Synthesis of (1R, 3R)-3-[2-(aminoethyl)-2,2-dimethylcyclobutyl]methanol and (1S,3R)-(3-amino-2,2-dimethylcyclobutyl)methanol from (+)-nopinone

Article abstract of DOI:10.1055/s-2000-7112

The title amino alcohols 6 and 7, which are of interest as intermediates in the synthesis of carbocyclic analogs of nucleosides, were synthesized from (+)-nopinone (8). Ring opening of α-isonitrosonopinone leads to a cyanoester which can be directly reduced to 6. Alternatively, a longer route from the lactam 12, one of the Beckmann rearrangement products of 8, leads also to 6, in a higher overall yield. Besides this the isomeric lactam 13 was transformed, upon hydrolytic opening, oxidative degradation of the lateral chain and reduction, into 7.

Full text of DOI:10.1055/s-2000-7112

PAPER
1459
Synthesis of (1R,3R)-3-[2-(Aminoethyl)-2,2-dimethylcyclobutyl]methanol and
(1S,3R)-(3-Amino-2,2-dimethylcyclobutyl)methanol from (+)-Nopinone
M. José Figueira, J. Manuel Blanco, Olga Caamaño,* Franco Fernández, Xerardo García-Mera, Carmen López
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15706-Santiago de Compostela,
Spain
Fax +34(981)594912; E-mail: qoolga@usc.es
Received 23 February 2000; revised 4 May 2000
low yield (6%); reduction with BH3∑SMe213 increased the
Abstract: The title amino alcohols 6 and 7, which are of interest as
yield to 44%. The structure of 6 was unequivocally estab-
intermediates in the synthesis of carbocyclic analogs of nucleosides,
were synthesized from (+)-nopinone (8). Ring opening of a-isoni-
trosonopinone leads to a cyanoester which can be directly reduced
lished on the basis of its 1H, 13C NMR and mass spectra,
and by preparation and characterization of the diacetyl de-
to 6. Alternatively, a longer route from the lactam 12, one of the rivative 11.
Beckmann rearrangement products of 8, leads also to 6, in a higher
overall yield. Besides this the isomeric lactam 13 was transformed,
upon hydrolytic opening, oxidative degradation of the lateral chain
and reduction, into 7.
O
ref 7
NH
ref 11
Key words: lactams, amino acids, amino alcohols, carbocycles, nu-
cleosides, terpenoids
8
OH
N
O
O
O
The antiviral properties of the carbocyclic nucleosides cy-
NH
+
clobut-A (1) and cyclobut-G (2)1-5 have previously led us
to synthesize and evaluate the biological activities of ana-
9
12
13
logs featuring structural and/or configurational alterations
of the carbocyclic moiety.6,7 This required prior prepara-
i) Cl2SO,
dioxane,-8 °C 72%
ii) MeOH, r.t.
12N HCl, ∆
93%
tion of the enantiomerically pure amino alcohols 3-5.8-10
In this paper we describe a convenient synthesis of
the amino alcohols 6 (a structural isomer of 5) and 7 (a
lower homologue of 3-6) starting from readily available
(-)-(1S)-b-pinene. Both 6 and 7 can be used as expedient
starting materials in the synthesis of new carbocyclic nu-
cleosides.
O
O
NH2·HCl
MeO
CN
10
HO
14·HCl
i) Dowex 50x8-200
ii) H2O, NH4OH
BH3·S(CH3)2, THF, ∆
44%
95%
O
NH2
NH2
HO
HO
NH2
N
O
N
N
N
N
N
6
NH
NH2
14
N
HO
HO
Ac2O, py, r.t.
55%
i) 2N HCl, ∆
ii) Amberlite
IRA-400 (OH)
95%
i) LiAlH4, THF, ∆
1
2
52%
HO
HO
ii) Ac2O, py, r.t.
NHAc
HO
NH2
HO
AcO
NH2
NH2
HO
11
3
4
5
Scheme 1
To synthesize 6 (Scheme 1), (1R)-isonitrosonopinone (9)
was first prepared in 83% yield from enantiomerically
very pure (+)-nopinone (8) using Meinwald et al.’s meth-
od.11 Treatment of 9 with thionyl chloride in dioxane at
low temperature,12 followed by reaction of the resulting
acid chloride with anhydrous MeOH, afforded the cya-
noester 10 in 72% yield from 9. Reduction of 10 with
LiAlH4 afforded the desired amino alcohol 6 in only very
We also explored an alternative route to 6 starting from
the lactam 12, which is obtainable in substantial quantities
as a readily isolated byproduct of the synthesis of 13 from
nopinone.7 The opening of 12 by hydrolysis in refluxing
12 N HCl for 12 hours afforded the hydrochloride of the
amino acid 14, which was easily converted to the free
amino acid by passage through an acidic ion exchange
resin. Reduction of 14 with LiAlH4 in THF, acetylation of
Synthesis 2000, No. 10, 1459–1463 ISSN 0039-7881 © Thieme Stuttgart · New York

1460
M. J. Figueira et al.
PAPER
Elmer 240B Elemental Analyser at the University of Santiago
Microanalysis Service.
the crude product and subsequent chromatographic purifi-
cation afforded the diacetylated amino alcohol 11 in 52%
yield from 14, and acid hydrolysis of 11 then gave a good
yield of the desired amino alcohol 6.
