Chiral version of the burgess reagent and its reactions with oxiranes: Application to the formal enantiodivergent synthesis of balanol

Article abstract of DOI:10.1021/np0705357

An efficient formal synthesis of a (-)-balanol intermediate (25a) from cyclohexadiene oxide was accomplished in eight steps. An asymmetric version of the Burgess reagent allows for an enantiodivergent approach to both enantiomers of balanol from a racemic starting material.

Full text of DOI:10.1021/np0705357

346
J. Nat. Prod. 2008, 71, 346–350
Chiral Version of the Burgess Reagent and Its Reactions with Oxiranes: Application to the
Formal Enantiodivergent Synthesis of Balanol†
Bradford Sullivan, Jacqueline Gilmet, Hannes Leisch, and Tomas Hudlicky*
Department of Chemistry and Centre for Biotechnology, Brock UniVersity, St. Catharines, Ontario, Canada, L2S 3A1
ReceiVed September 28, 2007
An efficient formal synthesis of a (-)-balanol intermediate (25a) from cyclohexadiene oxide was accomplished in eight
steps. An asymmetric version of the Burgess reagent allows for an enantiodivergent approach to both enantiomers of
balanol from a racemic starting material.
The reactivity of the Burgess reagent1 has been the focus of
several recent investigations. Originally designed to convert aliphatic
alcohols to olefins by intramolecular elimination, the reagent has
been employed in the preparation of urethanes from primary
alcohols,2 the synthesis of R- and ꢀ-glycosylamines,3 dehydration
of amides to nitriles,4 and the synthesis of oxazolines.5 It has been
featured in several total syntheses of natural products, such as those
of cedrene,6 Taxol,7 and narciclasine,8 among others. The most
recent application of the Burgess reagent allowed for the conversion
of thiols to symmetrical disulfides.9
The mixture of sulfamidates was treated with ammonium
benzoate to effect the inversion at the sulfamidate oxygen, and the
resulting benzoates were separated. Benzoate 19a, with the correct
absolute configuration for natural balanol, was converted to cyclic
carbamate 21 under basic conditions, as shown in Scheme 1. The
absolute configurations of 17, 18, and 19a and 19b were established
by hydrogenation, hydrolysis, and conversion to their cyclic
carbamates, then comparison of the physical and spectroscopic
properties with literature values of the saturated cyclic carbamate
derivative of 21 ([R]22 +7.0 (c 1.0, EtOH), lit.21 [R]22 +6.0 (c
D
D
Until recently, it was widely believed that oxiranes and aziridines
were inert10 to the action of the Burgess reagent. In 2003 we
published the first report on the conversion of epoxides to cyclic
sulfamidates with the Burgess reagent.11 These sulfamidates can
also be prepared by reactions of diols12 or epoxy alcohols13 with
the Burgess reagent. The two pathways share common mechanistic
features; for example, it has been shown that the reaction with
epoxides and diols requires 2 equiv of the Burgess reagent.11,13 It
seems likely that the formation of sulfamidates from certain diols
may proceed via initially formed oxiranes, which then yield cis-
fused sulfamidates according to the mechanistic rationale shown
in Figure 1.14 The corresponding trans-fused sulfamidates, not
available from epoxides, are accessible from cis diols.12,13
In 2006 we prepared the first asymmetric version of the Burgess
reagent14 and demonstrated its utility on the synthesis of both cis
and trans amino alcohols, which are synthesized in either enan-
tiomeric series by the reaction of the menthyl derivative of the
Burgess reagent (9) with oxiranes, Figure 2. Diastereomeric
sulfamidates of type 10 and 11 may be hydrolyzed to cis amino
alcohols following their sometimes arduous separation. Because
cyclic sulfamidates resemble cyclic sulfates in their reactivity with
nucleophiles, they yield the corresponding trans derivatives of
amino alcohols 13 and 14 via inversion with ammonium
benzoate.15,16 The benzoates are generally separated easily and yield
the trans amino alcohols upon hydrolysis, as shown in Figure 2.14
Thus both cis and trans derivatives of amino alcohols in both
enantiomeric series may be attained.
