Diastereoselective synthesis of protected 2,3-dihydroxynitriles from 2- hydroxy acids

Article abstract of DOI:10.1055/s-2000-6259

The DIBAL-H reduction of dioxolanones 2 prepared from 2-hydroxy acids followed by addition of acetone cyanohydrin affords the syn 2,3- dihydroxynitriles in high enantiomerical purities.

Full text of DOI:10.1055/s-2000-6259

220
SHORT PAPER
Diastereoselective Synthesis of Protected 2,3-Dihydroxynitriles from
2-Hydroxy Acids
Pierre Hutin, Marc Larchevêque*
Laboratoire de Synthèse Organique, UMR 7573 du CNRS, ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Fax +33(1)43257975; E-mail: larchm@ext.jussieu.fr
Received 27 July 1999; revised 16 October 1999
the free diols and not as the protected acetonide after basic
Abstract: The DIBAL-H reduction of dioxolanones 2 prepared
hydrolysis.
from 2-hydroxy acids followed by addition of acetone cyanohydrin
affords the syn 2,3-dihydroxynitriles in high enantiomerical puri-
ties.
We then decided to react directly on the aluminate result-
ing from the reduction of the dioxolanone by DIBAL-H.
Key words: Grignard compounds, nitrile, diastereoselective reduc- Using acetone cyanohydrin as a cyanating reagent, we
tion
succeeded in obtaining the dihydroxynitriles in good
yields, increasing the syn/anti ratio up to 80/20. We ob-
served also that the rate of the reaction was greatly en-
hanced by addition of a small amount of potassium
cyanide. However, due to the excess of cyanohydrin,
these dihydroxynitriles were difficult to purify. Thus, they
were protected again as acetonides using 2,2-dimethoxy-
propane and a catalytic amount of p-toluenesulfonic acid
Optically active cyanohydrins are an important class of
compounds in organic synthesis. It is a well established
source of 2-amino alcohols, which are useful chiral build-
ing blocks for biologically active compounds.1 In recent
years, a great number of procedures were developed in or-
der to access these compounds in an optically active
form.2 In contrast, the related 2,3-dihydroxynitriles are
more difficult to synthesize. The asymmetric dihydroxy-
lation is not available in this case,3 and they are generally
prepared by cyanation of protected a-hydroxy aldehydes.4
We report here, the synthesis of dihydroxynitriles in good
diastereoselectivity and high enantiomerical purities from
2-hydroxy acids.
Optically active 2-hydroxy acids may be easily prepared
by nitrous deamination of a-amino acids.5 Alternatively,
they could be isolated in nearly quantitative yield without
racemisation by aqueous lithium hydroxide hydrolysis of
a-hydroxy esters.6 When they are reacted with 2,2-
dimethoxypropane, the corresponding 1,3-dioxolan-4-
ones 2 are isolated in good yields. In analogy with the cy-
anation of 3-alkoxylactam that we have previously de-
scribed,7 we thought that it should be possible to reduce
compounds 2 to lactols and to react them with an appro-
priate cyanation agent. In a first attempt, compound 2a
was reacted with DIBAL-H in toluene at −60 °C. After
hydrolysis with 5M aqueous potassium cyanide, the 2,3-
dihydroxynitrile was isolated in a 1/1 mixture of syn- and
anti- isomers. Then, we isolated the hemiacetal resulting
from the acid hydrolysis of the aluminium salt 3 and stud-
ied its reaction with trimethylsilylcyanide in the presence
of a Lewis acid such as TiCl4 or SnCl4. Yields were rather
disappointing; the best (49%) was obtained with zinc io-
dide in CH2Cl2 and the two diastereomers were isolated in
a 67/33 ratio. By operating with tin tetrachloride in dichlo-
romethane at −78 °C, a diastereomeric excess of 0.7 was
obtained but the chemical yield was only 28%. The same
result was observed after transformation of the hemiacetal
hydroxyl moiety into a better leaving group such as a ben-
zoate. Moreover, in all cases the nitriles were isolated as
Product
2
R
4 / 5
Yield %
(4 + 5)
4 ee%
a
b
c
(CH3)2CH
(CH3)2CH-CH2
C6H5
72 / 28
70 / 30
80 / 20
70 / 30
69
61a
79
76
74
98
99
99
99
98
d
e
C6H5-CH2
n-C4H9-C∫C-CH2 69 / 31
a4-cyano-4-isobutyl-2,2-dimethyl-1,3-dioxolane was also isolated in
20% yield.
