Formal total synthesis of (-)- and (+)-balanol: two complementary enantiodivergent routes from vinyloxiranes and vinylaziridines

Article abstract of DOI:10.1016/j.tet.2008.10.070

Formal total syntheses of both enantiomers of balanol have been achieved by the preparation of the protected hexahydroazepine core 2. Two complementary routes have been investigated. The first relied on the regioselective opening of 1,2-epoxycyclohex-3-ene with a chiral-auxiliary version of the Burgess reagent to provide a diastereomeric pair of cis-fused cyclic sulfamidates. The sulfamidates were transformed to trans-amino benzoates with ammonium benzoate and, after separation, converted to (-)-2 and (+)-2 by oxidative cleavage and reductive amination. The second approach utilized vinylaziridines derived from 1-bromo-2,3-dihydroxycyclohexa-4,6-diene obtained by the whole-cell fermentation of bromobenzene with Escherichia coli JM109(pDTG601). Stereoselective opening of the aziridines generated the requisite trans-amino alcohol derivatives, which after saturation of the vinyl bromide moieties were converted to (-)-2 and (+)-2 by oxidative cleavage of the cis-diol and reductive amination. Experimental and spectral data are provided for all new compounds.

Full text of DOI:10.1016/j.tet.2008.10.070

Tetrahedron 65 (2009) 212–220
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formal total synthesis of (–)- and (þ)-balanol: two complementary
enantiodivergent routes from vinyloxiranes and vinylaziridinesq
*
Jacqueline Gilmet, Bradford Sullivan, Tomas Hudlicky
Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, ON, Canada L2S 3A1
a r t i c l e i n f o
a b s t r a c t
Article history:
Formal total syntheses of both enantiomers of balanol have been achieved by the preparation of the
protected hexahydroazepine core 2. Two complementary routes have been investigated. The first relied
on the regioselective opening of 1,2-epoxycyclohex-3-ene with a chiral-auxiliary version of the Burgess
reagent to provide a diastereomeric pair of cis-fused cyclic sulfamidates. The sulfamidates were trans-
formed to trans-amino benzoates with ammonium benzoate and, after separation, converted to (ꢀ)-2
and (þ)-2 by oxidative cleavage and reductive amination. The second approach utilized vinylaziridines
derived from 1-bromo-2,3-dihydroxycyclohexa-4,6-diene obtained by the whole-cell fermentation of
bromobenzene with Escherichia coli JM109(pDTG601). Stereoselective opening of the aziridines gener-
ated the requisite trans-amino alcohol derivatives, which after saturation of the vinyl bromide moieties
were converted to (ꢀ)-2 and (þ)-2 by oxidative cleavage of the cis-diol and reductive amination. Ex-
perimental and spectral data are provided for all new compounds.
Received 29 September 2008
Received in revised form 18 October 2008
Accepted 21 October 2008
Available online 26 October 2008
Keywords:
Chiral version of the Burgess reagent
Vinyloxiranes
Vinylaziridines
Enzymatic dihydroxylation of aromatics
Reductive amination
trans-Amino alcohols
Balanol
Ó 2008 Elsevier Ltd. All rights reserved.
Enantiodivergent synthesis
1. Introduction
Our own strategy has focused on the generation of this hex-
ahydroazepine core by the reductive amination of an appropriate
Following its isolation2 in 1993 by a group at Sphinx Pharma-
ceuticals, balanol (1) attracted focused attention of the synthetic
community, driven in no small part by the biological activity3 of
this interesting fungal metabolite as a potent inhibitor of protein
kinase C. Its synthesis, as well as the preparation of unnatural de-
rivatives, depends on efficient access to the hexahydroazepine core
containing the 1,2-trans-amino alcohol functionality. Following the
first published total syntheses by Nicolaou4a and the Sphinx Phar-
maceutical group of Lampe and Hughes4b many creative ap-
proaches to balanol were reported; 11 total4,5 and more than 20
formal1,6 syntheses in either enantiomeric series are now available
for comparison of strategy or practicality. The formal syntheses
focus on the generation of the hexahydroazepine core, which
usually contains the p-hydroxybenzamide moiety and a variety of
oxygen and nitrogen protecting groups such as the Boc, Cbz, or
benzyl functionalities. One intermediate frequently employed in
these formal syntheses is alcohol 2, which contains two benzyl
protecting groups (Fig. 1).7
dialdehyde provided by oxidative cleavage of the corresponding
1,2-diol. The 1,2-trans-amino alcohol moiety then becomes avail-
able via the nucleophilic opening of either an appropriate epoxide
or an aziridine. We have used both approaches to 2; both are
designed to be enantiodivergent and are shown in an abbreviated
form in Figure 2.
The first approach relies on the opening of vinyl oxirane 3 with
a chiral version of the Burgess reagent that we have recently de-
veloped8 to produce diastereomeric pairs of cyclic sulfamidates.
These compounds resemble cyclic sulfates in their reactions with
nucleophiles9 and yield easily trans-amino alcohols 4a and 4b,
whose separation provides, after the removal of the chiral auxiliary,
enantiomerically pure intermediates for the reductive amination to
(ꢀ)-2 and (þ)-2, respectively.
The second approach employs the single enantiomer of the
cis-dihydrodiol 5,10 available from the whole-cell fermentation of
bromobenzene with the recombinant strain Escherichia coli
JM109(pDTG601),11 which overexpresses toluene dioxygenase. Two
diastereomeric vinylaziridines 612 and 713 are prepared from the
acetonide-protected diol 5 and are transformed intothe trans-amino
alcohol derivatives 8 and 9, respectively, by nucleophilic opening
with acetic acid or water. Saturation and oxidative cleavage of the
cis-diol then set the stage for the reductive amination to (ꢀ)-2 and
(þ)-2, respectively.
q
See Ref. 1.
* Corresponding author.
E-mail address: thudlicky@brocku.ca (T. Hudlicky).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.070

J. Gilmet et al. / Tetrahedron 65 (2009) 212–220
213
HO
HO
OH
O
O
O
O
OH
H
H
N
OH
N
OH
OBn
N
H
N
O
O
Bn
1
2
Figure 1. Balanol and the protected hexahydroazepine intermediate.
An obvious advantage of the chemoenzymatic strategy is in the
transfer of asymmetry from the enzymatically generated cis-diol
moiety to either the syn or the anti aziridines. The attainment of
these intermediates defines the access to both enantiomers of
balanol and allows, following the saturation of the vinyl bromide
moiety, for the oxidative cleavage of the cis-diol and the subsequent
reductive amination to each enantiomer of 2. In addition, the two
complementary routes allow for the comparison of optical purities
of intermediates available from the Burgess-reagent route with
those obtained from the enantiomerically pure diol 5. In this paper,
we provide the details of both approaches and furnish the experi-
mental and spectral data for all compounds not reported
previously.
synthesis of the natural enantiomer of balanol, the details of which
we have already reported.1a Similarly, the antipodal benzoate 4b
was converted to the cyclic carbamate 12b and subjected to the
same sequence of reactions leading to final reductive amination.14
This sequence furnished the cyclic carbamate 14b, whose mild
23
hydrolysis (1 N NaOH, THF, ꢀ20 ꢁC to rt) gave (þ)-2 ([
a]
þ4.4 (c
D
0.2, CHCl3)), thereby completing the formal synthesis of
(þ)-balanol.
The enantiomeric purity of the product was evaluated by 19F
NMR of the corresponding Mosher ester and judged to be ap-
proximately 96:4. As the separation of the diastereomeric benzo-
ates was incomplete, the small amount of the minor diastereomer
4a contributed to the lower optical purity of the final product. We
have not been able to locate optical rotation data in the literature
for either (ꢀ)-2 or (þ)-2; therefore, we embarked on the synthesis
of both enantiomers of 2 in a manner that would guarantee abso-
lute optical integrity of the final product (Scheme 2).
2. Results and discussion
2.1. Diastereoselective Burgess-reagent-based strategy
The availability of the chiral version of the Burgess reagent (10)8
has permitted the synthesis of the diastereomeric cis-fused sulfa-
midates 11a and 11b in 36% yield, Scheme 1. Treatment of these
diastereomers with sodium benzoate provided a separable mixture
of the trans-functionalized menthyl carbamates 4a and 4b in 76%
yield, at which point the access to both enantiomers of balanol was
defined. Conversion of benzoate 4a to (ꢀ)-2 constitutes a formal
2.2. Enantioselective chemoenzymatic strategy
The optical purity of diol 5 obtained by the enzymatic dihy-
droxylation is absolute and has been amply demonstrated in many
total syntheses of naturally occurring substances.15 No di-
astereomeric impurities resulting from the antipodal diol have ever
been detected in the final products of the many synthetic
OAc
OBz
H
NAc
NHAc
N
O
(–)-2
O
Br
Br
O
O
O
O
4a
8
6
O
oxidative cleavage /
reductive amination
Br
OH
( )-3
OH
5
OBz
OH
O
H
N
NTs
O
O
NHTs
(+)-2
O
Br
Br
O
4b
O
7
9
Figure 2. Complementary strategies for the synthesis of hexahydroazepine 2 from vinyloxiranes and vinylaziridines.