1.0, EtOH)). Acylation of the cyclic carbamate 21, now freed of
the chiral auxiliary group, with p-benzyloxybenzoyl chloride
furnished 22 in 83% yield. Osmium tetraoxide-mediated oxidation
generated the cis diol 23 in a >95:5 ratio of diastereomers.
Oxidative cleavage of 23 with sodium periodate generated a
dialdehyde species that was immediately treated with benzylamine
under reductive amination conditions to furnish the hexahy-
droazepine derivative 24.22 Mild base hydrolysis of the cyclic
carbamate yielded the known hydroxy amide 25a ([R]23 –4.7 (c
D
0.02, CHCl3), which had been previously converted to (-)-
balanol.17f The optical purity of 25a, established by a complete
conversion to its Mosher ester and 19F NMR analysis, was shown
to be greater than 95%. We could not locate optical rotation data
for 25a in the literature despite the fact that three preparations have
been reported.17f,18f,p Optical rotation data has been reported for
the unprotected hexahydroazepine amino alcohol (lit.17f [R]25
D
-19.3 (c 0.171, MeOH), lit.18n [R]23 -20.0 (c 0.5, MeOH)).
D
The attainment of 25a in eight steps constitutes a formal total
synthesis of (-)-balanol. The unnatural enantiomer may be obtained
by an identical procedure from the trans benzoate 19b. Future
efforts in this area will focus on the synthesis of regioisomeric
derivatives of balanol and improving the design of more thermally
stable Burgess reagents.
Results and Discussion
An effective application of this methodology presented itself in
the enantiodivergent synthesis of balanol,17,18 a fungal metabolite
with significant inhibitory activities against protein kinase C (PKC)
isozymes.19 The synthesis began with the reaction of Burgess
reagent 9 with vinyl oxirane 16, followed by regioselective opening
at the allylic site to yield the two diasteromeric sulfamidates 17
and 18 in approximately 40% isolated yield.20
Experimental Section
General Experimental Procedures. All nonaqueous reactions were
carried out in an argon atmosphere using standard Schlenk techniques
for the exclusion of moisture and air. Methylene chloride was distilled
from calcium hydride. THF and benzene were dried over potassium/
benzophenone. Analytical thin-layer chromatography was performed
on Silicycle 60 Å 250 µm TLC plates with F-254 indicator. Flash
† Dedicated to Dr. G. Robert Pettit of Arizona State University for his
pioneering work on bioactive natural products.
* To whom correspondence should be addressed. Tel: 905-688 5550,
ext. 4956. Fax: 905-984 4841. E-mail: thudlicky@brocku.ca.
10.1021/np0705357 CCC: $40.75
2008 American Chemical Society and American Society of Pharmacognosy
Published on Web 01/19/2008

Chiral Version of the Burgess Reagent
Journal of Natural Products, 2008, Vol. 71, No. 3 347
Figure 1. Proposed mechanism for the formation of cyclic sulfamidates from epoxides and diols.
Figure 2. Synthesis of both enantiomers of cis and trans amino alcohols from epoxides with the Burgess reagent containing a menthyl
chiral auxiliary group.
column chromatography was performed using Natland 200–400 mesh
silica gel. Melting points were recorded on a Hoover Unimelt apparatus
and are uncorrected. IR spectra were obtained on a Perkin-Elmer One
FT-IR spectrometer. Optical rotation was measured on a Perkin-Elmer
salts formed during the reaction. The solvent was removed under
reduced pressure, and the residue was purified by flash column
chromatography (8:1 hexanes-ethyl acetate) to give 257 mg of
diastereomers 17 and 18 (1:1) as colorless crystals in 36% yield:
mp 115–118 °C (hexanes-ethyl acetate); Rf 0.55 (4:1 hexanes-ethyl
acetate); [R]D23 _54.5 (c 1.25, CHCl3); IR (film) ν 3443, 3031, 2959,
2930, 2873, 1731, 1599, 1457, 1432, 1371, 1331, 1307, 1241, 1217,
1
341 polarimeter. H, 19F, and 13C NMR spectra were recorded on a
Brucker (300 or 600 MHz) spectrometer. All chemical shifts are
referenced to TMS or residual undeuterated solvent (CHCl3, CH2Cl2).
