Bioreduction of 2-oxocyclopentanecarboxamides: Syntheses of optically active 2-aminomethyl- and 2-aminocyclopentanols

Article abstract of DOI:10.1016/S0957-4166(99)00016-6

The fungus Mortierella isabellina NRRL 1757 catalyzes the reduction of 2-oxocyclopentanecarboxamides with very high enantioselectivity giving; in most cases, the corresponding enantiopure 2-hydroxycyclopentanecarboxamides. The presence or absence of a sub

Full text of DOI:10.1016/S0957-4166(99)00016-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 473–486
Bioreduction of 2-oxocyclopentanecarboxamides: syntheses of
optically active 2-aminomethyl- and 2-aminocyclopentanols
Margarita Quirós, Francisca Rebolledo and Vicente Gotor ∗
Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, E-33071, Oviedo, Spain
Received 1 December 1998; accepted 13 January 1999
Abstract
The fungus Mortierella isabellina NRRL 1757 catalyzes the reduction of 2-oxocyclopentanecarboxamides
with very high enantioselectivity giving, in most cases, the corresponding enantiopure 2-
hydroxycyclopentanecarboxamides. The presence or absence of a substituent on the amidic nitrogen has a
strong influence on the diastereoselectivity achieved in these processes. Optically active hydroxyamides prepared
in these microbial reductions are used as starting materials for the preparation of optically active 2-aminomethyl-
and 2-aminocyclopentanols. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Preparation of chiral building blocks by means of the asymmetric reduction of carbonyl compounds is
a subject of current interest in organic chemistry.1 In this context, isolated enzymes and microorganisms,
baker’s yeast in particular, have been extensively used to enantioselectively reduce the prochiral ketone
group of a great variety of compounds of synthetic usefulness.2 Thus, baker’s yeast mediated reduction
of β-ketoesters is, at the present time, a well-established methodology for the preparation of optically
active β-hydroxyesters.2d,3 However, despite the broad variety of substrates reduced by microorganisms,
bioconversions of β-ketoamides into β-hydroxyamides are rarely reported, and only some specific β-
ketoamides have been reduced by baker’s yeast.4
Interest in this kind of process is obvious because optically active β-hydroxyamides are precursors
of other interesting compounds such as 1,3- and 1,2-amino alcohols, which are usually used as chiral
auxiliaries in asymmetric syntheses.5 Moreover, 1,2-amino alcohols are structural elements of biolo-
gically active compounds6 (β-blockers, antidepressants, adrenergic drugs, etc.).
Recently, we have demonstrated that the fungus Mortierella isabellina is an excellent catalyst
for the asymmetric reduction of different 3-oxo-3-phenylpropanamides and 3-oxobutyramides, the
∗
Corresponding author. E-mail: vgs@sauron.quimica.uniovi.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00016-6

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corresponding (S)-3-hydroxyamides being obtained with high chemical yields and enantiomeric
excesses.7 These good results encouraged us to investigate the microbial reduction of racemic cyclic
β-ketoamides, 2-oxocyclopentanecarboxamide and some of their N-alkyl derivatives. The reduction
of these substrates would allow us to investigate both diastereoselective and enantioselective activity
of the fungus Mortierella isabellina. In addition, derivatives of the resulting optically active 2-
hydroxycyclopentanecarboxamides are present in a great variety of biologically important molecules,8
and they have interesting applications as stereochemical control elements due to their conformational
restrictions.9
2. Results and discussion
In order to optimize the stereoselectivity of the process, 2-oxocyclopentanecarboxamide 1a was chosen
as a model substrate. Firstly, we carried out the reaction under the same conditions previously reported for
the bioreduction of acyclic β-ketoamides.7 Thus, when submitted to a culture of Mortierella isabellina
(NRRL 1757) grown for 24 h, 1a was converted (85% conversion after 5 days)† into a mixture of
trans- and cis-2-hydroxycyclopentanecarboxamides 2a and 3a (see Table 1) in a ratio of 70:30, both
diastereomers being easily separated by flash chromatography. The major isomer was identified as
trans-(1S,2S)-2a and its enantiomeric purity was >99%. The minor isomer proved to be cis-(1R,2S)-
3a, obtained with low enantiomeric excess (47%). Assignment of the absolute configurations for these
compounds will be discussed later.
Table 1
Microbial reduction of 1a–c
Because of the good result obtained for the major isomer 2a, we decided to modify the reduction
conditions in an attempt to improve the trans diastereoselectivity of the process. It is well known
that in the reduction of a carbonyl group by whole cells, unsatisfactory stereoselectivity is often the
result of the simultaneous action of several dehydrogenase systems displaying both different kinetic
†
No more progress of the reaction was observed after this time.

