Synthesis of 1,4-diaminocyclitols from L-serine methyl ester

Article abstract of DOI:10.1021/jo960691a

L-Serine methyl ester hydrochloride was converted to (S)-2-[N-(benzyloxycarbonyl)amino]-3-(tert-butyldimethylsiloxy)propana l (6). Homocoupling of 6 promoted by [V₂Cl₃(THF)₆]₂[Zn₂Cl₆] (1) gave C₂-symmetric diol (7). After manipulation of protecting groups and Swern oxidation, 7 was converted to a 1,6-dialdehyde 10. Intramolecular pinacol coupling of 10 with 1 gave a selectively protected 1,4-diamino-2,3,5,6-tetrahydroxycyclohexane, which is the key skeleton of Fortimicin AM and AK.

Full text of DOI:10.1021/jo960691a

5528
J . Org. Chem. 1996, 61, 5528-5531
Syn th esis of 1,4-Dia m in ocyclitols F r om L-Ser in e Meth yl Ester
Min Kang, J eonghan Park, Andrei W. Konradi, and Steven F. Pedersen*
Department of Chemistry, University of California, Berkeley, California 94720
Received April 16, 1996X
L-Serine methyl ester hydrochloride was converted to (S)-2-[N-(benzyloxycarbonyl)amino]-3-(tert-
butyldimethylsiloxy)propanal (6). Homocoupling of 6 promoted by [V2Cl3(THF)6]2[Zn2Cl6] (1) gave
C2-symmetric diol (7). After manipulation of protecting groups and Swern oxidation, 7 was converted
to a 1,6-dialdehyde 10. Intramolecular pinacol coupling of 10 with 1 gave a selectively protected
1,4-diamino-2,3,5,6-tetrahydroxycyclohexane, which is the key skeleton of Fortimicin AM and AK.
In tr od u ction
The fortimicins are a family of broad-spectrum anti-
biotics first isolated from the culture broths of a soil mold,
Micromonospora olivoasterospora.1 Several racemic and
enantioselective syntheses of fortamine and epi-fortamine
and the diaminocyclitol portions of many of the fortimicins
have been described.2 The majority of these syntheses
have relied on functional group manipulation of existing
six-membered rings. We felt that epi-fortamine, the
aglycon core of two minor fortimicins, namely fortimicin
AM and AK (Figure 1), could be constructed from two
pinacol coupling reactions as depicted in Figure 2.3 This
approach would involve an intermolecular, homocoupling
reaction to set the trans-diol unit, followed by an in-
tramolecular coupling to give the cis-diol. Formally, this
would involve coupling the dialdehyde shown in Figure
2. However, this substrate lacks a stereogenic center and
would exist in its tautomeric enol form. We therefore
turned our attention to a synthon of this dialdehyde,
namely a suitably protected serinal derivative. Herein,
we describe the details of this approach and the synthesis
of a protected, N-demethyl-epi-fortamine core.
F igu r e 1. Fortimicin AM (AK).
F igu r e 2.
Sch em e 1
Resu lts a n d Discu ssion
The synthesis of (S)-2-[N-(benzyloxycarbonyl)amino]-
3-(tert-butyldimethylsiloxy)propanal (N-Cbz-O-TBS-L-
serinal) 6, the protected serinal chosen for this route, is
illustrated in Scheme 1.4 It is worth mentioning that all
steps leading to 6 proceeded in high yield and, for the
purposes of this synthesis, did not require any purifica-
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) (a) Nara, T.; Yamamoto, M.; Kawamoto, I.; Takayama, K.;
Okachi, R.; Takasawa, S.; Sato, T.; Sato, S. J . Antibiot. 1977, 30, 533.
(b) Okachi, R.; Takasawa, S.; Sato, T.; Sato, S.; Yamamoto, M.;
Kawamoto, I.; Nara, T. J . Antibiot. 1977, 30, 541. (c) Egan, R. S.;
Stanaszek, R. S.; Cirovic, M.; Mueller, S. L.; Tadanier, J .; Martin, J .
