Synthesis of highly functionalized cyclopentanes as precursors of hydroxylated azidocarbonucleosides

Article abstract of DOI:10.1055/s-0029-1217088

Regio- and stereoisomers of functionalized azido amino alcohols with a cyclopentane skeleton were synthesized in enantiomerically pure forms. Enzymatic ring cleavage of racemic2-azabicyclo[2.2.1]hept-5-en-3-one gave the corresponding amino acid and one enantiomer of the lactam stereospecifically. These were protected by esterification and carbamoylation, and then epoxidized. The resulting oxiranes underwent cleavage by sodium azide with complementary stereoselectivities. The regioisomeric products were easily separated by crystallization or column chromatography.

Full text of DOI:10.1055/s-0029-1217088

PAPER
153
Synthesis of Highly Functionalized Cyclopentanes as Precursors of
Hydroxylated Azidocarbonucleosides
H
ighly Function
o
alize
d
Cyclo
r
pentane
á
s
nd Kiss,a Enikö Forró,a Reijo Sillanpää,c Ferenc Fülöp*a,b
a
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, 6720 Szeged, Hungary
Research Group of Stereochemistry of the Hungarian Academy of Sciences, University of Szeged, Eötvös u. 6, 6720 Szeged, Hungary
Fax 0036(62)545705; E-mail: fulop@pharm.u-szeged.hu
b
c
Department of Chemistry, University of Jyväskylä, 40351 Jyväskylä, Finland
Received 8 July 2009; revised 14 September 2009
synthesized via the corresponding azido derivatives.10d,e,12
Some azidonucleoside derivatives and their analogues
have been used in the synthesis of nucleoside-based pep-
tides. b-Amino acid-based peptide oligomers derived
Abstract: Regio- and stereoisomers of functionalized azido amino
alcohols with a cyclopentane skeleton were synthesized in enantio-
merically pure forms. Enzymatic ring cleavage of racemic 2-azabi-
cyclo[2.2.1]hept-5-en-3-one gave the corresponding amino acid
and one enantiomer of the lactam stereospecifically. These were from AZT (5) have been recently synthesized and charac-
protected by esterification and carbamoylation, and then epoxi-
dized. The resulting oxiranes underwent cleavage by sodium azide
with complementary stereoselectivities. The regioisomeric products
were easily separated by crystallization or column chromatography.
terized.13
N
N
NH2
NH2
N
N
Key words: amino acids, carbocycles, nucleosides, amino alco-
hols, enzymes
HO
HO
HO
N
N
N
N
OH
1
OH
HO
HO
2
N
N
For several decades chemists have been interested in the
synthesis of carbocyclic nucleosides because many of
these compounds have important biological activities,1,2
and some are potentially useful as agents for the treatment
of viral infections.3 Many synthetic carbocyclic nucleo-
sides exhibit antitumor,3 cerebroprotective, or
cardioprotective4 effects. Several naturally occurring car-
bocyclic nucleosides, such as aristeromycin (1)5 and nep-
lanocin A (2),6 as well as some of their derivatives,
display antitumor or antibiotic activities.7 The synthetic
carbocyclic nucleosides carbovir (3) and abacavir (4)
have significant antiviral properties, and are useful as
anti-HIV agents.8 The identification of 3¢-azido-3¢-deoxy-
thymidine (5; AZT) as a potent agent for the treatment of
AIDS, and of 3¢-azido-2¢,3¢-dideoxyuridine (6; AZDU) as
a potential anti-HIV agent,9 provoked considerable inter-
est in the synthesis of modified nucleosides. This led to
significant developments in the synthetic chemistry of
azidonucleosides, and other azidonucleoside derivatives
were found to be effective anti-HIV agents.9
H
O
NH
NH2
N
N
N
HO
N
N
N
NH2
3
4
O
O
O
O
N
N
NH
NH
HO
HO
O
O
N3
N3
6
5
Me
N
O
N
N
Me
HO
N
N
HN
OH
O
NH2
Azidonucleosides are also useful as starting materials for
the synthesis of aminonucleoside derivatives that may
have antibacterial or antitumor properties, such as ana-
logues of the antibiotic puromycin (7).9a,10 Whereas many
biologically active azidonucleoside derivatives have been
synthesized, azidocarbonucleosides have received much
less attention,11 despite reports that they are promising an-
tiviral agents and potential substrates for nucleoside ki-
nases.11 Carbocyclic puromycin analogues have been
MeO
7
Figure 1
We present the synthesis of a series of carbocyclic azido-
functionalized amino alcohol stereoisomers starting from
racemic 2-azabicyclo[2.2.1]hept-5-en-3-one (8; Vince’s
lactam); the products are potentially useful as precursors
of carbonucleosides. The synthetic strategy was based on
the functionalization of the olefinic bond of the readily
available lactam 8 by epoxidation through two different
SYNTHESIS 2010, No. 1, pp 0153–0160
x
x
.
x
x
.2
0
0
9
Advanced online publication: 26.10.2009
DOI: 10.1055/s-0029-1217088; Art ID: T13309SS
© Georg Thieme Verlag Stuttgart · New York

154
L. Kiss et al.
PAPER
routes with opposite stereoselectivities, followed by nol as the solvent in the presence of a catalytic amount of
cleavage of the oxirane ring with sodium azide.14
ammonium chloride, it gave two regioisomers, (+)-14 and
(+)-15, in a ratio of 2:1; these could be separated in good
yield by crystallization from hexane–ethyl acetate. The
formation of (+)-14 as the major regioisomer can be ex-
plained in terms of stereoelectronic factors. Because of
the electron-withdrawing inductive effect of N-4, attack
by the azide ion occurs predominantly at C-2, the position
farthest from the carbamate group and closest to the car-
boxylate function in (+)-14 (Scheme 2).