214
J. Gilmet et al. / Tetrahedron 65 (2009) 212–220
O
O O
S
O
S
N
O
S
N
O
O
O
N
NEt3
O
O
OMen
OMen
O
10
O
+
O
THF, 70 °C
11a
11b
( )-3
1. (a) PhCO2NH4, DMF,
55 °C, 12 h
(b) THF, H2O, H2SO4
Men = (–)-menthyl
OBz
OBz
H
N
H
OMen
OMen
N
O
O
4a
4b
1. 1 N NaOH, MeOH
2. NaH, THF, reflux
O
O
O
O
NR
NR
4-benzyloxybenzoyl chloride,
DCM, DMAP, NEt3, 0 °C-rt
12a R = H
13a R = p-COC6H4OBn
12b R = H
13b R = p-COC6H4OBn
1. OsO4, NMO, DCM, rt
2. (a) NaIO4, 8:2 acetone-H2O, rt,
(b) Bn-NH2, MeOH, AcOH,
NaCNBH3, 3 Å MS, -78 °C - rt,
OBn
OBn
O
N
O
O
O
N
O
O
N
N
Bn
14a
Bn
14b
1 N NaOH, THF, -20 °C
(–)-2
(+)-2
Scheme 1.
endeavors reported by our group and others.16 The yield of diol 5 in
whole-cell fermentations is very high (15–22 g/L) (it is also avail-
able commercially from Aldrich, sold as a suspension in phosphate
buffer, catalog #48,949-2). Diols derived from chlorobenzene (cat.
#48,950-6), naphthalene (cat. #49,032-6), and biphenyl (cat.
#48,963-8) are also available.
to provide the fully saturated derivative 15 (84%). Removal of both
acetyl groups was accomplished with NaOMe in MeOH, and the
free amine was converted to its methyl carbamate by exposure to
methyl chloroformate in 73% yield over the two steps. The hydroxy
carbamate was then treated with sodium hydride in tetrahydro-
furan to afford the cyclic carbamate 16, which was acylated with
4-benzyloxybenzoyl chloride to give 17 (82%). Hydrolysis of the
acetonide in aqueous acetic acid and tetrahydrofuran provided the
free cis-diol 18 as a single isomer, which corresponded in all re-
spects to the minor product obtained from OsO4 treatment of the
cyclic carbamate 13a, the intermediate from the chiral Burgess-
reagent route. Oxidative cleavage of the diol unit with sodium
periodate provided the dialdehyde, which was subjected, without
isolation or purification, to the reductive amination protocol with
We approached the synthesis of both enantiomers of hexahy-
droazepine derivative 2 by the general strategy depicted in Figure 2
with the preparation of two vinylaziridines that would yield, upon
hydrolytic opening, the requisite trans-amino alcohols for both
enantiomeric series. The stereochemical relationship of the amino
alcohol functionality with the biochemically generated cis-diol is of
no consequence because the diol unit itself is subjected to oxidative
cleavage once its purpose in transferring asymmetry has been
served. To this end diol 5 was converted to its acetonide, treated
with N-bromoacetamide in the presence of SnBr4 followed by
a KHMDS-mediated elimination to furnish aziridine 6 in 68% yield
over three steps. This procedure was adapted from the one reported
in Corey’s synthesis of oseltamivir.12 Treatment of 6 with acetic acid
in the presence of TMSOTf furnished a 4:1 mixture of trans- and cis-
acetate with the minor cis isomer resulting from the SN1 process
operating in the aziridine ring opening. After separation by column
chromatography, the trans isomer was subjected to hydrogenation
benzyl amine, adapted from a literature protocol.14 The cyclic car-
23
bamate 14a was converted to (ꢀ)-2 ([
a
]
ꢀ5.6 (c 0.2, CHCl3)), by
D
hydrolysis with aqueous sodium hydroxide and detailed analysis of
optical purity was performed by 19F NMR of its (S)-(þ)-Mosher
esters
(d
ꢀ71.26, (S)-(þ)-Mosher ester of (þ/ꢀ)-2
d
ꢀ71.26,
d
ꢀ71.58). Optical rotation data (higher in value than that reported
for the product of the Burgess route1a as a result of higher optical
purity) was provided for this compound and reported in our pre-
liminary disclosure earlier this year.1b

J. Gilmet et al. / Tetrahedron 65 (2009) 212–220
215
1. DMP, p-TsOH, r.t.
2. NBA, SnBr4
MeCN, -30 °C
3. KHMDS, nBu4NBr
DME, 0 °C
1. DMP, p-TsOH, r.t.
2. PhI=NTs, Cu(acac)2,
MeCN, 0 °C
Br
OH
OH
5
NAc
O
NTs
O
Br
Br
O
O
6
7
1. AcOH, TMSOTf
DCM, r.t.
2. PtO2, NEt3,
H2, 1 atm, EtOAc
1. DMSO, KOH
H2O, 30 °C
2. PtO2, MeOH
H2, 1 atm
OH
OAc
NHAc
NHTs
O
O
O
O
1. NaOMe, MeOH
reflux
2. methylchloroformate
NEt3, DCM, DMAP, r.t
3. NaH, THF, reflux
15
19
triphosgene, DCM
NEt3, 0 °C
O
O
O
O
O
O
NR
NR
O
O
4-benzyloxy-
benzoyl chloride,
DCM, NEt3
1. Na/ Naphthalene
DME, -78 °C
2. 4-benzyloxy-
benzoyl chloride,
NaH, THF, r.t
16 R = H
17 R = p-COC6H4OBn
20 R = Ts
21 R = p-COC6H4OBn
DMAP, r.t.
AcOH:THF:H2O (9:3:1), reflux
OBn
OBn
O
O
N
O
O
N
O
O
OH
OH
OH
OH
18
22
(a) NaIO4, 8:2 acetone-H2O, rt,
(b) Bn-NH2, MeOH, AcOH,
NaCNBH3, 3 Å MS, -78 °C - rt,
14a
14b
1 N NaOH, THF, -20 °C
(–)-2
(+)-2
Scheme 2.
To provide accurate data for the (þ)-enantiomer the anti-dis-
posed N-tosylaziridine 7, an intermediate that we have used in
several syntheses of Amaryllidaceae alkaloids was utilized.13 Pro-
tection of diol 5 as an acetonide followed by its reaction with the
Yamada–Jacobsen reagent17 furnished the aziridine in 63% yield
over two steps. The aziridine 7 was treated with aqueous potassium
hydroxide in DMSO followed by saturation of the vinyl bromide
moiety under PtO2-mediated hydrogenation to provide the trans-
amino alcohol derivative 19 as a single isomer in 86% yield over two
steps. After this material was converted to the cyclic N-tosyl car-
bamate 20 with triphosgene, the tosyl group was reductively re-
moved with sodium naphthalide in DME to provide, after acylation
with 4-benzyloxybenzoyl chloride, the fully saturated cyclic car-
bamate 21. Hydrolysis of the acetonide gave the free diol 22, which
was subjected to the oxidative cleavage and reductive amination to
furnish 14b in 72% yield over three steps. Final hydrolysis provided
23
(þ)-2, identical in all respects but optical rotation ([
a]
þ5.77 (c
D
0.75, CHCl3)) to the ꢀenantiomer obtained from either the syn
aziridine 6 or sulfamidate 11a.
3. Conclusion
Two complementary routes to (ꢀ)-2 and (þ)-2 have been pro-
vided via reactions of a chiral Burgess reagent with vinyloxiranes
and the regioselective opening of homochiral vinylaziridines de-
rived from diene diol 5. Detailed experimental procedures were
reported for all new compounds. Most importantly, accurate optical
data were provided for both enantiomers of 2, as this data were

216
J. Gilmet et al. / Tetrahedron 65 (2009) 212–220
absent from the literature despite several reported syntheses. Our
preparation of (ꢀ)-2 and (þ)-2 is comparable in efficiency to pre-
viously published routes.
4.3. Preparation of (3aS,7aS)-5-benzyl-3-(4-benzyl-
oxybenzoyl)-octahydro-1-oxa-3,5-diaza-azulen-
2-one (14b)
23
Yield 59%; [
a]
þ25.8 (c 0.9, CHCl3).