M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
475
and different selectivity towards the same substrate.10 Therefore, based on reported findings concerning
the stereocontrol of the microbial reductions, the following experiments were carried out: (a) use of
different Mortierella isabellina cultures after growing times ranging from 14 to 86 h,7 (b) addition of
dehydrogenase inhibitors such as methyl vinyl ketone and ethyl chloroacetate,11 and (c) treatments of
the mycelium prior to substrate addition12 (ageing of the mycelium, resuspension in 0.1 M phosphate
buffer pH=7, addition of an inorganic salt, and heating at 40–50°C11b). However, all our efforts were
disheartening since the results of these experiments revealed that no significant changes in the trans–cis
ratio were produced. Nevertheless, improvement in the activity of the microorganism was observed in
the culture grown for 38 h, obtaining a similar percentage of conversion (92%) after a shorter reaction
time (see Table 1).
On the other hand, we have also investigated the activity of the fungus Beauveria bassiana (ATCC
7159) in the reduction of 1a. This microorganism has been employed in the reduction of β-ketoesters.6e,13
Thus, when ketoamide 1a was submitted to different cultures of the fungus Beauveria bassiana after
growing times ranging from 14 to 86 h, the cis-2-hydroxycyclopentanecarboxamide 3a was isolated as
the only product of reduction with 51% ee. Although the remarkable feature of this bioreduction is its
diastereoselectivity — higher and opposite to that shown by Mortierella isabellina — the enantioselecti-
vity achieved was low.
In the light of these experiments, we decided to continue our studies with the fungus Mortierella
isabellina and carry out the bioreduction of other N-substituted 2-oxocyclopentanecarboxamides such
as N-allyl 1b and N-benzyl 1c (Table 1). In both cases, conversions and diastereoselectivities achieved
were higher than in the reduction of 1a, the reaction with 1c being remarkable. This substrate 1c was
completely reduced after 24 h of incubation and the corresponding hydroxyamides 2c and 3c were
obtained with a very high diastereomeric ratio (4:96), both isomers being enantiopure. Also of note,
is the effect the presence of the N-substituent had on the stereocontrol of the bioreduction; in this
case, the diastereoselectivity was reversed and cis-(1R,2S)-2b,c was obtained as the major isomer. This
change of diastereoselection could be due to the action of different dehydrogenases possessing different
specificities. Moreover, an enhancement of diastereoselectivity was obtained when the N-substituent
increased in size (compare reductions of 1b and 1c, Table 1). This fact is similar to that observed
in other microbial reductions, for which the stereoselectivity is usually driven by the steric difference
between the substituents that flank the carbonyl function. So the more different they are, the greater the
stereoselectivity.10b,d,14
However, it is noteworthy that in all cases the major diastereomer 2a or 3b,c is obtained enantio-
merically pure. This is an interesting result from the viewpoint of obtaining enantiomerically pure
cyclic 1,3- and 1,2-amino alcohols whose importance has already been mentioned. Thus, treatment of
hydroxyamides (1S,2S)-2a and (1R,2S)-3a–c with lithium aluminum hydride afforded the corresponding
2-(aminomethyl)cyclopentanols (1S,2R)-4 and (1S,2S)-5a–c (Scheme 1) in 75–87% yield. In the case of
3b a reduction of the allyl group and the corresponding N-propyl derivative (1S,2S)-5b was obtained.
1
These reduction processes took place without racemization because in the H NMR spectra of 4 and
5a–c only the presence of a diastereomer was detected.
On the other hand, (1S,2S)-2-aminocyclopentanol was obtained from enantiopure N-unsubstituted
hydroxyamide (1S,2S)-2a by a Hofmann rearrangement (Scheme 1), which was accomplished with
Hg(OAc)2 and NBS15 in the presence of benzyl alcohol. Thus, the alcoholysis of the isocyanate
intermediate was achieved, and the rearranged product was easily isolated as its benzyl carbamate
(1S,2S)-6. The hydrogenolysis of 6 yielded the enantiomerically pure (1S,2S)-2-aminocyclopentanol,
which was isolated as its hydrochloride (1S,2S)-7·HCl after treatment with 6 M HCl. In addition,
hydroxyamide (1R,2S)-3a (ee=51%) was also submitted to a Hofmann rearrangement through a recently

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M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
Scheme 1. Reagents and conditions: (i) LiAlH4, 1,4-dioxane, reflux, 24 h; (ii) Hg(OAc)2, NBS, BnOH, DMF, 50°C, 17 h; (iii)
Pd–C, 1,4-cyclohexadiene; (iv) 6 M HCl; (v) PhI(OAc)2, THF, MeOH; (vi) LiOH, H2O/MeOH reflux; (vii) CH2Cl2/3 M HCl
described procedure involving the use of an iodine reagent.16 Treatment of (1R,2S)-3a with PhI(OAc)2
in a mixture of THF–MeOH led to the oxazolidinone 8. In this case, the formation of the oxazolidinone
was favoured because both rings are cis-fused. Basic hydrolysis17 of 8 and subsequent treatment with 6
M HCl afforded (1S,2R)-9·HCl in a 68% overall yield.
To assign the cis:trans configuration of the hydroxyamides 2a and 3a obtained in the microbial
1
reductions, the analogous racemic mixtures trans-(ꢀ)-2a and cis-(ꢀ)-3a were prepared‡ and their H
NMR spectra compared. LiAlH4 reduction of trans-(ꢀ)-2a and cis-(ꢀ)-3a and subsequent carbonylation
(N,N0-carbonyldiimidazole, NaH) of the resulting racemic amino alcohols (ꢀ)-4 and (ꢀ)-5a afforded the
corresponding racemic perhydrocyclopentano[e]-1,3-oxazine-2-ones (ꢀ)-10 and (ꢀ)-11a, which were
1
analyzed by H NMR (Scheme 2). Similarly, to establish the cis-configuration of (1R,2S)-3b,c their
aminoalcohol derivatives (1S,2S)-5b and (1S,2S)-5c were converted into (4aS,7aS)-11b and (4aS,7aS)-
11c, respectively. Because of the bicyclic system present in these compounds, it is possible to assign the
configuration through the coupling constant values of the diastereotopic protons Ha and Hb with Hx. The
results of the 1H NMR analyses of ABX systems18 of compounds 10 and 11a–c§ are shown in Scheme 2.
Compound 10 showed coupling constant values of 10.8, 10.0 and 6.0 Hz. These values are in agreement
with geminal, axial–axial and axial–equatorial couplings, respectively, and they are consistent with a
trans-relationship of the hydrogen atoms at the stereogenic centres. The same analysis for the compounds
11a–c showed coupling constant values corresponding to geminal (12.0 Hz), equatorial–equatorial
‡
NaBH4 reduction of methyl 2-oxocyclopentanecarboxylate gave
a
1:1 mixture of methyl trans-(ꢀ):cis-(ꢀ)-2-
hydroxycyclopentanecarboxylates. This mixture was submitted to conventional ammonolysis (ammonia in methanol) yielding
the corresponding mixture of trans-(ꢀ):cis-(ꢀ)-2-hydroxycyclopentanecarboxamides 2a:3a, which was separated by flash
chromatography (firstly AcOEt:hexane 1.5:1 to isolate (ꢀ)-3a and then, AcOEt to isolate (ꢀ)-2a).
§
In order to simplify the spin system, the NH signal was irradiated in 10 and 11a.