The highly enantioselective (E > 200) hydrolysis of com-
mercial racemic Vince’s lactam (rac-8) by CAL-B (lipase
B from Candida antarctica, produced by submerged fer-
mentation of genetically modified Aspergillus oryzae and
adsorbed on a macroporous resin) in tert-butyl methyl
ether gave the enantiomerically pure amino acid (–)-9 (ee
> 99%) and the (+)-isomer of the lactam [(+)-10; ee >
99%] (Scheme 1).15
The presence of an oxirane moiety is important for the
preparation of 3¢-azido-3¢-deoxynucleosides. An earlier
elaborate study established that oxirane cleavage of fura-
nosyladenine or furanosyluracil epoxides by sodium azide
gave mixtures of the two possible regioisomers, generally
in a ratio of 9:1, with the attack occurring preferentially at
the C-3¢ position,9a,l,m which is the position equivalent to
C-2 in (+)-14 or to C-1 in (–)-13. When the corresponding
carbocyclic acetylated epoxy d-amino alcohol was treated
with sodium azide in aqueous 2-methoxyethanol in the
presence of ammonium chloride, cleavage of the oxirane
ring gave the two regioisomers in a ratio of 4:1, with the
attack by the azide ion occurring predominantly at C-3,12b
the position equivalent to C-2 in (+)-14 or to C-1 in (–)-
13. We are not aware of any previous reports of totally re-
gioselective opening reactions of the oxirane in such sys-
tems. The product with the azide function on C-2
[equivalent to C-3 in (+)-14] was always obtained as the
minor regioisomer in very low yield. Therefore, to obtain
the minor azido regioisomer in reasonable yield, instead
of the epoxy alcohol, we subjected the epoxy amino ester
(–)-13 to oxirane ring opening. It has been shown that
cleavage of the oxirane ring of an epoxidized acetylated g-
amino methyl ester gives an inseparable complex mix-
ture;12b however, cleavage of the oxirane ring of the pro-
tected amino ester (–)-13 gave two regioisomers that
O
O
HN
HN
1S
4R
COOH
H2N
CAL-B, H2O
t-BuOMe
1S
4R
+
8
(–)-9
(+)-10
Scheme 1 Preparation of enantiomerically pure g-amino acid (–)-9
and g-lactam (+)-10 from rac-8
The optically active b-amino acid (–)-9 was transformed
into the tert-butyloxycarbonyl (Boc)-protected amino es-
ter (–)-12 through the corresponding amino ester hydro-
chloride (–)-11 (see below). The next step in the synthetic
pathway was functionalization of the olefinic bond of the
b-amino ester (–)-12. A primary carbamate group has a
cis-stereodirecting effect in the epoxidation of a cycloalk-
ene with a peracid.16 Hence, epoxidation of amino ester
(–)-12 with m-chloroperoxybenzoic acid (MCPBA) in
CH2Cl2 at 0 °C gave a single diastereomer of the epoxy
amino ester (–)-13, in which the oxirane ring and the car-
bamate moiety displayed a cis orientation (Scheme 2).
NMR analysis did not indicate the formation of the trans
diastereoisomer.
The azido function was introduced into the cyclopentane
skeleton of (–)-13 by oxirane ring opening with sodium
azide. When the reaction was performed in aqueous etha-
2S
1S
4R
5R
1. SOCl2, EtOH
70 °C, 2 h, 72%
COOEt
1S
BocHN
4R
1S
4R
COOEt
BocHN
COOH
H2N
MCPBA, CH2Cl2
0 °C, 7 h, 67%
2. Boc2O, Et3N, THF
O
0 °C–20 °C
10 h, 81%
(–)-12
(–)-9
(–)-13
NaN3, NH4Cl, EtOH
H2O, 80 °C, 10 h
crystallization
4R
1R
1S
4R
COOEt
1S
BocHN
COOEt
4R
BocHN
COOEt
BocHN
NaOEt, EtOH
3S
2S
3S
2S
2R
3R
20 °C, 16 h, 68%
OH
N3
OH
N3
N3
HO
(+)-14
(–)-18
(+)-15 (25%)
(50%)
NaBH4, THF, 60 °C
4 h, 43%
NaBH4, THF
NaBH4, THF, 60 °C
4 h, 48%
60 °C, 4 h, 39%
4S
1R
4R
3S
1R
BocHN
4S
BocHN
1R
BocHN
OH
OH
OH
3S
2S
2S
2R
3R
OH
N3
OH
N3
N3
HO
(–)-19
(+)-17
(+)-16
Scheme 2 Preparation of epoxy amino ester (–)-13 by cis-stereoselective epoxidation and its conversion into the azido esters (+)-14, (+)-15,
and (–)-18 and the azido alcohol stereoisomers (+)-16, (+)-17, and (–)-19
Synthesis 2010, No. 1, 153–160 © Thieme Stuttgart · New York

PAPER
Highly Functionalized Cyclopentanes
155
could be readily separated by crystallization to give the the reaction could not be accomplished in common sol-
two stereoisomers, (+)-14 and (+)-15. An ORTEP view of vents such as ethanol or methanol; in the latter, no reduc-
the structure of (+)-14 is shown in Figure 2. (Note that be- tion took place even after 20 hours of heating, and only
cause the preliminary experiments were performed on ra- transesterification was observed.
cemic substances, the ORTEP view shows the structure of
Functionalization of the olefinic bond with complementa-
the racemic compound.) Interestingly, the epoxide cleav-
ry selectivity was based on the epoxidation of the protect-
age reactions of the corresponding (9-fluorenyl)methoxy-
ed g-lactam (+)-20. First, g-lactam (+)-10 was
carbonyl- or benzyloxycarbonyl-protected ethyl esters
both gave inseparable mixtures of regioisomers.
transformed into its N-tert-butyloxycarbonyl derivative
(+)-20,17 which to epoxidized with meta-chloroperoxy-
benzoic acid in dichloromethane at 0 °C to give the trans-
epoxy derivative (+)-2118 exclusively (Scheme 3).
