Synthesis of enantiopure cyclobutane amino acids and amino alcohols

Article abstract of DOI:10.1016/j.tetasy.2005.06.030

(-)-(1R,3S)-3-Amino-2,2-dimethylcyclobutanecarboxylic acid and (+)-(1R,3S)-3-amino-2,2-dimethylcyclobutylmethanol, which can be used to prepare enantiopure oligopeptides and cyclobutane-based carbocyclic nucleosides, were synthesized from (+)-(1R)-α-pinen

Full text of DOI:10.1016/j.tetasy.2005.06.030

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2593–2597
Synthesis of enantiopure cyclobutane amino acids
and amino alcohols
*
´
´
Carmen Balo, Olga Caamano, Franco Fernandez and Carmen Lopez
˜
Departamento de Quı´mica Orga´nica, Facultade de Farmacia, Universidade de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
Received 19 May 2005; accepted 16 June 2005
Abstract—(ꢀ)-(1R,3S)-3-Amino-2,2-dimethylcyclobutanecarboxylic acid and (+)-(1R,3S)-3-amino-2,2-dimethylcyclobutylmetha-
nol, which can be used to prepare enantiopure oligopeptides and cyclobutane-based carbocyclic nucleosides, were synthesized from
(+)-(1R)-a-pinene.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
particular, both cyclobut A and cyclobut G have been
obtained in their enantiopure forms,6 while the search
for more efficient stereoselective syntheses of these or
closely related compounds has resulted in the prepara-
tion of a number of enantiopure cyclobutane derivatives
that can be used as starting materials. For example, cyclo-
butanes with two methyls instead of a hydroxymethyl at
the 2-position have been prepared from (ꢀ)-(S)-verbe-
none and (+)-(1R)-nopinone.7,8 Herein, we report the
preparation, from (+)-(1R)-a-pinene 4, of the enantio-
pure starting compounds 3 and 11, of opposite configu-
ration to those prepared previously.7,8
Recent years have seen a great effort devoted to research
on amino acids, in which the amino and carboxyl groups
(or aminoalkyl and carboxyalkyl groups) are on small
rings, such as cyclobutane1 or cyclopentane.2 Such mole-
cules can be used to construct conformationally
restricted peptides, and can therefore interact with a
variety of biological molecules, notably GABA recep-
tors.3 Furthermore, the corresponding alcohols are
embedded in carbocyclic nucleosides such as cyclobut
A 1 and cyclobut G 2, both of which exhibit a broad
spectrum of antiviral activities.4
As a first step towards 3, commercial enantiopure (+)-
(1R)-a-pinene was transformed into (+)-pinonic acid 5
[(1S,3S)-3-acetyl-2,2-dimethylcyclobutylacetic acid] by
oxidation with sodium periodate under the catalysis of
ruthenium trichloride,9 and compound 5 was then
converted to amido acid 6a by treatment with hydr-
oxylamine-O-sulfonic acid and a Beckmann rearrange-
ment10 (Scheme 1). To remove the unwanted carbon
from the carboxymethyl group, we planned to perform
a classical Barbier–Wieland degradation, via methyl
ester 6b, diphenyl alcohol 7, diphenylvinylcyclobutane
derivative 9 and the oxidative cleavage of 9–10 (Scheme
1).
NH2
N
OH
N
N
N
N
N
HO
HO
N
N
NH2
OH
OH
2
1
Although most reported syntheses of compounds of this
type give racemic products, stereoselective syntheses
such as Adlington et al.ꢀs synthesis of the natural dipep-
tide antibiotic (1S,2S)-1-hydroxy-2-[(S)-valylamino]cyclo-
butane-1-acetic acid have begun to appear.5 In
Methylation of 6a in methanol containing p-toluenesulf-
onic acid was uneventful, but when 6b was refluxed for
15 h with a large excess of phenyllithium in THF, the
major product isolated was not 7 but a compound
that, following recrystallization from methanol, was
*
Corresponding author. Fax: +34 981594912; e-mail: qomcls@usc.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.030

2594
C. Balo et al. / Tetrahedron: Asymmetry 16 (2005) 2593–2597
O
HO2C
O
RO2C
c
a
b
NH
6a, R = H
4
5
6b, R = Me
d
O
NH
Ph
HO
O
Ph
Ph
Ph
e
g
NH
9
7
f
i
O
HO2C
NH2
HO2C
NH
11
10
h
O
HO
HO
g
NH
NH2
12
3
Scheme 1. Reagents and conditions: (a) NaIO4/RuCl3, CCl4–MeCN–H2O, rt; (b) H2NOSO3H, AcOH, reflux; (c) MeOH/p-TsOH, reflux; (d) LiPh,
THF, rt; (e) p-TsOH, toluene, reflux; (f) oxidizing agent; (g) 2 M HCl, reflux; (h) LiAlH4, THF, reflux; (i) 1, ClCO2Et/Et3N, THF, 0 ꢁC; 2, NaBH4/
MeOH, 10 ꢁC.
