Synthesis of two enantiomerically pure precursors of cyclobutane carbocyclic nucleosides

Article abstract of DOI:10.1016/j.tetasy.2003.09.033

Several bi-functionallized derivatives of cyclobutane have been synthesized by functional-group manipulation starting from (-)-cis-pinonic acid as a common precursor, the configuration of the pre-existing and newly formed stereogenic centers being determined by the configuration of the starting material, commercially available (-)-1S-α-pinene. Final products, (+)-(1S,1′R)-cis-1-[3′-(aminomethyl)-2′,2′- dimethylcyclobutyl]ethanol 5 and (+)-(1S,1′R)-cis-1-[3′-(2″- aminoethyl)-2′,2′-dimethylcyclobutyl]ethanol 6 are useful as precursors to cyclobutane carbocyclic nucleosides.

Full text of DOI:10.1016/j.tetasy.2003.09.033

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3773–3778
Synthesis of two enantiomerically pure precursors of cyclobutane
carbocyclic nucleosides
Antonio R. Hergueta, Carmen Lo´pez,* Franco Ferna´ndez, Olga Caaman˜o and Jose´ M. Blanco
Departamento de Qu´ımica Orga´nica, Facultade de Farmacia, Universidade de Santiago, E-15782 Santiago de Compostela, Spain
Received 1 August 2003; accepted 8 September 2003
Abstract—Several bi-functionallized derivatives of cyclobutane have been synthesized by functional-group manipulation starting
from (−)-cis-pinonic acid as a common precursor, the configuration of the pre-existing and newly formed stereogenic centers being
determined by the configuration of the starting material, commercially available (−)-1S-a-pinene. Final products, (+)-(1S,1%R)-cis-
1-[3%-(aminomethyl)-2%,2%-dimethylcyclobutyl]ethanol 5 and (+)-(1S,1%R)-cis-1-[3%-(2¦-aminoethyl)-2%,2%-dimethylcyclobutyl]ethanol 6
are useful as precursors to cyclobutane carbocyclic nucleosides.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Compounds 1 and 2 are active against a broad spectrum
of herpes viruses and, at least in vitro, against hepatitis
B virus.4 The presence of the hydroxymethyl group that
mimics the terminal carbon of the sugar in true
nucleosides is not an essential feature for interesting
biological activity, as it has been reported that a 6%-C-
methylneplanocin A 3a is more potent and/or selective
than neplanocin A 3b against a wide variety of viruses.5
In recent years there has been an increasing interest in
carbocyclic analogues of nucleosides (CANs), many of
which are potent antiviral or antineoplastic agents.1,2
Typical examples are COXT-A 1 and COXT-G 2,3 in
which a methylene replaces the oxygen of the oxetane ring
possessed by the oxetanocin family of natural antibiotics.
* Corresponding author. E-mail: qomcls@usc.es
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.033

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A. R. Hergueta et al. / Tetrahedron: Asymmetry 14 (2003) 3773–3778
We have been occupied for some years in the synthesis
and evaluation of the biological activities of CANs
featuring structural and/or configurational alterations
of the carbocyclic moiety.6 Recently, we found that
some adenine, hypoxanthine and 8-azadenine deriva-
tives of type 4 show interesting activity in tests against
respiratory syncytial virus and vaccinia virus, and/or
moderate activity against murine and human tumoral
cell lines.7 These preliminary results stimulated the
search for biological activities to other structurally
related analogues.
