Diastereoselective synthesis of (2R,4S,5S)-(+)-5-(2,2-Dichloroacetamido)- 4-(4-nitrophenyl)-2-aryl-1,3-dioxanes

Article abstract of DOI:10.1002/jhet.5570380236

(2R,4S,5S)-(+)-5-(2,2-Dichloroacetamido)-4-(4-nitrophenyl) -2-aryl-1,3-dioxanes 3-8 were synthesized with high diastereoselectivity and good yields. The structures of acetals were determined and the configurations were confirmed by 2D-NMR (NOESY) and X-ray crystallographic analysis.

Full text of DOI:10.1002/jhet.5570380236

Mar-Apr 2001
Diastereoselective Synthesis of (2R,4S,5S)-(+)-5-(2,2-
515
Dichloroacetamido)- 4-(4-nitrophenyl)-2-aryl-1,3-dioxanes
Liu Jun, Li Jun, Yang Shaorong, Li Hua, Hu Quanyuan,
Xu Hansheng and Hu Xianming*
College of Chemistry, Wuhan University, Wuhan 430072, P.R. China
Received December 24, 1999
(2R,4S,5S)-(+)-5-(2,2-Dichloroacetamido)-4-(4-nitrophenyl)-2-aryl-1,3-dioxanes 3-8 were synthesized
with high diastereoselectivity and good yields. The structures of acetals were determined and the
configurations were confirmed by 2D-NMR (NOESY) and X-ray crystallographic analysis.
J. Heterocyclic Chem., 38, 515 (2001).
Introduction.
production process of chloramphenicol. Compound 1 is
produced with high diastereoselectivity and in good yield.
By this method, only the above specified enantiomers were
obtained along with a only small amount of polymer. The
absolute configuration of these products was determined
using 2D-NMR and X-ray crystallographic analysis.
Acetals are important in synthetic pharmaceuticals [1]
and phytopharmaceuticals [2] as intermediates or as final
products. Protection of the carbonyl group of aldehydes or
ketones can be accomplished by acetalization[3].
Asymmetric reductions of prochiral aromatic ketones in
the presence of a hydroxymonosaccharide acetal have
been described[4].
Acetals can be synthesized in a number of ways. The most
common and general approach is the acid catalyzed reaction
of alcohols with aldehydes or ketones under (continuous)
azeotropic remove of water in a Dean-Stark trap [5], or by
dehydrating agents [6]. Most chiral acetals can be
synthesized from chiral substrate [7], diastereoselective
addition [8] or catalyzed by chiral catalyst [9]. In the cases
Results and Discussion.
By analysis of the space-filling model, we predicted that
the conformations of the products would be (2R,4S,5S)
(Figure 1). For the case of 5-(2,2-dichloroacetamido)-2-(3-
nitrophenyl)-4-(4-nitrophenyl)-1,3-dioxane 6, the
structure has been confirmed by a NOESY experiment
(Figure 2) [11]. The stereochemistry of 5-(2,2-dichloro-
acetamido)-2-(4-methyloxyphenyl)-4-(4-nitrophenyl)-1,3-
dioxane 7 was established unequivocally by X-ray
crystallographic analysis (Figure 3).
that the chiral 1,3-diol possesses a C axis of symmetry,
only one diasteromer is formed because transposition of the
2
nonoxygen ligands at the acetal center leads to the same
compound. If there is no C axis, two diastereomers can be
2
formed. In acetalization reactions with chiral diols without a
C symmetry axis, the formation of one diastereomer is
2
often favoured over the formation of the other one [10].
