Synthesis of amino acid derived seven-membered lactams by RCM and their evaluation against HIV protease

Article abstract of DOI:10.1016/j.bmc.2006.09.009

A versatile synthesis of hydroxylated and epoxy 1-azepin 2-ones substituted at N1, C-3 and C-4 or C-7 has been developed. The sequence involves ring-closing metathesis of an amino acid derived diene amide, followed by either epoxidation or dihydroxylation

Full text of DOI:10.1016/j.bmc.2006.09.009

Bioorganic & Medicinal Chemistry 14 (2006) 8323–8331
Synthesis of amino acid derived seven-membered lactams
by RCM and their evaluation against HIV protease
Shazia Zaman,a Pietro Campanerb and Andrew D. Abella,*
aDepartment of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand
bDepartment of Chemical Sciences, University of Trieste, via Giorgieri I, 1-34127 Trieste, Italy
Received 21 July 2006; revised 27 August 2006; accepted 7 September 2006
Available online 28 September 2006
Abstract—A versatile synthesis of hydroxylated and epoxy 1-azepin 2-ones substituted at N1, C-3 and C-4 or C-7 has been devel-
oped. The sequence involves ring-closing metathesis of an amino acid derived diene amide, followed by either epoxidation or dihydr-
oxylation, of the resulting alkene. Assay of the product epoxides (10, 18, 25) and diols (9a, 17, 24) against HIV protease reveals
micromolar inhibition.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
by epoxidation, or by conversion into a diol, to
give a new class of HIV protease inhibitor. The design
of the target lactams was based on the structure of some
well-known HIV protease inhibitors, cyclic ureas9a,b
(e.g., 3); related cyclic sulfonamides9b,c (4) and
phosphonamides;9d and six-membered lactams4 (e.g.,
5). The six-membered lactams, while being structurally
Medium-sized lactams are important components of
natural products that possess many and varied biologi-
cal properties, including antitumour, antibiotic, antithel-
mintic1,2 and insecticidal activity.3 They also find wide
use in organic synthesis,4 and as a basis of peptidomi-
metic scaffolds that accurately define and stabilize the
biologically active conformations of peptides and pro-
teins (e.g., HIV protease inhibitor 1,5 see Fig. 1). As
such, a good deal of effort has focussed over the years
on developing general synthetic approaches to simple
monocyclic lactams-based on ring closure, ring expan-
sion, cycloaddition and fragmentation reactions.1 Lac-
tamisation has traditionally been the method of choice
for cyclisation,6 however, ring-closing metathesis
(RCM)7 now provides access to highly functionalized
lactams under mild conditions and with a high degree
of functional group tolerance.4c,8
O
CO-Val-Val-OMe
N
Ph
O
1
1
3
R3
R4
R1
N
NH-Ala-H
R7
7
4
O
2
Ph
Ph
N
N
Ph
Ph
Metathesis has found particular importance in the con-
struction of peptidomimetic lactams8 and in this paper
we report methodology for the synthesis of seven-mem-
bered unsaturated peptidomimetic ring lactams [1,3,4,7-
tetrahydro 2H-azepin-2-one (2)] with substituents at
N-1, C-3 and C-4 or C-7. The newly formed double
bond at C-5 and C-6 is further derivatised either
OH
HO
3
O
N
O
O
N
S
Ph
Ph
Ph
Ph
Ph
N
Ph
HO
OH
OH Ph
Keywords: Ring-closing metathesis; Lactams; Diol; HIV protease.
*
5
4
Corresponding author. Tel.: +64 3 3642818; fax: +64 3 3632110;
e-mail: andrew.abell@canterbury.ac.nz
Figure 1.
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.09.009

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S. Zaman et al. / Bioorg. Med. Chem. 14 (2006) 8323–8331
well removed from the well-studied and potent cyclic
ureas and sulfonamides, are difficult to prepare and
are reported as weak inhibitors of HIV protease.4a By
contrast seven-membered lactam-based HIV protease
inhibitors, reported here for the first time, more closely
resemble the cyclic ureas and sulfonamides provide a
versatile framework for the further development of
HIV protease inhibitors and other lactam-based
peptidomimetics. The results of the assay of our
compounds (9a, 10, 17, 18, 24 and 25) against HIV
protease are presented, and discussed, as the first step
to developing this class.
by integration of the t-Bu protons in the 1H NMR spec-
trum) in 71% yield. The stereochemistry of the addition
sequence would thus appear to be controlled by factors
other than the nature of the ligand used. The most likely
explanation is that facial selectivity is dictated by the rel-
ative configuration of the adjacent NH-Boc group,
where addition is known to occur syn to such a group
due to hydrogen bonding between the NH and the inter-
mediate osmate ester.13 The absolute configuration of
the major product in which the diol and NH-Boc groups
are syn, as defined by NOE data (see below) and drawn
in 9a, supports these assignments and conclusions.
The major diol ( )-9a was isolated as a white solid by
fractional crystallization from the mixture and its rela-
tive configuration was determined on the basis of 2D
NOE data. Positive enhancements were observed be-
tween H-3, H-5 and H-6 (see Scheme 1 for numbering)
such that the substituents at these positions must be
syn. The minor diastereoisomer ( )-9b could not be sep-
arated from ( )-9a by chromatography and was thus
characterized as a mixture. The olefin ( )-8 was also
epoxidized on treatmentꢁwith dimethyldioxirane (gener-
ated in situ from Oxone /acetone)14 to give the racemic
epoxides 10 (63%) as a 1:1 mixture of diastereoisomers
that could not be separated by chromatography (see
Scheme 1 step iv).
2. Results and discussion
We initially targeted the simple racemic lactam 8 to
demonstrate the feasibility of the RCM methodology
(Scheme 1). The key precursor diene 7 was prepared as
a mixture of rotamers in 88% yield by coupling ( )-N-
Boc allyl glycine with allyl benzyl amine10 6 in the pres-
ence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodii-
mide hydrochloride (EDCI), hydroxybenzotriazole
(HOBT) and N-methylpyrrolidone (NMP). This was
then treated with Grubb’s first-generation catalyst
11,11 in dry CH2Cl2, to give the cyclic lactam ( )-8 in
76% yield. Introduction of a cis-diol into ( )-8 was
achieved by catalytic Sharpless cis-asymmetric dihydr-
oxylation.12 In particular, treatment of ( )-8 with either
(DHQD)2-PHAL or (DHQ)2-PHAL gave the same dia-
stereomeric mixture of cis diols ( )-9a and ( )-9b (9:1,
With these results in hand we set about introducing a
further aryl substituent at C-4 to better mimic known
HIV protease inhibitors 3 and 4 (see later for a discus-
sion). The key starting optically active acids (13a and
13b) were prepared by Claisen rearrangement15 of 12 (it-
self prepared in 92% by coupling ( )-N-Boc glycine to
Z-cinnamoyl alcohol with DCC and DMAP in CH2Cl2)
HN
Ph
O
O
BocHN
BocHN
Ph
N
OH
6
Ph
HO
O
i
BocHN
Ph
O
( )-N-Boc allyl glycine
( ) -7 (88%)
O
BocHN
OH
PCy3
i
11
Cl
Cl
ii
Ru
PCy3
Ph
12
quinidine
quinine
ii
ii
O
N
O
BocHN
BocHN
O
N
Ph
Ph
O
BocHN
Ph
BocHN
Ph
OH
OH
iv
O
( )-8 (67-76%)
( )-10a-b (63%)
13a (50%)
13b (47%)
iii
BocHN
iii
iii
O
O
1
3
BocHN
(10:1)
(1:3)
N
Ph
N
Ph
+
O
O
6
5
BocHN
BocHN
Ph
OH
( )-9b
OH
HO
HO
N
CO2Bn
14b
N
H
CO2Bn
H
( )-9a
(9:1, 71%)
Ph
14a
Scheme 1. Reagents and conditions: (i) EDCI, HOBT, NMP, rt, 16 h;
(ii) CH2Cl2, reflux, 24 h; (iii) (DHQD)2-PHAL or (DHQ)2-PHAL,
K2OsO2(OH)2, K2CO3, K3(FeCN)6, MeSO2NH2, t-BuOH/H2O, 0 ꢂC–
rt, 48 h; (iv) Oxoneꢁ/acetone, H2O, 0 ꢂC–rt, 16 h.
