RCM approaches toward the diastereoselective synthesis of vicinal trans-diaminocyclitols from L-serine

Article abstract of DOI:10.1021/jo0496547

Starting from L-serine, the asymmetric synthesis of four diaminocyclitol derivatives as sugar-based glycosidase inhibitors has been achieved using ring-closing metathesis (RCM) as a key step. Introduction of vicinal trans-diamino functionality onto the ac

Full text of DOI:10.1021/jo0496547

RCM Ap p r oa ch es tow a r d th e Dia ster eoselective Syn th esis of
Vicin a l tr a n s-Dia m in ocyclitols fr om L-Ser in e
Xin Cong,†,‡ Qing-J iang Liao,‡ and Zhu-J un Yao*,†
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China, and Department of
Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang Road, Nanjing 210009, China
yaoz@mail.sioc.ac.cn
Received March 2, 2004
Starting from L-serine, the asymmetric synthesis of four diaminocyclitol derivatives as sugar-based
glycosidase inhibitors has been achieved using ring-closing metathesis (RCM) as a key step.
Introduction of vicinal trans-diamino functionality onto the acyclic precursors was accomplished
by highly diastereoselective addition of Grignard reagent to imine, and the elaboration of
polyhydroxylic groups was effected via diastereoselective olefin epoxidation or dihydroxylation. The
absolute configurations of final products were confirmed by 2D NMR studies.
In tr od u ction
Recently, interest has continued to mount in new
applications of natural and unnatural glycosidase inhibi-
tors in basic research and biomedical investigations.1
Many D-glucose- and D-galactose-derived glycosylamines,2
polyhydroxylated piperidines,3 and various derivatives of
inositol4 and streptamine5 have been synthesized and
have shown inhibitory activities more potent than those
of their corresponding parent compounds or nonbasic
analogues. Because many of these agents represent early
intermediates in the inositol-phosphate cycle, they have
been used as probes for investigating the inositol phos-
phate cycle as well as potential competitive or selective
glycosidase inhibitors. Furthermore, many of these com-
pounds have potential for use in a wide range of treat-
ments of viral and parasitic protozoa infections, cancer,
diabetes, tuberculosis, and lysosomal storage diseases.6
Several diaminocyclitols have been synthesized and
reported to possess strong antibiotic activity.7 These
include streptamine and 2-deoxystreptamine isomers,
F IGURE 1. Vicinal trans-diaminocyclitols 1-4.
which feature a 1,3-arrangement of their two amino
groups. Preparations of vicinal cis-diamino inositol ana-
logues have also been reported.5a,8 Many of these reported
compounds were synthesized from cyclohexatomic or
cyclopentatomic derivatives. In addition, various cyclo-
hexylamine and cyclopentylamine derivatives have ap-
peared in nucleosides studies.9 Cyclopentylamine deriva-
tives as glycosidase inhibitors have also been examined.1a,10
In this paper, we would like to report syntheses of four
new carba-sugar derivatives, 6-deoxycyclohexyldiamines
(1 and 2) and 5-deoxycyclopentyldiamines (3 and 4)
(Figure 1). Common to all of these are carbon-frame
skeletons, vicinal trans-diamino functionalities, and poly-
hydroxyl groups. These carbon-frame skeletons provide
* To whom correspondence should be addressed. Tel: +8621
64163300 ext.1417. Fax: +8621 6416 6128.
† Chinese Academy of Sciences.
‡ China Pharmaceutical University.
(1) (a) Lillelund, V. H.; J ensen, H. H.; Liang, X.; Bols, M. Chem.
Rev. 2002, 102, 515-553. (b) Butters, T. D.; Dwek, R. A.; Platt, F. M.
Chem. Rev. 2000, 100, 4683-4696.
(2) Wang, L. X.; Sakairi, N.; Kuzuhara, H. Carbohydr. Res. 1995,
275, 33-47.
(3) (a) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H. Org. Lett.
2003, 5, 2527-2529. (b) Subramanian, T.; Lin, C. C.; Lin, C. C.
Tetrahedron Lett. 2001, 42, 4079-4082. (c) Heck, M. P.; Vincent, S.
P.; Murray, B. W.; Bellamy, F.; Wong, C. H.; Mioskowski, C. J . Am.
Chem. Soc. 2004, 126, 1971-1979.
(7) (a) Schurrle, K.; Beier, B.; Piepersberg, W. J . Chem. Soc., Perkin
Trans. 1991, 1, 2407-2412. (b) Sakairi, N.; Hayashida, M.; Amano,
A.; Kuzuhara, H. J . Chem. Soc., Perkin Trans. 1990, 1, 1301-1313.
(8) (a) Guedat, P.; Spieb, B.; Schlewer, G. Tetrahedron Lett. 1994,
35, 7375-7378. (b) Kresze, G.; Weiss, M. M.; Dittel, W. Liebigs Ann.
Chem. 1984, 203-212.
(4) Kwon, Y. U.; Lee, C.; Chung, S. K. J . Org. Chem. 2002, 67, 3327-
3338.
(5) (a) Paul, B. J .; Hobbs, E.; Buccino, P.; Hudlicky, T. Tetrahedron
Lett. 2001, 42, 6433-6435. (b) Russell, R. J . M.; Murray, J . B.; Lentzen,
G.; Haddad, J .; Mobashery, S. J . Am. Chem. Soc. 2004, 126, 3410-
3411.
(6) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.; Adachi,
I. J . Org. Chem. 2003, 68, 3603-3607.
(9) (a) Wang, J .; Vina, D.; Busson, R.; Herdewijn, P. J . Org. Chem.
2003, 68, 4499-4505. (b) Kim, K. H.; Miller, M. J . Tetrahedron Lett.
2003, 44, 4571-4573.
(10) (a) Badorrey, R.; Cativiela, C.; Diaz-de-Villegas, M. D.; Diez,
R.; Galvez, J . A. Tetrahedron Lett. 2004, 45, 719-722. (b) Soengas, R.
G.; Estevez, J . C.; Estevez, R. J . Org. Lett. 2003, 5, 1423-1425.
10.1021/jo0496547 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/01/2004
5314
J . Org. Chem. 2004, 69, 5314-5321

Synthesis of Vicinal trans-Diaminocyclitols
F IGURE 2. Retrosynthetic analysis for the four vicinal trans-diaminocyclitols 1-4.
SCHEME 1a
great chemical stability and flexibility. Key to our
preparation of vicinal trans-diamino functionality at an
acyclic stage is diastereoselective addition of allylmag-
nesium bromide to imine 12 derived from Garner alde-
hyde. Other features of our synthesis include catalytic
ring-closing metathesis (RCM)11 for construction of the
all-carbon rings and substrate-controlled diastereoselec-
tive epoxidation or dihydroxylation for the introduction
of polyhydroxyl groups with various configurations.
Resu lts a n d Discu ssion
The general retrosynthetic analysis of compounds 1-4
a
Reagents and conditions: (a) HCl, MeOH, reflux, 100%; (b)
is outlined in Figure 2. Compounds 1 and 2 can be
obtained from a common intermediate 5, which then can
be derived from acyclic diene 6 by an RCM reaction, while
olefin 6 is envisaged to be produced by a stereoselective
addition of vinylmagmesium bromide to an aldehyde
derived from alcohol 9 with anhydrous ZnCl2 as a
promotor.12 Similarly, compounds 3 and 4 can be pre-
pared from a common intermediate 7, which can be
derived from diene 8 by an RCM reaction. Like diene 6,
compound 8 also can be related to alcohol 9, which in
turn can be prepared from L-Garner aldehyde 10.13
The synthesis started from L-serine (Scheme 1). L-
Serine was readily converted to alcohol 11 according to
known procedure.14 Swern oxidation of the latter afforded
aldehyde 10, which was used immediately in the next
step. Treatment of the freshly prepared Garner aldehyde
10 with N-(4-methoxybenzyl)-hydroxylamine and anhy-
drous MgSO4 in dry CH2Cl2 at room temperature gave
nitrone 12 (74% yield from alcohol 11). Nitrone 12 was
then treated with allylmagnesium bromide (3.0 equiv)
in the presence of anhydrous ZnBr2 (1.0 equiv) at -70
°C with anhydrous tetrahydrofuran and anhydrous ether
(1:1, v/v) as the cosolvent.13,15 As expected, the desired
syn-adduct 13 was obtained as the predominant product
in 87% yield along with the anti-isomer 14 in 9% yield.
