Synthesis of 2-nitroalcohols by regioselective ring opening of epoxides with MgSO4/MeOH/NaNO2 system: A short synthesis of immunosuppressive agent FTY-720

Article abstract of DOI:10.1055/s-2001-16776

It has been demonstrated that a variety of epoxides can easily be opened with a system consisting of MgSO₄/MeOH/NaNO₂ giving the corresponding 2-nitroalcohols in excellent yields. This strategy has been applied to achieve a short synthesis of Immunosuppressive Agent FTY - 720.

Full text of DOI:10.1055/s-2001-16776

LETTER
1411
Synthesis of 2-Nitroalcohols by Regioselective Ring Opening of Epoxides with
MgSO4/MeOH/NaNO2 System: A Short Synthesis of Immunosuppressive
Agent FTY-720
Biswajit Kalita, Nabin C. Barua,* Maitreyee (Sarma) Bezbarua, Ghanashyam Bez
Organic Chemistry Division (Natural Products Chemistry), Regional Research Laboratory, Jorhat-785006,Assam,India
Fax +91(0376)370011; E-mail :ncbarua@hotmail.com
Received 8 June 2001
NaNO2 was used. However, we have observed that when
Abstract: It has been demonstrated that a variety of epoxides can
a variety of epoxides were treated with a system consist-
ing of MgSO4/NaNO2 in dry MeOH under reflux, the cor-
responding 2-nitro alcohols were formed in good to
excellent yields (Scheme 1).
easily be opened with a system consisting of MgSO4/MeOH/
NaNO2 giving the corresponding 2-nitroalcohols in excellent yields.
This strategy has been applied to achieve a short synthesis of Immu-
nosuppressive Agent FTY - 720.
Key words: 2-nitroalcohols, nitroaliphatics, epoxides, immuno-
suppressive agent FTY – 720, ring opening
The reaction has been generalized through entry 1 to 9 in
the Table.
It is evident from Table I that the reagent system MgSO4/
MeOH/ NaNO2 can efficiently open primary-secondary
epoxides (entry 1,3-9), and bis-secondary epoxides (entry
2), but, secondary-tertiary epoxides (3 -hydroxyc-
holestan-5,6-epoxide and cholestan-5,6-epoxide) and bis-
tertiary epoxides remain unaffected even after reflux for a
long time. We believe that Mg 2+ ions act as a promoter for
Epoxides are considered to be one of the main muscles of
organic synthesis1 because of the fact that they are easily
prepared from a variety of substrates and are easily
opened under a broad range of conditions giving a wide
spectrum of products. One very favorable aspect of the
ring opening reactions of epoxides is that they are usually
stereospecific, proceeding with inversion of configuration
at the site of the opening via a SN2 mechanism. However,
opening of epoxides with nucleophiles often requires
presence of promoters.2 In continuation of our interest on
the chemistry of nitroaliphatics3 we desired to develop a
straightforward method for preparation of -nitroalco-
hols,4 which are considered as an important class of com-
pounds often used as key intermediates in the synthesis of
numerous natural poducts.5 The versatility of 2-nitro alco-
hols as building block lies in the fact that the nitro group
can be reduced with retention of configuration6 and the re-
sulting amino alcohols are useful intermediates in the
elaboration of pharmacologically important products and
are also widely used in the preparation of chiral auxilia-
ries.7 Thus, the possibility of utilizing a nucleophilic nitro
addition to epoxides to provide 2-nitro alcohols was ex-
plored. But, because of low nucleophilicity of the nitro
group, the reaction did not proceed as desired, when only
–
nucleophilic opening of epoxides with NO2 and the inert-
ness of some of the epoxides towards this reagent system,
as mentioned above, is attributed mainly to the steric fac-
tor. The bulky substituents on either carbons of the cyclic
–
ether linkage don’t allow the Mg2+ and the NO2 ions to
come to close proximity of the active sites, as a result
these epoxides remain inert to this system. It is also evi-
dent from Table I that this reagent system is particularly
–
effective in opening of 2,3-epoxy alcohols with NO2
group at C-1. 2,3-epoxy alcohols, which, in principle,
contain three active sites for nucleophilic substitution cor-
responding to the carbon backbone, provide convenient
access to useful highly functionalized homochiral mole-
cules and therefore this strategy may be a useful alterna-
tive to the existing methods.