identified on the basis of H, 13C and DEPT 13C NMR
spectra (notably, lack of the methyl group of the acetyl
residue and appearance of an extra methylene group)
and MS data as (1S,3S)-2-aza-5,5-diphenyl-8,8-di-
methylbicyclo[5.1.1]nonan-3-one 8. The unusual emer-
gence of this product seems likely to have arisen,
following the formation of the alkoxide corresponding
to 7, through the diphenyl carbon being attacked by
the carbanion into which the acetyl group will have been
transformed in the strongly basic medium (Scheme 2).
When 6b was reacted with phenyllithium at room tem-
perature, compound 7 was, as expected, obtained in
good yield (89%).
the same oxidant, a 24% yield was obtained using cis-
cyclohexyl-18-crown-6 ether as catalyst, with a small
quantity of acetic acid acting as an accelerator and
dichloromethane as solvent.8 The best results were
achieved with NaIO4 as oxidant and ruthenium oxide
as catalyst in a mixture of acetonitrile, carbon tetrachlo-
ride and water;12 this afforded a maximum 44% yield of
compound 10 after 1 h.
1
Refluxing 10 in concentrated hydrochloric acid gave the
amino acid as its hydrochloride, while removing the HCl
by passage through a basic ion exchange column affor-
ded free amino acid, 11, in 74% yield from 10. Enantio-
merically pure 11, a conformationally restricted c-amino
acid, is of interest as a building block for the construc-
tion of oligopeptide mimics.7
Unsaturation of 7 by refluxing with p-toluenesulfonic
acid in toluene proceeded almost quantitatively. How-
ever, when oxidative cleavage of the resulting diphenyl-
vinylcyclobutane derivative 9 was attempted by the
classical procedure (using KMnO4 in benzene/water in
the presence of an aliquat as phase transfer catalyst),11
only traces of the desired product were obtained. With
Compound 3 was finally obtained from 11 by reducing
the carboxyl group with LiAlH4 in THF. The overall
yield in obtaining 3 from 10 (path gh in Scheme 1)
was 52%. A better overall yield (63% from 10) was
Li+
Ph
Ph
Ph
Ph
Ph
-:H2C
O
Ph
-O
H3C
NH
O
O
MeO
O
O
Li+
excess LiPh
H2O
N- Li+
Li+
N-
NH
THF, reflux
6b
Scheme 2. Suggested mechanism for the formation of unexpected compound 8.
8

C. Balo et al. / Tetrahedron: Asymmetry 16 (2005) 2593–2597
2595
achieved by following path ig, which involves the one-
pot treatment of 10 with ethyl chloroformate and then
NaBH4, to reduce the carboxyl group, followed by
hydrolytic deacetylation of hydroxymethyl amide 12
(63% from 10).
NMR data in agreement with those reported for the
enantiomer.10
3.4. (1S,3S)-N-[3-(2,2-Diphenyl-2-hydroxyethyl) 2,2-
dimethylcyclobutyl]acetamide 7
PhLi (52 mL, 93.6 mmol) was slowly added to a solution
of amido ester 6b (5.0 g, 23.5 mmol) in dry THF
(100 mL) and the mixture stirred overnight at room tem-
perature. Water-saturated ether was added, followed by
water and the resulting white precipitate filtered out.
After removal of the organic solvent, the filtrate was
extracted with EtOAc, and this organic phase washed
with brine, dried and concentrated under reduced pres-
sure. Chromatography of the resulting oil on a silica
gel column with 2:1 EtOAc/CH2Cl2 as eluent afforded
a white solid (7.03 g, yield 89%), an analytical sample
2. Conclusion
In conclusion, the previously unreported enantiopure
compounds 11 and 3 have been prepared from (+)-
(1R)-a-pinene. These products are potentially useful
starting materials for the synthesis of enantiopure oligo-
peptides and cyclobutane-based carbocyclic nucleosides.
