Nucleophilic opening of epoxyazepanes: Expanding the family of polyhydroxyazepane-based glycosidase inhibitors

Article abstract of DOI:10.1039/b518117h

A range of new tetra- and pentahydroxylated seven-membered iminoalditols has been efficiently synthesized from epoxyazepane precursors via nucleophilic opening with hydride or oxygenated species and subsequent hydrogenolysis. One tetrahydroxylated azepane

Full text of DOI:10.1039/b518117h

View Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Nucleophilic opening of epoxyazepanes: expanding the family of
polyhydroxyazepane-based glycosidase inhibitors†
Hongqing Li,a,c Catherine Schu¨tz,b Sylvain Favre,b Yongmin Zhang,a,c Pierre Vogel,b Pierre Sinay¨a,c and
Yves Ble´riot*a,c
Received 4th January 2006, Accepted 1st March 2006
First published as an Advance Article on the web 28th March 2006
DOI: 10.1039/b518117h
A range of new tetra- and pentahydroxylated seven-membered iminoalditols has been efficiently
synthesized from epoxyazepane precursors via nucleophilic opening with hydride or oxygenated species
and subsequent hydrogenolysis. One tetrahydroxylated azepane, a ring homologue of
deoxymannojirimycin, displays a selective and fairly good inhibition of a-L-fucosidase.
this new class of compounds and design new structures with
Introduction
potent glycosidase activity, we wanted to develop a versatile
Glycosidases, which are known to increase the rate of glycosidic
strategy enabling access to all stereoisomers at pseudo C-1 and
bond hydrolysis by a factor of 1017, making them among the most
C-2 positions of the polyhydroxylated azepane, such positions
proficient enzymes in Nature,1 play many fundamental roles in bio-
being crucial for glycosidase inhibition and selectivity. In this
chemistry and metabolism. As a consequence, iminosugar-based
paper, we report, starting from key epoxyazepanes, the efficient
glycosidase inhibitors have been the subject of extensive interest
synthesis of new 1,6-dideoxy-1,6-iminoheptitols. All the tetra- and
in the past three decades due to their therapeutic potential.2 Some
pentahydroxylated azepanes synthesized were then evaluated as
of them have already been tested or approved in the treatment of
glycosidase inhibitors. For clarity reasons, the numbering used
diabetes,3 Gaucher’s disease,4 HIV infection,5 viral infection6 or
for these compounds follows the numbering of the parent sugar
cancer7 and they are now expected to find an increasing number
thus emphasizing the analogy between the azepanes and the
of therapeutic applications.8 Extensive synthetic work has been
corresponding monosaccharides.
devoted to five- and six-membered iminosugars,9 which mimic
the ring size of the naturally occuring sugars. Despite promising
biological results10 and conformational flexibility that could
match the unusual conformation encountered in the glycosidase
transition state,11 the synthesis of seven-membered azasugars12 has
Results and discussion
Our strategy takes advantage of our previously reported
received only limited attention. As part of an ongoing project on
epoxyazepanes 4–7, obtained by m-CPBA epoxidation of an
the design of new carbohydrate mimetics based on conformational
azacycloheptene produced by ring-closing metathesis (RCM)
flexibility, we have previously reported the synthesis and biological
of the corresponding iminodiene.13 Epoxyazepane derivatives
evaluation of an a-nojirimycin homologue 1, a b-mannojirimycin
have been previously used in the synthesis of a) the optically
homologue 212a and an a-galactonojirimycin analogue 312b (Fig. 1).
active constituent of the antifungal antibiotic ophiocordin,14 b)
In order to establish a structure–activity relationship (SAR) for
azepanone-based inhibitors of human and rat cathepsin K,15 c)
azepane–glycoside antibiotics targeting the bacterial ribosome,16
d) protein kinase C inhibitor balanol.17 The stereochemistry of the
oxirane ring in epoxides 4–7 was deduced from the 1H-NMR J1,2
and J2,3 coupling constants (Fig. 2) and was compared to those
obtained for tricyclic epoxides 8 and 9 (Fig. 3).
Fig. 1 Structure of analogues 1–3.
aEcole Normale Supe´rieure, De´partement de Chimie, UMR 8642 associe´e
au CNRS, 24 rue Lhomond, 75231, Paris Cedex 05, France. E-mail:
Fig. 2 Structure and 1H-NMR J1,2 and J2,3 coupling constants of epoxides
yves.bleriot@ens.fr; Fax: +33 1 44 32 33 97; Tel: +33 1 44 32 33 35
bLaboratoire de glycochimie et de synthe`se asyme´trique, Swiss Federal
4–7.
Institute of Technology (EPFL) BCH, CH-1015, Lausanne-Dorigny,
Switzerland
Compound 8 has previously been reported by us and its crystal
structure solved.13 We were also able to solve the crystal structure
of compound 918 available in our laboratory (Fig. 4).
cInstitut de Chimie Mole´culaire (FR 2769), Universite´ Pierre et Marie Curie-
Paris 6, F-75005, Paris, France
† Dedicated to Professor Walter Szarek on the occasion of his 65th birthday.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1653–1662 | 1653
©

View Online
respectively in good yield (70–88%), the 1-deoxy derivatives 10 and
12 being the major products indicating a preferred nucleophilic
attack of the epoxide at C-1.22 Nucleophilic opening of simple
epoxyazepanes has been studied by the group of Tanner.23 They
observed a remarkable C-2 regioselective opening of these systems
invoking both a nitrogen substituent steric effect and a charge
control. We have previously obtained such selectivity during azide
opening of our epoxyazepanes,13 albeit with a lower degree of
regiocontrol. The opposite regioselectivity obtained for azide and
hydride oxirane ring opening of epoxyazepanes 4 and 5 is difficult
to rationalize due to the flexibility of the seven-membered ring.
Finally, hydrogenolysis of compounds 10–13 quantitatively af-
forded the corresponding tetrahydroxyazepanes 14–17 (Scheme 1),
compounds 14 and 16 being the exact homologues of deoxyman-
nojirimycin and deoxynojirimycin, respectively.
Fig. 3 Structure and 1H-NMR J1,2 and J2,3 coupling constants of epoxides
8 and 9.
Fig. 4 Crystal structure of epoxyazepane 9.
Discriminating J2,3 coupling constants were observed for the
oxirane rings cis and trans to the neighbouring C-3 substituent,
trans epoxides 5 and 7 displaying always higher J2,3 values than
the corresponding cis epoxides 4 and 6, a trend also observed with
tricyclic epoxides 8 and 9.
Scheme 1 Synthesis of tetrahydroxyazepanes 14–17. Reagents and con-
ditions: a) Super-HydrideꢀR , THF, 70–88% yield; b) H2, 10% Pd/C,
MeOH/1M HCl quant.
R
Oxirane ring opening with Super-Hydrideꢀ
The same sequence was uneventfully applied to diastereomeric
epoxides 6 and 7 to afford alcohols 18–21. Interestingly, alcohol
21 was only observed as traces.24 The corresponding tetrahydroxy-
azepanes 22–25 were obtained after hydrogenolysis (Scheme 2).
Some similar iminocyclitols displaying other stereochemistries
have been reported by Lin’s group.25
Regarding the previously reported polyhydroxylated azepanes, we
were particularly interested in the deoxygenation of the azepane
ring at C-1 to afford compounds which, for two of them, can be
seen as seven-membered analogues of the canonical inhibitors
deoxynojirimycin (DNJ)19 and deoxymannojirimycin (DMJ)20
(Fig. 5).
Oxirane ring opening with sodium nitrite
We have previously described the synthesis and inhibitory activity
of a-D-nojirimycin homologue 1 and b-D-mannojirimycin homo-
logue 2 in which a cis diol functionality is present at positions
C-1 and C-2 of the ring. Both compounds displayed potent
and selective glycosidase inhibition on a- and b-galactosidases
respectively.12a These biological results encouraged us to investi-
gate the synthesis and the biological evaluation of the correspond-
ing trans 1,2-diols, in particular the b-D-nojirimycin and a-D-
mannonojirimycin homologues. These latter should bring useful
insights into the role of the two hydroxyl groups present at these
positions in terms of selectivity and potency. Such structures
should be rapidly accessible from epoxides 4 and 5 via nucleophilic
opening with oxygenated species. We first envisioned the epoxide
opening with nucleophiles such as caesium acetate and potassium
Fig. 5 Analogy between DNJ, DMJ and azepane-based homologues.
Such compounds should be easily accessible from epoxy-
azepanes 4–7 via regioselective epoxide opening with hydride
species. Such an approach has been described in the case of
piperidine derivatives to have access to fagomine and congeners.21
R
Epoxides 4 and 513 were treated with Super-Hydrideꢀ in THF
to give the corresponding separable alcohols 10–11 and 12–13
1654 | Org. Biomol. Chem., 2006, 4, 1653–1662
This journal is
The Royal Society of Chemistry 2006
©

View Online
Scheme 4 Synthesis of b-L-homogulonojirimycin 32 and a-L-homoidono-
jirimycin 33. Reagents and conditions: a) NaNO2, DMF/H2O; b) 15% aq.
H2SO4, DMF (1 : 10); c) H2, 10% Pd/C MeOH, 1M aq. HCl, quant.
Inhibition on glycosidases
Scheme 2 Synthesis of tetrahydroxyazepanes 22–25. Reagents and con-
ditions: a) Super-HydrideꢀR , THF, 74–77% yield; b) H2, 10% Pd/C,
MeOH/1M HCl quant.
Iminoheptitols 14–17, 22–25, 28, 29, 32, 33 were assayed towards
a range of commercially available glycosidases.28 They did not
inhibit b-galactosidases from Escherichia coli and Aspergillus
oryzae at 1 mM. For the other enzymes assayed, the results are
shown in Tables 1 and 2. Pentahydroxylated azepanes 28, 29, 32,
33 bearing a trans diol at position C-1 and C-2 were found to be
only weak glycosidase inhibitors. This disappointing result is in
marked contrast with our previously reported pentahydroxylated
azepanes. The fact that these compounds do not significantly
inhibit glycosidases can be tentatively attributed to an important
conformational change imposed by the trans 1,2-diol in these
structures making these molecules unable to interact favorably
with the active site of the glycosidase. Work is now in progress to
determine the predominant conformation of these structures that
could explain the biological results.
Tetrahydroxylated azepanes 14–17 and 22–25 were also assayed
on several glycosidases. Unfortunately we were not able to test
these compounds against a-galactosidase from coffee beans which
was strongly inhibited by some of our previous compounds.
