Enantiodivergent synthesis of cyclobutyl-(Z)-α,β-dehydro-α-amino acid derivatives from (-)-cis-pinononic acid

Article abstract of DOI:10.1016/S0957-4166(02)00749-8

The two enantiomers of the title dehydroamino acids (DHAAs) have been synthesized through respective Wadsworth-Emmons condensations of a suitable phosphonate with enantiomeric cyclobutyl aldehydes. These compounds, in turn, were prepared by selective mani

Full text of DOI:10.1016/S0957-4166(02)00749-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 217–223
Enantiodivergent synthesis of cyclobutyl-(Z)-a,b-dehydro-a-amino
acid derivatives from (−)-cis-pinononic acid
Gemma P. Aguado, Albertina G. Moglioni† and Rosa M. Ortun˜o*
Departament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Received 22 October 2002; accepted 07 November 2002
Abstract—The two enantiomers of the title dehydroamino acids (DHAAs) have been synthesized through respective Wadsworth–
Emmons condensations of a suitable phosphonate with enantiomeric cyclobutyl aldehydes. These compounds, in turn, were
prepared by selective manipulation of the functional groups starting from (−)-cis-pinononic acid as the common chiral precursor.
The CD spectra of the prepared DHAAs are described. These products are suitable for the stereocontrolled synthesis of diferent
types of saturated cyclobutyl amino acids and their derivatives. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
tive synthesis of cyclobutyl amino acids from natural
terpenes,7–11 we have described the preparation of a,b-
dehydro amino acids through Wadsworth–Emmons
olefination of aldehydes obtained from (−)-a-pinene or
(−)-verbenone.7 Some of these cyclobutyl DHAA
underwent 1,3-dipolar cycloaddition of diazomethane
to afford pyrazolines that, under photolysis, gave cyclo-
propanes as single stereoisomers (Scheme 1).8 The
diastereoselectivity of the cycloaddition was governed
by the steric hindrance of the bulky cyclobutane moi-
ety, which shields one of the faces of the double bond
from the attack of diazomethane.
Unsaturated amino acids occur in nature, being incor-
porated into peptides (dehydro-peptides, DHP) present
in the structure of enzymes,1 hormones,2 antibiotics,3
and phytotoxins4 among other biologically active prod-
ucts. These amino acids are responsible for the binding
abilities of designed DHPs5 used as metal ligands and
can also act as b-turn inducers.6 Moreover, a,b-dehydro
amino acids (DHAAs) are believed to be biosynthetic
precursors to the
D-amino acid residues present in some
antibiotics.3b
In addition, DHAAs are valuable synthetic precursors
to a variety of designed saturated amino acids. Thus,
according to our research program on the stereoselec-
On the other hand, hydrogenation of the double bond
was accomplished by using chiral catalysts based on
chiraphos or duphos ligands (Scheme 1). From our
Scheme 1.
* Corresponding author. E-mail: rosa.ortuno@uab.es
† Permanent adress: Departamento de Qu´ımica Orga´nica, Facultad de Farmacia y Bioqu´ımica, Universidad de Buenos Aires, 1113 Buenos Aires,
Argentina.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00749-8

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G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 217–223
preliminary results, we could not conclude whether the
configuration of the newly formed stereogenic center
depends on the catalyst, on the substrate, or if it results
from double asymmetric induction promoted by both
reactants.9 Therefore, to pursue our hydrogenation
studies aimed at the diastereocontrolled synthesis of
cyclobutyl a-amino acids, we needed to obtain the
DHAAs in both enantiomeric forms.
Hydroxy ketal 2, easily prepared from (−)-cis-
pinononic acid, 1,7b was transformed into hydroxy
ketone 3 by treatment with pyridinium p-toluene-
sulphonate (PPTS) in boiling wet acetone for 5 h
(Scheme 3). Epimerisation of the a-carbonyl stereogenic
centre was prevented under such mild conditions.12
Lieben degradation of the resultant methyl ketone was
achieved through reaction with sodium hypobromite in
aqueous dioxane13 to afford a carboxylic acid that was
methylated with diazomethane to produce the hydroxy
ester (−)-4. Oxidation of the primary alcohol with pyri-
dinium dichromate (PDC) in dichloromethane provided
aldehyde 5 that was condensed with the anion (tBuOK)
of methyl 2-N-benzyloxycarbonylamino-2-dimethoxy-
phosphinyl acetate14 giving the DHAA derivative (−)-6,
[h]D −6.9. The (Z) stereochemistry of the double bond
was determined by NMR techniques by means of NOE
experiments as previously described for other similar
DHAAs.7 Alternatively, condensation with the N-acetyl
phosphonate led to compound 7. These two DHAAs
are conveniently protected for use as substrates for
asymmetric hydrogenation in the presence of different
catalysts.15
Herein, we describe the stereodivergent synthesis of the
two enantiomers of a cyclobutyl DHAA starting from
(−)-cis-pinononic acid, 1, as the common chiral precur-
sor (Scheme 2). This compound results from oxidative
cleavage of the double bond of (−)-verbenone.7 Scheme
2
shows the retrosynthetic pathways envisioned.
