Preparation of (R)-(1-adamantyl)glycine and (R)-2-(1-adamantyl)-2-aminoethanol: A combination of cobalt-mediated β-ketoester alkylation and enzyme-based aminoalcohol resolution

Article abstract of DOI:10.1016/S0957-4166(00)00428-6

Alkylation of the cobalt(II) complex of ethyl acetoacetate with 1-bromoadamantane affords ethyl 2-(1-adamantyl)acetoacetate, which was converted into rac-(1-adamantyl)glycine 1 and rac-2-(1-adamantyl)-2-aminoethanol 7. This was separated into enantiomers by means of vinyl acetate in the presence of Pseudomonas cepacea. Configuration R was assigned to the enantiomerically pure aminoalcohol (R)-7 on the basis of X-ray diffraction data. Further oxidation of N-protected aminoalcohol (R)-8 afforded enantiomerically pure amino acid (R)-1.

Full text of DOI:10.1016/S0957-4166(00)00428-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4549–4557
Preparation of (R)-(1-adamantyl)glycine and
(R)-2-(1-adamantyl)-2-aminoethanol: a combination of
cobalt-mediated b-ketoester alkylation and enzyme-based
aminoalcohol resolution
Jaume Clariana,a Santiago Garc´ıa-Granda,b Vicente Gotor,c,* Angel Gutie´rrez-Ferna´ndez,b
Amparo Luna,c Marcial Moreno-Man˜asa,* and Adelina Vallriberaa
aDepartment of Chemistry, Universitat Auto`noma de Barcelona, Cerdanyola, 08193-Barcelona, Spain
bDepartment of Physical and Analytical Chemistry, Chemistry Faculty, University of Oviedo, Oviedo, Spain
cDepartment of Organic and Inorganic Chemistry, Chemistry Faculty, University of Oviedo, Oviedo, Spain
Received 5 October 2000; accepted 23 October 2000
Abstract
Alkylation of the cobalt(II) complex of ethyl acetoacetate with 1-bromoadamantane affords ethyl
2-(1-adamantyl)acetoacetate, which was converted into rac-(1-adamantyl)glycine 1 and rac-2-(1-
adamantyl)-2-aminoethanol 7. This was separated into enantiomers by means of vinyl acetate in the
presence of Pseudomonas cepacea. Configuration R was assigned to the enantiomerically pure aminoalco-
hol (R)-7 on the basis of X-ray diffraction data. Further oxidation of N-protected aminoalcohol (R)-8
afforded enantiomerically pure amino acid (R)-1. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The preparation of a-amino acids in enantiomerically pure form is a topic of high interest.1–4
In particular, substituted glycines featuring bulky substituents confer decreased conformational
mobility to artificial peptides rendering them useful for studying peptide–receptor interactions.5–7
tert-Leucine (t-butylglycine) has been the object of an intense investigation and a review has
been published on its preparations and uses.8 In sharp contrast little is known on (1-
adamantyl)glycines (R)-1 and (S)-1 (Scheme 1). Racemic 1 was mentioned for the first time in
a difficult accessible document.9 Later, Belokon et al. reported the resolution of the racemic
methyl ester by a diastereoisomeric salt formation with (−)-dibenzoyltartaric acid. Isolation of
a pure salt (17%) and further transformations gave dextrorotatory (as hydrochloride) 1, shown
* Corresponding authors. E-mail: iqorb@cc.uab.es
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00428-6

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to be of (S)-configuration by examination of the CD spectra of transition metal complexes of
the Schiff bases of (S)-1 and other amino acids with an enantiomerically pure acetophenone
derivative.10
Scheme 1. Preparation of (S)-1 according to Ref. 11
Later, some of us reported the preparation of (S)-1 by the method in Scheme 1.11 Reaction
of 1-bromoadamantane 2 with the cobalt(II) complex 3, featuring Evans oxazolidinone, afforded
a mixture of both diastereomeric alkylation products (R)-4 and (S)-4. The severe experimental
conditions (140°C) resulted in a low diastereomeric excess of (R)-4. In fact the chiral auxiliary
worked more as a resolution agent rather than as a real chiral auxiliary. Diastereoisomers 4 were
separated by column chromatography and (R)-4 was converted into (S)-1 by Schmidt rearrange-
ment and hydrolysis.11 Alkylation of transition metal [mainly Co(II) and Cu(II) complexes of
b-dicarbonyl compounds] is performed in neutral media permitting introduction of carbon
radical precursors of stabilized free radicals.12
Therefore, we planned a different and more versatile approach, consisting of the preparation
of racemic 1, reduction to the corresponding racemic 2-(1-adamantyl)-2-aminoethanol 7, enzym-
atic resolution of aminoalcohol 7 and reoxidation to enantiomerically pure 1. This strategy
offers the added bonus of permitting the preparation of 7 in enantiomerically pure form.