almost quantitative yield of a mixture of diastereomers
1
of pinolic acid with H NMR signals for CH6 OH at l
3.72 (J=9.8, 6.2 Hz; major isomer) and 3.66 (J=9.6,
6.1 Hz; minor isomer) in the crude product. Applica-
tion of the Felkin–Anh model10 to the reduction of 8
predicts the preferred formation of (1R,1%S)-cis-pinolic
acid. Actually, after isolation by double recrystalliza-
tion from water, the major isomer 9 obtained in this
reaction had a specific rotation [h]2D5 of +26.5, almost
equal in magnitude but of opposite sign to the pub-
lished value (−27) for its enantiomer (1S,1%R)-cis-pino-
lic acid.11
Compounds of type 4, as well as a variety of other
purine and pyrimidine derivatives are best constructed
from secondary cyclobutane amino alcohols 5 or 6. As
full details of the preparation of 5 and 6 have not yet
been published, we disclose herein our studies on an
efficient synthesis of enantiomerically pure amino alco-
hols 5 and 6, which are prepared as shown in Scheme 1
from (−)-1S-a-pinene 7. The preparation of other pre-
cursors to cyclobutane carbocyclic nucleosides from
(−)-S-verbenone has been recently reported.8
Experiments carried out to optimize the stereoselectiv-
ity of the reduction of 8 identified L-Selectride and
NaBH4 as the reducing agents affording, respectively,
greatest and least selectivity for the (1R,1%S)-cis-isomer
and, respectively, least and greatest total yield of the
mixture of diastereomers (Table 1). Borane–dimethyl
sulphide complex reduced both the carbonyl and car-
boxyl groups of 8 (Scheme 2), affording a diol 9a, to
which the structure of (1S,1%R)-cis-1-[3%-(2-hydroxy-
ethyl)-2%,2%-dimethylcyclobutyl]ethanol was assigned
by assuming the absolute configuration at the sec-
ondary alcohol carbon as being the same as in the
analogous carbon of the major isomer of hydroxy acid
9.
Oxidative cleavage of
7 to (1R)-cis-(3-acetyl-2,2-
dimethylcyclobutyl)acetic acid [(−)-cis-pinonic acid] 8
was achieved by a well documented procedure.9 Keto
acid 8 was reduced by NaBH4 in ethanol to afford an
Scheme 1. Reagents and conditions: (a) NaIO4, RuCl3, CCl4–MeCN–H2O, rt, 24 h; (b) NaBH4, NaHCO3/H2O, EtOH, reflux, 6.5
h; (c) Ac2O, pyridine, rt, 18 h; (d) (1) EtOCOCl, acetone, Et3N, −10 to 0°C, 30 min; (2) NaN3/H2O, 0°C, 30 min; (3) toluene,
reflux, 1 h; (e) (1) 8N HCl/H2O, reflux, 45 min; (2) Ac2O, Et3N, rt, 14 h; (f) MeOH/toluene, reflux, 18 h; (g) (1) KOH/MeOH,
reflux, 18 h; then 2N H2SO4; (2) Amberlite IRA-400 (OH); (h) (1) EtOCOCl, THF, Et3N, −10 to 0°C, 2 h; (2) NH3 (g), rt, 30
min; (i) LiAlH4, THF, reflux, 18 h.

A. R. Hergueta et al. / Tetrahedron: Asymmetry 14 (2003) 3773–3778
3775
Table 1. Results obtained in the reduction of (−)-(1R)-cis-pinonic acid under different conditions
Reducing reagent
Solvent
Temp. (°C)
Time (h)
Global yield (%)
Major product
S/R ratioa
NaBH4
LiBH4
EtOH
THF
THF
THF
THF
78
65
25
3
20
8
3 (“1)
5
95
81
85
63
85
9
9
9
9
76/24
87/13
85/15
>99
Super-hydrideb
L-Selectridec
Me2S·BH3
−78 (“25)
65
9a
>95
a At the new stereogenic center, by 1H NMR.
b LiB(C2H5)3H.
c LiB[CH(CH3)CH2CH3]3H.
Scheme 2. Reagents and conditions: (a) Me2S·BH3, THF,
reflux, 5 h.
Scheme 3. Reagents and conditions: (a) 5-amino-4,6-
dichloropyrimidine, Et3N, BuOH, reflux, 72 h.
The hydroxyl group of 9 was protected in the form of
its acetate 10 with acetic anhydride and anhydrous
pyridine. Compound 10 was treated with ethyl chloro-
formate in the presence of triethylamine and subse-
quently with NaN3 to obtain the corresponding azide,
which underwent a Curtius rearrangement to isocya-
nate 11 when heated in refluxing anhydrous toluene.