According to route 1, the methyl-ketone group in 1
must be degraded to a formyl group, while the car-
boxylic acid must be reduced to an aldehyde in route 2.
Thus, the synthesis of the two enantiomers of a DHAA,
for a given R substituent, was achieved through selec-
tive transformations of the functional groups providing
enantiomeric cyclobutyl aldehydes and their subsequent
condensation with a suitable phosphonate that bears
the amino acid function conveniently protected.
For the synthesis of the enantiomer (+)-6, (−)-cis-
pinononic acid, 1, was reacted with tert-butanol in the
presence of dimethylaminopyridine (DMAP) and
dicyclohexylcarbodiimide16 to afford the tert-butyl ester
8 (Scheme 4). Lieben degradation of the methyl ketone
led to the hemi ester 9 that underwent selective reduc-
2. Results and discussion
The synthetic sequences developed for the preparation
of the two enantiomers (+)- and (−)-6 are depicted in
Schemes 3 and 4, respectively.
Scheme 2.
Scheme 3.

G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 217–223
219
Scheme 4.
Figure 1. CD spectra (mdeg) of enantiomers (+)-6 and (−)-6.
tion of the carboxyxlic acid group upon treatment with
catecholborane.17 The resultant hydroxy ester 10 did
not afford the expected hydroxy acid by treatment
under acid conditions. Instead, the corresponding d-lac-
tone and polymeric side products were obtained. There-
fore, protection of the primary alcohol prior to
hydrolysis of the tert-butyl ester became necessary.
Thus, 10 was allowed to react with tert-butyldiphenylsi-
lyl chloride in the presence of DMAP affording the silyl
ether 11. Subsequent treatment with trifluoroacetic acid
and triethylsilyl hydride in dichloromethane18 allowed
the selective deprotection of the tert-butyl ester to give
a carboxylic acid that was methylated with diazo-
methane. The resultant methyl ester, 12, was allowed
to react with n-tetrabutyl ammonium fluoride in order
to recover the alcohol, giving hydroxy ester (+)-4. This
compound was oxidized with PDC in dichloromethane
to afford the aldehyde 13. Subsequent condensation
with the anion of the N-Cbz phosphonate allowed the
synthesis of (+)-6, [h]D +6.9, to be accomplished.

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G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 217–223
The CD spectra of both enantiomers were superim-
posed showing good concordance (Fig. 1). A strong
positive band with a maximum of +12.2 mdeg at 210
nm and a weak negative band with a minimum of −3.0
mdeg at 238 nm were observed for (+)-6. The CD
spectrum of (−)-6 showed two bands of −11.9 and +3.5
mdeg at 210 and 238 nm, respectively (Fig. 1).
m/e (%) 157 (M+1, 100), 139 ([M+1]−H2O, 38), 127
([M+1)−CH2O, 10).