(1R)-6,6-Dimethyl-3-oximinobicyclo[3.1.1]heptan-2-one (9)
Isonitrosonopinone (9) was prepared as described by Meinwald et
al.11 A sample for analysis was obtained by recrystallization from
EtOAc; mp 177-179 ºC (Lit.11a mp 175-176 ºC, purified by subli-
mation).
The synthesis of amino alcohol 7 (Scheme 2) began with
the conversion of lactam 13 into amido acid 15,9 which
upon heating with Pb(AcO)4 and Cu(AcO)2 in benzene
in the presence of pyridine14 underwent oxidative decar-
boxylation to afford the unsaturated amide 16 in 50%
yield. After oxidative removal of the terminal methylene
group by KMnO4 in CH2Cl2 with cis-dicyclohexane-18-
crown-6 as phase transfer catalyst and a small amount of
AcOH as accelerator15 afforded a good yield of the amido
acid 17, which was then esterified almost quantitatively to
the amido ester 18 with CH2N2. Selective reduction of the
ester group of 18 using LiBH4 in THF under conventional
working conditions16 afforded only a 15% yield of the de-
sired hydroxy amide 19, and no improvement was
achieved by increasing the reaction time from 5 h to 18 h
(recovery of 50% of 18 upon chromatographic separation
of the crude reaction mixture suggested that the reactivity
of the ester carbonyl group was diminished by steric hin-
drance), but in a one-pot reaction the hydroxy amide 19
was obtained in 53% yield from 17 by treatment with eth-
yl chloroformate in THF and selective reduction of the
unisolated intermediate. Acid hydrolysis of 19 finally af-
forded the desired amino alcohol 7 in 79% yield.
IR (KBr): n = 3291, 2954, 2935, 1703, 1604, 1428, 1034, 972, 928,
841, 603 cm-1.
1H NMR (CDCl3): d = 10.24 (br s, 1 H D2O exch., OH), 2.86-2.82
(m, 2 H), 2.78-2.67 (m, 2 H), 2.36-2.30 (m, 1 H), 1.53 (d, 1 H,
J = 10.5 Hz, 1-H), 1.40 and 0.91 [2 s, 2 î 3 H, C(CH3)2].
13C NMR (CDCl3): d = 199.47 (CO), 153.23 (CN), 56.78 (C-1),
42.19 (C-5), 37.93 (C-6), 28.53 (C-4), 28.17 (C-7), 26.69 (CH3),
22.01 (CH3).
Methyl (1R,3R)-(-)-3-Cyanomethyl-2,2-dimethylcyclobutane-
carboxylate (10)
Oxime 9 (1.74 g, 10.41 mmol) was added in small portions to a so-
lution of SOCl2 (1.06 mL, 14.53 mmol) in dioxane (18 mL) cooled
in a salted ice bath and protected from moisture with a tube of
CaCl2. After addition of 9 was complete, the solution was stirred in
the ice bath for 30 min before addition of anhyd MeOH (1 mL), and
then for a further 4 h at 0 ºC. The solvents were removed, the oily
residue was taken into CH2Cl2 (30 mL), and this solution was
washed with H2O until pH was neutral and then dried (Na2SO4). The
CH2Cl2 was removed under vacuum, and chromatography of the
brown oily residue (1.84 g) on a column of silica gel using 6:1 hex-
ane/EtOAc as eluent afforded 10 (1.36 g, 72%) as an oil. An analyt-
ical sample was obtained by bulb-bulb distillation in a Kugelrohr
25
apparatus (oven temp. 165-170 ºC/12 Torr); [a]D -43.64 (c =
O
1.09, MeOH).
HO
Cu(AcO)2, Pb(AcO)4,
py, C6H6
IR (film): n = 2955, 2870, 2248, 1728, 1454, 1436, 1369, 1343,
NHAc
NHAc
ref 9
1236, 1198, 1144, 1120, 1026 cm-1.
13
50%
1H NMR (CDCl3): d = 3.65 (s, 3 H, COCH3), 2.75 (dd, 1 H, J = 9.9,
7.9 Hz, 1-H), 2.31-2.21 (m, 3 H), 2.18-2.12 (m, 1 H), 2.03-1.93
(m, 1 H), 1.28 and 0.98 [2 s, 2 î 3 H, C(CH3)2].
13C NMR (CDCl3): d = 173.08 (CO), 118.95 (CN), 51.80 (C-1),
46.28 (OCH3), 42.79 (C-2), 38.76 (C-3), 30.19 (CH3), 24.72 (C-4),
18.18 (CH2CN), 17.66 (CH3).
15
16
KMnO4, CH2Cl2,
AcOH, cis-dicyclohexane-
18-crown-6, r.t.