Scheme 2. Reagents and conditions: (i) (Z)-Cinnamyl alcohol, DCC,
DMAP, CH2Cl2; (ii) quinine or quinidine, LHMDS, Al(OiPr)3, THF,
ꢀ78 ꢂC–rt; (iii) (S)-Ala-OBnÆHCl, EDCI, HOBT, NMP, rt, 16 h.

S. Zaman et al. / Bioorg. Med. Chem. 14 (2006) 8323–8331
8325
in the presence of either quinine or quinidine to give 13a
(50%) and 13b (47%), respectively (Scheme 2). The opti-
cal purities of 13a and 13b were determined to be >90%
and >75%, respectively, by coupling each with (S)-ala-
nine benzyl ester hydrochloride, in the presence of
EDCI, HOBT and NMP, and determining the ratio of
14a and 14b by H NMR spectrum (Scheme 2). Isomer
13a was used in subsequent steps of the synthesis since it
was obtained in higher ee.
um syn to the N-Boc group of 16 due to hydrogen bond-
ing13 of NH to the intermediate osmate ester (cf.
reaction of ( )-8 to give 9a as the major product, see
Scheme 1 and earlier for a discussion). However, in this
case only a single isomer 17 was obtained, presumably
since the configuration of the C-4 phenyl group reinforc-
es the facial selectivity. Reaction of 16 with Oxoneꢁ and
acetone/water14 (Scheme 3) gave the epoxides 18 as a
mixture (ꢁ5:4) of two diastereoisomers (determined by
1H NMR), which could not be separated by crystalliza-
tion or column chromatography. As such, the configura-
tion of the diastereoisomers was not assigned.
1
The olefin-substituted amino acid 13a was coupled with
N-allyl benzyl amine 6 in the presence of EDCI, HOBT
and N-ethylmaleimide (NEM) to give the diene amide 15
in 44% yield (Scheme 3). The diene amide was found to
The introduction of a substituent at C-7 of the seven-
membered lactams was achieved using the substituted
N-benzylamine 21 as starting material, itself derived
from (S)-N-Boc-phenylalanine methyl ester 19 in three
steps16 (Scheme 4). In particular, DIBAL(H) reduction
of 19, in dry toluene at ꢀ78 ꢂC, gave the corresponding
aldehyde, which was immediately subjected to a Wittig
olefination using Ph3P+CH3Brꢀ and potassium bis(tri-
methylsilyl)amide (KHMDS) to give the allyl carbamate
20 in 45% yield (Scheme 4). Benzylation of 20 with NaH
and BnBr followed by removal of the Boc group
with TFA gave the allyl amine 21. This was then coupled
with (S)-N-Boc-allyl glycine in the presence of ben-
1
be a mixture of rotamers [2:1 based on H NMR]. The
diene 15 was subjected to ring-closing metathesis using
Grubb’s first-generation catalyst 11, in refluxing
CH2Cl2, under an argon atmosphere, to give the lactam
1
16 in 85% yield as a single isomer as determined by H
NMR spectroscopy (Scheme 3). The olefinic lactam 16
was then derivatised as for ( )-8 (see Scheme 3). Howev-
er, in this case Sharpless AD,12 using either (DHQD)2-
PHAL or (DHQ)2-PHAL, gave a single diastereoisomer
17 in 51% yield, along with recovered starting material
16 (36%). The configuration of the product was assigned
as shown in 17 based on 2D NOE data: enhancements
were observed between (i) H-4, the NH, and the C-5
and C-6 OH protons; and (ii) H-3, H-5 and the H-7
methylene. As for 9a, the relative configuration of 17
at C-3, C-5 and C-6 is consistent with addition of osmi-
NHBoc
Ph
NHR
i, ii
MeO2C
BocHN
Ph
19
20 R = Boc
21 R = Bn
iii
HN
Ph
O
O
O
BocHN
Ph
iv
N
Ph
Ph
BocHN
Ph
Ph
N
OH
O
6
BocHN
OH
i
22 (67%)
13a
15 (44%)
26
v
11 ii
O
O
O
O
BocHN
Ph
N
BocHN
BocHN
Ph
BocHN
Ph
N
Ph
Ph
N
Ph
N
Ph
vii
Ph
iv
O
O
16 (85%)
23 (92%)
25 (84%)
18 (87%)
vi
O
iii
O
NMes
Ph
MesN
Cl
BocHN
Ru
BocHN
Ph
Ph
Ph
N
N
Cl
Ph
PCy3
26
HO OH
24 (52%)
HO
OH
Scheme 4. Reagents and conditions: (i) DIBALH, toluene, ꢀ78 ꢂC; (ii)
Ph3P+CH3Brꢀ, KHMDS, THF, ꢀ78 ꢂC; (iii) NaH, BnBr, DMF, 0 ꢂC
followed by TFA, CH2Cl2; (iv) CH2Cl2, BOP, DIPEA, rt, 72 h; (v) 26,
CH2Cl2, reflux, 36 h; (vi) (DHQD)2-PHAL or (DHQ)2-PHAL or no
ligand, K2OsO2(OH)2, K2CO3, K3(FeCN)6, MeSO2NH2, t-BuOH/
H2O, 0 ꢂC–rt, 48 h; (vii) Oxoneꢁ/acetone, H2O, 0 ꢂC–rt, 16 h.
17 (51%)
Scheme 3. Reagents and conditions: (i) EDCI, HOBT, NEM, rt, 72 h;
(ii) CH2Cl2, reflux, 24 h; (iii) (DHQD)2-PHAL or (DHQ)2-PHAL,
K2OsO2(OH)2, K2CO3, K3(FeCN)6, MeSO2NH2, t-BuOH/H2O, 0 ꢂC–
rt, 48 h; (iv) Oxoneꢁ/acetone, H2O, 0 ꢂC–rt, 16 h.