Scheme
Synthesis 2000, No. 2, 220–222 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Diastereoselective Synthesis of Protected 2,3-Dihydroxynitriles from 2-Hydroxy Acids
Dioxolanones 2a-e; General Procedure
221
(PTSA) to give after chromatography on silica gel the
pure syn- or anti-2,3-dialkoxynitriles. The syn- and anti-
configurations were assigned by 1H NMR according to the
observation previously reported.8 In all cases the differ-
ence of chemical shift between the two methyl groups of
the acetonide is weaker for the syn compound (Dd ppm £
0.06) than for the anti compound (Dd ppm ≥ 0.22). The
enantiomerical purities were measured on the diols after
transformation to the bis trifluoroacetate and were found
in all cases to be better than 96%.
The hydroxy acids 1 (0.1 mol) and 2,2-dimethoxypropane (0.12
mol, 1.2 equiv) were dissolved in benzene (100 mL) and refluxed
for 4h in a Dean−Stark apparatus. After elimination of the MeOH,
the residual mixture was evaporated in vacuo and purified by liquid
chromatography on a silica gel column (Table 1).
Protected Dihydroxynitriles 4 and 5(a-e); General Procedure
Compounds 2 (2 mmol) were dissolved in anhyd toluene (10 mL)
and cooled to −70 °C. A solution of 1.5M DIBAL-H in toluene (2.2
mmol, 1.1 equiv) was slowly added and the solution was stirred for
2h at the same temperature. Acetone cyanohydrin (340 mg, 4 mmol,
2 equiv) and potassium cyanide (130 mg, 2 mmol, 1 equiv) were se-
quentially added and the mixture was warmed up to 25 °C under
vigorous stirring. After stirring for 2 h at r.t., 1N HCl (10 mL, 10
mmol) was added and the mixture was stirred for 1 h before extract-
ing with EtOAc. The organic layer was then dried (MgSO4) and
concentrated under reduced pressure. The crude mixture was dis-
solved in acetone (15 mL) and reacted for 16 h at 20 °C with
dimethoxypropane (4 mmol, 2 equiv, 490 ml) in the presence of a
catalytic amount of p-toluenesulfonic acid (30 mg). The acetone
was then removed under reduced pressure and the residual mixture
was hydrolysed with a soln of sat. NaHCO3 (10 mL) and extracted
with Et2O. The organic layer was dried (MgSO4) and concentrated
under reduced pressure to give a mixture of 4 and 5 which were sep-
arated by chromatography on a silica gel column (Table 2).
Products were purified by distillation or by medium pressure liquid
chromatography on a Jobin−Yvon Modulprep (Kieselgel 60H Mer-
ck) or by flash chromatography (Kieselgel 60 Merck: 230−400
mesh, solvent: cyclohexane/EtOAc) and analyzed by VPC (BP5, 25
m capillary column) or by TLC (silica gel 60F254). Optical rotations
were measured on a Perkin−Elmer 141 polarimeter. NMR spectra
were recorded on a Bruker AC at 200 MHz for 1H and 50 MHz for
13C NMR. CDCl3 was used as solvent with TMS as internal stan-
dard. IR spectra were recorded on a Perkin−Elmer 599 spectrome-
ter. Mass spectra were recorded on a NER MAG R10.10C. The
enantiomeric excesses were measured by GC after derivatization of
the dihydroxynitriles (CH2Cl2, (CF3CO)2O, 100 °C, 30 mn) on a
25m Chirasil-D-Val column (Chrompack).