(1S,2S)-(+)-2-Amino-1-(4-nitrophenyl)-1,3-propanediol 1
is a chiral 1,3-diol with chiral centers at the 1- and 2-posi-
Figure 1. Predicted conformation for 3-8.
tions and without a C symmetry axis. We carried out the
2
The anticipated cross-peaks between H-2 and H-4
(shown in Figure 1) are readily identified. These peaks
are denoted in the spectra with A and they clearly
demonstrate the mutual diaxial relationship between
H-2 and H-4. As to other probable conformational
relationships between H-2 and H-4: (a) eq H-2- ax H-4,
(b) ax H-2- eq H-4, (c) eq H-2- eq H-4, none of these
cross-peaks are seen in the spectrum. Although the
reaction of 1,3-diol 1 and aryl aldehydes under acidic
conditions. Here, we reported the results of diastereo-
selective synthesis and structural determination.
(2R,4S,5S)-(+)-5-(2,2-dichloroacetamido)-4-(4-nitro-
phenyl)-2-aryl-1,3-dioxanes 3-8 were obtained (Scheme 1)
from the reaction of substituted benzaldehydes and
(1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol 1,
the enantiomer that is discarded during the commercial
R = C H (3), O-HOC H (4), O-ClC H (5), m-NO C H (6), p-CH C H (7), 2-furyl (8).
6
5
6
4
6
4
2
6
4
3 6 4

516
L. Jun, L. Jun, Y. Shaorong, L. Hua, H. Quanyuan, X. Hansheng and H. Xianming
Vol. 38
Table I
Selected geometric parameters of 7 (bond lengths Å,)
Cl(1)-C(19)
O(1)-C(4)
O(5)-C(14)
N(1)-C(8)
C(1)-C(2)
C(4)-C(5)
1.765(4)
1.434(4)
1.373(5)
1.470(4)
1.530(5)
1.493(5)
Cl(2)-C(19)
O(2)-C(2)
O(5)-C(17)
N(2)-C(1)
C(1)-C(4)
1.774(5)
1.436(4)
1.446(6)
1.465(4)
1.540(5)
O(1)-C(3)
O(2)-C(3)
O(6)-C(18)
N(2)-C(18)
C(3)-C(11)
1.437(4)
1.422(4)
1.220(4)
1.342(4)
1.488(5)
Table II
Selected geometric parameters of 7 (bond angles, °)
P2
(ppm)
4.5
C(3)-O(1)-C(4)
O(4)-N(1)-C(8)
C(2)-C(1)-C(4)
O(2)-C(3)-C(11)
C(4)-C(5)-C(6)
C(3)-C(11)-(12)
O(6)-C(18)-N(2)
Cl(1)-C(19)-(18)
C(14)-O(5)-C(17)
N(2)-C(1)-C(2)
O(1)-C(3)-O(2)
O(1)-C(4)-C(5)
N(1)-C(8)-C(7)
O(5)-C(14)-C(13)
N(2)-C(18)-C(19)
111.3(2)
117.5(3)
108.0(3)
108.9(3)
121.6(3)
121.9(3)
124.3(3)
109.9(3)
117.4(4)
110.0(3)
109.6(3)
108.1(3)
117.7(3)
125.3(4)
113.8(3)
C(2)-O(2)-C(3)
C(1)-N(2)-C(18)
O(2)-C(2)-C(1)
O(1)-C(4)-C(1)
C(4)-C(5)-C(10)
C(3)-C(11)-C(16)
O(6)-C(18)-C(19)
Cl(2)-C(19)-C(18)
O(3)-N(1)-C(8)
N(2)-C(1)-C(4)
O(1)-C(3)-C(11)
C(1)-C(4)-C(5)
N(1)-C(8)-C(9)
O(5)-C(14)-C(15)
Cl(1)-C(19)-Cl(2)
112.4(3)
121.8(3)
110.0(3)
108.2(3)
119.4(3)
120.0(3)
121.9(3)
108.9(3)
118.7(3)
1110(3)
107.6(3)
113.1(3)
119.0(3)
114.4(4)
108.9(2)
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5
P1 (ppm)
Figure 2. NOESY spectrum of 6
conformational analysis of 6, we consider that its
1
absolute configuration is (2R,4S,5S). Because the H
and C-NMR spectra of all the synthesized acetals
absence of certain cross-peaks does not necessarily
prove that no interaction exists, it is likely that they
would have been if the mentioned conformational
relationship (a) to (c). Space-filling models show that
these three conformations between (a) and (c) are highly
unlikely, as a consequence of large unavoidable steric
hindrance by axial subsituents. According to the
13
resemble each other closely, we assume all these
compounds have the same configuration as that
described for 6. The result of X-ray crystallographic
analysis of 7 add more evidence for the configuration of
these acetals.