D
4. Experimental section
4.4. N-[(3S,4S)-Hexahydro-4-hydroxy-1-(phenylmethyl)-1H-
azepin-3-yl]-4-(phenylmethoxy)-benzamide ((D)-2)
4.1. Preparation of (3aS,7aS)-3a,6,7,7a-tetrahydro-3H-
benzoxazol-2-one (12b)
23
Yield 79%; [
a]
þ4.4 (c 0.2, CHCl3).
D
A round-bottomed flask was charged with 4b1a (500 mg,
1.25 mmol) and 25 mL of 1 N NaOH in methanol. The reaction
mixture was stirred at room temperature for 30 min before con-
centrating. The residue was dissolved in methylene chloride (5 mL)
and water (2 mL) was added. The mixture was extracted into
methylene chloride (3ꢂ2 mL). The combined organic layers were
washed with brine (3 mL) and dried over Na2SO4. Recrystallization
of the crude material from ethyl ether–hexanes afforded the free
alcohol (1R,6S)-(6-hydroxycyclohex-2-enyl)-carbamic acid (1R,2S,5R)-
2-isopropyl-5-methyl-cyclohexyl ester as a white solid (367 mg, 94%):
4.4.1. Determination of enantiomeric excess in (þ)-2 by 19F NMR of
its Mosher ester
To a stirred solution of (þ)-2 (4 mg, 0.009 mmol) in freshly
distilled methylene chloride (0.5 mL) were added triethylamine
(2.58 mL, 0.0185 mmol) and DMAP (catalytic amount). The reaction
mixture was cooled to 0 ꢁC and then (S)-(þ)-Mosher’s acid chloride
(1.67 mL, 0.0092 mmol) was added. The reaction mixture was stir-
red for 12 h and then diluted with methylene chloride (1 mL). The
organic layer was washed with cold 1 N HCl (1ꢂ1 mL) and then
with saturated NaHCO3 (1ꢂ1 mL). The combined organic layers
were washed with brine (1ꢂ1 mL) and dried over Na2SO4. The
crude product was subjected to flash column chromatography on
silica gel (6:1 hexanes–ethyl acetate) to afford 5 mg (83%) of the (S)-
mp 134–135 ꢁC (ethyl ether–hexanes); Rf 0.44 (2:1 hexanes–ethyl
23
acetate); [
a
]
ꢀ32.4 (c 0.78, CHCl3); IR (film)
n
3435, 2955, 2869,
D
1645, 1529, 1455 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
5.79–5.88 (m,
1H), 5.39 (d, J¼9.7 Hz, 1H), 4.65–4.75 (m, 1H), 4.56 (td, J¼4.1, 10.8 Hz,
1H), 4.06–4.15 (m, 1H), 3.61–3.70 (dq, J¼3.6, 10.7 Hz, 1H), 2.01–2.14
(m,1H),1.95–2.09 (m, 2H),1.84–1.99 (m, 2H),1.58–1.71 (m, 4H) 1.40–
1.54 (m, 1H), 1.26–1.40 (m, 1H), 1.07 (dq, J¼1.8, 13.1 Hz, 1H), 0.98 (q,
J¼11.8 Hz, 1H), 0.89 (d, J¼2.6 Hz, 3H), 0.86 (d, J¼2.6 Hz, 3H), 0.77 (d,
(þ)-Mosher ester: 19F NMR (282 MHz, CDCl3)
d
ꢀ71.58 ppm, ((S)-
(þ)-Mosher ester of (þ/ꢀ)-2
d –71.26, –71.58 ppm).
4.5. Preparation of (1S,4S,5S,6S)-7-acetyl-3-bromo-4,5-
isopropylidenedioxy-7-azabicyclo[4.1.0]hept-2-ene (6)
J¼6.78 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 158.2, 131.2, 125.2, 75.5,
73.6, 55.5, 47.5, 41.4, 34.2, 31.4, 29.1, 26.3, 24.0, 23.5, 22.0, 20.8,
16.5 ppm; MS (EI) m/z (%): 295(M), 41 (58), 43 (43), 54 (29), 55 (56),
56 (21), 57 (34), 67 (67), 68 (23), 69 (70), 71 (68), 81 (61), 82 (32), 83
(66), 95 (100), 96 (31), 113 (75), 123 (28), 138 (29); HRMS calcd for
C17H29NO3 295.2147, found 295.2147. Anal. Calcd: C 69.12, H 9.89;
found: C 68.96, H 9.89.
To a stirred solution of N-bromoacetamide (309 mg, 2.25 mmol)
and SnBr4 (0.28 mL of a 0.4 M solution in methylene chloride) in
acetonitrile (40 mL) was added a solution of the acetonide-pro-
tected diol 5 (432 mg, 1.87 mmol) in acetonitrile (20 mL) dropwise
over a period of 4 h at ꢀ40 ꢁC in the dark. The reaction mixture was
stirred for further 1 h at ꢀ40 ꢁC before the slow addition of satd
NaHCO3 (10 mL) followed by satd Na2SO3 (10 mL). The phases were
separated and the aqueous phase was extracted with methylene
chloride (5ꢂ50 mL). The combined organic layers were washed
with brine (1ꢂ100 mL), dried over Mg2SO4, and concentrated under
reduced pressure. The crude material was subjected to flash col-
umn chromatography on neutral alumina with methylene chloride
as the elution solvent to yield N-[(1S,4S,5R,6R)-3,6-dibromo-4,5-
(isopropylidenedioxy)cyclohex-2-en-1-yl] (524 mg, 76%) as colorless
A suspension of NaH (60% in mineral oil, 24 mg, 0.99 mmol) was
washed with hexanes (3ꢂ5 mL) and then dissolved in tetrahydro-
furan (15 mL). A solution of (1R,6S)-(6-hydroxycyclohex-2-enyl)-
carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester
(175 mg, 0.590 mmol) in tetrahydrofuran (7 mL) was added drop-
wise at 0 ꢁC. The reaction mixture was heated to reflux for 18 h.
After the mixture was cooled to room temperature, the reaction
mixture was quenched by the addition of satd NH4Cl (10 mL). The
mixture was concentrated before extracting the aqueous layer with
methylene chloride (3ꢂ15 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and evaporated to give the
crude product. Recrystallization of the crude material from diethyl
ether–hexanes afforded 12b (81 mg, 86%) as a white solid: mp 114–
crystals: Rf 0.71 (96:4 methylene chloride–methanol); mp 181–
23
182 ꢁC (methylene chloride); [
a]
þ188.2 (c 0.50, CHCl3); IR (film)
n
D
3684, 3019, 2400, 1675, 1498, 1424, 1216, 1063, 928 cmꢀ1; 1H NMR
(300 MHz, CDCl3)
6.21 (d, J¼9.0 Hz, 1H), 4.93 (m, 1H), 4.68 (d,
J¼5.1 Hz, 1H), 4.60 (t, J¼4.5 Hz, 1H), 4.21 (t, J¼3.6 Hz, 1H), 1.97 (s,
3H), 1.51 (s, 3H), 1.42 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
169.0,
d
115 ꢁC (diethyl ether–hexanes); Rf 0.36 (1:1 hexane–ethyl acetate);
23
[
a]
þ36.8 (c 1.25, CHCl3); IR (film)
n
3854, 3435, 3020, 1751, 1644,
5.88–6.15 (br s, 1NH),
D
d
1216, 769 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
128.0, 124.7, 112.0, 77.8, 75.8, 50.3, 44.4, 27.8, 26.5, 23.3 ppm; MS
(EI) m/z (%): 369 (M), 43 (100), 59 (10), 109 (21), 173 (10), 188 (11),
190 (11), 230 (34), 232 (33), 253 (11); HRMS (EI) calcd for
C11H15Br2NO3 366.9419, found 366.9380.
5.85 (dd, J¼9.1, 0.77 Hz, 1H), 5.50–5.65 (m, 1H), 4.14 (td, J¼12.3,
1.1 Hz, 1H), 4.07 (t, J¼11.4 Hz, 1H), 2.29–2.50 (m, 2H), 2.21–2.28 (m,
1H), 1.92 (td, J¼9.8, 0.94 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d
161.6, 128.4, 123.9, 81.3, 58.1, 25.3, 24.5 ppm; MS (EI) m/z (%):
To a stirred solution of N-[(1S,4S,5R,6R)-3,6-dibromo-4,5-(iso-
propylidenedioxy)cyclohex-2-en-1-yl] (2.50 g, 6.77 mmol) and
n-Bu4NBr (2.40 g, 7.44 mmol) in DME (65 mL) at 0 ꢁC was added
KHMDS (15 mL of a 0.5 M solution in toluene) dropwise over a pe-
riod of 2 h. The reaction mixture was allowed to stir for further 3 h
at 0 ꢁC before it was quenched by the addition of a pH 7 buffer
solution (65 mL of potassium phosphate monobasic-sodium hy-
droxide buffer). The layers were separated and then the aqueous
layer was extracted with ethyl acetate (3ꢂ100 mL). The combined
organic layers were washed with brine (1ꢂ50 mL) and dried over
Na2SO4. The crude material was subjected to flash column chro-
matography on silica gel (1:1 hexanes–ethyl acetate) to yield 6
139(M), 41 (22), 54 (100), 55 (11), 67 (55), 68 (17), 95 (13), 111 (26);
HRMS calcd for C7H9NO2 139.0633, found 139.0632.