3.3. Methyl (1R,3S)-3-hydroxymethyl-2,2-dimethylcy-
clobutane-1-carboxylate, (−)-4
An ice-cooled solution of NaOBr, prepared from
bromine (1.08 mL, 21.6 mmol) and NaOH (3.3 g, 82
mmol), in water (43 mL) was added to a solution of
ketone 3 (0.6 g, 3.8 mmol) in dioxane (67 mL) cooled at
−5°C. The resultant mixture was stirred at 0°C for 3 h
and at rt for 4 h. Then the reaction mixture was
extracted with ether and 40% aq NaHCO3 and conc
HCl was subsequently added to the basic aqueous
solution until acid pH was reached. The acid solution
was extracted with ether and all the combined ether
extracts were dried (MgSO4) and solvents were removed
at reduced pressure to afford a crude carboxylic acid
(370 mg, 61% yield). This compound was made to react
with a freshly distilled ethereal solution of dia-
zomethane at 0°C for 30 min. Then excess dia-
zomethane was destroyed by addition of benzoic acid,
the mixture was filtered and the solvent was evaporated
at reduced pressure. The residue was flash chro-
matographed (5:1 ethyl acetate–hexane) to afford pure
hydroxy ester (−)-4 (383 mg, 95% yield) as a hygro-
scopic oil unsuitable for microanalysis; ot 65–67°C
(0.02 torr), [h]D −9.2 (c 0.87, MeOH). IR (film) 3529–
3260 (broad), 1735 cm−1; 1H NMR (acetone-d6): 0.93 (s,
3H, c-2-CH3), 1.21 (s, 3H, t-2-CH3), 1.74–1.95 (com-
plex absorption, 2H, H4a, H4b), 2.06–2.21 (m, 1H, H3),
2.69 (dd, J1,4a=7.9 Hz, J1,4b=10.0 Hz, 1H, H1), 3.41–
3.57 (m, 2H, CH2OH), 3.59 (s, 3H, OCH3); 13C NMR
(acetone-d6): 17.52 (c-2-CH3), 21.91 (C4), 31.16 (t-2-
CH3), 42.52 (C2), 44.62 (C3), 46.17 (C1), 51.12 (OCH3),
63.02 (CH2OH), 173.64 (CꢀO); MS, m/e (%) 173 (M+1,
100), 157 (([M+1]−CH3, 15).
Thus, selective manipulation of the functional groups
starting from (−)-cis-pinononic acid, as the only chiral
immediate precursor, allowed the enantiodivergent syn-
thesis of the two DHAA derivatives (+)- and (−)-6.
These compounds are suitable to be used as synthetic
precursors for a variety of enantiomeric saturated
amino acids and are also convenient to study the
influence of the chiral catalysts in the hydrogenation of
the double bond. Such applications are under active
investigation in our laboratory.
3. Experimental
3.1. General
(−)-cis-Pinononic acid was prepared7b from commercial
(−)-verbenone (95% e.e.). Flash column chromatogra-
phy was carried out on Baker® silica gel (40 mM).
Melting points ere determined on a hot stage and are
uncorrected. Distillation of small amounts of material
was effected in a bulb-to-bulb distillation apparatus
with oven temperatures (ot) reported. CD data were
acquired on a spectropolarimeter equipped with a
diode-array detector and measurements were made
using methanol solutions contained in 1.0 mm path-
length cells. The CD spectra are the averages of four
scans acquired over a 1 h-period with the base-lines
1
subtracted. H and 13C NMR spectra were recorded at
250 and 62.5 MHz, respectively. Chemical shifts are
given on the l scale. Electron impact MS and HRMS
spectra were recorded at 70 eV.
3.4. Methyl (1%R,3%R)-2-N-benzyloxycarbonylamino-3-
(2%,2%-dimethyl-3%-methoxycarbonylcyclobutyl)-(Z)-2-
propenoate, (−)-6, and methyl (1%R,3%R)-2-N-acetylamino-
3-(2%,2%-dimethyl-3%-methoxycarbonylcyclobutyl)-(Z)-2-