5-(2,2-Dichloroacetamido)-2-(4-methyloxyphenyl)-4-
(4-nitrophenyl)-1,3-dioxane 7, C H O N Cl (Mr =
19 18
6
2
2
441.26), crystallizes in the orthorhombic space group
P2 2 2 , with four molecules in a unit cell. Crystal data
1 1 1
are a = 12.038(1), b = 12.855(1), c = 13.010(1) Å,
3
v = 2013.3(3) Å , R = 0.043, R = 0.043, Z = 4, Dc =
f
w
3
1.456g/cm . The six-member ring is in chair form. The
two large groups, p-nitrophenyl and p-methyloxyphenyl,
are all equatorial to avoid steric hindrance, and the
2,2-dichloroacetamido group is axial. The dihedral angle
between the two phenyl rings is 108.68° (13).
According to these results, a probable mechanism for the
diastereoselective acetal formation is shown in Scheme 2.
As the hemiacetal is formed, it combines with H ;
+
followed by elimination of water to form the carbocation.
The hydroxyl in 1-position can attach the carbocation from
the up face or the down face, and (2S,4S,5S)- or
(2R,4S,5S)-acetal is formed respectively. However, the
(2R,4S,5S)-acetal is thermodynamically more stable than
that of the (2S,4S,5S)-acetal.
Figure 3. X-ray crystal structure of 7.

Mar-Apr 2001
(2R,4S,5S)-(+)-5-(2,2-Dichloroacetamido)- 4-(4-nitrophenyl)-2-aryl-1,3-dioxanes
517
EXPERIMENTAL
(2R,4S,5S)-(+)-5-(2,2-Dichloroacetamido)-2-phenyl-4-(4-nitro-
phenyl)-1,3-dioxanes (3).
The (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol
1 was obtained from the Wuhan Pharmacy Plant and purified
by recrystallization in methanol. Melting points were
measured in a XT-4 melting point measurement and are uncor-
rected. Column chromatography was carried out using silica
gel. IR spectra were recorded on a 170 SX Nicolet FT-IR
instrument and are given in cm . H and C NMR were
recorded on XL-200 spectrometer, chemical shifts were given
in ppm (internal standard tetramethylsilane) and the NOESY
spectrum was acquired on INOVA-500 spectrometer. Mass
spectra were performed on a ZAB 3F-HF mass spectrometer.
Optical rotation values were obtained using a WZZ-2A
polarimeter. Elemental Analysis were determined by 240B
Elemental Autoanalyzer. X-ray crystal data was collected by
Nonius MAC DIP-2030K diffractometer.
Compound 3 was obtained in 65% yield, mp 102.7-103 °C;
21
[α] +28.6, ms (m/z): 409(M-1), 394, 380, 327, 305, 259, 241,
D
176, 153; ir (potassium bromide): 3303(NH), 1675(C=O), 1605,
-1
1
1520, 1348(NO ), 1100(C-O-C) cm ; H nmr (acetone-d ): δ
2
6
4.20 (m, 1, H5), 4.45 (m, 2H, H6), 5.57 (s, 1H, H4), 5.92 (s, 1H,
H2), 6.23(s, 1H, CHCl ), 7.36-7.58 (m, 5H, Ar), 7.60-8.20(m,
2
13
-1
1
13
5H, Ar & NH); C nmr (deuteriochloroform): δ 47.6, 65.9, 70.6,
78.5, 101.8, 123.5(2C), 125.9 (2C), 126.5(2C), 128.5(2C), 129.5,
136.9, 144.2, 147.5, 163.6.