Table 1 Dioxolanones 2 Prepared
Products
2
Yield
(%)
[a]2D0
(c, CHCl3)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3)
d
MS
m/z (%)
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(R)-2e
75
89
83
89
83
− 8.2
0.98 (d, 3 H, J = 6.8, CH3),
1.04 (d, 3 H, J = 6.8, CH3),
1.54 and 1.60 (s, 3 H, CH3),
2.15 (m, 1 H, CH),
16.3 (CH3), 18.3 (CH3),
25.8 (CH2), 26.6 (CH3),
29.9 (CH3), 78.4 (CH)
110.0 (C), 172.5 (C=O)
158 (0.5), 149 (39),
104 (15), 91 (33), 86
(29), 65 (41), 57 (62),
43 (100)
(3.58)a
Lit: − 15.4 (neat)
4.25 (d, 1 H, J = 3.8, CH-O)
− 9.0
0.94 (d, 3 H, J = 6.8, CH3),
0.95 (d, 3 H, J = 6.9, CH3),
1.56 (s, 3 H), 1.62 (s, 34)
1.5−1.9 (m, 3 H, CH and CH2),
4.38 (dd, 1 H, J = 4.1, 9.0, CH-O),
21.8 (CH3), 23.0 (CH3),
25.0 (CH3), 25.8 (CH3)
27.5 (CH), 40.8 (CH2)
72.8 (CH), 110.5 (C),
173.9 (C=O)
172 (0.5), 157 (6),
128 (10), 114 (9),
85 (43), 43 (100)
(5.54)
Lit9: − 9.9 (neat)
+ 56.2
1.67 (s, 3 H, CH3), 1.72 (s, 3 H, CH3)
5.41 (s, 1 H, CH), 7.3−7.5 (m, 5 H, C6H5)
26.1 (CH3), 27.2 (CH3),
75.9 (CH), 110.9 (C),
126.5(CH), 128.7 (CH),
128.9 (CH), 132.5 (C),
171.4 (C=O)
192 (2), 177 (2)
148 (96), 133 (20),
105 (52), 90 (100),
77 (54), 43 (86)
(2.11)b
Lit9: + 41
(2.0, CCl4)
−53.3
1.37 (s, 3 H, CH3), 1.51 (s, 3 H, CH3),
3.04 (dd, 1 H, J = 14.5, 6.4, CH2),
4.66 (dd, 1 H, J = 6.4, 4.2, CH-O),
7.2−7.4 (m, 5 H, Ph)
126.0 (CH3), 26.8 (CH3),
37.5 (CH2), 74.9 (CH),
110.7 (C), 126.9 (CH),
128.3 (CH), 129.7 (CH),
135.7 (C), 172.3 (C=O)
206 (11), 148 (10),
104 (6), 91 (100),
43 (43)
(0.82)
Lit10: − 51.7
(0.97, CHCl3)
− 16.4
0.92 (d, 3 H, J = 6.7, CH3),
1.40 (m, 4 H, CH2),
1.57 and 1.67 (s, 3H, CH3),
2.13 (m, 2 H, CH2), 2.71 (m, 2 H, CH2),
4.50 (t, 1 H, J = 2.4, CH-O)
13.4 (CH3), 18.2 (CH2),
21.7 and 22.4 (CH2),
26.2 and 26.9 (CH3),
30.7 (CH), 73.3 (CH-O),
73.6 (C≡C), 83.2 (C≡C),
171.6 (C=O)
210 (5), 109 (12),
73 (25), 43 (100)
(2.56)a
aMeOH
bCCl4
Synthesis 2000, No. 2, 220–222 ISSN 0039-7881 © Thieme Stuttgart · New York

222
P. Hutin, M. Larchevêque
SHORT PAPER
Table 2 syn-Protected Dihydroxynitriles 4 Prepared
Productsb
4
[a]2D0
(c, CHCl3) (%)
ee
1H NMR (CDCl3/TMS)
d, J(Hz)
13C NMR (CDCl3)
d
MS
m/z (%)
(2S,3S)-4a
−4.1
96
1.00 (d, 3 H, J = 6.8, CH3),
1.02 (d, 3 H, J = 6.8, CH3),
1.46 and 1.50 (s, 3 H, CH3),
1.88 (sext, 1 H, J = 6.8, CH),
4.13 (dd, 1 H, J = 6.8, 6.8, CH-O),
4.34 (d, 1 H, J = 6.6, CH-O)
17.8 (CH3), 18.3 (CH3),
24.6 (CH3), 26.4 (CH),
31.2 (CH3), 65.7 (CH),
85.2 (CH), 112.2(C),
118.3 (CN)
169 (1), 154 (39),
126 (15), 97 (34),
94 (89), 67 (30),
54 (30), 43 (100)
(1.83)a
(2S,3S)-4b −8.4
(3.81)
98
0.96 (d, 3 H, J = 6.6, CH3),
0.98 (d, 3 H, J = 6.4, CH3),
1.5–1.9 (m, 3 H, CH and CH2)
1.45 and 1.47 (s, 3 H, CH3),
4.19 (d, 1 H, J = 6.8, CH-O),
4.39 (m, 1 H, CH-O),
22.2 (CH3), 23.0 (CH3),
25.1 (CH3), 25.3 (CH3),
27.0 (CH), 41.8 (CH2),
68.1 (CH), 78.9 (CH),
112.3 (C), 117.8 (CN)