Enantiomerically pure aminoalcohols are important intermediates for the elaboration of chiral
ligands for transition metals, affording complexes useful in asymmetric catalysis.13–15 Moreover,
enzymatic resolution of 1,2-aminoalcohols has been carried out through an enzymatic amin-
olysis reaction.16 However, better results are obtained by a transesterification reaction following
prior N-protection of the amino group.17 Recently, different 1,2-aminoalcohols have been
resolved with very good enantioselectivities by enzymatic transesterification reaction of the
corresponding carbamates using Pseudomonas cepacia lipase (PSL) and vinyl acetate as acyl
donor.18

J. Clariana et al. / Tetrahedron: Asymmetry 11 (2000) 4549–4557
4551
2. Results and discussion
The chemistry leading to the racemic compounds was successful (Scheme 2). Reaction of the
cobalt(II) complex of ethyl acetoacetate with 1-bromoadamantane, 2, gave adamantylketoester
5. Schmidt rearrangement in DME19 gave the amino acid derivative 6 which was treated with
HCl to afford racemic 1·HCl. The free amino acid was obtained by the standard method by
treating with propylene oxide in ethanol. Reduction from both 1 or its hydrochloride is best
achieved by reaction with sodium borohydride and iodine in THF.20
Scheme 2. Key: (a) CoCl2(PPh3)2, LaBr3·6H2O, HCCl3, 140°C; (b) 3NaN3, MeSO3H, dimethoxyethane, rt; (c)
refluxing 7 M HCl; (d) propylene oxide, ethanol; (e) NaBH4, I2, THF, 0°C to rt
For the preparation of enantiomerically pure aminoalcohol 7 we have adopted the same
strategy used for the resolution of other aminoalcohols.18 Thus, compound 7 was conveniently
protected and the resolution of its N-Cbz derivative 8 was carried out in tert-butyl methyl ether
(TBME) at 40°C, using Pseudomonas cepacia lipase (PSL) as biocatalyst and vinyl acetate as the
acyl donor (Scheme 3).
The enzyme reacted faster with the (S)-enantiomer of carbamate 8, yielding the O-acetyl
derivative (S)-9 and the unreacted carbamate (R)-8. The enantiomeric ratio (E)21 measured by
means of the ee(s) and ee(p) was 59. This E value allowed us to obtain the remaining substrate
with an ee>99% by stopping the reaction at a conversion value of 54% or higher. In order to
obtain the absolute configuration, the optically active aminoalcohol (R)-7 was converted into

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J. Clariana et al. / Tetrahedron: Asymmetry 11 (2000) 4549–4557
Scheme 3. Key: (a) PhCH2OCOCl, Na2CO3, H2O–THF; (b) Pseudomonas cepacea, vinyl acetate, CH3-O–t-Bu; (c)
RuCl3·2H2O, NaIO4, water–tetrachloromethane–acetonitrile; (d) i. H2 (2 atm), 10% PdꢀC, methanol; ii. 7 M HCl; (e)
H2, 15% PdꢀC, methanol; (f) DMAP, CH2Cl2, Ac2O, Pyr
the perchlorate salt. The resulting (R)-7·HClO4 was crystallized from a chloroform/methanol
mixture for X-ray analysis.
