Preparation of highly enantiomerically enriched cyclobutane and cyclobutene diols

Article abstract of DOI:10.1016/j.tetasy.2004.02.018

Cyclobutene (+)-9, (+)-12, (+)-13, (+)-15, and cyclobutane (+)-19, (+)-22, (+)-23, (+)-25 diols were obtained in high enantiomeric excesses from monoacetates (-)-23 or (+)-16. An alternative method for obtaining (+)-22 and (+)-25 involved the resolution of cyclobutane 1,2-dicarboxylic acid.

Full text of DOI:10.1016/j.tetasy.2004.02.018

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1103–1111
Preparation of highly enantiomerically enriched cyclobutane and
cyclobutene diols
Christophe Pichon, Christian Alexandre* and Francois Huet*
ß
Laboratoire de Synthꢀese Organique, UMR CNRS 6011, Facultꢁe des Sciences, Universitꢁe du Maine, Avenue Olivier, Messiaen,
F-72085 Le Mans Cedex 9, France
Received 8 January 2004; accepted 13 February 2004
Abstract—Cyclobutene (+)-9, (+)-12, (+)-13, (+)-15, and cyclobutane (+)-19, (+)-22, (+)-23, (+)-25 diols were obtained in high
enantiomeric excesses from monoacetates ())-23 or (+)-16. An alternative method for obtaining (+)-22 and (+)-25 involved the
resolution of cyclobutane 1,2-dicarboxylic acid.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
or find application in obtaining asymmetric reagents or
catalysts. This is the reason why we envisaged preparing
several diols, which can be interesting in their own right,
or after substitution by amino or phosphino groups.
Chiral cyclobutene compounds derived from anhydride
1,1 such as monoester 2,2 and monoacetate 4,3;4 have
been used in the efficient syntheses of optically active
nucleoside analogues 3,2 5,5 and 6.5 Lactone 7, which is
equally available from 1 in both enantiomeric forms,3;6
also proved to be an intermediate in nucleoside syn-
thesis7 (Scheme 1).
2. Results and discussion
Other chiral cyclobutene and cyclobutane compounds,
can be used as building blocks in asymmetric synthesis
The starting material for the cyclobutene series was
monoacetate ())-4 obtained by enzymatic acetylation of
NH2
N
N
O
CO2Me
N
N
O
CO2H
2 (ref 2)
3 (ref 2)
1
O
HOH2C
CH2OH
OH
OH
OH
OAc
4 (ref 3,4)
or
1
N
N
N
N
O
O
5 (ref 5)
6 (ref 5)
N
NH
Me
O
O
NH2
1
O
or
O
(+)-7 (ref 3,6)
(−)-7 (ref 3)
Scheme 1.
* Corresponding authors. Tel.: +33-2-4383-3338/3096; fax: +33-2-4383-3902; e-mail addresses: fhuet@univ-lemans.fr; calexan@univ-lemans.fr
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.018

1104
C. Pichon et al. / Tetrahedron: Asymmetry 15 (2004) 1103–1111
the corresponding diol.4 It was oxidized to the acid (+)-
8,3 which was esterified with 9-fluorenol or diazome-
thane to yield ())-10a or (+)-10b, respectively (Scheme
2). We then subjected both esters to epimerization in the
presence of DBU. As expected, the trans/cis ratio, in
favor of the trans-isomer, was higher from the more
crowded compound ())-10a. These mixtures were
reduced with LiAlH4 leading to both diols. The trans-
isomer (+)-12 was then easily separated from the cis-
one. Similarly, reactions with PhMgBr led to compound
(+)-13. The cis-isomer, (+)-9 was available from lactone
())-73 (Scheme 2).8;9 We thought that it would also be
interesting to prepare a cyclobutene analogue (+)-15 of
TADDOL. As a result we oxidized (+)-13 to the acid
(+)-14: esterification with CH2N2 followed by reaction
with PhMgBr gave the expected product.
These methods were approximately the same for the
cyclobutane series (Scheme 3).8;9 However, in this case,
epimerization with DBU did not work with the less
acidic compounds (+)-20a and (+)-20b and so the
reaction was carried out with 2 equiv of (iPr)2NLi fol-
lowed by protonation. The optimal result for the latter
step was obtained with AcOH in THF. Although in
O
Ph Ph
CO2H
OAc
a
c
93%
b
OH
OAc
(−)-4>98% ee
OH
OH
O
84%
83%
(+)-8
(−)-7 98.2% ee
(+)-9
d (−)-10a
e(+)-10b
CO2R
(−)-10a
f
CO2R
OAc
7.5 : 1
11a
11b
96% from (−)-10a
94% from (+)-10b
OAc
(−)-10a R = Fl83%(87%)8
(+)-10b R = Me quantitative
(+)-10b
4.5 : 1
c
82%9 for R = Fl
78%9 for R = Fl
g
74%9 for R = Me
67%9 for R = Me
Ph Ph
OH
OH
Ph Ph
(+)-15
Ph Ph
Ph Ph
OH
CO2H
(+)-14
OH
OH
OH
OH
a
e,c
85%
86%
(+)-12 98.2% ee
(+)-13
Scheme 2. (a) CrO3, H2SO4, H2O (addition of the alcohol to the reagent); (b) (1) LiOH/THF, H2O, (2) 3 M H2SO4; (c) PhMgBr, THF;
(d) 9-fluorenol, DIC, CH2Cl2; (e) CH2N2; (f) DBU, CH2Cl2, rt, 8 days; (g) LiAlH4, THF.
O
Ph Ph
CO2H
OAc
a
c
b
OH
OAc
OH
OH
(+)-19
O
81%
87%
93%
(+)-17
(−)-18 99.9% ee
(+)-16 99.9% ee
d (−)-20a
e(+)-20b
CO2R
OAc
3.6 : 1
(+)-20a
(+)-20b
CO2R
f
21a
21b
71% from (+)-20a
69% from (+)-20b
OAc
(+)-20a R = Fl 82%
(+)-20b R = Me quantitative
2.3 : 1
c
69%9 for R = Fl
67%9 for R = Fl
g
51%9 for R = Me
53%9 for R = Me
Ph Ph
OH
OH
Ph Ph
(+)-25
Ph Ph
Ph Ph
OH
CO2H
(+)-24
OH
OH
OH
OH
a
e,c
82%
89%
(
(+)-23
+)-22 99.9% ee
Scheme 3. (a) CrO3, H2SO4, H2O (addition of the alcohol to the reagent); (b) (1) LiOH/THF, H2O, (2) 3 M H2SO4; (c) PhMgBr, THF;
(d) 9-fluorenol, DIC, DMAP, CH2Cl2; (e) CH2N2; (f) (1) LDA, THF, (2) AcOH, THF; (g) LiAlH4, THF.

C. Pichon et al. / Tetrahedron: Asymmetry 15 (2004) 1103–1111
1105
were higher via the methyl esters and in the case of (+)-
22 and (+)-23. They were higher via the 9-fluorenyl
esters (Scheme 4).