M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
477
(2.0–2.8 Hz) and axial–equatorial (4.8–6.0 Hz) couplings, which are consistent with a cis-relationship of
the hydrogen atoms at the stereogenic centres, and with the conformation shown in the Scheme 2.
Scheme 2. Reagents and conditions: (i) LiAlH4, 1,4-dioxane, reflux, 24 h (see Scheme 1); (ii) CDI, NaH, THF, reflux
On the other hand, the results obtained in the Hofmann rearrangement of (1S,2S)-2a and (1R,2S)-3a
(see Scheme 1) corroborate the cis:trans assignment. Whereas the cis-isomer 3a yielded the oxazolidi-
none 8, the trans-isomer 2a could not undergo intramolecular alcoholysis because this would involve the
formation of two strained trans-fused 5-membered rings. That is why intermolecular alcoholysis product
6 is the only one isolated.¶ On the basis of these arguments, the cis:trans configuration of the obtained
diastereomeric hydroxyamides has been unambiguously established.
The absolute configurations of these compounds were assigned as follows. For (1S,2S)-2a by compa-
rison of the sign for the specific rotations of its derivatives (1S,2S)-6 and (1S,2S)-7·HCl (see Scheme 1)
with the reported values.19 Similarly, configuration (1R,2S) for 3a was assigned by comparison of the
sign for the specific rotations of its derivatives (3aR,6aS)-8 and (1S,2R)-9·HCl (see Scheme 1) with those
published for (3aR,6aS)-89a and (1R,2S)-9,19b respectively.
In the case of hydroxyamides 3b and 3c, the absolute configuration (1R,2S) was established on
the basis of the configuration for the hydroxyamide (1R,2S)-3a before being assigned. The stra-
tegy, outlined in Scheme 3, firstly involved the preparation of the same derivative, N-acetylated 2-
(aminomethyl)cyclopentanol (1S,2S)-12, from the stereochemically well-defined (1R,2S)-3a and from
the enantiopure cis-3c. To obtain enantiopure cis-12 from cis-3c, the latter was transformed into N-
(benzylaminomethyl)cyclopentanol cis-5c (see Scheme 1) and the benzyl group was removed by hy-
drogenolysis yielding the corresponding cis-2-(aminomethyl)cyclopentanol, which was isolated as its
formic salt cis-13·HCO2H. Conventional acetylation of cis-13 led to N-acetylated amino alcohol cis-
12. Comparison of the signs for the optical rotations of both compounds cis-12 obtained from 3a and 3c
establishes the (1R,2S) configuration for 3c. To assign the configuration of enantiopure cis-3b, compound
cis-13·HCO2H prepared from (1R,2S)-3c was treated with propanoic anhydride (Scheme 3) and the
resulting propanamide was reduced with LiAlH4 yielding (1S,2S)-N-(propylaminomethyl)cyclopentanol
(1S,2S)-5b. Comparison of the signs for the optical rotations of both compounds 5b obtained according
to Schemes 1 and 3 clearly establishes the (1R,2S) configuration for cis-3b.
¶
The same results were obtained when racemic (ꢀ)-2a and (ꢀ)-3a were subjected to Hofmann rearrangement in the same
reaction conditions, that is, Hg(OAc)2, DMF and methanol. From (ꢀ)-3a the oxazolidinone was obtained, but (ꢀ)-2a gave the
corresponding methyl carbamate.

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M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
Scheme 3. Reagents and conditions: (i) LiAlH4 (see Scheme 1); (ii) Ac2O, CH2Cl2, Et3N; (iii) Pd–C, HCO2H/MeOH; (iv)
(EtCO)2O, THF, Et3N
Reductions with Mortierella isabellina have usually been reported to fit13b,20 to Prelog’s rule.14a In this
context, the absolute configuration of hydroxyamides 2a and 3a–c obtained in this work are in accordance
with this rule. For this, taking into account the results obtained and by application of the Prelog’s rule,
we have tentatively assigned the (1S,2S) configuration to the minor diastereomers 2b and 2c.
Enantiomeric excesses of the obtained hydroxyamides were determined as follows. For compounds
(1S,2S)-2a–c and (1R,2S)-3a,c they were determined by chiral HPLC analysis: (1S,2S)-2c and (1R,2S)-
3c as the compounds themselves; (1S,2S)-2a after conversion into its O-acetyl derivative; (1S,2S)-
2b and (1R,2S)-3a after transformation into their O-tert-butyldiphenylsilyl derivatives. In the case of
hydroxyamide (1R,2S)-3b it was transformed with (R)-MTPA-Cl into its MTPA-ester derivative,21 which
was subsequently analyzed by 19F NMR (see the Experimental section for details).
3. Conclusion
We have shown that the fungus Mortierella isabellina (NRRL 1757) is an effective biocatalyst for
the reduction of 2-oxocyclopentanecarboxamides 1. Reactions proceeded with very high enantioselec-
tivities and with moderate to excellent diastereoselectivities. Although the N-substituent of substrate
1 has a great influence on the cis:trans diastereoselection of the fungus, in all cases the major dias-
tereomer of the product was enantiopure. This is of great importance since such optically active 2-
hydroxycyclopentanecarboxamides 2 and 3 can be valuable chiral synthons. Thus, through very sim-
ple procedures, enantiopure 2-(aminomethyl)cyclopentanols (1S,2R)-4 and (1S,2S)-5b,c and (1S,2S)-2-
aminocyclopentanol were obtained from the microbial products. In our opinion, this microbial process
contributes to broaden the range of applicability of biotransformations in organic synthesis.