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S. Zaman et al. / Bioorg. Med. Chem. 14 (2006) 8323–8331
zotriazol-1-yloxytris(dimethylamino)phosphonium hexa-
fluorophosphate (BOP) and diisopropylethyl amine (DI-
PEA), at room temperature in dry CH2Cl2, to give the
diene 22 in 67% yield (Scheme 4). The progress of the
coupling was monitored by TLC and turnover was in-
creased with the addition of a further four equivalents
of BOP in portions after every 14 h to the reaction
mixture.17
O
O
1
3
P2
P1
P2'
N
P1'
HO
OH
P2
P1'
O
H
H
N
N
N
N
The diene 22 was treated with Grubb’s second-genera-
tion catalyst18 26, in refluxing CH2Cl2, to give 92% of
the olefinic lactam 23 (Scheme 4). The olefin of 23 was
then subjected to Sharpless AD12 using both
(DHQD)2-PHAL or (DHQ)2-PHAL as ligands to give
the same diastereoisomeric diol in each case (ꢁ52–60%
yield), assigned structure 24 (Scheme 4). The absolute
configuration of this diol was assigned on the basis of
the known configuration of the starting materials and
2D NOE data: enhancements were observed between
H3, H5, H6 and the benzylic methylene at C-7. Again,
for reasons discussed earlier, diol formation occurs syn
to the NH-Boc group, a preference reinforced by the rel-
ative configuration of the C-7 benzyl group. It is inter-
esting to note that treatment of 23 with potassium
osmate, potassium carbonate, potassium ferricyanide
and methane sulfonamide in the presence of t-BuOH
and water gave the same product 24 (59%) as a single
diastereoisomer.
H
H
O
P1
O
P2'
scissile bond
natural peptide substrate
Figure 2. Comparison of cyclic HIV protease inhibitors and a natural
peptide substrate depicting the P1–Pn and P10–Pn0 (Schechter–Berger)
nomenclature.22
Table 1. HIV inhibition data for the inhibitors
Compound
HIV inhibition IC50 (lM)
( ) 9a
( ) 10
17
95.3
10.5
75
18
24
19.3
55.3
15.7
25
Reaction of 23 with Oxoneꢁ and acetone/water14 (step vii,
Scheme 4) gave the epoxides 25 as a mixture of two diaste-
more potent than the corresponding diols (9a, 17 and
24). It is interesting to note that there are few reports
of epoxide-based inhibitors of HIV protease.9b,23 The re-
sults suggest that the absolute configuration of the
inhibitors may influence activity, with the epoxide and
diol inhibitors 24 and 25 (IC50 = 55.3 and 15.3 lM,
respectively) being more potent than the corresponding
diol analogues 17 and 18 (IC50 = 75 and 19 lM, respec-
tively). However, it should be noted that 24/25 have a
benzyl substituent at C-7 (P10) while 17/18 have a phenyl
substituent at C-4 (P1), and the observed differences in
potency may reflect the relative ‘fit’ of these substituents
in the protease binding pocket. Somewhat surprisingly,
the most potent inhibitor in the series proved to be
the seven-membered racemic lactam epoxide 10
(IC50 = 10.5 lM) which lacks both P1 and P10 substitu-
ents. The most potent reported six-membered lactam-
based inhibitor of HIV protease has a Ki of 9.4 lM.4a
1
reoisomers (ꢁ1:1 as determined by H NMR) in 84%
yield, which could not be separated by crystallization or
column chromatography. Again, the configurations of
these diastereoisomers were not assigned.
2.1. Assay against HIV protease
The design of our compounds was based on known
structure–activity relationship data (SAR)9 for related
cyclic ureas (e.g., 3), cyclic sulfonamides (e.g., 4) and
some limited data on lactams of type 5.4a In all these
cases potency is favoured by a hydrophobic group
(e.g., an aryl substituent) at the N1/C-3, and C-4/C-7
positions, the so-called P2/P20 and P1/P10 substituents
that interact with the complementary S2/S20 and S1/
S10 binding pockets in the protease active site (see
Fig. 2 for a definition of the nomenclature). The inhibi-
tors prepared in this paper possess a syn diol, rather
than anti, as is found in most of the literature inhibitors
of types 3 and 4. However, it is important to note that
the few literature examples of cyclic ureas with a syn
diol, and the appropriate absolute configuration, are
of approximately equal potency to the anti ana-
logues.19,20 As such a syn diol is a valid geometry to
target in our system. The synthetic derivatives ( )-9a,
( )-10, 17, 18, 24 and 25 were assayed against HIV
protease21 and the IC50 values are given in Table 1.
The seven-membered lactam-based inhibitors of HIV
protease reported here for the first time offer some
potential advantages over related but symmetrical HIV
protease inhibitors (e.g., 3): (i) a lack of symmetry can
impart improved solubility, (ii) our synthesis provides
a means to incorporate a range of ring substituents to
allow optimisation of interactions with the enzyme,
and (iii) the Boc protecting group offers potential to
incorporate these analogues into a peptide or peptide-
like sequence. In essence, our seven-membered lactam-
based HIV protease inhibitors provide a versatile
framework for further development of inhibitors, and
other lactam-based peptidomimetics. The task of intro-
ducing a fourth aryl substituent onto the ring, to give
All the inhibitors showed modest activity in the micro-
molar range, as might be expected given that they lack
an aryl substituent at all available ring positions. Of
these compounds the epoxides (10, 18 and 25) are all

S. Zaman et al. / Bioorg. Med. Chem. 14 (2006) 8323–8331
8327
a fully substituted analog of the literature ureas 3, is the
subject of ongoing research. By comparison, existing
six-membered lactam-based HIV protease inhibitors4a
are structurally well removed from the potent cyclic
ureas and sulfonamides, difficult to prepare, and modest
in activity.
diene (1.0 equiv) in dry degassed CH2Cl2 under argon.
The solution was refluxed for 24–36 h. Excess water
was added, the organic layer was separated and the
aqueous layer was back-extracted with CH2Cl2 (3·).
The combined organic phases were washed with brine,
evaporated under reduced pressure and the crude resi-
due was purified by flash column chromatography.
3. Conclusion
4.4. General procedure C: diol preparation
Seven-membered lactam-based inhibitors of HIV prote-
ase have been prepared for the first time by ring-closing
metathesis followed by hydroxylation or epoxidation of
the resulting alkene. Dihydroxylation has been shown to
occur syn to a tert-butylcarbamate substituent that is
positioned b to the reacting olefin. Substituents at C-4
and C-7 substituents with appropriate stereochemistry
enhance this syn-stereoselectivity. The epoxides are
more potent inhibitors of HIV-1 protease than the
corresponding diols.