In view of our experience with the cleavage of oxirane
rings in amino esters by sodium azide,16 we attempted to
convert the trans-epoxy lactam (+)-21 into the corre-
sponding trans-epoxy amino ester 26. Although treatment
of a previous epoxy b-lactam with sodium ethoxide readi-
ly gave the corresponding trans-epoxy b-amino ester,16
opening of the g-lactam ring of (+)-21 under different re-
Figure 2 ORTEP view of compound 15 (racemic mixture). Only
action conditions did not lead to 26; instead, cleavage of
the main component (64%) of the disordered methyl group at C-13 is
the oxirane ring gave the hydroxy amino esters 2218
shown.
(Scheme 3). Because the desired trans-epoxy amino ester
could not be prepared, we attempted to introduce the azide
function by cleavage of the oxirane ring in the epoxide of
the corresponding reduced alcohol. Accordingly, epoxy
Both (+)-14 and (+)-15 could be readily converted into the
corresponding azido tert-butyloxycarbonyl-protected
amino alcohol stereoisomers (+)-16 (ee > 98%) and (+)-
lactam (+)-21 was transformed into epoxy alcohol (–)-
2319 by treatment with sodium borohydride in methanol at
room temperature (Scheme 3). When trans-epoxy alcohol
(–)-23 was treated with sodium azide in aqueous ethanol
containing ammonium chloride, cleavage of the oxirane
resulted in the two possible isomers (+)-24 and (–)-25 in a
ratio of 4:1 (Scheme 4).
17 (ee > 98%), respectively, by reduction of the ester
function with sodium borohydride in refluxing tetrahy-
drofuran (Scheme 2). Treatment of amino ester (+)-15
with sodium ethoxide in ethanol at room temperature for
16 hours gave stereoisomer (–)-18 through epimerization
at C-1; subsequent reduction of the ester unit with sodium
borohydride in tetrahydrofuran at 60 °C gave the amino
alcohol stereoisomer (–)-19 (ee > 98%) (Scheme 2). Re-
duction of esters (+)-14 and (+)-15 gave the correspond-
ing alcohols in only moderate yields. It is noteworthy that
The structures of products (+)-24 and (–)-25 was deter-
mined by two-dimensional NMR analyses. This agreed
well with results of earlier experiments in which cleavage
of an oxirane ring in the corresponding acetylated cis-ep-
O
O
HN
BocN
1S
2S
1R
4S
5S
Boc2O, Et3N, DMAP
BocHN
4R
1S
OH
4R
THF, 0 °C to 20 °C
12 h, 93%
O
(+)-10
(+)-20
(–)-23
MCPBA, CH2Cl2
NaBH4, MeOH
0 °C to 20 °C, 7 h, 61%
20 °C, 12 h, 65%
O
COOR
BocN
COOR
BocHN
BocHN
NaOR, ROH
0 °C, 2 h
4R
1S
X
5S
6R
HO
O
O
R = Me: 22a; 59% from rac-21
R = Et: 22b; 64% from rac-21
26
(+)-21
Scheme 3 Preparation of epoxy lactam (+)-21 by trans-stereoselective epoxidation and opening of the lactam ring of 21 with sodium alkoxide,
and the preparation of the trans-epoxy alcohol (–)-23
4R
4S
1S
1S
2S
1R
4S
BocHN
BocHN
BocHN
OH
OH
OH
NaN3, NH4Cl
3R
2R
+
2S
3S
5S
EtOH–H2O
70 °C, 6 h
N3
HO
OH
N3
O
(+)-24 (39%)
(–)-23
(–)-25 (10%)
Scheme 4 Synthesis of azido alcohol stereoisomers (+)-24 and (–)-25. Azido alcohol stereoisomers (+)-24 (ee > 98%) and (–)-25 (ee > 98%)
were readily separated and isolated by column chromatography on silica gel with elution by hexane–EtOAc (1:1).
Synthesis 2010, No. 1, 153–160 © Thieme Stuttgart · New York

156
L. Kiss et al.
PAPER
MeOH (20 mL) was added, and the mixture was maintained at 25 °C
for 10 min and then evaporated to dryness. The residue was dis-
solved in 95:5 hexane–i-PrOH (2 mL) then filtered and injected.
oxy d-amino alcohol gave the two regioisomers in a simi-
lar ratio.12b In the present case, the selectivity can be
explained in terms of stereoelectronic factors. The induc-
tive electron-withdrawing effect of the carbamate nitro-
gen makes a greater contribution to the reaction transition
state, because attack by the azide ion on the oxirane ring
occurs predominantly at the position C-1 in (–)-23, the
farthest position from the carbamate. In this case, the mi-
nor isomer (–)-25 is formed in a much smaller amount
than is the case with the epoxy amino ester (–)-13 (1:4 in
comparison with 1:2). Although a solvent effect has been
observed in similar oxirane cleavage reactions of epoxy
O-nucleosides,9a in our experiments not one of the sol-
vents examined (N,N-dimethylformamide, methanol, and
acetonitrile) had a significant effect on the ratio of the two
products. Note, however, that the total yield decreased
drastically with all three solvents (8–10% in comparison
with 49% in aqueous ethanol). When the reactions were
carried out in the same solvents, but with the addition of
water, moderate yields were obtained. We can therefore
assume that the presence of water is essential for oxirane
cleavage by sodium azide.