On the other hand, oxidation of enantiomerically pure (R)-8 with ruthenium(III) chloride and
sodium periodate afforded N-Cbz protected amino acid (R)-10 (Scheme 3), which upon
hydrogenolysis and further treatment with 7 M HCl afforded (R)-(1-adamantyl)glycine hydro-
chloride, (R)-1·HCl, featuring a specific rotation of opposite sign compared with that previously
described for the (S)-enantiomer.11

J. Clariana et al. / Tetrahedron: Asymmetry 11 (2000) 4549–4557
4553
3. Experimental
3.1. Ethyl 2-(1-adamantyl)acetoacetate 5
An improved procedure22 was followed. A mixture of Co(II) complex of ethyl acetoacetate
(1.526 g, 4.2 mmol), 1-bromoadamantane (2.012 g, 9.4 mmol), cobalt(II) chloride bis-
triphenylphosphine (0.315 g, 0.5 mmol), lanthanum(III) bromide hexahydrate (0.215 g, 0.50
mmol) and chloroform (4 ml) was heated at 140°C in a closed glass reactor for 44 h (GLC
monitoring). The cooled reaction mixture was partitioned between dichloromethane and 1N
HCl. The organic phase was dried with sodium sulfate and evaporated. The residue was purified
through a column of silica gel with hexanes–diethyl ether (98:2) as eluent to afford (0.891 g,
81%) as an oil: bp 125°C/0.4 mmHg (lit.22 bp 170–175°C/4 mmHg); IR (film) 2907, 2851, 1729
(br) cm−1. 1H NMR (250 MHz, CDCl3): l 1.28 (t, J=7.3 Hz, 3H), 1.68–1.99 (12H), 2.23 (s, 3H),
3.20 (3H), 4.17 (q, J=7.3 Hz, 2H). 13C NMR (62.5 MHz, CDCl3): l 14.0, 28.4, 31.8, 36.5, 39.8,
60.4, 69.5, 168.3, 202.7; MS (m/z) 264 (M+, 1), 135 (100).
3.2. Ethyl N-acetyl-2-(1-adamantyl)glycinate 6
Methanesulfonic acid (67 ml) was added into a magnetically stirred solution of 5 (14.842 g,
56.0 mmol) in dimethoxyethane (80 ml) maintained at −30°C (acetonitrile–liquid nitrogen bath).
After 5 min sodium azide (11.364 g, 174.8 mmol) was added in three portions. The mixture was
stirred for 15 min at −30°C and left to reach room temperature until evolution of gases ceased.
Then more dimethoxyethane (20 ml) and finally aqueous ammonia were added until pH 8–9 was
reached. The mixture was partially evaporated and the solution was extracted with
dichloromethane. The organic phase was washed with water, dried, and evaporated. The residue
was passed through a column of silica gel with mixtures of hexanes–ethyl acetate (v/v 8:1 to 1:3).
Starting material 5 (0.940 g) and amidoester 6 (10.950 g, 70%) were obtained. Compound 6: mp
111–113°C (hexanes–ethyl acetate); IR (KBr) 3269, 2926, 2902, 2851, 1734, 1648 cm−1. 1H NMR
(250 MHz, CDCl3): l 1.30 (t, J=7.3 Hz, 3H), 1.53–1.73 (12H), 2.00 (s, 3H), 2.05 (s, 3H), 4.19
(q, J=7.3 Hz, 2H), 4.34 (d, J=9.5 Hz, 1H). 13C NMR (62.5 Mz, CDCl3): l 14.0, 23.3, 28.2,
36.7, 38.7, 60.6, 60.9, 169.7, 171.3; MS (m/z) 279 (M+, 1), 135 (100). Anal. calcd for C16H25NO3:
C, 68.79; H, 9.02; N, 5.01. Found: C, 69.16 and 68.96; H, 8.90 and 8.80; N, 4.89 and 4.90.
3.3. rac-2-(1-Adamantyl)glycine hydrochloride 1·HCl
A stirred mixture of amidoester 6 (10.935 g, 39.0 mmol) and 7 M hydrochloric acid (300 ml)
was refluxed for 12 h. The mixture was filtered at room temperature and the solid was washed
with cold 7 M HCl, with diethyl ether, and dried to afford 1·HCl (8.129 g, 85%), mp 238–241°C
(dec) (lit.11 mp (S-isomer) 236–240°C (dec)); IR (KBr) 3555, 3484, 3025–2451 (br), 1737 cm−1.
1H NMR (250 MHz, methanol-D4): l 1.50–1.71 (12H), 1.93 (3H), 3.40 (s, 1H). 13C NMR (62.5
MHz, methanol-D4): l 29.6, 35.7, 37.3, 39.3, 63.5, 170.4.