Again and as previously observed, compounds 14–17 with an R
configured hydroxymethyl group are better inhibitors than the
corresponding S configured compounds 22–25. While most of the
tetrahydroxylated compounds synthesized herein show only weak
inhibition on glycosidases, compound 14, a D-manno configured
azepane, does not inhibit the corresponding mannosidase but
displays a competitive inhibition towards bovine kidney a-L-
fucosidase (Ki 10 lM). Similar inhibition values have been
reported for this enzyme with other hydroxylated azepanes.10,29
Compound 16, the ring homologue of deoxynojirimycin, did not
show significant inhibition of glycosidases while its azocane ana-
logue was found to be a fairly good inhibitor of a-L-rhamnosidase
(IC50 110 lM).30 Having now in hand many structures and
biological results, work is now in progress to establish a SAR
for this class of compounds towards glycosidases.
hydroxide, but no trans diol was isolated and only starting material
was recovered. These results led us to evaluate the opening of these
epoxides under acidic conditions. Treatment of epoxide 4 with aq.
sulfuric acid in DMF afforded the expected diols 26 and 27 albeit
in low yield.26 Unfortunately epoxide 5, under the same conditions,
yielded a complex mixture of compounds. Milder conditions were
thus needed that could be applied to each epoxide and afford all the
possible stereoisomers. A known procedure using sodium nitrite
proved to be successful.27 Treatment of epoxide 4 with sodium
nitrite in aqueous DMF gave the corresponding trans 1,2-diols
26 and 27 in a low unoptimized 30% yield and 1 : 1 ratio. The
same conditions were applied to epoxide 5 to yield compounds 26
and 27 in very similar yield and ratio. Subsequent hydrogenolysis
furnished the corresponding a-homomannonojirimycin 28 and b-
homonojirimycin 29 in quantitative yield (Scheme 3).
Scheme 3 Synthesis of a-D-homomannonojirimycin 28 and b-D-homono-
jirimycin 29. Reagents and conditions: a) NaNO2, DMF/H2O; b) 15% aq.
H2SO4, DMF (1 : 10); c) H2, 10% Pd/C, MeOH, 1M aq. HCl, quant.
Conclusion
In conclusion, using a straightforward strategy based on nucle-
ophilic opening of previously reported epoxyazepanes, we have
obtained twelve new seven-membered ring iminoheptitols. Eight
tetrahydroxylated azepanes 14–17 and 22–25 were synthesized via
The same conditions were uneventfully applied to epoxides
6 and 7 to afford the b-L-homogulonojirimycin 32 and a-L-
homoidonojirimycin 33 (Scheme 4).
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1653–1662 | 1655
©

View Online
Table 1 Inhibitory activity of compounds 14–17, 28 and 29 towards glycosidasesa
Compound/enzyme
14
15
16
17
28
29
a-L-Fucosidase
Bovine kidney
a-Galactosidase
Coffee bean
b-Galactosidase
Bovine liver
a-Glucosidase
Yeast
Rice
93% (10 lM)
ND
30%
ND
56%
NI
NI
40%
35%
24%
NI
31%
29%
22%
ND
40%
ND
29%
52%
NI
NI
NI
NI
NI
NI
NI
NI
NI
40%
Amyloglucosidase
Aspergillus niger
Rhizopus mold
b-Glucosidase
Sweet almonds
a-Mannosidase
Jack bean
b-Mannosidase
Snail
b-Xylosidase
Aspergillus niger
NI
20%
57%
55%
NI
NI
NI
NI
NI
ND
NI
ND
NI
NI
ND
NI
40%
NI
NI
NI
NI
ND
NI
NI
28%
38%
NI
16%
ND
NI
NI
ND
NI
NI
27%
67%
b-N-Acetylglucosaminidase
Jack bean
Bovine kidney
NI
NI
NI
NI
NI
NI
20%
NI
41%
38%
NI
NI
a % of inhibition at 1 mM concentration, optimal pH, 35 ◦C, ND = not determined, NI = no inhibition at 1 mM concentration of the inhibitor.
Table 2 Inhibitory activity of compounds 22–25, 32 and 33 towards glycosidasesa
Compound/enzyme
22
23
24
25
32
33
a-L-Fucosidase
Bovine kidney
a-Galactosidase
Coffee bean
b-Galactosidase
Bovine liver
51%
ND
33%
NI
NI
NI
21%
NI
24%
NI
ND
NI
ND
NI
ND
24%
19%
30%
a-Glucosidase
Yeast
Rice
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
16%
NI
Amyloglucosidase
Aspergillus niger
Rhizopus mold
b-Glucosidase
Sweet almonds
a-Mannosidase
Jack bean
b-Xylosidase
Aspergillus niger
b-N-Acetylglucosaminidase
Jack bean NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
ND
NI
ND
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
NI
17%
NI
a % of inhibition at 1 mM concentration, optimal pH, 35 ◦C, ND = not determined, NI = no inhibition at 1 mM concentration of the inhibitor.
1656 | Org. Biomol. Chem., 2006, 4, 1653–1662
This journal is
The Royal Society of Chemistry 2006
©

View Online
R
Super-Hydrideꢀ oxirane opening and hydrogenolysis. Two of them
C-2ꢀ), 55.25, 55.22 (C-1ꢀ, C-1), 43.17, 42.94 (C-7ꢀ, C-7); m/z (CI,
+
can be seen as ring homologues of classic DNJ (deoxynojirimycin)
and DMJ (deoxymannojirimycin), the latter displaying a good
and selective inhibition on a-L-fucosidase. Four pentahydroxylated
azepanes 28, 29, 32, 33 were also synthesized via sodium nitrite
oxirane opening and hydrogenolysis. These compounds, albeit
similar to previously reported pentahydroxylated azepanes and
only differing by the presence of a trans 1,2-diol on the ring, do
not show significant inhibition of glycosidases.
NH3): 580 (M + H+, 100%), 597 (M + NH4 , 60%); HRMS (CI,
NH3): Calcd for C36H38O6N (M + H+): 580.2699, Found 580.2695.
Compound 5. [a]D −43 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.42–7.33 (m, 40H, 8 × Ph), 5.25–5.11 (m, 4H, 4 ×
NCOOCHPh), 5.05– 4.76 (m, 6H, 6 × CHPh), 4.62 (app. d, 1H,
J = 16.0 Hz, H-7ꢀa), 4.55–4.34 (m, 8H, 6 × CHPh, H-5, H-7a),
4.25 (ddd, 1H, J = 2.5 Hz, J = 4.7 Hz, J = 8.0 Hz, H-5ꢀ), 3.88 (t,
1H, J = 9.8 Hz, H-4), 3.86–3.76 (m, 5H, H-3, H-4ꢀ, H-6a, H-6ꢀa,
H-7b), 3.74 (dd, 1H, J = 1.9 Hz, J = 9.7 Hz, H-3ꢀ), 3.73 (d, 1H,
J = 15.8 Hz, H-7ꢀb), 3.64 (dd, 1H, J = 2.4 Hz, J = 10.2 Hz, H-6b),
3.58 (dd, 1H, J = 2.5 Hz, J = 10.0 Hz, H-6ꢀb), 3.26 (dd, 1H, J =
1.9 Hz, J = 4.4 Hz, H-2ꢀ), 3.25 (dd, 1H, J = 1.9 Hz, J = 4.4 Hz,
H-2), 3.13 (dd, 1H, J = 1.7 Hz, J = 4.3 Hz, H-1ꢀ), 3.07 (dd, 1H,
J = 1.7 Hz, J = 4.3 Hz, H-1); 13C NMR (CDCl3, 100 MHz): d
Experimental
General
Solvents were freshly distilled from Na/benzophenone (THF,
toluene), or P2O5 (CH2Cl2). Reactions were carried under Ar,
unless otherwise stated. Melting points were recorded on a Bu¨chi
535 and are uncorrected. Optical rotations were measured on a
Perkin Elmer 241 digital polarimeter with a path length of 1 dm.
Mass spectra were recorded on a JMS-700 spectrometer, using
chemical ionisation with ammonia or methane. NMR spectra were
recorded on a Bru¨ker DRX-400 (400 MHz and 100.6 MHz, for
1H and 13C, respectively). TLC was performed on silica gel 60
F254 (Merck) and developed by charring with conc. H2SO4. Flash
column chromatography was performed using silica gel 60 (230–
400 mesh, Merck).
=
156.69, 156.34 (2 × C O), 138.25, 138.12, 137.97, 137.94, 137.81,
136.61 (Cipso), 128.41–127.58 (40 × aromatic C), 80.55, 80.43 (C-3,
C-3ꢀ), 76.06, 76.05 (C-4, C-4ꢀ), 75.20, 74.89, 73.59, 73.12, 73.08,
73.04 (6 × CH2Ph), 69.76, 69.62 (C-6, C-6ꢀ), 67.65, 67.49 (2 ×
NCOOCH2Ph), 57.66, 57.09 (C-5ꢀ, C-5), 57.43 (C-2, C-2ꢀ), 53.88,
53.80 (C-1ꢀ, C-1), 40.69, 40.62 (C-7, C-7ꢀ); m/z (CI, NH3): 580
(M + H+, 30%), 597 (M + NH4 , 100%); HRMS (CI, NH3):
+
Calcd for C36H38O6N (M + H+): 580.2699, Found 580.2703.
Compound 6. [a]D −1 (c = 1.1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.43–7.34 (m, 40H, 8 × Ph), 5.32–5.15 (m, 4H, 4 ×
NCOOCHPh), 4.87–4.73 (m, 8H, 6 × CHPh, H-5, H-7ꢀa), 4.65–
4.48 (m, 8H, 6 × CHPh, H-5ꢀ, H-7a), 4.04 (dd, 1H, J = 2.4 Hz,
J = 8.9 Hz H-3), 4.00 (dd, 1H, J = 2.8 Hz, J = 8.6 Hz, H-3ꢀ),
3.97 (dd, 1H, J = 3.9 Hz, J = 8.9 Hz, H-4), 3.86 (dd, 1H, J =
3.8 Hz, J = 8.3 Hz, H-4ꢀ), 3.85 (dd, 1H, J = 4.9 Hz, J = 10.2 Hz,
H-6a), 3.78 (dd, 1H, J = 5.2 Hz, J = 10.2 Hz, H-6ꢀa), 3.71 (t,
1H, J = 9.5 Hz, H-6b), 3.61 (t, 1H, J = 9.5 Hz, H-6ꢀb), 3.54 (d,
1H, J = 16.2 Hz, H-7b), 3.48 (d, 1H, J = 15.9 Hz, H-7ꢀb), 3.23
(dd, 2H, J = 2.6 Hz, J = 4.2 Hz, H-2, H-2ꢀ), 3.17 (t, 1H, J =
4.1 Hz, H-1ꢀ), 3.09 (t, 1H, J = 4.1 Hz, H-1); 13C NMR (CDCl3,
NOTE: For compounds 4–7, 10–13, 18–20, 26–27, 30–31
bearing a benzyloxycarbonyl group on nitrogen, NMR spectra
are provided for the mixture of rotamers.
Typical procedure for epoxidation
Azacycloheptene (330 mg, 0.586 mmol) was dissolved in dry
CH2Cl2 (10 mL) under argon and m-CPBA (560 mg, 3.256 mmol,
5.6 eq.) was added to the solution cooled at 0 ◦C. The r◦eaction
mixture was stirred at RT for 48 h and then cooled to 0 C and
quenched with Me2S (0.5 mL) stirring for 15 min at RT. The
reaction mixture was then diluted with AcOEt, washed with a
saturated aq. Na2CO3 solution and brine. The organic layer was
dried over MgSO4 and concentrated. Purification by flash column
chromatography (cyclohexane/AcOEt 4 : 1) afforded epoxide 4
(99 mg, 29% yield) as a colorless oil. Further elution afforded
epoxide 5 (181 mg, 53% yield) as a colorless oil.