R.; Collum, P.; Goldstein, A. W.; De Vault, R. L.; Sinclair, A. C.; Fager,
E. E.; Mitscher, L. A. J . Antibiot. 1977, 30, 552.
(2) (a) Knapp, S.; Sebastian, M. J .; Ramanathan, H. J . Org. Chem.
1983, 48, 4786. (b) Knapp, S.; Sebastian, M. J .; Ramanathan, H.;
Bharadwaj, P.; Potenza, J . A. Tetrahedron 1986, 42, 3405. (c) Kuo, C.
H.; Wendler, N. L. Tetrahedron Lett. 1984, 25, 3429. (d) Kobayashi,
S.; Kamiyama, K.; Ohno, M. J . Org. Chem. 1990, 55, 1169. (e) Sakairi,
N.; Hayashida, M.; Amanl, A.; Kuzuhara, H. J . Chem. Soc., Perkin
Trans. 1 1990, 1301. (f) Liu, P.; Vandewalle, M. Tetrahedron Lett. 1993,
34, 3625.
(3) (a) Freudenberger, J . H.; Konradi, A. W.; Pedersen, S. F. J . Am.
Chem. Soc. 1989, 111, 8014. (b) Takahara, P. M.; Freudenberger, J .
H.; Konradi, A. W.; Pedersen, S. F. Tetrahedron Lett. 1989, 30, 7177.
(c) Konradi, A. W.; Pedersen, S. F. J . Org. Chem. 1990, 55, 4506. (d)
Park, J .; Pedersen, S. F. J . Org. Chem. 1990, 55, 5924. (e) Raw, A. S.;
Pedersen, S. F. J . Org. Chem. 1991, 56, 830. (f) Konradi, A. W.;
Pedersen, S. F. J . Org. Chem. 1992, 57, 28. (g) Park, J .; Pedersen, S.
F. Tetrahedron 1992, 48, 2069. (h) Konradi, A. W.; Kemp, S. J .;
Pedersen, S. F. J . Am. Chem. Soc. 1994, 116, 1316.
tion steps. Aldehyde 6 was then added to [V2Cl3-
(THF)6]2[Zn2Cl6] (1), prepared in situ from VCl3(THF)3
and zinc dust. After stirring for 4 h, the reaction mixture
was worked up with 10% aqueous sodium tartrate. 1H
and 13C NMR spectroscopy of the product were consistent
with the desired, C2-symmetric, diamino diol 7 (Scheme
1). The 3,4-diol unit in 7 was protected with cyclohex-
anone diethyl ketal followed by removal of the tert-
butyldimethysilyl groups using tetrabutylammonium
fluoride to yield diol 9 (Scheme 2). Swern oxidation of 9
gave dialdehyde (10) in 95% mass recovery.
(4) The optical purity of the aldehyde (6) was confirmed as follows.
A sample of the aldehyde (6) was reduced with NaBH4, giving another
sample of the alcohol 5b. A racemic sample of the alcohol 5c was
prepared by partial protection of N-Cbz-2-amino-1,3-propanediol with
tert-butyldimethylchlorosilane. The Mosher esters of 5a , 5b, and 5c
were compared by 1H NMR spectroscopy and gas chromatography.
S0022-3263(96)00691-3 CCC: $12.00 © 1996 American Chemical Society

Synthesis of 1,4-Diaminocyclitols
J . Org. Chem., Vol. 61, No. 16, 1996 5529
Sch em e 2
F igu r e 3.