M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
479
4. Experimental
4.1. General
The fungi Mortierella isabellina and Beauveria bassiana were purchased from NRRL and ATCC
culture collections, respectively. All reagents were purchased from Aldrich Chemie. Substrates 1 were
prepared by enzymatic ammonolysis of the corresponding β-ketoesters as previously described.22 Sol-
vents were distilled over an adequate desiccant and stored under nitrogen. Flash chromatography was
performed using Merck silica gel 60 (230–400 mesh). For chiral HPLC analyses, a Chiralcel-OD column
(Daicel) was used. Solvents were distilled over an adequate desiccant and stored under nitrogen. Melting
points were taken using a Gallenkamp apparatus and are uncorrected. Mass spectra were recorded on a
Finnigan MAT/95 spectrometer. Elemental analyses were performed on a Perkin–Elmer analyzer 2400.
Optical rotations were measured using a Perkin–Elmer 241 polarimeter. IR spectra were recorded on a
1
Perkin–Elmer 1720-X FT Infrared spectrophotometer. H and 13C NMR spectra were carried out using
a Bruker AC-200 (200.13 MHz for 1H and 50.3 MHz for 13C) or Bruker AC-300 (300 MHz for 1H and
75.5 MHz for 13C) spectrometer.
4.2. Culture conditions
The experimental procedure was as follows. Mortierella isabellina (NRRL1757) was precultured and
cultured as previously described,23 in a growing medium prepared by dissolving of tryptic soy broth
(Difco, 30 g) and D-glucose (17.5 g) in 1 L of distilled water. After 38 h of culture (350 mL, in a 1
L Erlenmeyer flask), the mycelium was harvested by filtration and resuspended in distilled water (350
mL) and then substrate was added. In the case of reductions by Beauveria bassiana (ATCC 7159) the
general procedure was the same except that the composition of the growing medium was: D-glucose (30
g), peptone (10 g), K2HPO4 (1 g), MgSO4 (0.5 g), KCl (0.5 g), ZnSO4 (0.3 g) and FeSO4·7H2O (0.01
g) in distilled water (1 L).
4.3. Biotransformation of 1
4.3.1. General procedure
The corresponding 2-oxocyclopentanecarboxamide 1 was added to the culture as an ethanolic solution
(100 mg/mL of ethanol) to reach a concentration of 1 mg/mL. Incubation was then carried out (rotary
shaker, 200 rpm, 28°C) until no more progress of the reaction was observed (TLC monitoring). The
mycelium was filtered out, washed with distilled water, and the combined aqueous phases continuously
extracted with AcOEt (24 h). After drying and elimination of the solvent, a mixture of the corresponding
diastereomeric 2-hydroxycyclopentanecarboxamides 2 and 3 was obtained. Flash column chromatogra-
phy (the eluent is indicated in every case) of the mixture yielded pure 2 and 3.
4.3.2. (1S,2S)-trans-2-Hydroxycyclopentanecarboxamide 2a
20
Eluent, AcOEt (once 3a was isolated); white solid; yield, 51%; mp 122–123°C; [α]D +78.0 (c 0.61,
EtOH; ee >99%); IR (KBr) 1663 cm−1; 1H NMR (CD3OD) δ (ppm) 1.72–2.00 (m, 4H, CH2), 2.08–2.20
(m, 2H, CH2), 2.73 (m, 1H, CHCONH2), 4.46 (m, 1H, CHOH); 13C NMR (CD3OD) δ (ppm) 23.78
(CH2), 29.67 (CH2), 36.11 (CH2), 54.80 (CH), 77.81 (CH), 180.66 (C_O); MS (70 eV) m/z (relative
intensity) 129 (M+, 3), 101 (34), 85 (15), 72 (100). Anal. calcd for C6H11NO2: C, 55.80; H, 8.58; N,
10.84. Found: C, 55.73; H, 8.69; N, 10.83. For the chiral HPLC analysis, (1S, 2S)-2a was conventionally

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M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
(Ac2O, Et3N, THF) converted into its O-acetylderivative: tR 15.81 min. For the O-acetylderivative of
(ꢀ)-2a two peaks at tR 13.72 and 16.40 min; RS=2.4 (hexane:propan-2-ol, 90:10; 0.8 mL/min).
4.3.3. (1R,2S)-cis-2-Hydroxycyclopentanecarboxamide 3a
20
Eluent, AcOEt:hexane (1.5:1); white solid; yield, 20%; mp 95–96°C; [α]D +15.7 (c 0.62, EtOH;
1
ee 51%); IR (KBr) 1678 cm−1; H NMR (CD3OD) δ (ppm) 1.75–2.25 (m, 6H, CH2), 2.77 (m, 1H,
CHCONH2), 4.56 (m, 1H, CHOH); 13C NMR (CD3OD) δ (ppm) 23.04 (CH2), 27.84 (CH2), 35.65
(CH2), 51.41 (CH), 75.51 (CH), 179.70 (C_O); MS (70 eV) m/z (relative intensity) 129 (M+, 3), 101
(16), 85 (5), 72 (100). Anal. calcd for C6H11NO2: C, 55.80; H, 8.58; N, 10.84. Found: C, 55.92; H,
8.70; N, 10.46. For the chiral HPLC analysis, (1R, 2S)-3a was transformed (TBDPSCl, imidazol, THF)24
into its O-tert-butyldiphenylsilyl derivative: tR 9.67 min. For the O-tert-butyldiphenylsilyl derivative of
(ꢀ)-3a two peaks at tR 9.27 and 11.15 min; RS=1.85 (hexane:propan-2-ol, 95:5; 0.8 mL/min).
4.3.4. (1S,2S)-trans-N-Allyl 2-hydroxycyclopentanecarboxamide 2b
20
Eluent, AcOEt:hexane (1:1); white solid; yield, 15%; mp 78–79°C; [α]D +49.3 (c 0.80, CHCl3; ee
1
98%); IR (KBr) 1640, 1549 cm−1; H NMR (CDCl3) δ (ppm) 1.49–2.08 (m, 6H, CH2), 2.46 (m, 1H,
CHCONHR), 3.33 (bs, 1H, OH), 3.86 (m, 2H, CH2N), 4.24 (m, 1H, CHOH), 5.08–5.21 (m, 2H, _CH2),
5.72–5.88 (m, 1H, _CH), 6.28 (bs, 1H, NH); 13C NMR (CDCl3) δ (ppm) 21.46 (CH2), 26.39 (CH2),
34.36 (CH2), 41.68 (CH2), 53.11 (CH), 76.52 (CH), 115.99 (CH2), 134.07 (CH), 174.56 (C_O); MS
(70 eV) m/z (relative intensity) 169 (M+, 14), 128 (29), 112 (68), 57 (100), 41 (66). Anal. calcd for
C9H15NO2: C, 63.88; H, 8.93; N, 8.28. Found: C, 63.85; H, 9.25; N, 8.16. For the chiral HPLC analysis,
(1S, 2S)-2b was transformed (TBDPSCl, imidazol, THF) into its O-tert-butyldiphenylsilyl derivative:
tR 4.63 min. For the O-tert-butyldiphenylsilyl derivative of (ꢀ)-2b two peaks at tR 4.84 and 5.98 min;
RS=2.4 (hexane:propan-2-ol, 97:3; 0.8 mL/min).
4.3.5. (1R,2S)-cis-N-Allyl-2-hydroxycyclopentanecarboxamide 3b
20
Eluent, AcOEt:hexane (1:1); white solid; yield, 71%; mp 93–94°C; [α]D +4.8 (c 0.76, CHCl3; ee
>98%); IR (KBr) 1655, 1634 cm−1; 1H NMR (CDCl3) δ (ppm) 1.58–2.12 (m, 6H, CH2), 2.45 (m, 1H,
CHCONHR), 3.90 (m, 2H, CH2N), 4.20 (bs, 1H, OH), 4.44 (m, 1H, CHOH), 5.10–5.28 (m, 2H, _CH2),
5.73–6.05 (m, 2H, _CH and NH); 13C NMR (CDCl3) δ (ppm) 21.87 (CH2), 27.53 (CH2), 34.17 (CH2),
41.51 (CH2), 49.48 (CH), 73.90 (CH), 116.23 (CH2), 133.72 (CH), 175.07 (C_O); MS (70 eV) m/z
(relative intensity) 169 (M+, 10), 128 (11), 112 (100), 57 (97), 41 (55). Anal. calcd for C9H15NO2: C,
63.88; H, 8.93; N, 8.28. Found: C, 63.74; H, 8.85; N, 7.90. 19F NMR data for the diastereomeric MPTA-
esters derived from (ꢀ)-3b, δ −72.17 and −72.24 ppm (CFCl3/CDCl3 as an external standard). For the
MPTA-ester derived from (1R,2S)-3b only one signal to −72.17 ppm.
4.3.6. (1S,2S)-trans-N-Benzyl-2-hydroxycyclopentanecarboxamide 2c
20
Eluent, AcOEt:hexane (1:1); white solid; yield, 3%; mp 141–142°C; [α]D +53.6 (c 0.53, EtOH; ee
>99%); IR (KBr) 1634 cm−1; 1H NMR (CD3OD) δ (ppm) 1.74–1.95 (m, 4H, CH2), 2.14–2.25 (m, 2H,
CH2), 2.76 (m, 1H, CHCONH), 4.51 (m, 1H, CHOH), 4.57 (s, 2H, CH2Ph), 7.35–7.53 (m, 5H, Ph); 13
C
NMR (CD3OD) δ (ppm) 23.82 (CH2), 29.73 (CH2), 36.16 (CH2), 44.36 (CH2), 55.35 (CH), 77.80 (CH),
128.40 (CH), 128.74 (CH), 129.78 (CH), 140.36 (C), 177.65 (C_O); MS (70 eV) m/z (relative intensity)
219 (M+, 52), 128 (13), 106 (55), 91 (100). Anal. calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39.
Found: C, 70.87; H, 8.01; N, 6.30. Chiral HPLC analysis: (1S, 2S)-2a, tR 11.63 min; (ꢀ)-2a, tR 6.47 and
11.33 min; RS=3.6 (hexane:propan-2-ol, 90:10; 0.8 mL/min).