Boc2O, Et3N, THF, 88%; (c) 2,2-DMOP, BF3‚Et2O, acetone, 94%;
(d) LAH, anhydrous THF, -10 °C, 98%; (e) DMSO, (COCl)2, Et3N,
CH2Cl2; (f) N-(4-methoxybenzyl)-hydroxylamine, anhydrous Mg-
SO4, CH2Cl2, 74% (for 2 steps); (g) anhydrous ZnBr2, allylmagne-
sium bromide in Et2O, anhydrous THF/Et2O 1:1 (v/v), -70 °C, 4
h; 13 (87%), 14 (9%).
TABLE 1. Resu lts of Ad d ition of Allylm a gn esiu m
Br om id e to Nitr on e 12a
entry Lewis acid
solvent
THF
THF
Et2O
syn-13 (%) anti-14 (%) 13:14
1
2
3
4
none
66
78
59
87
30
19
9
2.2:1
4.1:1
6.6:1
9.7:1
ZnBr2
ZnBr2
ZnBr2
THF/Et2O 1:1
9
a
All reactions were carried out at -70 °C.
These two diastereomers could be easily separated by
silica gel column chromatography. The absolute config-
uration of 13 was ultimately confirmed by NMR studies
on compound 20 (1H NMR, NOESY) at a later stage.
1
Direct assignments of H NMR chemical shifts of both
the NOH of syn-isomer 13 (6.99 ppm) and anti-isomer
14 (5.36 ppm) matched referenced patterns.13 As shown
in Table 1, ZnBr2 and the THF/ether cosolvent system
were critical for good diastereoselectivity to be obtained.
Reductive cleavage of the N-O bond of the major
adduct 13 was achieved using zinc-copper(II) in acetic
acid/water to give the corresponding secondary amine 15
in high yield (Scheme 2). Amine 15 was then treated with
(11) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(12) Toda, A.; Mimura, A. N.; Ohno, H.; Fujii, N.; Ibuka, T. J . Org.
Chem. 1998, 63, 7053-7061.
(13) Merino, P.; Anoro, S.; Franco, S.; Gascon, J . M.; Martin, V.;
Merchan, F. L.; Revuelta, J .; Tejero, T.; Tunon, V. Synth. Commun.
2000, 30, 2989-3021.
(14) (a) Mckillop, A.; Taylor, R. J . K.; Waston, R. J .; Lewis, N.
Synthesis 1994, 3, 31-33. (b) Dondoni, A.; Perrone, P. Synthesis 1997,
5, 527-529. (c) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361-
2364.
(15) (a) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetra-
hedron: Asymmetry 1998, 9, 629-646. (b) Merino, P.; Castillo, E.;
Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron 1998, 54, 12301-
12322.
J . Org. Chem, Vol. 69, No. 16, 2004 5315

Cong et al.
SCHEME 2a
a
Reagents and conditions: (a) Zn-Cu(OAc)2, AcOH/H2O, 70 °C; (b) CbzCl, EtOAc/saturated aqueous NaHCO3; (c) p-TsOH‚H2O (cat.),
MeOH, reflux (85% overall).
SCHEME 3a
a
Reagents and conditions: (a) DMSO, (COCl)2, Et3N, CH2Cl2; (b) anhydrous ZnCl2, vinylmagnesium bromide, anhydrous THF, -70 to
-30 °C (79% yield for 2 steps); (c) Grubbs catalyst (8 mol %), CH2Cl2; 5 (83%), 19 (7%); (d) H2, 20% Pd(OH)2/C (cat.), MeOH; (e) 3 N HCl,
MeOH, rt (83% for 2 steps).
benzyl chloroformate (CbzCl) in ethyl acetate and satur-
ated aqueous NaHCO3 (1:1, v/v) at room temperature to
afford compound 16 quantitatively. Selective acetonide
hydrolysis in methanol in the presence of p-TsOH hy-
drate yielded the primary alcohol 9, which was a common
key intermediate for the synthesis of all four final
products.
As shown in Scheme 3, treatment of aldehyde 17,
freshly prepared by Swern oxidation of alcohol 9, with
vinylmagnesium bromide (3.0 equiv) and anhydrous
ZnCl2 (1.5 equiv) in tetrahydrofuran at -30 °C gave a
mixture of epimeric dienes 18 (79% yield in 2 steps). In
the presence of bis(tricyclohexylphosphine)benzylidene
ruthenium(IV) dichloride (Grubbs catalyst), RCM reac-
tion of the diastereomeric mixture 18 in anhydrous CH2-
Cl2 under N2 afforded the separable cyclohexene deriva-
tive 5 and its diastereoisomer 19 in 90% yield (ratio of
5:19 ) 92:8). The relative configuration (and by conse-
quence the absolute) of major product 5 was confirmed
by NMR analysis of 20, which was obtained by hydro-
genation of 5 and subsequent treatment with hydrochlo-
ric acid. The results of NOESY studies of 20 are shown
in Scheme 3.
with 3-chloroperoxybenzoic acid (m-CPBA) to give ep-
oxide 22 in 72% yield. Subsequent regioselective opening
of the epoxide by water was realized under acidic condi-
tion on treatment with 0.2 N H2SO4/dioxane (1:1, v/v)16
to afford the triol 23 in 82% yield as a single product as
determined by HPLC and 1H NMR measurements.
Finally, protective groups of 23 were removed with 12 N
HCl in refluxed methanol to afford final product 2, whose
relative configuration (and by consequence the absolute)
was also confirmed by NOESY experiment.
As shown in Figure 2, for the syntheses of cyclopentane
derivatives 3 and 4, diene 8 was the initially proposed
precursor for RCM reaction. In practice, Wittig reaction
of aldehyde 17 with Ph3PCH3Br under various conditions
could not afford the desired product 8. The reaction
mixture was very complicated and the starting material
decomposed under the strong basic conditions. However,
treatment of aldehyde 17 with (carbethoxymethylene)-
triphenylphosphorane (Ph3PdCHCOOEt) in tetrahydro-
furan furnished (2E)-2,7-diene 24 as a single product in
high yield (93% for 2 steps, Scheme 5). RCM reaction of
diolefin 24 under the above-mentioned conditions af-
forded cyclopentene 7 in excellent yield.
After confirming the stereochemistry of key intermedi-
ate 5, our attentions were directed to the elaboration of
hydroxyls in the cyclohexene ring (Scheme 4). Treatment
of cyclohexene 5 with a catalytic amount of OsO4 and
4-methylmorpholine N-oxide (NMO) as a co-oxidant gave
predominantly the trans-adduct 21 (93%). The diastereo-
isomeric ratio of dihydroxylation products is 89.6:10.4 as
determined by HPLC analysis. Full deprotection of 21
with 12 N HCl in refluxed methanol afforded final
product 1 in 92% yield. The relative configuration was
confirmed by NOESY studies. Compound 5 was treated
Cyclopentene 7 was then treated with NMO and a
catalytic amount of OsO4 to give a diastereomeric mixture
of diols in 94% yield with product 25 predominating in a
95:5 ratio as determined by HPLC. Deprotection of 25
with 12 N HCl in MeOH afforded 3 in 95% yield.