propenoate, 7 through aldehyde, 5
3.2. (1R,3S)-3-Hydroxymethyl-2,2-dimethylcyclobutyl
methyl ketone, 3
A mixture of ketal 2 (1.4 g, 6.7 mmol) and PPTS (0.6 g,
2.2 mmol) in wet acetone (91 mL) was heated under
reflux for 5 h. The reaction mixture was cooled and
solvent was removed at reduced pressure. The residue
was poured into ether (84 mL) and the resultant solu-
tion was washed with saturated aq NaHCO3 and dried
(MgSO4). The solvent was evaporated under vacuo and
the residue was flash chromatographed (EtOAc) to
afford ketone 3 (985 mg, 90% yield) as a hygroscopic
oil unsuitable for microanalysis; ot 75–78°C (0.02 torr),
[h]D −42 (c 1.33, MeOH). IR (film) 3510–3255 (broad),
1703 cm−1; 1H NMR (acetone-d6): 0.88 (s, 3H, c-2-
CH3), 1.33 (s, 3H, t-2-CH3), 1.62–1.90 (complex
absorption, 2H, H4a, H4b), 1.95 (s, COCH3), 2.08–2.20
(m, 1H, H3), 2.88 (dd, J1,4a=7.5 Hz, J1,4b=10.0 Hz,
1H, H1), 3.34–3.54 (complex absorption, 3H, CH2OH);
13C NMR (acetone-d6): 17.08 (c-2-CH3), 20.36 (C4),
29.95, 31.41 (2C, t-2-CH3, COCH3), 43.01 (C2), 44.32
(C3), 53.98 (C1), 62.96 (CH2OH), 207.93 (CꢀO); MS,
A mixture of alcohol 4 (340 mg, 2.0 mmol) and PDC (1
g, 2.7 mmol) in dry dichloromethane was stirred at rt
for 6 h under nitrogen atmosphere. Then a small por-
tion of Florisil was added and stirring was pursuit for
30 min. The reaction mixture was filtered on Celite and
solvent was removed at reduced pressure to afford
crude aldehyde 5 (300 mg, 89% yield) as a rather
unstable oil that was identified by their IR and 1H
NMR spectroscopic data and immediately used in the
condensation step without purification. IR (film) 2926,
1
1736 (broad, two CꢀO) cm−1; H NMR (acetone-d6):
0.96 (s, 3H, c-2-CH3), 1.40 (s, 3H, t-2-CH3), 1.07–2.02
(complex absorption, 2H, H4a, H4b), 2.59 (dd, J1,4a
1,4b=10.2 Hz, H1), 2.80–3.02 (m, 1H, H3), 3.62 (s, 3H,
OCH3), 9.72 (d, J=1.5 Hz, CHO).
=
J
A solution of methyl 2-N-benzyloxycarbonylamino-2-
dimethoxyphosphinyl acetate (0.9 g, 2.8 mmol) in dry

G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 217–223
221
dicloromethane (4.5 mL) was slowly added to a suspen-
sion of KtBuO (0.26 g, 2.3 mmol) in dry
dichloromethane (5 mL) cooled at −78°C under nitro-
gen atmosphere. The mixture was stirred at −78°C for
30 min and aldehyde 5 (0.2 g, 1.2 mmol) in dry
dichloromethane (3.5 mL) was added dropwise. The
resultant mixture was allowed to warm to rt, then
stirred for 64 h. Water (10 mL) was added and layers
were separated. The aqueous layer was extracted with
dichloromethane (4×25 mL), the combined organic
phases were dried (MgSO4) and solvent was removed
under reduced pressure. The residue was chro-
matographed (1:3 ethyl acetate–hexane) to afford (−)-6
(170 mg, 38% yield) as an oil, [h]D −6.9 (c 0.86,
0.64, MeOH); IR (film) 1726, 1709 cm−1; 1H NMR
(CDCl3): 0.90 (s, 3H, c-2-CH3), 1.39 (s, 3H, t-2-CH3),
1.42 (s, 9H, C(CH3)3), 1.65–2.01 (m, 1H, H4a), 2.03 (s,
COCH3), 2.48–2.69 (complex absorption, 2H, H4b, H1),
2.81 (dd, J3,4b=10.6 Hz, J3,4a=7.9 Hz, 1H, H3); 13C
NMR (CDCl3): 17.81 (c-2-CH3), 19.14 (C4), 28.16 (C-
(CH3)3), 29.93, 30.25 (t-2-CH3, -COCH3), 44.79 (C2),
45.82 (C1), 53.02 (C3), 80.36 (CO2-C(CH3)3), 171.43
t
(CO2 Bu), 207.20 (COCH3). Anal. calcd for C13H22O3:
C, 68.99; H, 9.80. Found: C, 68.74; H, 9.71%.