Optical and analytical data for intermediates in the synthesis of
(þ)-2. For experimental details pertaining to the synthesis of (ꢀ)-2
see Ref. 1a.
4.2. (3aS,7aS)-3-(4-Benzyloxybenzoyl)-3a,6,7,7a-tetrahydro-
3H-benzoxazol-2-one (13b)
23
Yield 83%; [
a
]
D
þ98.2 (c 0.78, CHCl3). Anal. Calcd: C 72.19, H
5.48; found: C 72.22, H 5.55.

J. Gilmet et al. / Tetrahedron 65 (2009) 212–220
217
(1.17 g, 60%) as white crystals: mp 128 ꢁC; Rf 0.44 (1:1 hexanes–
11.1 Hz, 1H), 4.29 (dd, J¼5.7, 11.0 Hz, 1H) 4.23 (dd, J¼3.2, 5.9 Hz, 1H),
4.13 (td, J¼2.4, 9.4 Hz, 1H), 1.96 (m, 1H), 1.94 (s, 3H), 1.82 (s, 3H), 1.73
(td, J¼4.4, 9.3 Hz, 1H), 1.47 (td, J¼4.4, 9.1 Hz, 1H), 1.42 (s, 3H), 1.33–
23
ethyl acetate); [
a
]
D
ꢀ57.6 (c 0.75, CHCl3); IR (film)
n
3016, 2937,
1703, 1215, 1062, 894 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
6.70 (d,
J¼4.8 Hz, 1H), 4.72 (dd, J¼0.9, 6.9 Hz, 1H), 4.46 (dd, J¼4.2, 6.9 Hz,
1.39 (m, 1H), 1.24 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
d 171.3,
1H), 3.19 (dd, J¼5.1, 6.0 Hz, 1H), 3.11 (dd, J¼0.9, 6.0 Hz, 1H), 2.14 (s,
170.0, 108.7, 75.7, 73.3, 70.0, 50.7, 27.3, 25.2, 25.1 (2ꢂC), 23.3,
21.1 ppm; MS (EI) m/z (%): 256 (MꢀCHþ3 ), 43 (100), 60 (32), 84 (43),
94 (45), 111 (48), 112 (36), 153 (57), 213 (31); HRMS calcd for
C12H18NO5 256.1180, found 256.1187.
3H), 1.53 (s, 3H), 1.39 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d 181.7,
129.9, 122.8, 108.5, 76.6, 71.9, 39.6, 36.7, 27.0, 24.9, 23.2 ppm; MS
(EI) m/z (%): 287 (M), 43 (100), 80 (16), 109 (18), 150 (17), 100 (22),
108 (44), 272 (13), 274 (12); HRMS (EI) calcd for C11H14BrNO3
287.0157, found 287.0162.
4.7. Preparation of (3aR,5aR,8aS,8bS)-2,2-dimethyl-
hexahydro-[1,3]dioxolo[40,50:3,4]benzo[2,1-d]oxazol-
7-one (16)
4.6. Preparation of (3aS,4S,5R,7aR)-4-acetylamino-2,2-
dimethyl-hexahydro-benzo[1,3]dioxol-5-yl ester
acetic acid (15)
To a stirred solution of (3aS,4S,5R,7aR)-4-acetylamino-2,2-di-
methyl-hexahydro-benzo[1,3]dioxol-5-yl ester acetic acid (15)
(300 mg, 1.11 mmol) in methanol (5 mL) was added Na (254 mg,
11.1 mmol) portionwise until completely dissolved (30 min). The
reaction mixture was brought to reflux and stirred for 18 h, and
then cooled to room temperature and quenched by the slow ad-
dition of H2O (5 mL). The reaction mixture was concentrated under
reduced pressure and then extracted into CHCl3 (5ꢂ1 mL). The
combined organic layers were dried over Na2SO4 and concentrated
to yield the (3aS,4S,5R,7aR)-4-amino-2,2-dimethyl-hexahydro-ben-
zo[1,3]dioxol-5-ol as a pale yellow oil, which was used without
To a stirred solution of (1S,4S,5S,6S)-7-acetyl-3-bromo-4,5-iso-
propylidenedioxy-7-azabicyclo[4.1.0]hept-2-ene (6) (50 mg, 0.17 mmol)
and acetic acid (0.19 mL, 3.5 mmol) in methylene chloride (0.5 mL) was
added trimethylsilyl trifluoromethanesulfonate (3.1 mL, 0.017 mmol).
The reaction mixture was allowed to stir at room temperature for
12 h and then filtered through a plug of SiO2 and Na2SO4 before
concentrating under reduced pressure. The crude material was
subjected to flash column chromatography on silica gel with a sol-
vent gradient of 3:1 and then 1:1 (hexanes–ethyl acetate) to yield
the trans isomer (43 mg, 70%) and the cis isomer (11 mg, 18%) as
white solids.
further purification: 1H NMR (300 MHz, CD3OD)
d 4.33–4.39 (m,
1H), 4.22 (dt, J¼5.6, 8.5 Hz,1H), 3.54 (td, J¼4.6, 9.5 Hz,1H), 2.64 (dd,
J¼3.6, 9.6 Hz, 1H), 1.80–1.95 (m, 2H), 1.54–1.66 (m, 1H), 1.48 (s, 3H),
1.35 (s, 3H), 1.30–1.33 (m, 1H) ppm; 13C NMR (75 MHz, CD3OD)
4.6.1. trans Isomer: (3aS,4S,5R,7aS)-4-acetylamino-7-bromo-2,2-
dimethyl-3a,4,5,7a-tetrahydro-benzo[1,3]dioxol-5-yl ester, acetic
acid
d
108.4, 77.0, 74.2, 70.6, 55.6, 28.6, 27.0, 26.7, 24.5 ppm.
To a stirred solution of the (3aS,4S,5R,7aR)-4-amino-2,2-di-
Rf 0.35 (1:3 hexanes–ethyl acetate); mp 168–169 ꢁC (ethyl ace-
methyl-hexahydro-benzo[1,3]dioxol-5-ol (178 mg, 0.951 mmol),
triethylamine (0.26 mL, 1.9 mmol), and DMAP (catalytic amount) in
methylene chloride (1 mL) was added methyl chloroformate
(80.5 m
L, 1.05 mmol) at 0 ꢁC. The reaction mixture was allowed to
warm to room temperature over 12 h and then diluted with
methylene chloride (1 mL), washed with satd NaHCO3 (1ꢂ1 mL)
and brine (1 mL), and then dried over Na2SO4. The crude material
was purified via flash column chromatography on silica gel (60:1
CHCl3–MeOH) to yield ((3aS,4S,5R,7aR)-5-hydroxy-2,2-dimethyl-
hexahydro-benzo[1,3]dioxol-4-yl)-carbamic acid methyl ester (197 mg,
23
tate–hexanes); [
a]
ꢀ111.4 (c 1.00, CHCl3); IR (film)
n
3583, 3272,
6.03
D
1743, 1655, 1371, 1226, 1043 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
(d, J¼9.85 Hz, 1H), 6.02 (d, J¼2.0 Hz, 1H), 5.45 (dt, J¼2.1, 9.3 Hz, 1H),
4.62 (dd, J¼1.98, 5.04 Hz, 1H), 4.41 (td, J¼2.3, 9.5 Hz, 1H), 4.39 (t,
J¼3.3 Hz, 1H), 2.05 (s, 3H), 1.97 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H) ppm;
13C NMR (150 MHz, CDCl3)
d 171.1, 170.1, 129.4, 124.7, 110.7, 77.3,
76.0, 69.4, 50.8, 27.4, 26.4, 23.3, 20.1 ppm; MS (EI) m/z (%): 347 (M),
43 (100), 84 (45), 142 (79); HRMS calcd for C13H18BrNO5 347.0368,
found 347.0384. Anal. Calcd: C 44.84, H 5.21; found: C 44.60, H 5.24.