3.4. rac-2-(1-Adamantyl)glycine 1
Propylene oxide (40 ml) was added to a solution of 1·HCl (2.619 g, 11.0 mmol) in absolute
ethanol (70 ml). The mixture was stirred at room temperature for 48 h, a white precipitate being
formed. The solid was filtered, washed with absolute ethanol to afford free amino acid 1 (2.165

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J. Clariana et al. / Tetrahedron: Asymmetry 11 (2000) 4549–4557
1
g, 97%), mp 287–288°C (ethanol); IR (KBr) 3081, 2906, 2850, 1649, 1627 cm−1. H NMR (250
MHz, methanol-D4): l 1.59–1.75 (12H), 1.95 (3H), 3.03 (s, 1H).
3.5. rac-2-(1-Adamantyl)-2-aminoethanol 7
Amino acid 1 (4.541 g, 22.0 mmol) was added into a stirred suspension of sodium borohy-
dride (2.512 g, 66.0 mmol) in anhydrous THF (55 ml) under argon atmosphere. The stirred
mixture was cooled at 0°C and then a solution of iodine (6.230 g, 25.0 mmol) in anhydrous THF
(30 ml) was added dropwise during 20 min. When the evolution of gas ceased the mixture was
heated to reflux for 16 h. After cooling, methanol was added until transparency and stirring was
continued for an additional 30 min. Solvents were evaporated and the pasty residue was
dissolved into 20% aqueous sodium hydroxide and the alkaline solution was stirred for 4 h and
then extracted with dichloromethane (4×50 ml). The organic extracts were dried and evaporated
to afford aminoalcohol 7 (4.168 g, 97%), mp 97–98°C (dichloromethane); IR (KBr) 3444, 3369,
1
2905, 2850 cm−1. H NMR (250 MHz, CDCl3): l 1.25–1.75 (15H (6CH2+NH2+OH)), 1.99 (3H),
2.32 (dd, J=10.2 and 3.7 Hz, 1H), 3.24 (t, J=10.2 Hz, 1H), 3.70 (dd, J=10.2 and 3.7 Hz, 1H).
13C NMR (62.5 MHz, CDCl3): l 28.3, 35.1, 37.2, 38.6, 61.2, 62.1; MS (m/z) 196 (M+, 1), 164
(100). Aminoalcohol 7 reacted with one equivalent of phenylisocyanate in toluene at room
temperature to afford the phenylurea, N-(1-adamantyl)-2-hydroxyethyl-N%-phenylurea, mp 189–
1
190°C; IR (KBr) 3341, 2905, 2849, 1652 cm−1. H NMR (250 MHz, CDCl3): l 1.59–1.70 (12H),
1.90 (3H), 3.37 (dd, J=7.3 and 2.9 Hz, 1H), 3.45 (dd, J=11.0 and 7.3 Hz, 1H), 3.72 (dd,
J=11.0 and 2.9 Hz, 1H), 6.86 (dt, J=7.3 and 1.5 Hz, 1H), 7.14 (t, J=7.3 Hz, 2H), 7.27
(apparent d, J=11.0 Hz, 2H). 13C NMR (62.5 MHz, CDCl3): l 28.8, 36.7, 37.6, 39.7, 59.7, 60.9,
118.2, 121.6, 129.6, 141.8, 156.4; MS (m/z) 315 (M+, 1), 283 (23), 164 (77), 135 (42), 93 (100).
Anal. calcd for C19H26N2O2: C, 72.58; H, 8.33; N, 8.91. Found: C, 72.38 and 72.33; H, 8.18 and
8.13; N, 8.60 and 8.83.
3.6. rac-N-(Benzyloxycarbonyl)-2-(1-adamantyl)-2-aminoethanol 8
Benzyl chloroformate (0.95 ml, 6.7 mmol) was added via syringe into a stirred mixture of
aminoalcohol 7 (0.989 g, 5.1 mmol) and sodium carbonate (0.683 g, 6.4 mmol) in the solvent
system water (10 ml)–THF (3 ml) maintained at 0°C. The mixture was stirred at room
temperature for 18 h (TLC monitoring) and then partitioned between dichloromethane and
water. The organic phase was dried and evaporated to afford a white solid which was passed
through a column of silica gel with hexanes–ethyl acetate (v/v 2:1) to afford 8 (1.198 g, 72%),
1
mp 125–127°C; IR (KBr) 3377, 3239, 2901, 2849, 1695 cm−1. H NMR (250 MHz, CDCl3): l
1.52–1.73 (12H), 1.89 (s, 1H (OH)), 1.98 (3H), 3.40 (m, 1H), 3.57 (dd, J=10.6 and 8.5 Hz, 1H),
3.86 (dd, J=10.6 and 2.0 Hz, 1H), 4.90 (d, J=9.1 Hz, 1H), 5.12 (s, 2H), 7.34–7.39 (m, 5H). 13C
NMR (62.5 MHz, CDCl3): l 28.2, 35.7, 36.9, 38.9, 61.2, 61.9, 67.0, 128.1, 128.5, 136.4, 157.6;
MS (m/z) 254 (46), 135 (44), 91 (100). Anal. calcd for C20H27NO3: C, 72.92; H, 8.26; N, 4.25.