3. Experimental
of which was obtained by recrystallization from toluene.
25
All chemicals used were of reagent grade and were
obtained from the Aldrich Chemical Co. and used
without further purification. Mps were measured in a
Reichert Kofler Thermopan and are uncorrected. Infra-
red spectra were recorded on a Perkin–Elmer 1640
FTIR spectrophotometer. 1H and 13C NMR spectra
were recorded in a Bruker AMX-300 spectrometer at
300 and 75 MHz, respectively, using TMS as the inter-
nal standard (chemical shifts in d values, J in Hz).
Microanalysis was performed in a Perkin–Elmer 240B
Elemental Analyser at the University of Santiago
Microanalysis service. Analyses indicated by the sym-
bols of elements were within 0.4% of the theoretical
values. Flash chromatography was performed on silica
gel (Merck 60, 230–240 mesh) and analytical TCL on
pre-coated silica gel plates (Merck 60, F254, 0.25 mm).
EIMS and HRMS spectra were determined on a HP
5988A apparatus and on a Micromass Autospec appa-
ratus, respectively.
Mp 140–142 ꢁC. ½aꢁD ¼ ꢀ31.4 (c 1.06, CH2Cl2). IR (m):
3321, 2956, 1625, 1539, 1054, 749, 609 cmꢀ1. H NMR
1
(CDCl3) d: 0.92 (3H, s, CH3), 1.04 (3H, s, CH3), 1.20
(1H, q, J = 10.0, 4-HH), 1.76–1.98 (3H, m, 4-HH +
30-H + D2O exch., OH), 1.91 (3H, s, COCH3), 2.16
(1H, dd, J = 13.9, 9.2, CHH), 2,42 (1H, dd, J = 13.9,
3.4, CHH), 3.86 (1H, dd, J = 9.8, 7.6, 10-H), 5.28 (1H,
d, J = 6.8, D2O exch., NH), 7.18–7.41 (10H, m,
2 · Ph). 13C NMR (CDCl3) d: 16.72 (CH3), 23.60
(CH3), 28.52 (CH3), 33.81 (CH2), 35.05 (CH), 42.53
(CH2), 44.52 (C), 51.21 (CH), 126.35 (CH), 126.45
(CH), 127.18 (CH), 127.44 (CH), 128.45 (CH), 128.65
(CH), 147.33 (C), 147.66 (C), 169.95 (CO). EIMS, m/z
(%): 184 (14), 183 (100), 105 (68), 86 (15), 77 (32). Calcd
for C22H27NO2 (337.5): C, 78.30; H, 8.06; N, 4.15.
Found: C, 78.02; H, 7.89; N, 4.33.
3.5. (1S,7S)-2-Aza-5,5-diphenyl-8,8-dimethylbicyclo-
[5.1.1]nonan-3-one 8
3.1. (1S,3S)-(3-Acetyl-2,2-dimethylcyclobutyl)-
acetic acid 5
PhLi (10.6 mL, 19.6 mmol) was slowly added to a solu-
tion of amido ester 6b (1.05 g, 4.9 mmol) in dry THF
(20 mL) and the mixture refluxed for 15 h. Work-up as
for compound 7 gave an oil that when chromatographed
on a silica gel column using 2:1 EtOAc/CH2Cl2 as eluent
afforded a white solid (0.90 g, yield 58%) that was
recrystallized from methanol. Mp 133–134 ꢁC.
½aꢁD ¼ ꢀ77.3 (c 1.0, MeOH). H NMR (DMSO-d6) d:
0.84 (3H, s, 8-CH3), 0.88 (3H, s, 8-CH3), 1.42 (1H, q,
J = 10.5, 9-HH), 1.58 (1H, dt, J = 10.7, 7.7, 9-HH),
1.66–1.76 (1H, m, 7-H), 2.16 and 2.33 (2H, AB part of
an ABX system, JAB = 13.8, JAX = 9.0, JBX = 3.2, 6-
HH), 3.62 (1H, dt, J = 9.6, 8.2, 1-H), 3.71 and 3.75
(2H, AB system, JAB = 15.8, 4-HH), 5.34 (1H, br s,
D2O exch., NH), 7.12 (1H, t, J = 7.3, para-Ph), 7.14
(1H, t, J = 7.3, para-Ph0), 7.23 (2H, t, J = 7.7, meta-
Ph), 7.26 (2H, t, J = 7.7, meta-Ph0), 7.41 (4H, t,
J = 7.1, ortho-(Ph + Ph0)). 13C NMR (DMSO-d6) d:
16.54 (CH3), 28.74 (CH3), 32.48 (CH2), 34.77 (CH),
41.70 (CH2), 44.04 (C), 50.31 (CH), 61.58 (CH2), 76.58
(C), 126.22 and 126.30 (CH), 126.42 (CH), 127.88 and
128.07 (CH), 148.77 and 149.15 (C), 171.57 (CO).