=
100 MHz): d 156.29, 156.15 (2 × C O), 138.30, 138.29, 138.17,
138.14, 137.66, 137.58, 136.58, 136.30 (Cipso), 128.35–127.40 (40 ×
aromatic C), 78.72, 78.23 (C-4ꢀ, C-4), 77.13, 76.72 (C-3, C-3ꢀ),
73.43, 73.41, 72.95, 72.89, 72.86, 72.71 (6 × CH2Ph), 67.65, 67.31
(2 × NCOOCH2Ph), 64.74, 64.52 (C-6ꢀ, C-6), 54.89, 54.24 (C-
2, C-2ꢀ), 54.52, 54.15 (C-1ꢀ, C-1), 52.99, 52.66 (C-5ꢀ, C-5), 38.91,
38.88 (C-7ꢀ, C-7); m/z (CI, NH3): 580 (M + H+, 100%), 597 (M +
Compound 4. [a]D −63 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.39–7.30 (m, 40H, 8 × Ph), 5.24–5.10 (m, 4H, 4 ×
NCOOCHPh), 4.97–4.37 (12 × d, 12H, 12 × CHPh), 4.36 (dd,
1H, J = 6.3 Hz, J = 15.8 Hz, H-7a), 4.27 (m, 1H, H-5ꢀ), 4.22
(dd, 1H, J = 6.8 Hz, J = 17.0 Hz, H-7ꢀa), 4.11 (m, 1H, H-5),
3.91–3.80 (m, 5H, H-3, H-3ꢀ, H-4, H-4ꢀ, H-6ꢀa), 3.78 (dd, 1H, J =
4.8 Hz, J = 9.9 Hz, H-6a), 3.62 (dd, 1H, J = 2.8 Hz, J = 10.0 Hz,
H-6ꢀb), 3.58–3.52 (m, 2H, H-6b, H-1), 3.44–3.38 (m, 2H, H-7ꢀb,
H-1ꢀ), 3.36 (dd, 1H, J = 3.8 Hz, J = 16.2 Hz, H-7b), 3.30 (dd,
1H, J = 0.7 Hz, J = 4.5 Hz, H-2), 3.23 (dd, 1H, J = 0.8 Hz,
J = 4.4 Hz, H-2ꢀ); 13C NMR (CDCl3, 100 MHz): d 156.10, 155.79
NH4 , 65%); HRMS (CI, NH3): Calcd for C36H38O6N (M + H+):
+
580.2699, Found 580.2696.
Compound 7. [a]D +56 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.46–7.30 (m, 40H, 8 × Ph), 5.28–5.16 (m, 4H, 4 ×
NCOOCHPh), 5.06 (dt, 1H, J = 4.2 Hz, J = 8.1 Hz, H-5), 4.96–
4.43 (m, 14H, 12 × CHPh, H-5ꢀ, H-7ꢀa), 4.39 (dd, 1H, J = 5.5 Hz,
J = 15.3 Hz, H-7a), 3.91 (dd, 1H, J = 4.1 Hz, J = 10.7 Hz, H-6a),
3.90–3.75 (m, 6H, H-3, H-3ꢀ, H-4, H-4ꢀ, H-6ꢀa, H-6b), 3.72 (dd,
1H, J = 8.7 Hz, J = 10.2 Hz, H-6ꢀb), 3.48 (dt, 1H, J = 5.6 Hz, J =
7.4 Hz, H-1ꢀ), 3.35 (dt, 1H, J = 5.3 Hz, J = 8.2 Hz, H-1), 3.13 (t,
2H, J = 4.4 Hz, H-2, H-2ꢀ), 2.94 (dd, 1H, J = 8.2 Hz, J = 15.2 Hz,
H-7b), 2.93 (d, 1H, J = 7.4 Hz, J = 14.6 Hz, H-7ꢀb); 13C NMR
=
(2 × C O), 138.30, 138.24, 138.19, 138.02, 138.01, 137.90, 136.42,
136.25 (Cipso), 128.39–127.51 (40 × aromatic C), 80.01 (C-3, C-3ꢀ),
75.26, 74.95 (2 × CH2Ph), 74.44, 74.41 (C-4, C-4ꢀ), 74.33, 74.18,
73.05, 72.99 (4 × CH2Ph), 69.47, 69.41 (C-6, C-6ꢀ), 67.65, 67.47
(2 × NCOOCH2Ph), 57.21, 57.00 (C-5, C-5ꢀ), 56.10, 55.97 (C-2,
=
(CDCl3, 100 MHz): d 155.99, 155.69 (2 × C O), 138.14, 137.99,
137.90, 137.86, 137.82, 136.39, 136.23 (Cipso), 128.50–127.38 (40 ×
aromatic C), 78.59, 78.23 (C-3, C-3ꢀ), 77.15, 76.79 (C-4, C-4ꢀ),
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1653–1662 | 1657
©

View Online
74.31, 74.05, 72.84, 72.78, 72.72 (6 × CH2Ph), 67.57, 67.44 (2 ×
NCOOCH2Ph), 65.44, 65.22 (C-6, C-6ꢀ), 57.03, 56.86 (C-2, C-2ꢀ),
55.15, 54.15 (C-5ꢀ, C-5), 51.77, 51.40 (C-1ꢀ, C-1), 43.58, 43.36 (C-7,
1H, J = 3.8 Hz, J = 9.8 Hz, H-6ꢀb), 3.65 (m, 1H, H-4), 3.59 (dd,
1H, J = 3.7 Hz, J = 9.8 Hz, H-6b), 3.31 (dd, 1H, J = 8.7 Hz,
J = 14.5 Hz, H-7ꢀb), 3.13 (dd, 1H, J = 10.8 Hz, J = 15.0 Hz,
H-7b), 2.48 (s, 2H, OH, OHꢀ), 2.41 (m, 1H, H-2a), 2.30 (dd, 1H,
J = 3.9 Hz, J = 14.1 Hz, H-2ꢀa), 1.94 (ddd, 1H, J = 7.3 Hz,
J = 8.7 Hz, J = 14.1 Hz, H-2ꢀb), 1.86 (dt, 1H, J = 9.0 Hz, J =
14.0 Hz, H-2b); 13C NMR (CDCl3, 100 MHz): d 156.15, 155.94
C-7ꢀ); m/z (CI, NH3): 580 (M + H+, 100%), 597 (M + NH4 , 10%);
+
HRMS (CI, NH3): Calcd for C36H38O6N (M + H+): 580.2699,
Found 580.2698.
Compound 9. [a]D −101 (c = 1 in CHCl3); mp 175–176 ◦C
(ethyl acetate/cyclohexane); 1H NMR (CDCl3, 400 MHz): d 4.43–
4.37 (m, 3H, H-6a, H-6b, H-7a), 4.24–4.16 (m, 3H, H-3, H-4, H-5),
3.53 (d, 1H, J = 4.5 Hz, H-2), 3.49 (ddd, 1H, J = 1.4 Hz, J =
4.5 Hz, J = 5.8 Hz, H-1), 3.29 (dd, 1H, J = 1.4 Hz, J = 16.6 Hz,
H-7b), 1.50 (s, 3H, CH3), 1.48 (s, 3H, CH3); 13C NMR (CDCl3,
=
(2 × C O), 138.19, 138.15, 138.04, 137.98, 137.95, 136.59, 136.35
(Cipso), 128.47–127.56 (40 × aromatic C), 79.84, 79.40 (C-3ꢀ, C-
3), 78.93, 78.72 (C-4, C-4ꢀ), 74.34, 73.62, 73.13, 73.01, 72.97 (6 ×
CH2Ph), 69.50, 69.12 (C-6ꢀ, C-6), 68.40, 66.82 (C-1, C-1ꢀ), 67.51,
67.20 (2 × NCOOCH2Ph), 58.70, 58.19 (C-5, C-5ꢀ), 50.88, 50.26
(C-7ꢀ, C-7), 39.15, 37.56 (C-2, C-2ꢀ); m/z (CI, CH4): 582 (M +
H+, 100%); HRMS (CI, CH4): Calcd for C36H40O6N (M + H+):
582.2856, Found 582.2853.
=
100 MHz): d 157.57 (C O), 111.25 (C(CH3)2), 75.00 (C-3), 72.00
(C-4), 62.15 (C-6), 54.79 (C-2), 53.45 (C-1), 52.48 (C-5), 41.99 (C-
7), 26.84 (CH3), 26.63 (CH3); m/z (CI, NH3): 242 (M + H+, 55%),
+
259 (M + NH4 , 100%); HRMS (CI, CH4): Calcd for C11H16O5N
Compound 12. [a]D −4 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): 7.43–7.31 (m, 40H, 8 × Ph), 5.27–5.16 (m, 4H, 4 ×
NCOOCHPh), 5.14–4.35 (m, 12H, 12 × CHPh), 4.31 (dt, 1H, J =
2.6 Hz, J = 9.8 Hz, H-5), 4.14 (dt, 1H, J = 2.6 Hz, J = 9.6 Hz, H-
5ꢀ), 4.04 (dt, 1H, J = 3.3 Hz, J = 15.0 Hz, H-7ꢀa), 3.91 (dt, 1H, J =
3.3 Hz, J = 15.4 Hz, H-7a), 3.88–3.79 (m, 4H, H-4, H-4ꢀ, H-6a,
H-6ꢀa), 3.75–3.67 (m, 2H, H-2, H-2ꢀ), 3.69 (dd, 1H, J = 2.6 Hz, J =
9.8 Hz, H-6b), 3.60 (dd, 1H, J = 2.5 Hz, J = 9.7 Hz, H-6ꢀb), 3.50
(t, 1H, J = 9.0 Hz, H-3), 3.44 (t, 1H, J = 9.0 Hz, H-3ꢀ), 3.24 (s, 1H,
OH), 3.20–3.07 (m, 3H, H-7b, H-7ꢀb, OHꢀ), 2.12–2.05 (m, 2H, H-
1a, H-1ꢀa), 1.78–1.63 (m, 2H, H-1b, H-1ꢀb); 13C NMR (CDCl3, 100
(M + H+): 242.1028, Found 242.1026.
R
Typical procedure for epoxide ring opening with Super-Hydrideꢀ
Epoxide 4 (50 mg, 0.086 mmol) was dissolved in dry THF
◦
R
(0.4 mL) and the solution was cooled to 0 C. Super-Hydrideꢀ
(0.6 mL, 0.6 mmol, 1M solution in THF) was added and the
reaction mixture was stirred at RT for 16 h by which time
TLC (cyclohexane/AcOEt 2:1) showed a complete reaction. The
reaction mixture was diluted with AcOEt and washed with 1 M
aq. HCl solution, water and brine. The organic layer was dried
over MgSO4 and concentrated. Purification by flash column
chromatography (cyclohexane/AcOEt 4 : 1) afforded alcohol 10
(20 mg, 40% yield) as a colorless oil. Further elution afforded
alcohol 11 (15 mg, 30% yield) as a colorless oil.