(32.1 mmol) of L-serine methyl ester hydrochloride (2) and 15.9
g (96.4 mmol) of K2CO3‚1.5 H2O in 25 mL of H2O was added a
solution of 5.05 mL (6.03 g, 35.4 mmol) of benzyl chloroformate
in 25 mL of THF. The two phases were stirred vigorously for
4 h while warming to rt, and then 25 mL of hexanes was
added. The aqueous layer was extracted with Et2O (2 × 25
mL). The combined organic layers were washed with 5% citric
acid (25 mL) and saturated NaCl (25 mL), dried with MgSO4,
and evaporated to give 8.17 g (mass recovery 100%) of a clear
1
oil. On the basis of TLC and H NMR spectroscopy, the crude
product was judged pure enough for use in the next step
without purification. An analytical sample was purified by
flash chromatography on silica gel using EtOAc/hexanes: 1H
NMR (500 MHz, CDCl3) δ 7.34-7.29 (m, 5H), 5.79 (d, J ) 6.7,
1H), 5.10 (s, 2H), 4.43 (t, J ) 3.7, 1H), 3.97 (dd, J ) 2.7, J )
10.9, 1H), 3.89 (dd, J ) 2.5, J ) 11.0, 1H), 3.75 (s, 3H), 2.03
(bs, 1H); 13C NMR (125 MHz, CDCl3) δ 171.0, 156.2, 136.0,
128.5, 128.2, 128.1, 67.2, 63.2, 56.0, 52.7; [R]D +7.4° (c 0.0199,
CHCl3). Anal. Calcd for C12H15NO5: C, 56.91; H, 5.97; N, 5.53.
Found: C, 57.23; H, 5.92; N, 5.28.
Several conditions were explored for affecting the
intramolecular pinacol coupling of 10. We eventually
found that it is crucial for 10 to be added slowly (3 h) to
a solution of 1 in the presence of 10 equiv of dimethyl-
formamide.5 One role that dimethylformamide was
expected to play in this reaction was competing with
binding of the benzyloxy carbonyl groups in the substrate
(i.e. the Cbz groups). If binding of one of these groups
were to take place (forming a chelate with a vanadium-
(II) ion that included one of the aldehyde oxygens), then
the resulting transition state required to bring the second
aldehyde into the coordination sphere of the vanadium
ion would be quite strained (i.e. “boat like”). As can be
seen in Figure 3, if the benzyloxy carbonyl groups are
not involved in binding, then a chair-like transition state
would be available for coupling. The overall yield of 11
from 9 was 71%. The expected cis-diol stereochemistry
of 11 was confirmed by X-ray analysis of a derivative.6
In conclusion, we have accomplished the synthesis of
N-demethyl-epi-fortamine, a 1,4-diaminocyclitol, from
commercially available L-serine methyl ester hydrochlo-
ride (2) in nine steps and an overall yield of 36%.
Furthermore, in only two steps was purification by
chromatography required (one of these being of the final
product). Our approach utilizes two stereoselective pi-
nacol coupling reactions to generate the cyclitol skeleton
and can conceivably be used to generate other cyclitols
starting from simple, acyclic aldehydes.
(2S)-2-[N -(Be n zyloxyca r b on yl)a m in o]-3-(t er t -b u t yl-
d im eth ylsiloxy)p r op a n oic Acid , Meth yl Ester (4). To a
solution of 7.97 g (31.3 mmol) of crude 3 and 2.62 g (38.5 mmol)
of imidazole in 30 mL of DMF was added 5.32 g (35.3 mmol)
of tert-butyldimethylchlorosilane. The mixture was stirred
under an atmosphere of N2 for 8 h, during which time a solid
precipitate formed. The reaction mixture was poured into 150
mL of ice-water, and the resulting suspension was sequen-
tially extracted with Et2O (150 mL) and hexanes (150 mL).