Alternatively, epoxidation of 7 with m-CPBA in the
presence of NaHCO3 afforded the single syn-epoxide 26
(16) Crotti, P.; Bussolo, V. D.; Favero, L.; Pineschi, M.; Marianucci,
F.; Renzi, G.; Amici, G.; Roselli, G. Tetrahedron 2000, 56, 7513-7524.
5316 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis of Vicinal trans-Diaminocyclitols
SCHEME 4a
a
Reagents and conditions: (a) OsO4;(cat.), NMO, acetone/H2O, rt, 9:1 (v/v), 93%; (b) 12 N HCl, reflux, 92%; (c) m-CPBA, Na2HPO4,
CH2Cl2, 15 °C, 72%; (d) 0.2 N H2SO4, dioxane, 10 °C, 82%; (e) 12 N HCl, reflux, 87%.
SCHEME 5a
rated either by substrate-controlled diastereoselective
epoxidation/epoxide opening or direct dihydroxylation.
Stereochemistries of these final products were well-
controlled and confirmed by NMR studies. Utilization of
these vicinal diamino polyhydroxycycloalkane derivatives
in biological studies is under way in our laboratory, and
these results will be reported in due course.
a
Reagents and conditions: (a) Ph3PdCHCOOEt, THF, 93%
from alcohol 9; (b) Grubbs catalyst (5 mol %), CH2Cl2, 99%.
Exp er im en ta l Section
in 78% yield; its anti-diastereomer was not observed.17
(Z)-N-[(4R)-3-(ter t-Bu t oxyca r b on yl)-2,2-d im et h yl-1,3-
oxa zolid in -4-ylid en e]- 4-m eth oxyben zyla m in e N-Oxid e
(12). To a solution of oxalyl chloride (3.9 mL, 4.5 mmol, 1.5
equiv) in dry CH2Cl2 (150 mL) was added slowly DMSO (6.5
mL, 90 mmol, 3.0 equiv) in dry CH2Cl2 (25 mL) at -78 °C
under N2. After 30 min, alcohol 11 (7.0 g, 30 mmol) in dry CH2-
Cl2 (100 mL) was added dropwise at -78 °C. The mixture was
stirred for additional 2 h at -78 °C, and then Et3N (30 mL)
was added at -78 °C. After 20 min, the mixture was warmed
to room temperature, and saturated aqueous NH4Cl (100 mL)
was added. The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 100 mL). The combined
organic layers were washed with saturated aqueous NH4Cl (3
× 100 mL) and brine (3 × 100 mL), dried (MgSO4), and
concentrated in vacuo to give Garner aldehyde 10, which was
used directly without further purification.
However, the regioselectivity was very poor (as measured
by HPLC and H NMR) when the epoxide 26 was treated
1
with 0.2 N H2SO4/dioxane (1:1, v/v) to give a diastereo-
meric mixture of anti-diols 27. This unexpected result
led us to explore the possibilities of regio- and stereose-
lective epoxide opening by an intramolecular nucleophilic
approach. Treatment of 26 with catalytic amount of
D-camphor-10-sulfonic acid18 in dichloromethane smoothly
gave 28 (86% yield) as a single product. The structure
and relative configuration of 28 were confirmed by
NOESY studies. Refluxing 28 in 12 N HCl and then
recrystallization from MeOH afforded 4 in 94% yield
(Scheme 6).
To a solution of the above freshly prepared aldehyde 10 in
dry CH2Cl2 (100 mL) was added sequentially anhydrous
MgSO4 (7.2 g, 60 mmol, 2.0 equiv) and N-hydroxy(4-methoxy-
benzyl) methanamine19 (4.6 g, 30 mmol, 1.0 equiv). The
resulting mixture was stirred at room temperature overnight.
The solid in the mixture was filtered, and the filtrate was
concentrated in vacuo to yield the crude product, which was
purified by flash column chromatography on silica gel (petro-
leum ether/ethyl acetate ) 1:2) to give nitrone 12 (8.1 g, 74%
for 2 steps) as a white solid, mp 55-56 °C. [R]23D -56.5 (c 1.15,
CHCl3). IR (KBr): 3078, 3011, 2975, 2936, 1702, 1614, 1516,
Su m m a r y
In conclusion, four carbocyclic sugar-like derivatives
of 6-deoxycyclohexyl diamine or 5-deoxycyclopentyl di-
amine with vicinal trans-diamino functionalities and
polyhydroxy groups have been synthesized diastereose-
lectively through a common intermediate 9. The vicinal
trans-diamino moieties were introduced by a highly
diastereoselective addition reaction. The cycloalkene
rings were efficiently constructed by RCM reactions from
diene precursors, and polyhydroxylic groups were elabo-
1
1382, 1255, 1176, 1089, 853 cm-1. H NMR (300 MHz, 55 °C,
CDCl3): δ 1.39 (s, 9H), 1.46-1.55 (m, 6H), 3.80 (s, 3H), 4.01-
4.04 (m, 1H), 4.17 (dd, J ) 6.9, 9.6 Hz, 1H), 4.80 (s, 2H), 4.92-
(17) Baron, E.; O’Brien, P.; Towers, T. D. Tetrahedron Lett. 2002,
43, 723-726.
(18) Crimmins, M. T.; Tabet. E. A. J . Org. Chem. 2001, 66, 4012-
(19) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
1971, 93, 2897-2904.
4018.
J . Org. Chem, Vol. 69, No. 16, 2004 5317

Cong et al.
SCHEME 6a
a
Reagents and conditions: (a) OsO4 (cat.), NMO, acetone/H2O, rt, 9:1 (v/v), 94%; (b) 12 N HCl, reflux, 95%; (c) m-CPBA, NaHCO3,
CH2Cl2, 15 °C, 78%; (d) cat. D-CSA, CH2Cl2, 86%; (e) 12 N HCl, reflux, 94%; (f) 0.2 N H2SO4, dioxane, 10 °C, 75%.
(br, 1H), 6.66 (bs, 1H), 6.90 (d, J ) 8.1 Hz, 2H), 7.30 (d, J )
8.4 Hz, 2H) ppm. ESIMS (m/z, %): 365.2 (M + H+, 100%).
Anal. Calcd for C19H28N2O5: C 62.62, H 7.74, N 7.69. Found:
C 62.52, H 7.90, N 7.53.
(M + Na+, 10%). Anal. Calcd for C22H34N2O5: C 65.00, H 8.43,
N 6.89. Found: C 65.28, H 8.30, N 6.97.
Secon d a r y Am in e 15. To a solution of copper(II) acetate
(385 mg, 2.1 mmol, 0.1 equiv) in acetic acid (25 mL) was added
Zn dust (6.83 g, 105 mmol, 5.0 equiv). The mixture was stirred
at 25 °C for 15 min under N2. A solution of the hydroxylamine
13 (8.5 g, 21 mmol) in acetic acid (25 mL) and water (12 mL)
was then added and the reaction was heated at 70 °C for 2 h.