However, regardless of pH used to perform the hydro-
lysis of 11, the major and only isolable product of this
reaction was not amino alcohol 5 but the urea 12. To
circumvent this undesired result, the toluene solution of
11 was refluxed after addition of methanol to obtain the
carbamate 13 (in 61% yield from acid 10), and hydroly-
sis of 13 in basic medium, followed by passage of the
reaction mixture through an ion exchange resin,
afforded amino alcohol 5 in 85% yield.
assigned to the 1-hydroxyethyl or 1-acetoxyethyl moiety
of compounds 9–14, was made by X-ray crystallo-
graphic analysis of a single crystal of compound 17
(Fig. 1),12 a synthetic intermediate obtained by reaction
of 5 with 5-amino-4,6-dichloropyrimidine (Scheme 3).7
To obtain amino alcohol 6, the mixed anhydride
derived from compound 10 and ethyl chloroformate in
the presence of triethylamine was treated with gaseous
ammonia to convert it to the amide 15, which was
reduced with LiAlH4 to give 6 as an oily product in a
fair yield. Though this product was initially colourless,
gave proper spectra and could be satisfactorily used for
subsequent synthetic steps within a few minutes of its
preparation, it rapidly altered turning reddish. When
not for immediate use, it is best kept in the form of its
diacetyl derivative 16, from which it can be recovered
by the same procedure of saponification and isolation
as described in the preparation of 5 from 13.
Compound 5 was fully characterized by spectroscopic
methods and by the preparation of its diacetyl deriva-
tive, 14. An indirect though definitive confirmation of
the structure of 5, and hence of the (S)-configuration
2. Experimental
Melting points are uncorrected and were determined in
a Reichert Kofler Thermopan or in capillary tubes in a
Bu¨chi 510 apparatus. Observed rotations at the NaD
line were determined at 25°C in a Perkin–Elmer 241
polarimeter. IR spectra of samples as KBr disks (for
solids) or films between NaCl plates (for oils) were
recorded in a Perkin–Elmer FTIR 1640 spectrometer.
1H NMR spectra (300 MHz) and 13C NMR (75 MHz)
spectra were recorded in a Bruker WM spectrometer,
using TMS as internal standard (chemical shits in l
values, J in Hz). EIMS and HRMS spectra were deter-
Figure 1. ORTEP plot of the molecular structure of 17 in the
solid state.

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A. R. Hergueta et al. / Tetrahedron: Asymmetry 14 (2003) 3773–3778
mined on a HP 5988A apparatus and on a Micromass
Autospec apparatus, respectively. Microanalyses were
performed in a Fisons EA-1108 by the Microanalysis
Service of the University of Santiago. Flash chromatog-
raphy was performed on silica gel (Merck 60, 230–240
mesh). Progress of the reactions and separations by
flash chromatography were followed by analytical TLC,
that was performed on pre-coated silica gel plates
(Merck 60 F254, 0.25 mm).
The organic phase obtained upon extraction with
EtOAc was washed with 2N HCl, then with brine, and
dried (Na2SO4). Removal of the solvent at low pressure
afforded 10 as a colourless oil in quantitative yield (4.92
g). [h]2D5=−52.0 (c 2, EtOH). IR (w): 2960, 1730, 1705,
1
1371, 1248, 1034 cm−1. H NMR (CDCl3) l: 0.76 (3H,
s, t-2-CH3), 0.94 (3H, d, J=6.1, CH3
c-2-CH3), 1.13 (1H, q, J=9.8, 4-H
CH3CO), 1.86–2.00 (2H, m, 1-H+4-HH
J=10.3, 7.8, CHHCO), 2.17 (1H, dd, J=10.3, 7.0,
CHHCO), 2.22–2.37 (1H, m, 3-H), 4.65 (1H, dq, J=
6
CH<), 0.98 (3H, s,
H), 1.88 (3H, s,
), 2.10 (1H, dd,
6
6
6
2.1. (1R,1%S)-cis-[3-(1%-Hydroxyethyl)-2,2-dimethyl-
cyclobutyl]acetic acid [(1R,1%S)-cis-pinolic acid] 9
6
10.2, 6.1 Hz, 1%-H), 10.58 (1H, broad s, D2O exchang.,
CO2H). 13C NMR (CDCl3) l: 17.09, 17.97, 21.78,
26.75, 30.71, 35.28, 38.17, 40.25, 47.44, 72.20, 171.01,
179.63. HRMS m/z calcd for [C12H20O4] 228.1362,
found: 228.1365.
