LETTER
Stereocontrolled Synthesis of (1R,3R,4S)- and (1S,3R,4S)-3,4-diaminocyclopentanols
427
ammonium formate, formic acid and methanol in the pres-
ence of Pearlman’s catalyst. The alcohol 7 was recovered
and then heated with ammonia in methanol to afford the
product 1. The last two steps suffered low yield because
of isolation problems. On the other hand, the hydrochloric
salt of product 1 was obtained in 93% yield when 6a was
hydrogenated in methanol and hydrochloric acid (pH~2)
in the presence of Pearlman’s catalyst. Under the latter
condition, salt 1 can be obtained directly from diazide 5 in
98% yield. The overall yield from cyclopentadiene to 1 is
about 30%. It is noteworthy that the overall yield of cis-
syn diamine 1 from trans-3,4-epoxycyclopentanol benzyl
ether is 74% and can be done within a week on a gram
scale. The cis-anti diamine 2 has also been synthesized by
the same procedure. The structures of 1 and 2 have been
confirmed by X-ray crystallography of their platinum
complexes.14
O
Ph
O
Ph
NaN3 / NH4Cl
4
O
N3
OH
3
1. MsCl/Py
2. NaN3
OH
O
Ph
Pd(OH)2 / C / H2
MeOH/HCl
2 HCl
H2N
NH2
N3
N 3
1
5
Experimental Procedure: A solution of 3 (816 mg, 4.3
mmol), 40 ml ethanol, 8 ml water, 836 mg sodium azide
and 690 mg ammonium chloride was refluxed for 12
hours. The mixture was cooled to room temperature. Ad-
ditional water (20 ml) was added and the residue extracted
with ether (4x20 ml). The ether layer was washed with 20
ml brine and dried by sodium sulfate. The solvent was re-
moved by reduced pressure and the residue purified by sil-
ica gel chromatography to give compound 4 (957 mg, 4.1
mmol, 96%) as a colorless liquid (8:1=hexanes: ethyl ac-
etate). IR (cm-1): 3500, 2200; 1H NMR (CDCl3): 7.38 (m,
5H), 4.45 (s, 2H), 4.21 (dd, 13.0, 7.0, 1H), 4.06 (m, 1H),
3.60 (dd, 13.0, 7.3, 1H), 2.43 (m, 1H), 2.14 (ddd, 14.3, 7.3,
4.0, 1H), 1.79 (m, 1H); 13C NMR (CDCl3): 137.9, 128.3,
127.6, 76.0, 75.6, 70.9, 66.8, 39.1, 35.7; LC-MS (CI): cal-
cd. for C12H15N3O2: 233, found 234 (M+H).
OH
O
Ph
RHN
NHR
RHN
NHR
7 R = COCF3
6a R = H, b R = COCF3
Scheme
A mixture of 5 (567 mg, 2.2 mmol), 30 ml methanol, 200
mg of 20% palladium hydroxide on carbon (Pearlman’s
catalyst) and 3 ml 2N hydrochloric acid was stirred at 60
psi hydrogen for 6 hours. Removal of the methanol from
the filtrate and lyophilization of the aqueous residue gave
compound 1 as a white amorphous solid (405 mg, 2.1
A solution of 0.29 ml mesyl chloride (3.7 mmol) and 2 ml
dichloromethane was introduced into a mixture of 4 (761
mg, 3.3 mmol), 30 ml dichloromethane and 0.33 ml dry
pyridine at room temperature under nitrogen. The above
solution was stirred for 6 hours, then 5 % aqueous sodium
bicarbonate solution (10 ml) added, and the mixture ex-
tracted with dichloromethane (3x20 ml). The organic lay-
er was washed with 20 ml brine and dried with sodium
sulfate. Removal of the solvent left a semisolid residue,
which was used for next reaction without further purifica-
tion. 1H NMR (CDCl3) confirmed formation of mesylate:
7.30 (m, 5H), 4.95 (dd, 12.3, 7.0, 1H), 4.23 (s, 2H), 4.10
(m, 1H), 3.96 (m, 1H), 3.04 (s, 3H), 2.42 (m, 2H), 2.10 (m,
1H), 1.82 (m, 1H). The mixture of mesylate residue, 30 ml
DMF, 1 ml pyridine and 6 ml water was heated with 424
mg sodium azide at 130 °C for 12 hours. The reaction was
quenched with 20 ml cold water and extracted with ether
(4x20 ml). The crude product was purified by column
chromatography to yield compound 5 (632 mg, 2.4 mmol,
76% of two steps) as a colorless liquid (5:1=hexanes: eth-
1
mmol, 98%). mp 140-145 °C(color change to black); H
NMR (D2O): 4.37 (m, 1H), 3.87 (m, 2H), 2.36 (m, 2H),
1.84 (m, 2H); 13C NMR (D2O): 72.1, 54.5, 39.6; LR-MS
(CI): calcd. for C5H12N2O 116, found 117 (M+H).
Salt 2 was obtained by same reaction conditions as a white
amorphous solid. mp 130-135 °C(color change to black);
1H NMR (D2O): 4.44 (m, 1H), 3.98 (m, 2H), 2.10 (m, 4H);
13C NMR: 70.3, 53.9, 40.0; LR-MS (CI): calcd. for
C5H12N2O 116, found 117 (M+H).
Acknowledgement
The United States Department of Energy (DOE DE-FG02-
97ER62340) has supported this work.
References and Notes
(1) (a) Bitha, P.; Carvajal, S.G.; Citarella, R.V.; Child, R.G.; De-
los Santos, E.F.; Dunne, T.S.; Durr, F.E.; Hlavka, J.J.; Lang,
Jr., S.A.; Linday, H.L.; Morton, G.O.; Thomas, J.P.; Wallace,
R.E.; Lin, Y.; Haltiwanger, R.C. and Pierpont, C.G.; J. Med.
Chem., 1989, 32, 2015; (b) de Costa, B.R.; Bowen, W.D.; Hel-
lewell, S.B.; George, C.; Rothman, R.B.; Reid, A.A.; Walker,
J.M. Jacobson, A.E. and Rice, K.C.; J. Med. Chem., 1989, 32,
1996; (c) Gust, R.; Gelbcke, M.; Angermaier, B.; Bachmann,
1
yl acetate). IR (cm-1): 2200; H NMR (CDCl3): 7.32 (m,
5H), 4.50 (s, 2H), 4.01 (m, 1H), 3.77 (m, 2H), 2.27 (m,
2H), 2.02 (m, 2H); 13C NMR (CDCl3): 137.7, 128.3,
127.6, 75.0, 71.2, 62.5, 35.5; LR-MS (CI): calcd. for
C12H14N6O: 258, found: 259 (M+H).
Synlett 1999, No. 4, 426–428 ISSN 0936-5214 © Thieme Stuttgart · New York