73%
O
O
CH2N2, Et2O,
MeOH, 0 °C
MeO
NHAc
HO
NHAc
EIMS: m/z (%) = 150 (15), 122 (6), 114 (77) 109 (15), 99 (15), 97
(9), 95 (34), 94 (19), 87 (70), 83 (100), 82 (30), 81 (21), 80 (17), 79
(15), 77 (10), 69 (15), 68 (37), 67 (25), 59 (13), 58 (35), 57 (13), 55
(86), 53 (24).
94%
18
17
HO
NH2
LiBH4,THF
15%
7
79%
Anal. calcd for C10H15NO2 (181.2): C, 66.27; H, 8.34; N, 7.73.
Found: C, 66.47; H, 8.51; N, 7.84.
i) 2N HCl, ∆
i) ClCO2Et, Et3N, THF, -7 °C
ii) NaBH4, THF, MeOH, 10 °C
ii) Amberlyte IRA,
400(OH), MeOH
HO
NHAc
19
(1R,3R)-3-(2-Aminoethyl)-2,2-dimethylcyclobutanecarboxylic
Acid (14)
53%
A solution of 127 (0.50 g, 3.27 mmol) in 12 N HCl (12 mL) was re-
fluxed for 12 h. The solvent was evaporated and the solid remaining
was dried by three dissolution-evaporation cycles, using absolute
EtOH (20 mL) and then toluene (2 î 20 mL) to form the corre-
sponding azeotropes. The white solid obtained was the hydrochlo-
ride of 14 (0.63 g, 93%). An analytical sample was prepared by
Scheme 2
Silica gel (230 mesh) was purchased from Merck. All other chemi-
cals used were of reagent grade and were obtained from Aldrich
Chemical Co. (+)-Nopinone (8) was prepared by ozonolysis of
(-)-b-pinene.11,17 Melting points were measured on a Reichert
Kofler thermopan and are uncorrected, and Na D line polarimetry
was carried out at 25 °C in a Perkin-Elmer 241 polarimeter. IR spec-
tra were recorded on a Perkin-Elmer 1640 FTIR spectrophotometer,
1H and 13C NMR spectra on a 300 MHz Bruker AMX 300 spectrom-
eter (TMS as internal reference), and mass spectra using a Kratos
MS-59 spectrometer. Microanalyses were performed in a Perkin-
25
recrystallization from EtOH/Et2O; mp 243-244 ºC; [a]D +11.79
(c = 0.58, H2O).
IR (KBr): n = 2927, 1706, 1518, 1403, 1195, 826, 698 cm-1.
1H NMR (DMSO-d6): d = 11.96 (br s, 1H D2O exch., CO2H), 8.02
+
(br s, 3 H D2O exch., NH3 ), 2.64-2.58 (m, 3 H), 1.97-1.83 (m, 2
H), 1.71-1.65 (m, 1 H), 1.62-1.57 (m, 1 H), 1.55-1.43 (m, 1 H),
1.12 and 0.87 [2 s, 2 î 3 H, C(CH3)2].
Synthesis 2000, No. 10, 1459–1463 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of (1R,3R)-3-[2-(Aminoethyl)-2,2-dimethylcyclobutyl]methanol
1461
13C NMR (DMSO-d6): d = 173.92 (CO2H), 45.62 (C-1), 41.90 (C-
2), 38.87 (H2NCH2CH2), 37.42 (C-3), 30.22 (CH3), 28.20
(H2NCH2CH2), 24.31 (C-4), 17.67 (CH3).
(1R,3R)-(+)-3-(2-Acetamidoethyl)-2,2-dimethylcyclobutylme-
thyl Acetate (11)
Method A: A mixture of 6 (0.2 g,1.27 mmol) in Ac2O (1.09 mL) and
anhyd pyridine (0.96 mL) was stirred at r.t. for 24 h. The mixture
was concentrated to dryness and the residue obtained was dissolved
in CH2Cl2 (45 mL) and washed with aq sat NaHCO3 solution and
H2O. The organic layer was separated, dried (Na2SO4) and concen-
trated to an oily residue (0.26 g) which was chromatographed on sil-
ica gel (12 g) using 1:1 hexane/EtOAc and EtOAc as eluents. Ester
11 (0.17 g, 55%) was isolated as a colorless oil. An analytical sam-
ple was obtained by bulb-bulb distillation in a Kugelrohr apparatus
(oven temp. 150 ºC / 0.01 Torr); [a]D25 +27.65 (c = 1.21, MeOH).
A solution of 14•HCl (0.28 g, 1.35 mmol) in H2O (20 mL) was de-
posited at the top of a column of Dowex 50W î 8-200 (11 mL of
resin, 20 mL of H2O) which was then eluted with H2O (until the elu-
ate had pH £ 6) followed by 14 M NH4OH (45 mL). Concentration
of the ammoniacal eluate under reduced pressure gave 14 (0.22 g,
96%). An analytical sample was prepared by recrystallization from
EtOH/H2O; mp 260-263 °C.