M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
481
4.3.7. (1R,2S)-cis-N-Benzyl-2-hydroxycyclopentanecarboxamide 3c
20
Eluent, AcOEt:hexane (1:1); white solid; yield, 85%; mp 83–84°C; [α]D +5.0 (c 0.75, CHCl3;
1
ee >99%); IR (KBr) 1645 cm−1; H NMR (CDCl3) δ (ppm) 1.52–2.10 (m, 6H, CH2), 2.42 (m, 1H,
CHCONH), 4.41 (m, 4H, CHOH, OH and CH2Ph), 6.65 (bs, 1H, NH), 7.20–7.40 (m, 5H, Ph); 13C NMR
(CDCl3) δ (ppm) 21.87 (CH2), 27.47 (CH2), 34.16 (CH2), 43.13 (CH2), 49.55 (CH), 73.90 (CH), 127.40
(CH), 127.46 (CH), 128.60 (CH), 137.82 (C), 175.04 (C_O); MS (70 eV) m/z (relative intensity) 219
(M+, 72), 106 (80), 91 (100). Anal. calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.11; H,
8.10; N, 6.48. Chiral HPLC analysis: (1R, 2S)-3c, tR 14.15 min; (ꢀ)-3c, tR 14.14 and 18.09 min; RS=2.4
(hexane:propan-2-ol, 90:10; 0.8 mL/min).
4.4. Reduction of 2-hydroxycyclopentanecarboxamides by lithium aluminum hydride
4.4.1. General procedure
A suspension of the corresponding hydroxyamide 2a, 3a–c (0.5 mmol) in anhydrous 1,4-dioxan (2 mL)
was added dropwise with stirring to a slurry of LiAlH4 (5 mmol) in anhydrous 1,4-dioxane (7 mL) under
nitrogen. The mixture was refluxed for 24 h and then cooled to 0–5°C and water (0.8 mL) was added
dropwise with stirring. After 1 h, the mixture was treated with hot MeOH and filtered through a thin
pad of Celite. The filtrates were combined and the solvents were removed in vacuum. The solid residue
was extracted with hot CHCl3 and the resulting organic solution evaporated to give the corresponding
product, which was pure in most cases. For analytical purposes it was purified by flash chromatography
using as eluents: propan-2-ol:CH2Cl2:(30% NH4OH) (2:2:0.1) for 4 and 5a,b and CH2Cl2:MeOH (10:1)
for 5c.
4.4.2. (1S,2R)-trans-2-(Aminomethyl)cyclopentanol 4
Prepared from (1S,2S)-2a. Oil; yield, 84%; [α]D20 +9.5 (c 0.83, CHCl3; ee >99%); 1H NMR (CDCl3)
δ (ppm) 1.20–1.18 (m, 1H, CHH), 1.45–2.00 (m, 6H, CH2, CHH and CH), 2.24 (bs, 3H, NH2 and
OH), 2.60 (dd, 1H, CHHNH2, J=12.0, J=9.0), 2.97 (dd, 1H, CHHNH2, J=12.0, J=3.0), 3.85 (q, 1H,
CHOH); 13C NMR (CDCl3) δ (ppm) 21.13 (CH2), 27.35 (CH2), 34.02 (CH2), 45.73 (CH), 49.41 (CH2),
77.95 (CH); MS (70 eV) m/z (relative intensity) 115 (M+, 3), 98 (94), 68 (100), 67 (80). Anal. calcd for
C6H13NO: C, 62.57; H, 11.38; N, 12.16. Found: C, 62.81; H, 11.40; N, 11.91.
4.4.3. (1S,2S)-cis-2-(Aminomethyl)cyclopentanol 5a
Prepared from (1R,2S)-3a. Oil; yield, 80%; [α]D20 +14.3 (c 0.87, CHCl3, ee 51%); 1H NMR (CDCl3)
δ (ppm) 1.30–1.90 (m, 7H, CH2 and CH), 2.75–2.95 (m, 2H, CH2NH2), 3.33 (bs, 3H, NH2 and OH),
4.25 (m, 1H, CHOH); 13C NMR (CDCl3) δ (ppm) 21.93 (CH2), 26.62 (CH2), 34.66 (CH2), 41.66 (CH),
45.08 (CH2), 75.16 (CH); MS (70 eV) m/z (relative intensity) 115 (M+, 5), 98 (19), 68 (100), 67 (88).
Anal. calcd for C6H13NO: C, 62.57; H, 11.38; N, 12.16. Found: C, 62.47; H, 11.29; N, 12.28.
4.4.4. (1S,2S)-cis-2-(N-Propylaminomethyl)cyclopentanol 5b
20
Prepared from (1R,2S)-3b. Oil; yield, 75%; [α]D +27.0 (c 1.07, CHCl3; ee >98%); IR (neat) 3293,
2959, 2874, 1466 cm−1; 1H NMR (CDCl3) δ (ppm) 0.91 (t, 3H, CH3, J=7.3), 1.35–2.02 (m, 9H, CH2,
CH and CH3CH2CH2N), 2.46–2.66 (m, 2H, CH3CH2CH2N), 2.76–3.92 (m, 2H, CHCH2N), 3.44 (bs,
2H, NH and OH), 4.29 (m, 1H, CHOH); 13C NMR (CDCl3) δ (ppm) 11.58 (CH3), 22.29 (CH2), 22.80
(CH2), 27.32 (CH2), 34.54 (CH2), 42.00 (CH), 50.44 (CH2), 51.61 (CH2), 75.47 (CH); MS (70 eV) m/z
(relative intensity) 157 (M+, 3), 128 (35), 72 (100). Anal. calcd for C9H19NO: C, 68.74; H, 12.1; N, 8.91.
Found: C, 68.51; H, 12.30; N, 8.80.