A mixture of 89 (5.00 g, 27.1 mmol), 0.5N NaHCO3 (55
mL), NaBH4 (1.00 g, 26.5 mmol) and EtOH (10 mL)
was refluxed for 6.5 h, cooled to 0°C, and brought to
pH 1 by addition of 2N HCl (20 mL). The organic
phase obtained upon extraction with EtOAc was
washed with saturated NaCl solution and dried with
Na2SO4, and removal of the solvent at low pressure
afforded a mixture of 7 and its (1R,1%R)-cis epimer as a
white solid (4.80 g, 95%; 1%S/1%R ratio 76:24, according
to 1H NMR spectrometry). Double recrystallization
2.3. (1S,1%S)-cis-3-(1%-Acetoxyethyl)-2,2-dimethylcyclo-
butylmethyl isocyanate 11
Ethyl chloroformate (1.70 mL, 17 mmol) was slowly
added to a cold (−10° to 0°C) solution of 10 (3.50 g,
15.3 mmol) and dry triethylamine (2.30 mL) in anhy-
drous acetone (11 mL), and after 15 minutes stirring
was treated with a solution of NaN3 (1.95 g, 30 mmol)
in H2O (6 mL). After a further 30 min stirring at 0°C
the reaction mixture was poured on to ice and the
resulting basic solution was extracted with toluene. The
organic phase was dried (Na2SO4), filtered, and refluxed
for 1 h, after which the toluene was removed at low
pressure to obtain 11 as a yellowish oil (2.65 g, 77%).
IR (w): 2959, 2259, 1734, 1458, 1374, 1248 cm−1.
1
from water removed the H NMR signal corresponding
to the 1%R epimer. Mp 120–121°C; [h]2D5=+26.5 (c 3.84,
EtOH) [lit.11 −27 (c 3.84, EtOH), for the (1S,1%R)-cis
isomer]. IR (w): 3303, 1684, 1296, 1276, 1256, 1200,
1081, 1030 cm−1. 1H NMR (CDCl3) l: 1.02 (3H, s,
t-2-CH3), 1.05 (3H, d, J=6.2, CH3
c-2-CH3), 1.18 (1H, q, J=10.2, 4-H
J=10.1, 8.0, 4-HH), 1.96–2.05 (1H, m, 1-H), 2.17 (1H,
dd, J=10.1, 8.1, CHHCO), 2.27 (1H, dd, J=10.1, 7.9,
CHHCO), 2.37 (1H, dt, J=10.0, 7.9, 3-H), 2.84 (1H,
6
CH<), 1.14 (3H, s,
6
H), 1.76 (1H, dt,
6
6
6
broad s, D2O exchang., OH), 3.72 (1H, dq, J=9.8, 6.2,
1%-H), 11.24 (1H, broad s, D2O exchang., CO2H). 13C
NMR (CDCl3) l: 17.02, 21.44, 26.73, 31.14, 35.15,
37.89, 40.10, 50.50, 69.53, 170.10. Anal. calcd for:
C10H18O3: C, 64.49; H, 9.74. Found: C, 64.54; H, 10.02.