Potassium osmate (0.05 equiv) was added to a heteroge-
neous slurry of the olefinic lactam (1 equiv), t-BuOH
(3 mL), water (3 mL), potassium carbonate (3 equiv),
potassium ferricyanide (3 equiv), ligand (DHQD)2-
PHAL or (DHQ)2-PHAL (0.05 equiv) and methane sul-
fonamide (2 equiv) under argon and cooled in an ice
bath. The mixture was warmed to room temperature
slowly and after stirring for 48 h, the mixture was again
cooled in an ice bath. Sodium sulfite was added and the
mixture was allowed to warm to room temperature with
stirring over 1–2 h. Ethyl acetate was added, the organic
layer was separated, and the aqueous phase was further
extracted with ethyl acetate. The combined organic frac-
tions were washed with 2 N KOH (aq), dried (MgSO4)
and concentrated under reduced pressure to give the
crude diol which was purified by flash column
chromatography.
4. Experimental
4.1. General experimental methods
1H NMR spectra were recorded on a Varian Inova spec-
trometer (operating at 500 MHz) and 13C NMR spectra
on a Varian Unity 300 (operating at 75 MHz) at 23 ꢂC in
CDCl3 (unless otherwise stated). Spectra were refer-
enced relative to internal TMS (assigned 0 ppm). Optical
4.5. General procedure D: epoxide formation
To a solution of the olefinic lactam (1 equiv) in acetone
(12 mL) and water (10 mL) was added sodium hydrogen
carbonate (34 equiv). The mixture was stirred vigorously
for 15 min at room temperature, cooled in an ice bath,
and Oxoneꢁ (10 equiv) was added in portions over
5 min. The resulting mixture was vigorously stirred at
this temperature for 2 h and then at room temperature
for 16 h. The acetone was removed under reduced pres-
sure, ethyl acetate and water were added and the organic
layer was separated, and the aqueous layer was back-ex-
tracted with ethyl acetate (3·). The combined organic
fractions were dried (MgSO4), filtered, concentrated un-
der reduced pressure, and the resulting residue was puri-
fied by silica gel column chromatography.
rotations were measured on a Perkin-Elmer polarimeter
25
model 341 with a 10 mm path length. The ½aꢂ values
D
are reported in units deg cm2 gꢀ1, with concentration
given in 10ꢀ1 g cmꢀ3. IR spectra were recorded on a Shi-
madzu 8201PC series FTIR spectrophotometer. IR
spectra were obtained neat on either KBr disc or in solid
KBr. All reactions were carried out in oven-dried glass-
ware under an argon atmosphere. CH2Cl2 was distilled
from CaH2. DMF was dried over P2O5 and distilled
from CaH2 under reduced pressure. The acids 13a–b,15
amine 2116 and N-allyl benzyl amine 610 were prepared
by literature methods.
4.2. General procedure A: amide bond formation
4.5.1. ( )-tert-Butyl(1-{[allyl(benzyl)amino]carbonyl}but-
3-en-1-yl) carbamate (7). A solution of EDCI (1.11 g,
5.80 mmol), HOBT (1.57 g, 11.61 mmol), NMP
(1.67 mL, 17.42 mmol), ( )-N-Boc allylglycine (1.248 g,
EDCI (or DCC, 1 equiv), HOBT (2 equiv) and base (3.0
equiv) were added to a solution of the acid (1.0 equiv)
and amine (1.0 equiv) in dry solvent (DMF or CH2Cl2)
under an argon atmosphere with stirring at room tem-
perature. After stirring for 16–72 h, the solution was
diluted with water and ethyl acetate (10 mL), the organ-
ic phase separated and the aqueous phase was back-ex-
tracted with ethyl acetate (3·). The combined organic
fractions were washed successively with H2O, NaHCO3
soln (aq), brine, dried (MgSO4) and evaporated under
reduced pressure to give the crude diene which was puri-
fied by column chromatography.
5.80 mmol) and N-allylbenzyl amine
6
(795 mg,
5.80 mmol) in DMF (30 mL) was stirred at room tem-
perature for 16 h according to the general procedure
A. The crude product was purified by flash column chro-
matography (petroleum ether/ethyl acetate = 9:1–7:3) to
give 1.77 g (88%) of ( )-7 as a cream solid (2:5 mixture
1
of rotamers by H NMR). Data for mixture: mmax cmꢀ1
1
(solid KBr) 1645, 1655. H NMR d 1.42 (s, 9H, t-Bu,
minor), 1.44 (s, 9H, t-Bu, major), 2.31–2.54 (m, 2H,
CHCH2), 3.89–4.08 (m, 2H, NCH2), 4.48–4.75 (m, 3H,
CH2Ph and NCH), 5.07–5.21 (m, 4H, @CH2), 5.67–
5.81 (m, 2H, @CH), 7.19–7.36 (m, 5H, ArH). 13C
NMR d 28.3, 37.7 (minor), 37.8 (major), 47.9 (minor),
48.2 (major), 49.0 (major), 49.8 (major), 49.9 (minor),
4.3. General procedure B: ring-closing metathesis
The catalyst (either 11 or 26, 0.08 equiv), dissolved in
dry degassed CH2Cl2, was added to a solution of the

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S. Zaman et al. / Bioorg. Med. Chem. 14 (2006) 8323–8331
50.1 (minor), 79.5, 117.6 (major), 117.7 (minor), 118.6,
126.8, 127.4, 127.7, 128.0, 128.5, 128.8, 132.3 (minor),
132.5 (major), 132.7 (minor), 132.8 (major), 136.2,
136.9, 155.1 (minor), 155.2 (major), 172.0 (minor),
172.2, (major). TOF MS ES+ [MH]+: Found:
345.2178; Calcd for C20H29N2O3: 345.2178.
6.06 (bd, 1H, J = 5.5 Hz, NH), 7.16–7.34 (m, 5H,
ArH). 13C NMR d 28.3, 38.7, 46.1, 51.7, 68.1, 68.4,
69.9, 79.9, 127.8, 128.2, 128.7, 136.6, 167.8, 172.7.