Ph Ph
OH
OH
CO2H
OAc
OH
OH
(+)-8
(+)-13
(
+)-12
We also tested an alternative method based on mild
oxidation to (+)-16, followed by epimerization accord-
ing to a known procedure.11 Interestingly, this led to a
large amount of the predominant trans-isomer 27, an
excellent precursor for alcohols (+)-22 and (+)-23
(Scheme 5). This method was more efficient than the
previous one in the case of these compounds. Unfortu-
nately it did not work in the cyclobutene series due to
the instability of the intermediate aldehyde.12
Me
Fl
Me
Fl
65%
64%
72%
68%
Ph Ph
OH
OH
CO2H
OAc
(+)-17
OH
OH
(+)-23
(+)-22
Me
Fl
Me
Fl
34%
39%
33%
40%
Scheme 4. Overall yields from (+)-8 and (+)-17.
A third methodology was based on the resolution of the
diacid 28 (Scheme 6). One method has been reported
using diastereomer salts formed by treatment with qui-
nine or cinchonidine;13 however the yields and enantio-
meric excesses have not been indicated in the
corresponding publications. A second method has also
been described for obtaining ())-30 by reaction of ())-
menthyl succinate with 1,2-dibromoethane;14 however
the diastereomeric excess was not measured and the
reaction led to a mixture of the cis- and trans-isomers.
We then tried to carry out the resolution by preparing
())-menthyl esters. We thus obtained a mixture of 29
and ())-30 in 97% yield with respect to the ())-menthol.
Both products could not be separated by chromato-
graphy but two successive crystallizations in methanol
these reactions, several unidentified by-products were
formed, however mixtures of 21a and ())-20a or 21b and
(+)-20b, used for the following step, could be obtained
by column chromatography.
Eight diols were prepared in high enantiomeric purities.
The cis-products (+)-9 and (+)-19 were obtained in a
direct way, whereas obtaining the trans-products (+)-12,
(+)-13, (+)-22, (+)-23 then (+)-15 and (+)-25 involved a
succession of esterification then epimerization steps.
Compound (+)-25 has already been obtained by a
method involving epimerization of another chiral cyclo-
butane compound.10 Overall yields depended upon
several parameters: in the case of (+)-12 and (+)-13 they
CHO
CHO
(−)-26
OAc
b
a
OH
OAc
(+)-16 99.9%ee
OAc
84%
96%
27
(−)-26
17 : 1
d,e,f
9
c
9
90%
77%
Ph Ph
OH
OH
OH
OH
(+)-22, 99.9% ee
(+)-23
Scheme 5. (a) DMSO, oxalyl chloride, Et3N, CH2Cl2; (b) Et3N; (c) LiAlH4, THF; (d) CrO3, H2SO4, H2O (addition of the alcohol to the reagent);
(e) CH2N2; (f) PhMgBr, THF.
CO2H
CO2H
(+)-28
CO2H
CO2H
CO2(−)-Menth
CO2(
CO2(
−
)-Menth
)-Menth
a
CO2(−)-Menth
−
(−)-28
29
(−)-30
50: 50
63% yield, 44% de
31% yield, 99.9% de
(after two crystallizations)
b
c
98%
96%
CH2OH
b
CH2OH
(+)-22
100%
Ph Ph
OH
OH
Ph Ph
(+)-25
CO2(+)-Menth
CO2(+)-Menth
CO2H
CO2H
d
CO2H
CO2H
e,f
92%
59%
(+)-30, 99.9% de
(−)-28, 44% ee
(+)-28
(after two crystallizations)
Scheme 6. (a) ())-Menthol, pTsOH, toluene, reflux; (b) LiOH, MeOH, H2O; (c) LiAlH4, THF; (d) (+)-menthol, pTsOH, toluene, reflux; (e) CH2N2;
(f) PhMgBr, THF.

1106
C. Pichon et al. / Tetrahedron: Asymmetry 15 (2004) 1103–1111
led to isolation of ())-30 in 31% yield and 99.9% dia-
stereomeric excess. The absolute configuration and
diastereomeric excess were determined thanks to a
reduction into (+)-22. After separation of the pure ())-
30, compound 29 was recovered in 63% yield. The dia-
stereomeric ratio (44%) was measured either from the
inverse gate decoupling 13C NMR spectrum or by
reduction into ())-22 followed by measurement of the
enantiomeric excess of the latter. Saponification fol-
lowed by esterification with (+)-menthol led to (+)-30 in
59% yield and 99.9% ee after two successive crystalli-
zations. Obviously reduction into the alcohol (+)-22 (or
its enantiomer) was not the only way of measuring the
diastereomeric excesses of the esters, but it was a useful
method of obtaining this alcohol. On the other hand, the
menthyl esters proved to react poorly with phenyl
magnesium bromide. Therefore, to obtain (+)-25, the
menthyl ester ())-30 was saponified, then esterified with
diazomethane before reaction with phenyl magnesium
bromide. Finally the method worked very well in
obtaining (+)-22 and (+)-28 and it might also be used to
prepare their enantiomers.
100 mL with acetone. Compound ())-44 of 98.2% ee
(1.401 g, 9 mmol) in acetone (30 mL) was then added
dropwise to a solution of JonesÕ reagent previously
prepared (9 mL) in acetone (30 mL) and stirred at
)10 °C for 1h. The reaction was allowed to proceed for
0.5 h after which isopropanol was added dropwise at the
same temperature until discoloration. After 0.5 h stirring
at room temperature, Celite (1g) was added. After fil-
tration over Celite, washing with acetone (3 · 30 mL)
and evaporation, CH2Cl2 (100 mL) and an aqueous
solution of 10% HCl saturated with NaCl (50 mL) were
added to the residue. Decantation, extraction with
CH2Cl2 (3 · 50 mL), drying of the combined organic
phases with MgSO4, and evaporation, afforded the acid
20
D
1.1, CHCl3), 98.2% ee [presumed identical to the ee of
(+)-83 as a colorless oil (1.271 g 83%). ½aŠ ¼ +118.5 (c
1
the precursor ())-4]. H NMR (CDCl3) d 2.02 (s, 3H),
2.65 (s, 1H), 3.50 (ddd, 1H, J ¼ 6:9, 5.9, 4.9 Hz), 3.81
(dd, 1H, J ¼ 4:9, 0.9 Hz), 4.19 (dd, 1H, J ¼ 11:8,
5.9 Hz), 4.41(dd, 1H, J ¼ 11:8, 6.9 Hz), 6.17 (d, 1H,
J ¼ 2:9 Hz), 6.19 (dd, 1H, J ¼ 2:9, 0.9 Hz). 13C NMR
(CDCl3) d 20.6, 45.5, 47.3, 63.5, 134.8, 138.9, 171.1,
177.1. IR (m cmꢀ1) 3467, 1741, 1704, 1386, 1367, 1273,
1037. Anal. Calcd for C8H10O4: C, 56.47; H, 5.92.
Found: C, 56.19, H, 5.81. Acid (+)-8 (680 mg, 4 mmol)
was added to an ice-cooled solution of 1:1 THF/water
mixture (8 mL). Lithium hydroxide (576 mg, 24 mmol)
was then added portionwise and the reaction mixture
stirred for 26 h at room temperature. The THF was
evaporated, after which 20 mL of 3 M H2SO4 was added
at 0 °C and NaCl then added until saturation. After 3 h
stirring at 0 °C, extraction of the aqueous phase with
CH2Cl2 (5 · 30 mL), washing of the combined organic
phases with brine (30 mL), drying over MgSO4, and
evaporation led to an oil. Purification by column chro-
3. Conclusion
In conclusion we prepared several diols in efficient ways.