2.4. Hydrolysis of 11
A solution of 11 (0.73 g, 3.24 mmol) in THF (2 mL)
was treated with 8N HCl (6.5 mL), and the mixture was
refluxed for 45 min, basified with 5N NaOH (15 mL)
and extracted with EtOAc. The organic phase was dried
(Na2SO4), and removal of the solvent at low pressure
left a reddish oily liquid (0.32 g) that was dissolved in
dry triethylamine (5 mL) and added to acetic anhydride
(5 mL). This mixture was stirred overnight at room
temperature, and after cooling to 0°C and addition of
water, stirring was continued for 1 h. The organic phase
obtained upon extraction with Et2O was washed with
2N HCl, saturated NaHCO3 and brine, dried (Na2SO4),
and concentrated under reduced pressure to an oily
residue (0.21 g). Flash chromatography (1:2 CH2Cl2/
EtOAc) yielded as a colourless oil, N,N%-bis[(1S,1%S)-
cis-3-(1%-acetoxyethyl)-2,2-dimethylcyclobutylmethyl]-
urea 12. Compound 12 was likewise obtained when 11
was hydrolysed with 10N NaOH in refluxing THF or
with neutral water. [h]2D5=−6.8 (c 0.25, CHCl3). IR (w):
3292, 1731, 1633, 1568, 1463, 1369, 1245, 1039 cm−1. 1H
NMR (CDCl3) l: 0.92 [6H, s, 2×(t-2-CH3)], 1.08 [6H,
The product obtained upon reduction of 8 with
borane–dimethyl sulphide complex was spectroscopi-
cally identified as (1S,1%R)-cis-1-[3%-(2-hydroxyethyl)-
2%,2%-dimethylcyclobutyl]ethanol 9a. IR (w): 3344, 2957,
1463, 1365, 1293, 1166, 1052, 986 cm−1. 1H NMR
(CDCl3) l: 0.98 (3H, s, t-2%-CH3), 1.01 (3H, d, J=6.3,
CH3
4%-HH), 1.40 (1H, ddd, J=13.5, 8.5, 6.6, 4%-HH
1.61 (1H, m, CHHCH2O), 1.67 (1H, dt, J=10.1, 7.9,
CHHCH2O), 1.77–1.83 (1H, m, 3%-H), 1.88 (1H, dt,
J=9.8, 7.9, 1%-H), 2.50–2.68 (2H, broad s, D2O
6
CH<), 1.09 (3H, s, c-2%-CH3), 1.06–1.16 (1H, m,
6
6
), 1.54–
6
6
exchang., 2×OH), 3.52 (2H, t, J=6.9, CH6 2OH), 3.68
(1H, dq, J=9.9, 6.2, 1-H). 13C NMR (CDCl3) l: 17.04,
21.48, 26.84, 31.64, 33.64, 38.75, 39.93, 50.52, 61.62,
69.53. HRMS m/z calcd for [C12H20O3] 172.1463,
found: 172.1467.
2.2. (1R,1%S)-cis-[3-(1%-Acetoxyethyl)-2,2-dimethyl-
cyclobutyl]acetic acid 10
d, J=6.3, 2×(CH3
1.20 [2H, dt, J=13.2, 10.1, 2×(4-H
m, 2×(1-H+3-H+4-HH)], 2.01 [6H, s, 2×(CH3CO)], 3.08
[2H, dd, J=6.6, 5.4, 2×(CHHN)], 3.11 [2H, dd, J=7.5,
5.4, 2×(CHHN)], 4.13 [2H, broad s, D2O exchang.,
6
CH<)], 1.11 [6H, s, 2×(c-2-CH3)],
6
H)], 1.66–2.17 [6H,
A mixture of 9 (4.03 g, 21.6 mmol), anhydrous pyridine
(50 mL) and acetic anhydride (50 mL) was successively
stirred at room temperature for 18 h, cooled to 0°C
and, after addition of water, stirred for a further 1 h.
6
6
6

A. R. Hergueta et al. / Tetrahedron: Asymmetry 14 (2003) 3773–3778
3777
2×(NH)], 4.79 [2H, dq, J=10.2, 6.0, J(t)=2×(1%-H)].
13C NMR (CDCl3) l: 16.77, 17.83, 21.54, 21.68, 24.61,
31.32, 39.47, 41.70, 46.73, 72.06, 158.93, 170.81. EIMS,
m/z (%): 425 (M+1, 0.9); 424 (M+, 0.4); 365 (15); 337
(11); 123 (13); 100 (11); 95 (13); 85 (17); 84 (18); 83 (11);
82 (31); 81 (15); 79 (13), 69 (17); 67 (30); 58 (11); 57
(13); 56 (19); 55 (28), 43 (100). HRMS m/z calcd for
[C23H40N2O5] 424.2937, found: 424.2944.