3.6. tert-Butyl (1S,3R)-3-Hydroxymethyl-2,2-dimethyl-
cyclobutane-1-carboxylate, 10 through (1R,3S)-3-tert-
butoxycarbonyl-2,2-dimethylcyclobutane-1-carboxylic
acid, 9
1
MeOH); IR (film) 3326 (broad), 1729, 1653 cm−1; H
NMR (acetone-d6): 0.94 (s, 3H, c-2%-CH3), 1.18 (s, 3H,
t-2%-CH3), 2.11–2.21 (complex absorption, 2H, H4%a,
H4%b), 2.70–3.15 (complex absorption, 2H, H3%, H1%),
3.65 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 5.14 (s, 2H,
PhCH2O), 6.57 (d, J3,1%=8.9 Hz, H3), 7.25–7.49 (com-
plex absorption, 5H, Ph), 7.55 (broad s, 1H, NH); 13C
NMR (acetone-d6): 18.64 (c-2%-CH3), 24.63 (C4%), 29.38
(t-2%-CH3), 40.22 (C1%), 45.08 (C2%), 46.01 (C3%), 50.86
(OCH3), 51.86 (OCH3), 66.63 (PhCH2O), 127.90 (Ca),
128.25, 128.29 (5C, CHPh), 137.41 (Cipso), 137.58 (Cb),
154.92 (NHCO2CH2Ph), 165.11 (MeO2C-CꢀC-), 172.73
(CO2CH3); HRMS: Calcd for C20H25NO6 (M):
375.1682. Found: 375.1669. Calcd for C14H15NO4 [M−
C6H10NO2]: 261.1001. Found: 261.1004.
Following the procedure described above for Lieben
degradation of ketone 3, hemiester 9 was obtained as
an oil in 63% yield, identified by their NMR spectro-
scopic data, and used in the next step without further
1
purification. H NMR (CDCl3): 1.01 (s, 3H, c-2-CH3),
1.30 (s, 3H, t-2-CH3), 1.41 (s, 9H, C(CH3)3), 1.90–2.05
(m, 1H, H4a), 2.39–2.55 (m, 1H, H4b), 2.59–2.86 (com-
plex absorption, 2H, H1, H3), 5.42 (broad s, 1H,
COOH); 13C NMR (CDCl3): 18.16 (c-2-CH3), 20.06
(C4), 28.19 (C-(CH3)3), 30.03 (t-2-CH3), 44.44 (C2),
45.17 (C3), 46.10 (C1), 80.55 (CO2-C(CH3)3), 171.50
t
(CO2 Bu), 177.98 (CO2H).
A mixture of hemiester 9 (200 mg, 0.9 mmol) and
catecholborane (2.8 mL of a 1 M solution in THF, 2.8
mmol) was stirred at rt for 12 h under nitrogen atmo-
sphere. Ethanol and water was subsequently added to
destroy the excess hydride and solid sodium bicarbon-
ate was added to reach pH 8. The solution was
extracted with chloroform and the combined organic
extracts were dried (MgSO4). Solvents were removed
under reduced pressure and the residue was chro-
matographed (2:1 dichloromethane–ethyl acetate) to
afford hydroxy ester 10 as a pale yellow oil (103 mg,
55% yield), [h]D +11.4 (c 0.88, MeOH); IR (film) 3438
(broad, 1726 cm−1; 1H NMR (CDCl3): 0.99 (s, 3H,
c-2-CH3), 1.23 (s, 3H, t-2-CH3), 1.42 (s, 9H, C(CH3)3),
1.61 (broad s, 1H, OH), 1.75–1.97 (complex absorption,
Following a similar protocol but using 2-N-acetyl-
amino-2-dimethoxyphosphinyl acetate, compound 7
was synthesized in 31% yield as an oil, [h]D +2.25 (c
1.80, MeOH); IR (film) 3274 (broad), 1731, 1668 cm−1;
1H NMR (acetone-d6): 0.94 (s, 3H, c-2%-CH3), 1.20 (s,
3H, t-2%-CH3), 1.98 (s, 3H, COCH3), 2.10–2.17 (com-
plex absorption, 2H, H4%a, H4%b), 2.77–2.85 (m, 1H, H3%),
2.91–3.02 (m, 1H, H1%), 3.62 (s, 3H, OCH3), 3.67 (s, 3H,
OCH3), 6.51 (d, Jb,1%=8.6 Hz, Hb), 8.27 (broad s, 1H,
NH); 13C NMR (acetone-d6): 19.05 (c-2%-CH3), 22.75
(t-2%-CH3), 25.06 (C4%), 30.49 (COCH3), 40.82 (C1%),
45.42 (C2%), 46.42 (C3%), 51.28 (OCH3), 52.19 (OCH3),
128.44 (Ca), 137.34 (Cb), 165.53 (2×CO2CH3), 173.19
(COCH3). Anal. calcd for C14H21NO5: C, 59.35; H,
7.47; N, 4.94. Found: C, 59.33; H, 7.43; N, 4.76.