Found: C, 73.09 and 73.02; H, 8.04 and 8.11; N, 4.09 and 4.00.
3.7. Enzymatic resolution of compound 8. Preparation of (R)-N-(benzyloxycarbonyl)-2-
(1-adamantyl)-2-aminoethanol (R)-8 and (S)-N-(benzyloxycarbonyl)-2-
(1-adamantyl)-2-aminoethanol acetate (S)-9
Vinyl acetate (2 mmol) and 1 mmol of carbamate 8 were added to a suspension of

J. Clariana et al. / Tetrahedron: Asymmetry 11 (2000) 4549–4557
4555
Pseudomonas cepacia lipase (PSL, from Amano Pharmaceuticals Co.) (320 mg) in tert-butyl
methyl ether (3 ml) under nitrogen. The mixture was shaken at 40°C and 200 rpm during 24
hours. The enzyme was then filtered off and washed with dichloromethane (2×10 ml) and the
organic solvents were evaporated off. The crude residue was subjected to column chromatogra-
phy, with hexane–ethyl acetate (v/v 2:1) as eluent.
3.8. (S)-N-(Benzyloxycarbonyl)-2-(1-adamantyl)-2-aminoethanol acetate (S)-9
The above described procedure gave 96% of (S)-9 as a white solid, mp 75–77°C; IR (KBr)
1
3337, 1718, 1544, 1232 cm−1. H NMR (300 MHz, CDCl3): l 1.59–1.70 (m, 12H), 1.98 (br s,
6H), 3.60 (m, 1H), 4.17 (m, 2H), 4.79 (d, J=9.7 Hz, 1H), 5.12 (apparent q, 2H), 7.27–7.40 (m,
5H). 13C NMR (75 MHz, CDCl3): l 20.7, 28.0, 32.7, 36.6, 38.7, 58.5, 62.8, 66.6, 127.6, 127.9,
128.1, 128.3, 136.4, 156.5; 171. 1; MS (m/z) 371 (100), 135 (100), 298 (80). [h]2D3=−3.38 (c=0.59,
CHCl3). Determination of ee for (S)-9, 84% by chiral HPLC (Chiralcel OD), hexane–propan-2-
ol (90:10 v/v); in isochratic conditions (flux 0.8 ml min−1) and the u was 210 nm. The retention
times of the enantiomers were 8.77 min for (R)-9 and 10.55 min for (S)-9.
3.9. (R)-N-(Benzyloxycarbonyl)-2-(1-adamantyl)-2-aminoethanol (R)-8
The above described procedure gave 82% of (R)-8 as a white solid, mp 114–116°C; [h]2D3=
−3.86 (c=0.75, CHCl3). Determination of ee for (R)-8, >99% by chiral HPLC after derivatiza-
tion to the known ester (R)-9. The retention time of the enantiomer (R)-8 was 8.77 min; Rs,
2.06.
3.10. (R)-2-(1-Adamantyl)-2-aminoethanol (R)-7·HClO4
A solution of (R)-8 (0.170 g, 0.52 mmol) in absolute methanol (3 ml) was hydrogenated in the
presence of 15% Pd/C (0.026 g) at room temperature for 12 h. The mixture was filtered (Celite)
and washed with methanol. Then, perchloric acid (0.050 ml, 0.83 mmol) was added and the
mixture was stirred for 5 min. The solvent was evaporated to afford (R)-7·HClO4, mp
233–235°C; [h]2D3=−15.6 (c=0.68, methanol).