2.7. (1S,1%R)-cis-1-[3%-(Acetamidomethyl)-2%,2%-dimethyl-
cyclobutyl]ethyl acetate 14
A mixture of 5 (0.50 g, 3.18 mmol), anhydrous pyri-
dine (20 mL) and acetic anhydride (20 mL) was stirred
at room temperature for 18 h, and after cooling to
0°C and addition of water, stirring was continued for
a further 1 h. The organic phase obtained upon
extraction with EtOAc was successively washed with
2N HCl, saturated NaHCO3 solution and brine, dried
(Na2SO4), and condensed under reduced pressure to a
brown oil (0.90 g) that upon flash chromatography
(EtOAc) afforded a quantitative yield of 14 as a white
solid (0.76 g). A analytical sample was obtained by
recrystallization from cyclohexane. Mp 75–76°C.
[h]2D5=−4.7 (c 1.06, MeOH). IR (w): 3303, 2863, 1730,
1646, 1558, 1457, 1368, 1245, 1039 cm−1. 1H NMR
(CDCl3) l: 0.90 (3H, s, t-2%-CH3), 1.04 (3H, d, J=6.1,
2.5. Methyl N-[(1S,1%S)-cis-3-(1%-acetoxyethyl)-2,2-
dimethylcyclobutylmethyl]carbamate 13
To a solution of 11 in toluene, obtained from 10
(10.80 g; 47.3 mmol) as described above and kept at
room temperature, anhydrous MeOH (75 mL) was
slowly added and the resulting mixture was refluxed
for 18 h. Removal of the solvents at low pressure left
a yellowish oily liquid (9.76 g) that upon flash chro-
matography (9:1 CH2Cl2/EtOAc) afforded a colourless
CH3
10.4, 4%-H
1.91 (3H, s, CH3CO), 1.97 (3H, s, CH3CO), 3.13 (1H,
dd, J=13.6, 7.1, CHHN), 3.17 (1H, dd, J=13.6, 7.2,
CHH
6
CH<), 1.07 (3H, s, c-2%-CH3), 1.18 (1H, q, J=
6
H), 1.88–2.12 (3H, m, 4%-HH+1%-H+3%-H),
6
1
oil that H NMR spectroscopy showed to be virtually
pure 13 (7.43 g; 61% from 10). [h]2D5=−0.8 (c 1,
EtOH). IR (w): 3370, 1732, 1529, 1465, 1370, 1247,
6
1
1194, 1145, 1075 cm−1. H NMR (CDCl3) l: 0.90 (3H,
6
N), 4.74 (1H, dq, J=10.1, 6.1, 1-H), 5.53 (1H,
broad s, D2O exchang., NH). 13C NMR (CDCl3) l:
17.03, 17.96, 21.82, 23.67, 24.85, 31.41, 39.71, 40.66,
41.42, 46.90, 72.09, 170.39, 170.86. Anal. calcd for:
C13H23NO3: C, 64.70; H, 9.61; N, 5.80. Found: C,
64.54; H, 9.83; N, 5.71.
s, t-2-CH3), 1.05 (3H, d, J=6.1, CH3
s, c-2-CH3), 1.20 (1H, dt, J=13.1, 10.0, 4-H
1.94 (1H, m, 4-HH), 1.98 (3H, s, CH3CO), 1.99 (1H,
quint, J=8.6, 1-H), 2.18 (1H, dt, J=11.7, 10.0, 3-H),
3.08 (1H, t, J=6.6, CHHN), 3.12 (1H, t, J=6.6,
CHH
6
CH<), 1.08 (3H,
6
H), 1.88–
6
6
6
N), 3.62 (3H, s, CH3O), 4.55 (1H, broad s, D2O
exchang., NH), 4.74 (1H, dq, J=10.0, 6.1, 1%-H). 13C
NMR (CDCl3) l: 16.80, 17.80, 21.67, 24.50, 31.25,
39.48, 41.54, 41.94, 46.68, 52.27, 71.96, 157.17, 170.71.
HRMS m/z calcd for [C13H23NO4] 257.1627, found:
257.1630.