2H, H4a, H4b), 2.07–2.19 (m, 1H, H3), 2.59 (dd, J1,4a
=
7.85 Hz, J1,4b=10.02 Hz, 1H, H1), 3.52–3.67 (m, 2H,
CH2OH); 13C NMR (CDCl3): 17.20 (c-2-CH3), 21.09
(C4), 28.23 (C(CH3)3), 30.95 (t-2-CH3), 41.84 (C2),
43.72 (C3), 46.38 (C1), 63.42 (CH2OH), 80.07 (CO2-
3.5. tert-Butyl (1S,3R)-3-acetyl-2,2-dimethylcyclobu-
tane-1-carboxylate, 8
t
Solutions of tert-butanol (0.95 mL, 10 mmol) and
DMAP (43 mg, 0.35 mmol) in dry THF (4 mL) and
DCC (0.8 g, 3.8 mmol) in dry THF (2 mL) were
subsequently added to an ice-cooled solution of acid 1
(0.6 g, 3.5 mmol) in dry THF (4 mL) under nitrogen
atmosphere. The mixture was allowed to reach room
temperature and stirred overnight. The solid produced
was filtered and washed with dichloromethane and the
filtrate was subsequently washed with 5% HCl and
aqueous NaHCO3. The organic phase was dried
(MgSO4) and solvents were removed under reduced
pressure. The residue was chromatographed (3:1 ethyl
acetate–dichloromethane) to afford 0.5 g (60% yield) of
pure ester 8 as a white solid; mp 44–47°C; [h]D −40.6 (c
C(CH3)3), 172.52 (CO2 Bu).
3.7. tert-Butyl (1S,3R)-3-tert-butyldiphenylsilyl-
oxymethyl-2,2-dimethylcyclobutane-1-carboxylate, 11
tert-Butyldiphenylchlorosilane (2.1 mL, 8.4 mmol) was
added to an ice-cooled solution of alcohol 10 (1.0 g, 4.7
mmol) and DMAP (1.7 g, 14.0 mmol) in anhydrous
dichloromethane (5 mL). After stirring at rt overnight,
under nitrogen atmosphere, the mixture was diluted
with dichloromethane and 1% HCl, and washed with
water. The organic phase was dried (MgSO4) and sol-
vent was evaporated under vacuo. The residue was
chromatographed (1:1 dichloromethane–hexane) to give

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G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 217–223
compound 11 (1.8 g, 84% yield) as a colorless oil, [h]D
3.10. Methyl (1%S,3%S)-2-N-benzyloxycarbonylamino-3-
(2%,2%-dimethyl-3%-methoxycarbonylcyclobutyl)-(Z)-2-
propenoate, (+)-6
1
+5.7 (c 0.53, MeOH); IR (film) 1726 cm−1; H NMR
(CDCl3): 1.01 (s, 12H, c-2-CH3, SiC(CH3)3), 1.26 (s,
3H, t-2-CH3), 1.42 (s, 9H, CO2C(CH3)3), 1.66–1.85
(complex absorption, 2H, H4a, H4b), 2.11–2.24 (m, 1H,
H3), 2.57 (dd, J1,4a=8.0 Hz, J1,4b=10.2 Hz, 1H, H1),
3.49–3.65 (complex absorption, 2H, CH2OSi), 7.32–
7.67 (complex absorption, 10H, 2Ph); 13C NMR
(CDCl3): 17.09 (c-2-CH3), 19.13 (SiC(CH3)3), 20.79
(C4), 26.78 (SiC(CH3)3), 28.27 (CO2C(CH3)3), 31.02
(t-2-CH3), 42.16 (C2), 43.54 (C3), 46.40 (C1), 64.41
(CH2OSi), 79.89 (CO2C(CH3)3), 127.60 (4C, CHmeta),
129.54 (2C, CHpara), 133.86 (2C, Cipso), 135.55 (4C,
CHortho), 172.57 (CO2C(CH3)3). Anal. calcd for
C28H40O3Si: C, 74.29; H, 8.91. Found: C, 74.24; H,
8.85.
Following the same procedure described above in Sec-
tion 3.3, compound (+)-6 was synthesized from (+)-4
1
in 36% yield. [h]D +6.9 (c 0.87, MeOH). The IR, H
and 13C NMR spectroscopic data were in good agree-
ment with those described above for its enantiomer,
(−)-6a. Anal. calcd for C20H25NO6: C, 63.98; H, 6.71;
N, 3.73. Found: C, 63.93; H, 6.79; N, 3.62%.