The disodium salt of EDTA (23.4 g, 63 mmol, 3.0 equiv) was
added at room temperature, and the pH was adjusted to 10
by addition of 4 N NaOH. The solution was extracted with
ethyl acetate (3 × 250 mL). The combined organic layers were
washed with saturated aqueous EDTA (3 × 250 mL), saturated
aqueous NH4Cl (3 × 250 mL), and brine (3 × 250 mL), dried
(Na2SO4), and concentrated in vacuo to yield crude product
15 as a colorless oil, which could be used directly without
further purification. An analytical sample of 15 was obtained
by column chromatography on silica gel (petroleum ether/ethyl
Hyd r oxyla m in es 13 a n d 14. To a stirred solution of
nitrone 12 (8.0 g, 22 mmol) in anhydrous THF and anhydrous
Et2O (400 mL, 1:1) at room temperature under N2 was added
anhydrous ZnBr2 (4.95 g, 22 mmol). After being stirred at room
temperature for 30 min, the reaction mixture was cooled to
-70 °C and treated with allylmagnesium bromide (1.0 M in
Et2O, 66 mL, 66 mmol, 3.0 equiv) dropwise. The resulting
suspension was stirred at -70 °C for an additional 4 h until
it was quenched with 1 N NaOH (200 mL) at -70 °C and
warmed to room temperature. The layers were separated, and
the aqueous layer was extracted with Et2O (3 × 100 mL). The
combined organic layers were washed with saturated aqueous
NH4Cl (3 × 100 mL) and brine (3 × 100 mL), dried (Na2SO4),
and concentrated in vacuo to give the crude mixture of
hydroxylamines 13 and 14, which were separated and purified
by column chromatography on silica gel (petroleum ether/ethyl
acetate ) 40:1 to 20:1) to afford syn-isomer 13 (7.85 g, 87%)
and trans-isomer 14 (0.82 g, 9%) as colorless oils. Data for 13:
acetate ) 5:1). [R]20 -14.4 (c 1.03, CHCl3). IR (neat): 3346,
D
3075, 2978, 2937, 1699, 1613, 1513, 1390, 1366, 1246, 1176
cm-1. 1H NMR (300 MHz, CDCl3): δ 1.47 (s, 9H), 1.51 (bs, 6H),
1.93-2.05 (m, 1H), 2.41-2.43 (m, 1H), 3.01-3.08 (m, 1H),
3.69-3.77 (m, 2H), 3.79 (s, 3H), 3.91 (m, 1H), 4.03-4.13 (m,
2H), 5.06-5.13 (m, 2H), 5.68-5.75 (m, 1H), 6.84 (d, J ) 8.0
Hz, 2H), 7.23 (d, J ) 8.0 Hz, 2H) ppm. ESIMS (m/z, %): 391.1
(M + H+, 100%). Anal. Calcd for C22H34N2O4: C 67.66, H 8.78,
N 7.17. Found: C 67.46, H 8.49, N 6.99.
[R]19 -22.10 (c 1.28, CHCl3). IR (neat): 3357, 3075, 2979,
D
2937, 1670, 1514, 1410, 1249, 1174, 1107 cm-1. H NMR (300
1
MHz, CDCl3): δ 1.43 (s, 3H), 1.50 (s, 3H), 1.52 (s, 9H), 2.04-
2.13 (m, 1H), 2.70-2.76 (m, 1H), 2.81-2.91 (m, 1H), 3.73 (d,
J ) 13.8 Hz, 1H), 3.78 (s, 3H), 3.86-3.93 (m, 2H), 4.01-4.06
(m, 1H), 4.05 (d, J ) 13.8 Hz, 1H), 5.02-5.13 (m, 2H), 5.93-
6.02 (m, 1H), 6.80 (d, J ) 8.7 Hz, 2H), 6.99 (s, 1H, ex. D2O),
7.25 (d, J ) 8.7 Hz, 2H) ppm. ESIMS (m/z, %): 407.1 (M +
Alcoh ol 9. To a solution of crude 15 (21 mmol) in ethyl
acetate (100 mL) was added saturated aqueous NaHCO3 (100
mL) in one portion. Benzyl chloroformate (3.0 mL, 21 mmol,
1.0 equiv) was added dropwise at 0 °C, and the reaction
mixture was stirred at room temperature overnight. The layers
were separated, and the aqueous layer was extracted with
ethyl acetate (3 × 100 mL). The combined organic layers were
washed with saturated aqueous NH4Cl (3 × 100 mL) and brine
(3 × 100 mL), dried (Na2SO4), and concentrated in vacuo to
give the crude product 16 as a colorless oil, which was used
directly for the next step without further purification.
H+, 100%), 429.1 (M
+
Na+, 15%). Anal. Calcd for
C
22H34N2O5: C 65.00, H 8.43, N 6.89. Found: C 64.96, H 8.63,
N 7.01. Data for 14: [R]19 -20.25 (c 1.18, CHCl3). IR (neat):
D
3472, 3076, 2978, 2936, 1699, 1614, 1514, 1394, 1250, 1175,
1085 cm-1. 1H NMR (300 MHz, 55 °C, CDCl3): δ 1.24 (bs, 3H),
1.48 (s, 9H), 1.68 (bs, 3H), 2.27-2.30 (m, 1H), 2.68-2.75 (m,
1H), 3.13-3.28 (m, 1H), 3.71-3.78 (m, 1H), 3.77 (s, 3H), 3.80-
3.83 (m, 1H), 3.92-4.09 (m, 1H), 4.07 (d, J ) 9.0 Hz, 1H), 4.24
(d, J ) 9.0 Hz, 1H), 5.01-5.13 (m, 2H), 5.36 (s, 1H, ex. D2O),
5.75-5.83 (m, 1H), 6.82 (d, J ) 8.7 Hz, 2H), 7.22 (d, J ) 8.7
Hz, 2H) ppm. ESIMS (m/z, %): 407.1 (M + H+, 100%), 429.1
To a solution of crude 16 (21 mmol) in MeOH (750 mL) was
added a catalytic amount of p-TsOH hydrate (200 mg, 0.05
equiv) at room temperature. The reaction mixture was heated
5318 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis of Vicinal trans-Diaminocyclitols
to reflux for 1 h. The solvent was evaporated, and the residue
was diluted with ethyl acetate (500 mL), washed with satur-
ated aqueous NaHCO3 (3 × 100 mL) and brine (3 × 100 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (petro-
leum ether/ethyl acetate ) 3:1) to give alcohol 9 (8.64 g, 85%
H+ - Boc, 100%), 483.1 (M + H+, 98%), 505.1 (M + Na+, 25%).
Anal. Calcd for C27H34N2O6: C 67.20, H 7.10, N 5.81. Found:
C 67.08, H 7.18, N 5.59. Data for 19: [R]19 -19.1 (c 1.43,
D
CHCl3). IR (KBr) 3439, 3065, 3033, 2976, 2933, 1701, 1613,
1
1514, 1247, 1171 cm-1. H NMR (300 MHz, 55 °C, CDCl3): δ
1.42 (s, 9H), 1.69 (br, 1H, ex. D2O), 2.11-2.17 (m, 1H), 2.19-
2.29 (m, 1H), 3.77 (s, 3H), 3.97-4.05 (m, 1H), 4.17 (d, J ) 15.9
Hz, 1H), 4.24-4.34 (m, 2H), 4.70 (d, J ) 15.0 Hz, 1H), 5.14 (d,
J ) 12.0 Hz, 1H), 5.23 (d, J ) 12.0 Hz, 1H), 5.72-5.75 (m,
2H), 6.80 (d, J ) 8.4 Hz, 2H), 7.13 (d, J ) 8.4 Hz, 2H), 7.28
(br, 5H) ppm. ESIMS (m/z, %): 383.2 (M + H+ - Boc, 40%),
483.3 (M + H+, 100%), 505.1 (M + Na+, 20%). Anal. Calcd for
from 13) as a colorless oil. [R]20 -5.9 (c 0.97, CHCl3). IR
D
(neat): 3413, 3069, 2978, 2935, 1687, 1613, 1514, 1249, 1175
1
cm-1. H NMR (300 MHz, CDCl3): δ 1.41 (s, 9H), 2.34-2.50
(m, 2H), 3.45-3.55 (m, 2H), 3.79 (s, 3H), 3.77-3.84 (m, 1H),
4.23 (d, J ) 15.9 Hz, 1H), 4.34-4.36 (m, 1H), 4.56 (d, J ) 15.9
Hz, 1H), 4.91-5.03 (m, 2H), 5.16-5.26 (m, 2H), 5.47-5.57 (m,
1H), 6.81 (d, J ) 8.7 Hz, 2H), 7.12 (d, J ) 8.1 Hz, 2H), 7.31-
7.40 (m, 5H) ppm. ESIMS (m/z, %): 485.1 (M+ + H, 15%), 507.1
(M + Na+, 100%). Anal. Calcd for C27H36N2O6: C 66.92, H 7.49,
N 5.78. Found: C 67.16, H 7.56, N 5.64.