Retention times (min): ( )-16 [hexane–i-PrOH (98:2, 1.0 mL/min)]:
46.3 and 54.2 ; ( )-17 [hexane–i-PrOH (95:5, flow: 0.8 mL/min)]
21.1 and 27.2; ( )-24 [hexane–i-PrOH (96.5:3.5; 0.8 mL/min]: 18.8
and 22.8.
Compounds ( )-19 and ( )-25 were derivatized with trimethylsilyl
2,2,2-trifluoro-N-(trimethylsilyl)ethanimidoate (BSTFA) and sepa-
rated by GC on a Chirasil-L-VAL column (Chrompack). Samples (2
mg) were dissolved in CH2Cl2 (100 mL), BSTFA (10 mL) was add-
ed, and the mixture was kept at 25 °C for 20 min and then injected.
Retention times (min): ( )-19 (constant, 160 °C, 20 psi): 8.08 and
8.48; ( )-25 (constant 140 °C, 20 psi): 21.09 and 22.23.
Ethyl (1S,4R)-4-Aminocyclopent-2-ene-1-carboxylate Hydro-
chloride [(–)-11]
SOCl2 (3 mL) was added dropwise to a mixture of amino acid (–)-9
(3 g, 23.6 mmol) and EtOH (15 mL) at 0 °C. The mixture was
stirred at 70 °C for 2 h then concentrated under reduced pressure.
The residue was crystallized (i-Pr2O–EtOH) to give a white precip-
itate; yield: 72%; mp 125–126 °C; [a]D20 –175 (c 0.14, CH2Cl2).
IR (KBr): 2965, 1736, 1487, 1341, 1189 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 8.10 Hz, 3 H, CH3),
2.33–2.40 (m, 2 H, CH2), 3.59–3.62 (m, 1 H, H-1), 4.14–4.23 (m, 2
H, OCH2), 4.48–4.50 (m, 1 H, H-4), 6.16–6.18 (m, 1 H, H-2), 6.31–
6.33 (m, 1 H, H-3), 8.52 (br s, 2 H, NH).
13C NMR (400 MHz, DMSO): d = 14.0, 31.1, 49.1, 55.2, 60.5,
130.3, 134.4, 172.2.
In conclusion, we have developed a simple method for the
synthesis of azido-functionalized cyclopentanol stereo-
isomers in enantiomerically pure forms from racemic
Vince lactam. These compounds are not only highly func-
tionalized pentacyclic amino alcohols, but are also poten-
tially useful as precursors of azidocarbonucleosides.
Anal. Calcd. for C8H14ClNO2: C, 50.13; H, 7.36; N, 7.31. Found: C,
49.83; H, 7.14; N, 7.10.
The chemicals were purchased from Aldrich or Fluka. Melting
points were determined with a Kofler apparatus. NMR spectra were
recorded on a Bruker DRX 400 spectrometer. Chemical shifts are
given in ppm relative to TMS as an internal standard with CDCl3 or
DMSO as the solvent. The solvents were used as received from the
supplier. Optical rotations were measured with a Perkin-Elmer 341
polarimeter. The IR spectra were recorded on a PerkinElmer Spec-
trum 100 FTIR spectrometer. The mass spectra were recorded on a
Finnigan MAT 95S spectrometer. Elemental analyses were per-
formed with a Perkin-Elmer 2400 Series II CHNS Elemental Ana-
lyzer.
Ethyl (1S,4R)-4-(tert-Butoxycarbonylamino)cyclopent-2-ene-
carboxylate [(–)-12]:
Boc2O (2.13 g, 9.8 mmol) was added to a soln of amino ester hydro-
chloride (–)-11 (1.87 g, 9.8 mmol) and Et3N (3 g, 29.7 mmol) in
THF (25 mL) at 0 °C. The mixture was stirred at r.t. for 10 h, diluted
with EtOAc (60 mL), washed with H2O (3 × 50 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude mix-
ture was chromatographed (hexane–EtOAc) to give a colorless oil;
yield: 81%; Rf = 0.65 (hexane–EtOAc, 3:1); [a]D20 –45.2 (c 0.44,
CH2Cl2).
IR (KBr): 3374, 2980, 1714, 1706, 1504, 1246, 1171 cm–1.
X-ray Crystallography
1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 8.10 Hz, 3 H, CH3),
1.44 (s, 9 H, CH3), 1.81–1.99 (m, 1 H, CH2), 2.43–2.54 (m, 1 H,
CH2), 3.43–3.48 (m, 1 H, H-1), 4.11–4.20 (m, 2 H, OCH2), 4.76–
4.79 (m, 1 H, H-4), 4.90 (s, 1 H, NH), 5.85–5.88 (m, 2 H, H-2 and
H-3).
13C NMR (400 MHz, DMSO): d = 14.0, 28.2, 33.9, 48.4, 55.7, 60.1,
77.6, 130.2, 134.7, 154.9, 173.0.
Crystallographic data were collected at 173 K with a Nonius-Kappa
CCD area detector diffractometer, using graphite-monochroma-
tized Mo-K radiation (l = 0.71073 Å), as reported earlier.20 The
structures were solved by direct methods with the SHELXS-97 pro-
gram, and full-matrix, least-squares refinements on F2 were per-
formed with the SHELXL-97 program.21 The CH hydrogen atoms
were included at fixed distances with the fixed displacement param-
eters from their host atoms. Supplementary crystallographic data for
this paper have been deposited with the accession numbers CCDC
647641, 647642, and 647643, and can be obtained free of charge
from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail: depos-
it@ccdc.cam.ac.uk; Web site: www.ccdc.cam.ac.uk/conts/retriev-
ing.html.
Anal. Calcd. for C13H21NO4: C, 61.16; H, 8.29; N, 5.49. Found: C,
60.88; H, 8.40; N, 5.09.