Anal. Calcd. for C H N O Cl (411.24): C, 52.57; H, 3.92;
18 16
2
5
2
N, 6.81. Found: C, 52.55; H,3.90; N, 6.80.
(2R,4S,5S)-(+)-5-(2,2-Dichloroacetamido)-2-(2-hydroxyphenyl)-
4-(4-nitrophenyl)-1,3-dioxanes (4).
Compound 4 was obtained in 72% yield, mp 101-102.5 °C;
21
D
[α] +38.0, ms (m/z): 426(M), 390, 305, 291, 275, 241, 221, 191,
170, 153; ir (potassium bromide): 3415(OH), 3308(NH),
(1S,2S)-2-dichloroacetamido-1-(4-nitrophenyl)-1,3-propanediol (2).
-1 1
1677(C=O), 1605, 1521, 1349(NO ), 1088(C-O-C) cm ; H nmr
2
A mixture of 30 g (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-
propanediol 1, 16.7 ml methyl dichloroacetate and 50 ml
methanol was heated to 70 °C and kept for 2 hours, cooled to
collect precipitate, followed by recrystallization of the reaction
product 2 from methanol. Yield 44.7 g (97.8 %) of light yellow
crystal. mp 149-150 °C, lit. [12] mp 150 °C.
(acetone-d ): δ 4.20 (m, 1H, H5), 4.52 (m, 2H, H6), 5.58 (s, 1H,
6
H4), 6.18 (s, 1H, H2), 6.24 (s, 1H, CHCl ), 6.92-7.28
2
13
(m, 4H, Ar), 7.64-8.20 (m, 5H, Ar & NH), 8.38 (s, 1H, OH);
C
nmr (deuteriochloroform): δ 47.8, 65.9, 70.8, 79.0, 102.2, 117.4,
120.4, 121.4, 123.8(2C), 126.5(2C), 127.6, 131.2, 143.5, 147.8,
154.6, 163.9.
Anal. Calcd. for C H N O Cl (427.24): C, 50.60; H, 3.77;
18 16
2
6
2
General Procedure for the Preparation of (2R,4S,5S)-(+)-2-Aryl-
5-(2,2-dichloroacetamido)-4-(4-nitrophenyl)-1,3-dioxanes 3-8.
N, 6.56. Found: C, 50.60; H, 3.77; N, 6.60.
(2R,4S,5S)-(+)-2-(2-Chlorophenyl)-5-(2,2-dichloroacetamido)-
4-(4-nitrophenyl)-1,3-dioxanes (5).
This procedure is based on literature methods [13]. A mixture
of 2 (3 g, 9.2 mmol), aryl aldehyde (19 mmol) and p-toluene-
sulfonic acid (0.06 g) in dry benzene (200 ml) was refluxed and
the water removed by continuous azeotropic distillation
(3 hours). The solvent was distillated under vacuum and the
residue was taken up in ether. The ethereal extract was washed
Compound 5 was obtained in 70% yield, mp 79.5-79.9 °C;
21
D
[α] +31.0, ms (m/z): 443(M-1), 428, 414, 361, 330, 317, 305,
207, 153; ir (potassium bromide): 3296(NH), 1674(C=O), 1604,
1
1519, 1349(NO ), 1100(C-O-C); H nmr (acetone-d ): δ 4.20 (m,
2
6
1, H5), 4.51 (m, 2H, H6), 5.65 (s, 1H, H4), 6.16 (s, 1H, H2), 6.22
with cold sodium carbonate (Na CO ) (50 ml, 5%) solution,
2
3
(s, 1H, CHCl ), 7.40-7.86 (m, 4H, Ar), 7.66-8.18 (m, 5H, Ar &
2
water and saturated brine (2 × 50 ml) respectively, then dried
13
NH); C nmr (deuteriochloroform): δ 47.5, 66.0, 70.9, 79.148,
100.1, 123.5(2C), 126.6(2C), 127.1, 127.8, 130.1, 130.8, 132.8,
134.2, 143.9, 147.6, 163.6.
with sodium sulfate (Na SO ) over night. The solution was
2
4
filtered and concentrated. The residue was recrystallized from
benzene-petroleum ether (1:2) or purified by column-
chromatogram.