2.8. (1S,1%R)-cis-1-[3%-(Carbamoylmethyl)-2%,2%-dimethyl-
cyclobutyl]ethyl acetate 15
A solution of 10 (9.00 g, 39.4 mmol) and dry triethy-
lamine (11 mL) in anhydrous THF (45 mL) was added
to a cold (−10° to 0°C) solution of ethyl chlorofor-
mate (7.50 mL, 78.5 mmol) in anhydrous THF (45
mL), and the mixture was stirred for 2 h at 0°C and
then allowed to come to room temperature before dry
gaseous NH3 was bubbled through it for 30 min, after
which it was poured into CH2Cl2. The solid was
filtered out and the mother liquor was washed with
5% NaHCO3 solution and brine, dried (Na2SO4) and
evaporated under reduced pressure to leave 15 as a
yellowish solid (7.54 g, 84%). The analytical data that
follow are those of the white solid obtained upon
recrystallization from hexane/toluene. Mp 122–124°C.
[h]2D5=+10.8 (c 0.49, MeOH). IR (w): 3374, 3198, 2957,
1732, 1664, 1627, 1348, 1245, 1030 cm−1. 1H NMR
(CDCl3) l: 0.88 (3H, s, t-2%-CH3), 1.06 (3H, d, J=6.1,
2.6. (1S,1%R)-cis-1-[3%-(Aminomethyl)-2%,2%-dimethylcy-
clobutyl]ethanol 5
A mixture of 13 (3.60 g, 14.0 mmol) and 5N KOH (25
mL) in MeOH (50 mL) was refluxed for 18 h and
brought to pH 3 with 2N H2SO4. Removal of the
solvents at low pressure afforded a white solid (10 g)
that was extracted with MeOH, the extract was passed
through basic ion exchange resin (Amberlite IRA-
400(OH), 100 mL), and the eluate was concentrated
under reduced pressure to a brown oil (2.81 g) that
upon flash chromatography (1:1 EtOAc/MeOH)
1
afforded a colourless oil that H NMR spectroscopy
showed to be virtually pure 5 (1.87 g, 85%). [h]2D5=+
22.6 (c 0.52, MeOH). IR (w): 3287, 2956, 1652, 1599,
1
CH
4%-H
CH3CO), 2.03–2.09 (1H, m, 3%-H), 2.10 (1H, dd, J=
10.5, 5.4, CHHCO), 2.20 (1H, dd, J=10.5, 5.6,
CHHCO), 2.23 (1H, dt, J=10.2, 5.6, 1%-H), 4.77 (1H,
6
3CH<), 1.09 (3H, s, c-2%-CH3), 1.24 (1H, q, J=8.8,
1455, 1366, 1165, 1102, 991 cm−1. H NMR (CDCl3)
6
H), 1.96–2.04 (1H, m, 4%-HH), 1.99 (3H, s,
6
l: 1.03 (3H, s, t-2%-CH3), 1.04 (3H, d, J=6.2,
CH3
c-2%-CH3), 1.23–1.41 (3H, broad s, D2O exchang.,
NH2+OH), 1.69 (1H, dt, J=10.1, 7.9, 4%-HH), 1.81
(1H, dq, J=10.0, 7.5, 3%-H), 1.92 (1H, dt, J=9.9, 7.8,
1%-H), 2.52 (1H, dd, J=12.4, 7.5, CHHN), 2.70 (1H,
6 CH<), 1.07 (1H, q, J=10.2, 4%-H6 H), 1.17 (3H, s,
6
6
6
dq, J=10.2, 6.1, 1-H), 5.45 (1H, broad s, D2O
exchang., NH), 5.63 (1H, broad s, D2O exchang.,
NH). 13C NMR (CDCl3) l: 17.22, 18.01, 21.82, 26.97,
30.75, 37.06, 38.82, 40.31, 47.44, 72.17, 170.92, 175.07.
Anal. calcd for: C12H21NO3: C, 63.41; H, 9.31; N,
6.16. Found: C, 63.64; H, 9.18; N, 5.91.
6
dd, J=12.4, 7.3, CHH6 N), 3.69 (1H, dq, J=9.9, 6.2,
1-H). 13C NMR (CDCl3) l: 16.93, 21.61, 24.97, 32.39,
39.63, 43.43, 45.13, 50.09, 69.69. HRMS m/z calcd for
[C9H19NO] 157.1467, found: 157.1472.