C
27H34N2O6: C 67.20, H 7.10, N 5.81. Found: C 67.28, H 7.12,
N 5.79.
(1R,2R,3S)-2,3-Dia m in ocycloh exa n ol H yd r och lor id e
(20). A mixture of compound 5 (482 mg, 1 mmol) and 20%
palladium hydroxide on activated charcoal (48 mg, 10% w/w)
in MeOH (10 mL) was stirred under H2 atmosphere (1 atm)
at 35 °C for 24 h. The solid was filtered off, and the filtrate
was evaporated. The residue was treated with 3 N HCl in
MeOH (20 mL) at 0 °C and then stirred at room temperature
overnight. MeOH was removed in vacuo. The residue was
recrystallized from EtOH to afford 20 (168 mg, 83%) as an
off-white solid. [R]20D -7.3 (c 1.78, H2O). IR (KBr): 3336, 2869,
Diolefin 18. A routine Swern oxidation of alcohol 9 (5.8 g,
12 mmol) gave the corresponding crude aldehyde 17, which
was used directly for the next step without further purification.
To a solution of anhydrous ZnCl2 (2.46 g, 18 mmol, 1.5 equiv)
in anhydrous THF (300 mL) was added vinylmagnesium
bromide (1.0 M in THF, 36 mL, 36 mmol, 3.0 equiv) at -70 °C
under N2. After the mixture was stirred at this temperature
for 30 min, a solution of freshly prepared aldehyde 17 in
anhydrous THF (60 mL) was added dropwise. The whole
mixture was stirred at -70 °C for 2 h and warmed to -30 °C
for additional 4 h, before it was quenched with 1 N NaOH (120
mL) at -30 °C. The resulting mixture was warmed to room
temperature, and the layers were separated. The aqueous
layer was extracted with ethyl acetate (3 × 100 mL). The
combined organic layers were washed with saturated aqueous
NH4Cl (3 × 100 mL) and brine (3 × 100 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl
acetate ) 6:1) to give a diastereomeric mixture 18 (4.8 g, 79%
for 2 steps) as a colorless oil. IR (neat): 3421, 3074, 2961, 2930,
2618, 1510, 1071, 1014 cm-1 1H NMR (500 MHz, D2O): δ
.
1.21-1.32 (m, 2H, H5a, H6a), 1.37-1.50 (m, 1H, H4a), 1.70-
1.75 (m, 1H, H5e), 1.93-1.95 (m, 1H, H6e), 1.99-2.04 (m, 1H,
H
4e), 3.06 (dd, 1H, J 1,2 ) 10.2 Hz, J 2,3 ) 10.8 Hz, H2), 3.35 (td,
1H, J 2,3 ) J 3,4a ) 10.8 Hz, J 3,4e ) 4.2 Hz, H3), 3.54 (td, 1H, J 1,2
) J 1,6a ) 10.2 Hz, J 1,6e ) 4.5 Hz, H1) ppm. 13C NMR (125 MHz,
D2O): δ 21.98, 31.19, 34.17, 53.08, 60.13, 71.60 ppm. ESIMS
(m/z, %): 131.2 (M + H+, 100%). HR-MALDI-MS calcd for
C6H15N2O (M + H+) 131.1179, found 131.1185.
(1R,2S,3S,4S,6S)-{6-[Ben zyloxyca r b on yl-(4-m et h oxy-
b en zyl)-a m in o]-2,3,4-t r ih yd r oxy-cycloh exyl}-ca r b a m ic
Acid ter t-Bu tyl Ester (21). To a solution of 5 (241 mg, 0.5
mmol) in a mixture of acetone and water (10 mL, 9:1, v/v) was
added 4-methyl morpholine N-oxide (150 mg, 1.1 mmol, 2.2
equiv) and a catalytic amount of OsO4 (2 drops of 2.5% OsO4
1691, 1613, 1514, 1249, 1176 cm-1 1H NMR (300 MHz,
.
CDCl3): d 1.39 (s, 9H), 2.33-2.42 (m, 2H), 2.26-2.30 (br, 1H,
ex. D2O), 3.79 (s, 3H), 3.81-3.86 (m, 1H), 4.25-4.44 (m, 3H),
4.85-4.94 (m, 2H), 5.13-5.32 (m, 5H), 5.44 (br, 1H), 5.81-
5.85 (m, 1H), 6.81-6.88 (m, 2H), 7.13-7.15 (m, 2H), 7.27-
7.32 (m, 5H) ppm. ESIMS (m/z, %): 511.3 (M + H+, 100%),
533.2 (M + Na+, 40%). Anal. Calcd for C29H38N2O6: C 68.21,
H 7.50, N 5.49. Found: C 68.19, H 7.66, N 5.61.
t
solution in BuOH) at room temperature. After being stirred
at room temperature overnight, the reaction mixture was
quenched with a few drops of saturated aqueous NaHSO3. The
solvent was evaporated. The residue was diluted with ethyl
acetate (20 mL) and washed with brine (3 × 10 mL), dried
(Na2SO4), and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica gel (petro-
leum ether/ethyl acetate ) 1:5) to give triol 21 (239 mg, 93%)
(1R,2R,6S)-{6-[Ben zyloxyca r bon yl-(4-m eth oxyben zyl)-
a m in o]-2-h yd r oxy-cycloh ex-3-en yl}-ca r ba m ic Acid ter t-
Bu tyl Ester (5) a n d (1R,2S,6S)-{6-[Ben zyloxyca r bon yl-
(4-m eth oxyben zyl) -a m in o]-2-h yd r oxy-cycloh ex-3-en yl}-
ca r ba m ic Acid ter t-Bu tyl Ester (19). To a solution of alcohol
18 (4.8 g, 9.4 mmol) in anhydrous CH2Cl2 (500 mL) was added
bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichlo-
ride (Grubbs catalyst) (618 mg, 0.75 mmol, 0.08 equiv) under
N2. The reaction mixture was stirred at room temperature
overnight. After all starting material disappeared, water (50
mL) was added and stirred vigorously at room temperature
for 1 h. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 50 mL). The combined organic
layers were washed with brine (3 × 100 mL), dried (Na2SO4),
and concentrated in vacuo. The crude mixture was separated
and purified by column chromatography on silica gel (petro-
leum ether/ethyl acetate ) 8:1 to 4:1) to afford 5 (3.20 g, 83%)
and 19 (0.31 g, 7%) as pale brown waxes, and repeated (twice
to trice) silica gel column chromatography was performed in
as a white wax. [R]20 -20.4 (c 0.64, CHCl3). IR (KBr): 3406,
D
2932, 1691, 1614, 1514, 1248, 1174 cm-1. H NMR (300 MHz,
1
55 °C, CDCl3): δ 1.41 (s, 9H), 1.70 (bs, 1H), 1.83-1.88 (m, 1H),
3.38-3.41(m, 1H), 3.61-3.65 (m, 1H), 3.77 (s, 3H), 3.98-3.99
(m, 1H), 4.17 (d, J ) 15.6 Hz, 1H), 4.30 (br, 2H), 4.60 (d, J )
15.6 Hz, 1H), 5.11 (d, J ) 11.7 Hz, 1H), 5.19 (d, J ) 12.0 Hz,
1H), 6.79 (d, J ) 8.1 Hz, 2H), 7.10 (br, 2H), 7.28 (br, 5H) ppm.