In the case of the cyclobutene compounds (+)-9, (+)-12,
(+)-13, and (+)-15 we propose the method correspond-
ing to Scheme 2, preferably via the methyl ester (+)-10b.
Diol (+)-19 is available by reaction with lactone ())-18
(Scheme 3). Obtaining diols (+)-22 and (+)-25 is efficient
via diester ())-30 (Scheme 6) and the enantiomers might
be available from (+)-30. Another good method for
preparing (+)-22 is via the aldehyde 27, which is also a
good intermediate for the preparation of (+)-23. In the
case of these last three diols, the method corresponding
to Scheme 3 is a less efficient alternative.
matography on silica gel (CH2Cl2/Et2O, 10:0 fi 9:1)
20
provided lactone ())-7 as an oil (371mg, 84%). ½aŠ
¼
D
1
)338 (c 1, CHCl3), 98.2% ee (determined by GPC). H
NMR (CDCl3) d 3.62 (m, 1H), 3.66 (d, 1H, J ¼ 3:5 Hz),
4.29 (m, 2H), 6.33 (d, 1H, J ¼ 3:0 Hz), 6.37 (d, 1H,
J ¼ 3:0 Hz). 13C NMR (CDCl3) d 41.2, 46.5, 68.0, 139.0,
141.5, 177.3. IR (m cmꢀ1) 3056, 1758, 1560, 1373, 1168.
4. Experimental
4.1. General
4.3. (+)-(1R,4S)-4-(Hydroxymethylcyclobut-2-enyl)diphen-
ylmethanol, (+)-9
NMR spectra were recorded on a Bruker AC 400
spectrometer at 400 and 100.6 MHz, respectively. All
melting points are uncorrected. Elemental analyses were
performed by the service of microanalyses, CNRS,
ICSN, Gif sur Yvette. High resolution mass spectra
were recorded on a Varian Mat 311 or ZabSpec TOF
Micromass spectrometer at the CRMPO, Rennes.
Infrared spectra were measured with an FT infrared
spectrometer Genesis Matteson instrument. Enantio-
meric excesses were determined by gas phase chroma-
tography with a Hewlett-Packard HP 6890 Series
apparatus equipped either with a Restek-b Dex Sm
(25 m · 0.25 mm) column or with a R+bDEXCST
(25 m · 0.25 mm) column.
A solution of ())-7 (370 mg, 3.36 mmol) in dry THF
(7 mL) was added dropwise at 0 °C under nitrogen to a
stirred 1M THF solution of PhMgBr (13.5 mL,
13.5 mmol). After 15 min stirring at room temperature,
and 30 min at 40 °C, the mixture was hydrolyzed at 0 °C
with 10 mL of an aqueous solution of saturated NH4Cl.
THF was evaporated and 40 mL of water added.
Extraction with CH2Cl2 (3 · 60 mL), washing of the
combined organic phases with brine (50 mL), drying
over MgSO4, and evaporation, left a solid, which slowly
crystallized at room temperature after solubilization in
20 mL of cyclohexane at 60 °C. Compound (+)-9 was
thus obtained as white crystals (829 mg, 3.12 mmol,
20
D
4.2. (1R,5S)-3-Oxabicyclo[3.2.0]hept-6-en-2-one, ())-73
93%). Mp 127–128 °C (C6H12); ½aŠ ¼ +126 (c 1,
CHCl3), 98.2 ee [presumed identical to the ee of the
precursor ())-7]. 1H NMR (CDCl3) d 2.93 (s, 1H), 3.21–
3.29 (m, 2H), 3.59 (dd, 1H, J ¼ 11:9, 5.9 Hz), 4.16 (d,
Jones’ reagent was prepared from 26.7 g of CrO3 and
23 mL of 18 M H2SO4 and the solution made up to

C. Pichon et al. / Tetrahedron: Asymmetry 15 (2004) 1103–1111
1107
1H, J ¼ 1:9 Hz), 6.10 (d, 1H, J ¼ 2:9 Hz), 6.18 (d, 1H,
J ¼ 2:9 Hz), 7.14–7.34 (m, 6H), 7.42–7.46 (m, 2H), 7.53–
7.58 (m, 2H); 13C NMR (CDCl3) d 49.7, 56.5, 60.1, 76.1,
125.8, 125.9, 126.5, 126.8, 128.0, 128.3, 137.1, 137.5,
146.5, 147.0; IR (m cmꢀ1) 3270, 3006, 1320, 1130. Anal.
Calcd for C18H18O2: C, 81.17; H, 6.81. Found: C, 81.16,
H, 6.37.
perature. Evaporation, addition of Et2O (10 mL),
washing with a 0.3 M aqueous solution of NH4Cl
(10 mL), water (10 mL) then brine (10 mL), drying over
MgSO4 then evaporation, provided a mixture of 11a and
())-10a in a 7.5:1ratio, respectively, (322 mg, 96%)
which was used as such in the following step. Data for
11a: 1H NMR (CDCl3) d 1.91 (s, 3H), 3.37 (m, 1H), 3.54
(m, 1H), 4.18 (dd, 1H, J ¼ 11:3, 5.6 Hz), 4.22 (dd, 1H,
J ¼ 11:3, 7.0 Hz), 6.18 (d, 1H, J ¼ 2:8 Hz), 6.21(dd, 1H,
J ¼ 2:8, 0.9 Hz), 6.81(s, 1H), 7.28–7.32 (m, 2H), 7.50–
7.56 (m, 2H), 7.57–7.59 (m, 1H), 7.67 (d, 1H,
J ¼ 7:5 Hz).
4.4. ())-(1R,4S)-4-Acetoxymethylcyclobut-2-ene carbox-
ylic acid 9H-fluoren-9-yl ester, ())-10a
A solution of DIC (1.2 mL, 7.7 mmol) in dry CH2Cl2
(8 mL) was added slowly at 0 °C to a stirred suspension
of fluorenol (1.400 g, 7.7 mmol), DMAP (40 mg), and
(+)-8 (1.191 g, 7 mmol) in dry CH2Cl2 (14 mL). After 4 h
at room temperature, oxalic acid (100 mg) was added.