Combustion analyses were performed by Atlantic Microlabs, Norcross,
GA. Mass spectra were recorded on a Kreatus/MsI Concept 1S mass
spectrometer at Brock University.
1
1189, 1170, 1125 cm-1; H NMR (300 MHz, CDCl3) (rotamers) δ
0.74–0.85 (m, 3H), 0.87–0.96 (m, 6H), 1.00–1.31 (m, 3H), 1.39–1.75
(m, 5H), 1.82–2.44 (m, 5H), 4.66–4.84 (m, 2H), 5.13–5.33 (m, 1H),
5.56–5.85 (m, 1H), 6.02–6.28 (m, 1H); 13C NMR (rotamers) (75
MHz, CDCl3) δ 18.7, 18.7, 18.8, 18.9, 19.9, 20.3, 21.2, 22.1, 22.6,
23.7, 23.9, 24.2, 29.3, 29.3, 29.5, 32.0, 37.7, 37.9, 38.6, 44.7, 44.8,
44.9, 45.2, 51.5, 53.2, 53.2, 72.8, 72.9, 74.6, 75.1, 75.3, 75.5, 79.2,
81.6, 81.7, 117.9, 119.0, 119.0, 129.5, 135.0, 147.9; MS (EI) m/z
(%) 357 (M); 220(16), 140(14), 139(90), 137(33), 97(24), 95(24),
83(100), 81(36), 80(11), 79(47), 69(43), 67(19), 57(35), 55(49),
53(12); HRMS calcd for C17H27NO5S 357.1610, found 357.1593.
(3aR,7aS)-2,2-Dioxo-3a,6,7,7a-tetrahydro-2λ6-1,2,3-benzoxathia-
zole-3-carboxylic acid-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl
ester (17) and (3aS,7aR)-2,2-Dioxo-3a,6,7,7a-tetrahydro-2λ6-1,2,3-
benzoxathiazole-3-carboxylic acid-(1R,2S,5R)-2-isopropyl-5-meth-
ylcyclohexyl ester (18). To a solution of oxirane 16 (186 mg, 2.0
mmol) in THF (5 mL) was added menthol Burgess reagent 9 (1.668
g, 4.6 mmol). The resulting reaction mixture was stirred at 70 °C
until complete consumption of the oxirane (TLC), then cooled to
room temperature and filtered through a plug of silica to remove

348 Journal of Natural Products, 2008, Vol. 71, No. 3
SulliVan et al.
Scheme 1. Formal Enantiodivergent Synthesis of (-)- and (+)-Balanola
a Reagents and conditions: (a) 9, THF, reflux, 1.5 h, 36%; (b) (i) ammonium benzoate, DMF, 45 °C, 12 h; (ii) THF, H2O, H2SO4, 76%; (c) 1 N NaOH, MeOH, 2 h,
94%; (d) NaH, THF, reflux, 86%; (e) 4-benzyloxybenzoyl chloride, DCM, DMAP, NEt3, 0 °C-rt, 83%; (f) OsO4, NMO, DCM, rt, 24 h, 83%; (g) (i) NaIO4, 8:2
acetone-H2O, rt, 6 h; (ii) Bn-NH2, MeOH, AcOH, NaCNBH3, 3 Å molecular sieves, -78 °C to rt, 16 h, 68%; (h) 1 N NaOH, -20 °C, 12 h, 81%.