4.5.4. ( )-tert-Butyl(3-benzyl-4-oxo-8-oxa-3-azabicyco-
[5,1,0]oct-5-yl]) carbamate (10). The olefinic lactam
( )-8 (138 mg, 0.44 mmol) in acetone (12 mL) and water
(10 mL) was treated with sodium hydrogen carbonate
(1.24 g, 14.80 mmol) and Oxoneꢁ (2.68 g, 4.35 mmol)
as described in the general procedure D. The resulting
crude epoxide was purified by column chromatography
(petroleum ether/ethyl acetate = 7:3) to give 91 mg
(63%) of ( )-10 as a white solid (1:1 by 1H NMR). Data
4.5.2. ( )-tert-Butyl(1-benzyl-2-oxo-2,3,4,7-tetrahydro-
1H-azepin-3-yl) carbamate (8). Catalyst 11 (16 mg,
0.02 mmol), dissolved in dry degassed CH2Cl2 (3 mL),
was added to a solution of the diene ( )-7 (95 mg,
0.25 mmol), in dry degassed CH2Cl2 (20 mL) under ar-
gon, according to the general procedure B. The mixture
was refluxed for 24 h. The crude product was purified by
flash column chromatography (petroleum ether/ethyl
acetate = 9:1 then 8:2) to give 66 mg (76%) of ( )-8 as
1
from mixture: mmax cmꢀ1 (solid KBr) 1652. H NMR d
1.45 (s, 9H), 1.91 (t, 0.5H J = 12.5 Hz), 2.03 (t, 0.5H,
J = 12.5 Hz), 2.50–2.81 (m, 0.5H), 2.65 (dd, 0.5H,
J = 14.5, 2.5 Hz), 2.90 (dd, 0.5H, J = 11, 6 Hz), 3.01–
3.06 (m, 1H), 3.18 (t, 0.5H, J = 5.5 Hz), 3.59–3.67 (m,
1.5H), 3.92 (d, 0.5H, J = 15.5 Hz), 3.96 (d, 0.5H,
J = 17 Hz), 4.33 (d, 0.5H, J = 14.5 Hz), 4.40–4.43 (m,
0.5H), 4.55–4.59 (m, 0.5H), 4.95 (d, 0.5H,
J = 14.5 Hz), 5.27 (d, 0.5H, J = 15 Hz), 5.73 (bd, 0.5H,
J = 7 Hz), 5.86 (bd, 0.5 H, J = 6.5 Hz), 7.21–7.35 (m,
10H). 13C NMR d 28.3, 30.4, 31.3, 44.2, 47.2, 47.7,
48.3, 50.0, 51.1, 51.2, 52.2, 52.4, 52.7, 79.6, 79.7, 127.6,
127.8, 128.0, 128.2, 128.6, 128.8, 136.2, 136.8, 154.8,
154.9, 171.3, 172.2; TOFMS ES+ [MH]+: Found:
333.1811; Calcd for C18H25N2O4: 333.1814.
1
a brown solid. mmax cmꢀ1 (solid KBr) 1647. H NMR
d 1.38 (s, 9H, t-Bu), 2.20 (m, 1H, CHCHAB), 2.60 (dd,
1H, J = 18 Hz, 4 Hz, CHCHAB), 3.27 (dd, 1H,
J = 7.5 Hz, 17.5 Hz, NCHABCH), 4.21 (td, 1H,
J = 17.5 Hz, 3 Hz, NCHABCH), 4.51–4.64 (m, 2H,
NCH2Ph), 4.86–4.91 (m, 1H, CHNH), 5.52–5.64 (m,
2H, @CH), 5.82 (bd, 1H, J = 7 Hz, NH), 7.12–7.24 (m,
5H, ArH). 13C NMR d 28.3, 33.3, 45.1, 49.9, 51.4,
79.4, 124.1, 127.4, 127.7, 128.5, 130.0, 136.7, 154.9,
172.4. TOFMS ES+ [MH]+: Found: 317.2242; Calcd
for C18H25N2O3: 317.1856.
4.5.3. (3R*,5S*,6R*)- and (3R*,5R*,6S*)-tert-Butyl [1-
benzyl-5,6-dihydroxy-2-oxoazepan-3-yl] carbama-te (9a)
and (9b). A mixture of potassium osmate (3 mg,
0.01 mmol), olefinic lactam ( )-8 (52 mg, 0.16 mmol),
t-BuOH (3 mL), water (3 mL), potassium carbonate
(68 mg, 0.49 mmol), potassium ferricyanide (162 mg,
0.49 mmol), ligand (DHQD)2-PHAL or (DHQ)2-PHAL
(6.4 mg, 0.002 mmol) and methane sulfonamide (31 mg,
0.33 mmol) was reacted according to the general method
C. The crude product, obtained as a mixture, was puri-
fied by flash column chromatography (petroleum ether/
ethyl acetate/acetone = 5:1:4) to give 41 mg (71%) of a
mixture of ( )-9a and ( )-9 b (9:1 by 1H NMR). Recrys-
tallization (CHCl3/petroleum ether) gave the major iso-
mer ( )-9a as a white solid and ( )-9b as a mixture with
( )-9a. Data for major isomer ( )-9a. mmax cmꢀ1 (solid
KBr) 3417, 2977, 1701, 1652. 1H NMR (CD3CN) d
1.23 (s, 9H, t-Bu), 1.53 (m, 1H, CHCHAB), 1.67 (dd,
1H, J = 12.5 Hz, 4.0 Hz, CHCHAB), 2.94 (d, 1H,
J = 4 Hz, NCH2CHOH), 3.04 (d, 1H, J = 5.0 Hz,
CHCH2CHOH), 3.14 (dd, 1H, J = 15.5 Hz, 6 Hz,
NCHAB), 3.23–3.26 (m, 1H, NCHAB), 3.54 (bm, 1H,
CHCH2CH), 3.65 (br s, 1H, NCH2CH), 3.71 (d, 1H,
J = 15.0 Hz, NCHABPh), 4.01–4.05 (m, 1H, CH), 5.16
(d, 1H, J = 15 Hz, NCHABPh), 5.72 (br s, 1H, NH),
7.03–7.14 (m, 5H, ArH). 13C NMR d 28.4, 34.6, 46.9,
49.0, 53.1, 68.4, 72.3, 79.9, 127.6, 128.1, 128.7, 136.9,
155.2, 171.6. TOFMS ES+ [MH]+: Found: 351.1922;
Calcd for C18H27N2O5: 351.1920. Data for ( )-9b from
mixture: 1H NMR d 1.44 (s, 9H, t-Bu), 1.83 (t, 1H,
J = 12.5 Hz, CHCHAB), 2.23–2.35 (m, 1H, CHCHAB),
2.92–3.09 (m, 2H, NCH2), 3.31–3.34 (m, 1H,
NCH2CHOH), 4.12 (br s, 1H, CHCH2CHOH), 4.48
(d, 1H, J = 15.0 Hz, NCHABPh), 4.75 (d, 1H,
J = 14.5 Hz, NCHABPh), 4.84–4.87 (m, 1H, NHCH),
4.5.5. (S)-Benzyl-2-[(2R,3R)-2-(tert-butyloxycarbonyl)-3-
phenylpent-4-enamido]propanoate (14a). EDCI (66 mg,
0.34 mmol), HOBT (92 mg, 0.68 mmol) and NMP
(10 lL, 1.03 mmol) were added to a solution of the acid
13a (100 mg, 0.34 mmol) and (S)-alanine benzyl ester
hydrochloride (73 mg, 0.34 mmol), according to general
procedure A. Crude 14a (containing <10% of a second
diastereoisomer tentatively assigned 14b) was purified
by column chromatography (petroleum ether/ethyl ace-
tate = 8.5:1.5) to give 90 mg (58%) of 14a as a white sol-
1
id. H NMR d 1.30 (d, 3H, J = 7 Hz, CH3), 1.39 (s, 9H,
t-Bu), 3.98 (t, 1H, J = 6.5 Hz, PhCH), 4.46 (m, 1H,
CHCH), 4.51–4.56 (m, 1H, CH3CH), 4.96 (bd, 1H,
J = 6 Hz, NH), 5.14–5.19 (m, 4H, @CH2, CO2CH2),
6.04–6.11 (m, 1H, @CH), 6.26 (d, 1H, J = 7.5 Hz,
NH), 7.22–7.39 (m, 10H, ArH). 13C NMR d 18.3,
28.2, 48.2, 51.1, 58.2, 67.1, 80.2, 118.1, 127.2, 128.1,
128.2, 128.3, 128.4, 128.5, 128.6, 128.7, 130.9, 136.0,
139.1, 155.3, 169.8, 172.2; TOFMS ES+ [MH]+: Found:
451.2437; Calcd for C27H35N2O4: 451.2597.