The combined organic layers were washed with H2O (3 × 100
mL) and saturated NaCl (100 mL), dried with MgSO4, and
evaporated to give 11.00 g (mass recovery 96% from 3) of a
1
clear oil. On the basis of TLC and H NMR spectroscopy, the
crude product was judged pure enough for use in the next step
without purification. An analytical sample was purified by
flash chromatography on silica gel using EtOAc/hexanes: 1H
NMR (500 MHz, CDCl3) δ 7.37-7.31 (m, 5H), 5.60 (d, J ) 8.1,
1H), 5.14 (d, J ) 12.2, 1H), 5.10 (d, J ) 12.2, 1H), 4.42 (m,
1H), 4.06 (dd, J ) 2.4, J ) 10.0, 1H), 3.83 (dd, J ) 2.9, J )
10.0, 1H), 3.73 (s, 3H), 0.84 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 170.9, 155.9, 136.2, 128.5,
128.15, 128.11, 67.0, 63.6, 55.9, 52.3, 25.6, 18.1, -5.6, -5.7;
[R]D +18.6° (c 0.0227, CHCl3). Anal. Calcd for C18H29NO5Si:
C, 58.83; H, 7.95; N, 3.81. Found: C, 58.50; H, 7.90; N, 4.03.
(2R)-2-[N-(Ben zyloxyca r b on yl)a m in o]-3-(ter t-b u t yl-
d im eth ylsiloxy)-1-p r op a n ol (5). To a 0 °C solution of 10.80
g (30.3 mmol) of crude 4 and 7.13 g (64.2 mmol) of CaCl2 in
THF (40 mL) and absolute ethanol (60 mL) was added 4.86 g
(128.4 mmol) of NaBH4. The mixture was stirred under an
atmosphere of N2 for 3 h while warming to rt and then poured
into 5% citric acid (200 mL) at 0 °C, causing the evolution of
gas. The resulting suspension was extracted with Et2O (2 ×
150 mL), and the combined organic layers were washed with
saturated NaHCO3 (2 × 75 mL), H2O (2 × 75 mL), and
saturated NaCl (75 mL); dried with MgSO4; and evaporated
to give 9.43 g (mass recovery 94% from 4) of a clear oil. On
Exp er im en ta l Section
See ref 3e for general experimental details.
(2S)-2-[N-(Ben zyloxyca r b on yl)a m in o]-3-h yd r oxyp r o-
p a n oic Acid , Meth yl Ester (3). To a 0 °C solution of 5.00 g
(5) For the intramolecular pinacol coupling reaction of 1,4-ketoal-
dehydes, we found that the addition of 5 equiv of DMF increases the
yield of cyclized product. See ref 3e.
(6) The stereochemistry of 11 was confirmed by X-ray analysis of a
derivative, 13. The authors have deposited atomic coordinates for this
structure with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
1
the basis of TLC and H NMR spectroscopy, the crude product
was judged pure enough for use in the next step without
purification. An analytical sample was purified by flash
chromatography on silica gel using EtOAc/hexanes: 1H NMR
(500 MHz, CDCl3) δ 7.35-7.31 (m, 5H), 5.39 (d, J ) 6.0, 1H),
5.10 (s, 2H), 3.84 (dd, J ) 10.6, J ) 2.7, 1H), 3.81 (dd, J )
10.2, J ) 2.7, 1H), 3.77 (dd, J ) 10.8, J ) 3.0, 1H), 3.72 (m,
1H), 3.69 (dd, J ) 10.8, J ) 4.3, 1H), 2.27 (bs, 1H), 0.87 (s,
9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
156.4, 136.3, 128.5, 128.14, 128.10, 66.8, 63.9, 63.8, 52.9, 25.8,

5530 J . Org. Chem., Vol. 61, No. 16, 1996
Kang et al.
18.1, -5.61, -5.63; [R]D +14.9° (c 0.0215, CHCl3). Anal. Calcd
for C17H29NO4Si: C, 60.14; H, 8.61; N, 4.13. Found: C, 59.92;
H, 8.59; N, 4.11.