=
MHz): d 155.87, 155.42 (2 × C O), 138.14, 138.10, 138.02, 137.98,
137.84, 136.55, 136.48 (Cipso), 128.58–127.49 (40 × aromatic C),
86.09, 85.91 (C-3ꢀ, C-3), 77.50, 77.34 (C-4ꢀ, C-4), 76.13, 76.07,
75.56, 75.31, 73.12, 73.06 (6 × CH2Ph), 73.29, 73.04 (C-2ꢀ, C-2),
70.06, 69.83 (C-6ꢀ, C-6), 67.34, 67.33 (2 × NCOOCH2Ph), 57.82,
57.78 (C-5ꢀ, C-5), 40.10, 39.95 (C-7ꢀ, C-7), 33.06, 32.44 (C-1, C-1ꢀ);
m/z (CI, CH4): 582 (M + H+, 100%); HRMS (CI, CH4): Calcd for
C36H40O6N (M + H+): 582.2856, Found 582.2850.
Compound 10. [a]D −27 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.39–7.28 (m, 40H, 8 × Ph), 5.20–5.08 (m, 4H, 4 ×
NCOOCHPh), 4.93–4.37 (m, 12H, 12 × CHPh), 4.29 (t, 1H, J =
9.4 Hz, H-4), 4.26 (t, 1H, J = 9.3 Hz, H-4ꢀ), 4.25–4.18 (m, 3H,
H-2, H-2ꢀ, H-5), 4.09 (dt, 1H, J = 3.5 Hz, J = 9.2 Hz, H-5ꢀ), 3.85
(dd, 1H, J = 4.3 Hz, J = 9.8 Hz, H-6a), 3.79 (m, 1H, H-7ꢀa), 3.76
(dd, 1H, J = 4.3 Hz, J = 9.8 Hz, H-6ꢀa), 3.68 (dd, 1H, J = 2.8 Hz,
J = 9.8 Hz, H-6b), 3.65 (m, 1H, H-7a), 3.63 (dd, 1H, J = 1.5 Hz,
J = 8.6 Hz, H-3), 3.59 (dd, 1H, J = 2.8 Hz, J = 9.8 Hz, H-6ꢀb),
3.58 (dd, 1H, J = 1.8 Hz, J = 9.8 Hz, H-3ꢀ), 3.35 (ddd, 1H, J =
1.6 Hz, J = 11.5 Hz, J = 13.7 Hz, H-7b), 3.27 (ddd, 1H, J =
3.2 Hz, J = 10.7 Hz, J = 14.2 Hz, H-7ꢀb), 2.51 (s, 2H, OH, OHꢀ),
1.92–1.71 (m, 4H, H-1a, H-1ꢀa, H-1b, H-1ꢀb); 13C NMR (CDCl3,
Compound 13. [a]D −43 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.39–7.28 (m, 40H, 8 × Ph), 5.24–5.06 (m, 4H, 4 ×
NCOOCHPh), 4.88–4.36 (m, 12H, 12 × CHPh), 4.27 (m, 1H, H-
5ꢀ), 4.25 (dt, 1H, J = 4.0 Hz, J = 7.8 Hz, H-5), 4.16–4.05 (m, 3H,
H-1, H-1ꢀ, H-7a), 3.95 (dd, 1H, J = 5.3 Hz, J = 9.9 Hz, H-6ꢀa), 3.91
(dd, 1H, J = 1.9 Hz, J = 7.9 Hz, H-3), 3.87 (dd, 1H, J = 2.1 Hz,
J = 6.9 Hz, H-3ꢀ), 3.84–3.79 (m, 2H, H-4ꢀ, H-7ꢀa), 3.78 (dd, 1H, J =
4.4 Hz, J = 9.8 Hz, H-6a), 3.71 (dd, 1H, J = 4.5 Hz, J = 10.0 Hz,
H-6ꢀb), 3.70 (t, 1H, J = 7.8 Hz, H-4), 3.61 (dd, 1H, J = 3.6 Hz, J =
9.8 Hz, H-6b), 3.58 (dd, 1H, J = 2.8 Hz, J = 14.1 Hz, H-7ꢀb), 3.47
(s, 1H, OH), 3.41 (dd, 1H, J = 2.6 Hz, J = 15.9 Hz, H-7b), 2.27
(ddd, 1H, J = 1.7 Hz, J = 6.2 Hz, J = 14.2 Hz, H-2a), 2.15 (ddd,
1H, J = 1.6 Hz, J = 6.5 Hz, J = 14.2 Hz, H-2ꢀa), 2.06 (s, 1H, OHꢀ),
1.98 (ddd, 1H, J = 4.0 Hz, J = 8.6 Hz, J = 14.3 Hz, H-2ꢀb), 1.92
(ddd, 1H, J = 4.1 Hz, J = 9.6 Hz, J = 14.1 Hz, H-2b); 13C NMR
=
100 MHz): d 155.88, 155.67 (2 × C O), 138.34, 138.25, 138.20,
138.11, 136.70, 136.58 (Cipso), 128.46–127.45 (40 × aromatic C),
84.05, 83.99 (C-3, C-3ꢀ), 75.07, 74.72, 74.15, 74.04, 72.97, 72.92
(6 × CH2Ph), 73.71, 73.55 (C-4ꢀ, C-4), 69.93, 69.69 (C-6ꢀ, C-6),
69.58, 69.47 (C-2, C-2ꢀ), 67.21, 67.10 (2 × NCOOCH2Ph), 58.01,
57.76 (C-5ꢀ, C-5), 39.44, 39.24 (C-7, C-7ꢀ), 32.84, 32.04 (C-1, C-1ꢀ);
m/z (CI, CH4): 582 (M + H+, 100%); HRMS (CI, CH4): Calcd for
C36H40O6N (M + H+): 582.2856, Found 582.2849.
=
(CDCl3, 100 MHz): d 159.04 (2 × C O), 138.52, 138.20, 138.11,
137.95, 136.15, 136.09 (Cipso), 128.64–127.50 (40 × aromatic C),
80.43, 79.61 (C-4, C-4ꢀ), 77.73, 77.46 (C-3, C-3ꢀ), 74.24, 73.76,
73.04, 73.01, 72.97, 72.63 (6 × CH2Ph), 69.42, 69.16 (C-6, C-6ꢀ),
67.98, 67.53 (2 × NCOOCH2Ph), 67.68, 66.70 (C-1, C-1ꢀ), 58.79,
57.68 (C-5ꢀ, C-5), 50.33, 49.02 (C-7ꢀ, C-7), 38.50, 38.00 (C-2, C-2ꢀ);
m/z (CI, CH4): 582 (M + H+, 100%); HRMS (CI, CH4): Calcd for
C36H40O6N (M + H+): 582.2856, Found 582.2851.
Compound 11. [a]D −20 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.38–7.28 (m, 40H, 8 × Ph), 5.19–5.07 (m, 4H, 4 ×
NCOOCHPh), 4.86–4.37 (m, 12H, 12 × CHPh), 4.31 (m, 1H,
H-5ꢀ), 4.23 (dt, 1H, J = 4.4 Hz, J = 8.1 Hz, H-5), 4.00–3.88 (m,
5H, H-1, H-1ꢀ, H-4ꢀ, H-6ꢀa, H-7a), 3.85 (dd, 1H, J = 4.7 Hz, J =
14.6 Hz, H-7ꢀa), 3.81–3.72 (m, 3H, H-3, H-3ꢀ, H-6a), 3.68 (dd,
1658 | Org. Biomol. Chem., 2006, 4, 1653–1662
This journal is
The Royal Society of Chemistry 2006
©

View Online
Compound 18. [a]D +25 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.38–7.29 (m, 40H, 8 × Ph), 5.29–5.03 (m, 4H, 4 ×
NCOOCHPh), 4.76 (dt, 1H, J = 5.2 Hz, J = 10.2 Hz, H-5ꢀ), 4.71–
4.40 (m, 13H, 12 × CHPh, H-5), 4.25 (dd, 1H, J = 5.2 Hz, J =
7.4 Hz, H-4ꢀ), 4.21 (m, 2H, H-2, H-2ꢀ), 4.17 (dd, 1H, J = 5.1 Hz,
J = 7.4 Hz, H-4), 4.08 (dd, 1H, J = 2.7 Hz, J = 7.5 Hz, H-3), 4.05
(dd, 1H, J = 2.6 Hz, J = 7.4 Hz, H-3ꢀ), 3.83–3.76 (m, 1H, H-7a),
3.79 (t, 1H, J = 9.0 Hz, H-6ꢀa), 3.74 (t, 1H, J = 9.2 Hz, H-6a),
3.69 (m, 1H, H-7ꢀa), 3.59 (dd, 1H, J = 5.5 Hz, J = 8.9 Hz, H-6ꢀb),
3.48 (dd, 1H, J = 5.5 Hz, J = 8.9 Hz, H-6b), 3.19–3.10 (m, 2H,
H-7b, H-7ꢀb), 1.97–1.76 (m, 4H, H-1a, H-1ꢀa, H-1b, H-1ꢀb), 1.71
(s, 2H, OH, OHꢀ); 13C NMR (CDCl3, 100 MHz): d 155.71, 155.49
(6 × CH2Ph), 67.84, 67.39 (C-6, C-6ꢀ), 67.37, 66.23 (C-1ꢀ, C-1),
67.16, 66.92 (2 × NCOOCH2Ph), 54.38, 54.31 (C-5ꢀ, C-5), 50.18,
49.46 (C-7ꢀ, C-7), 34.43, 33.29 (C-2ꢀ, C-2); m/z (CI, CH4): 582
(M + H+, 100%); HRMS (CI, CH4): Calcd for C36H40O6N (M +
H+): 582.2856, Found 582.2847.
Typical procedure for trans diol formation
Epoxide opening with sodium nitrite. Epoxide 4 (90 mg,
0.155 mmol) and NaNO2 (381 mg, 5.52 mmol) were suspended in
a DMF/water (1.3 mL/0.4 mL) solution and the suspension was
stirred at 90 ◦C for 48 h by which time TLC (cyclohexane/AcOEt
1 : 1) showed a complete reaction. The reaction mixture was then
diluted with AcOEt, washed with water and brine. The organic
layer was dried over MgSO4 and concentrated. Purification by
flash column chromatography (cyclohexane/AcOEt 3 : 2) afforded
diol 26 (19 mg, 16% yield) as a colorless oil. Further elution
afforded diol 27 (13 mg, 14% yield) as a colorless oil.
=
(2 × C O), 138.34, 138.18, 138.02, 137.98, 137.92, 137.84, 137.00,
136.88 (Cipso), 128.48–127.49 (40 × aromatic C), 81.07, 80.96 (C-3,
C-3ꢀ), 74.78, 74.62 (C-4ꢀ, C-4), 74.16, 74.03, 73.85, 73.11, 73.06
(6 × CH2Ph), 69.66, 69.39 (C-2, C-2ꢀ), 67.80, 67.38 (C-6, C-6ꢀ),
67.03, 66.93 (2 × NCOOCH2Ph), 54.92, 54.84 (C-5ꢀ, C-5), 39.51,
39.12 (C-7, C-7ꢀ), 34.10, 33.36 (C-1ꢀ, C-1); m/z (CI, CH4): 582
(M + H+, 100%); HRMS (CI, CH4): Calcd for C36H40O6N (M +
H+): 582.2856, Found 582.2853.