Acknowledgements
G.P.A. thanks the MECD for a predoctoral fellow-
ship. Financial support from DGI (MCyT) through
the project BQU2001-1907 is gratefully acknowledged.
3.8. Methyl (1S,3R)-3-tert-butyldiphenylsilyloxymethyl-
2,2-dimethylcyclobutane-1-carboxylate, 12
A mixture of 11 (0.5 g, 1.1 mmol), triethylsilane (0.4
mL, 2.5 mmol) and trifluoroacetic acid (1.2 mL, 15.6
mmol) in anhydrous dichloromethane (3 mL) was
stirred at rt for 1 h. The solution was concentrated at
reduced pressure, water was added and the resultant
aqueous solution was extracted with ether. The com-
bined organic extracts were dried (MgSO4) and solvent
was removed under vacuo to afford a carboxylic acid
(330 mg, 75% yield) that was used in the next step
without purification. Thus this acid (250 mg, 0.6
mmol) was reacted with excess diazomethane in the
usual way (see Section 3.2) to provide a methyl ester
that was purified by flash column chromatography (2:1
dichloromethane–hexane) to provide pure 12 (232 mg,
90% yield) as a colorless oil, [h]D +6.8 (c 0.73,
References
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1
MeOH); IR (film) 1736 cm−1; H NMR (CDCl3): 0.97
(s, 3H, c-2-CH3), 1.01 (s, 9H, SiC(CH3)3), 1.28 (s, 3H,
t-2-CH3), 1.73–1.91 (complex absorption, 2H, H4),
2.14–2.28 (m, 1H, H3), 2.67 (dd, J1,4a=8.2 Hz, J1,4b
=
5. Swiatek-Kozlowska, J.; Brasun, J.; Chruscinski, L.; Chr-
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9.9 Hz, 1H, H1), 3.50–3.66 (complex absorption, 2H,
CH2OSi), 3.63 (s, 3H, CO2CH3), 7.32–7.65 (complex
absorption, 10H, 2Ph); 13C NMR (CDCl3): 17.29 (c-2-
CH3), 19.14 (SiC(CH3)3), 20.80 (C4), 26.82
(SiC(CH3)3), 31.04 (t-2-CH3), 42.30 (C2), 43.65 (C3),
45.67 (C1), 51.09 (CO2CH3), 64.34 (CH2OSi), 127.61
(4C, CHmeta), 129.58 (2C, CHpara), 133.87 (2C, Cipso),
135.58 (4C, CHortho), 173.51 (CO2Me). Anal. calcd for
C25H34O3Si:, 73.12; H, 8.35. Found: C, 73.06; H, 8.41.
6. Pietrzynski, G.; Rzeszotarska, B.; Ciszak, E.; Lisowski,
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´
8. Moglioni, A. G.; Garc´ıa-Expo´sito, E.; Alvarez-Larena,
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clobutane-1-carboxylate, (+)-4
´
G.; Ortun˜o, R. M. Tetrahedron: Asymmetry 2001, 12, 25.
´
A mixture of compound 12 (1.4 g, 3.4 mmol) and
n-Bu4F (4.9 mL of a 1 M solution in THF, 4.9 mmol)
in anhydrous THF (3 mL) was stirred at rt for 30
min. Then solvent was removed and the residue was
chromatographed (1:2 ethyl acetate–hexane) to give
hydroxy ester (+)-4 as an oil (470 mg, 80% yield), [h]D
+9.8 (c 0.41, MeOH). The IR, 1H and 13C NMR
spectroscopic data were in good agreement with those
described above for its enantiomer, (−)-4.
10. Moglioni, A. G.; Muray, E.; Castillo, J. A.; Alvarez-
Larena, A.; Moltrasio, G. Y.; Branchadell, V.; Ortun˜o,
R. M. J. Org. Chem. 2002, 67, 2402.
´
11. Moglioni, A. G.; Brousse, B. N.; Alvarez-Larena, A.;
Moltrasio, G. Y.; Ortun˜o, R. M. Tetrahedron: Asymme-
try 2002, 13, 451.
12. Sterkycki, R. Synthesis 1979, 724.
13. Webster, F. X.; Rivas-Enterrios, J.; Silverstein, R. M. J.
Org. Chem. 1987, 52, 689.

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18. Mehta, A.; Jaouhari, R.; Benson, T. J.; Douglas, K. T.
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