ESIMS (m/z, %): 517.3 (M + H+, 100%). Anal. Calcd for
C
27H36N2O8: C 62.78, H 7.02, N 5.42. Found: C 62.48, H 7.30,
N 5.13.
(1S,2S,3S,4R,5S)-4,5-Diam in ocycloh exan e-1,2,3-tr iol h y-
d r och lor id e (1). A mixture of triol 21 (130 mg, 0.25 mmol)
and 12 N HCl (10 mL) was refluxed for 2 days under N2. The
solvent was removed in vacuo to give the crude product, which
was recrystallized from MeOH to afford 1 (55 mg, 93%) as an
off-white solid. [R]20D +15.9 (c 0.66, H2O). IR (KBr): 3366, 2908,
1601, 1506, 1037 cm-1. 1H NMR (400 MHz, D2O): δ 1.75 (ddd,
1H, J 1,6a ) 2.4 Hz, J 5,6a ) 12.3 Hz, J 6a,6e ) 14.4 Hz, H6a), 2,17
(ddd, 1H, J 1,6e ) 3.9 Hz, J 5,6e ) 4.5 Hz, J 6a,6e ) 14.4 Hz, H6e),
3.12 (dd, 1H, J 3,4 ) 9.9 Hz, J 4,5 ) 10.5 Hz, H4), 3.46 (dd, 1H,
J 1,2 ) 3.0 Hz, J 2,3 ) 9.6 Hz, H2), 3.64 (ddd, 1H, J 4,5 ) 10.5 Hz,
J 5,6e ) 4.5 Hz, J 5,6a ) 12.3 Hz, H5), 3.71 (dd, 1H, J 2,3 ) 9.6 Hz,
J 3,4 ) 9.9 Hz, H3), 4.02-4.05 (m, 1H, H1) ppm. 13C NMR (100
MHz, D2O): δ 35.30, 49.32, 58.30, 69.37, 71.56, 75.63 ppm.
order to obtain off-white waxes for analysis. Data for 5: [R]18
D
-48.0 (c 1.49, CHCl3). IR (KBr): 3348, 3066, 2959, 1696, 1614,
1514, 1309, 1248, 1174 cm-1 1H NMR (300 MHz, 55 °C,
.
CDCl3): δ 1.43 (s, 9H), 2.03-2.10 (m, 1H), 2.30-2.39 (m, 1H),
3.24 (br, 1H, ex. D2O), 3.78 (s, 3H), 3.74-3.83 (m, 1H), 4.20
(d, J ) 16.5 Hz, 1H), 4.12-4.23 (m, 2H), 4.60 (d, J ) 16.5 Hz,
1H), 5.15 (d, J ) 12.3 Hz, 1H), 5.23 (d, J ) 12.3 Hz, 1H), 5.54-
5.62 (m, 2H), 6.81 (d, J ) 8.4 Hz, 2H), 7.13 (d, J ) 8.1 Hz,
2H), 7.24-7.38 (br, 5H) ppm. ESIMS (m/z, %): 383.1 (M +
J . Org. Chem, Vol. 69, No. 16, 2004 5319

Cong et al.
ESIMS (m/z, %): 163.1 (M + H+, 100%). HR-MALDI-MS calcd
for C6H15N2O3 (M + H+) 163.1077, found 163.1079.
colorless oil. [R]D -22.3 IR (neat): 3350, 3066, 1987, 2906,
19
1727, 1687, 1612, 1513, 1249, 1222 cm-1. H NMR (300 MHz,
1
CDCl3): δ 1.28 (m, 3H), 1.41 (s, 9H), 2.31-2.39 (m, 1H), 2.41-
2.51 (m, 1H), 3.65-3.76 (m, 1H), 3.80 (s, 3H), 4.12-4.19 (m,
2H), 4.26 (d, J ) 16.8 Hz, 1H), 4.39 (d, J ) 16.2 Hz, 1H), 4.43-
4.44 (m, 1H), 4.92-5.04 (m, 2H), 5.14-5.28 (m, 2H), 5.46-
5.61 (m, 1H), 5.76-5.95 (m, 1H), 6.62-6.72 (m, 1H), 6.80 (d,
J ) 8.4 Hz, 2H), 7.10 (d, J ) 8.7 Hz, 2H), 7.24-7.39 (m, 5H)
ppm. 1H NMR (300 MHz, CDCl3, 327 K): δ 1.28 (t, J ) 7.2
Hz, 3H), 1.42 (s, 9H), 2.42 (br, 2H), 3.73-3.75 (m, 1H), 3.80
(s, 3H), 4.19 (q, J ) 7.2 Hz, 2H), 4.35-4.42 (m, 3H), 4.94-
4.99 (m, 2H), 5.15-5.24 (m, 2H), 5.49-5.61 (m, 1H), 5.87 (d,
J ) 15.6 Hz, 1H), 6.69 (dd, J ) 6.0, 15.6 Hz, 1H), 6.82 (d, J )
8.1 Hz, 2H), 7.13 (br, 2H), 7.33 (br, 5H) ppm. ESIMS (m/z, %):
453.2 (M + H+ - Boc, 100%), 553.2 (M + H+, 55%), 575.2 (M
+ Na+, 50%). Anal. Calcd for C31H40N2O7: C 67.37, H 7.30, N
5.07. Found: C 67.36, H 7.39, N 4.94.
(1S,2S,3R,4S,6R)-{4-[Ben zyloxyca r b on yl-(4-m et h oxy-
ben zyl)-a m in o]-2-h yd r oxy-7-oxa -bicyclo[4.1.0]h ep t-3-yl}-
ca r ba m ic Acid ter t-Bu tyl Ester (22). To a stirred suspen-
sion of 5 (482 mg, 1.0 mmol) and Na2HPO4 (284 mg, 2.0 mmol,
2.0equiv) in CH2Cl2 (10 mL) was added m-CPBA (336 mg, 70%,
1.5 mmol, 1.5 equiv) in one portion at 0 °C. The resulting
suspension was stirred at 15 °C for 24 h before saturated
aqueous Na2SO3 (10 mL) was added to quench the reaction.
The resulting two-phase mixture was stirred vigorously for 15
min. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were washed with saturated aqueous Na2SO3 (3 × 10
mL), saturated aqueous NaHCO3 (3 × 10 mL), and brine (3 ×
10 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash column chromatography on silica
gel (petroleum ether/ethyl acetate ) 2:1) to give epoxide 22
(1S,5S)-{5-[Ben zyloxyca r b on yl-(4-m et h oxy-b en zyl)-
a m in o]-cyclop en t-2-en yl}-ca r ba m ic Acid ter t-Bu tyl Ester
(7). To a solution of diolefin 24 (3.5 g, 6.3 mmol) in anhydrous
CH2Cl2 (630 mL) was added bis(tricyclohexyl phosphine)-
benzylidene ruthenium(IV) dichloride (Grubbs catalyst) (260
mg, 0.315 mmol, 0.05 equiv) under N2. The reaction mixture
was stirred at 35 °C for 24 h. After all starting material
disappeared, water (50 mL) was added, and the whole mixture
was stirred vigorously at room temperature for 1 h. The layers
were separated, and the aqueous layer was extracted with CH2-
Cl2 (3 × 50 mL). The combined organic layers were washed
with brine (3 × 100 mL), dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy on silica gel one time (petroleum ether/ethyl acetate )
5:1) to give compound 7 (2.84 g, 99%) as a pale brown oil, and
further twice repeated column chromatography on silica gel
(359 mg, 72%) as a white wax. [R]19 -34.17 (c 0.66, CHCl3).
