Conformational analysis and selective hydrolysis of 2,5-disubstituted-1,3-dioxane-2-carboxylic acid esters

Article abstract of DOI:10.1016/j.tetlet.2006.12.117

5-Alkyl-2-methyl-2-carbomethoxy-1,3-dioxanes were found to have a cis preferential configuration in the equilibrium state, and the ester hydrolysis rate of the trans-isomers was faster than that of the cis-isomers. Conformational analysis and charge calculation of the carbomethoxy group in both dioxanes elucidated this selectivity.

Full text of DOI:10.1016/j.tetlet.2006.12.117

Tetrahedron Letters 48 (2007) 1443–1446
Conformational analysis and selective hydrolysis of
,5-disubstituted-1,3-dioxane-2-carboxylic acid esters
2
a,
b
a
*
Tetsuji Harabe, Takatoshi Matsumoto and Takayuki Shioiri
a
Graduate School of Environmental and Human Sciences, Meijo University, Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
Institute of Multidisciplinary Research of Advanced Materials, Tohoku University, 2-1-1, Katahira, Aoba, Sendai 980-8577, Japan
b
Received 6 November 2006; revised 14 December 2006; accepted 15 December 2006
Available online 23 December 2006
Abstract—5-Alkyl-2-methyl-2-carbomethoxy-1,3-dioxanes were found to have a cis preferential configuration in the equilibrium
state, and the ester hydrolysis rate of the trans-isomers was faster than that of the cis-isomers. Conformational analysis and charge
calculation of the carbomethoxy group in both dioxanes elucidated this selectivity.
Ó 2007 Elsevier Ltd. All rights reserved.
Axial preference of the carboalkoxy group in various
-carboalkoxy-1,3-dioxane compounds is now well
this type of 1,3-dioxanes, the substituent effect of 5-posi-
tion on cis/trans ratio as well as on the reactivity of the
carboalkoxy group is an interesting subject to attain a
2
1
recognized as an anomeric effect. For example, 2,4-di-
methyl-2-carboethoxy-1,3-dioxane can open the ring
and equilibrate the isomers A and E in the presence of
acid with axial preference of the 2-carboethoxy group
due to the large free energy difference between the
3
,4
selective synthesis of some challenging chemicals.
Four kinds of dioxane compounds 1a–d were straight-
forwardly obtained from diols 3a–d, which were pre-
pared by reduction of the corresponding diethyl
0
2
isomers (DG > 3 kcal/mol), as shown in Figure 1.
malonates 2 with LiCl–NaBH , as shown in Scheme 1.
4
In the meantime, 2,5-disubstituted-2-carbomethoxy-1,3-
dioxanes can also have cis and trans-isomers 1, though
the substituent effect of these compounds on the prefer-
Conversion of the diols 3 into the dioxanes 1 was accom-
plished by the reaction with 1 equiv of methyl pyruvate
in the presence of 1 equiv of BF ÆEt O. This reaction
3
2
3
ence of their isomers is not well known. In the case of
proceeded under 15 °C to give a 1/1 ratio of the cis/trans
mixture, then the ratio reached equilibrium at 25 °C.
The obtained dioxanes 1a–d were found in preference
to the cis-isomers within the ratio of 2.1–6.8. The results
CO2Et
Me
Me
H+
Me
Me
5
O
O
O
O
of the conformational analysis using RHF/STO-3G
CO Et
2
were in good agreement with those of the experiments
(Table 1).
A
E
The cis and trans configurations of the dioxane deriva-
O
O
O
tives 1 together with their conformations were deter-
R
CO2Me
Me
H
CO2Me
Me
1
mined by the
H
NMR spectral studies. The
H
R
O
observation of a higher d value (ppm) of the C -proton
5
cis-1
and larger coupling constant between the C4,6-axial pro-
trans-1
tons and C -proton of the cis-isomer shows that the
5
Figure 1. 2-Carboalkoxy-2,4- and 2,5-disubstituted dioxanes.
C -proton of the cis-isomer is axial and that of the
5
trans-isomer is equatorial (Table 2). To ensure the assign-
ments of the cis/trans configurations, we analyzed the
alcohol derivatives cis-4 and trans-4 obtained by the
Keywords: 1,3-Dioxane derivative; Conformational analysis; Selective
hydrolysis; Charge calculation.
*
Corresponding author. Tel.: +81 75 321 9090; fax: +81 75 321
039; e-mail: t.harabe@po.nippon-shinyaku.co.jp
NaBH –LiCl reduction of cis-1 and trans-1, respectively.
4
9
The C -protons of both alcohols can be identified as the
5
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.117