The utility of this novel ring opening reaction has been
demonstrated by achieving a short synthesis of a new
immunosuppressive agent FTY-720 (Scheme 2) which is
Scheme 1 R1 = R2 = H, Alkyl, Aryl; R3 = H, R4 = H, Alkyl. i. MgSO4/MeOH/ NaNO2, reflux
Synlett 2001, No. 9, 1411–1414 ISSN 0936-5214 © Thieme Stuttgart · New York

1412
B. Kalita et al.
LETTER
Table Synthesis of -Nitroalcohols from Epoxides with MgSO4-MeOH-NaNO2
aThe starting epoxides were prepared using literature procedures and were characterized by
IR,NMR and Mass spectra. bProducts were characterized by IR,NMR & Mass spectra. cYield
refers to yields of pure isolated products. dFrom cholesterol series.
endowed with an original mechanism of action.7a The syn- at RT which was converted into the nitro alcohol 7a by
thesis of this important molecule was first achieved by treating with the reagent system consisting of MgSO4-
Fujita et al.8 followed by a recent synthesis by Durand et NaNO2 in the ratio of (1:5)in dry MeOH under reflux,
al.9
giving 7a in 76% yield. The nitrodiol 7a was treated with
chlorotrimethylsilane and sodium iodide11 in acetonitrile
and the deoxygenated product 10 (61%) was hydrogenat-
ed with 10% Pd/C to give compound 11 in 76% yield.
Compound 11 was bis-formylated by treating with aque-
ous formaldehyde solution in presence of Amberlyst A-21
resin12 to give compound 12 in 51% yield. The final prod-
uct FTY-720 was obtained in 82% yield by reducing the
bis-formylated compound 12 with H2/Raney-Ni, for
which analogy exists in the literature.8
Coupling reaction of the oganozinc iodide derived from
octyl iodide with p-chlorobenzaldehyde under the influ-
ence of Ni(0) as per procedure reported by Lipshutz et
al.10 gave 4-octyl-benzaldehyde, in 71% yield as a gum,
which on treatment with 1.1 equivalent of freshly pre-
pared vinyl magnesium bromide in dry ether at 0 °C gave
the corresponding allyl phenyl alcohol in 81% yield also
as a gum. The conversion of allyl phenyl alcohol into the
1,3-epoxide (entry 7) was effected by m-CPBA in CH2Cl2
Synlett 2001, No. 9, 1411–1414 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Nitroalcohols by Regioselective Ring Opening
1413
Scheme 2 i, CTMS-NaI(1:1), dry CH3CN, RT (61%) ii, H2,10% Pd/C, Absolute EtOH, RT, 40 bar,1 h (76%) iii, HCHO, Amberlyst A-21,
CH2Cl2, 7h(51%) iv, H2/Raney-Ni (82%)
Chiba, K.; Europian Patent EP0627406, Dec. 07, 1994;
Chem. Abstr. 1995, 122, 239193 b) Mishina, T; Sasaki, S.
Acknowledgement
The authors thank Director, RRL, Jorhat, for providing facilities for
this work.
(8) Adachi, K.; Kohara, T.; Nakao, N.; Arita, M.; Chiba, K.;
Mishima, T.; Sasaki, S.; Fujita, T. Bioorg. Med. Chem. Lett.
1995, 5, 853.
(9) Durand, P.; Peralba, P.; Sierra, F.; Renaut, P.; Synthesis 2000,
505.
References and Notes
(10) Bruce, H. L.; Blomgren, P. A.; Kim, Sung-Kyu Tetrahedron
Lett.1999, 40, 197.
(11) Barua, N. C.; Sharma, R. P. Tetrahedron Lett. 1982, 23, 1365.
(12) Bez, G.; Barua, N. C. Unpublished data.
(1) Behrens, C.H.; Ko, S.Y.; Sharpless, K.B.; Walker, F.J.;
J. Org. Chem. 1985, 50, 5687-5696.
(2) Rampaalli, S.; Chaudhauri,S.C.; Akamanchi, G.K.; Synthesis
2000, 78.
(13) Typical Procedure: To a solution of the styrene oxide (entry 1,
Table 1) [1g 8.3 mmol] in dry MeOH (50 mL) was added
MgSO4 (2 g, 16.6 mmol) and NaNO2 (5 g, 72.5 mmol) and the
mixture refluxed for 4.5 hours. When TLC indicated
disappearance of the starting material, methanol was distilled
off under reduced pressure and the residue washed with
chloroform (3 50 mL). The CHCl3 washings were combined
and distilled off to give a gummy product which was purified
by preparative TLC to yield 1a as a yellow liquid (1.04 g, 6.23
mmol, 75%).