(1S,4R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.1]hept-5-en-
3-one [(+)-20]:
Boc2O (7.2 g, 33 mmol) was added to a soln of lactam (+)-10 (3 g,
27.5 mmol), Et3N (8.3 g, 82.5 mmol), and DMAP (670 mg, 5.5
mmol) in THF (50 mL) at 0 °C. The mixture was stirred at r.t. for
12 h, diluted with EtOAc (120 mL), washed with H2O (3 × 100
mL). The organic phase was dried (Na2SO4) and concentrated under
reduced pressure, and the crude product was purified by column
chromatography [silica gel, hexane–EtOAc (3:1)] to give a white
solid; yield: 93%; mp 65–67 °C (Lit.17 68–70 °C); Rf = 0.6 (hexane–
Separation of Enantiomers
The racemic compounds ( )-16, ( )-17, and ( )-24 were derivatized
with BzCl and separated by chiral HPLC on a Chiralcel OD-H col-
umn (Daicel). Samples (2 mg) were dissolved in CH2Cl2 (200 mL),
and BzCl (10 mL) and Et3N (30 mL) were added. After 10 min,
Synthesis 2010, No. 1, 153–160 © Thieme Stuttgart · New York

PAPER
Highly Functionalized Cyclopentanes
157
EtOAc, 4:1); [a]D20 +184.2 (c 0.43, CH2Cl2). [Lit.17 –94.6 (c 1.2,
CHCl3)].
(+)-14: Colorless oil; yield: 50%; Rf = 0.53 (hexane–EtOAc, 2:1);
[a]D20 +25.9 (c 0.32, CH2Cl2).
IR (KBr): 2978, 1754, 1709, 1332, 1309, 1166, 1153 cm–1.
IR (KBr): 3389, 2980, 2106, 1719, 1704, 1696, 1253 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.50 (s, 9 H, CH3), 2.12–2.16 (m,
1 H, CH2), 2.32–2.36 (m, 1 H, CH2), 3.37–3.39 (m, 1 H, H-4), 4.94–
4.96 (m, 1 H, H-1), 6.64–6.66 (m, 1 H, H-5), 6.88–6.91 (m, 1 H, H-
6).
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 8.2 Hz, 3 H, CH3),
1.45 (s, 9 H, CH3), 1.84–1.91 (m, 1 H, CH2), 2.35–2.43 (m, 1 H,
CH2), 2.68–2.75 (m, 1 H, H-1), 3.95–4.06 (m, 3 H, H-2, H-3 and H-
4), 4.17–4.25 (m, 2 H, OCH2), 5.15 (br s, 1 H, NH).
13C NMR (400 MHz, DMSO): d = 26.2, 27.6, 47.6, 49.3, 52.4, 58.5,
82.0, 149.1, 172.9.
13C NMR (400 MHz, CDCl3): d = 14.5, 28.7, 31.8, 46.2, 52.7, 62.1,
69.1, 77.6, 80.6, 152.2, 156.8.
Anal. Calcd. for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C,
62.79; H, 7.48; N, 6.27.
MS (ES): m/z = 315 [M + 1].
Anal. Calcd. for C13H22N4O5: C, 49.67; H, 7.05; N, 17.82. Found:
C, 49.20; H, 7.39; N, 17.59.
Ethyl (1S,2S,4R,5R)-4-[(tert-Butoxycarbonyl)amino]-6-oxabi-
cyclo[3.1.0]hexane-2-carboxylate [(–)-13]
(+)-15: White crystals; yield: 25%; mp 115–116 °C; Rf = 0.50 (hex-
ane–EtOAc, 2:1); [a]D20 +15.5 (c 0.31, CH2Cl2).
IR (KBr): 3352, 2987, 2108, 1737, 1682, 1536, 1296 cm–1.
1H NMR (400 MHz, DMSO): d = 1.18 (t, J = 8.2 Hz, 3 H, CH3),
1.39 (s, 9 H, CH3), 1.80–1.91 (m, 1 H, CH2), 1.97–2.05 (m, 1 H,
CH2), 2.90–3.00 (m, 1 H, H-1), 3.57–3.65 (m, 2 H, H-3 and H-4),
3.95–4.09 (m, 3 H, OCH2 and H-2), 5.66 (br s 1H, OH), 7.16 (br s,
1 H, NH).
13C NMR (400 MHz, DMSO): d = 14.1, 28.1, 30.5, 44.6, 52.1, 59.8,
70.7, 73.6, 77.9, 155.0, 171.8.
MS (ES): m/z = 315 [M + 1]+.
70% MCPBA (3.2 g, 12.8 mmol) was added to a soln of amino ester
(–)-12 in CH2Cl2 (40 mL) at 0 °C. The mixture was stirred for 7 h,
diluted with CH2Cl2 (70 mL), washed with sat. aq NaHCO3 (3 × 80
mL), dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by column chromatography [silica gel,
hexane–EtOAc (3:1)] to give a white solid; yield: 67%; mp 86–
88 °C; Rf = 0.45 (hexane–EtOAc, 2:1); [a]D20 –18 (c 0.28, CH2Cl2).
IR (KBr): 3371, 2983, 1724, 1683, 1513, 1236 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 8.2 Hz, 3 H, CH3),
1.46 (s, 9 H, CH3), 1.49–1.53 (m, 1 H, CH2), 2.10–2.22 (m, 1 H,
CH2), 2.85–2.93 (m, 1 H, H-2), 3.54–3.55 (m, 1 H, H-1), 3.71–3.72
(m, 1 H, H-5), 4.16–4.23 (m, 2 H, OCH2), 4.21–4.24 (m, 1 H, H-4),
4.79 (br s, 1 H, NH).
Anal. Calcd. for C13H22N4O5: C, 49.67; H, 7.05; N, 17.82. Found:
C, 49.22; H, 7.41; N, 17.61.