2H), 0.86 (s, 18H), 0.04 (s, 6H), 0.03 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 156.0, 136.5, 128.5, 128.11, 128.08, 109.4, 74.9,
66.8, 63.0, 51.3, 36.6, 25.8, 25.0, 23.8, 18.1, -5.4, -5.6; TLC
(30% ethylacetate in hexane) Rf 0.77.
(2S)-2-[N -(Be n zyloxyca r b on yl)a m in o]-3-(t er t -b u t yl-
d im eth ylsiloxy)p r op a n a l (6). To a stirred solution of 2.05
mL (23.5 mmol) of oxalyl chloride in 50 mL of dry CH2Cl2 at
-63 °C (dry ice/CHCl3) was added a solution of 2.22 mL (31.3
mmol) of dry DMSO in 50 mL of CH2Cl2 over 15 min. After 5
min of stirring, a solution of 5.32 g (15.7 mmol) of crude 5 in
50 mL of CH2Cl2 was added over 15 min, resulting in a cloudy
solution which was stirred for 30 min. Neat triethylamine
(8.73 mL, 62.6 mmol) was then added over 10 min, generating
first a clear solution and later a solid precipitate after stirring
for 30 min at -63 °C. TLC of the reaction mixture at this
point showed no starting material. After the cooling bath was
removed, 20% saturated KHSO4 (80 mL) and hexanes (200 mL)
were added to the reaction mixture, which was stirred vigor-
ously while warming, generating two phases. The phases were
separated, and the aqueous layer was extracted with Et2O (200
mL). The combined organic layers were washed with satu-
rated NaHCO3 (80 mL × 2), H2O (80 mL × 3), saturated NaCl
(80 mL × 2), then dried over MgSO4, and evaporated in vacuo,
at or below rt, giving 5.05 g (mass recovery 95% from 5) of a
clear oil. To minimize racemization, the crude product was
used immediately in the next step without purification: 1H
NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 7.37-7.31 (m, 5H), 5.62
(bd, J ) 6.6, 1H), 5.13 (s, 2H), 4.31 (pent, J ) 3.6, 1H), 4.21
(dd, J ) 2.9, J ) 10.4, 1H), 3.87 (dd, J ) 4.1, J ) 10.4, 1H),
0.84 (s, 9H), 0.02 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 198.8,
156.0, 128.5, 128.2, 128.1, 67.0, 61.8, 61.2, 25.6, 18.1, -5.69,
-5.71.
(2S,3R,4R,5S)-2,5-Bis[N-(b en zyloxyca r b on yl)a m in o]-
3,4-cycloh exylid en e-1,3,4,6-h exa n etetr ol (9). The crude
product 8 was dissolved in THF (20 mL) and treated with 18.9
mL of TBAF (1.0 M, THF solution) for 15 min. The reaction
mixture was then diluted with CH2
Cl2 (100 mL), washed with
water (50 mL) and brine (50 mL), dried over MgSO4, and
concentrated to give an oil. The product was purified by flash
chromatography on silica gel using ethyl acetate/hexanes to
give 1.93 g (70% from 7) of a white oily foam: IR (CH2
Cl2,
cm-1) ν 3533, 3429, 2941, 1718, 1510, 1070; 1H NMR (400 MHz,
CDCl3) δ 7.34-7.28 (m, 10H), 5.44 (d, J ) 9.2, 2H), 5.08 (s,
4H), 3.93 (m, 4H), 3.75 (dd, J ) 11.3, 3.4, 2H), 3.65 (dd, J )
11.2, 5.3, 2H), 2.59 (bs, 2H, OH), 1.53 (m, 8H), 1.36 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 156.8 (C), 136.1 (C), 128.4 (CH),
128.0 (CH), 127.9 (CH), 109.8 (C), 76.8 (CH), 67.0 (CH2), 63.7
(CH2), 51.0 (CH), 36.2 (CH2), 24.8 (CH2), 23.7 (CH2); [R]D
)
-15.1° (c 0.0075, CH2
Cl2); TLC (100% ethyl acetate) Rf 0.61;
Anal. Calcd for C28H36N2O8: C, 63.62; H, 6.86; N, 5.30.