1444
T. Harabe et al. / Tetrahedron Letters 48 (2007) 1443–1446
O
R
CO Me
2
MeCOCO2Me
BF3•Et2O
H
Me
O
OH
OH
CO2Et
CO2Et
LiCl, NaBH4
R
R
(cis) 1a-1d
1a: 48%
1b: 79%
1c: 80%
+
H
H
THF, EtOH
toluene
O
1
d: 79%
H
CO2Me
Me
O
R=
R
3
a: 86%
2
2
2
2
a: Et
3
3
3
b: 84%
c: 99%
d: 45%
b: n-Bu
c: Bn
(trans) 1a-1d
d: tert-Bu
Scheme 1.
Table 1. Observed and calculated results of cis/trans ratio of 1,3-dioxane derivatives 1
a
Dioxane
R
Experimental ratio
Calculated ratio
(cis/trans)
DEExperiment
(kcal/mol)
DECalculation
(kcal/mol)
(
cis/trans)
b
1
1
1
1
a
b
c
Et
n-Bu
Bn
3.7
3.7
2.1
6.8
4.1
4.3
2.0
6.0
0.775
0.775
0.440
1.062
0.840
0.870
0.420
1.060
b
b
c
d
tert-Bu
a
b
c
DECalculation = DEtrans À DEcis
.
Determined by GC.
1
Determined by H NMR.
1
Table 2. H NMR spectral data of 1a–d
CO2Me
CO2Me
a
Dioxane
d (ppm)
O
O
Et
He
Me
Me
4
,6-Hequatorial
4,6-Haxial
5-H
O
O
Ha
Et
b
1
1
1
1
a
b
c
Cis
3.97 dd
11.8, 4.4)
3.96 dd
3.39 dd
(11.8, 11.8)
3.81 dd
1.94m
cis-1a
trans-1a
d
(
(
c
c
c
b
Trans
1.29m
12.0, 3.3)
(12.0, 2.4)
b
Cis
3.95 dd
10.9, 4.8)
3.96 dd
3.39 dd
(10.9, 10.9)
3.79 dd
2.00m
1.34m
H
(
(
H
H
H
OH
Me
H
Ha
Ha
Trans
4
4
He
Et
Ha
2
He
Ha
10.8, 2.0)
(10.8, 2.4)
2
O
O
Et
2
CH OH
b
5
6 O
Cis
3.90 dd
12.2, 4.4)
3.94 dd
3.49 dd
(12.2, 12.2)
3.78 dd
2.35m
1.61m
5
6 O
H
He
Ha
e
Ha
(
(
Trans
cis-4
trans-4
10.5, 2.7)
(10.5, 1.5)
b
Figure 2. NOE correlations of cis-4 and trans-4.
d
Cis
4.02 dd
10.6, 4.4)
4.03 dd
3.64 dd
(11.0, 10.6)
3.92 dd
1.82m
1.38m
(
(
Trans
12.2, 4.8)
(12.2, 4.8)
lysis of the cis and trans mixture to obtain pure cis-
isomer. The initial hydrolysis attempts seemed to be
promising and detailed studies revealed that trans-iso-
mers were hydrolyzed with base approximately ten-
times faster than cis-isomers based on pseudo first order
kinetics. 1,3-Dioxanes 1a–d obtained as a mixture of cis/
trans-isomers were subjected to the selective hydrolysis
of trans-isomers to give rise to over 90% diastereomeric
excess of cis esters (Scheme 2, Fig. 3).
a
Each isomer was separated from
chromatography.
Measured by 200 MHz in CDCl .
3
Measured by 300 MHz in CDCl .
3
J Values (in Hz) in parentheses.
a 1/1 mixture by column
b
c
d
axial position on the basis of their large diaxial coupling
constants (cis-4: J = 7.5 Hz, trans-4: J = 10.4 Hz) and
the strong NOE from the C4,6-equatorial protons. They
The steric effect on the hydrolysis of both isomers can-
not explain the faster reaction rate of the trans-isomer,
because both isomers are dominated by the axial confor-
mation based on conformational analyses. Another pos-
sible factor that affects the different hydrolysis rates is
the charge difference between the carbonyl carbons of
the cis- and trans-forms (Fig. 4). The charge was calcu-
are also supported by the strong NOE between the C4,6
axial protons and 2-hydroxymethyl protons in cis-4 and
-methyl protons in trans-4, respectively (Fig. 2).
-
2
Due to the difficulty to attain high cis-ratio of 1 in the
ring formation reaction, we challenged selective hydro-