73% over two steps) as a yellow oil: Rf 0.43 (10:1 CHCl3–MeOH);
23
4.6.2. cis Isomer: (3aS,4S,5S,7aS)-4-acetylamino-7-bromo-2,2-
dimethyl-3a,4,5,7a-tetrahydro-benzo[1,3]dioxol-5-yl ester, acetic
acid
[a
]
ꢀ24.7 (c 0.7, MeOH); IR (film)
n
3433, 2988, 2940, 1695, 1645,
D
1241, 1219, 1035, 1077 cmꢀ1
;
1H NMR (600 MHz, CO(CD3)2)
d
5.98
(br d, J¼4.9 Hz, 1NH), 4.36 (dd, J¼3.6, 5.5 Hz, 1H), 4.29 (dd, J¼2.8,
5.6 Hz,1H), 3.89 (br s, OH), 3.67–3.77 (m, 2H), 3.63 (s, 3H),1.93–1.99
(m, 1H), 1.79–1.86 (m, 1H), 1.53–1.61 (m, 1H), 1.44 (s, 3H), 1.37–1.42
Rf 0.21 (1:3 hexane–ethyl acetate); mp 95–97 ꢁC (ethyl acetate–
23
hexanes); [
a]
þ102.6 (c 1.28, CHCl3); IR (film)
n
3391, 2947, 2835,
6.38
D
1731, 1653, 1375, 1250, 1031 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
(m, 1H), 1.28 (s, 3H) ppm; 13C NMR (150 MHz, CO(CD3)2)
d 158.8,
(d, J¼5.7 Hz,1H), 6.14 (d, J¼9.0 Hz,1H), 5.17 (t, J¼5.1 Hz,1H), 4.64 (d,
J¼6.0 Hz, 1H), 4.54–4.61 (m, 1H), 4.41–4.45 (m, 1H), 2.06 (s, 3H),
2.04 (s, 3H), 1.44 (s, 3H), 1.38 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
107.9, 76.1, 73.8, 67.8, 55.9, 51.1, 28.6, 27.2, 26.1, 24.8 ppm; MS (EI)
m/z (%): 230 (MꢀCHþ3 ), 43 (34), 59 (43), 76 (38), 95 (31), 99 (34),130
(100), 143 (33); HRMS calcd for C10H16NO5 230.1028, found
230.1028.
d
170.4, 169.9, 129.6, 127.2, 111.3, 76.9, 75.0, 67.3, 45.8, 27.3, 26.3,
23.2, 20.9 ppm; MS (EI) m/z (%): 347 (M), 43 (100), 56 (45), 57 (52);
HRMS calcd for C13H18BrNO5 347.0368, found 347.0368.
To a stirred suspension of NaH (128 mg, 5.34 mmol) in tetra-
hydrofuran (4 mL) was added a solution of ((3aS,4S,5R,7aR)-5-hy-
droxy-2,2-dimethyl-hexahydro-benzo[1,3]dioxol-4-yl)-carbamic acid
methyl ester (131 mg, 0.534 mmol) in tetrahydrofuran (2.5 mL). The
reaction mixture was brought to reflux and stirred for 24 h, and
then cooled to room temperature and quenched by the addition of
satd NH4Cl (5 mL). The reaction mixture was extracted into EtOAc
(5ꢂ2 mL), and the combined organic layers were washed with
brine (2 mL) and dried over Na2SO4. Recrystallization of the crude
To a stirred solution of (3aS,4S,5R,7aS)-4-acetylamino-7-bromo-
2,2-dimethyl-3a,4,5,7a-tetrahydro-benzo[1,3]dioxol-5-yl ester, acetic
acid (753 mg, 2.16 mmol) and triethylamine (2.10 mL,15.1 mmol) in
ethyl acetate (3 mL) was added platinum(IV)oxide (12 mg,
0.43 mmol) before purging the reaction flask with H2. The reaction
mixture was stirred at room temperature and 1 atm of H2 for 36 h
before filtering through a plug of SiO2 and concentrating. The crude
material was purified via flash column chromatography on silica gel
with a solvent gradient of 1:2 and then 1:5 (hexanes–ethyl acetate)
materials from acetone yielded 16 (95 mg, 83%) as white needles: Rf
23
0.21 (1:3 hexanes–ethyl acetate); mp 179–181 ꢁC (acetone); [
a]
D
to yield 15 (493 mg, 84%) as a clear oil: Rf 0.30 (1:5 hexanes–ethyl
ꢀ19.7 (c 0.75, CHCl3); IR (film)
n
3459, 2983, 2925, 1733, 1639,
5.88 (br s, 1NH), 4.51–4.61
23
acetate); [
a]
ꢀ49.2 (c 1.24, CHCl3); IR (film)
n
3286, 2939, 2988,
1H NMR
7.99 (d, J¼8.7 Hz, 1NH), 4.79 (dt, J¼5.8,
1136 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
D
1735, 1657, 1547, 1374, 1243, 1041, 868, 755 cmꢀ1
(600 MHz, DMSO-d6)
;
(m, 1H), 4.43–4.51 (m, 2H), 3.49 (dd, J¼1.9, 12.1 Hz, 1H), 2.22–2.37
d
(m, 1H), 1.99–2.17 (m, 1H), 1.76–1.94 (m, 2H), 1.49 (s, 3H), 1.31 (s,

218
J. Gilmet et al. / Tetrahedron 65 (2009) 212–220
3H) ppm; 13C NMR (75 MHz, CDCl3)
58.3, 26.1, 23.8, 22.2, 21.9 ppm; MS (EI) m/z (%): 213 (M), 43 (92), 59
(41), 67 (45), 94 (42), 99 (100), 198 (64); HRMS calcd for C10H15NO4
213.1001, found 213.0998.
d
160.6, 109.5, 73.8, 73.5, 70.9,
filtered through a plug of silica gel and concentrated under reduced
pressure to yield (4S,5R)-3-(4-benzyloxybenzoyl)-2-oxo-5-(3-
oxo-propyl)-oxazolidine-4-carbaldehyde, which was used without
further purification. The crude dialdehyde was dissolved in dry
MeOH (2 mL) and cooled to ꢀ78 ꢁC in an acetone and liquid N2
bath. To this solution was added 3 Å molecular sieves (75 mg),
4.8. Preparation of (3aR,5aR,8aS,8bS)-8-(4-benzyloxy-
benzoyl)-2,2-dimethyl-hexahydro-[1,3]dioxolo-
[40,50:3,4]benzo[2,1-d]oxazol-7-one (17)
followed by NaCNBH3 (6 mg, 0.09 mmol) and then AcOH (8.9
mL,
0.156 mmol), and finally benzyl amine (9.4 L, 0.086 mmol). The
m
reaction mixture was warmed to room temperature slowly over
24 h before concentrating under reduced pressure. The resulting
residue was triturated with ethyl acetate (3ꢂ2 mL) and washed
with NaHCO3 (1ꢂ1 mL). The organic layer was washed with brine
(1 mL) and then dried over Na2SO4. The crude material was
recrystallized from ethyl ether–hexanes to yield 14a as a pale yel-
To a stirred solution of (3aR,5aR,8aS,8bS)-2,2-dimethyl-hexahydro-
[1,3]dioxolo[4’,5’:3,4]benzo[2,1-d]oxazol-7-one (16) (40 mg, 0.19 mmol),
triethylamine (104 mL, 0.750 mmol), and DMAP (catalytic) in
methylene chloride (0.25 mL) was added 4-benzyloxybenzoyl
chloride (51 mg, 0.21 mmol) at 0 ꢁC. The reaction mixture was
allowed to warm to room temperature slowly over 16 h and then
diluted with methylene chloride (0.5 mL), washed with cold 1 N
NaOH (1ꢂ0.5 mL) and brine (1ꢂ0.5 mL), and dried over Na2SO4. The
crude material was purified via flash column chromatography with
a solvent gradient of 6:1 and then 4:1 (hexanes–ethyl acetate) to
low solid (23 mg, 64% over two steps): mp 126–128 ꢁC (ethyl ether–
23
hexanes); Rf 0.68 (2:1 hexanes–ethyl acetate); [
CHCl3); IR (film)
1119 cmꢀ1; 1H NMR (300 MHz, CDCl3)
a]
ꢀ29.9 (c 0.8,
D
n
3029, 2835, 1783, 1679, 1604, 1300, 1253,
d
7.73 (d, J¼8.7 Hz, 2H), 7.29–
7.37 (m, 10H), 6.98 (d, J¼8.7 Hz, 2H), 5.10 (s, 2H), 4.90 (td, J¼3.2,
10.5 Hz, 1H), 4.39 (td, J¼7.1, 9.6 Hz, 1H), 3.71 (d, J¼13.2 Hz, 1H), 3.64
(d, J¼13.2 Hz, 1H), 3.44 (dd, J¼6.6, 11.1 Hz, 1H), 2.50–2.73 (m, 3H),
2.35–2.45 (m, 1H), 1.66–1.78 (m, 3H) ppm; 13C NMR (75 MHz,
yield 17 (65 mg, 82%) as a white solid: Rf 0.38 (2:1 hexanes–ethyl
23
acetate); mp 153–154 ꢁC (MeOH); [
a
]
ꢀ163.8 (c 0.43, CHCl3); IR
(film)
n
3433, 1638, 1259, 1027 cmꢀ1; 1DH NMR (600 MHz, CO(CD3)2)
d
7.79 (d, J¼8.7 Hz, 2H), 7.55 (d, J¼7.6 Hz, 2H), 7.45 (t, J¼7.6 Hz, 2H),
CDCl3)
d
169.7, 162.8, 154.1, 138.9, 136.1, 132.3 (3ꢂC), 128.7 (2ꢂC),
7.39 (t, J¼7.6 Hz, 1H), 7.12 (d, J¼8.7 Hz, 2H), 5.22 (s, 2H), 4.94 (dd,
J¼3.4, 7.2 Hz, 1H), 4.77 (ddd, J¼7.7, 10.2, 12.1 Hz, 1H), 4.66 (dt, J¼3.2,
7.2 Hz, 1H), 4.11 (dd, J¼3.4, 12.1 Hz, 1H), 2.27–2.36 (m, 1H), 2.14–
2.20 (m, 2H), 1.89–1.98 (m, 1H), 1.53 (s, 3H), 1.32 (s, 3H) ppm; 13C
128.4 (2ꢂC), 128.2, 127.5 (3ꢂC), 125.2, 114.1 (3ꢂC), 78.0, 70.1, 63.0,
61.8, 55.3, 51.4, 31.2, 26.4 ppm; MS (EI) m/z (%): 412 (M–CO2); 44
(20), 91 (100), 160 (76), 161 (10); HRMS (MꢀCO2) calcd for
C27H28N2O2 412.2151, found 412.2151.