EIMS, m/z (%): 319 (M+, 0.1), 293 (2), 284 (1), 184
(14), 183 (100), 149 (15), 105 (52), 77 (20). HRMS: Calcd
for C22H25NO, 319.1936. Found: 319.1942.
(+)-1R-a-Pinene was oxidized to 5 by the method used
by Moglioni et al.9 for its enantiomer. Mp 68–69 ꢁC
25
(hexane), ½aꢁD ¼ þ79.5 (c 0.8, CHCl3). {lit. for the
25
enantiomer: mp 65–68 ꢁC (ether), ½aꢁD ¼ ꢀ77.8 (c 2.03,
25
25
1
MeOH);9 mp 68–69 ꢁC, ½aꢁD ¼ ꢀ77.5 (c 5.0, CHCl3)}.13
1H and 13C NMR data in agreement with those reported
for the enantiomer.13
3.2. (1S,3S)-(3-Acetamido-2,2-dimethylcyclobutyl)-
acetic acid 6a
The procedure used was the same as described for its
25
enantiomer.10 Mp 133–134 ꢁC, ½aꢁD ¼ ꢀ112.6 (c 1.05,
25
EtOH); [lit. for the enantiomer: ½aꢁD ¼ þ111.3 (c 1.0,
EtOH)].10 1H and 13C NMR data in agreement with
those reported for the enantiomer.10
3.3. (1S,3S)-Methyl (3-acetamido-2,2-dimethylcyclo-
butyl)acetate 6b
25
½aꢁD ¼ ꢀ109.3 (c 1.1, EtOH), {lit. for the enantio-
25
mer: ½aꢁD ¼ þ110.4 (c 1.0, EtOH)}.10 1H and 13C

2596
C. Balo et al. / Tetrahedron: Asymmetry 16 (2005) 2593–2597
3.6. (1S,3S)-N-[3-(2,2-Diphenylethenyl)-2,2-dimethyl-
cyclobutyl]acetamide 9
(22). Calcd for C9H15NO3 (185.2): C, 58.36; H, 8.16;
N, 7.56. Found: C, 58.09; H, 8.33; N, 7.26.
A solution of alcohol 7 (7.06 g, 21 mmol) and p-tolu-
enesulfonic acid (1.0 mg) in toluene (75 mL) was
refluxed for 16 h in a flask with a Dean–Stark trap,
cooled to room temperature and extracted several
times with toluene. The organic extract was dried over
Na2SO4 and concentrated with chromatography of the
residue with 1:3 EtOAc/CH2Cl2 as eluent to afford 9 as
a white solid (6.50 g, yield 98%), an analytical sample
3.8. (1R,3S)-3-Amino-2,2-dimethylcyclobutanecarboxylic
acid 11
A solution of 10 (0.3 g, 1.62 mmol) in 2 M HCl (20 mL)
was refluxed for 36 h. Evaporation of the solvent left a
residue that was dissolved in water and passed through
a column of Dowex 50W, eluting first with water (to
neutrality) and then with 1 M NH3 solution (250 mL).
Removal of the solvent from the fraction eluted with
aqueous NH3 left 11 as a yellow solid (0.17 g, yield
74%), an analytical sample of which was obtained by
of which was obtained by recrystallization from
25
cyclohexane. Mp 125–126 ꢁC. ½aꢁD ¼ ꢀ38.7 (c 1.01,
CH2Cl2). IR (m): 3298, 2955, 1647, 1559, 1490, 1458,
1
1443, 1367, 764, 702 cmꢀ1. H NMR (CDCl3) d: 1.03
recrystallization from AcOEt. Mp 255–257 ꢁC.