The reaction mixture then stirred for 3 h. Evaporation,
then purification by column chromatography on silica
4.7. (1S,4S)-4-Acetoxymethylcyclobut-2-ene carboxylic
acid methyl ester, 11b
The previous experimental procedure was applied to the
synthesis of 11b, starting from (+)-10b (1.503 g,
8.1mmol). After 8 days a mixture of 11b and ())-10b in a
4.5:1ratio, respectively, (1.404 g, 94%). was obtained. It
was used as such in the following step. Data for 11b: 1H
NMR (CDCl3) d 2.06 (s, 3H), 3.30 (ddd, 1H, J ¼ 6:6,
5.7, 1.6 Hz), 3.41 (dd, 1H, J ¼ 1:6, 0.9 Hz), 3.70 (s, 3H),
4.16 (dd, 1H, J ¼ 11:3, 5.7 Hz), 4.26 (dd, 1H, J ¼ 11:3,
6.6 Hz), 6.14 (d, 1H, J ¼ 2:8 Hz), 6.20 (dd, 1H, J ¼ 2:8,
0.9 Hz).
gel (C6H12/Et2O, 90:10 fi 70:30) afforded ())-10a as a
20
paste (2.031g, 87%). ½aŠ ¼ )2 (c 1, CHCl3), 98.2% ee
D
1
[presumed identical to the ee of the precursor ())-4]. H
NMR (CDCl3) d 1.85 (s, 3H), 3.46 (m, 1H), 3.89 (dt, 1H,
J ¼ 4:7, 1.0 Hz), 4.26 (dd, 1H, J ¼ 11:4, 5.6 Hz), 4.37
(dd, 1H, J ¼ 11:4, 6.9 Hz), 6.18 (dt, 1H, J ¼ 2:9,
1.0 Hz), 6.21 (m, 1H), 6.80 (s, 1H), 7.30 (tdd, 2H,
J ¼ 7:4, 7.4, 2.8 Hz), 7.41(m, 2H), 7.55 (m, 1H), 7.67
(m, 1H); 13C NMR (CDCl3) d 20.6, 45.9, 47.7, 63.6,
75.4, 120.0, 126.1, 127.9, 129.5, 135.2, 138.8, 141.0,
141.8, 170.9, 172.3; IR (m cmꢀ1) 3009, 2978, 1743, 1738,
1410. Anal. Calcd for C21H18O4: C, 75.43; H, 5.43.
Found: C, 75.27, H, 5.37.
4.8. (+)-(1S,4S)-(4-Hydroxymethylcyclobut-2-enylmeth-
anol, (+)-122
A 1:4.5 mixture of (+)-10b and 11b (920 mg, 5 mmol)
was dissolved in dry THF (10 mL) and this solution
added dropwise under nitrogen, at 0 °C and with stir-
ring, to a suspension of LiAlH4 (380 mg, 10 mmol) in
dry THF (10 mL). The reaction mixture was refluxed for
15 min, cooled to 0 °C, hydrolyzed by an aqueous solu-
tion of 2 M KOH (2.3 mL), stirred for 3 h then filtered
on a sintered glass funnel. Washing of the solid with hot
THF (4 · 4 mL), evaporation of the combined organic
phases then column chromatography on silica gel
4.5. (+)-(1R,4S)-4-Acetoxymethylcyclobut-2-ene carbox-
ylic acid methyl ester, (+)-10b
A solution of diazomethane in Et2O was added with
stirring to a solution of (+)-8 (1.270 g, 7.47 mmol) in
Et2O (10 mL). Addition was stopped when the yellow
coloration began to persist. The reaction mixture was
stirred for 5 min, then acetic acid (90 lL, 1.5 mmol) was
added. After 10 min stirring, the solution was evapo-
(CH2Cl2/AcOEt 5:5 fi 0:10) successively led to the cis-
20
rated affording (+)-10b as an oil (1.373 g, 7.46 mmol,
diol and then to (+)-12 (423 mg, 74%) as oils. ½aŠ ¼
D
20
quant). ½aŠ ¼ +4.2 (c 1.1, CHCl3), 98.2% ee [presumed
+4.1( c 1, CHCl3), ee 98.2% [deduced from the ee of the
reduction product, which was determined by GPC]. This
product was obtained by the same experimental method
D
identical to the ee of the precursor ())-4]. 1H NMR
(CDCl3) d 2.02 (s, 3H), 3.46 (ddd, 1H, J ¼ 6:9, 5.4,
4.9 Hz), 3.70 (s, 3H), 3.77 (m, 1H), 4.15 (dd, 1H,
J ¼ 11:3, 5.4 Hz), 4.32 (dd, 1H, J ¼ 11:3, 6.9 Hz), 6.16
(d, 1H, J ¼ 3:4 Hz), 6.17 (d, 1H, J ¼ 3:4 Hz); 13C NMR
(CDCl3) d 20.2, 45.3, 47.3, 51.7, 63.6, 135.2, 138.7,
170.8, 171.9; IR (m cmꢀ1) 3015, 2970, 1743, 1739, 1560.
Anal. Calcd for C9H12O4: C, 55.80; H, 7.02. Found: C,
55.66, H, 7.12.
1
as for ())-4. H NMR (CDCl3) d 2.69 (dd, 2H, J ¼ 9:7,
4.7 Hz), 3.56 (dd, 2H, J ¼ 10:9, 9.7 Hz), 3.79 (dd, 2H,
J ¼ 10:9, 4.7 Hz), 3.85 (br s, 2H), 6.11 (s, 2H); 13C NMR
(CDCl3) d 49.4, 64.2, 137.0; IR (m cmꢀ1) 3210, 1565,
1420. The same alcohol can also be obtained in 82%
yield by reduction of the ())-10a and 11a mixture with
LiAlH4.
4.6. (1S,4S)-4-Acetoxymethylcyclobut-2-ene carboxylic
acid 9H-fluoren-9-yl ester, 11a
4.9. (+)-(1S,4S)-(4-Hydroxymethylcyclobut-2-enyl)di-
phenylmethanol, (+)-13
DBU (0.37 mL, 3 mmol) was added dropwise at 0 °C
while stirring to a solution of ())-10a (335 mg, 1mmol)
in dry CH2Cl2 (10 mL). The reaction mixture, sheltered
from light was then stirred for 15 days at room tem-
Reaction of the ())-10a and 11a or (+)-10b and 11b
mixture with PhMgBr [see preparation of (+)-9] pro-
vided crude mixtures of (+)-9 and (+)-13. Purification by
column chromatography on silica gel (C6H12/Et2O

1108
C. Pichon et al. / Tetrahedron: Asymmetry 15 (2004) 1103–1111
20
D
90:10 fi 70:30), successively provided (+)-13 then (+)-9.
Compound (+)-13 was thus obtained as an oil in 78%
and 67% yield, respectively. ½aŠ ¼ +75 (c 1, CHCl3),
obtained in 81% yield as an oil. ½aŠ ¼ +9.1( c 1,
CHCl3), ee 99.9% (determined by GPC). 1H NMR
(CDCl3) d 1.80–1.90 (m, 1H), 2.03 (s, 3H), 2.10–2.17 (m,
2H), 2.34–2.43 (m, 1H), 2.95–3.04 (m, 1H), 3.28–3.36
(m, 1H), 4.21 (dd, 1H, J ¼ 11:3, 6.5 Hz), 4.27 (dd, 1H,
J ¼ 11:3, 7.3 Hz), 9.80 (br s, 1H); 13C NMR (CDCl3) d
20.7, 21.0, 21.5, 36.3, 39.3, 64.6, 171,2, 179.2; IR (m
cmꢀ1) 3390, 1740, 1702. Anal. Calcd for C8H12O4: C,
55.80; H, 7.02. Found: C, 55.66, H, 7.12. Lactone ())-18
20
D
98.2% ee [presumed identical to the ee of the precursor
1
())-4]. H NMR (CDCl3) d 2.75 (s, 1H), 2.87 (m, 1H),
3.47 (m, 2H), 3.69 (s, 1H), 6.20 (dd, 1H, J ¼ 2:9, 0.9 Hz),
6.25 (dd, 1H, J ¼ 2:9, 0.7 Hz), 7.18–7.34 (m, 6H), 7.42–
7.49 (m, 4H); 13C NMR (CDCl3) d 46.4, 55.8, 63.9, 76.8,
125.7, 126.5, 127.0, 128.0, 128.1, 137.0, 140.4, 145.8 et
145.8; IR (m cmꢀ1) 3200, 3008, 2975, 1610, 1420. Anal.