IR (KBr): n = 2962, 2228, 1638, 1558, 1506, 1456, 1391, 1202,
1159, 781, 521 cm-1.
IR (film): n = 3295, 2956, 1740, 1652, 1558, 1457, 1368, 1243,
1H NMR (D2O): d = 2.81-2.67 (m, 2 H, 4-H2), 2.46-2.40 (m, 1 H,
1-H), 1.86-1.78 (m, 1 H), 1.75-1.67 (m, 1 H), 1.62-1.49 (m, 2 H),
1.46-1.33 (m, 1 H), 0.99 and 0.74 [2 s, 2 î 3 H, C(CH3)2].
13C NMR (D2O): d = 182.63 (CO2H), 49.01 (C-1), 42.04
((H2NCH2CH2), 38.57 (C-3), 38.40 (C-2), 29.87 (CH3), 28.14
(H2NCH2CH2), 25.70 (C-4), 17.03 (CH3).
1031 cm-1.
1H NMR (CDCl3): d = 5.55 (br s, 1 H D2O exch., NH), 4.00 and 3.92
(AB part of ABM system, 2 H, JAB = 11.1 Hz, JAM = 8.5 Hz,
JBM = 6.5 Hz, OCH2), 3.12 (dt, 2 H, J = 7.5, 5.8 Hz, NCH2), 2.21-
2.06 (m, 1 H), 2.00 (s, 3 H, CO2CH3), 2.04-1.91 (m, 1 H), 1.94 (s,
3 H, NCOCH3), 1.87-1.73 (m, 1 H), 1.60-1.48 (m, 1 H), 1.42-1.30
(m, 1 H), 1.27-1.17 (m, 1 H), 1.06 and 0.91 [2 s, 2 î 3 H, C(CH3)2].
13C NMR (CDCl3): d = 171.54 (NCO), 170.37 (CH3CO), 65.34
(OCH2), 41.09 (C-1), 40.66 (C-3), 40.03 (C-2), 38.49 (NCH2CH2),
30.91 (CH3), 30.68 (NCH2CH2), 26.80 (C-4), 23.73 (CH3), 21.37
(CH3), 16.87 (CH3).
Anal. calcd for C9H17NO2 (171.2): C, 63.13; H, 10.01; N, 8.18.
Found: C, 63.27; H, 10.25; N, 8.31.
(1R,3R)-(+)-(2-Aminoethyl)-2,2-dimethylcyclobutyl]methanol
(6)
Method A: BH3∑SMe2 (0.78 mL, 7.8 mmol) was added dropwise to
a solution of 10 (0.50 g, 2.76 mmol) in refluxing anhyd THF
(3.5 mL) under argon. After the addition was complete, the reflux-
ing was continued with stirring for 24 h, after which the mixture was
left to cool and 3 N HCl (1.45 mL) was added. This solution was
stirred for 5 h, refluxed for 1 h, left to cool, brought to pH 10 by the
addition of 6 N NaOH solution, and extracted with EtOAc (4 î 20
mL). The combined organic extracts were dried (Na2SO4), and re-
moval of the solvent left a yellow oil (0.34 g) that when chromato-
graphed on silica gel (12 g) with 1:2 CH2Cl2/MeOH as eluent
afforded the amino alcohol 6 as a yellowish oil (0.19 g, 44%). An
analytical sample of 6 was obtained by bulb-bulb distillation in a
Kugelrohr apparatus (oven temp. 105-110 ºC/0.01 Torr); [a]D
+22.08 (c = 1.04, MeOH).
IR (film): n = 3359, 2950, 1598, 1463, 1382, 1364, 1013 cm-1.
1H NMR (CDCl3): d = 3.65 (t, 1 H, D2O exch., J = 5.8 Hz, OH),
3.60 and 3.49 (AB part of ABM system, 2 H, JAB = 10.7 Hz,
EIMS: m/z (%) = 242 (M + 1, 1), 198 (1), 183 (1), 182 (5), 168 (3),
141 (6), 122 (12), 114 (42), 113 (19), 107 (9), 86 (11), 83 (6), 82
(60), 81 (9), 79 (10), 73 (11), 72 (100), 71 (10), 70 (8), 69 (16), 68
(48), 67 (40), 60 (42), 56 (6), 55 (15), 53 (11).
Anal. calcd for C13H23NO3 (241.3): C, 64.70; H, 9.61; N, 5.80.
Found: C, 64.87; H, 9.75; N, 5.91.
Method B: Amino acid 14 (0.22 g, 1.28 mmol) was added in one
portion to a cooled (0 ∞C) and stirred suspension of LiAlH4 (0.12 g,
3.16 mmol) in anhyd THF (9 mL) under argon. The suspension was
refluxed for 5.5 h and then stirred vigorously, cooled to 0 ∞C and
quenched by slow addition of H2O (5 mL) from a dropping funnel.
After a further 15 min stirring the solvents were evaporated and the
resulting residue was dried by successive dissolution-evaporation
cycles using absolute EtOH (10 mL) and then toluene (2 î10 mL).