Found: C, 63.28; H, 6.94; N, 5.21.
(2S,3R,4R,5S)-2,5-Bis[N-(b en zyloxyca r b on yl)a m in o]-
3,4-cycloh exylid en e-3,4-d ih yd r oxy-1,6-h exa n ed ia l (10).
This dialdehyde was synthesized using the procedure described
1
for synthesis of 6. A white foam was obtained whose H NMR
was consistent with the desired product (95% mass recovery).
To minimize racemization, the crude product was used im-
mediately in the next step without purification.
(1S,2S,3R,4R,5S,6R)-2,5-Bis[N-(ben zyloxycar bon yl)am i-
n o]-3,4-cycloh exylid en e-1,3,4,6-cycloh exa n etetr ol (11).
(2S,3R,4R,5S)-2,5-Bis[N-(b en zyloxyca r b on yl)a m in o]-
1,6-bis(ter t-bu tyld im eth ylsiloxy)-3,4-h exa n ed iol (7). Un-
der an atmosphere of N2, a mixture of 6.05 g (16.2 mmol) of
VCl3(THF)3, 578 mg (8.84 g atoms) of zinc dust, and 30 mL of
dry CH2Cl2 was stirred vigorously for 30 min, giving a green
solution. A solution of 4.72 g (14.0 mmol) of crude 6 in 50 mL
of CH2Cl2 was added rapidly, generating a dark brown
solution. After 4 h of stirring, the reaction mixture was opened
to the air and poured into 10% aqueous sodium tartrate (150
mL). The two phases were stirred vigorously for 12 h, giving
a green aqueous layer and a pale yellow CH2Cl2 layer. The
aqueous phase was separated and extracted with CH2Cl2 (3
× 40 mL). The combined organic layers were dried with
MgSO4, filtered through Celite, and evaporated to give 4.60 g
(mass recovery 97% from 6) of a white solid. On the basis of
Under an atmosphere of N2
, a mixture of 1.58 g (4.22 mmol)
of VCl3(THF)3, 0.17 g (2.53 g atoms) of zinc dust, and 15 mL
of dry CH2Cl2 was stirred vigorously for 30 min, giving a green
solution. DMF (1.54 g, 21.1 mmol) was added. A solution of
1.01 g (1.92 mmol) of crude 10 in 5 mL of CH2
Cl2 was added
over 3 h by syringe pump. After stirring for an additional 3
h, the reaction mixture was opened to air and poured into 10%
aqueous sodium tartrate solution (40 mL) and CH2
Cl2 (50 mL).
The two phases were stirred vigorously together for 12 h,
giving a green aqueous layer and a pale yellow CH2Cl2 layer.
The aqueous phase was extracted with CH2Cl2 (3 × 100 mL).
The combined organic layers were dried with MgSO4, filtered
through Celite, and evaporated, to give a yellowish foam. The
residue was purified by flash chromatography on silica gel
using EtOAc/hexanes to give 0.71 g (71% from 9) of a white
1
TLC and H NMR spectroscopy, the crude product was judged
pure enough for use in the next step without purification. An
analytical sample was purified by flash chromatography on
silica gel using EtOAc/hexanes to give a white solid: mp 92-
93 °C; 1H NMR (400 MHz, (CD3)2SO) δ 7.39-7.27 (m, 5H), 6.56
(d, J ) 9.0, 1H), 5.03 (d, J ) 12.6, 1H), 4.93 (d, J ) 12.6, 1H),
4.41 (bs, 1H), 3.70 (q, J ) 7.3, 1H), 3.59-3.55 (m, 2H), 3.47
(dd, J ) 6.3, J ) 9.4, 1H), 0.82 (s, 9H), 0.00 (s, 3H), -0.01 (s,
3H); 13C NMR (100 MHz, (CD3)2SO) δ 155.9, 137.1, 128.2,
127.7, 127.5, 68.7, 65.2, 62.2, 53.7, 25.7, 17.8, -5.4, -5.5; [R]D
+22.0° (c 0.0126, CHCl3). Anal. Calcd for C34H56N2O8Si2: C,
60.32; H, 8.34; N, 4.14. Found: C, 60.32; H, 8.09; N, 4.30.