Calcd for C18H18O2: C, 81.17; H, 6.81. Found: C, 81.16,
H, 6.67.
was then obtained from (+)-17 [see preparation of
20
D
())-7] in 87% yield as an oil. ½aŠ ¼ )62 (c 1.3, CHCl3),
1
99.9% ee (determined by GPC). H NMR (CDCl3) d
2.08–2.21(m, 2H), 2.37–2.45 (m, H1 ), 2.50–2.61(m,
1H), 3.08–3.14 (m, 1H), 3.16–3.22 (m, 1H), 4.23 (m, 1H),
4.36 (m, 1H); 13C NMR (CDCl3) d 23.4, 25.3, 34.3, 38.1,
74.1, 180.8; IR (m cmꢀ1) 2975, 2880, 1759.
4.10. (+)-(1S,4S)-(4-Hydroxydiphenylmethyl)cyclobut-2-
ene carboxylic acid, (+)-14
Oxidation of (+)-13 [see preparation of (+)-8] yielded
(+)-14 as an oil (86%). An analytical sample was
obtained by column chromatography on silica gel (C6H12/
4.13. (+)-(1R,2S)-(2-Hydroxymethylcyclobutyl)diphenyl-
methanol, (+)-19
20
Et2O, 90:10 fi 75:25). ½aŠ ¼ +170 (c 1 , CHCl), ee
3
D
98.2% [presumed identical to the ee of the precursor ())-
Reaction of ())-18 with PhMgBr [see preparation of (+)-
9] led to (+)-19 as white crystals in 93% yield. Mp 136–
1
4]. H NMR (CDCl3) d 1.36 (s, 1H), 3.55 (m, 1H), 4.20
20
(m, 1H), 6.19 (ddd, 1H, J ¼ 2:8, 1.2, 0.7 Hz), 7.18–7.33
(m, 6H), 7.41–7.44 (m, 4H); 13C NMR (CDCl3) d 46.7,
55.3, 77.0, 125.8, 126.1, 127.2, 128.2, 137.5, 139.0, 144.8,
145.3, 178.1; IR (m cmꢀ1) 3400, 1708, 1420,1166. Anal.
Calcd for C18H16O3, 0.2H2O: C, 76.15; H, 5.82. Found:
C, 76.40, H, 5.78.
137 °C (C6H12); ½aŠ ¼ +72 (c 1 , CHCl), 99.9% ee
3
D
[presumed identical to the ee of the precursor ())-18]. 1H
NMR (CDCl3) d 1.66–1.82 (2m, 2H), 2.01 (m, 1H,
J ¼ 11:2, 8.9 Hz), 2.20 (br s, 1H), 2.33 (m, 1H, J ¼ 9:9,
1.1 Hz), 2.76 (m, 1H), 3.53 (dd, 1H, J ¼ 11:9, 3.0 Hz),
3.63 (m, 2H), 4.77 (br s 1H), 7.15 (m, 1H), 7.20–7.26 (m,
4H), 7.30–7.35 (m, 4H), 7.51–7.54 (m, 1H); 13C NMR
(CDCl3) d. 19.9, 21.3, 40.0, 45.7, 62.4, 125.7, 126.1,
126.3, 126.6, 127.8, 128; IR (m cmꢀ1) 3285, 2970, 2920,
2875, 1410, 1150. Anal. Calcd for C18H20O2: C, 80.56;
H, 7.56. Found: C, 80.69, H, 7.64.
4.11. (1S,4S)-[4-(Hydroxydiphenylmethyl)cyclobut-2-
enyl]diphenylmethanol, (+)-15
Reaction of (+)-14 with CH2N2 [see preparation of (+)-
10b] led to the corresponding methyl ester as a yellow oil
20
D
(quant). ½aŠ ¼ +176 (c 1 , CHC3l), 98.2% ee [presumed
4.14. (+)-(1R,2S)-2-Acetoxymethylcyclobutane carbox-
ylic acid 9H-fluoren-9-yl ester, (+)-20a
identical to the ee of the precursor ())-4]. 1H NMR
(CDCl3) d 2.48 (s, 2H), 3.54 (m, 1H), 3.57 (s, 3H), 4.19
(m, 1H), 6.19 (dt, 1H, J ¼ 2:9, 1.0 Hz), 6.28 (ddd, 1H,
J ¼ 2:9, 1.0, 0.5 Hz), 7.19–7.33 (m, 6H), 7.41–7.46 (m,
4H); 13C NMR (CDCl3) d 46.7, 52.1, 55.3, 77.0, 125.8,
126.1, 127.2, 128.2, 137.5, 139.0, 144.8, 145.3, 178.1; IR
(m cmꢀ1) 3220, 1740, 1420, 1320, 1160. Anal. Calcd for
C19H18O3: C, 77.53; H, 6.16. Found: C, 77.38, H, 6.12.
Reaction of this ester with PhMgBr [see preparation of
Esterification of (+)-17 with fluorenol [see preparation
of ())-10a] provided compound ())-20a as a paste in
20
82% yield. ½aŠ ¼ +16 (c 1, CHCl3), 99.9% ee [presumed
D
identical to the ee of the precursor (+)-16]. H NMR
1
(CDCl3) d 1.90 (s, 3H), 1.91 (m, 1H), 2.16 (m, 2H), 2.47
(m, 1H), 2.97 (m, 1H), 3.39 (m, 1H), 4.26 (d, 2H,
J ¼ 6:8 Hz), 6.78 (s, 1H), 7.30 (dd, 1H, J ¼ 7:5, 2.5 Hz),
7.41(td, 2H, J ¼ 7:5, 0.6 Hz), 7.57 (td, 2H, J ¼ 7:7,
0.6 Hz), 7.66 (d, 2H, J ¼ 7:5 Hz); 13C NMR (CDCl3) d
20.6, 21.2, 21.5, 36.1, 39.4, 64.5, 75.2, 119.8, 125.9,
126.0, 127.7 127.8, 129.3, 140.9, 141.8, 141.9, 170.8,
174.0; IR (m cmꢀ1) 3007, 2948, 1736, 1731, 1452, 1365,
1240, 1170, 1039, 762, 742. Anal. Calcd for C21H20O4: C,
74.98; H, 5.99. Found: C, 75.16, H, 6.17.
(+)-9] yielded (+)-15 as a white solid in 85% yield. Mp
20
D
135–140 °C (dec); ½aŠ ¼ +76 (c 1, CHCl3), ee 98.2%
1
[presumed identical to the ee of the precursor ())-4]. H
NMR (CDCl3) d 3.59 (s, 2H), 5.52 (br s, 2H), 6.13 (s,
2H), 6.76–6.79 (m, 4H), 6.90 (tt, 2H, J ¼ 7:4, 1.1 Hz),
7.14–7.41 (m, 14H); 13C NMR (CDCl3) d 50.0, 78.2,0,
125.8, 126.1, 127.6, 127.7, 128.2, 128.3, 139.0, 144.7,
145.5; IR (m cmꢀ1) 3215, 3006, 1610, 1332. Anal. Calcd
for C30H26O2: C, 86.09; H, 6.26. Found: C, 86.14, H,
6.31.