(1S,2R)-Benzoic acid-2-(1R,2S,5R)-(2-isopropyl-5-methylcyclo-
hexyloxycarbonylamino)cyclohex-3-enyl ester (19a) and (1R,2S)-
Benzoic acid-2-(1R,2S,5R)-(2-isopropyl-5-methylcyclohexyloxycar-
bonylamino)cyclohex-3-enyl ester (19b). To a stirred solution of 17
and 18 (320 mg, 1.25 mmol) in dry DMF (5 mL) was added ammonium
benzoate (346 mg, 2.49 mmol). The solution was heated to 55 °C and
stirred for 18 h. The solvent was evaporated, and the residue was
dissolved in freshly distilled THF (3 mL). Three drops of H2O and
three drops of concentrated H2SO4 were added, and the reaction mixture
was stirred for 12 h. After the pH was adjusted to 9 (saturated NaHCO3),
the layers were separated, the aqueous layer was extracted with CH2Cl2
(3 × 5 mL), and the organic layers were combined, washed with brine,
dried over Na2SO4, and evaporated. The crude material was recrystal-
lized from ethyl acetate–hexanes to afford a mixture of diastereomers
(279 mg, 76%) as a white solid. The diastereomers were separated via
flash column chromatography (400:1 CH2Cl2-MeOH) to afford 19a
and 19b as a white solid.
19a: mp 103–105 °C (ethyl acetate–hexanes); Rf 0.67 (400:1
CH2Cl2-MeOH); [R]23D -100.8 (c 0.25, CHCl3); IR (film) 3436, 3019,
2962, 1713, 1602, 1511, 1424, 1277, 1117, 1048, 1028 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.72 (d, J ) 5.8 Hz, 3H), 0.78 (d, J ) 6.6 Hz,
3H), 0.87 (d, J ) 7.1 Hz, 3H), 0.98–1.04 (m, 1H), 1.21–1.27 (m, 1H),
1.26–1.42 (m, 2H), 1.59–1.72 (m, 4H), 1.88–1.93 (m, 1H), 1.96–2.00
(m, 1H), 2.08–2.11 (m, 1H), 2.25–2.28 (m, 2H), 4.46 (dt, J ) 10.7,
3.9 Hz, 1H), 4.52–4.62 (m, 1H), 4.66 (d, J ) 9.2 Hz, 1H), 5.04–5.11
(m, 1H), 5.69 (dd, J ) 9.5 Hz, 1.5, 1H), 5.85 (d, J ) 10.2 Hz, 1H),
7.44 (t, J ) 7.8 Hz, 2H), 7.56 (t, J ) 7.4 Hz, 1H), 8.07 (d, J ) 7.4 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 16.5, 20.8, 21.9, 23.5, 24.0, 26.3,
26.4, 31.2, 34.2, 41.0, 47.2, 51.7, 73.9, 74.8, 126.8, 128.3 (2×C), 129.5,
129.8 (2×C), 130.2, 133.0, 156.2, 166.5; MS (EI) m/z (%) 399; 41(18),
43(22), 44(15), 55(22), 47(18), 69(26), 71(21), 77(26), 81(15), 83(24),
95(18), 105(100), 112(12), 121(14), 123(8), 139(27), 294(6); HRMS
calcd for C24H33NO4 399.2410, found 399.2403; anal. calcd C 72.15,
H 8.33, found C 72.42, H 8.44.
(600 MHz, CDCl3) δ 0.42 (d, J ) 6.6 Hz, 3H), 0.65 (d, J ) 6.6 Hz,
3H), 0.85–0.97 (m, 6H), 1.21 (t, J ) 11.5 Hz), 1.41–1.49 (m, 1H),
1.54–1.71 (m, 3H), 1.91–2.03 (m, 2H), 2.06–2.13 (m, 1H), 2.23–2.29
(m, 2H), 4.49 (td, J ) 10.8, 3.7 Hz, 1H), 4.55–4.61 (m, 1H), 4.70 (d,
J ) 9.5 Hz, 1H), 5.04–5.12 (m, 1H), 5.59 (dq J ) 9.8, 2.2 Hz, 1 H),
5.84 (d, J ) 8.6 Hz, 1H), 7.44 (t, J ) 7.8 Hz, 2H), 7.56 (t, J ) 7.5 Hz,
1H), 8.06 (d, J ) 7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 16.1,
20.5, 22.0, 23.5, 24.0, 26.2, 26.6, 31.3, 34.2, 41.4, 47.3, 51.7, 73.7,
74.5, 127.0, 128.3 (2×C), 129.3, 129.8 (2×C), 130.1, 132.9, 156.0,
166.5; MS (EI) m/z (%) 399; 41 (15), 43 (14), 55 (23), 57 (19), 69
(32), 71 (16), 77 (27), 79 (10), 81 (15), 83 (39), 95 (20) 105 (100),
112 (19), 113 (14), 121 (12), 123 (10), 138 (11), 139 (47), 156 (15),
251 (15), 294 (12); HRMS calcd for C24H33NO4 399.2410, found
399.2410.