(3) a) Sarma, B.K.; Barua, N. C.; Tetrahedron 1993, 49, 2250.
b) Sarma, B.K.; Barua, N.C.; Ind. J. Chem. Sec.B 1993, 328,
615. c) Saikia, A.K.; Hazarika, M.J.; Barua, N C.; Bezbarua,
M.S.; Sharma, R.P.; Ghosh, A.C.; Synthesis 1996, 981.
d) Bezbarua, M.S.; Saikia, A.K.; Barua, N.C.; Kalita, D.;
Ghosh, A.C.; Synthesis 1996, 1289. e) Bez, G.; Bezbarua,
M.S.; Barua, N.C.; Synthesis 2000, 357. f) Baruah, A.; Kalita,
B.; Barua, N.C.; Synlett 2000, 1064.
(4) Ballini, R.; Boseki, G.; Marcantoni, E.; Vita, P.; Bartoli, G.;
J. Org. Chem. 2000, 65, 5854.
(14) IR values are expressed in cm–1 and 1H NMR (300 MHz)
values are expressed in scale 1a: Yellow liquid, b.p.18
142-3 °C (lit.15a bp15 163-165 °C) IR: 3400, 1550, 1425, 1395,
1195 cm–1. NMR: 7.2 (s, 5H, aromatic), 5.2 (dd, J = 5 & 6Hz,
1H, -CH-OH), 4.3 (d, J = 6Hz, 2H, -CH2-NO2), 2.5 (br, 1H,
-OH); 2a:b.p. 81 °C (lit15b b.p. 82-84 °C), IR: 3600, 2900,
1550, 1380, 1275 cm–1. NMR: 4.4 (m, 1H, -CH-NO2), 3.5
(m, 1H, -CH-OH), 1.3(br, 8H, -CH2-); 3a: gum, IR: 3400,
2900, 1550, 13450 cm-1. NMR: 4.6 (m, 1H, -CH-NO2), 4.57
(m, 1H, -CH-OH), 3.67 (d, J = 3Hz, -CH2-Cl), 2.99 (br, 1H,
-OH). MS m/z 140 (M++1), 122,104, etc.; 4a: gum IR: 3417,
2929, 1630, 1555, 1095 cm-1. NMR: 7.0 (s, 5H, aromatic), 4.3
(d, J = 3.5Hz, 2H, -CH2-NO2), 3.4 (s, 2H, -CH2-O-), 3.3 (t,
J = 3.5 Hz, 1H, -CH-OH). MS: m/z 212(M++1), 193,117, etc.;
5a: gum IR: 3300, 2910, 1550 cm-1, NMR: 7.20 (m, 4H,
aromatic), 4.45 (d, J = 6Hz, 2H, -CH2-NO2), 2.71 (m, 2H,
-CH-OH), MS m/z 232 (M++1), 213, 196, 178, 161, etc.;
6a: gum IR : 3500, 1540, 1250cm-1. NMR: 6.7 (m, 3H,
aromatic), 4.2 (d, J = 6Hz, 2H, -CH2-NO2), 3.7 (s, 3H, -OMe),
3.4 (m,1H,-CH-OH), 2.55 (d, J = 5Hz,-CH2-). MS m/z 228
(M++1), 209, 194, etc.; 7a:gum, IR: 3300, 2900, 1600, 1555,
(5) a) Hakomori, S. In Handbook of Lipid Research Sphinolipid
Biochemistry, Kanfer, J.N.; Hakomori, S.; Eds., Plenum Press,
New York 1983, vol.1. b) Williams, T.M.; Crumbie, R.;
Mosher, H.S.; J. Org. Chem. 1985, 50, 91. c) Rosini, G. In
Comprehensive Organic Synthesis: Trost, B.M.; Flemming, I.;
Eds., Pergamon Press: Oxford 1991, vol2, 321. d) Ballini, R.;
In Studies in Natural Products Chemistry, Atta-ur-Rahman;
Ed., Elsevier, Amsterdam 1997; vol. 19; 117. e) Morgan, B.;
Sarikonda, B.R.; Dodds, D.R.; Homen, M.J.; Vail, R.;
Tetrahedron Asymmetry 1999, 10, 3681.
(6) a) Barrett, A.G.M.; Spilling, C.D.; Tetrahedron Lett. 1988, 29,
5733. b) Bordwell, F.G.; Garbisch, E.N.; J. Org. Chem. 1963,
28, 1765. c) Bordwell, F.G.; Arnold, R.L.; J. Org. Chem.