183 (1), 168 (63),
126 (19), 108 (38),
99 (27), 97 (43),
81 (49), 68 (16),
54 (29), 43 (100)
(2S,3S)-4c
−30.4
(6.74)
99
99
1.63 and 1.64 (s, 3 H, CH3),
4.41 (d, 1 H, J = 7.4, CH-O),
5.34 (d, 1 H, J = 7.4, CH-O),
7.4–7.5 (m, 5 H, C6H5)
25.2 (CH3), 26.7 (CH3),
70.3 (CH), 113.2 (C)
117.3 (CN), 126.1 (CH),
129.1 (CH), 129.4 (CH),
132.5 (C)
203 (18), 188 (7), 177 (5),
163 (6), 91 (18), 77 (26),
54 (57), 43 (100)
(2S,3S)-4d −21.9
1.48 and 1.51 (s, 3 H, CH3),
2.95 (dd, 1 H, J = 6.1, 14.1, CHH),
3.07 (dd, 1 H, J = 4.3, 14.1, CHH),
4.35 (d, 1 H, J = 6.4, CH-O),
4.65 (q, 1 H, J = 6.3, CH-O),
7.2–7.4 (m, 5 H, C6H5)
25.2 (CH3), 27.0 (CH3),
38.9 (CH2), 66.9 (CH),
80.7 (CH), 112.9 (C),
117.7 (CN), 127.4 (CH),
127.4 (CH), 128.9 (CH),
129.4 (CH), 135.4 (C)
217 (3), 202 (15),
159 (14), 91 (35),
68 (13), 77 (9),
43 (100)
(4.85)
(2R,3R)-4e 8.5
98
0.91 (t, 3 H, J = 7.0, CH3),
1.46 (s, 3 H, CH3),
1.51−1.54 (m, 4 H, CH2),
1.57 (s, 3 H, CH3),
2.1–2.2 (m, 2 H, CH2),
2.5–2.7 (m, 2 H, CH2)
4.33 (dt, 1 H, J = 5.2, 8.4, CH-O),
4.88 (d, 1 H, J = 5.2, CH-O)
13.4 (CH3), 18.2 (CH2),
21.8 (CH2), 23.3 (CH3),
25.1 (CH3), 26.7 (CH2),
29.8 (CH2), 30.6 (CH3),
67.1 (CH), 72.7 (C≡C),
78.5 (CH), 84.4 (C≡C),
113.1 (C), 117.8 (CN)
221 (5), 206 (17),
164 (3), 126 (82),
68 (18), 43 (100)
(1.79)
a MeOH
b For new compounds satisfactory microanalyses were obtained : C 0.3, H 0.21
Physics of Lipids 1976, 16, 115.
Li, W-R.; Ewing, W. R.; Harris, B. D.; Joullié, M. M. J. Am.
Chem. Soc. 1990, 112, 7659.
Degerbeck, F.; Fransson, B.; Grehn, L.; Ragnarsson, U. J.
Chem. Soc., Perkin Trans. 1 1993, 11.
References
(1) Krepski, L. R.; Jensen, K. M.; Heilmann, M.; Rasmussen, J.
K. Synthesis 1986, 301.
Brussee, J.; Dofferhoff, F.; Kruse, C. G.; Van der Gen, A.
Tetrahedron 1990, 46, 1653.
Urabe, H.; Aoyama, Y.; Sato, F. J. Org. Chem. 1992, 57,
5056.
(6) Larchevêque, M.; Petit, Y. Bull. Soc. Chim. Fr. 1989, 130.
(7) Durand, J. O.; Larchevêque, M.; Petit, Y. Tetrahedron Lett.
1998, 39, 5743.
(8) Althoff, W.; Korsdorf, R.; Tinapp, P. Arch. Pharm.
(Weinheim, Ger.) 1981, 314, 518.
(9) Polonski, T. Tetrahedron 1983, 39, 3131.
(10) Kim, H. O.; Friedrich, D.; Huber, E.; Peet, N. P. Synth.
Commun. 1996, 26, 3453.
(2) Hwang, C. D.; Hwang, D. R.; Uang, B. J. J. Org. Chem. 1998,
63, 6762; and references cited herein.
(3) Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
(4) Reetz, M. T.; Kesseler, K.; Jung, A. Angew. Chem. Int. Ed.
Engl. 1985, 24, 989.
Effenberger, F.; Hopf, M.; Ziegler, T.; Hudelmayer, J. Chem.
Ber. 1991, 124, 1651.
(5) Brewster, P.; Hiron, F.; Hughes, E. D.; Ingold, C. K.; Rao, P.
A. D. S. Nature 1950, 166, 179.
Article Identifier:
1437-210X,E;2000,0,02,0220,0222,ftx,en;Z05899SS.pdf
Lok, C. M.; Ward, J. P.; van Dorp, D. A. Chemistry and
Synthesis 2000, No. 2, 220–222 ISSN 0039-7881 © Thieme Stuttgart · New York