25
(3H, s, CH3), 1,04 (3H, s, CH3), 1.65 (1H, q,
J = 10.3, 4-HH), 1.96 (3H, s, COCH3), 2.31 (1H, dt,
J = 10.8, 7.8, 4-HH), 2.49 (1H, dt, J = 9.9, 7.8, 3-H),
3.94 (1H, dd, J = 9.8, 8.0, 1-H), 5.43 (1H, d, J = 7.2,
D2O exch., NH), 5.98 (1H, d, J = 9.7, CH@), 7.11–
7.39 (10H, m, 2 · Ph). 13C NMR (CDCl3) d: 17.66
(CH3), 23.65 (CH3), 28.85 (CH3), 33.31 (CH2), 39.39
(CH), 46.67 (C), 50.44 (CH), 127.48 (CH), 127.56
(CH), 127.66 (CH), 128.51 (CH), 129.38 (CH), 130.39
(CH), 140.34 (C), 142.98 (C), 143.74 (C), 170.11
(CO). EIMS, m/z (%): 319 (11), 234 (18), 219 (49),
206 (100), 205 (34), 204 (22), 203 (16), 202 (11), 191
(32), 165 (16), 128 (22), 91 (41). Calcd for C22H25NO
(319.4): C, 82.72; H, 7.89; N, 4.38. Found: C, 82.75;
H, 7.81; N, 4.20.
½aꢁD ¼ ꢀ21.5 (c 0.57, MeOH). [No lit. value for its enan-
tiomer was found]. IR (m): 3439, 2963, 1635, 1569, 1508,
1415, 1026, 785 cmꢀ1 1H NMR (D2O), d: 0.90 (3H,
.
s, CH3), 1.10 (3H, s, CH3), 1.96 (1H, dt, J = 11.6, 9.5,
4-HH), 2.16 (1H, dt, J = 11.6, 7.8, 4-HH), 2.44 (1H,
dd, J = 9.8, 7.7, 1-H), 3.26 (1H, t, J = 8.4, 3-H). 13C
NMR (D2O), d: 16.47 (CH3), 25.74 (CH3), 27.92
(CH2), 42.80 (CH), 46.21 (C), 51.10 (CH), 180.42
(CO). Calcd for C7H13NO2: C, 58.72; H, 9.15; N, 9.78.
Found: C, 58.50; H, 9.00; N, 9.99.
3.9. (1S,3R)-N-(3-Hydroxymethyl-2,2-dimethylcyclo-
butyl)acetamide 12
Ethyl chloroformate (0.20 mL) was added dropwise
(with temperature monitoring to ensure that the temper-
ature did not exceed ꢀ5 ꢁC) to a solution of 10 (0.38 g,
2.05 mmol) and Et3N (0.28 mL) in dry THF (4 mL) in a
salted ice bath. The mixture was stirred for 30 min at
this temperature, and the solid formed filtered out and
washed with dry THF (4 · 5 mL). The pooled washings
and filtrate were placed in an ice bath at 10 ꢁC and trea-
ted with a single portion of NaBH4 (0.26 g, 6.8 mmol)
followed by 1.22 mL of dry methanol (added dropwise
with monitoring to ensure that the temperature did
not exceed 10 ꢁC). After 30 min stirring at this tempera-
ture, the reaction mixture was treated with water
(16 mL) followed by 2 M HCl (3 mL), with stirring in
both cases. The THF was removed under reduced pres-
sure, the aqueous phase extracted several times with
EtOAc, and the pooled organic extract was dried and
concentrated to dryness under reduced pressure. Chro-
matography of the residue on silica gel with 9:1
CH2Cl2/MeOH as eluent afforded 12 (0.25 g, yield
73%), an analytical sample of which was obtained by
recrystallization from EtOAc. Mp 138–140 ꢁC.