(1S,6R)-(6-Hydroxycyclohex-2-enyl)carbamic acid (1R,2S,5R)-2-
isopropyl-5-methylcyclohexyl ester (20). A round-bottomed flask was
charged with 19a (122 mg, 0.305 mmol) and 1 N NaOH (12 mL) in
methanol. The resulting solution was stirred at room temperature for
1 h and then concentrated before the residue was dissolved in 5 mL of
water, and the aqueous layer was extracted with CH2Cl2 (3 × 7 mL).
The combined organic layers were washed with brine, dried with
Na2SO4, and evaporated to give the crude product. Recrystallization
of the crude material from ethyl ether-hexanes afforded 85 mg (94%)
of the alcohol as a white solid: mp 115–116 °C (ethyl ether-hexanes);
Rf 0.44 (2:1 hexanes-ethyl acetate); [R]23 -72.9 (c 0.775, CHCl3);
D
IR (film) 3435, 2955, 2869, 1645, 1529, 1455 cm-1. H NMR (300
1
MHz, CDCl3) δ 0.74 (d, J ) 6.8 Hz, 3H), 0.84 (d, J ) 2.2 Hz, 3H),
0.86 (d, J ) 2.2 Hz, 3H), 0.89–1.07 (m, 2H), 1.21–1.32 (m, 1H),
1.36–1.48 (m, 1H), 1.54–1.63 (m, 2H), 1.63–1.69 (m, 1H), 1.82–1.96
(m, 2H), 1.96–2.02 (m, 1H), 2.03–2.13 (m, 2H), 3.01–3.18 (br s, 1H),
3.60 (dq, J ) 10.7 Hz, 3.6, 1H), 3.96–4.16 (m, 1H), 4.51 (td, J ) 9.9,
1.6 Hz, 1H), 4.73 (d, J ) 6.4 Hz, 1H), 5.36 (d, J ) 9.8 Hz, 1H), 5.77
(d, J ) 8.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 16.4, 20.8, 22.0,
23.4, 23.9, 26.2, 28.9, 31.3, 34.2, 41.3, 47.3, 55.3, 73.2, 75.4, 125.4,
130.9, 157.8; MS (EI) m/z (%) 295; 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),
19b: mp 107–109 °C (ethyl acetate–hexanes); Rf 0.62 (400:1
CH2Cl2-MeOH); [R]23 +16.2 (c 0.4, CHCl3); IR (film) 3369, 3033,
D
2954, 2928, 2869, 1714, 1523, 1277, 1241, 1116, 1027 cm-1; 1H NMR

Chiral Version of the Burgess Reagent
Journal of Natural Products, 2008, Vol. 71, No. 3 349
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 68.86,
H 9.89.
(2 × 5 mL). The resulting solution was filtered through a plug of silica
gel and concentrated under reduced pressure to yield the dialdehyde,
which was used without further purification. It was dissolved in dry
MeOH (3 mL) and cooled to –78 °C in an acetone and liquid N2 bath.
To this solution was added 3 Å molecular sieves (150 mg), followed
by NaCNBH3 (10 mg, 0.166 mmol), then AcOH (17.3 µL, 0.302 mmol),
and finally benzylamine (18.2 µL, 0.166 mmol). The reaction was
warmed to room temperature slowly over 24 h before concentrating
under reduced pressure. The resulting residue was triturated with ethyl
acetate (3 × 5 mL) and washed with NaHCO3 (1 × 3 mL). The organic
layer was washed with brine (3 mL), then dried with Na2SO4 before
concentrating. The crude material was recrystallized from ethyl
ether-hexanes to yield 47 mg (68%) of the title compound as a pale
yellow solid: mp 126–128 °C (ethyl ether-hexanes); Rf 0.68 (2:1
(3aR,7aR)-3a,6,7,7a-Tetrahydro-3H-benzoxazol-2-one (21).