4.5.6. tert-Butyl(1R,2R)-1-{[allyl(benzyl)amino]carbon-
yl}-2-phenylbut-3-en-1-yl] carbamate (15). EDCI
(200 mg, 1.03 mmol), HOBT (334 mg, 2.47 mmol),
NEM (258 mg, 2.06 mmol), N-allyl benzyl amine 6
(2.06 mg, 5.80 mmol) and 13a (300 mg, 1.03 mmol) in
CH2Cl2 (30 mL) were reacted for 72 h according to gen-
eral procedure A. The crude product was purified by
flash column chromatography (petroleum ether/ethyl
acetate = 9:1–8.5:1.5) to give 183 mg (44%) of the de-
sired diene 15 as a white solid (2:1 mixture of rotamers
by 1H NMR). Data for mixture: mmax cmꢀ1 (solid
1
KBr) 1697, 1647. H NMR d 1.28 (s, 9H, t-Bu, minor),
1.30 (s, 9H, t-Bu, major), 3.66–4.21 (m, 3H, PhCH,

S. Zaman et al. / Bioorg. Med. Chem. 14 (2006) 8323–8331
8329
NCH2), 4.33–4.78 (m, 2H, NCH2Ph), 4.92–5.04 (m, 1H,
NHCH), 5.08–5.20 (m, 4H, @CH2) 5.63–5.77 (m, 1H,
@CH), 5.92–6.13 (m, 1H, @CH), 7.16–7.34 (m, 10H,
ArH). 13C NMR d 28.1 (major), 28.3 (minor), 47.9 (min-
or), 48.3 (major), 49.2 (major), 50.0 (minor), 53.1 (ma-
jor), 53.2 (minor), 53.7 (major), 53.7 (minor), 79.6
(major and minor), 117.7 (minor), 117.9 (major),
126.9, 127.2, 127.4, 127.6, 128.4, 128.5, 128.6 (major
and minor), 132.4 (major), 132.7 (major), 136.3 (minor),
136.6 (minor), 136.7 (major), 136.9 (minor), 139.3 (ma-
4.5.9. tert-Butyl[(1S*,5R,6R,7R*)-3-benzyl-6-phenyl-4-
oxo-8-oxa-3-azabicyclo-[5.1.0]oct-5-yl]carbamate (18).
The olefinic lactam 16 (40 mg, 0.10 mmol) in acetone
(6 mL) and water (5 mL) was treated with sodium
hydrogen carbonate (291 mg, 3.46 mmol) and Oxoneꢁ
(627 mg, 1.02 mmol) as described in the general proce-
dure D. The resulting crude epoxide was purified by col-
umn
acetate = 7:3) to give 36 mg (87%) of 18 (5:4 mixture
chromatography
(petroleum
ether/ethyl
1
by H NMR) as a white solid. Data for mixture: mmax
1
jor), 139.4 (minor), 154.7 (minor), 154.8 (major), 171.3
cmꢀ1 (solid KBr) 1654. H NMR d 1.16 (s, 9H, t-Bu,
20
D
(minor), 171.5 (major); ½aꢂ +50.0 (c 1.0, CHCl3); TOF-
major), 1.26 (s, 9H, t-Bu, minor), 3.00–3.28 (m, 3H),
3.69–3.76 (m, 1H), 3.92-4.01 (m), 3.98–4.36 (m), 4.22
(d, J = 16.5 Hz), 4.34 (d, J = 15 Hz), 4.82–4.90 (m,
1H), 5.05 (d, J = 14 Hz), 5.24 (d, 1H, J = 10 Hz), 5.33
(d, J = 15.5 Hz), 5.41 (d, 1H, J = 9 Hz), 7.26–7.53 (m,
10H). 13C NMR d 28.0, 29.7, 43.9, 47.3, 47.6, 50.4,
51.3, 52.1, 52.2, 54.5, 56.4, 57.0, 68.4, 79.3, 80.4, 127.3,
127.7, 128.5, 128.7, 129.0, 129.6, 136.2, 136.9, 139.3,
154.6, 155.2, 169.4, 171.4. TOFMS ES+ [M+H]+:
Found: 409.2124; Calcd for C24H29N2O4: 409.2127.
MS ES+ [MH]+: Found: 421.2498; Calcd for
C26H33N2O3: 421.2491.
4.5.7. tert-Butyl[(3R,4R)-1-benzyl-4-phenyl-2-oxo-2,3,4,7-
tetrahydro-1H-azepin-3-yl] carbamate (16). Catalyst 11
(68.5 mg, 0.08 mmol) in CH2Cl2 (3 mL) was reacted
with 15 (175 mg, 0.42 mmol), in CH2Cl2 (20 mL)
according to the general procedure B. The mixture was
refluxed for 24 h and the crude product was purified
by flash column chromatography (petroleum ether/ethyl
acetate = 4:1) to give 139 mg (85%) of 16 as a white crys-
4.5.10. tert-Butyl (1S)-1-({benzyl[(1S)-1-benzylprop-2-en-
1-yl]amino}carbonyl)but-3-en-1-yl carbamate (22). (S)-N-
Boc allyl glycine (250 mg, 1.16 mmol), BOP24 (513 mg,
1.16 mmol) and DIPEA (620 lL, 3.48 mmol) were add-
ed to a solution of 2116 (275 mg, 1.16 mmol) in CH2Cl2
(20 mL) under argon with stirring at room temperature
for 72 h. Four additional equivalents of BOP were add-
ed in portions to the reaction mixture to increase the
turnover of the reaction.17 The solution was diluted with
water and ethyl acetate (10 mL), organic layer was sep-
arated and aqueous layer back-extracted with ethyl ace-
tate (3·). The combined organic fractions were washed
successively with H2O, NaHCO3 soln (aq), brine and
dried (MgSO4). Evaporation under reduced pressure
and flash column chromatography (petroleum ether/eth-
yl acetate = 9:1) gave 336 mg (67%) of 22 as a clear oil
1
talline solid. mmax cmꢀ1 (solid KBr) 1641. H NMR d
1.10 (s, 9H, t-Bu), 3.33–3.42 (m, 2H, PhCH, NCHAB),
4.45 (d, 1H, J = 17 Hz, NCHAB), 4.62 (s, 2H, NCH2Ph),
5.16 (t, 1H, J = 10.5 Hz, CH), 5.41 (bd, 1H, J = 9 Hz,
NH), 5.64–5.67 (m, 1H, @CH), 5.70–5.74 (m, 1H,
@CH), 7.12–7.27 (m, 10H, ArH). 13C NMR d 27.8,
44.6, 49.4, 51.4, 53.7, 79.0, 124.4, 126.9, 127.5, 127.9,
128.1, 128.6, 129.2, 134.5, 136.6, 140.1, 154.6, 172.1;
TOFMS ES+ [MH]+: Found: 393.2204; Calcd for
C24H29N2O3: 393.2178.