D
IR (KBr): 3362, 2976, 2931, 1699, 1613, 1514, 1248, 1173 cm-1
.
1H NMR (300 MHz, 55 °C, CDCl3): δ 1.42 (s, 9H), 1.92-2.01
(m, 1H), 2.03-2.08 (m, 1H), 2.84 (br, 1H, ex. D2O), 3.13-3.16
(m, 1H), 3.32-3.34 (m, 1H), 3.79 (s, 3H), 3.82-3.89 (m, 2H),
4.03-4.21 (m, 2H), 4.52 (d, J ) 13.1 Hz, 1H), 5.12 (d, J ) 12.3
Hz, 1H), 5.21 (d, J ) 12.3 Hz, 1H), 6.82 (d, J ) 8.7 Hz, 2H),
7.12 (d, J ) 8.7 Hz,2H), 7.30 (br, 5H) ppm. ESIMS (m/z, %):
499.3 (M + H+, 90%), 521.2 (M + Na+, 100%). Anal. Calcd for
C
27H34N2O7: C 65.04, H 6.87, N 5.62. Found: C 65.26, H 7.16,
N 5.32.
(1R,2S,3R,4S,6S)-{6-[Ben zyloxyca r b on yl-(4-m et h oxy-
ben zyl)-a m in o]-2,3,4-tr i h yd r oxyl-cycloh exyl}-ca r ba m ic
Acid ter t-Bu tyl Ester (23). To a mixture of 0.2 N H2SO4 and
dioxane (20 mL, 1:1, v/v) was added epoxide 22 (396 mg, 0.79
mmol) at 0 °C. The reaction mixture was stirred at 10 °C for
8 h and then treated with saturated aqueous NaHCO3 (20 mL).
The mixture was extracted with ethyl acetate (3 × 20 mL).
The combined organic layers were washed with brine (3 × 10
mL), dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate ) 1:5) to give triol 23 (334 mg,
gave a colorless oil for analysis. [R]18 +48.1 (c 1.04, CHCl3).
D
IR (neat): 3345, 3064, 3034, 2977, 2935, 1695, 1614, 1514,
1
1365, 1247, 1173 cm-1. H NMR (300 MHz, 55 °C, CDCl3): δ
1.44 (s, 9H), 2.40 (br, 2H), 3.79 (s, 3H), 4.42-4.72 (m, 3H),
4.87 (br, 1H), 5.15 (bs, 2H), 5.64 (br, 1H), 5.74 (br, 1H), 6.82
(d, J ) 8.4 Hz, 2H), 7.11 (bs, 2H), 7.19-7.29 (m, 5H) ppm.
ESIMS (m/z, %): 353.2 (M + H+ - Boc, 70%), 453.3 (M + H+,
100%). Anal. Calcd for C26H32N2O5: C 69.01, H 7.13, N 6.19.
Found: C 68.70, H 7.33, N 6.25.
82%) as a white wax. [R]20 -37.0 (c 1.09, CHCl3). IR (KBr):
D
3404, 2976, 2932, 1691, 1614, 1514, 1248, 1174 cm-1. 1H NMR
(300 MHz, 55 °C, CDCl3): δ 1.34 (s, 9H), 1.52-1.56 (m, 1H),
1.97-2.10 (m, 1H), 3.70 (s, 3H), 3.81 (bs, 2H), 3.97-3.98 (m,
1H), 4.17 (d, J ) 15.6 Hz, 1H), 4.28 (br, 2H), 4.49 (d, J ) 15.6
Hz, 1H), 5.07 (d, J ) 12.3 Hz, 1H), 5.13 (d, J ) 12.3 Hz, 1H),
6.71 (d, J ) 8.7 Hz, 2H), 7.05 (d, J ) 8.7 Hz, 2H), 7.18-7.22
(m, 5H) ppm. ESIMS (m/z, %): 417.3 (M + H+ - Boc, 40%),
517.3 (M + H+, 100%). Anal. Calcd for C27H36N2O8: C 62.78,
H 7.02, N 5.42. Found: C 63.02, H 7.26, N 5.14.
(1R,2R,3S,5S)-{5-[Ben zyloxyca r bon yl-(4-m eth oxy-ben -
zyl)-a m in o]-2,3-d ih yd r oxy-cyclop en tyl}-ca r ba m ic Acid
ter t-Bu tyl Ester (25). Compound 7 (864 mg, 1.88 mmol) was
converted into diol 25 according to a similar procedure as for
triol 21. Purification by flash column chromatography on silica
gel (petroleum ether/ethyl acetate ) 1:1) afforded 25 (855 mg,
94%) as a white wax. [R]19 +30.54 (c 1.10, CHCl3). IR (KBr):
D
3421, 3034, 2977, 2934, 1699, 1614, 1514, 1248, 1174 cm-1
.
1H NMR (300 MHz, CDCl3): δ 1.43 (s, 9H), 1.74-1.79 (m, 1H),
2.00-2.05 (m, 1H), 2.58 (br, 1H, ex. D2O), 2.93 (br, 1H, ex.
D2O), 3.79 (s, 3H), 4.06-4.26 (m, 3H), 4.37-4.48 (m, 2H),
4.80-4.82 (m, 1H), 5.14 (bs, 2H), 6.82 (d, J ) 8.1 Hz, 2H),
7.08-7.10 (m, 2H), 7.21-7.32 (m, 5H) ppm. ESIMS (m/z, %):
487.2 (M + H+, 100%). Anal. Calcd for C26H36N2O7: C 64.18,
H 7.04, N 5.76. Found: C 64.26, H 7.25, N 5.67.
(1S,2R,3S,4R,5S)-4,5-Diam in ocycloh exan e-1,2,3-tr iol Hy-
d r och lor id e (2). Triol 23 (260 mg, 0.5 mmol) was converted
into compound 2 (103 mg, 87%) according to a similar
procedure for compound 1, as an off-white solid. [R]20 -18.0
D
(c 0.91, H2O). IR (KBr): 3360, 2926, 1602, 1505, 1039 cm-1
.
1H NMR (500 MHz, D2O): δ 1.82-1.98 (m, 2H, H6a, H6e), 3.32
(dd, 1H, J 3,4 ) 10.3 Hz, J 4,5 ) 10.6 Hz, H4), 3.53 (td, 1H, J 4,5
) J 5,6a ) 11.1 Hz, J 5,6e ) 4.9 Hz, H5), 3.76-3.82 (m, 2H, H2,
H3), 3.89-3.91 (m, 1H, H1) ppm. 13C NMR (125 MHz, D2O): δ
32.61, 49.49, 55.49, 69,68, 69.87, 72.89 ppm. ESIMS (m/z, %):
163.1 (M + H+, 100%). HR-MALDI-MS calcd for C6H15N2O3
(M + H+) 163.1077, found 163.1078.