13C NMR (400 MHz, DMSO): d = 14.1, 25.4, 28.2, 42.9, 51.0, 55.3,
Ethyl (1R,2S,3S,4R)-3-Azido-4-[(tert-butoxycarbonyl)amino]-
2-hydroxycyclopentanecarboxylate [(–)-18]
56.4, 60.2, 150.4, 161.8.
MS (ES): m/z = 294 [M + Na]+.
NaOEt (104 mg, 1 equiv) was added in portions to a stirred soln of
azido ester (+)-15 (0.5 g, 1.6 mmol) in EtOH (8 mL) at 0 °C. After
16 h, the mixture was concentrated under reduced pressure at 40 °C.
The residue was taken up in EtOAc (30 mL), washed with H2O
(3 × 20 mL), dried (Na2SO4), and concentrated. The crude product
was purified by column chromatography [silica gel, hexane–
EtOAc, (3:1)] to give a white solid; yield: 68%; mp 112–114 °C;
Rf = 0.48 (hexane–EtOAc, 2:1); [a]D20 –22 (c 0.17, CH2Cl2).
Anal. Calcd. for C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C,
57.21; H, 7.50; N, 4.79.
(1R,2S,4R,5S)-6-(tert-Butoxycarbonyl)-3-oxa-6-azatricy-
clo[3.2.1.02,4]octane-7-one [(+)-21]
This compound was prepared similarly to (–)-13, starting from lac-
tam (+)-20 (10 mmol), as a white solid; yield: 61%; mp 90–92 °C
[Lit.18 115–116 °C; (–)-isomer]; Rf = 0.55 (hexane–EtOAc, 2:1);
[a]D20 +80 (c 0.39, CH2Cl2) [Lit.18 –94.5 (c 0.7, CH2Cl2; (–)-iso-
mer].
IR (KBr): 3356, 2982, 2109, 1733, 1687, 1524, 1173 cm–1.
1H NMR (400 MHz, DMSO): d = 1.18 (t, J = 8.1 Hz, 3 H, CH3),
1.38 (s, 9 H, CH3), 1.72–1.82 (m, 1 H, CH2), 1.95–2.06 (m, 1 H,
CH2), 2.65–2.72 (m, 1 H, H-1), 3.52–3.68 (m, 2 H, H-3 and H-4),
3.81–3.90 (dd, J1 = 7.3 Hz, J2 = 14.5 Hz, 1 H, H-2), 4.04–4.10 (m,
2 H, OCH2), 5.75 (br s, 1 H, OH), 7.18 (br s, 1 H, NH).
13C NMR (400 MHz, CDCl3): d = 14.9, 29.0, 31.0, 47.0, 53.6, 61.9,
71.6, 71.6, 80.4, 153.6, 155.2.
IR (KBr): 2987, 1770, 1713, 1328, 1310, 1134, 1119 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.51 (s, 9 H, CH3), 1.62–1.66 (m,
1 H, CH2), 1.79–1.84 (m, 1 H, CH2), 3.05–3.08 (m, 1 H, H-4), 3.61–
3.63 (m, 1 H, H-5), 3.77–3.79 (m, 1 H, H-6), 4.61–4.63 (m, 1 H, H-
1).
MS (ES): m/z = 315 [M + 1]+.
Anal. Calcd. for C11H15NO4: C, 58.66; H, 6.71; N, 6.22. Found: C,
58.20; H, 7.03; N, 5.97.
Anal. Calcd. for C13H22N4O5: C, 49.67; H, 7.05; N, 17.82. Found:
C, 49.25; H, 7.42; N, 17.56.
Ethyl (1S,2R,3R,4R)-2-Azido-4-[(tert-butoxycarbonyl)amino]-
3-hydroxycyclopentanecarboxylate [(+)-14] and Ethyl
(1S,2S,3S,4R)-3-Azido-4-[(tert-butoxycarbonyl)amino]-2-hy-
droxycyclopentanecarboxylate [(+)-15]
NaN3 (1.2 g, 18.5 mmol) and NH4Cl (150 mg) were added to a soln
of epoxy amino ester (–)-13 (2.5 g, 9.25 mmol) in EtOH (20 mL)
and H2O (2 mL). The mixture was stirred at 80 °C for 10 h then con-
centrated. The residue was taken up in EtOAc (100 mL) and the or-
ganic layer was washed with H2O (3 × 40 mL), dried (Na2SO4), and
concentrated. The crude product (+)-15 was crystallized from hex-
ane–EtOAc, and the filtrate was concentrated and purified by col-
umn chromatography [silica gel, hexane–EtOAc (3:1)] to give (+)-
14.
Methyl (3S*,4S*)-4-[(tert-Butoxycarbonyl)amino]-3-hydroxy-
cyclopent-1-enecarboxylate (22a)18b
(N.B. The experiments were performed on the racemic substance
only). NaOMe (243 mg, 1 equiv) was added in portions to a stirred
soln of epoxy lactam 21 (1 g, 4.5 mmol) in EtOH or MeOH (15 mL),
respectively, at 0 °C. After 2 h, the mixture was concentrated under
reduced pressure at 40 °C. The residue was taken up in EtOAc (70
mL), washed with H2O (3 × 40 mL), dried (Na2SO4), and concen-
trated. The crude mixture was purified by column chromatography
[silica gel, hexane–EtOAc (2:1)] to give white crystals; yield: 59%;
mp 135–137 °C; Rf = 0.40 (hexane–EtOAc, 2:1).
IR (KBr): 3277, 2977, 1721, 1675, 1537, 1284 cm–1.