Epoxide opening with sulfuric acid. Epoxide
4 (9 mg,
0.015 mmol) was dissolved in 15% aq. H2SO4/DMF (0.08 mL,
0.5 mL) and the solution was stirred at RT for 48 h. The
reaction mixture was then diluted with AcOEt, washed with
aq. saturated NaHCO3, water and brine. The organic layer was
dried over MgSO4 and concentrated. Purification by flash column
chromatography (cyclohexane/AcOEt 3 : 2) afforded diol 26
(3 mg, 28% yield) as a colorless oil. Further elution afforded diol
27 (traces) as a colorless oil.
Compound 19. [a]D +16 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.39–7.27 (m, 40H, 8 × Ph), 5.25–5.06 (m, 4H, 4 ×
NCOOCHPh), 4.81 (dt, 1H, J = 5.0 Hz, J = 9.9 Hz, H-5ꢀ), 4.71
(dt, 1H, J = 5.4 Hz, J = 10.0 Hz, H-5), 4.78–4.43 (m, 12H, 12 ×
CHPh), 4.29 (dd, 1H, J = 4.9 Hz, J = 7.0 Hz, H-4ꢀ), 4.24 (m, 1H,
H-7ꢀa), 4.22 (dd, 1H, J = 5.1 Hz, J = 6.9 Hz, H-4), 4.18 (dd, 1H,
J = 5.4 Hz, J = 15.5 Hz, H-7a), 4.17–4.10 (m, 2H, H-1, H-3), 4.06
(ddd, 1H, J = 2.0 Hz, J = 5.0 Hz, J = 6.8 Hz, H-3ꢀ), 4.00 (m, 1H,
H-1ꢀ), 3.87 (t, 1H, J = 8.8 Hz, H-6ꢀa), 3.81 (t, 1H, J = 9.2 Hz,
H-6a), 3.73 (dd, 1H, J = 5.2 Hz, J = 8.7 Hz, H-6ꢀb), 3.59 (dd, 1H,
J = 5.6 Hz, J = 8.9 Hz, H-6b), 3.51 (d, 1H, J = 6.7 Hz, OH), 3.42
(d, 1H, J = 13.8 Hz, H-7ꢀb), 3.38 (d, 1H, J = 14.1 Hz, H-7b), 3.08
(d, 1H, J = 9.9 Hz, OHꢀ), 2.27 (m, 1H, H-2a), 2.13 (m, 1H, H-2ꢀa),
2.07–1.98 (m, 2H, H-2b, H-2ꢀb); 13C NMR (CDCl3, 100 MHz): d
Compound 26. [a]D −39 (c = 0.95 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.39–7.22 (m, 40H, 8 × Ph), 5.22–5.01 (m, 4H, 4 ×
CHPh), 4.82–4.36 (m, 12H, 12 × CHPh), 4.21 (dt, 1H, J = 4.3 Hz,
7.3 Hz, H-5), 4.16 (app. d, 1H, J = 3.8 Hz, H-2), 4.09 (m, 1H, H-
5ꢀ), 4.07 (t, 1H, J = 7.8 Hz, H-4), 4.01 (app. dd, 1H, J = 3.0 Hz,
J = 15.7 Hz, H-7a), 4.01–3.89 (m, 6H, H-1, H-1ꢀ, H-2ꢀ, H-3ꢀ, H-4ꢀ,
H-7ꢀa), 3.88 (dd, 1H, J = 1.3 Hz, J = 8.1 Hz, H-3), 3.77 (dd,
1H, J = 4.7 Hz, J = 9.8 Hz, H-6a), 3.75 (s, 1H, OH-1), 3.74–3.69
(m, 2H, H-6ꢀa, H-6ꢀb), 3.63 (m, 1H, H-7ꢀb), 3.60 (dd, 1H, J =
3.8 Hz, J = 9.8 Hz, H-6b), 3.54 (dd, 1H, J = 1.7 Hz, J = 15.4 Hz,
H-7b), 2.66 (s, 1H, OH-2), 2.62 (s, 1H, OH-1ꢀ), 2.42 (d, 1H, J =
=
157.82, 156.52 (2 × C O), 138.36, 138.09, 138.08, 138.02, 137.91,
137.56, 136.92, 136.55 (Cipso), 128.35–127.49 (40 × aromatic C),
77.16, 76.95 (C-3ꢀ, C-3), 76.59, 76.09 (C-4, C-4ꢀ), 73.83, 73.72,
73.09, 73.06, 72.16, 71.61 (6 × CH2Ph), 70.35, 69.43 (C-1, C-1ꢀ),
67.52, 67.11 (2 × NCOOCH2Ph), 67.51, 67.01 (C-6, C-6ꢀ), 55.26,
55.18 (C-5, C-5ꢀ), 47.64, 47.51 (C-7ꢀ, C-7), 33.21, 32.49 (C-2ꢀ, C-2);
m/z (CI, CH4): 582 (M + H+, 100%); HRMS (CI, CH4): Calcd for
C36H40O6N (M + H+): 582.2856, Found 582.2861.
ꢀ
13
=
3.3 Hz, OH-2 ); C NMR (CDCl3, 100 MHz): d 159.22 (2 × C O),
138.20, 138.13, 137.93, 137.90, 135.96 (Cipso), 128.62–127.50 (40 ×
aromatic C), 81.56, 81.40 (C-3, C-3ꢀ), 74.24, 73.94, 73.48, 72.93,
72.91 (6 × CH2Ph), 73.82 (C-4, C-4ꢀ), 73.61, 73.39 (C-2, C-2ꢀ),
72.41, 70, 77 (C-1, C-1ꢀ), 68.97, 68.89 (C-6, C-6ꢀ), 68.06, 67.50 (2 ×
NCOOCH2Ph), 59.58, 57.71 (C-5, C-5ꢀ), 46.94, 44.91 (C-7, C-7ꢀ);
m/z (CI, NH3): 598 (M + H+, 100%); HRMS (CI, CH4): Calcd
for C36H40O7N (M + H+): 598.2805, Found 598.2798.
Compound 20. [a]D −1 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): 7.39–7.30 (m, 40H, 8 × Ph), 5.30–5.03 (m, 4H, 4 ×
NCOOCHPh), 4.81 (dt, 1H, J = 5.5 Hz, J = 10.2 Hz, H-5ꢀ), 4.66–
4.40 (m, 13H, 12 × CHPh, H-5), 4.25 (dd, 1H, J = 5.4 Hz, J =
6.9 Hz, H-4ꢀ), 4.19 (dd, 1H, J = 5.4 Hz, J = 6.8 Hz, H-4), 4.14 (m,
1H, H-1), 4.05 (ddd, 1H, J = 1.6 Hz, J = 5.1 Hz, J = 6.8 Hz, H-3),
4.02 (m, 1H, H-1ꢀ), 3.99 (ddd, 1H, J = 1.7 Hz, J = 5.0 Hz, J =
6.9 Hz, H-3ꢀ), 3.89–3.78 (m, 4H, H-6a, H-6ꢀa, H-7a, H-7ꢀa), 3.69
(dd, 1H, J = 5.8 Hz, J = 8.9 Hz, H-6ꢀb), 3.58 (dd, 1H, J = 5.7 Hz,
J = 8.9 Hz, H-6b), 3.39 (dd, 1H, J = 9.2 Hz, J = 13.1 Hz, H-7b),
3.37 (dd, 1H, J = 9.9 Hz, J = 13.8 Hz, H-7bꢀ), 3.18 (s, 1H, OH),
2.34 (m, 1H, H-2a), 2.29–2.20 (m, 2H, H-2ꢀa, OHꢀ), 2.05–1.92 (m,
2H, H-2b, H-2ꢀb); 13C NMR (CDCl3, 100 MHz): d 156.10, 155.63
Compound 27. [a]D +3 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.42–7.30 (m, 40H, 8 × Ph), 5.27–5.12 (m, 4H, 4 ×
NCOOCHPh), 5.11–4.32 (m, 12H, 12 × CHPh), 4.25 (dt, 1H, J =
2.5 Hz, J = 9.8 Hz, H-5), 4.08 (dt, 1H, J = 2.5 Hz, J = 9.6 Hz,
H-5ꢀ), 4.03 (dd, 1H, J = 3.7 Hz, J = 14.5 Hz, H-7ꢀa), 3.93 (dd, 1H,
J = 3.6 Hz, J = 14.9 Hz, H-7a), 3.87 (t, 1H, J = 9.5 Hz, H-4ꢀ), 3.84
(t, 1H, J = 9.4 Hz, H-4), 3.79 (dd, 1H, J = 3.1 Hz, J = 9.9 Hz,
H-6a), 3.74 (dd, 1H, J = 3.3 Hz, J = 9.7 Hz, H-6ꢀa), 3.68 (m, 1H,
H-1ꢀ), 3.64 (dd, 1H, J = 2.4 Hz, J = 9.8 Hz, H-6b), 3.62 (m, 1H,
H-1), 3.56 (dd, 1H, J = 2.5 Hz, J = 9.7 Hz, H-6ꢀb), 3.51 (t, 1H,
J = 9.0 Hz, H-2ꢀ), 3.51–3.44 (m, 2H, H-2, H-3), 3.42 (t, 1H, J =
9.2 Hz, H-3ꢀ), 3.25 (s, 1H, OH-2), 3.22 (dd, 1H, J = 10.3 Hz, J =
=
(2 × C O), 138.30, 138.25, 138.12, 138.06, 137.93, 136.87, 136.56
(Cipso), 128.35–127.09 (40 × aromatic C), 76.35, 76.21 (C-4ꢀ, C-4),
73.94, 73.82 (C-3, C-3ꢀ), 73.75, 73.61, 73.00, 72.97, 71.28, 71.12
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1653–1662 | 1659
©

View Online
14.8 Hz, H-7b), 3.21 (s, 1H, OH-2ꢀ), 3.16 (dd, 1H, J = 11.5 Hz,
J = 14.5 Hz, H-7ꢀb), 2.79 (d, 1H, J = 2.0 Hz, OH-1ꢀ), 2.69 (d,
1H, J = 1.5 Hz, OH-1); 13C NMR (CDCl3, 100 MHz): d 155.85,
J = 7.5 Hz, H-4), 3.88 (dd, 1H, J = 2.0 Hz, J = 7.5 Hz, H-3),
3.84 (dd, 1H, J = 7.5 Hz, J = 12.2 Hz, H-6b), 3.53 (ddd, 1H,
J = 5.3 Hz, J = 7.7 Hz, J = 13.5 Hz, H-7a), 3.35 (ddd, 1H, J =
3.9 Hz, J = 7.5 Hz, J = 7.5 Hz, H-5), 3.22 (ddd, 1H, J = 5.0 Hz,
J = 7.7 Hz, J = 13.5 Hz, H-7b), 2.24 (dddd, 1H, J = 5.3 Hz,
J = 7.5 Hz, J = 9.3 Hz, J = 15.5 Hz, H-1a), 2.07 (dddd, 1H, J =
2.8 Hz, J = 5.0 Hz, J = 7.7 Hz, J = 15.5 Hz, H-1b); 13C NMR
(D2O, 100 MHz): d 77.04 (C-3), 68.41 (C-4), 68.30 (C-2), 62.24
(C-5), 60.27 (C-6), 42.35 (C-7), 26.45 (C-1); m/z (CI, NH3): 178
(M + H+, 100%); HRMS (CI, NH3): Calcd for C7H16O4N (M +
H+): 178.1079, Found 178.1074.