4.15. ())-(1R,2S)-2-Acetoxymethylcyclobutane carbox-
ylic acid methyl ester, (+)-20b
4.12. (1R,5S)-3-Oxabicyclo[3.2.0]hept-6-en-2-one,
())-1815
Esterification of (+)-17 with diazomethane [see prepa-
ration of (+)-10b] quantitatively led to compound (+)-
20
D
20b as a yellow oil. ½aŠ ¼ +38 (c 1 , CHC3l), 99.9% ee
Compound (+)-164 was oxidized into acid (+)-17 with
JonesÕ reagent [see preparation of (+)-8]. This acid was
[presumed identical to the ee of the precursor (+)-16]. 1H
NMR (CDCl3) d 1.77–1.86 (m, 1H), 2.02 (s, 3H), 2.05–

C. Pichon et al. / Tetrahedron: Asymmetry 15 (2004) 1103–1111
1109
2.15 (m, 2H), 2.35–2.44 (m, 1H), 2.90–3.00 (m, 1H),
3.25–3.33 (m, 1H), 3.67 (s, 3H), 4.15 (dd, 1H, J ¼ 11:3,
6.4 Hz), 4.20 (dd, 1H, J ¼ 11:3, 7.5 Hz); 13C NMR
(CDCl3) d 20.9, 21.4, 21.6, 38.2, 38.2, 51.1, 64.6, 170.1,
179.3; IR (m cmꢀ1) 2985, 2970, 1742, 1738, 1440. Anal.
Calcd for C9H14O4: C, 58.08; H, 7.58. Found: C, 58.05,
H, 7.63.
preparation of (+)-9] or from the 27 and ())-26 mixture.
It was obtained as an oil. Yields are given in the
20
D
identical to the ee of the precursor (+)-16]. H NMR
schemes. ½aŠ ¼ +99 (c 1 , CHC3l), 99.9% ee [presumed
1
(CDCl3) d 1.91–2.42 (m, 6H), 3.11 (dd, 1H, J ¼ 11:5,
5.4 Hz), 3.20 (br s, 1H), 3.63 (dd, 1H, J ¼ 11:5, 6.7 Hz),
4.21 (br s, 1H), 7.15–7.34 (m, 10H); 13C NMR (CDCl3) d
23.2, 24.5, 38.7, 45.7, 68.6, 89.5, 26.1, 126.2, 126.9,
127.0, 127.2, 143.1, 143.6; IR (m cmꢀ1) 3300, 2970, 1420,
1170. Anal. Calcd for C18H20O2: C, 80.56; H, 7.56.
Found: C, 80.69, H, 7.64.
4.16. (1S,2S)-2-Acetoxymethylcyclobutane carboxylic
acid 9H-fluoren-9-yl ester, 21a
Epimerization of (+)-20a with LDA [see preparation of
21b] provided a mixture of (+)-20a and 21a, which were
not separated. The ratio 1:3.6, respectively, was deduced
4.20. (+)-(1S,2S)-(2-Hydroxydiphenylmethyl)cyclobutane
carboxylic acid, (+)-24
1
from the H NMR spectrum of the crude product and
from the ratio of both alcohols [cis-(2-hydroxymethyl-
cyclobutyl)methanol and (+)-22] obtained after reduc-
tion (see below).
Oxidation of (+)-23 [see preparation of (+)-8] yielded
(+)-24 as an oil (82%). An analytical sample was
obtained by column chromatography on silica gel (C6H12/
20
Et2O, 90:10 fi 75:25). ½aŠ ¼ +93 (c 1, CHCl3), 99.9% ee
D
4.17. (1S,2S)-2-Acetoxymethylcyclobutane carboxylic
acid methyl ester, 21b
[presumed identical to the ee of the precursor (+)-16]. 1H
NMR (CDCl3) d 2.01–2.07 (m, 2H), 2.19–2.25 (m, 2H),
2.28–2.38 (m, 1H), 3.31 (br s, 1H), 3.58–3.63 (m, 1H),
7.22–7.42 (m, 5H), 7.42 (dd, 2H J ¼ 7:2, 7.2 Hz), 7.58
(dd, 1H, J ¼ 7:1, 7.1 Hz), 7.91 (d, 2H, J ¼ 7:1Hz); 13C
NMR (CDCl3) d 21.8, 22.9, 44.1, 46.1, 79.5, 125.9,
126.0, 126.1, 127.3, 128.1, 144.7, 145.2, 178.2.; IR (m
cmꢀ1) 3430, 1709, 1424,1170. Anal. Calcd for C18H18O3,
0.2 H2O: C, 75.61; H, 6.49. Found: C, 75.77, H, 6.78.
A solution of (+)-20b (1.029 g, 6 mmol) in THF (10 mL)
was added at )78 °C to a solution of LDA in THF
prepared from 1.8 mL (15.6 mmol) of iPr2NH, 9.4 mL of
a 1.6 M solution of nBuLi in hexane (15 mmol) and THF
(40 mL). After 1h stirring at this temperature, hydroly-
sis with 10 mL of a 2 M solution of AcOH in THF fol-
lowed by evaporation led to an oil, which was dissolved
in CH2Cl2 (200 mL). Washing with an aqueous solution
of saturated NH4Cl (100 mL), water (100 mL) then brine
(100 mL), drying over MgSO4, and evaporation, pro-
vided a mixture of 21b and (+)-20b in a 2.3:1ratio,
respectively. Purification by column chromatography on
silica gel (CH2Cl2/Et2O 10:1 fi 8/2) provided the mixture
of both products in the same ratio (712 mg, 69%). Data
4.21. (1S,2S)-[(2-Hydroxydiphenylmethyl)cyclobutyl]-
diphenyl-methanol, (+)-2510
Reaction of (+)-24 with CH2N2 [see preparation of (+)-
10b] led to the corresponding methyl ester as an oil
20
D
identical to the ee of the precursor (+)-16]. H NMR
(quant). ½aŠ ¼ +135 (c 1 , CHC3l), 99.9% ee [presumed
1
1
for 21b: H NMR (CDCl3) d 1.72–1.83 (m, 1H), 1.97
(CDCl3): d 1.99–2.05 (m, 2H), 2.18–2.25 (m, 2H), 2.27–
2.35 (m, 1H), 3.47 (br s, 1H), 3.58–3.63 (m, 1H), 3.59 (s,
3H), 7.22–7.42 (m, 5H), 7,42 (dd, 2H, J ¼ 7:2, 7.2 Hz),
7.58 (dd, 1H, J ¼ 7:1, 7.1 Hz), 7.93 (d, 2H, J ¼ 7:1Hz);
13C NMR (CDCl3) d 21.9, 22.8, 44.0, 45.8, 50.8, 79.4,
125.9, 126.0, 126.1, 127.3, 128.1, 144.7, 145.2, 175.7; IR
(m cmꢀ1) 3210, 2970, 1741, 1445, 1355, 1154. Anal. Calcd
for C19H20O3: C, 77.00; H, 6.80. Found: C, 76.89, H,
6.89. Reaction of this ester with PhMgBr [see prepara-
(dddd, 1H, J ¼ 17:3, 9.1, 3.2, 0.9 Hz), 2.07 (s, 3H), 2.06–
2.23 (2 m, 2H), 2.81–2.91 (m, 1H), 2.91–2.99 (m, 1H),
3.68 (s, 3H), 4.05 (dd, 1H, J ¼ 11:3, 5.5 Hz), 4.11 (dd,
1H, J ¼ 11:3, 6.0 Hz); 13C NMR (CDCl3) d 20.7, 20.9,
21.5, 37.6, 51.6, 66.3, 171.1, 174.6; IR (cmꢀ1) 2980, 2920,
2870, 1741, 1739, 1410. Anal. Calcd for C9H14O4: C,
58.05; H, 7.58. Found: C, 58.09, H, 7.65.