(2S,3R,4R,5S)-2,5-Bis[N-(b en zyloxyca r b on yl)a m in o]-
1,6-b is(ter t-b u t yld im et h ylsiloxy)-3,4-cycloh exylid en e-
3,4-h exa n ed iol (8). To a stirred solution of 7 (3.55 g, 5.24
mmol) in 60 mL of benzene were added cyclohexanone diethyl
ketal (1.35 g, 7.84 mmol) and a catalytic amount of p-
toluenesulfonic acid (16 mg). After refluxing for 30 min, TLC
showed no starting material. Benzene (40 mL) was removed
by distillation. The remaining solution was cooled to rt and
partitioned between aqueous saturated NaHCO3 (150 mL)
solution and ether (300 mL). The aqueous layer was separated
and extracted with ether (300 mL). The combined organic
layers were washed with brine (100 mL), dried over MgSO4,
and concentrated to give 3.97 g of an oil (mass recovery 99%).
On the basis of TLC and 1H NMR spectroscopy, the crude
product was judged pure enough for use in the next step
without purification: 1H NMR (400 MHz, CDCl3) δ 7.35-7.30
(m, 10H), 5.13 (m, 2H), 5.02 (m, 4H), 4.05 (s, 2H, NH), 3.82
(m, 2H), 3.68 (m, 2H), 3.57 (m, 2H), 1.54 (m, 8H), 1.35 (m,
Cl2, cm-1) ν 3423, 3087, 2941,
solid: mp 176-179 °C; IR (CH2
1
1722, 1514, 1274; H NMR (400 MHz, (CD3)2SO, at 105 °C) δ
7.27-7.26 (m, 10H), 6.71 (d, J ) 9.3, 1H, NH), 6.58 (bs, 1H,
NH), 5.06 (d, J ) 4.1, 4H), 3.86 (t, J ) 2.9, 1H), 3.75 (m, 2H),
3.64 (m, 1H), 3.46 (dd, J ) 9.4, 3.0, 1H), 3.39 (t, J ) 9.9, 1H),
2.96 (bs, 2H, OH), 1.56 (m, 8H), 1.36 (m, 2H);
13C NMR (125
MHz, CDCl3) δ 156.1 (C), 136.2 (C), 128.44 (CH), 128.38 (CH),
128.2 (CH), 128.1 (CH), 128.0 (CH), 112.6 (C), 75.9 (CH), 72.3
(CH), 67.5 (CH), 66.9 (CH), 54.0 (CH), 52.0 (CH), 36.2 (CH2
),
36.1 (CH2), 24.9 (CH2), 23.5 (CH2); high resolution FAB MS
calcd for C28H35N2O8 (MH+) 527.2393, found 527.2389; TLC
(5% methanol in dichloromethane) Rf 0.13.