Anal. Calcd. for C H N O Cl (445.69): C, 48.51; H, 3.39;
18 15
2
5
3
N, 6.29. Found: C,48.50; H,3.41; N, 6.32.

518
L. Jun, L. Jun, Y. Shaorong, L. Hua, H. Quanyuan, X. Hansheng and H. Xianming
Vol. 38
(2R,4S,5S)-(+)-(2,2-Dichloroacetamido)-2-(3-nitrophenyl)-4-(4-
nitrophenyl)-1,3-dioxanes (6).
Anal. Calcd. for C H N O Cl (401.20): C, 47.90; H, 3.52;
16 14 2 6 2
N, 6.98. Found: C, 47.87; H, 3.51; N, 6.99.
Compound 6 was obtained in 75% yield; mp 178-179°C;
Acknowledgements.
21
[α] +21.2; ms (m/z): 454(M-1), 439, 425, 409, 391, 372, 355,
D
This work was supported by the fundation of China National
Education Committee, the science and technology fundation of
Wuhan city and Wuhan Red Heart K (Group) Co. Ltd.; We are
grateful to Prof. Chui Yuxing (Beijing Medical University, NMR
Lab) and Prof. Zheng Qitai and Prof. Lu Ming (Beijing Institute of
Pharmaceutical Chemistry, X-ray Lab) for technical assistance.
341, 325, 304, 221, 153; ir (potassium bromide): 3359(NH),
1
1714(C=O), 1603, 1521, 1348(NO ), 1106(C-O-C); H nmr
2
(acetone-d ): δ 4.26 (m, 1H, H5), 4.60 (m, 2H, H6), 5.66 (s, 1H,
6
H4), 6.09 (s, 1H, H2), 6.16 (s, 1H, CHCl ), 7.68-8.00 (m, 4H,
2
13
Ar), 7.80-8.38 (m, 5H, Ar&NH); C nmr (deuteriochloroform):
δ 47.6, 65.9, 70.8, 79.2, 100.1, 121.2, 123.6(2C), 124.3, 126.6(2),
129.6, 132.1, 138.9, 143.7, 147.6, 148.1, 163.7.
REFERENCES AND NOTES
Anal. Calcd. for C H N O Cl (456.24): C, 47.39; H, 3.31;
18 15
3
7
2
N, 9.21. Found: C, 47.40; H, 3.31; N, 9.27.
[1] J. Wolinski, A. Czerwinska, Acta Pol. Pharm., 33, 696(1976)
K. A. M. Walker, U.S. Patent, 4,150,153
[2] H. Moeller, J. Conrad, C. Gloxhuber, H. J. Thimm, German
Patent(DOS), 2,533,0486, 195071e (1977).
[3a] E. J. Corey, E. J. Trybulski, J. W. Suggs, Tetrahedron Lett.,
4577 (1976); [b] E. J. Corey, R. A. Ruden, J. Org. Chem., 38, 834 (1973).
[c] C. E. Loader, H. J. Anderson, Synthesis, 295. (1978); [d] E. J. Corey,
J. W. Suggs, Tetrahedron Lett., 3775 (1975).
[4a] N. Yamazaki, J. Chem. Soc. Chem. Commun., 807, (1979);
[b] N. Yamazaki, J. Org. Chem., 44, 1720 (1979).
(2R,4S,5S)-(+)-5-(2,2-Dichloroacetamido)-2-(4-methyl-
oxyphenyl)-4-(4-nitrophenyl)-1,3-dioxanes (7).