NMR (150 MHz, CO(CD3)2)
d
169.2, 162.6, 154.2, 136.9, 132.0 (2ꢂC),
128.5, 128.0 (2ꢂC), 127.7 (2ꢂC), 125.8, 114.0 (2ꢂC), 108.9, 73.9, 71.3,
70.1, 69.8, 60.2, 25.4, 23.2, 21.6, 20.9 ppm; MS (EI) m/z (%): 423 (M),
43 (24), 83 (23), 91 (100), 211 (26), 423 (21); HRMS calcd for
C24H25NO6 423.1682, found 423.1662.
4.11. Preparation of benzamide, N-[(3R,4R)-hexahydro-4-
hydroxy-1-(phenylmethyl)-1H-azepin-3-yl]-4-
(phenylmethoxy)benzamide (L)-2
To
a stirred solution of (3aR,7aR)-5-benzyl-3-(4-benzyloxy-
4.9. Preparation of (3aR,4S,5R,7aR)-3-(4-benzyloxybenzoyl)-
4,5-dihydroxy-hexahydro-benzooxazol-2-one (18)
benzoyl)-octahydro-1-oxa-3,5-diaza-azulen-2-one (14a) (21 mg,
0.046 mmol) in tetrahydrofuran (0.3 mL) was added 1 N NaOH
(1.5 mL) at ꢀ20 ꢁC. The reaction mixture was warmed and allowed
to warm to room temperature slowly over 12 h before concen-
trating under reduced pressure. The resulting residue was diluted
with H2O (1 mL) and extracted into EtOAc (5ꢂ1 mL), washed with
brine (1 mL), and dried over Na2SO4. The crude material was pu-
rified via flash column chromatography with a solvent system of
A stirred solution of (3aR,5aR,8aS,8bS)-8-(4-benzyloxybenzoyl)-
2,2-dimethyl-hexahydro-[1,3]dioxolo[40,50:3,4]benzo[2,1-d]oxazol-7-
one (17) (65 mg, 0.15 mmol) in 1 mL of 9:3:1 (AcOH–tetrahydro-
furan–H2O) was brought to reflux for 16 h and then cooled to room
temperature and concentrated under reduced pressure. The
resulting residue was triturated with benzene (2ꢂ1 mL) and CHCl3
(2ꢂ1 mL), filtered through a plug of SiO2, and then recrystallized
3:1 (hexanes–ethyl acetate) to yield (ꢀ)-2 (17 mg, 86%) as a pale
23
yellow oil: Rf 0.31 (3:2 ethyl acetate–hexanes); [
a
]
ꢀ5.6 (c 0.2,
D
from CHCl3 to yield 18(52 mg, 88%) as a white solid: Rf 0.33 (1:3
CHCl3); IR (film)
n
3407, 3377, 2955, 1638, 1611, 1298, 1140 cmꢀ1; 1H
7.47–7.39 (m, 4H), 7.39–7.31 (m, 7H), 7.31–
23
hexanes–ethyl acetate); mp 174–175 ꢁC (CHCl3); [
a]
ꢀ68.4 (c 0.5,
NMR (300 MHz, CDCl3) d
D
MeOH); IR (film)
n
3435, 2918, 1786, 1660, 1604, 1220, 1036 cmꢀ1
;
7.23 (m, 1H), 6.99 (d, J¼6.8 Hz, 2H), 6.54 (d, J¼8.7 Hz, 1H), 5.15 (s,
2H), 3.88 (m, 1H), 3.69–3.78 (m, 1H), 3.63 (d, J¼13.2 Hz,1H), 3.42 (d,
J¼13.2 Hz, 1H), 3.00 (m, 1H), 2.93 (dd, J¼2.0, 14.2 Hz, 1H), 2.73 (dd,
J¼1.9, 14.3 Hz, 1H), 2.50 (m, 1H), 1.85–1.95 (m, 2H), 1.60–1.85 (m,
1H NMR (600 MHz, CDCl3)
d
7.78 (d, J¼8.7 Hz, 2H), 7.38–7.44 (m,
4H), 7.34 (t, J¼7.1 Hz, 1H), 7.00 (d, J¼8.7 Hz, 2H), 5.09 (s, 2H), 4.79–
4.82 (m, 1H), 4.66 (td, J¼3.5, 11.6 Hz, 1H), 3.86–3.91 (m, 1H), 3.78
(dd, J¼1.5, 11.5 Hz, 1H), 2.24–2.29 (m, 1H (1OH)), 2.02–2.15 (m, 2H)
2H) ppm; 13C NMR (150 MHz, CDCl3)
d
167.8, 161.4, 136.4 (2ꢂC),
1.65–1.80 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3)
d
170.0, 162.9,
129.5 (2ꢂC), 129.0, 128.9 (2ꢂC), 128.7 (2ꢂC), 128.2 (2ꢂC), 127.5
(2ꢂC), 127.4 (2ꢂC), 126.4, 114.5 (2ꢂC), 77.5, 70.1, 64.2, 59.9, 58.0,
54.4, 31.5, 29.7 ppm; MS (FAB) m/z (%) 431 (MþHþ), 41 (34), 43 (43),
57 (51), 71 (34), 91 (71), 149 (100); HRMS calcd for C27H31N2O3
431.2310, found 431.2312.
154.7, 136.1, 132.4 (2ꢂC), 128.7, 128.3 (2ꢂC), 127.6, 127.5, 124.9, 114.3
(2ꢂC), 73.6, 70.2, 69.6, 67.3, 64.3, 27.4, 25.4 ppm; MS (EI) m/z (%):
383 (M), 43 (15), 65 (10), 91 (100), 92 (25), 121 (13), 211 (19); HRMS
calcd for C21H21NO6 383.1369, found 383.1372.