The residue was stirred in Ac2O (10 mL) and pyridine (10 mL) at
r.t. for 20 h, the solvent was evaporated, and the oil remaining was
dissolved in aq NaHCO3 solution (30 mL). This solution was ex-
tracted with CH2Cl2 (3 î25 mL), and EtOAc (30 mL) and the com-
bined organic extracts were dried (Na2SO4), and concentrated to an
oily residue (0.28 g) which was chromatographed on silica gel (8 g)
using 1:1 hexane/EtOAc and EtOAc as eluents. The acetyl deriva-
tive 11 (0.16 g, 52%) was isolated as a colorless oil identical to that
provided by Method A.
25
JAM = 7.7 Hz, JBM = 6.2 Hz, OCH2), 2.59 (t, 2 H, J = 7.3 Hz, 4-H2),
2.09-1.92 (m, 2 H, H2NCH2), 1.88-1.77 (m, 1 H, 1-H), 1.61-1.43
(m, 3 H, 1 after D2O exch., 3-H + NH2), 1.38-1.21 (m, 1 H), 1.20-
1.12 (m, 1 H), 1.09 and 0.94 [2 s, 2 î 3 H, C(CH3)2].
13C NMR (CDCl3): d = 64.10 (HOCH2), 44.93 (C-1), 40.98
(H2NCH2CH2), 40.52 (C-3), 39.96 (C-2), 34.97 (H2NCH2CH2),
31.39 (CH3), 26.91 (C-4), 16.90 (CH3).
(1R,3S)-(+)-N-(3-Ethenyl-2,2-dimethylcyclobutyl)acetamide
(16)
EIMS: m/z (%) = 158 (M + 1, 6), 142 (9), 140 (5), 99 (11), 98 (14),
88 (8), 85 (37), 84 (8), 83 (55), 82 (11), 81 (16), 79 (13), 72 (86), 71
(100), 70 (28), 69 (47), 68 (16), 67 (38), 58 (16), 57 (33), 56 (46),
55 (60), 54 (12), 53 (32), 51 (8).
Amido acid 159 (5.55 g, 26.06 mmol) was added in one portion to a
suspension of Cu(AcO)2 (0.83 g, 4.62 mmol), Pb(AcO)4 (18.23 g,
41.12 mmol) and anhyd pyridine (2.64 mL) in anhyd benzene
(264 mL) under argon, and the mixture was refluxed with vigorous
stirring for 90 min and then left to cool. Ethylene glycol (8.30 mL)
and H2O (222 mL) were added, the organic and aqueous layers were
separated, the latter was extracted with Et2O (3 î 220 mL), and the
combined organic extracts were washed successively with aq sat
solutions of NaHCO3 and NaCl and dried (Na2SO4). Removal of the
solvent under vacuum left a brown oil (2.96 g) that when chromato-
graphed on silica gel with 1:1 hexane/EtOAc as eluent afforded 16
(2.19 g, 50%) as a yellow oil. An analytical sample was obtained by
bulb-bulb distillation in a Kugelrohr apparatus (oven temp. 85-90
ºC / 0.01 Torr); [a]D25 +133.96 (c = 2.86, MeOH).
Anal. calcd for C9H19NO (157.3): C, 68.74; H, 12.18; N, 8.91.
Found: C, 68.89; H, 12.24; N, 8.85.
Method B: A solution of 11 (100 mg, 0.41 mmol) in 2 N HCl
(10 mL) was refluxed for 17 h. The solvent was evaporated and the
remaining solid was dried by three dissolution-evaporation cycles,
using absolute EtOH (10 mL) and then toluene (2 î10 mL) to form
the corresponding azeotropes. The residue obtained (100 mg) was
dissolved in MeOH (20 mL) and passed through a column packed
with Amberlite IRA-400 resin in HO- form (4.5 mL). Concentra-
tion of the basic eluate under reduced pressure gave 6 (62 mg, 95%)
as a colorless oil identical to that provided by Method A.
Synthesis 2000, No. 10, 1459–1463 ISSN 0039-7881 © Thieme Stuttgart · New York

1462
M. J. Figueira et al.
PAPER
IR (film):n = 3281, 3082, 2964, 2865, 1654, 1560, 1459, 1368,
J = 8.9 Hz, 3-H), 3.66 (s, 3 H, CO2CH3), 2,60 (dd, 1 H, J = 9.7, 7.8
Hz, 1-H), 2.33 (dt, 1 H, J = 11.7, 8.0 Hz, 4-H), 2.07 (dt, 1 H,
J = 11.7, 9.6 Hz, 4-H), 1.97 (s, 3 H, COCH3), 1.29 and 0.89 [2 s, 2
î 3 H, C(CH3)2].
13C NMR (CDCl3): d = 173.76 (NHCO), 170.28 (CO2), 51.88 (C-1),
50.30 (C-3), 46.31 (C-2), 43.56 (OCH3), 29.31 (CH3), 26.52 (C-4),
23.55 (CH3), 17.57 (CH3).