A
suspension of NaH (60% in mineral oil, 33 mg, 1.35 mmol, prewashed
with hexanes (5 mL × 3)) in THF (15 mL) at 0 °C was added dropwise
to a solution of alcohol 20 (200 mg, 6.77 mmol) in freshly distilled
THF (7 mL), then the reaction mixture was brought to reflux. After
stirring for 12 h, the mixture was cooled to room temperature and the
reaction was quenched by the addition of saturated NH4Cl and then
concentrated before extracting the aqueous layer with CH2Cl2 (3 × 15
mL). The combined organic layers were washed with brine, dried with
Na2SO4, and evaporated to give the crude product. Recrystallization
of the crude material from ethyl ether-hexanes afforded 81 mg (86%)
of the title compound as a white solid: mp 114–115 °C (ethyl
hexanes-ethyl acetate); [R]23 -27.9 (c 0.7, CHCl3); IR (film) 3029,
D
2835, 1783, 1679, 1604, 1300, 1253, 1119 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.69–1.78 (m, 3H), 2.33–2.45 (m, 1H), 2.50–2.73 (m, 1H),
3.40–3.47 (m, 1H), 3.68 (q, J ) 18.6 Hz, 2H), 4.39 (q, J ) 8.7 Hz,
2H), 4.90 (t, J ) 8.5 Hz, 1H), 5.11 (s, 2H), 6.98 (d, J ) 8.6 Hz, 2H),
7.28–7.44 (m, 10H), 7.74 (d, J ) 8.6 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 26.3, 31.2, 51.4, 55.3, 61.8, 63.0, 70.1, 78.0, 114.1, 125.2,
127.2, 127.5, 128.2, 128.4, 128.7, 132.3, 136.1, 138.9, 154.1, 162.8,
169.7; MS (EI) m/z (%): 412 (M – CO2); 44(20), 91(100), 160(76),
161(10); HRMS (M – CO2) calcd for C27H28N2O2 412.2151, found
412.2151.
ether-hexanes); Rf 0.36 (1:1 hexane-ethyl acetate); [R]23 -37.7 (c
D
1.37, CHCl3); IR (film) 3854, 3435, 3020, 1751, 1644, 1216, 769 cm-1
.
1H NMR (300 MHz, CDCl3) δ 1.92 (td, J ) 9.8, 0.94 Hz, 1H),
2.21–2.28 (m, 1H), 2.29–2.50 (m, 2H), 4.07 (t, J ) 11.4 Hz, 1H), 4.14
(td, J ) 12.3, 1.1 Hz, 1H), 5.50–5.65 (m, 1H), 5.85 (dd, J ) 9.1, 0.77
Hz, 1H), 5.88–6.15 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 24.5,
25.3, 58.1, 81.3, 123.9, 128.4, 161.6; MS (EI) m/z (%) 139; 41(22),
54(100), 55(11), 67(55), 68(17), 95(13), 111(26); HRMS calcd for
C7H9NO2 139.0633, found 139.0632.