=
155.64 (2 × C O), 137.97, 137.95, 137.85, 137.83, 137.68, 136.33,
136.30 (Cipso), 128.63–127.56 (40 × aromatic C), 82.42, 82.24 (C-
3ꢀ, C-3), 79.01, 78.94 (C-2ꢀ, C-2), 77.34, 77.25 (C-4ꢀ, C-4), 76.31,
76.22, 75.69, 75.44, 73.17, 73.11 (6 × CH2Ph), 71.80, 70.98 (C-1,
C-1ꢀ), 69.72, 69.51 (C-6ꢀ, C-6), 67.63, 67.50 (2 × NCOOCH2Ph),
58.14, 58.05 (C-5ꢀ, C-5), 45.17, 44.90 (C-7ꢀ, C-7); m/z (CI, CH4):
598 (M + H+, 100%); HRMS (CI, CH4): Calcd for C36H40O7N
(M + H+): 598.2805, Found 598.2797.
Compound 30. [a]D +7 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.38–7.28 (m, 40H, × Ph), 5.28–5.00 (m, 4H, 4 ×
NCOOCHPh), 4.73–4.40 (m, 14H, H-5, H-5ꢀ, 12 × CHPh), 4.25
(dd, 1H, J = 5.3 Hz, J = 7.3 Hz, H-4ꢀ), 4.13 (m, 2H, H-3, H-4),
4.04 (dd, 1H, J = 2.8 Hz, J = 7.3 Hz, H-3ꢀ), 3.99 (app. dd, 1H, J =
2.0 Hz, J = 8.0 Hz, H-2), 3.94–3.86 (m, 2H, H-1, H-2ꢀ), 3.84–3.70
(m, 5H, H-1ꢀ, H-6a, H-6ꢀa, H-7a, H-7ꢀa), 3.61 (dd, 1H, J = 5.5 Hz,
J = 8.8 Hz, H-6ꢀb), 3.51 (dd, 1H, J = 5.5 Hz, J = 8.9 Hz, H-6b),
3.39 (s, 1H, OH-1), 3.28 (dd, 1H, J = 10.3 Hz, J = 13.8 Hz, H-
7ꢀb), 3.27 (dd, 1H, J = 10.2 Hz, J = 13.9 Hz, H-7b), 2.72 (s, 2H,
OH-1ꢀ, OH-2), 2.44 (d, 1H, J = 9.1 Hz, OH-2ꢀ); 13C NMR (CDCl3,
Compound 15. [a]D +5 (c = 0.45 in CH3OH);1H NMR (D2O,
400 MHz): d 4.36 (app. tt, 1H, J = 4.7 Hz, J = 9.3 Hz, H-1), 4.06
(dd, 1H, J = 3.6 Hz, J = 12.3 Hz, H-6a), 3.86 (dd, 1H, J = 7.5 Hz,
J = 12.3 Hz, H-6b), 3.84 (ddd, 1H, J = 2.9 Hz, J = 8.7 Hz, J =
9.2 Hz, H-3), 3.71 (t, 1H, J = 8.7 Hz, H-4), 3.42 (dd, 1H, J =
4.7 Hz, J = 14.3 Hz, H-7a), 3.37 (dd, 1H, J = 4.2 Hz, J = 14.3 Hz,
H-7b), 3.26 (ddd, 1H, J = 3.6 Hz, J = 7.5 Hz, J = 8.8 Hz, H-
5), 2.37 (ddd, 1H, J = 2.9 Hz, J = 5.1 Hz, J = 14.8 Hz, H-2a),
1.94 (dt, 1H, J = 9.3 Hz, J = 14.8 Hz, H-2b); 13C NMR (D2O,
100 MHz): d 72.39 (C-4), 70.49 (C-3), 63.35 (C-1), 62.76 (C-5),
59.96 (C-6), 51.84 (C-7), 37.08 (C-2); m/z (CI, NH3): 178 (M +
H+, 100%); HRMS (CI, NH3): Calcd for C7H16O4N (M + H+):
178.1079, Found 178.1082.
=
100 MHz): d 155.97, 155.61 (2 × C O), 138.18, 138.09, 138.04,
137.69, 137.63, 137.57, 136.76, 136.47 (Cipso), 128.48–127.45 (40 ×
aromatic C), 78.54, 78.26 (C-3ꢀ, C-3), 74.93, 74.82 (C-2ꢀ, C-2),
74.59, 74.33 (C-4, C-4ꢀ), 74.16, 74.10, 73.91, 73.86, 73.11, 73.00
(6 × CH2Ph), 72.21, 71.02 (C-1, C-1ꢀ), 67.64, 67.19 (C-6, C-6ꢀ),
67.33, 67.06 (2 × NCOOCH2Ph), 54.10, 53.84 (C-5ꢀ, C-5), 44.58,
44.40 (C-7, C-7ꢀ); m/z (CI, CH4): 598 (M + H+, 100%); HRMS (CI,
CH4): Calcd for C36H40O7N (M + H+): 598.2805, Found 598.2800.
Compound 31. [a]D +15 (c = 1 in CHCl3);1H NMR (CDCl3,
400 MHz): d 7.39–7.26 (m, 40H, 8 × Ph), 5.26–5.13 (m, 4H, 4 ×
NCOOCHPh), 4.75–4.48 (m, 14H, H-5, H-5ꢀ, 12 × CHPh), 4.23
(app. t, 1H, J = 4.8 Hz, H-4ꢀ), 4.15 (app. t, 1H, J = 4.6 Hz, H-4),
4.07 (m, 1H, H-7ꢀa), 4.04 (m, 1H, H-7a), 3.93–3.73 (m, 10H, H-1,
H-1ꢀ, H-2, H-2ꢀ, H-3, H-3ꢀ, H-6a, H-6ꢀa, H-6ꢀb, H-7b), 3.69 (m, 1H,
H-7ꢀb), 3.60 (m, 2H, H-6b, OH), 3.22 (s, 1H, OH), 2.77 (d, 1H, J =
6.1 Hz, OH), 1.85 (s, 1H, OH); 13C NMR (CDCl3, 100 MHz): d
Compound 16. [a]D +20 (c = 1 in CH3OH);1H NMR (D2O,
400 MHz): d 3.99 (dd, 1H, J = 3.8 Hz, J = 12.5 Hz, H-6a), 3.93
(dd, 1H, J = 6.3 Hz, J = 12.5 Hz, H-6b), 3.80 (ddd, 1H, J =
3.4 Hz, J = 7.6 Hz, J = 9.3 Hz, H-2), 3.75 (dd, 1H, J = 8.4 Hz,
J = 9.4 Hz, H-4), 3.58 (t, 1H, J = 8.1 Hz, H-3), 3.50 (ddd, 1H, J =
3.8 Hz, J = 6.3 Hz, J = 9.4 Hz, H-5), 3.42 (ddd, 1H, J = 3.7 Hz,
J = 6.6 Hz, J = 13.9 Hz, H-7a), 3.31 (ddd, 1H, J = 3.6 Hz, J =
9.6 Hz, J = 13.9 Hz, H-7b), 2.14 (ddt, 1H, J = 3.6 Hz, J = 6.6 Hz,
J = 15.8 Hz, H-1a), 2.06 (dddd, 1H, J = 3.7 Hz, J = 9.5 Hz, J =
9.5 Hz, J = 15.8 Hz, H-1b); 13C NMR (D2O, 100 MHz): d 78.87
(C-3), 71.33 (C-2), 69.28 (C-4), 59.15 (C-6), 58.56 (C-5), 40.76 (C-
7), 27.86 (C-1); m/z (CI, NH3): 178 (M + H+, 100%); HRMS (CI,
NH3): Calcd for C7H16O4N (M + H+): 178.1079, Found 178.1074.
Compound 17. [a]D +17 (c = 0.6 in CH3OH);1H NMR (D2O,
400 MHz): d 4.37 (app. tt, 1H, J = 3.4 Hz, J = 6.5 Hz, H-1), 4.06
(ddd, 1H, J = 2.6 Hz, J = 8.5 Hz, J = 9.9 Hz, 1H, H-3), 4.04 (dd,
1H, J = 3.6 Hz, J = 12.5 Hz, H-6a), 3.89 (dd, 1H, J = 7.6 Hz, J =
12.5 Hz, H-6b), 3.67 (t, 1H, J = 8.3 Hz, H-4), 3.51 (dd, 1H, J =
3.5 Hz, J = 13.9 Hz, H-7a), 3.41 (ddd, 1H, J = 3.7 Hz, J = 7.8 Hz,
J = 7.8 Hz, H-5), 3.19 (dd, 1H, J = 6.6 Hz, J = 13.9 Hz, H-7b),
2.27 (ddd, 1H, J = 2.7 Hz, J = 6.3 Hz, J = 14.9 Hz, H-2a), 1.98
(ddd, 1H, J = 3.2 Hz, J = 9.9 Hz, J = 14.9 Hz, H-2b); 13C NMR
(D2O, 100 MHz): d 71.66 (C-4), 68.24 (C-3), 62.46 (C-1), 61.87
(C-5), 59.61 (C-6), 49.21 (C-7), 37.71 (C-2); m/z (CI, NH3): 178
(M + H+, 100%); HRMS (CI, NH3): Calcd for C7H16O4N (M +
H+): 178.1079, Found 178.1076.
=
157.48, 156.18 (2 × C O), 137.95, 137.76, 137.28, 136.91, 136.52,
136.27 (Cipso), 128.54–127.57 (40 × aromatic C), 79.06, 78.94 (C-3,
C-3ꢀ), 77.99, 77.89 (C-4, C-4ꢀ), 75.14, 74.18 (C-1, C-1ꢀ), 74.46, 74.33
(2 × CH2Ph), 73.82, 72.88 (C-2, C-2ꢀ), 73.29, 73.12, 73.09, 72.95
(4 × CH2Ph), 67.75, 67.39 (2 × NCOOCH2Ph), 66.93, 66.37 (C-6,
C-6ꢀ), 54.73, 54.68 (C-5ꢀ, C-5), 45.58, 44.62 (C-7, C-7ꢀ); m/z (CI,
NH3): 598 (M + H+, 100%), 615 (M + NH4 , 20%); HRMS (CI,
+
CH4): Calcd for C36H40O7N (M + H+): 598.2805, Found 598.2803.