EIMS: m/z (%) = 199 (M+, 2), 168 (4), 156 (2), 126 (24), 115 (17),
113 (27), 98 (6), 96 (5), 86 (7), 85 (100), 83 (23), 82 (11), 81 (9), 79
(5), 71 (34), 70 (7), 59 (5), 56 (18), 55 (19), 53 (6).
1297, 996, 926, 906, 751 cm-1.
1H NMR (CDCl3): d = 6.09 (br s, 1 H D2O exch., NH), 5.69 (ddd, 1
H, J = 17.0, 10.4, 6.6 Hz, 1’-H), 4.95 (virtual d, 1 H, J = 10.4 Hz,
2’-HH), 4.90 (dd, 1 H, J = 17.0, 1.1 Hz, 2’-HH), 4.00 (dt, 1 H,
J = 9.9, 8.0 Hz, 1-H), 2.32-2.21 (m, 2 H, 4-H2), 1.92 (s, 3 H,
OCCH3), 1.71-1.60 (m, 1 H, 3-H), 1.08 and 0.80 [2 s, 2 î 3 H,
C(CH3)2].
13C NMR (CDCl3): d = 169.88 (CO), 137.31 (CH=CH2), 115.09
(CH=CH2), 49.89 (C-1), 45.23 (C-3), 42.74 (C-2), 29.64 (CH3),
28.31 (C-4), 23.04 (CH3), 16.56 (CH3).
Anald. Calcd for C10H17NO3 (199.3): C, 60.28; H, 8.60; 7.03.
Found: C, 60.39; H, 8.76; N, 7.28.
EIMS: m/z (%) = 113 (4), 105 (100), 86 (6), 71 (7), 69 (6), 67 (7),
58 (83).
Method B: To a solution of 17 (0.85 g, 4.54 mmol) in MeOH
(40 mL) was added a solution of CH2N2 in Et2O18 (20 mL, 1.68 g,
40.00 mmol). The solution was allowed to stand at r.t. for 30 min
after which the solvents were evaporated in vacuo to obtain a white
solid (0.88 g, 94%) identical to that provided by Method A.
Anal. calcd for C10H17NO (167.25): C, 71.81; H, 10.12; N, 8.37.
Found: C, 71.99; O, 10.24; N, 8.49.
(1S,3R)-(+)-3-(2-Acetamido)-2,2-dimethylcyclobutanecarboxy-
lic Acid (17)
KMnO4 (1.58 g, 10.00 mmol) was added in small portions to a vig-
orously stirred solution of 16 (0.5 g, 2.99 mmol), AcOH (1.42 mL,
24.81 mmol) and cis-dicyclohexane-18-crown-6 (0.17 g, 0.46
mmol) in CH2Cl2 (8.70 mL), care being taken to keep the tempera-
ture below 30 ∞C. When the addition was complete, the stirring was
continued for 21 h. The mixture was then diluted with H2O (6 mL),
NaHSO3 (0.28 g) was added in small portions with stirring over
20 min, the pH was brought to 1 with 12 N HCl, and the organic and
aqueous layers were separated. The aqueous layer was extracted
with EtOAc (5 î 20 mL), the combined organic extracts were dried
(Na2SO4), and removal of the solvent yielded 17 as a white solid
(0.4 g, 73%) which was recrystallized from acetone for analysis; mp
225-228 ºC; [a]D25 +198.33 (c = 0.54, MeOH).
(1R,3S)-(+)-N-(3-Hydroxymethyl-2,2-dimethylcyclobutyl)ace-
tamide (19)
Method A: A suspension of LiBH4 (120 mg, 5.37 mmol) in anhyd
THF (10 mL) was refluxed with stirring for 1 h, and 18 (300 mg,
1.5 mmol) in anhyd THF (10 mL) was then added dropwise. The
mixture was refluxed with stirring for 5.25 h, and once cold was
added to ice water (10 mL). After removal of THF under vacuum,
the mixture was extracted with CH2Cl2 (3 î 15 mL) and EtOAc
(2 î 15 mL). The combined organic layers were dried (Na2SO4)
and the solvent was evaporated. The oily residue obtained (250 mg),
which crystallized spontaneously, was chromatographed on silica
gel (8 g), using 10:0.5 CH2Cl2/MeOH as eluent. The first compound
to be eluted from the chromatography column, 18 (130 mg) was
followed by 19 (40 mg, 15%), which was isolated as white crystals
IR (KBr): n = 3348, 2961, 1697, 1653, 1624, 1558, 1257, 1221,
25
on recrystallization from EtOAc; mp 135-138ºC; [a]D +99.33
1076 cm-1.
(c = 0.30, MeOH).
1H NMR (DMSO-d6): d = 12.01 (br s, 1 H, D2O exch., CO2H), 7.83
(d, J = 7.7 Hz, 1 H, D2O exch., NH), 3.86 (q, 1 H, J = 9.1 Hz, on
addition of D2O, this signal simplifies to a triplet, J = 9.1 Hz, 3-H),
2.51-2.45 (m, 1 H, 1-H), 2.07-1.97 (m, 2 H, 4-H2), 1.78 (s, 3 H,
COCH3), 1.14 and 0.80 [2 s, 2 î 3 H, C(CH3)2].