(3aR,7aR)-3-(4-Benzyloxybenzoyl)-3a,6,7,7a-tetrahydro-3H-ben-
zoxazol-2-one (22). To a stirred solution of 21 (57 mg, 0.409 mmol)
in freshly distilled CH2Cl2 (7 mL) were added triethylamine (0.11 mL,
0.819 mmol) and DMAP (17 mg, 0.122 mmol). The reaction was cooled
to 0 °C, then 4-benzyloxybenzoyl chloride (101 mg, 0.409 mmol) was
added in portions over a period of 30 min. The reaction was stirred for
12 h and then diluted with CH2Cl2 (5 mL). The organic layer was
washed with cold 1 N HCl (3 × 3 mL) and then with saturated NaHCO3
(1 × 3 mL). The combined organic layers were washed with brine,
dried with Na2SO4, and then evaporated. The crude product was
subjected to flash column chromatography (6:1 hexanes-ethyl acetate),
then recrystallized from ethyl ether-hexanes to afford 102 mg (72%)
of the title compound as a white solid: mp 167–169 °C (ethyl
Benzamide, N-[(3R,4R)-hexahydro-4-hydroxy-1-(phenylmethyl)-
1H-azepin-3-yl]-4-(phenylmethoxy)benzamide (25a). To a stirred
solution of 24 (12 mg, 0.0263 mmol) in freshly distilled THF (0.2 mL)
was added 1 N NaOH (1 mL) at -20 °C. The reaction was warmed to
room temperature slowly over 12 h before concentrating under reduced
pressure. The reaction was concentrated, extracted into ethyl ether (5
× 1 mL), washed with brine, and then dried over Na2SO4. The crude
product was subjected to flash column chromatography (3:1 hexanes-
ethyl acetate) to yield 9 mg (81%) of the title compound as a yellow
oil: Rf 0.31 (3:2 ethyl acetate–hexanes); [R]23 -4.7 (c 0.2, CHCl3);
D
IR (film) 3407, 3377, 2955, 1638, 1611, 1298, 1140 cm-1; H NMR
1
(300 MHz, CDCl3) δ 1.55–1.99 (m, 4H), 2.50 (m, 1H), 2.73 (dd, J )
1.9, 14.3 Hz, 1H), 2.93 (dd, J ) 2.0, 14.2 Hz, 1H), 3.00 (m, 1H), 3.42
(d, J ) 13.2 Hz, 1H), 3.74–3.78 (m, 2H), 3.88 (m, 1H), 5.15 (s, 2H),
6.54 (d, J ) 8.7 Hz, 1H), 6.99 (d, J ) 6.8 Hz, 2H), 7.22–7.50 (m,
12H); MS (FAB) m/z (%) 431 (M + H+); 41(34), 43(43), 57(51),
71(34), 91(71), 149(100); HRMS calcd for C27H31N2O3 431.2310, found
431.2312.
ether-hexanes); Rf 0.47 (2:1 hexanes-ethyl acetate); [R]23 -104.6
D
(c 0.5, CHCl3); IR (film) 2922, 1790, 1674, 1604, 1298, 1140 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.97–2.07 (m, 1H), 2.27–2.45 (m, 2H),
2.45–2.55 (m, 1H), 4.24–4.38 (m, 1H), 4.50 (d, J ) 8.6 Hz, 1H), 5.10
(s, 2H), 5.68 (dd, J ) 6.6, 3.2 Hz, 1H), 6.13 (dd, J ) 9.6, 1.3 Hz, 1H),
6.98 (d, J ) 8.6 Hz, 2H), 7.31–7.45 (m, 5H), 7.77 (d, J ) 8.6 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 24.4, 25.3, 60.4, 70.2, 78.5, 114.3,
123.1, 125.1, 127.6, 128.3, 128.7, 128.8, 132.3, 136.2, 155.2, 162.9,
169.9; MS (EI) m/z (%) 349; 43(11), 83(10), 91(100), 113(10), 167(56),
168(16), 183(18), 184(15), 211(12), 226(27), 349(18); HRMS calcd
for C21H19NO4 349.1314, found 349.1314; anal. calcd C 72.19, H 5.48,
found C 72.22, H 5.55.