Compound 7 was obtained in 85% yield; mp 181-181.5 °C;
21
D
[α] +25.7; ms (m/z): 440, 404, 368, 357, 289, 274, 256, 236,
191, 153; ir (potassium bromide): 3399(NH), 1705(C=O), 1614,
1
1518, 1354(NO ), 1245, 1099(C-O-C); H nmr (acetone-d ): δ
2
6
3.80(s, 3H, CH ), 4.20(m, 1H, H5), 4.44 (m, 2H, H6), 5.55
3
(s, 1H, H4), 5.90 (s, 1H, H2), 6.25 (s, 1H, CHCl ), 7.00-7.50
2
13
(m, 4H, Ar), 7.70-8.20 (m, 5H, Ar & NH); C-NMR (deuterio-
[5] L. C. Anderson, H. W. Pinnick, J. Org. Chem., 43, 3417
(1978).
chloroform): δ 47.6, 55.4, 65.9, 70.6, 78.9, 101.9, 113.9(2C),
123.5(2C), 126.6(2C), 127.3(2C), 129.4, 144.2, 147.6, 160.5,
163.6.
[6a] D. P. Roelofsen, H. Van. Bekkum, Synthesis, 419 (1972);
[b] V. I. Stenberg, D. A. Kubik, J. Org. Chem., 39, 2815 (1974).
[7a] N. Maezaki, M. Soejima, M. Takeda A Sakamoto, Y.
Matsumori, T. Tanaka and C. Iwata, Tetrahedron, 52, 6527 (1996); [b] R.
Sterzycki, Synthesis, 724, (1979); [c] T. H. Chan, M. A. Brook, T. Chaly,
Synthesis, 203, (1983); [d] X. M. Hu, R. M. Kellogg, Trav. Chim. Pays-
Bas, (1996), 115, 407
[8] P. A. Evans and L. T. Garber, Tetrahedron Lett., 37, 2927
(1996).
[9] H. Brunner and M. Prommesberger, Tetrahedron: Asymmetry,
9, 3231 (1998).
Anal. Calcd. for C H N O Cl (441.27): C, 51.72; H, 4.11;
19 18
2
6
2
N, 6.35. Found: C,51.70; H,4.11; N, 6.36.
(2R,4S,5S)-(+)-5-(2,2-dichloroacetamido)-2-furyl-4-(4-nitro-
phenyl)-1,3-dioxanes (8).
Compoud 8 was obtained in 70% yield; mp 74.5-75 °C;
21
D
[α] +26.3 (c 0.0092g/ml, acetic ester); ir (potassium
bromide): 3351(NH), 1689(C=O), 1605, 1522, 1351(NO ),
2
[10a] A. Alexakis and P. Mangeney, Tetrahedron: Asymmetry, 1,
477 (1990); [b] J. K. Whitesell, Chem. Rev., 89, 1581 (1989).
[11a] E. L. Eliel and M. C. Knoeber, J. Am. Chem. Soc., 90, 3444
(1968); 3444. [b] E. L. Eliel, Angew. Chem. Internat. Edit., 11, 739
(1972).
1245, 1096(C-O-C); ms (m/z):401, 317, 305, 274, 249, 221,
213, 164, 153; H nmr (deuteriochloroform): 4.28 (m, 2H,
H6), 4.44 (m, 1H, H5), 5.26 (s, 1H, H4), 5.64 (s, 1H, H2), 5.85
1
(s, 1H, CHCl ), 6.40 (m, 1H, -CH=CH-O-), 6.53(d, 1H, =
2
CH-), 7.19(d, 1H, =CH-O-), 7.44-8.20 (m, 5H, Ar & NH);
[12] K. Jan, N. Jindrich M. Miluse and J. Jiri, Czech CS 225, 278;
Chem. Abstr., 104, 109258g (1986).
13
C-nmr (deuteriochloroform): δ 47.6, 65.9, 70.7, 78.9, 108.5,
110.5, 123.5(2C), 126.6(2C), 128.3, 143.1, 143.8, 147.6,
149.4, 163.7.
[13] P. Ramaiah and A. S. Pao, Organic Preparations and
Procedures Int., 19, 173 (1987).