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M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
4.4.5. (1S,2S)-cis-2-(N-Benzylaminomethyl)cyclopentanol 5c
20
Prepared from (1R,2S)-3c. White solid; yield, 87%; mp 83–85°C; [α]D +26.4 (c 0.76, CHCl3; ee
>99%); IR (KBr) 3430, 2953, 1454 cm−1; 1H NMR (CDCl3) δ (ppm) 1.35–1.85 (m, 6H, CH2), 2.02 (m,
1H, CHCH2NH), 2.81–2.93 (m, 2H, CH2NH–), 3.47 (bs, 2H, NH and OH), 3.71–3.85 (m, 2H, CH2Ph),
4.32 (m, 1H, CHOH), 7.25–7.35 (m, 5H, Ph); 13C NMR (CDCl3) δ (ppm) 22.29 (CH2), 27.41 (CH2),
34.51 (CH2), 42.26 (CH), 49.62 (CH2), 53.74 (CH2), 74.95 (CH), 127.28 (CH), 128.23 (CH), 128.44
(CH), 138.58 (C); MS (70 eV) m/z (relative intensity) 205 (M+, 5.2), 120 (91), 106 (71), 91 (100). Anal.
calcd for C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C, 76.11; H, 9.21; N, 7,05.
4.5. Benzyl (1S,2S)-trans-N-(2-hydroxycyclopentyl)carbamate 6
A solution of NBS (0.5 g, 2.8 mmol) in DMF (1.6 mL) was added under nitrogen to a solution of
(1S,2S)-2a (0.26 g, 2 mmol) and Hg(OAc)2 (0.96 g, 3 mmol) in DMF (2.8 mL) and benzyl alcohol
(2.8 mL). The reaction was stirred at 50°C and once completed the white precipitate was removed by
filtration. The solution was evaporated and the solid residue extracted with CH2Cl2. The organic solution
was successively washed with 10% NH4OH. After the aqueous layer was continuously extracted (24 h)
with more CH2Cl2, both organic solutions were combined, dried and concentrated. Compound 6 was
purified by flash chromatography using AcOEt:hexane as eluent; firstly in a ratio 1:4 in order to remove
20
the BnOH in excess and then 1:2. White solid; yield, 70%; mp 57–59°C; [α]D −10.7 (c 0.71, CHCl3;
ee >99%); IR (KBr) 1688 cm−1; 1H NMR (CDCl3) δ (ppm) 1.29–1.47 (m, 1H, CH2), 1.59–2.18 (m, 5H,
CH2), 3.64–3.78 (m, 1H,CHOH), 3.90 (bs, 1H, OH), 4.00–4.07 (m, 1H, CHNH), 5.05 (bs, 1H, NH),
5.11 (s, 2H, CH2Ph), 7.30–7.42 (m, 5H, Ph); 13C NMR (CDCl3) δ (ppm) 20.74 (CH2), 30.24 (CH2),
32.14 (CH2), 60.52 (CH), 66.89 (CH2), 79.14 (CH), 128.04 (CH), 128.14 (CH), 128.47 (CH), 136.07
(C), 157.28 (C_O); MS (70 eV) m/z (relative intensity) 235 (M+, 7.5), 144 (76), 91 (100). Anal. calcd
for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.34; H, 7,53; N, 5.88.
4.6. (1S,2S)-trans-2-Aminocyclopentanol hydrochloride 7·HCl
Palladium hydroxide on carbon (90 mg) and 1,4-cyclohexadiene (0.36 mL; 3.8 mmol) was added to a
solution of (1S,2S)-6 (90 mg; 0.38 mmol) in ethanol (3 mL) the mixture then stirred at room temperature
for 4 h. Catalyst was filtered off on a pad of Celite and washed with ethanol. HCl 6 M was added to the
resulting ethanolic solution and after stirring for 1 h, solvents were evaporated to give the corresponding
hydrochloride, which was purified by recrystallization from CH2Cl2–MeOH. White solid; yield, 91%;
mp 180–182°C; [α]D20 +30.1 (c 0.65, EtOH; ee >99%); 1H NMR (CD3OD) δ (ppm) 1.70–2.10 (m, 4H,
CH2), 2.12–2.46 (m, 2H, CH2), 3.46 (m, 1H, CHN), 4.28 (m, 1H, CHOH); 13C NMR (CD3OD) δ (ppm)
21.48 (CH2), 29.08 (CH2), 33.56 (CH2), 59.96 (CH), 76.94 (CH); MS (FAB+, NBA matrix) m/z (relative
intensity) 101 (M+, 15), 84 (7), 56 (100). Anal. calcd for C5H11NO·HCl: C, 43.64; H, 8.79; N, 10.18.
Found: C, 43.35; H, 8.76; N, 10.00.
4.7. (3aR,6aS)-cis-Perhydrocyclopenta[d]oxazol-2-one 8
PhI(OAc)2 (0.8 g, 2.5 mmol) was added under nitrogen to a solution of (1R,2S)-3a (0.25 g, 1.9 mmol)
in a mixture of THF (13 mL) and methanol (5 mL). The mixture was stirred at room temperature until
disappearance of the starting material (TLC monitoring, 90 min) and then it was heated at 50°C for
30 min. At this point solvents were removed under vacuum and the resulting residue was submitted to
flash chromatography (AcOEt:hexane, 1:1.5) to afford compound 8 as a white solid. Yield, 85%; mp