(1S,2S,3R,4R,5S,6R)-5-Am in o-2-[N-(b en zyloxyca r b o-
n yl)a m in o]-5-N,6-O-ca r bon yl-3,4-cycloh exylid en e-1,3,4,6-
cycloh exa n etetr ol (12). To a solution of 0.81 g (1.53 mmol)
of 11 in 25 mL of 60% aqueous 1,3-dioxane was added 0.16 g
(1.53 mmol) of Na2CO3. After stirring overnight, water (40
mL) was added and the resulting suspension was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were
dried over Na2SO4 and concentrated to give a foam. The
product was purified by flash chromatography on silica gel
using methanol/CH2Cl2 (2%) to give 0.24 g, (30%) of 11 and
0.33 g (51%) of a white foam: IR (CH2Cl2, cm-1) ν 3433, 3340,
3062, 1765, 1724, 1516, 1132, 1070; 1H NMR (400 MHz, (CD3)2-
SO, at 100 °C) δ 7.78 (s, 1H, NH), 7.37-7.28 (m, 5H), 7.22 (d,
J ) 7.9, 1H, NH), 5.06 (d, J ) 1.3, 2H), 4.79 (dd, J ) 8.7, 3.1,
1H), 4.06 (dd, J ) 10.2, 8.1, 1H), 3.87 (t, J ) 8.4, 1H), 3.76 (m,
2H), 3.52 (t, J ) 9.8, 1H), 2.49 (bs, 1H, OH), 1.57 (m, 8H),
1.37 (m, 2H); high resolution FAB MS calcd for C21H27N2O7

Synthesis of 1,4-Diaminocyclitols
J . Org. Chem., Vol. 61, No. 16, 1996 5531
(MH+) 419.1818, found 419.1818; TLC (5% methanol in dichlo-
romethane) Rf 0.16.
(C), 135.7 (C), 133.9 (CH), 132.8 (CH), 132.5 (C), 129.9 (CH),
129.6 (CH), 128.9 (CH), 128.7 (CH), 128.6 (CH), 128.3 (CH),
128.1 (CH), 127.8 (CH), 113.8 (C), 78.4 (CH), 75.0 (CH), 73.5
(CH), 71.7 (CH), 69.3 (CH2), 57.7 (CH), 55.9 (CH), 36.6 (CH2),
36.3 (CH2), 24.8 (CH2), 23.7 (CH2), 23.6 (CH2); high resolution
FAB MS calcd for C35H35N2O9 (MH+) 627.2343, found 627.2333;
TLC (50% ethyl acetate in hexane) Rf 0.42.
(1S,2S,3R,4R,5S,6R)-5-a m in o-2-[N-(b en zyloxyca r b o-
n yl)a m in o]-5-N,6-O-ca r bon yl-3,4-cycloh exylid en e-1-O,5-
N-d iben zoyl-1,3,4,6-cycloh exa n etetr ol (13). To a solution
of 80 mg (0.19 mmol) of oxazolidinone 12 in 3 mL of dichlo-
romethane were added DMAP (46 mg, 0.38 mmol) and tri-
ethylamine (38 mg, 0.38 mmol) followed by benzoyl chloride
(53 mg, 0.38 mmol). After the mixture was stirred for 5 min,
ether (20 mL) was added and the mixture was washed with
5% aqueous citric acid (8 mL), saturated NaHCO3 (8 mL), brine
(8 mL), then dried over Na2SO4, and concentrated to give a
solid. The product was purified by flash chromatography on
silica gel using ethyl acetate/hexanes. The first fraction gave
99 mg (83%) of a white solid. An analytical sample was
recrystalized from ethyl acetate: mp 245-246 °C; IR (CH2-
Cl2, cm-1) ν 3434, 1794, 1728, 1699, 1095; 1H NMR (400 MHz,
CDCl3) δ 8.07-8.05 (m, 2H), 7.69-7.65 (m, 3H), 7.54-7.50 (m,
3H), 7.35-7.31 (m, 7H), 5.60 (m, 3H), 5.12 (s, 2H), 5.02 (t, J )
7.2, 1H), 4.15 (m, 2H), 3.69 (bs, 1H), 1.79-1.33 (m, 10H); 13C
NMR (100 MHz, CDCl3) δ 169.1 (C), 165.2 (C), 155.9 (C), 152.8
Ack n ow led gm en t. S.F.P. is grateful to the National
Institutes of Health (GM38735) for support of this
research.
Su p p or tin g In for m a tion Ava ila ble: An ORTEP drawing
and details of data aquisition for compound 13 (2 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O960691A