4.5.8. tert-Butyl[(3R,4R,5S,6R)-1-benzyl-5,6-dihydroxy-
4-phenyl-2-oxoazepan-3-yl] carbamate (17). Potassium
osmate (2.2 mg, 0.003 mmol), olefinic lactam 16
(25 mg, 0.06 mmol), t-BuOH (3 mL), water (3 mL),
potassium carbonate (26 mg, 0.19 mmol), potassium
ferricyanide (63 mg, 0.19), ligand (DHQD)2-PHAL or
(DHQ)2-PHAL (2.5 mg, 0.0003 mmol) and methane
sulfonamide (12 mg, 0.13 mmol) were reacted accord-
ing to the general method C with stirring for 48 h.
The crude product (single isomer by 1H NMR) was
purified by flash column chromatography (petroleum
ether/ethyl acetate = 1:1–1:4) to give 14 mg (51%) of
17 as a colourless oil, along with 9 mg (36%) of recov-
ered 16. Data for 17: mmax cmꢀ1 (KBr disc) 3417,
2977, 1701, 1654. 1H NMR d 1.21 (s, 9H, t-Bu),
1.70 (br s, 1H, CH2CHOH), 1.90 (br s, 0.5 H,
CHCHOH), 2.74 (br s, 0.5 H, CHCHOH), 3.09 (t,
1H, J = 10 Hz, CHPh), 3.56 (dd, 1H, J = 16.5 Hz,
6.0 Hz, NCHABCH), 3.62–3.68 (m, 1H, NCHABCH),
4.02 (d, 1H, J = 15 Hz, NCHABPh), 4.07 (dd, 1H,
J = 11, 3.5 Hz, PhCHCH), 4.15–4.17 (m, 1 H,
CH2CH), 4.76 (t, 1 H, J = 9.5 Hz, NHCH), 5.43 (d,
1H, J = 9 Hz, NH), 5.59 (d, 1H, J = 14.5 Hz,
NCHABPh), 7.27–7.36 (m, 10 H, ArH). 13C NMR d
28.1, 46.4, 49.8, 51.3, 53.0, 68.5, 76.7, 79.3, 127.6,
127.8, 128.2, 128.7, 128.7, 136.6, 136.9, 155.1,
171.8; TOFMS ES+ [MH]+: Found: 427.2309;
Calcd for C24H31N2O5: 427.2233. Data for 16 as
above.
1
(3:2 mixture of rotamers by H NMR). Data for mix-
ture: mmax cmꢀ1 (KBr disc) 1647, 1633. 1H NMR d
1.42 (s, 9H, t-Bu, major), 1.43 (s, 9H, t-Bu, minor),
1.96–2.21 (m, 2H, CHCHAB, CHCHABPh), 2.72–3.12
(m, 2H, CHCHAB, CHCHABPh), 4.26–4.51 (m, 2H,
CHCHABPh, NCHABPh,), 4.51–4.87 (m, NCHABPh,
NHCH), 4.95–5.31 (m, @CH2, NCHABPh), 5.53–6.01
(m, 2H, @CH), 7.05–7.29 (m, 10H, ArH). 13C NMR d
28.3 (major), 29.6 (minor), 37.3 (minor), 37.6 (major),
38.4 (major), 38.6 (minor), 46.5 (minor), 49.7 (major),
49.7 (minor), 50.7 (major), 60.9 (major), 61.1 (minor),
79.5 (major), 79.6 (minor), 117.6 (minor), 118.0 (major),
118.1 (minor), 118.2 (major), 126.4, 126.7, 126.8, 127.0,
127.3, 27.5, 128.3, 128.6, 128.7, 129.3 (major and min-
or), 133.0 (major), 133.2 (minor), 135.7 (major), 136.2
(minor), 137.1 (major), 137.4 (minor), 138.1 (major),
138.4 (minor), 155.1 (major), 155.2 (minor), 172.7 (ma-
20
D
jor), 172.9 (minor); ½aꢂ ꢀ66.2 (c 1.0, CHCl3); TOFMS
ES+ [MH]+: Found: 435.2635; Calcd for C27H35N2O3:
435.264.
4.5.11.
tert-Butyl[(3S,7S)-1-benzyl-7-benzyl-2-oxo-
2,3,4,7-tetrahydro-1H-azepin-3-yl] carbamate (23). Cata-
lyst 26 (46 mg, 0.05 mmol) in CH2Cl2 (3 mL) was react-
ed with 22 (291 mg, 0.67 mmol) in CH2Cl2 (20 mL)

8330
S. Zaman et al. / Bioorg. Med. Chem. 14 (2006) 8323–8331
according to the general procedure B. The mixture was
refluxed for 36 h and the crude product was purified
by flash column chromatography (petroleum ether/ethyl
acetate = 9:1 then 4:1) to give 250 mg (92%) of 23 as a
brown oil. mmax cmꢀ1 (KBr disc) 1649. 1H NMR d
1.48 (s, 9H, t-Bu), 2.30 (dt, 1H, J = 14.5, 2 Hz,
CHCHAB), 2.66 (dd, 1H, J = 18, 4 Hz, CHCHAB),
3.03–3.11 (m, 2H, CHCH2Ph), 3.56 (d, 1H,
J = 15.5 Hz, NCHABPh), 3.92 (dd, 1H, J = 14 Hz,
6.5 Hz, CHCH2Ph), 4.82–4.86 (m, 1H, NHCH), 5.07
(d, 1H, J = 15 Hz, NCHABPh), 5.46 (t, J = 10 Hz, 1H,
NCHCH), 5.77 (dd, 1H, J = 11.5, 6 Hz, CHCH2CH),
6.03 (bd, 1H, J = 6.5 Hz, NH), 7.09–7.35 (m, 10H,
ArH). 13C NMR d 28.4, 32.5, 42.4, 52.3, 52.4, 61.4,
1.97 mmol) as described in general procedure D. The
1
resulting crude epoxide (ꢁ1:1, based on H NMR) was
purified by column chromatography (petroleum ether/
ethyl acetate = 7:3) to give 70 mg (84%) of 25 as a white
1
foam (ꢁ1:1 mixture of diastereoisomers by H NMR).