3778
A. R. Hergueta et al. / Tetrahedron: Asymmetry 14 (2003) 3773–3778
2.9.
(1S,1%R)-cis-1-[3%-(2¦-Aminoethyl)-2%,2%-dimethyl-
References
cyclobutyl]ethanol 6
1. Ichikawa, E.; Kato, K. Synthesis 2002, 1–28.
A solution of 15 (2.16 g, 9.50 mmol) in anhydrous THF
(50 mL) was added to a suspension of LiAlH4 (2.70 g,
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was refluxed for 18 h, and the solvent was then evapo-
rated at low pressure. The solid residue left was
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the extract under reduced pressure yielded an oil that
upon flash chromatography (7:3 EtOAc/MeOH)
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1
afforded a colourless oil that H NMR spectroscopy
showed to be virtually pure 6 (1.04 g, 64%). [h]2D5=+
24.6 (c 0.78, MeOH). IR (w): 3360, 2956, 1651, 1462,
1
1365, 1243, 1097, 1042, 876 cm−1. H NMR (CDCl3) l:
1.00 (3H, s, t-2%-CH3), 1.03 (3H, d, J=6.1, CH3
1.08 (1H, q, J=10.2, 4%-HH), 1.11 (3H, s, c-2%-CH3),
1.23–1.37 (3H, broad s, D2O exchang., NH2+OH), 1.35
(1H, q, J=8.1, 4%-HH), 1.49–1.58 (1H, m, CHHCH2N),
1.68 (1H, dt, J=10.1, 8.0, CHHCH2N), 1.71–1.80 (1H,
6 CH<),
6
6
6
6
m, 3%-H), 1.89 (1H, dt, J=10.1, 7.7, 1%-H), 2.47 (2H, t,
J=7.6, CH2N), 3.70 (1H, dq, J=10.1, 6.1, 1-H). 13C
NMR (CDCl3) l: 16.91, 21.59, 26.89, 31.27, 32.10,
38.37, 39.92, 42.81, 50.50, 69.81. HRMS m/z calcd for
[C10H21NO] 171.1623, found: 171.1629.
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2.10. (1S,1%R)-cis-1-[3%-(2¦-Acetamidoethyl)-2%,2%-
dimethylcyclobutyl]ethyl acetate 16
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Obtained from 6 in the same way as 14 from 5. White
foam. [h]2D5=+10.7 (c 0.50, MeOH). IR (w): 3288, 3090,
1731, 1651, 1557, 1454, 1371, 1244, 1041 cm−1. 1H
NMR (CDCl3) l: 0.86 (3H, s, t-2%-CH3), 1.06 (3H, d,
J=6.1, CH3
J=10.1, 4%-H
dt, J=7.4, 6.1, CH
6
CH<), 1.06 (3H, s, c-2%-CH3), 1.15 (1H, q,
H), 1.37 (1H, q, J=7.9, 4%-HH), 1.52 (2H,
2CH2N), 1.76 (1H, ddt, J=10.4, 7.6,
6
6
6
4.3, 3%-H), 1.95 (1H, dt, J=10.2, 7.9, 1%-H), 1.96 (3H, s,
CH3CO), 2.00 (3H, s, CH3CO), 3, 14 (2H, dt, J=7.4,
6.1, CH2N), 4.76 (1H, dq, J=10.2, 6.1, 1-H), 5.37 (1H,
broad s, D2O exchang., NH). 13C NMR (CDCl3) l:
16.99, 18.03, 21.84, 23.73, 26.74, 30.56, 31.13, 38.47,
40.01, 40.08, 47.32, 72.28, 170.38, 170.94. HRMS m/z
calcd for [C14H25NO3] 255.1834, found: 255.1838.
11. Harispe, M.; Mea, D.; Horeau, A.; Jacques, J. Bull. Soc.
Chim. Fr. 1962, 885.
Acknowledgements
12. The crystallographic data of 17 have been deposited with
the Cambridge Crystallographic Data Centre as Supple-
mentary Publication No. CCDC 216007. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK.
The authors thank the Xunta de Galicia for financially
supporting
this
work
through
the
projects
PGIDT01PXI20302PR and PGIDIT02BTF20305PR.