M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
483
98–100°C; [α]D −19.6 (c 0.70, CHCl3; ee 51%); IR (KBr) 1738 cm−1; H NMR (CDCl3) δ (ppm)
1.45–1.85 (m, 5H, CH2, CHH), 2.01–2.12 (m, 1H, CHH), 4.24 (m, 1H, CHN), 5.03 (m, 1H, CHO),
6.66 (bs, 1H, NH); 13C NMR (CDCl3) δ (ppm) 21.71 (CH2), 33.61 (CH2), 34.13 (CH2), 56.63 (CH),
82.14 (CH), 160.44 (C_O); MS (70 eV) m/z (relative intensity) 127 (M+, 100), 98 (80). Anal. calcd for
C6H9NO2: C, 56.68; H, 7.14; N, 11.02. Found: C, 56.72; H, 6.91; N, 10.82.
20
1
4.8. (1S,2R)-cis-2-Aminocyclopentanol hydrochloride 9·HCl
Compound 8 (0.048 g, 0.38 mmol) was added to a solution of LiOH (0.028 g, 2 mmol) in a
water:methanol (8:1, 0.7 mL) mixture. After heating at reflux for 3 h, solvents were removed under
vacuum and the solid residue extracted with dichloromethane. The organic solution was evaporated to
give the corresponding crude aminoalcohol 9, which was immediately treated with CH2Cl2:6 M HCl
giving the hydrochloride as a white solid, which was purified by recrystallization from CH2Cl2:MeOH.
Yield, 80%; mp 219–221°C; [α]D20 +10.0 (c 0.5, EtOH; ee 51%); 1H NMR (CD3OD) δ (ppm) 1.75–2.30
(m, 6H, CH2), 3.62 (m, 1H, CHN), 4.43 (m, 1H, CHOH); 13C NMR (CD3OD) δ (ppm) 21.61 (CH2),
28.77 (CH2), 33.89 (CH2), 55.86 (CH), 72.08 (CH); MS (FAB+, NBA matrix) m/z (relative intensity) 102
[(M+1)+, 100]. Anal. calcd for C5H11NO·HCl: C, 43.64; H, 8.79; N, 10.18. Found: C, 43.82; H, 8.51; N,
10.25.
4.9. (ꢀ)-trans-Perhydrocyclopenta[e]-1,3-oxazin-2-one (ꢀ)-10
Prepared from (ꢀ)-trans-2-(aminomethyl)cyclopentanol [(ꢀ)-4], which was previously obtained from
(ꢀ)-2a19 as described for enantiopure (1S,2R)-4. A solution of (ꢀ)-4 (0.023 g, 0.2 mmol) in dry THF (1.5
mL) was added under nitrogen, to a suspension of NaH (0.009 g, 0.39 mmol) in dry THF (1.5 mL). Then
N,N0-carbonyldiimidazole (CDI) (0.063 g, 0.39 mmol) was added and the resulting mixture stirred and
heated at reflux for 16 h. After being cooled, the mixture was treated with a saturated NH4Cl solution.
Solvents were evaporated and the residue was dissolved in distilled water and extracted with CH2Cl2.
The organic layer were dried and concentrated under reduced pressure to give crude (ꢀ)-10, which was
purified by flash chromatography (AcOEt:hexane, 2:1). White solid; yield, 45%; mp 131–133°C; IR
(KBr) 1672 cm−1; 1H NMR (CDCl3) δ (ppm) 1.10–1.40 (m, 1H, CHH), 1.55–2.20 (m, 6H, CH2, CHH,
CH), 3.09 (m, 1H, CHHNH, J=10.8, J=10.0), 3.46 (ddd, 1H, CHHNH, J=10.8, J=6.0), 4.07 (m, 1H,
CHO), 6.39 (bs, 1H, NH); 13C NMR (CDCl3) δ (ppm) 20.21 (CH2), 24.01 (CH2), 28.25 (CH2), 38.24
(CH), 45.20 (CH2), 82.00 (CH), 155.81 (C_O); MS (70 eV) m/z (relative intensity) 141 (M+, 64), 96
(100), 80 (44). Anal. calcd for C7H11NO2: C, 59.56; H, 7.85; N, 9.92. Found: C, 59.60; H, 7.71; N,
10.11.
4.10. (ꢀ)-cis-Perhydrocyclopenta[e]-1,3-oxazin-2-one (ꢀ)-11a
Prepared from (ꢀ)-cis-2-(aminomethyl)cyclopentanol [(ꢀ)-5a] (0.023 g, 0.2 mmol) as described for
(ꢀ)-10. Yield, 43%; IR (KBr) 1694 cm−1; 1H NMR (CDCl3) δ (ppm) 1.60–2.01 (m, 6H, CH2), 2.25 (m,
1H, CH), 3.21 (ddd, CHHNH, J=12.0, J=2.8), 3.54 (ddd, CHHNH, J=12.0, J=4.8), 4.69 (m, 1H, CHO),
6.46 (bs, 1H, NH); 13C NMR (CDCl3) δ (ppm) 21.80 (CH2), 26.39 (CH2), 33.23 (CH2), 35.54 (CH),
40,58 (CH2), 82.44 (CH), 154.85 (C_O); MS (70 eV) m/z (relative intensity) 141 (M+, 28), 96 (22), 80
(100). Anal. calcd for C7H11NO2: C, 59.56; H, 7.85; N, 9.92. Found: C, 59.31; H, 7.94; N, 9.68.