Data for mixture: mmax cmꢀ1 (solid KBr) 1645. 1H
NMR d 1.45 (s, 9H), 2.00–2.10 (m, 1H), 2.55 (m,
0.5H), 2.69 (d, J = 14.5 Hz, 0.5H), 2.89–2.98 (m,
1.5H), 3.11–3.20 (m, 1H), 3.27–3.32 (m, 1.5H), 3.63 (d,
0.5H, J = 14.5 Hz), 3.92 (dd, 0.5H, J = 14.5, 7 Hz),
4.11 (m, 0.5H), 4.40 (s, 1H), 4.55–4.65 (m, 1H), 5.05
(d, 0.5H, J = 15 Hz,), 5.79 (bd, J = 6.5 Hz, 0.5H), 5.97
(bd, J = 6.5 Hz, 0.5H), 6.92 (d, J = 7.5 Hz, 1H), 7.14–
7.36 (m, 9H). 13C NMR d 28.4, 29.8, 32.2, 37.5, 38.6,
46.9, 50.6, 52.4, 53.1, 53.3, 53.7, 54.8, 55.3, 58.8, 58.9,
79.8, 80.4, 126.9, 127.1, 127.8, 127.9, 128.5, 128.7,
128.9, 129.0, 129.3, 136.2, 137.0, 137.2, 137.5, 155.0,
171.2, 172.2. TOFMS ES+ [MH]+: Found: 423.2284;
Calcd for C25H31N2O4: 423.2284.
79.5, 126.9, 127.4, 127.4, 127.5, 128.2, 128.6, 128.6,
20
D
129.1, 136.9, 137.5, 155.1, 172.1; ½aꢂ ꢀ29.8 (c 1.0,
CHCl3); TOFMS ES+ [MH]+: Found: 429.2157; Calcd
for C25H31N2NaO3: 429.2154.
4.5.12. tert-Butyl[(3S,5R,6S,7S)-1-benzyl-5,6-dihydroxy-
7-benzyl-2-oxoazepan-3-yl] carbamate (24). Method A:
potassium osmate (2 mg, 0.005 mmol), 23 (20 mg,
0.05 mmol), t-BuOH (3 mL), water (3 mL), potassium
carbonate (21 mg, 0.15 mmol), potassium ferricyanide
(49 mg, 0.15), ligand (DHQD)2-PHAL or (DHQ)2-
PHAL (4 mg, 0.002 mmol) and methane sulfonamide
(10 mg, 0.1 mmol) were reacted according to general
method C with stirring for 48 h. The crude product (ob-
Acknowledgments
The work was supported by a Royal Society of New
Zealand Marsden grant. The authors also thank Profes-
sor Fabio Benedetti (Department of Chemical Sciences
Trieste, Italy) for assistance with the HIV-I protease
inhibition assay.
1
tained as a single diastereoisomer, based on H NMR)
was purified by flash column chromatography (petro-
leum ether/ethyl acetate = 1:1–1:4) to give 11 mg (52%)
of 24 as a white oily solid. mmax cmꢀ1 (solid KBr)
References and notes
1
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195.
2. Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2004, 67, 1216;
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D.; Lenz, J.; Lockhoff, O.; Wachendorff, U.; Wendisch, D.
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4. (a) De Lucca, G. V. Bioorg. Med. Chem. Lett. 1997, 7, 501;
(b) Battisini, L.; Rassu, G.; Pinna, L.; Zanardi, F.;
Casiraghi, G. Tetrahedron: Asymmetry 1999, 10, 765; (c)
Humphries, M. E.; Murphy, J.; Phillips, A. J.; Abell, A. D.
J. Org. Chem. 2003, 68, 2432.
5. Hoog, S. S.; Zhao, B.; Winborne, E.; Fisher, S.; Green, D.
W.; DesJarlais, R. L.; Newlander, K. A.; Callahan, J. F.;
Moore, M. L.; Huffman, W. F. J. Med. Chem. 1995, 38,
3246.
3423, 2977, 1701, 1685. H NMR (CD3CN) d 1.30 (s,
9H, t-Bu), 1.64–1.74 (m, 2H, CHCH2), 2.49 (dd,
J = 13.5, 6 Hz, 1H, CHCHABPh), 2.76 (br s, 1H,
CHCHOH), 2.86 (dd, 1H, J = 13.5, 10 Hz,
CHCHABPh), 2.99 (br s, 1H, CH2CHOH), 3.51 (br s,
1H, CHCHOH), 3.61–3.66 (m, 1H, CHCH), 3.96 (d,
1H, J = 14.5 Hz, NCHABPh), 4.01–4.03 (m, 1H,
CH2CHOH), 4.15–4.18 (m, 1H, CHCH2CH), 4.69 (d,
1H, J = 14.5 Hz, NCHABPh), 5.82 (br s, 1H, NH),
6.76–7.09 (m, 5 H, ArH), 7.13–7.19 (m, 5H, ArH). 13C
NMR d 28.4, 33.9, 37.2, 50.0, 54.8, 63.4, 68.6, 69.7,
79.8, 127.0, 128.0, 128.55, 128.79, 128.8, 129.2, 137.1,
20
137.3, 155.2, 171.4; ½aꢂ +18.1 (c 1.0, CHCl3). TOFMS
D
ES+ [MH]+: Found: 441.2389; Calcd for C25H33N2O5:
441.2389. Method B: potassium osmate (2 mg,
0.005 mmol), olefinic lactam 23 (20 mg, 0.05 mmol), t-
BuOH (3 mL), water (3 mL), potassium carbonate
(21 mg, 0.15 mmol), potassium ferricyanide (49 mg,
0.15) and methane sulfonamide (10 mg, 0.1 mmol) were
reacted according to general method C in the absence of
ligand with stirring for 48 h. The crude product 24 (ob-
´
6. For lactamizations, see: Bosch, I.; Romea, P.; Urpı, F.;
Vilarrasa, J. Tetrahedron Lett. 1993, 34, 4671; Rico, I.;
Halvorsen, K.; Dubrule, C.; Lattes, A. J. Org. Chem.
1994, 59, 415; Huang, W.; Kalivretenos, A. G. Tetrahe-
dron Lett. 1995, 36, 9113.
1
tained as a single diastereoisomer, based on H NMR)
7. Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am.
Chem. Soc. 1996, 118, 9606; Rutjes, F. P. J. T.; Schoe-
maker, H. E. Tetrahedron Lett. 1997, 38, 677; Belvisi, L.;
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9. (a) Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.;
DeLucca, G. V.; Eyermann, C. J.; Chang, C.-H.; Emmett,
G.; Holler, E. R.; Daneker, W. F.; Li, L.; Confalone, P.
was purified by flash column chromatography (petro-
leum ether/ethyl acetate = 1:1–1:4) to give 12.5 mg
(59%) of 24 as a white oily solid. Data as above.
4.5.13. tert-Butyl[(1S*,2S,5S,7R*)-2,3-dibenzyl-4-oxo-8-
oxa-3-azabicyclo[5,1,0]oct-5-yl] carbamate (25). A solu-
tion of 23 (80 mg, 0.20 mmol) in acetone (12 mL) and
water (10 mL) was treated with sodium hydrogen car-
bonate (562 mg, 6.70 mmol) and Oxoneꢁ (1.21 g,

S. Zaman et al. / Bioorg. Med. Chem. 14 (2006) 8323–8331
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