4.10. Preparation of (3aR,7aR)-5-benzyl-3-(4-benzyloxy-
benzoyl)-octahydro-1-oxa-3,5-diaza-azulen-2-one (14a)
4.11.1. Determination of enantiomeric excess in (ꢀ)-2 by 19F NMR
of its Mosher ester
To a stirred solution of (ꢀ)-2 (6 mg, 0.0139 mmol) in freshly
To a stirred solution of (3aR,4S,5R,7aR)-3-(4-benzyloxybenzoyl)-
4,5-dihydroxy-hexahydro-benzooxazol-2-one (18) (30 mg, 0.078
mmol) in 10:1 acetone–H2O (1 mL) was added NaIO4 (167 mg,
0.780 mmol). The resulting suspension was stirred at room tem-
perature for 6 h, and then the solvent was removed and the crude
residue was triturated with ethyl acetate (3ꢂ5 mL), and then
washed with brine (2ꢂ5 mL). The resulting organic layers were
distilled methylene chloride (0.3 mL) were added triethylamine
(3.86 mL, 0.0279 mmol) and DMAP (catalytic amount). The reaction
mixture was cooled to 0 ꢁC and then (S)-(þ)-Mosher’s acid chloride
(2.42 mL, 0.0139 mmol) was added in portions over a period of
5 min. The reaction mixture was stirred until the starting material
had been completely consumed (12 h) and then diluted with
methylene chloride (1 mL). The organic layer was washed with cold

J. Gilmet et al. / Tetrahedron 65 (2009) 212–220
219
1 N HCl (1ꢂ1 mL) and then with saturated NaHCO3 (1ꢂ1 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, and evaporated. The crude product was subjected to flash
column chromatography on silica gel (6:1 hexanes–ethyl acetate)
to afford 7 mg (77%) of the (S)-(þ)-Mosher ester: 19F NMR
resulting residue was diluted with H2O (1 mL) and extracted into
ethyl acetate (5ꢂ1 mL), and then the combined organic layers were
washed with brine (1 mL) and dried over Na2SO4. The crude ma-
terial was purified via flash column chromatography with a solvent
system of 3:1 (hexanes–ethyl acetate) to yield (þ)-2 (6.5 mg, 56%)
23
(282 MHz, CDCl3)
d
ꢀ71.26 ppm, ((S)-(þ)-Mosher ester of (þ/ꢀ)-2
as a pale yellow oil: Rf 0.31 (3:2 hexane–ethyl acetate); [
a
]
D
þ5.77
23
d
ꢀ71.26, ꢀ71.58 ppm).
(c 0.75, CHCl3), [
a
]
D
þ5.80 (c 0.20, CHCl3); IR (film)
n
3407, 3377,
2955, 1638, 1611, 1298, 1140 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
4.12. Preparation of N-((3aS,4R,5S,7aR)-5-hydroxy-2,2-
dimethyl-hexahydro-benzo[1,3]dioxol-4-yl)-4-methyl-
benzenesulfonamide (19)
d
7.22–7.50 (m, 12H), 6.99 (d, J¼6.8 Hz, 2H), 6.54 (d, J¼8.7 Hz, 1NH),
5.11 (s, 2H), 3.88 (m, 1H), 3.69–3.78 (m, 1H), 3.63 (d, J¼13.2 Hz, 1H),
3.42 (d, J¼13.2 Hz, 1H), 3.00 (m, 1H), 2.93 (dd, J¼2.0, 14.2 Hz, 1H),
2.73 (dd, J¼1.9, 14.3 Hz, 1H), 2.50 (m, 1H), 1.85–1.95(m, 2H), 1.60–
To a stirred solution of (1R,4S,5S,6R)-3-bromo-4,5-(isopropy-
lidenedioxy)-7-(40-methylphenylsulfonyl)-7-azabicyclo[4.1.0]hept-2-ene
(7)13c (200 mg, 0.499 mmol) in dimethyl sulfoxide (1.5 mL) was
added 10% KOH (1.5 mL). The reaction temperature was raised to
40 ꢁC and stirred for 2 h before being cooled to room temperature.
The reaction mixture was then neutralized with satd NH4Cl and
extracted with ethyl acetate (3ꢂ5 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated. The crude
material was recrystallized from hexane–ethyl acetate to yield
N-((3aS,4R,5S,7aS)-7-bromo-5-hydroxy-2,2-dimethyl-3a,4,5,7a-tetra-
hydro-benzo[1,3]dioxol-4-yl)-4-methyl-benzenesulfonamide (196 mg,
1.85 (m, 2H); 13C NMR (150 MHz, CDCl3)
d
167.8, 161.4, 136.4 (2ꢂC),
129.5 (2ꢂC), 129.0, 128.9 (2ꢂC), 128.7 (2ꢂC), 128.2 (2ꢂC), 127.5
(2ꢂC), 127.4 (2ꢂC), 126.4, 114.5 (2ꢂC), 77.5, 70.1, 64.2, 59.9, 58.0,
54.4, 31.5, 29.7 ppm; MS (FAB) m/z (%): 431 (MþHþ), 41 (34), 43
(43), 57 (51), 71 (34), 91 (71), 149 (100); HRMS calcd for C27H31N2O3
431.2310, found 431.2312.
Acknowledgements
The authors are grateful to the following agencies for financial
support: Natural Science and Engineering Research Council
(NSERC), TDC Research Foundation, Canada Foundation for In-
novation (CFI), Ontario Innovation Trust (OIT), Research Corpora-
tion, TDC Research, Inc., and Brock University.
94%) as white crystals: mp 155–156 ꢁC (hexanes–ethyl acetate); Rf
23
0.43 (1:1 hexanes–ethyl acetate); [
(film)
(300 MHz, CDCl3)
a
]
ꢀ22.7 (c 0.7, CHCl3); IR
D
n
3445, 2993, 2087, 1646, 1216, 1065 cmꢀ1 1H NMR
;
d
7.79 (d, J¼8.1 Hz, 2H), 7.32 (d, J¼8.1 Hz, 2H),
6.24 (d, J¼3.1 Hz, 1H), 5.48 (br s, 1NH), 4.58 (d, J¼5.6 Hz, 1H), 4.17 (t,
J¼6.7 Hz, 1H), 3.99 (br s, 1H (1OH)), 3.79 (d, J¼4.7 Hz, 1H), 3.33 (t,
J¼6.8, 1H), 2.41 (s, 3H), 1.28 (s, 3H), 1.06 (s, 3H) ppm; 13C NMR
Supplementary data
(75 MHz, CDCl3) d 144.2, 135.9, 134.1, 129.9, 127.6, 120.6, 111.4, 76.3,
Experimental procedures for the preparation of 20, 21, 22, and
14b and 1H and 13C NMR spectra of compounds (ꢀ)-2, (þ)-2, 6, 12b,
13b, 14a, 14b, 15, 16, 17, 18, 19, 20, 21, and 22. Supplementary data
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.10.070.
75.9, 70.0, 56.7, 27.2, 25.9, 21.6 ppm; MS (EI) m/z (%): 402 (MꢀCHþ3 ),
43 (40), 59 (32), 65 (30), 91 (85), 92 (16), 97 (15), 98 (48), 99 (68),
139 (30), 155 (26), 254 (100), 255 (15); HRMS calcd for
C15H17BrNO5S 402.0011, found 402.0004.
To a stirred solution of N-((3aS,4R,5S,7aS)-7-bromo-5-hydroxy-
2,2-dimethyl-3a,4,5,7a-tetrahydro-benzo[1,3]dioxol-4-yl)-4-methyl-
benzenesulfonamide (196 mg, 0.468 mmol), in MeOH (2 mL) were
added K2CO3 (10 mg) and platinum(IV)oxide (catalytic amount)
before purging the reaction flask with H2. The reaction mixture was
stirred at room temperature and 1 atm of H2 for 36 h before fil-
tering through a plug of SiO2 and concentrating. The crude material
was purified via flash column chromatography with a solvent
gradient of 1:1 and then 1:2 (hexanes–ethyl acetate) to yield 19
References and notes
1. For preliminary disclosures see: (a) Sullivan, B.; Gilmet, J.; Leisch, H.; Hudlicky,
T. J. Nat. Prod. 2008, 71, 346–351; (b) Chemoenzymatic route: Sullivan, B.;
Hudlicky, T. Tetrahedron Lett. 2008, 49, 5211–5213.
2. Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.; Janzen, W. P.; Ballas, L.
M.; Loomis, C. R.; Jiang, J. B.; Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1993, 115,
6452–6453.
3. For survey of biological activities see: (a) Ohshima, S.; Yanagisawa, M.; Katoh,
A.; Fujii, T.; Sano, T.; Matsukuma, S.; Furumai, T.; Fujiu, M.; Watanabe, K.; Yo-
kose, K.; Arisawa, M.; Okuda, T. J. Antibiot. 1994, 47, 639–647; (b) Setyawan, J.;
Koide, K.; Diller, T. C.; Bunnage, M. E.; Taylor, S.; Nicolaou, K. C.; Brunton, L. L.
Mol. Pharm. 1999, 56, 370–376.
4. (a) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402–
8403; (b) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H. J. Org.
Chem. 1994, 59, 5147–5148.