3.7. (1R,3S)-3-Acetamido-2,2-dimethylcyclobutane-
carboxylic acid 10
A solution of NaIO4 (2.0 g, 9.5 mmol) in water (29 mL)
was added to a solution of 9 (1.0 g, 3.13 mmol) in 1:1
MeCN/CCl4 (24 mL), and the mixture was stirred at
room temperature for a few minutes. RuO2ÆH2O
(10.42 mg, 0.069 mmol) was added, and stirring contin-
ued until TLC monitoring showed a complete reaction
(1 h). Water was added, the aqueous phase extracted
with EtOAc and the pooled organic phases vacuum-
filtered through Celite. The filtrate was washed with
Na2CO3 solution and the aqueous phase acidified with
6 M HCl and extracted repeatedly with EtOAc. Concen-
tration of the pooled organic extract to dryness afforded
10 (0.25 g, yield 44%), an analytical sample of which was
obtained by recrystallization from toluene/ethanol. Mp
25
221–223 ꢁC. ½aꢁD ¼ ꢀ195.35 (c 1.02, MeOH), (its enan-
25
tiomer is described as an oil, ½aꢁD ¼ þ38.3 (c 2.14,
25
MeOH) or solid, mp 226–228 ꢁC, ½aꢁD ¼ þ198.3 (c
25
25
0.54, MeOH)).8 IR (m): 3347, 2962, 1697, 1623, 1557,
½aꢁD ¼ ꢀ97.4 (c 0.51, MeOH), {lit.8 ½aꢁD ¼ þ99.3 (c
1
1376, 1335, 1254, 1220, 736 cmꢀ1. H NMR (DMSO-
0.30, MeOH) for its enantiomer}. IR (m): 3274, 2956,
1
d6) d: 0.80 (3H, s, CH3), 1.16 (3H, s, CH3), 1.79 (3H,
s, COCH3), 1.92–2.08 (2H, m, 4-H2), 2.46–2.54 (1H,
m, 1-H), 3.86 (1H, q, J = 8.1; it turns into a triplet
(J = 8.1), after D2O exchange, 3-H), 7.82 (1H, d,
J = 7.8, D2O exch., NH), 12.03 (1H, br s, D2O exch.,
CO2H). 13C RMN (DMSO-d6) d: 17.15 (CH3), 22.72
(CH3), 25.00 (CH2), 29.25 (CH3), 42.56 (CH), 45.98
(C), 49.38 (CH), 168.00 (CO), 173.87 (CO). EIMS: m/z
(%): 185 (M+, 0.2), 183 (3), 129 (3), 128 (4), 113 (16),
100 (26), 87 (2), 86 (9), 85 (100), 83 (11), 71 (37), 56
1652, 1557, 1540, 1373, 1020 cmꢀ1. H NMR (CDCl3)
d: 0.97 (3H, s, CH3), 1.21 (3H, s, CH3), 1.39 (1H, q,
J = 10.2, 4-HH), 1.89–1.99 (1H, m, 4-HH), 1.96 (3H,
s, COCH3), 2.30 (1H, dt, J = 11.0, 7.9, 3-H), 3.59
and 3.62 (2H, AB part of an ABX system, JAB
=
10.9, JAX = 6.4, JBX = 7.6, CH2OH), 4.04 (1H, q,
J = 8.6, 1-H), 5.50 (1H, br s, D2O exch., NH). 13C
NMR (CDCl3) d: 16.40 (CH3), 23.72 (CH3), 28.75
(CH2), 30.02 (CH3), 41.49 (CH), 43.56 (C), 50.32
(CH), 63.86 (CH2), 171.00 (CO). Calcd for C9H17NO2

C. Balo et al. / Tetrahedron: Asymmetry 16 (2005) 2593–2597
2597
(171.2): C, 63.13; H, 10.01; N, 8.18. Found: C, 63.34; H,
9.82; N, 7.98.
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2465–2471.
3. (a) Nielsen, L.; Brehm, L.; Krogsgaard-Larsen, P. J. Med.
Chem. 1990, 33, 71–77; (b) Kubota, H.; Katsurabayashi,
S.; Moorhouse, A. J.; Murakami, N.; Koga, H.; Akaike,
N. J. Physiol. (Cambridge, UK) 2003, 551, 263–276.
4. (a) Colacino, J. M.; Staschke, K. A. Prog. Drug Res. 1998,
sample of which was obtained by sublimation. Mp 74–
25
76 ꢁC. ½aꢁD ¼ þ20.6 (c 1.05, MeOH) {its enantiomer is
50, 261–322; (b) Ireland, C.; Leeson, P. A.; Castaner, J.