Typical procedure for hydrogenolysis
Compound 10 (20 mg, 0.034 mmol) was dissolved in CH3OH
(2 mL) and a 1 M HCl aq. solution (0.08 mL) was added followed
by 10% Pd/C (20 mg). The suspension was hydrogenated for 16 h,
filtered through a 0.45 lM rotilaboꢀ filter eluted with CH3OH
Compound 22. [a]D −1 (c = 0.65 in CH3OH);1H NMR (D2O,
400 MHz): d 4.09–4.05 (m, 2H, H-2, H-3), 3.97 (d, 1H, J = 4.9 Hz,
H-4), 3.87–3.71 (m, 3H, H-5, H-6a, H-6b), 3.40 (dt, 1H, J = 4.6 Hz,
J = 13.6 Hz, H-7a), 3.33 (ddd, 1H, J = 3.6 Hz, J = 10.8 Hz, J =
13.6 Hz, H-7b), 2.30 (dddd, 1H, J = 4.4 Hz, J = 10.8 Hz, J =
10.8 Hz, J = 15.4 Hz, H-1a), 1.87 (m, 1H, H-1b); 13C NMR (D2O,
100 MHz): d 72.58 (C-3), 69.46 (C-2), 67.92 (C-4), 60.97 (C-6),
R
and concentrated to afford the corresponding polyhydroxylated
azepane 14 as an oil.
Compound 14. [a]D +4 (c = 0.6 in CH3OH);1H NMR (D2O,
400 MHz): d 4.31 (ddd, 1H, J = 2.0 Hz, J = 2.7 Hz, J = 9.3 Hz,
H-2), 4.02 (dd, 1H, J = 3.9 Hz, J = 12.2 Hz, H-6a), 3.93 (t, 1H,
1660 | Org. Biomol. Chem., 2006, 4, 1653–1662
This journal is
The Royal Society of Chemistry 2006
©

View Online
54.78 (C-5), 41.81 (C-7), 25.56 (C-1); m/z (CI, NH3): 178 (M +
H+, 100%); HRMS (CI, NH3): Calcd for C7H16O4N (M + H+):
178.1079, Found 178.1077.
J = 7.3 Hz, J = 12.5 Hz, H-6b), 3.87 (t, 1H, J = 9.1 Hz, H-4), 3.74
(t, 1H, J = 6.9 Hz, H-2), 3.67 (dd, 1H, J = 6.9 Hz, J = 8.8 Hz,
H-3), 3.43 (dd, 1H, J = 3.2 Hz, J = 14.1 Hz, H-7a), 3.39 (dd, 1H,
J = 6.2 Hz, J = 14.1 Hz, H-7b), 3.37 (ddd, 1H, J = 3.7 Hz, J =
7.3 Hz, J = 9.4 Hz, H-5); 13C NMR (D2O, 100 MHz): d 76.04 (C-
3), 75.57 (C-2), 68.81 (C-4), 67.95 (C-1), 60.93 (C-5), 59.36 (C-6),
46.34 (C-7); m/z (CI, NH3): 194 (M + H+, 100%); HRMS (CI,
NH3): Calcd for C7H16O5N (M + H+): 194.1028, Found 194.1029.
Compound 23. [a]D −13 (c = 1 in CH3OH);1H NMR (D2O,
400 MHz): d 4.34 (tt, 1H, J = 3.0 Hz, J = 8.7 Hz, H-1), 4.12
(ddd, 1H, J = 4.4 Hz, J = 5.5 Hz, J = 6.7 Hz, H-3), 4.01 (d, 1H,
J = 4.4 Hz, H-4), 3.88 (dd, 1H, J = 8.9 Hz, J = 15.6 Hz, H-6a),
3.79 (dd, 1H, J = 8.7 Hz, J = 15.6 Hz, H-6b), 3.78 (ddd, 1H,
J = 0.6 Hz, J = 8.8 Hz, J = 8.8 Hz, H-5), 3.50 (ddd, 1H, J =
1.1 Hz, J = 3.0 Hz, J = 13.2 Hz, H-7a), 3.18 (dd, 1H, J = 8.7 Hz,
J = 13.2 Hz, H-7b), 2.38 (dddd, 1H, J = 1.1 Hz, J = 3.0 Hz,
J = 5.5 Hz, J = 15.0 Hz, H-2a), 2.00 (ddd, 1H, J = 6.8 Hz, J =
8.7 Hz, J = 15.0 Hz, H-2b); 13C NMR (D2O, 100 MHz): d 70.80
(C-4), 69.83 (C-3), 64.05 (C-1), 60.80 (C-6), 58.34 (C-5), 51.57 (C-
7), 38.91 (C-2); m/z (CI, NH3): 178 (M + H+, 100%); HRMS (CI,
NH3): Calcd for C7H16O4N (M + H+): 178.1079, Found 178.1074.
Compound 24. [a]D +4 (c = 1 in CH3OH);1H NMR (D2O,
400 MHz): d 4.37 (m, 1H, H-1), 4.11 (ddd, 1H, J = 3.0 Hz, J =
5.3 Hz, J = 5.3 Hz, H-3), 3.97 (d, 1H, J = 4.9 Hz, H-4), 3.84 (dd,
1H, J = 5.3 Hz, J = 11.9 Hz, H-6a), 3.79 (dd, 1H, J = 8.8 Hz, J =
11.9 Hz, H-6b), 3.62 (ddd, 1H, J = 0.6 Hz, J = 5.3 Hz, J = 8.8 Hz,
H-5), 3.47 (dd, 1H, J = 4.2 Hz, J = 13.3 Hz, H-7a), 3.28 (dd, 1H,
J = 7.8 Hz, J = 13.3 Hz, H-7b), 2.22 (ddd, 1H, J = 2.9 Hz, J =
9.4 Hz, J = 15.0 Hz, H-2a), 2.13 (ddd, 1H, J = 3.0 Hz, J = 5.6 Hz,
J = 15.0 Hz, H-2b); 13C NMR (D2O, 100 MHz): d 69.74 (C-4),
68.00 (C-3), 61.91 (C-1), 60.77 (C-6), 57.98 (C-5), 51.47 (C-7),
37.27 (C-2); m/z (CI, NH3): 178 (M + H+, 100%); HRMS (CI,
NH3): Calcd for C7H16O4N (M + H+): 178.1079, Found 178.1081.
Compound 25. [a]D −18 (c = 0.5 in CH3OH);1H NMR (D2O,
400 MHz): d 3.89 (d, 1H, J = 2.8 Hz, H-4), 3.88 (ddd, 1H, J =
1.8 Hz, J = 6.5 Hz, J = 10.1 Hz, H-2), 3.82 (dd, 1H, J = 5.3 Hz,
J = 11.8 Hz, H-6a), 3.79 (dd, 1H, J = 2.8 Hz, J = 6.5 Hz, H-3),
3.73 (dd, 1H, J = 8.9 Hz, J = 11.8 Hz, H-6b), 3.53 (ddd, 1H,
J = 2.6 Hz, J = 6.4 Hz, J = 13.6 Hz, H-7a), 3.50 (dd, 1H, J =
5.3 Hz, J = 8.9 Hz, H-5), 3.18 (ddd, 1H, J = 2.2 Hz, J = 11.1 Hz,
J = 13.6 Hz, H-7b), 2.17 (dddd, 1H, J = 2.5 Hz, J = 10.8 Hz,
J = 10.8 Hz, J = 15.6 Hz, H-1a), 1.90 (ddt, 1H, J = 2.1 Hz, J =
6.4 Hz, J = 15.6 Hz, H-1b); 13C NMR (D2O, 100 MHz): d 77.80
(C-3), 74.57 (C-2), 69.79 (C-4), 61.15 (C-6), 57.84 (C-5), 44.12 (C-
7), 28.47 (C-1); m/z (CI, NH3): 178 (M + H+, 100%); HRMS (CI,
NH3): Calcd for C7H16O4N (M + H+): 178.1079, Found 178.1077.
Compound 32. [a]D +1 (c = 1 in CH3OH);1H NMR (D2O, 400
MHz): d 4.16 (dd, 1H, J = 2.3 Hz, J = 6.2 Hz, H-3), 4.10 (ddd,
1H, J = 3.6 Hz, J = 6.5 Hz, J = 8.2 Hz, H-1), 4.07 (dd, 1H, J =
1.8 Hz, J = 6.2 Hz, H-4), 3.98 (dd, 1H, J = 2.3 Hz, J = 8.2 Hz,
H-2), 3.84 (dd, 1H, J = 5.3 Hz, J = 12.1 Hz, H-6a), 3.79 (dd, 1H,
J = 8.6 Hz, J = 12.1 Hz, H-6b), 3.64 (ddd, 1H, J = 1.8 Hz, J =
5.3 Hz, J = 8.6 Hz, H-5), 3.45 (dd, 1H, J = 3.6 Hz, J = 13.9 Hz,
H-7a), 3.35 (dd, 1H, J = 6.5 Hz, J = 13.9 Hz, H-7b); 13C NMR
(D2O, 100 MHz): d 73.03 (C-2), 72.30 (C-3), 68.02 (C-4), 66.55
(C-1), 60.36 (C-6), 58.59 (C-5), 48.79 (C-7); m/z (CI, NH3): 194
(M + H+, 100%); HRMS (CI, NH3): Calcd for C7H16O5N (M +
H+): 194.1028, Found 194.1030.
Compound 33. [a]D −19 (c = 1 in CH3OH);1H NMR (D2O,
400 MHz): d 4.18 (ddd, 1H, J = 2.4 Hz, J = 8.7 Hz, J = 10.0 Hz,
H-1), 3.99 (d, 1H, J = 4.6 Hz, H-4), 3.93 (app. t, 1H, J = 4.6 Hz,
H-3), 3.82 (dd, 1H, J = 5.2 Hz, J = 11.9 Hz, H-6a), 3.75 (dd,
1H, J = 8.8 Hz, J = 11.9 Hz, H-6b), 3.68 (dd, 1H, J = 4.6 Hz,
J = 8.7 Hz, H-2), 3.58 (dd, 1H, J = 5.2 Hz, J = 8.8 Hz, H-5),
3.46 (dd, 1H, J = 2.4 Hz, J = 13.6 Hz, H-7a), 3.16 (dd, 1H, J =
10.0 Hz, J = 13.6 Hz, H-7b); 13C NMR (D2O, 100 MHz): d 79.09
(C-2), 75.58 (C-3), 69.00 (C-4), 67.61 (C-1), 60.75 (C-6), 57.78 (C-
5), 48.14 (C-7); m/z (CI, NH3): 194 (M + H+, 100%); HRMS (CI,
NH3): Calcd for C7H16O5N (M + H+): 194.1028, Found 194.1026.
Acknowledgements
We thank Patrick Herson from the Centre de Re´solution des
Structures (Universite´ Pierre et Marie Curie, Paris) for solving the
X-ray structure of compound 9. Hongqing Li gratefully acknowl-
edges the China Scholarship Council and Guizhou University for
financial support.