5. Total syntheses of balanol: (a) Nicolaou, K. C.; Koide, K.; Bunnage, M. E. Chem.d
Eur. J. 1995, 1, 454–466; (b) Adams, C. P.; Fairway, S. M.; Hardy, C. J.; Hibbs, D. E.;
Hursthouse, M. B.; Morley, A. D.; Sharp, B. W.; Vicker, N.; Warner, I. J. Chem. Soc.,
Perkin Trans. 1 1995, 2355–2362; (c) Tanner, D.; Almario, A.; Ho¨gberg, T. Tet-
rahedron 1995, 51, 6061–6070; (d) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.;
Smith, S. H.; Hu, H. J. Org. Chem. 1996, 61, 4572–4581; (e) Barbier, P.; Stadl-
wieser, J. Chimia 1996, 50, 530–532; (f) Tanner, D.; Tedenborg, L.; Almario, A.;
Pettersson, I.; Cso¨regh, I.; Kelly, N. M.; Andersson, P. G.; Ho¨gberg, T. Tetrahedron
1997, 53, 4857–4868; (g) Miyabe, H.; Torieda, M.; Kiguchi, T.; Naito, T. Synlett
1997, 580–582; (h) Miyabe, H.; Toreida, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.;
Naito, T. J. Org. Chem.1998, 63, 4397–4407; (i) Srivastava, A. K.; Panda, G. Chem.d
Eur. J. 2008, 14, 4675–4688.
(123 mg, 77%) as a white solid: mp 155–156 ꢁC (hexanes–ethyl
23
acetate); Rf 0.30 (1:2 hexanes–ethyl acetate); [
CHCl3); IR (film)
1088, 753 cmꢀ1; 1H NMR (300 MHz, CDCl3)
a
]
ꢀ105.2 (c 1.32,
D
n
3381, 3255, 2985, 2934, 2893, 2765, 1597, 1155,
d
7.81 (d, J¼8.2 Hz, 2H),
7.27 (d, J¼8.1 Hz, 2H), 5.48 (d, J¼6.9 Hz, 1H), 4.17–4.10 (m, 1H), 3.72
(dd, J¼8.4, 4.9 Hz, 1H), 3.51 (d, J¼3.0 Hz, 1H), 3.50–3.35 (m, 1H),
2.97, (q, J¼17.4, 8.3 Hz,1H), 2.39 (s, 3H), 2.11–2.03 (m, 1H), 1.88–1.80
(m, 1H), 1.72–1.57 (m, 2H), 1.18 (s, 3H), 0.937 (s, 3H) ppm; 13C NMR
(75 MHz, CDCl3)
d 143.4, 137.1, 129.7, 129.4, 127.8, 127.4, 108.9, 78.7,
73.6, 70.7, 63.0, 27.5, 27.4, 26.1, 23.2, 21.5 ppm; MS (EI) m/z (%): 341
(M), 43 (21), 59 (34), 65 (29), 82 (35), 83 (20), 91 (100),100 (28), 128
(65), 155 (34); HRMS calcd for C16H23NO5S 341.1297, found
341.1297.
4.13. Preparation of N-[(3S,4S)-hexahydro-4-hydroxy-1-
(phenylmethyl)-1H-azepin-3-yl]-4-(phenylmethoxy)-
benzamide (D)-2
6. Formal syntheses of balanol and approaches to the hexahydroazepine unit: (a)
Mueller, A.; Takyar, D. K.; Wit, S.; Konig, W. A. Liebigs Ann. Chem. 1993, 651–655;
(b) Hughes, P. F.; Smith, S. H.; Olson, J. T. J. Org. Chem. 1994, 59, 5799–5802; (c)
Hu, H.; Jagdmann, G. E., Jr.; Hughes, P. F.; Nichols, J. B. Tetrahedron Lett. 1995, 36,
3659–3662; (d) Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.;
Zanirato, V. Synlett 1996, 29–30; (e) Tuch, A. T.; Saniere, M.; LeMerrer, Y.; De-
pezay, J. C. Tetrahedron: Asymmetry 1996, 7, 2901–2909; (f) Wu, M. H.; Jacobsen,
E. N. Tetrahedron Lett. 1997, 38, 1693–1696; (g) Albertini, E.; Barco, A.; Benetti,
S.; De Risi, C.; Pollini, G. P.; Zanirato, V. Tetrahedron 1997, 53, 17177–17194; (h)
Coulon, E.; Cano de Andrade, M. C.; Ratovelomanana-Vidal, V.; Geneˆt, J. P.
To a stirred solution of 14b (12 mg, 0.026 mmol) in tetrahy-
drofuran (0.3 mL) was added 1 N NaOH (1.5 mL) at ꢀ20 ꢁC. The
reaction mixture was allowed to warm to room temperature slowly
over 12 h before concentrating under reduced pressure. The

220
J. Gilmet et al. / Tetrahedron 65 (2009) 212–220
Tetrahedron Lett. 1998, 39, 6467–6470; (i) Morie, T.; Kato, S. Heterocycles 1998,
12. Aziridine 6 was prepared by modification of a procedure for the synthesis of N-ace-
tylaziridines: Yeung, Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310–6311.
13. (a) Hudlicky, T.; Tian, X.; Ko¨nigsberger, K.; Rouden, J. J. Org. Chem. 1994, 59,
4037–4039; (b) Tian, X.; Hudlicky, T.; Ko¨nigsberger, K. J. Am. Chem. Soc. 1995,
117, 3643–3644; (c) Hudlicky, T.; Tian, X.; Konigsberger, K.; Maurya, R.; Rouden,
J.; Fan, B. J. Am. Chem. Soc. 1996, 118, 10752–10765.
14. Painter, G. F.; Falsaw, A.; Wong, H. Org. Biomol. Chem. 2004, 2, 1007–1012.
15. For reviews on applications of the arene cis-dihydrodiols in the synthesis of
natural products, see: (a) Carless, H. A. J. Tetrahedron: Asymmetry 1992, 3, 795–
798; (b) Brown, S. M.; Hudlicky, T. In Organic Synthesis: Theory and Applications;
Hudlicky, T., Ed.; JAI: London, 1993; Vol. 2, p 113; (c) Hudlicky, T.; Reed, J. W. In
Advances in Asymmetric Synthesis; Hassner, A., Ed.; JAI: London, 1995; Vol. 1,
p 271; (d) Hudlicky, T. Chem. Rev. 1996, 96, 3–30; (e) Boyd, D. R.; Sheldrake, G. N.
Nat. Prod. Rep. 1998, 309–324; (f) Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Al-
drichimica Acta 1999, 32, 35; (g) Hudlicky, T.; Reed, J. W. The Way of Synthesis:
Evolution of Design and Methods in Organic Synthesis; Wiley–VCH: Weinheim,
Germany, 2007.
48, 427–431; (j) Cook, G. R.; Shanker, P. S.; Peterson, S. L. Org. Lett. 1999, 1, 615–
617; (k) Herdeis, C.; Mohareb, R. M.; Neder, R. B.; Schwabenla¨nder, F.; Telser, J.
Tetrahedron: Asymmetry 1999, 10, 4521–4537; (l) Phansavath, P.; Paule, S. D.;
Ratovelomanana-Vidal, V.; Geneˆt, J. P. Eur. J. Org. Chem. 2000, 3903–3907; (m)
Riber, D.; Hazell, R.; Skrystrup, T. J. Org. Chem. 2000, 65, 5382–5390; (n) Masse,
C. E.; Morgan, A. J.; Panek, J. S. Org. Lett. 2000, 2, 2571–2573; (o) Fu¨rstner, A.;
Thiel, O. R. J. Org. Chem. 2000, 65, 1738–1742; (p) Yadav, J. S.; Srinivas, Ch.
Tetrahedron Lett. 2002, 43, 3837–3839; (q) Yadav, J. S.; Srinivas, Ch. Tetrahedron
2003, 59, 10325–10329; (r) Raghavan, S.; KumarCh, N. Tetrahedron Lett. 2006,
47, 1585–1588; (s) Unthank, M. G.; Hussain, N.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2006, 45, 7066–7069; (t) Trost, B. M.; Fandrick, D. R.; Brodmann, T.;
Stiles, D. T. Angew. Chem., Int. Ed. 2007, 46, 6123–6125.
7. For syntheses of the bis-benzyl derivative 2 see Refs. 1,5d,6f,p.
8. Leisch, H.; Saxon, R.; Sullivan, B.; Hudlicky, T. Synlett 2006, 445–449.
9. For review of reactivity and chemistry of cyclic sulfates, see: (a) Byun, H.-S.; He,
L.; Bittman, R. Tetrahedron 2000, 56, 7051–7091; (b) Gao, Y.; Sharpless, K. B. J.
Am. Chem. Soc. 1988, 110, 7538–7539.
16. For a recent compilation of arene cis-dihydrodiols, see: Johnson, R. A. Org. react.
2004, 63, 117–264.
17. (a) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975, 361–362; (b) Evans,
D. A.; Faul, M. M.; Bilodeau, M. T. J. Org Chem. 1991, 56, 6744–6746.
10. Endoma, M. A.; Bui, V. P.; Hansen, J.; Hudlicky, T. Org. Process Res. Dev. 2002, 6,
525–532.
11. Zylstra, G. J.; Gibson, D. T. J. Biol. Chem. 1989, 264, 14940–14946.