1962, 27, 4426. d) Nielson, A.T.; J. Org. Chem. 1962, 27,
1998.
(7) a) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Hoh, N.;
Shibasaki, M.; J. Org. Chem. 1995, 60, 7388. b) Chiba, K.;
Drugs Future 1998,23,94; and references cited therein
c) Troncoso, P.; Kahan, B.D.; Clin. Biochem. 1998, 31, 369.
d) Fujita, T.; Sasaki, S.; Yoneta, M.; Mishina, T.; Adachi, K.;
Synlett 2001, No. 9, 1411–1414 ISSN 0936-5214 © Thieme Stuttgart · New York

1414
B. Kalita et al.
LETTER
C,74.21%, H, 9.50%, N,4.98%; 11: gum, IR : 2900, 1600,
1470, 1380, 1200 cm–1. NMR: 7.2 (m, 4H, aromatic), 4.5 (d,
J = 6Hz, 2H, -CH2-NO2), 2.66 (m, 2H, - CH-OH), 1.60 (m,
2H, -CH2-NO2), 1.27 (br, 12H, -CH2-), 0.87(t, J = 6.5 Hz, 3H,
-CH3), Calculated for: C17H27NO4, C, 65.99%, H, 8.80%, N,
4.53%; Found: C, 65.92%, H, 8.74%, N, 4.51%; 8a:gum, IR:
3300, 2900,1550, 1475, 1390, cm-1. NMR: 4.3 (d, J = 3.5Hz,
2H, -CH2-NO2), 3.4 (m, 5H, -CH2-O-CH2&-CH-OH), 2.5 (br,
1H, -OH),1.2(br,12H, -CH2-), 0.81(t,J = 6.7 Hz,3H,-CH2-
CH3). MS m/z 234 (M++1), 205, 190, 176,162, etc.; 9a: gum,
IR: 3600, 2900, 1550, 1470, 1380, 1275 cm-1.NMR: 5.2 (t,
J = 4.5 Hz, 1H, vinyl), 4.2 (d, J = 3.5 Hz, 2H, -CH2-NO2), 3.4
(m, 4H,-CH2-O-, -CH-O-, -CH-OH), Calculated for:
C30H51NO4, C, 73.58%, H, 10.50%, N, 2.86%; Found: C,
73.49%, H, 10.53%, N, 2.81% 10a:gum, IR : 2900, 1600,
1540, 1460 cm–1. NMR: 7.2 (br, 4H, aromatic), 5.75 (d,
J = 12Hz, 1H, Ph-CH = C-), 5.5 (m, 1H, -Ph-C=CH-), 4.6 (d,
J = 6.5Hz, 2H, -CH2-NO2),1.62 (m,2H,-CH2-aromatic), 1.27
(br, 12H, -CH2), 0.88 (t, J = 6.5 Hz, 3H, -CH3), Calculated for
C17H27NO2, C,74.14%, H,9.15%, N,5.08%; Found:
1550, 1500, 1380 cm-1. NMR: 7.35 (m, 4H aromatic), 4.35
(t, J = 6.9Hz, 2H, -CH2NO2), 3.18 (t, J = 7Hz, 4H, -CH2-),
2.72 (t, J = 7.3Hz,2H,-CH2-), 2.35 (m, 2H,-CH2-), 1.84 (m,
4H, -CH2-), 1.36 (m, 6H, -CH2-), 0.86 (t, J = 6.9Hz, 3H,
-CH3), Calculated for: C17H27NO2, C, 73.61%, H, 9.81%, N,
5.05%; Found: C,73.58%, H, 9.85%, N, 5.10%, 12: gum, IR:
3400, 2900, 1662, 1552, 1494, 1383 cm-1. NMR: 7.34
(4H, aromatic), 3.8 (br,4H,-CH2-OH), 3.20 (t,J = 7Hz, 4H,
-CH2-), 1.30 (m, 14H,-CH2-), 0.89 (t, J = 6.9 Hz, 3H, -CH3),
Calculated for: C19H31NO4,C, 67.63%, H,9.26%, N,4.56%;
Found: C, 67.58%, H, 9.21%, N, 4.50%.
(15) a)Dictionary of organic compounds, 6th edition, vol. 5, p 4810,
Chapman & Hall. b) ibid, p 4773.
Article Identifier:
1437-2096,E;2001,0,09,1411,1414,ftx,en;D09601ST.pdf
Synlett 2001, No. 9, 1411–1414 ISSN 0936-5214 © Thieme Stuttgart · New York