Determination of Enantiomeric Excess in 25a by 19F NMR of
Its Mosher’s Ester. To a stirred solution of 25a (8 mg, 0.0185 mmol)
in freshly distilled CH2Cl2 (0.5 mL) were added triethylamine (5.16
µL, 0.0370 mmol) and DMAP (catalytic amount). The reaction was
cooled to 0 °C; then (S)-(+)-Mosher’s acid chloride (3.34 µL, 0.0185
mmol) was added in portions over a period of 10 min. The reaction
was stirred until the starting material had been completely consumed
(12 h) and then diluted with CH2Cl2 (1 mL). The organic layer was
washed with cold 1 N HCl (1 × 1 mL) and then with saturated NaHCO3
(1 × 1 mL). The combined organic layers were washed with brine,
dried with Na2SO4, and evaporated. The crude product was subjected
to flash column chromatography (6:1 hexanes-ethyl acetate) to afford
(3aR,7aR)-3-(4-Benzyloxybenzoyl)-4,5-dihydroxyhexahydroben-
zoxazol-2-one (23). To a stirred solution of 22 (93 mg, 0.266 mmol)
in freshly distilled CH2Cl2 (5 mL) were added N-methylmorpoline-N-
oxide (47 mg, 3.99 mmol), one drop of distilled water, and a catalytic
amount of OsO4. The reaction was stirred at room temperature for 36 h
before filtering through a plug of Celite and silica gel. The crude
material was recrystallized from ethyl ether-hexanes and then dried
over P2O5 to yield 84 mg (83%) of the title compound as a white solid:
mp 178–180 °C (ethyl ether-hexanes); Rf 0.35 (1:3 hexanes-ethyl
acetate); [R]23D -77.2 (c 0.5, CHCl3); IR (film) 2922, 1790, 1674, 1604,
1
9 mg (77%) of the Mosher’s ester: H NMR (300 MHz, CDCl3) δ
1.39–1.48 (m, 2H), 1.65–1.76 (m, 2H), 2.27–2.37 (m, 2H), 3.43 (s,
3H), 2.98–3.02 (m, 1H), 3.08–3.12 (m, 1H), 3.90–3.95 (m, 1H), 4.13
(q, J ) 7.1, 2H), 4.26–4.29 (m, 1H), 5.15 (s, 2H), 6.35–6.40 (m, 1H),
6.89–6.96 (m, 2H), 7.41–7.64 (m, 15H), 7.96–8.06 (m, 2H); 19F NMR
(282 MHz, CDCl3) δ –71.26 (major isomer), -71.58 (minor isomer);
MS (FAB) m/z (%) 647 (M + H+); 41(34), 43(43), 57(51), 71(34),
91(71), 149(100); HRMS calcd for C37H37F3N2O5 647.2709, found
647.2711.
1
1298, 1140 cm-1; H NMR (300 MHz, CDCl3) δ 1.65–1.75 (m, 2H),
2.02–2.07 (m, 1H), 2.22–2.28 (m, 1H), 3.75 (dd, J ) 11.1, 0.93 Hz,
1H), 3.81–3.91 (m, 1H), 4.60–4.68 (m, 1H), 4.75–4.80 (m, 1H), 5.10
(s, 2H), 6.98 (d, J ) 7.9 Hz, 2H), 7.31–7.34 (m, 1H), 7.36–7.42 (m,
4H), 7.76 (d, J ) 8.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 24.4,
25.3, 60.4, 70.2, 78.5, 114.3, 123.1, 125.1, 127.6, 128.3, 128.7, 128.8,
132.3, 136.2, 155.2, 162.9, 169.9; MS (EI) m/z (%) 349; 43(11), 83(10),
91(100), 113(10), 167(56), 168(16), 183(18), 184(15), 211(12), 226(27),
349(18); HRMS calcd for C21H19NO4 349.1314, found 349.1314.
(3aR,7aR)-5-Benzyl-3-(4-benzyloxybenzoyl)octahydro-1-oxa-3,5-
diaza-azulen-2-one (24). To a stirred solution of 23 (58 mg, 0.151
mmol) in acetone (3 mL) was added a suspension of NaIO4 (322 mg,
1.51 mmol) in distilled water. The reaction was stirred at room
temperature for 6 h, then the solvent was removed. The crude residue
was triturated with ethyl acetate (3 × 5 mL), then washed with brine
Acknowledgment. The authors are grateful to the following agencies
for financial support: Natural Science and Engineering Research Council
(NSERC), TDC Research Foundation, Canada Foundation for Innova-
tion (CFI), Ontario Innovation Trust (OIT), Research Corporation, TDC
Research, Inc., and Brock University.
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(23) The less-than-absolute optical purity is probably due to a small degree
of contamination of benzoate 19a with its diastereomer 19b.
NP0705357