13C NMR (DMSO-d6): d = 173.85 (CO2H), 169.43 (NHCO), 49.38
(C-1), 45.88 (C-2), 42.56 (C-3), 29.24 (CH3), 25.09 (C-4), 22.71
(CH3), 17.43 (CH3).
IR (KBr): 3303, 2951, 2869, 1646, 1545, 1460, 1370, 1302, 1020
cm-1.
1H NMR (CDCl3): d = 5.48 (br s, 1 H D2O exch., NH), 4.04 (q, 1 H,
J = 8.3 Hz, 1-H), 3.62-3.60 (m, 2 H, HOCH2), 2.32 (dt, 1 H,
J = 10.9, 7.9 Hz, 3-H), 2.00-1.90 (m, 1 H, 4-HH), 1.96 (s, 3 H,
COCH3), 1.39 (q, 1 H, J = 9.8 Hz, 4-HH), 1.25 (br s, 1 H, D2O
exch., OH), 1.20 and 0.97 [2 s, 2 î 3 H, C(CH3)2].
13C NMR (CDCl3): d = 170.15 (CO), 63.67 (HOCH2), 50.29 (C-1),
43.35 (C-2), 41.49 (C-3), 29.91 (CH3), 28.67 (C-4), 23.69 (CH3),
16.38 (CH3).
EIMS: m/z (%) = 186 (M + 1, 0.2), 185 (M+, 0.2), 170 (0.3), 128 (1),
126 (5), 113 (33), 98 (10), 85 (100), 83 (14), 82 (11), 81 (12), 79 (8),
71 (37), 70 (9), 56 (18), 55 (11).
EIMS: m/z (%) = 154 (7), 113 (38), 112 (12), 94 (7), 87 (13), 86
(93), 85 (82), 81 (7), 71 (100), 70 (15), 69 (13), 58 (6), 57 (12), 56
(37), 55 (12), 53 (7).
Anald. calcd for C9H15NO3 (185.2): C, 58.36; H, 8.16; N, 7.56.
Found: C, 58.51; H; 8.29; N, 7.63.
Anal. Calcd. for C9H17NO2 (171.2): C, 63.13; H, 10.01; N, 8.18.
Found: C: 63.47; H, 9.95; N, 8.23.
Methyl (1S,3R)-(+)-3-Acetamido-2,2-dimethylcyclobutanecar-
boxylate (18)
Method A: A mixture of 17 (260 mg, 1.40 mmol), p-toluenesulfonic
acid (1.3 mg, 6.8 mmol) and anhyd MeOH (20 mL) was stirred under
reflux for 18 h. Removal of the solvent under vacuum left an oily
residue (0.37 g) which was dissolved in EtOAc (20 mL). After
washing with aq 5% NaOH solution (2 î 10 mL) and brine (2 î 10
mL), removal of the solvent left a yellow solid (0.14 g). This was
chromatographed on silica gel with 9.75:0.25 CH2Cl2/MeOH as
eluent to afford 18 (90 mg, 32%) as a white solid which was recrys-
Method B: Ethyl chloroformate (0.10 mL, 0.81 mmol) was added
over 3 min to a cold solution (-7 °C) of 17 (0.10 g, 0.54 mmol) and
Et3N (0.1 mL, 1.36 mmol) in anhyd THF (3 mL). The mixture was
stirred under the same conditions for 35 min, and the solid thus
formed was filtered under vacuum and washed with anhyd THF (5
mL). To the filtrate, at 10 °C, was added NaBH4 (80 mg, 2.11
mmol) in one portion followed by dropwise addition of MeOH (0.5
mL) over 35 min. The mixture was stirred at 10 °C for 30 min, after
which 1 N HCl (5 mL) was added. The resulting solution was ex-
tracted with CH2Cl2 (3 î15 mL) and EtOAc (3 î40 mL). After the
solvent was evaporated, the residue was chromatographed on silica
gel (10:0.5 CH2Cl2/MeOH) to furnish 19 (49 mg, 53%) as a white
solid identical to that provided by Method A.
25
tallized from EtOAc/hexane for analysis; mp 137-139 ºC; [a]D
+160.99 (c = 0.40, MeOH).
IR (KBr): n = 3290, 2968, 1732, 1639, 1559, 1459, 1374, 1296,
1236, 1193, 1082 cm-1.