Compound 28. [a]D +15 (c = 1 in CH3OH);1H NMR (D2O,
400 MHz): d 4.16 (ddd, 1H, J = 3.6 Hz, J = 7.2 Hz, J = 7.2 Hz,
H-1), 4.09 (dd, 1H, J = 1.7 Hz, J = 7.2 Hz, H-2), 4.07 (dd, 1H,
J = 1.7 Hz, J = 8.6 Hz, H-3), 3.98 (dd, 1H, J = 4.0 Hz, J =
12.4 Hz, H-6a), 3.96 (t, 1H, J = 7.5 Hz, H-4), 3.81 (dd, 1H, J =
8.2 Hz, J = 12.4 Hz, H-6b), 3.54 (dd, 1H, J = 3.6 Hz, J = 14.1 Hz,
H-7a), 3.37 (ddd, 1H, J = 4.0 Hz, J = 6.8 Hz, J = 8.2 Hz, H-5),
3.15 (dd, 1H, J = 7.2 Hz, J = 14.1 Hz, H-7b); 13C NMR (D2O,
100 MHz): d 72.48 (C-2), 72.23 (C-3), 66.76 (C-1), 66.56 (C-4),
62.89 (C-5), 60.16 (C-6), 45.96 (C-7); m/z (CI, NH3): 194 (M +
H+, 100%); HRMS (CI, NH3): Calcd for C7H16O5N (M + H+):
194.1028, Found 194.1026.
References and notes
1 R. Wolfenden, X. Lu and G. Young, J. Am. Chem. Soc., 1998, 120,
6814–6815.
2 V. H. Lillelund, H. H. Jensen, X. Liang and M. Bols, Chem. Rev., 2002,
102, 515–553; O. R. Martin and P. Compain, Curr. Top. Med. Chem.,
2003, 3, i–iv.
3 A. Mitrakou, N. Tountas, A. E. Raptis, R. J. Bauer, H. Schulz and S. A.
Raptis, Diabetic Med., 1998, 15, 657.
4 T. D. Butters, R. A. Dwek and F. M. Platt, Curr. Top. Med. Chem.,
2003, 3, 561–574.
5 J. E. Groopman, Rev. Infect. Dis., 1990, 12, 908–911; I. Robina, A. J.
Moreno-Vargas, A. T. Carmona and P. Vogel, Curr. Drug Metab., 2004,
5, 329–361.
6 W. G. Laver, N. Bischofberger and R. G. Webster, Sci. Am., 1999, 280,
78–87; P. Greimel, J. Spreitz, A. E. Stu¨tz and T. M. Wrodnigg, Curr.
Top. Med. Chem., 2003, 3, 513–523.
7 N. Zitzmann, A. S. Mehta, S. Carroue´e, T. D. Butters, F. M. Platt, J.
McCauley, B. S. Blumberg, R. A. Dwek and T. M. Block, Proc. Natl.
Acad. Sci. USA, 1999, 96, 11878–11882.
Compound 29. [a]D +17 (c = 0.62 in CH3OH);1H NMR (D2O,
400 MHz): d 4.09 (ddd, 1H, J = 3.2 Hz, J = 6.2 Hz, J = 6.2 Hz,
H-1), 4.04 (dd, 1H, J = 3.7 Hz, J = 12.5 Hz, H-6a), 3.89 (dd, 1H,
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1653–1662 | 1661
©

View Online
8 A. C. van der Spoel, M. Jeyakumar, T. D. Butters, H. M. Charlton,
H. D. Moore, R. A. Dwek and F. M. Platt, Proc. Natl. Acad. Sci. USA,
2002, 99, 17173–17178; N. Asano, Glycobiology, 2003, 13, 93R–104R.
9 A. Stu¨tz, Iminosugars as glycosidase inhibitors: Nojirimycin and Beyond,
Wiley-VCH, Weinheim, 1999; for recent reviews on six-membered
azasugars see: M. S. M. Pearson, M. Mathe´-Allainmat, V. Fargeas and
J. Lebreton, Eur. J. Org. Chem., 2005, 2159–2191; K. Afarinkia and A.
Bahar, Tetrahedron: Asymmetry, 2005, 16, 1239–1287; for recent work
on five-membered azasugars see: A. J. Moreno-Vargas, A. T. Carmona,
F. Mora, P. Vogel and I. Robina, Chem. Commun., 2005, 39, 4949–4951.
10 X. Qian, F. Moris-Varas, M. C. Fitzgerald and C.-H. Wong, Bioorg.
Med. Chem., 1996, 4, 2055–2069; F. Moris-Varas, X.-H. Qian and C.-H.
Wong, J. Am. Chem. Soc., 1996, 118, 7647–7652.
18 Selected crystal structure data for compound 9 (C11H15NO5; M
241.24); crystal system orthorhombic; space group P212121; Z = 4;
˚
cell parameters: a = 6.◦0153(5), b = 12.4888(9), c = 15.2629(10) A,
3
˚
a = 90, b = 90, c = 90 , V = 1146.60(13) A , T = 250 K; radiation
(MoKa) k = 0.71073 A, l = 1.11 cm−1; 156 variables for 1911 reflections;
˚
final R = 0.0595, RW = 0.0531. CCDC reference number 279321.
For crystallographic data in CIF or other electronic format see DOI:
10.1039/b518117h.
19 S. Inouye, T. Tsuruoka, T. Ito and T. Niida, Tetrahedron, 1968, 24, 2125;
M. Yagi, T. Kouno, Y. Aoyagi and H. Murai, Nippon Nogei Kagaku
Kaishi, 1976, 50, 571–572; S. Murao and S. Miyata, Agric. Biol. Chem.,
1980, 44, 219–221.
20 L. E. Fellows, E. A. Bell, D. G. Lynn, F. Pikiewicz, I. Miura and
K. Nakanishi, J. Chem. Soc., Chem. Commun., 1979, 977–979; D. J.
Hardick, D. W. Hutchinson, S. J. Trew and E. M. H. Wellington,
Tetrahedron, 1992, 48, 6285–6296; T. Furumoto, N. Asano, Y. Kameda
and K. Matsui, J. Antibiot., 1989, 42, 1302–1303.
21 Y. Banba, C. Abe, H. Nemoto, A. Kato, I. Adachi and H. Takahata,
Tetrahedron: Asymmetry, 2001, 12, 817–819.
22 The regioselectivity of the epoxide opening was deduced from the
chemical shift and multiplicity of the 1H-NMR signals for H-1 and
H-2.
23 D. Tanner, L. Tedenborg, A. Almario, I. Pettersson, I. Cso¨regh, N. M.
Kelly, P. G. Andersson and T. Ho¨gberg, Tetrahedron, 1997, 53, 4857–
4868.
24 Alcohol 21 was obtained in a satisfying yield via a hydroboration–
oxidation sequence starting from the corresponding azacycloheptene,
unpublished results.
25 C.-C. Lin, Y. S. Pan, L. N. Patkar, H.-M. Lin, D.-L. M. Tzou, T.
Subramanian and C.-C. Lin, Bioorg. Med. Chem., 2004, 12, 3259–
3267.
11 A. Vasella, G. J. Davies and M. Bo¨hm, Curr. Opin. Chem. Biol., 2002,
6, 619–629.
12 For deoxynojirimycin homologues see: (a) H. Li, Y. Ble´riot, C.
Chantereau, J.-M. Mallet, M. Sollogoub, Y. Zhang, E. Rodriguez-
Garcia, P. Vogel, J. Jimenez-Barbero and P. Sinay¨, Org. Biomol. Chem.,
2004, 2, 1492–1499; (b) H. Li, Y. Ble´riot, J.-M. Mallet, Y. Zhang,
E. Rodriguez-Garcia, P. Vogel, S. Mari, J. Jimenez-Barbero and P.
Sinay¨, Heterocycles, 2004, 64, 65–74; (c) D. D. Dhivale, S. D. Markad,
N. S. Karanjule and J. Prakasha Reddy, J. Org. Chem., 2004, 69,
4760–4766; (d) O. M. Saavedra and O. R. Martin, Ph.D. Thesis,
Universite´ d’Orle´ans, 1998; (e) for nojiritetrazole homologues see: K.
Tetzuka, P. Compain and O. R. Martin, Synlett, 2000, 1837–1839;
(f) for swainsonine homologues see: K. B. Lindsay and S. G. Pyne,
Tetrahedron, 2004, 60, 4173–4176; (g) for imidazolosugar homologues
see: K. Weinberg, S. Jankowski, D. Le Nouen and A. Frankowski,
Tetrahedron Lett., 2002, 43, 1089–1092.
13 H. Li, Y. Ble´riot, J.-M. Mallet, E. Rodriguez-Garcia, P. Vogel, Y. Zhang
and P. Sinay¨, Tetrahedron: Asymmetry, 2005, 16, 313–319.
14 A. Mu¨ller, D. K. Takyar, S. Witt and W. A. Ko¨nig, Liebigs Ann. Chem.,
1993, 651–655.
26 M. Podeschwa, O. Plettenburg, J. vom Brocke, O. Block, S. Adelt and
H.-J. Altenbach, Eur. J. Org. Chem., 2003, 10, 1958–1972.
27 A. Defoin, H. Sarazin and J. Streith, Tetrahedron, 1997, 53, 13783–
13796.
28 A known protocol was applied: R. Saul, J. P. Chambers, R. J. Molyneux
and A. D. Elbein, Arch. Biochem. Biophys., 1983, 221, 593; A. Brandi,
S. Cicchi, F. M. Cordero, R. Frignoli, A. Goti, S. Picasso and P. Vogel,
J. Org. Chem., 1995, 60, 6806–6812. We verified that the delay of in-
hibitor/enzyme incubation did not affect the inhibition measurements.
Under standard conditions, optimal inhibitory activities were measured
after five minutes of incubation.
15 R. W. Marquis, Y. Ru, S. M. LoCastro, J. Zeng, D. S. Yamashita, H.-J.
Oh, K. F. Erhard, L. D. Davis, T. A. Tomaszek, D. Tew, K. Salyers,
J. Proksch, K. Ward, B. Smith, M. Levy, M. D. Cummings, R. C.
Haltiwanger, G. Trescher, B. Wang, M. E. Hemling, C. J. Quinn, H.-Y.
Cheng, F. Lin, W. W. Smith, C. A. Janson, B. Zhao, M. S. McQueney,
K. D’Alessio, C.-P. Lee, A. Marzulli, R. A. Dodds, S. Blake, S.-M.
Hwang, I. E. James, C. J. Gress, B. R. Bradley, M. W. Lark, M. Gowen
and D. F. Veber, J. Med. Chem., 2001, 44, 1380–1395.
16 S. Barluenga, K. B. Simonsen, E. S. Littlefield, B. K. Ayida, D.
Vourloumis, G. C. Winters, M. Takahashi, S. Shandrick, Q. Zhao, Q.
Han and T. Hermann, Bioorg. Med. Chem. Lett., 2004, 14, 713–718.
17 D. Tanner, A. Almario and T. Ho¨gberg, Tetrahedron, 1995, 51, 6061–
6070.
29 S. Moutel, M. Shipman, O. R. Martin, K. Ikeda and N. Asano,
Tetrahedron: Asymmetry, 2005, 16, 487–491.
30 G. Godin, E. Garnier, P. Compain, O. R. Martin, K. Ikeda and N.
Asano, Tetrahedron Lett., 2004, 45, 579–581.
1662 | Org. Biomol. Chem., 2006, 4, 1653–1662
This journal is
The Royal Society of Chemistry 2006
©