4.18. (+)-(1S,2S)-(2-Hydroxymethylcyclobutyl)methanol,
(+)-22
tion of (+)-9] yielded (+)-25 as a white solid in
85% yield. Mp 181–182 °C (C6H12); ½aŠ ¼ +189 (c 2,
20
D
CHCl3), 99.9% ee [presumed identical to the ee of the
1
This alcohol was prepared by reduction with LiAlH4 of
the (+)-20a and 21a or (+)-20b and 21b mixtures [see
preparation of (+)-12] or of the 27 and ())-26 mixture or
precursor (+)-16]. H NMR (CDCl3) d 1.65–1.77 (m,
2H), 1.83–1.95 (m, 2H), 3.21–3.28 (m, 2H), 3.52 (br s,
2H), 7.16–7.36 (m, 20H); 13C NMR (CDCl3) d 21.7,
44.1, 79.4, 126.7, 127.6, 128.0, 128.1, 145.0, 146.5; IR (m
cmꢀ1) 3217, 2975, 2910, 2874, 1615, 1430, 1142. Anal.
Calcd for C30H28O2: C, 85.68; H, 6.71. Found: C, 85.71,
H, 6.73. The same alcohol was also obtained by reaction
of the dimethyl ester derived from (+)-28 with PhMgBr.
of ())-30. It was obtained as an oil. Yields are given in
20
the schemes. ½aŠ ¼ +4.8 (c 1 , CHC3l), 99.9% ee (deter-
D
mined by GPC). 1H NMR (CDCl3) d 1.56–1.68 (m, 2H),
1.82–1.95 (m, 2H), 2.19–2.30 (m, 2H), 3.05 (br s, 2H),
3.40 (dd, 2H, J ¼ 11:1, 5.4 Hz), 3.67 (dd, 2H, J ¼ 11:1,
9.1Hz); IR ( m cmꢀ1) 3240, 2950, 2875, 1420, 1210.
4.22. (1R,2S)-(2-Hydroxymethyl)cyclobutane carbalde-
hyde, ())-26
4.19. (+)-(1S,2S)-(2-Hydroxymethylcyclobutyl)diphenyl-
methanol, (+)-23
A solution of DMSO (2 mL, 28.2 mmol) in CH2Cl2
(68 mL) was cooled to )78 °C under nitrogen after
which oxalyl chloride (1.20 mL, 14 mmol) was added
This alcohol was prepared by reaction with PhMgBr of
the ())-20a and 21a or ())-20b and 21b mixtures [see

1110
C. Pichon et al. / Tetrahedron: Asymmetry 15 (2004) 1103–1111
dropwise with stirring. After 5 min, a solution of com-
pound (+)-164 (1.563 g, 9.9 mmol) in CH2Cl2 (48 mL)
was added dropwise. After 1h between )50 °C and
)78 °C, dry Et3N (7 mL, 50 mmol) was added. The
reaction mixture was then warmed to room temperature
and stirred for a further 30 min. Adding of CH2Cl2
(300 mL), washing with a 0.3 M aqueous solution of
NH4Cl (2 · 100 mL), water (2 · 100 mL) then brine
washed with an aqueous solution of 10% K2CO3
(200 mL) water (200 mL) and brine (200 mL), dried over
MgSO4, and evaporated to yield a mixture of 29 and
())-30 (25.24 g, 97%) as an oil. After dilution with
MeOH (150 mL) and cooling to )25 °C overnight, a
mixture of crystals, an oil and a solution were obtained.
Warming to 4 °C for 8 h led to solubilization of the oily
fraction. The mixture was then alternately cooled
()25 °C) and warmed (4 °C) over a week. The crystals
were then filtered at )25 °C on a sintered glass funnel
and washed with cold methanol ()25 °C, 20 mL). Two
recrystallizations (heating with 30 mL in dry MeOH, 7 h
at room temperature, one night at 4 °C, 3 h at )25 °C),
washing (10 mL of MeOH, )25 °C) and drying under
(100 mL), drying over MgSO4 then evaporation, led to
20
())-26 as an oil. ½aŠ ¼ )31.5 (c 1, CHCl3), 99.9% ee
D
[presumed identical to the ee of the precursor (+)-16]. 1H
NMR (CDCl3) d 1.72–1.81 (m, 1H), 1.98–2.06 (m, 1H),
2.03 (s, 3H), 2.12–2.21 (m, 1H), 2.41–2.49 (m, 1H), 2.99–
3.12 (m, 1H), 3.30–3.36 (m, 1H), 4.12 (dd, 1H, J ¼ 11:4,
8.1 Hz), 4.19 (dd, 1H, J ¼ 11:4, 5.5 Hz), 9.85 (d, 1H,
J ¼ 1:8 Hz); 13C NMR (CDCl3) d 18.3, 20.8, 21.2, 37.2,
47.1, 64.2, 170.7, 202.4; IR (m cmꢀ1) 1741, 1725, 1360,
1237.
reduced pressure, yielded ())-30 as crystals (8.07 g,
20
31%). Mp 53–54 °C (MeOH); ½aŠ ¼ )69 (c 1, CHCl3),
D
99.9% de [presumed identical to the ee of the reduction
product (+)-22]. 1H NMR (CDCl3) d 0.75 (d, 6H,
J ¼ 6:9 Hz), 0.81–1.11 (m, 4H), 0.88 (d, 6H, J ¼ 7:1Hz),
0.90 (d, 6H, J ¼ 6:9 Hz), 1.37 (ddt, 2H, J ¼ 12:9, 9.3,
3.1 Hz), 1.42–1.56 (m, 2H), 1.64–1.71 (m, 4H), 1.83 (dtd,
2H, J ¼ 13:9, 6.9, 2.7 Hz), 1.94–2.08 (m, 2H,
J ¼ 11; 9 Hz), 2.13–2.17 (m, 4H), 3.32–3.37 (m, 2H),
4.62 (td, 2H, J ¼ 11:9, 4.4 Hz); 13C NMR (CDCl3) 16.4,
20.8, 21.8, 22.1, 23.5, 26.3, 31.4, 34.3, 40.92, 40.94, 74.4,
173.2; IR (m cmꢀ1) 2995, 2930, 2870, 2850, 1740, 1430,
1320, 1260. Anal. Calcd for C24H42O4: C, 72.99; H,
10.64. Found C, 73.06, H, 10.54. The other organic
fractions were combined and evaporated affording 29
(16.4 g, 63%). The de (44%) was deduced from the in-
verse gate decoupling 13C NMR spectrum.
4.23. (1S,2S)-(2-Hydroxymethyl)cyclobutane carbalde-
hyde, 27
Oxygen was removed by argon from 90 mL of dry Et3N,
then ())-26 (1.407 g, 9 mmol) added. Stirring under
argon for 10 days, evaporation and purification by column
chromatography
on
silica
gel
(CH2Cl2/Et2O
99:1 fi 80:20) led to a (1:17) mixture of ())-26 and 27
1
(1.182 g, 84%). Data for 27: H NMR (CDCl3) d 1.56–
1.76 (m, 2H), 1.94–2.02 (m, 1H), 2.04 (s, 3H), 2.07–2.16
(m, 1H), 2.25–2.36 (m, 1H), 2.46–2.62 (m, 3H), 4.01 (dd,
1H, J ¼ 11:2, 7.0 Hz), 4.07 (dd, 1H, J ¼ 11:2, 5.8 Hz),
9.72 (d, 1H, J ¼ 1:8 Hz); 13C NMR (CDCl3) d 20.9, 21.7,
24.8, 33.1, 40.4, 50.1, 67.3, 171.1, 201.5.