1H NMR (CDCl3): d = 5.72 (s, 1 H, D2O exch., NH). 4.12 (q, 1 H,
J = 8.4 Hz, on addition of D2O this signal simplifies to a triplet
Synthesis 2000, No. 10, 1459–1463 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of (1R,3R)-3-[2-(Aminoethyl)-2,2-dimethylcyclobutyl]methanol
1463
(1S,3R)-(-)-(3-Amino-2,2-dimethylcyclobutyl)methanol (7)
A solution of 19 (40 mg, 0.23 mmol) in a mixture of 2 N HCl (3 mL)
was refluxed for 18 h. The solvent was evaporated and any H2O re-
maining in the residue was removed by azeotropic codestillation
with EtOH (6 mL) and toluene (2 î 6 mL). The dark solid residue
was dissolved in MeOH (10 mL) and passed through a column of
Amberlite IRA-400 resin in HO- form (2 mL), eluting with MeOH.
The eluate (20 mL) was concentrated under reduced pressure to af-
ford an ochre oil (24 mg), which was chromatographed on silica gel
(4 g) using 1:2 CH2Cl2/MeOH as eluent. Amino alcohol 7 (22 mg,
79%) was isolated as a waxy solid. An analytical sample was ob-
(4) Yang, H.R.; Drain, R.L.; Franco, C.A.; Clark, J.M. Antivir.
Res. 1996, 29, 233.
(5) Tenney, D.J.; Yamanaka, G.; Voss, S.M.; Cianci, C.W.;
Tuomari, A.V.; Sheaffer, A.K.; Alam, M.; Colonno, R.J.
Antimicrob. Agents Chemother. 1997, 41, 2680.
(6) Borges, J.E.R.; Fernández, F.; García X.; Hergueta, A.R.;
López, C.; Andrei G.; Snoeck, R.; Witvroundw, M.; Balzarini,
J.; De Clercq, E. Nucleosides & Nucleotides 1998, 17, 1237.
(7) Figueira, M.J.; Blanco, J.M.; Caamaño, O; Fernández, F;
García-Mera, X.; López, C.; Andrei, G.; Snoeck, R.; Padalko,
E.; Neyts J., Balzarini J., De Clercq, E. Arch Pharm.-Pharm.
Med. Chem. 1999, 332, 348.
(8) Fernández, F.; López, C.; Hergueta, A.R. Tetrahedron 1995,
37, 10317.
(9) Blanco, J.M.; Caamaño, O.; Fernández, F.; Gómez, G.; Nieto,
I. Synthesis 1996, 281.
(10) Borges, J.E.R.; Fernández, F.; García, X.; Hergueta, A.R.;
López, C. Org. Prep. Proc. Int. 1997, 29, 303.
(11) Meinwald, J.; Gassman, P.G. J. Am. Chem. Soc. 1960, 82,
5445.
(12) SOCl2 cleaves a-hydroximino ketones to cyano acyl
chlorides: Billett, E.H.; Fleming, I.; Hanson S.W. J. Chem.
Soc., Perkin Trans. I 1973, 1661.
25
tained by sublimation, mp 73-75 ºC; [a]D -19.07 (c = 0.82,
MeOH).
IR (KBr): n = 3355, 2922, 1558, 1541, 1508, 1458, 1419, 1108
cm-1.
1H NMR (DMSO-d6): d = 3.32-325 (m, 2 H, only observed when
the sample was treated with D2O, OCH2), 2.86 (t, 1 H, J = 7.7 Hz,
3-H), 2.08-1.98 (m, 1 H, 4-HH), 1.79-1.66 (m, 1 H, 4-HH), 1.36-
1.26 (m, 1 H), 1.22 (br s, 1 H D2O exch., OH),1.02 and 0.90 [2 s, 2
î 3 H, C(CH3)2].
13C NMR (DMSO-d6): d = 61.67 (HOCH2), 52.51 (C-3), 41.62 (C-
2), 41.10 (C-1), 29.37 (CH3), 29.18 (C-4), 15.37 (CH3).
(13) (a)Brown, H.C.; Choi, Y. M.; Narasimhan, S. Synthesis 1981,
605.
Anal. Calcd for C7H15NO (129.20): C, 65.07; H, 11.70; N, 10.84.
Found: C, 65.23; H, 11.98; N, 11.02.
(b) Brown, H.C.; Choi, Y. M. Synthesis 1981, 439.
(14) Patel, D.V.; VanMiddlesworth, F; Donaubauer, J.; Gannett,
P.; Sih, C.J. J. Am. Chem. Soc. 1986, 108, 4603.
(15) Lee, D. G.; Chang, V. S. J. Org. Chem. 1978, 43, 1532.
(16) Nieto, M.I.; Blanco, J.M.; Caamaño, O.; Fernández, F.;
Gómez, G. Tetrahedron 1998, 54, 7819.
Acknowledgement
Authors thank Spanish Ministry of Education and Science (MEC-
DGICYT, PB94-0617) and Xunta de Galicia (XUGA 20309B98)
for financially supporting this work.
(17) (a) Grimshaw, J.; Grimshaw, J.T.; Juneja, H.R. J. Chem. Soc.
Perkin Trans. I 1972, 50.
(b) Konopelski, J.P.; Djerassi, C. J. Org. Chem. 1980, 45,
2297.
References
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Article Identifier:
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Synthesis 2000, No. 10, 1459–1463 ISSN 0039-7881 © Thieme Stuttgart · New York