T. Harabe et al. / Tetrahedron Letters 48 (2007) 1443–1446
1445
Table 3. Distribution of each conformer of 1 (unit: %)
Dioxane Cis series Trans series
cis-A cis-E cis-TB trans-A trans-E trans-TB
O
O
O
O
H
CO Me
2
R
CO2Me
Me
R
Me
H
(
cis) 1a-1d
(trans) 1a-1d
1a
b
74.39 0.79
75.24 0.66
61.89 1.50
77.07 0.36
0.50
0.50
0.47
2.15
21.73
20.94
34.19
16.71
2.19
2.22
1.64
2.14
0.41
0.43
0.32
1.57
1
OH-
1c
1
kcis
ktrans
OH-
<
d
O
O
O
H
CO H
2
R
CO2H
Me
R
Me
O
Table 4. Weighted charge on the carbon atom in the carbonyl group
of 1
H
Scheme 2.
Dioxane
Cis series
Trans series
cis-A cis-E cis-TB trans-A trans-E trans-TB
1
1
1
1
a
b
c
0.843 0.671 0.694
0.835 0.684 0.706
0.836 0.684 0.713
0.842 0.725 0.668
0.958
0.960
0.976
0.977
0.747
0.759
0.796
0.766
0.757
0.764
0.767
0.774
1
00
9
8
7
6
5
4
3
0
0
0
0
0
0
0
d
the faster hydrolysis of the trans-isomers than that of
the cis-isomers.
In conclusion, 1,3-dioxane derivatives 1a–d were ob-
tained as a cis and trans mixture with preferential equi-
librium of the cis-isomer. The ratio from the
experiments was in agreement with that from the con-
formational analysis. Selective hydrolysis of the cis
and trans mixture combined with the preferential equi-
librium to cis-isomer gave the over 90% de of cis-isomer.
We believe the faster hydrolysis rate of the trans-isomers
is caused by the higher charge and larger population of
trans-A. Work is underway to elucidate the selective
hydrolysis of 1,3-dioxane derivatives.
1
d
1b 1a 1c
1
00
90
80
70
60
50
Yield (%)
Figure 3. Diastereomeric excess (de) of the cis esters versus yield of the
remaining esters after the hydrolysis of 1 by treatment with aq NaOH
in MeOH at 298 K [1 (100 mg) in MeOH (1 ml)].
CO Me
CO Me
Acknowledgement
2
2
O
Me
O
Me
R
This work was financially supported in part by a Grant-
in-Aid for Scientific Research from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan.
O
O
cis-A
R
trans-A
Me
Me
O
CO Me
O
CO Me
2
2
R
O
O
References and notes
R
cis-E
trans-E
1
. (a) Tschierske, C.; Kohler, H.; Zaschke, H.; Kleinpeter, E.
Tetrahedron 1989, 45, 6987–6998; See also: (b) Kirby, A. J.
The Anomeric Effect and Related Stereoelectronic Effects at
Oxygen; Springer: New York, 1983; (c) Mishnev, A. F.;
Bleidelis, Y. Y.; Liepin’sh, E. E.; Ramzaeva, N. P.;
Goncharova, I. N. Chem. Heterocycl. Compd. 1979, 15,
R
O
O
CO2Me
Me
R
O
Me
O
CO2Me
cis-TB
trans-TB
7
98–804; (d) Denmark, S. E.; Almstead, N. G. J. Am.
Chem. Soc. 1991, 113, 8089–8110.
Figure 4.
2
3
4
. Bailey, W. F.; Eliel, L. E. J. Am. Chem. Soc. 1974, 96,
1
798–1806.
. Garbi, A.; Mina, J. G.; Steel, P. G.; Longstaff, T.; Vile, S.
Tetrahedron Lett. 2005, 46, 7175–7178.
. Solomom, D.; Kitov, P. I.; Paszkiewicz, E.; Grant, G. A.;
Sadowska, J. M.; Bundle, D. R. Org. Lett. 2005, 7, 4369–
lated using the RHF/STO-3G basis set, which can be
applied to larger molecules with an efficient computa-
tional time cost. The distribution of each conformation
and charges on the carbon in the carbonyl groups of
4
372.
both cis-1 and trans-1 are summarized in Tables 3 and
5
. All the conformational isomers of the dioxanes 1 gener-
6
4
. The charge order was found to be as follows: trans-
7
ated by CONFLEX 3.6/MM3 (92) as conformational
A
group > cis-A group > trans-E and trans-TB
searching program were optimized by Gaussian 98
8
9
group > cis-E and cis-TB group. This clearly explains
Rev.A.11. 1 RHF/STO-3G.

1446
T. Harabe et al. / Tetrahedron Letters 48 (2007) 1443–1446
6
. The charges on the carbon in the carbonyl group were
calculated using the electrostatic potential Mertz–Singh–
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A.
G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,
A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople,
J. A. Gaussian 98, Revision A.11.1.; Gaussian: Pittsburgh,
PA, 2001.
1
0
8
Kollman method in Gaussian 98 Rev.A.11.1 RHF/
9
STO-3G.
7
. (a) Goto, H.; Osawa, E. J. Chem. Soc., Perkin Trans. 2
1993, 187–198; (b) Goto, H.; Osawa, E. J. Mol. Struct.,
(THEOCHEM) 1993, 285, 157–168; (c) Goto, H.; Osawa,
E. Tetrahedron Lett. 1992, 33, 1343–1346; (d) Goto, H.;
Osawa, E. J. Am. Chem. Soc. 1989, 111, 8950–8951.
. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.;
Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.;
Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.;
Cui, Q.; Morokuma, K.; Salvador, P.; Dannenberg, J. J.;
8
9. (a) Hehre, W. J.; Stewart, R. F.; Pople, J. A. J. Chem.
Phys. 1969, 51, 2657–2664; (b) Collins, J. B.; Schleyer, P.
v. R.; Binkley, J. S.; Pople, J. A. J. Chem. Phys. 1976, 64,
5142–5151.
10. (a) Besler, B. H.; Mertz, K. M., Jr.; Kollman, P. A.
J. Comp. Chem. 1990, 11, 431–439; (b) Singh, U. C.;
Kollman, P. A. J. Comp. Chem. 1984, 5, 129–145.