. Med. Chem. Lett.
1999, 9, 3217–3322. (d) Rodgers, J. D.; Sun, J. H. U.S. Patent
5,532,357, 1996; Chem. Abstr. 1995, 125, 168034. (e) Lam,
P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; De
Lucca, G. V.; Rodgers, J. D. US Patent 5,610,294, 1997;
Chem. Abstr. 1997, 126, 293367.
10. (a) Sprott, K. T.; Hanson, P. R. J. Org. Chem. 2000, 65,
7913–7918. (b) Sprott, K. T.; McReynolds, M. D.; Hanson,
P. R. Synthesis 2001, 612–620.
11. (a) Sprott, K. T.; McReynolds, M. D.; Hanson, P. R. Org. Lett.
2001, 3, 3939–3942. (b) McReynolds, M. D.; Sprott, K. T.;
Hanson, P. R. Org. Lett. 2002, 4, 4673–4676.
12. Dougherty, J. M.; Probst, D. A.; Robinson, R. E.; Moore, J. D.;
Klein, T. A.; Snelgrove, K. A.; Hanson, P. R. Tetrahedron
2000, 56, 9781–9790.
13. Wittig reaction of Boc-protected valine with methyltriphenyl-
phosphonium bromide gave the allylic amine 18, see:
(a) Fehrentz, J.-A.; Castro, B. Synthesis 1983, 676–678.
(b) Saari, W. S.; Fischer, T. E. Synthesis 1990, 453–454.
14. Poss, S. P.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9–17.
15. IMesH2¼1,3-dimesityl-4,5-dihydroimidazol-2-ylidene.
16. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953–956.
´
6. (a) Hulten, J.; Bonham, N. M.; Nillroth, U.; Hansson, T.;
˚
Zuccarello, G.; Bouzide, A.; Aqvist, J.; Classon, B.;
17. Utilization of the pKa difference of the sulfonyl carbamate
N–H (pKa,4) and sulfamide N–H groups in a selective
Mitsunobu/deprotection sequence was first developed by
Montero and later exploited by Groutas. (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.
´
¨
Danielson, U. H.; Karlen, A.; Kvarnstrom, I.; Samuelsson,
B.; Hallberg, A. J. Med. Chem. 1997, 40, 885–897.
(b) Baeckbro, K.; Loewgren, S.; Oesterlund, K.; Atepo, J.;
´ ´
Unge, T.; Hulten, J.; Bonham, N. M.; Schaal, W.; Karlen, A.;
´
Hallberg, A. J. Med. Chem. 1997, 40, 898–902. (c) Hulten, J.;
Andersson, H. O.; Schaal, W.; Danielson, H. U.; Classon, B.;
´
¨
Kvarnstrom, I.; Karlen, A.; Unge, T.; Samuelsson, B.;
Hallberg, A. J. Med. Chem. 1999, 42, 4054–4061.
´
¨
¨ ¨
(d) Markgren, P.-O.; Schaal, W.; Hamalainen, M.; Karlen,
A.; Hallberg, A.; Samuelsson, B.; Danielson, U. H. J. Med.
Chem. 2002, 45, 5430–5439.
18. (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.
7. Schaal, W.; Karlsson, A.; Ahlsen, G.; Lindberg, J.; Andersson,
H. O.; Danielson, U. H.; Classon, B.; Unge, T.; Samuelsson,
19. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100–110.
´
B.; Hulten, J.; Hallberg, A.; Karlen, A. J. Med. Chem. 2001,
´
20. The practicality of this procedure has been significantly
advanced by the commercial availability of nonracemic,
protected-glycidol derivatives. In addition, these derivatives
can now be readily prepared via the Jacobsen asymmetric
kinetic resolution of racemic protected-glycidols Davoille,
R. J.; Rutherford, D. T.; Christie, S. D. R. Tetrahedron Lett.
2000, 41, 1255–1259.
44, 155–169.
8. (a) Wilkerson, W. W.; Dax, S.; Cheatham, W. W. J. Med.
Chem. 1997, 40, 4079–4088. (b) 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. (c) Patel, M.; Kaltenbach, R. F., III; Nugiel, D. A.;
McHugh, R. J., Jr.; Jadhav, P. K.; Bacheler, L. T.; Cordova,
21. Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics
1996, 15, 1518–1520.