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M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
4.11. (4aS,7aS)-cis-3-Propylperhydrocyclopenta[e]-1,3-oxazin-2-one 11b
Prepared from (1S,2S)-5b (0.068 g, 0.43 mmol) as described for (ꢀ)-10. In this case, AcOEt:hexane
20
(1:1.5) was used as an eluent. Oil; yield, 72%; [α]D −51.2 (c 0.57, CHCl3; ee >98%); IR (neat) 1690
cm−1; 1H NMR (CDCl3) δ (ppm) 0.92 (t, 3H, CH3, J=7.4), 1.50–2.10 (m, 8H, CH2 and CH2CH3), 2.34
(m, 1H, CHCH2N, J=2.0, J=6.0), 3.13 (dd, 1H, CHHN, J=12.0, J=2.0), 3.29 (t, 2H, CH2CH2N, J=6.0),
3.55 (dd, 1H, CHHN, J=12.0, J=6.0), 4.67 (m, 1H, CHO); 13C NMR (CDCl3) δ (ppm) 11.03 (CH3),
20.31 (CH2), 22.01 (CH2), 27.10 (CH2), 33.46 (CH2), 36.93 (CH), 46.43 (CH2), 50.75 (CH2), 81.87
(CH), 153.80 (C_O); MS (70 eV) m/z (relative intensity) 183 (M+, 100), 154 (62), 110 (83), 81 (99).
Anal. calcd for C10H17NO2: C, 65.54; H, 9.35; N, 7.64. Found: C, 65.60; H, 9.58; N, 7.91.
4.12. (4aS,7aS)-cis-3-Benzylperhydrocyclopenta[e]-1,3-oxazin-2-one 11c
Prepared from (1S,2S)-5c (0.040 g, 0.2 mmol) as described for (ꢀ)-10. In this case, AcOEt:hexane
20
(1:1.5) was used as eluent. White solid; yield, 71%; mp 103–105°C; [α]D −73.9 (c 0.57, CHCl3;
1
ee >99%); IR (KBr) 1670 cm−1; H NMR (CDCl3) δ (ppm) 1.49–2.10 (m, 6H, CH2), 2.28 (m, 1H,
CHCH2N, J=2.4, J=5.4), 3.05 (dd, 1H, CHHN, J=12.0, J=2.4), 3.41 (dd, 1H, CHHN, J=12.0, J=5.4),
4.57 (q, 2H, CH2Ph, J=14.6), 4.71 (m, 1H, CHO), 7.15–7.49 (m, 5H, Ph); 13C NMR (CDCl3) δ (ppm)
21.92 (CH2), 26.98 (CH2), 33.40 (CH2), 36.72 (CH), 45.59 (CH2), 52.34 (CH2), 82.11 (CH), 127.56
(CH), 128.11 (CH), 128.55 (CH), 136.73 (C), 154.22 (C_O); MS (70 eV) m/z (relative intensity) 231
(M+, 76), 186 (61), 162 (80), 91 (100). Anal. calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found:
C, 72.81; H, 7.25; N, 6.21.
4.13. (1S,2S)-cis-2-(N-Acetylaminomethyl)cyclopentanol 12
A solution of (1S,2S)-5a (0.060 g, 0.52 mmol) in dry CH2Cl2 (0.8 mL) was cooled at 0°C and treated
with Et3N (0.04 mL, 0.58 mmol) and acetic anhydride (0.032 mL, 0.58 mmol). After stirring at room
temperature for 90 min, the solvents were evaporated. The residue was dissolved in distilled water and
extracted with a mixture of CHCl3:propan-2-ol (9:1). The organic solution was dried and concentrated
to afford 12 as a crude product, which was purified by recrystallization from ether:hexane. White solid;
yield, 90%; mp 97–98°C; [α]D20 −38.9 (c 0.50, CHCl3; ee 51%); IR (KBr) 1643 cm−1; 1H NMR (CDCl3)
δ (ppm) 1.30–1.85 (m, 7H, CH2 and CH), 1.98 (s, 3H, CH3), 2.98–3.06 (m, 1H, CHHN), 3.43–3.58 (m,
1H, CHHN), 4.02 (m, 1H, CHOH), 4.45 (bs, 1H, OH), 6.73 (bs, 1H, NH); 13C NMR (CDCl3) δ (ppm)
21.82 (CH2), 22.91 (CH3), 26.28 (CH2), 33.40 (CH2), 39.15 (CH2), 47.47 (CH), 72.01 (CH), 171.75
(C_O); MS (70 eV) m/z (relative intensity) 157 (M+, 15), 129 (41), 114 (19), 100 (47), 72 (67), 43 (100).
Anal. calcd for C8H15NO2: C, 61.11; H, 9.62; N, 8.91. Found: C, 61.24; H, 9.58; N, 8.63.
4.14. (1S,2S)-cis-2-(Aminomethyl)cyclopentanol formic salt 13·HCO2H
(1S,2S)-5c (0.6 g, 2.9 mmol) was dissolved in a methanolic solution of formic acid (4.4%, 30 mL)
and the solution added to a suspension of palladium black catalyst (0.6 g) in the same formic acid
methanolic solution (30 mL). The mixture was continuously stirred under nitrogen atmosphere until
disappearance of the starting material (TLC monitoring, 120 min), and then the catalyst was filtered off
onto a pad of Celite and washed with methanol. Solvents were removed in vacuum, and the resulting
crude (1S,2S)-13·HCO2H (97% yield) was employed without further purification in the reactions shown
in the Scheme 3. The 1H and 13C NMR data of the crude product are as follows: 1H NMR (CD3OD) δ

M. Quirós et al. / Tetrahedron: Asymmetry 10 (1999) 473–486
485
(ppm) 1.60–2.35 (m, 7H, CH2 and CH), 3.05–3.50 (m, 2H, CH2N), 4.45 (m, 1H, CHOH), 8.63 (s, 1H,
HCOOH); 13C NMR (CD3OD) δ (ppm) 23.14 (CH2), 28.28 (CH2), 35.99 (CH2), 41.29 (CH2), 43.87
(CH), 74.28 (CH), 167.49 (C_O).
Acknowledgements
Financial support of this work by Comisión Interministerial de Ciencia y Tecnología (CICYT;
project BIO 95-0687) and by the Principado de Asturias (II P.R.I.; project PB-MAT96-16) is gratefully
acknowledged.
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