Synthesis 2010, No. 1, 153–160 © Thieme Stuttgart · New York

158
L. Kiss et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 1.46 (s, 9 H, CH3), 2.28–2.37 (m,
1 H, CH2), 3.01–3.10 (m, 1 H, CH2), 3.76 (s, 3 H, OCH3), 3.91–4.01
(m, 1 H, H-4), 4.80–4.84 (m, 1 H, H-3), 4.99 (br s, 1 H, NH), 6.65–
6.66 (m, 1 H, H-2).
13C NMR (400 MHz, DMSO): d = 28.2, 36.1, 51.5, 59.3, 77.7, 79.7,
133.7, 143.7, 155.3, 164.5.
13C NMR (400 MHz, DMSO): d = 29.3, 32.8, 43.4, 52.2, 63.5, 98.9,
76.4, 78.6, 155.9.
MS (ES): m/z = 273 [M + 1]+.
Anal. Calcd. for C11H20N4O4: C, 48.52; H, 7.40; N, 20.58. Found:
C, 48.17; H, 7.68; N, 20.11.
(1S,2S,3R,5R)-3-[(tert-Butoxycarbonyl)amino]-2-azido-
5-(hydroxymethyl)cyclopentanol [(+)-17]
Ethyl (3S*,4S*)-4-[(tert-Butoxycarbonyl)amino]-3-hydroxy-
cyclopent-1-enecarboxylate (22b)
This was prepared as for compound 22a, except that NaOEt (292
White solid; yield: 43%; mp 96–98 °C; Rf = 0.40 (hexane–EtOAc,
1:2); [a]D20 +5.8 (c 0.32, CH2Cl2).
mg, 1 equiv) was used instead of NaOMe.
IR (KBr): 3356, 2979, 2935, 2104, 1704, 1691, 1516 cm–1.
White crystals; yield: 64%; mp 125–127 °C; Rf = 0.40 (hexane–
EtOAc, 2:1).
IR (KBr): 3272, 2981, 1717, 1665, 1564, 1299 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.8 Hz, 3 H, CH3),
1.46 (s, 9 H, CH3), 2.27–2.37 (m, 1 H, CH2), 3.00–3.10 (m, 1 H,
CH2), 3.90–4.00 (m, 1 H, H-4), 4.14–4.25 (m, 2 H, OCH2), 4.78–
4.82 (m, 1 H, H-3), 5.01 (br s, 1 H, NH), 6.64–6.66 (m, 1 H, H-2).
13C NMR (400 MHz, DMSO): d = 14.0, 28.2, 36.1, 59.3, 60.0, 77.7,
79.7, 133.9, 143.5, 155.3, 164.0.
1H NMR (400 MHz, DMSO): d = 1.38 (s, 9 H, CH3), 1.90–2.11 (m,
3 H, CH2 and H-5), 3.32–3.39 (m, 1 H, OCH2), 3.52–3.61 (m, 3 H,
OCH2, H-2 and H-3), 3.81–3.87 (dd, J1 = 5.5 Hz, J2 = 11.5 Hz, 1 H,
H-1), 4.22 (br s, 1 H, OH), 5.24 (br s, 1 H, OH), 7.05 (br s, 1 H, NH).
13C NMR (400 MHz, DMSO): d = 29.1, 32.8, 41.6, 53.6, 60.5, 61.8,
72.6, 75.0, 155.9.
MS (ES): m/z = 273 [M + 1]+.
Anal. Calcd. for C11H20N4O4: C, 48.52; H, 7.40; N, 20.58. Found:
C, 48.19; H, 7.76; N, 20.16.
{(1S,2S,4S,5R)-4-[(tert-Butoxycarbonyl)amino]-6-oxabicy-
clo[3.1.0]hex-2-yl}methanol [(–)-23]
(1S,2S,3R,5S)-3-[(tert-Butoxycarbonyl)amino]-2-azido-
5-(hydroxymethyl)cyclopentanol [(–)-19]:
NaBH4 (0.85 g, 2 equiv) was added in portions to a soln of lactam
epoxide (+)-21 (2.4 g, 11 mmol) in MeOH (20 mL) at 0 °C, and the
mixture was stirred at 20 °C for 12 h. Sat. aq NH4Cl (6 mL) was
then added and the soln was concentrated to one third of its volume
at 40 °C. The residue was taken up in EtOAc (60 mL), washed with
H2O (3 × 30 mL), dried (Na2SO4), and concentrated. The residue
was purified by column chromatography [silica gel, hexane–EtOAc
(1:2)] to give a white solid; yield: 65%; mp 118–120 °C (Lit.19 118–
White solid; yield: 39%; mp 132–135 °C; Rf = 0.40 (hexane–
EtOAc, 1:2); [a]D20 –1.5 (c 1.6, CH2Cl2).
IR (KBr): 3354, 2983, 2931, 2105, 1706, 1686, 1522 cm–1.
1H NMR (400 MHz, DMSO): d = 1.34 (s, 9 H, CH3), 1.46–1.54 (m,
1 H, CH2), 1.72–1.80 (m, 2 H, CH2 and H-5), 3.17–3.21 (m, 1 H, H-
3), 3.32–3.38 (m, 2 H, H-1 and H-2), 3.51–3.66 (m, 2 H, OCH2),
4.46 (br s, 1 H, OH), 5.29 (br s, 1 H, OH), 6.82 (br s, 1 H, NH).
13C NMR (400 MHz, DMSO): d = 29.1, 29.7, 43.3, 58.0, 63.5, 65.3,
78.5, 80.2, 156.6.
20
119 °C; (+)-enantiomer); Rf = 0.50 (hexane–EtOAc, 1:2); [a]D
–24.2 (c 0.43, CH2Cl2) [Lit.19 +23.14 (c 0.6, CH2Cl2); (+)-enan-
tiomer].
IR (KBr): 3437, 3304, 2978, 1690, 1538, 1171 cm–1.