(1S,2R,3R,4S)-3,4-Dia m in ocyclop en t a n e-1,2-d iol H y-
d r och lor id e (3). Diol 25 (243 mg, 0.5 mmol) was converted
into compound 3 (97 mg, 95%) according to a similar procedure
as for compound 1, as an off-white solid. [R]20 +20.9 (c 1.20,
D
H2O). IR (KBr): 3370, 2995, 1589, 1489, 1046, 816 cm-1. H
1
NMR (300 MHz, D2O): d 1.86 (dt, 1H, J 5R,5â ) 14.4 Hz, J 1,5R
J 4,5R ) 6.5 Hz, H5R), 2.25 (ddd, 1H, J 1,5â ) 4.8 Hz, J 4,5â ) 9.6
Hz, J 5R,5b ) 14.4 Hz, H5â), 3.70 (dd, 1H, J 2,3 ) 5.8 Hz, J 3,4
)
(4S,5S,2E)-Eth yl {5-[Ben zyloxyca r bon yl-(4-m eth oxy-
b en zyl)a m in o]-(4-t-b u t oxyca r b on yl a m in o)oct a -2,7-d i-
en a te (24). To a solution of freshly prepared aldehyde 17 (3.5
g, 7.2 mmol) in THF (250 mL) was added in one portion
(carbethoxymethylene)triphenylphosphorane (Ph3PdCHCOOEt)
(5.0 g, 14.4 mmol, 2.0 equiv) at 0 °C. The reaction mixture
was stirred at room temperature overnight. The solvent was
removed in vacuo, and the crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl
acetate ) 6:1) to afford (2E)-2,7-diene 24 (3.72 g, 93%) as a
)
10.5 Hz, H3), 3.91 (dt, 1H, J 4,5â ) 9.6 Hz, J 3,4 ) J 4,5R ) 6.4 Hz,
H4), 4.22-4.26 (m, 2H, H1, H2) ppm. 13C NMR (75 MHz, D2O):
δ 36.53, 54.75, 57.46, 73.62, 73.65 ppm. ESIMS (m/z, %): 115.2
(M + H+ - H2O, 55%), 133.2 (M + H+, 100%). HR-MALDI-
MS calcd for C5H13N2O2 (M + H+) 133.0972, found 133.0971.
(1R,2R,3S,5S)-{3-[Ben zyloxyca r bon yl-(4-m eth oxy-ben -
zyl)-a m in o]-6-oxa - bicyclo[3.1.0]h ex-2-yl}-ca r ba m ic Acid
5320 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis of Vicinal trans-Diaminocyclitols
ter t-Bu tyl Ester (26). To a stirred suspension of 7 (1.36 g,
3.0 mmol) and NaHCO3 (0.51 g, 6.0 mmol, 2.0 equiv) in CH2-
Cl2 (60 mL) was added m-CPBA (1.35 g, 70%, 6.0 mmol, 2.0
equiv) in one portion at 0 °C. The resulting suspension was
stirred at 15 °C for 24 h before saturated aqueous Na2SO3 (50
mL) was added. The resulting two-phase mixture was stirred
vigorously for 15 min. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with saturated aqueous
Na2SO3 (3 × 50 mL), saturated aqueous NaHCO3 (3 × 50 mL),
and brine (3 × 50 mL), dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate ) 5:1) to give
epoxide 26 (1.09 g, 78%) as a white wax. [R]19D +31.33 (c 1.26,
CHCl3). IR (KBr): 3340, 2978, 2936, 1703, 1613, 1515, 1248,
CDCl3): δ 1.45 (s, 9H), 1.73-1.77 (m, 1H), 1.88 (bs, 1H, ex.
D2O), 1.96-2.01 (m, 1H), 3.55 (bs, 1H), 3.80 (s, 3H), 4.06 (d, J
) 14.7 Hz, 1H), 4.13 (dd, J ) 5.1, 6.9 Hz, 1H), 4.53-4.57 (m,
2H), 5.02 (d, J ) 14.7 Hz, 1H), 5.48 (d, J ) 4.5 Hz, 1H, ex.
D2O), 6.86 (d, J ) 8.7 Hz, 2H), 7.29 (d, J ) 8.4 Hz, 2H) ppm.
ESIMS (m/z, %): 379.2 (M + H+, 100%). Anal. Calcd for
19H26N2O6: C 60.30, H 6.93, N 7.40. Found: C 60.27, H 7.00,
N 7.21.
(1R,2R,3R,4S)-3,4-Dia m in ocyclop en t a n e-1,2-d iol Hy-
C
d r och lor id e (4). Compound 28 (118 mg, 0.31 mmol) was
converted into compound 4 (60 mg, 94%) according to a similar
procedure as for compound 1, as an off-white solid. [R]20D +16.6
(c 2.68, H2O). IR (KBr): 3370, 3003, 1599, 1489, 1047, 816
1
cm-1. H NMR (300 MHz, D2O): δ 1.61 (ddd, 1H, J 4,5â ) 4.5
Hz, J 1,5â ) 4.2 Hz, J 5R,5â ) 14.6 Hz, H5â), 2.52 (ddd, 1H, J 1,5â
)
1
1173 cm-1. H NMR (300 MHz, CDCl3): δ 1.44 (s, 9H), 1.96-
5.5 Hz, J 4,5R ) 9.0 Hz, J 5R,5â ) 14.6 Hz, H5R), 3.72 (ddd, 1H,
J 3,4 ) 6.0 Hz, J 4,5â ) 5.0 Hz, J 4,5R ) 9.0 Hz, H4), 3.81 (dd, 1H,
J 2,3 ) 6.0 Hz, J 3,4 ) 6.0 Hz, H3), 4.00-4.04(m, 1H, H1), 4.08-
4.10(m, 1H, H2) ppm. 13C NMR (75 MHz, D2O): δ 37.19, 5437,
2.14 (m, 2H), 3.43 (bs, 1H), 3.55 (bs, 1H), 3.79 (s, 3H), 4.29 (d,
J ) 16.2 Hz, 1H), 4.40-4.78 (m, 3H), 5.14-5.23 (m, 2H), 6.82
(d, J ) 8.4 Hz, 2H), 7.07-7.12 (m, 2H), 7.22-7.42 (m, 5H) ppm.
ESIMS (m/z, %): 469.3 (M + H+, 100%), 491.2 (M + Na+, 10%).
Anal. Calcd for C26H32N2O6: C 66.65, H 6.88, N 5.98. Found:
C 66.62, H 6.99, N 5.88.
5789, 76.88, 77.01 ppm. ESIMS (m/z, %): 115.2 (M + H+
-
H2O, 40%), 133.2 (M + H+, 100%). HR-MALDI-MS calcd for
C5H13N2O2 (M + H+) 133.0972, found 133.0972.
(1R,5S,6R,7R)-[7-Hyd r oxy-4-(4-m eth oxy-ben zyl)-3-oxo-
2-oxa -4-a za -bicyclo [3.2.1]oct-6-yl]-ca r ba m ic Acid ter t-
Bu tyl Ester (28). To a solution of epoxide 26 (580 mg, 1.23
mmol) in CH2Cl2 (60 mL) was added D-camphor-10-sulfonic
acid (143 mg, 0.62 mmol, 0.5 equiv) at 0 °C. The reaction
mixture was stirred at room temperature for 24 h before it
was quenched with saturated aqueous NaHCO3 (20 mL). The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were
washed with brine (3 × 20 mL), dried (Na2SO4), and concen-
trated in vacuo. The crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl
acetate ) 1:1) to give compound 28 (403 mg, 86%) as a white
wax. [R]19D -27.99 (c 1.09, CHCl3). IR (KBr): 3437, 2930, 1681,
Ack n ow led gm en t. This work was financially sup-
ported by the Major State Basic Research and Develop-
ment Program (G2000077500), NSFC Team Grant,
Chinese Academy of Sciences (KGCX2-SW-209) and
Shanghai Municipal Commission of Science and Tech-
nology (03DZ19203). The authors thank Dr. Terrence
R. Burke, J r. for English correction.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 1-4 and 20 and NOESY spectra of
compounds 1-3, 20, and 28. This material is available free of
charge via the Internet at http://pubs.acs.org.
1614, 1514, 1461, 1248, 1174 cm-1
.
1H NMR (300 MHz,
J O0496547
J . Org. Chem, Vol. 69, No. 16, 2004 5321