Drugs Future 1997, 22, 359–370; (c) Norbeck, D. W.;
Kern, E.; Hayashi, S.; Rosenbrook, W.; Sham, H.; Herrın,
T.; Plattner, J. J.; Erickson, J.; Clement, J.; Swanson, R.;
˜
25
described as a solid, mp 73–75 ꢁC, ½aꢁD ¼ ꢀ19.1 (c
0.82, MeOH)}.8 IR (m): 3357, 2930, 1560, 1510, 1418,
´
1
760 cmꢀ1. H NMR (DMSO-d6) d: 1.00 (3H, s, CH3),
´
1.17 (3H, s, CH3), 1.31 (1H, q, J = 10.3, 4-HH), 1.41
(1H, br s, D2O exch., OH), 2.15–2.25 (1H, m, 4-HH),
2.22 (1H, dt, J = 9.7, 7.7, 1-H), 2.85 (1H, t, J = 8.2,
3-H), 3.49 and 3.52 (2H, AB part of an ABX system,
JAB = 10.6, JAX = 6.7, JBX = 8.2, thus observed after
treating the sample with D2O, CH2O). 13C NMR
(DMSO-d6) d: 15.27 (CH3), 29.54 (CH3), 31.71 (CH2),
41.05 (CH), 42.30 (C), 54.09 (CH), 62.02 (CH2). EIMS,
m/z (%): 86 (3), 85 (2), 84 (66), 71 (2), 68 (5), 66 (100), 61
(2), 58 (5), 52 (1). Calcd for C7H15NO (129.2): C, 65.07;
H, 11.70; N, 10.84. Found: C, 64.86; H, 11.41; N, 10.52.
Shipkowitz, N.; Ardı, D.; Marsh, K.; Atnett, G.; Shannon,
W.; Broder, S.; Mitsuya, H. J. Med. Chem. 1990, 33, 1281–
1285; (d) Ichikawa, E.; Kato, K. Synthesis 2002, 1–
28.
5. Baldwin, J. E.; Adlington, R. M.; Parisi, M. F.; Ting,
H. H. Tetrahedron 1986, 42, 2575–2586.
6. (a) Ichikawa, Y.; Narita, A.; Shiozawa, A.; Hayashi, Y.;
Narasaka, K. J. Chem. Soc., Chem. Commun. 1989, 24,
1919–1921; (b) Bisacchi, G. S.; Braitman, A.; Cianci, C.
W.; Clark, J. M.; Field, A. K.; Hagen, M. E.; Hockstein,
D. R.; Malley, M. F.; Mitt, T.; Slursarchyk, W. A.;
Sundeen, J. E.; Terry, B. J.; Tuomari, A. V.; Weaver, E.;
Young, M. G.; Zahler, R. J. Med. Chem. 1991, 34, 1415–
1421.
3.11. Preparation of compound 3 from 12
7. Rouge, P. D.; Moglioni, A. G.; Moltrasio, G. Y.; Ortuno,
˜
R. M. Tetrahedron: Asymmetry 2003, 14, 193–195.
A mixture of 12 (0.2 g, 1.16 mmol) and 2 M HCl (7 mL)
was refluxed for 17 h, the solvent evaporated under
reduced pressure and the residual oil dissolved in MeOH
and passed through a basic ion exchange resin. The sol-
vent was then removed under reduced pressure, leaving
3 as an oil (0.12 g, yield 86%) that solidified on standing
under reduced pressure.
´
8. Figueira, M. J.; Blanco, J. M.; Caamano, O.; Fernandez,
˜
´
F.; Garcia-Mera, X.; Lopez, C. Synthesis 2000, 10, 1459–
1463.
´
´
9. Moglioni, A. G.; Garcıa-Exposito, E.; Aguado, G. P.;
Parella, T.; Branchadell, V.; Moltrasio, G. Y.; Ortuno, R.
˜
M. J. Org. Chem. 2000, 65, 3934–3940.
´
´
10. Borges, J. E. R.; Fernandez, F.; Garcıa, X.; Hergueta, A.
´
R.; Lopez, C. Org. Prep. Proced. Int. 1997, 29, 303–308.
11. Krapcho, A. P.; Larson, J. R.; Eldridge, J. M. J. Org.
Chem. 1977, 42, 3749–3753.
12. Schuda, P. F.; Phillips, S. L.; Morgan, T. M. J. Org.
Chem. 1986, 51, 2742–2751.
Acknowledgements
Authors thank Xunta de Galicia for financial support
under project PGIDIT02BTF20305PR.
´
´
13. Fernandez, F.; Lopez, C.; Hergueta, A. R. Tetrahedron
1995, 51, 10317–10322.