Anal. Calcd. for C11H20N4O4: C, 48.52; H, 7.40; N, 20.58. Found:
C, 48.15; H, 7.64; N, 20.13.
1H NMR (400 MHz, CDCl3): d = 1.45 (s, 9 H, CH3), 2.07–2.17 (m,
1 H, CH2), 2.38–2.42 (m, 1 H, CH2), 3.42–3.43 (m, 2 H, H-1 and H-
5), 3.65–3.69 (m, 1 H, OCH2), 3.88–3.93 (m, 1 H, OCH2), 4.24–
4.26 (m, 1 H, H-2), 5.78 (br s, 1 H, NH).
13C NMR (400 MHz, CDCl3): d = 29.1, 33.6, 41.0, 60.1, 60.4, 63.9,
80.6, 158.2.
(1R,2R,3R,5S)-5-[(tert-Butoxycarbonyl)amino]-2-azido-3-(hy-
droxymethyl)cyclopentanol [(+)-24] and (1S,2S,3S,5S)-3-[(tert-
Butoxycarbonyl)amino]-2-azido-5-(hydroxymethyl)cyclopen-
tanol [(–)-25]
NaN3 (0.55 g, 2 equiv) and NH4Cl (100 mg) were added to a soln of
epoxy alcohol (–)-23 (1 g, 4.1 mmol) in EtOH (15 mL) and H2O (1
mL). The mixture was stirred under reflux for 4 h and then concen-
trated, taken up in EtOAc (25 mL), washed with H2O (3 × 15 mL),
and dried (Na2SO4). The crude product was purified by column
chromatography [silica gel, hexane–EtOAc (1:2)].
MS (ES): m/z = 230 [M + 1]+.
Anal. Calcd. for C11H19NO4: C, 57.62; H, 8.35; N, 6.11. Found: C,
57.28; H, 8.69; N, 5.87.
Reduction of Azido Esters; General Procedure
(+)-24: White solid; yield: 39%; mp: 122–124 °C; Rf = 0.45 (hex-
ane–EtOAc, 1:2); [a]D20 +7.2 (c 0.34, CH2Cl2).
NaBH4 (120 mg, 2 equiv) was added to a soln of azido ester (+)-14,
(+)-15, or (–)-18 (0.5 g, 1.6 mmol) in THF (10 mL), and the mixture
was stirred under reflux for 4 h. The mixture was then concentrated
to half its volume, diluted with EtOAc (40 mL), washed with H2O
(2 × 15 mL), dried (Na2SO4), and concentrated. The crude residue
was purified by column chromatography [silica gel, hexane–EtOAc
(1:2)].
1H NMR (400 MHz, DMSO): d = 1.12–1.23 (m, 1 H, H-3), 1.28 (s,
9 H, CH3), 1.92–1.98 (m, 1 H, CH2), 2.16–2.21 (m, 1 H, CH2), 3.30–
3.37 (m, 1 H, H-5), 3.39–3.52 (m, 2 H, H-1 and H-2), 3.72–3.77 (m,
2 H, OCH2), 4.46 (br s, 1 H, OH), 5.27 (br s, 1 H, OH), 6.80 (br s, 1
H, NH).
13C NMR (400 MHz, DMSO): d = 29.1, 32.5, 41.0, 56.6, 61.9, 68.6,
(1R,2R,3S,5R)-5-[(tert-Butoxycarbonyl)amino]-2-azido-
3-(hydroxymethyl)cyclopentanol [(+)-16]
78.4, 80.2, 156.2.
MS (ES): m/z = 273 [M + 1]+.
Colorless oil; yield: 48%; Rf = 0.45 (hexane–EtOAc, 1:2);
[a]D20 +26.6 (c 0.47, CH2Cl2).
Anal. Calcd. for C11H20N4O4: C, 48.52; H, 7.40; N, 20.58. Found:
C, 48.12; H, 7.70; N, 20.20.
1H NMR (400 MHz, DMSO): d = 1.22–1.32 (m, 1 H, CH2), 1.36 (s,
9 H, CH3), 1.73–1.79 (m, 1 H, H-3), 1.90–1.97 (m, 1 H, CH2), 3.31–
3.40 (m, 2 H, OCH2), 3.49–3.53 (dd, J1 = 1.9 Hz, J2 = 6.8 Hz, 1 H,
H-2), 3.62–3.80 (m, 2 H, H-1 and H-5), 4.72 (br s, 1 H, OH), 5.20
(br s, 1 H, OH), 6.11 (br s, 1 H, NH).
(–)-25: Colorless oil; yield: 10%; Rf = 0.35 (hexane–EtOAc, 1:2);
[a]D20 –3.0 (c 1.85, CH2Cl2).
IR (KBr): 3346, 2979, 2933, 2106, 1690, 1684, 1518 cm–1.
Synthesis 2010, No. 1, 153–160 © Thieme Stuttgart · New York

PAPER
Highly Functionalized Cyclopentanes
159
1H NMR (400 MHz, DMSO): d = 1.18–1.25 (m, 1 H, CH2), 1.28 (s,
9 H, CH3), 1.62–1.71 (m, 1 H, H-5), 1.88–1.95 (m, 1 H, CH2), 3.27–
3.38 (m, 1 H, OCH2), 3.42–3.48 (m, 1 H, OCH2), 3.53–3.57 (m, 1
H, H-3), 3.58–3.62 (m, 1 H, H-2), 3.90–3.97 (m, 1 H, H-1), 4.52 (br
s, 1 H, OH), 5.11 (br s, 1 H, OH). 6.88 (br s, 1 H, NH).
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Acknowledgment
We are grateful to the Hungarian Research Foundation (OTKA No.
F67970 and T049407) and the Bolyai János Fellowship for financial
support for L.K. and E.F.
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