3.11. (R)-N-(Benzyloxycarbonyl)-2-(1-adamantyl)glycine (R)-10
Ruthenium(III) chloride dihydrate (0.009 g, 3.7×10−2 mol) was added into a stirred mixture of
carbamate (R)-8 (0.328 g, 1.0 mmol), sodium periodate (0.905 g, 4.2 mmol), tetrachloromethane
(2 ml), acetonitrile (2 ml), and water (3 ml). The mixture darkened immediately. It was stirred
overnight at room temperature, then dichloromethane was added and the organic layer
separated, dried, and evaporated to give a residue which was dissolved in diethyl ether. The
ether solution was passed through Celite and evaporated. The residue was chromatographed
through a column of silica gel with mixtures of hexanes–ethyl acetate of increasing polarity to
afford (R)-10 (0.193 g, 56%), mp 184–186°C (hexanes–ethyl acetate); IR (KBr) 3402, 2910, 2852,
1728, 1696 cm−1. 1H NMR (250 MHz, CDCl3): l 1.63–1.72 (12H), 2.00 (3H), 4.09 (d, J=9.6 Hz,
1H), 5.11 (s, 2H), 5.38 (d, J=9.6 Hz, 1H (NH)), 7.34–7.36 (m, 5H), 10.31 (br s, 1H (COOH)).
13C NMR (62.5 MHz, CDCl3): l 28.2, 36.3, 36.5, 38.5, 62.9, 67.2, 128.2, 128.5, 136.4, 156.6,
176.1; [h]D=−14 (c=0.85, chloroform).

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J. Clariana et al. / Tetrahedron: Asymmetry 11 (2000) 4549–4557
3.12. (R)-2-(1-Adamantyl)glycine hydrochloride (R)-1·HCl
A solution of (R)-10 (0.182 g, 0.5 mmol) in methanol (10 ml) was hydrogenated overnight at
2 atmospheres under stirring in the presence of 10% PdꢀC. Then, 7 M HCl was added and the
mixture was stirred for 10 min, then filtered through Celite, and the Celite eluted with more
methanol. The solvent was evaporated to afford (R)-1·HCl (0.120 g, 92%), mp 237–241°C (dec);
[h]D=−18 (c=0.67, methanol) (lit.11 [h]D (S-isomer)=+16 (c=0.50, methanol)).
3.13. X-Ray of (R)-7·HClO4
Colourless crystal, size 0.3×0.2×0.1 mm. Throughout the experiment Cu Ka radiation was
used with a graphite crystal monochromator on an Nonius KappaCCD single-crystal diffrac-
23
,
tometer (u=1.54178 A). Data collection was divided in 4 ꢀ-scans with a total amount of 414
frames, each one 1° width and being exposed during 12 s. Data were scaled and merged together
and cell refined over 15479 reflections24 with a final Rint=0.066 resulting in 1477 ‘unique’
reflections in the hkl range (−25, 0, 0) and (27, 8, 9) (2.72<q<50.45). The space group was
determined to be P21212 from systematic absences and structure determination.
The structure was solved by Patterson methods using DIRDIF.25 Initial isotropic and further
anisotropic least-squares refinement, using SHELX97,26 converged to a final R=0.051 and
WR2=0.110 for 847 ‘observed’ reflections and R=0.099 an WR2=0.132 for all data. Empirical
absorption correction27 was made with minimum and maximum transmission factor of 0.205
and 1.000. All non-hydrogen atoms except C34 were anisotropically refined. Hydrogen atoms
were geometrically placed. The function minimised was Sw(Fo−Fc)2, w=1/[|2(Fo )+(0.0786P)2]
2
2
2
with |(Fo ) from counting statistics and P=(max(Fo , O)+2*Fc2)/3. The maximum shift to e.s.d.
ratio in the last full-matrix least-squares cycle was 0.014 and the final difference Fourier map
−3
−3
,
,
showed no peaks higher than 0.25 e A nor deeper than −0.23 e A . Absolute configuration
was checked refining Flack parameter28 =−0.02(5). The ORTEP type diagram was obtained
using EUCLID package.29
Acknowledgements
We acknowledge financial support from DGICYT and DGESIC (MEC of Spain, projects
PB93-0896 and PB98-0902 (UAB) and BIO98-0770 (Oviedo)), CIRIT (Generalitat de
Catalunya, project SGR98-0056), Universitat Auto`noma de Barcelona (predoctoral scholarship
to J.C.), and CONACYT (Me´xico, predoctoral scholarship to A.L.). We thank Dr. Ignacio
Alfonso for his constructive suggestions.
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