4.26. (1S,2S)-Cyclobutane (1,2)-dicarboxylic acid,
(+)-2813
4.24. Intermediates between 27and (+)-23
Water (8 mL), LiOH (360 mg) and MeOH (4 mL) were
successively added to a solution of diester ())-30
(3.948 g, 10 mmol) in THF (8 mL). The reaction mixture
was heated at reflux for 6 h then cooled. Organic sol-
vents were evaporated and water (20 mL) added to the
resulting aqueous solution. Extraction with Et2O
(4 · 30 mL) and removal of the organic phase, acidifi-
cation of the aqueous phase by a 6 M aqueous solution
of HCl until pH 2, addition of NaCl until saturation,
extraction with Et2O (5 · 30 mL), drying over MgSO4
then evaporation provided (+)-28 as a white powder
(1.366 g, 95%) (when the residue was oily, 10 mL of
Oxidation of the ())-26 and 27 mixture with JonesÕ
reagent [see preparation of ())-8] led to the corre-
sponding acids. H NMR (CDCl3) of the major isomer
1
(93% yield): d 1.71–1.82 (m, 1H), 1.96 (dddd, 1H,
J ¼ 17:3, 9.1, 3.2, 0.9 Hz), 2.07 (s, 3H), 2.05–2.21 (2 m,
2H), 2.79–2.89 (m, 1H, J ¼ 8:8, 6.1Hz), 2.89–2.97 (m,
1H, J ¼ 8:9 Hz), 3.68 (s, 3H), 4.05 (dd, 1H, J ¼ 11:3,
5.5 Hz), 4.11 (dd, 1H, J ¼ 11:3, 6.0 Hz). Esterification of
these acids with CH2N2 [see preparation of (+)-10b]
provided the corresponding methyl esters 21b in quan-
titative yield.
toluene was added, then crystallization occurred during
20
evaporation). Mp 128–130 (Et2O); ½aŠ ¼ +155 (c 1,
D
EtOH), 99.9% ee (determined by GPG). 1H NMR
(acetone-d6) d 2.12–2.17 (m, 4H), 3.35–3.39 (m, 2H),
10.1 (very br s, 2H); 13C NMR (acetone-d6) d 22.2, 40.7,
175.0.
4.25. ())-(1S,2S)-Cyclobutane-1,2-dicarboxylic acid
di())-menthyl ester, ())-3013 and (1R,2R)-cyclobutane-
1,2-dicarboxylic acid di())-menthyl ester, 29
A racemic mixture of diacid ( )-28 (10.00 g, 69.4 mmol),
())-menthol (20.6 g, 131.9 mmol) and pTsOH (900 mg)
was heated at reflux in toluene (150 mL) with stirring. A
small amount of water was removed by azeotropic dis-
tillation with a Dean–Stark apparatus. The reaction was
allowed to proceed for 21h and the mixture cooled and
evaporated at reflux. The oily residue was dissolved in
CH2Cl2 (600 mL) and the organic phase was successively
4.27. (1R,2R)-Cyclobutane (1,2)-dicarboxylic acid, ())-28
The mixture of both diastereomers 29 (16.4 g,
41.55 mmol) was saponified with LiOH [see preparation
of (+)-28]. Compound ())-28 was thus obtained as a
white powder [5.736 g, 96%, 44% ee (determined by
GPC)].

C. Pichon et al. / Tetrahedron: Asymmetry 15 (2004) 1103–1111
1111
4. Pichon, C.; Hubert, C.; Alexandre, C.; Huet, F. Tetrahe-
dron: Asymmetry 2000, 11, 2429–2434.
5. Hubert, C.; Alexandre, C.; Aubertin, A.-M.; Huet, F.
Tetrahedron 2002, 58, 3775–3778.
6. Gourdel-Martin, M.-E.; Comoy, C.; Huet, F. Tetrahe-
dron: Asymmetry 1999, 10, 403–404.
7. Gourdel-Martin, M.-E.; Huet, F. J. Org. Chem. 1997, 62,
2166–2172.
8. In the presence of DMAP the reaction time was shortened
(17 h fi 4 h) and the yield was increased to 87% but 5% of
the trans-product was obtained together with the cis-
product.
4.28. (1R,2R)-Cyclobutane-1,2-dicarboxylic acid di(+)-
menthyl ester, (+)-30
Diacid ())-28 (5.736 g, 39.8 mmol) was esterified with
(+)-(menthol) (11.82 mg, 75.9 mmol) [see preparation of
())-30]. A mixture of both esters was obtained. It was
crystallized by the same procedure as for ())-30, to give
20
diester (+)-30 (9.269 g, 59%). ½aŠ ¼ +69 (c 1 , CHCl),
3
D
99.9% de.
9. Isolated yield after removal of the cis-product.
10. Ito, Y. N.; Ariza, X.; Beck, A. K.; Bohac, A.; Gunter, C.;
Acknowledgements
€
Gawley, R. E.; Kuhnle, F. N. M.; Tuleja, J.; Wang, Y. M.;
Seebach, D. Helv. Chim. Acta 1994, 77, 2071–2110.
We thank MENRT for a fellowship to C.P.
ꢁ
11. Nicalaou, K. C.; Namoto, K.; Ritzen, A.; Ulven, T.; Shoji,
M.; Li, J.; Altmann, K.-H.; Giannakakou, P. J. Am.
Chem. Soc. 2001, 123, 9313–9323.
12. Pichon, C.; Martin-Gourdel, M.-E.; Chauvat, D.; Alex-
andre, C.; Huet, F. J. Mol. Cat. B 2004, 27, 65–68.
13. Brunet, J.-J.; Herbosky, D.; Neibecker, D. Synth. Com-
mun. 1996, 26, 483–493, and references cited therein.
14. Misumi, A.; Iwanaga, K.; Furuta, K.; Yamamoto, H.
J. Am. Chem. Soc. 1985, 107, 3343–3345.
15. Kasel, W.; Hultin, P. G.; Jones, J. B. J. Chem. Soc., Chem.
Commun. 1985, 1563–1564, for pioneering work in the
production of enantiomerically enriched products by
enzyme-catalyzed reactions see; Jones, J. B. Tetrahedron
1986, 42, 3351–3403, and references cited therein.
References and notes
1. For a recent preparation of 1 see: Gauvry, N.; Comoy, C.;
Lescop, C.; Huet, F. Synthesis 1999, 574–576.
2. Jung, M. E.; Sledeski, A. W. J. Chem. Soc., Chem.
Commun. 1993, 589–591; Jung, M. E.; Trifunovich, I. D.;
Sledeski, A. W. Heterocycles 1993, 35, 273–279.
3. Binns, F.; Hayes, R.; Hodgetts, K. J.; Saengchantara, S.
T.; Wallace, T. W.; Wallis, C. J. Tetrahedron 1996, 52,
3631–3658.