Thermal degradation of designed carbohydrate N-oxides: A single methodology for the synthesis of ketoses, enol ethers and branched-chain sugars from N-oxides derived from D-altrose aminosugars

Full text of DOI:10.1021/jo982199s

J . Org. Chem. 1999, 64, 9715-9718
9715
Sch em e 1a
Th er m a l Degr a d a tion of Design ed
Ca r boh yd r a te N-Oxid es: A Sin gle
Meth od ology for th e Syn th esis of Ketoses,
En ol Eth er s, a n d Br a n ch ed -Ch a in Su ga r s
fr om N-Oxid es Der ived fr om D-Altr ose
Am in osu ga r s†
Bindu Ravindran and Tanmaya Pathak*
Organic Chemistry Division (Synthesis), National Chemical
Laboratory, Pune 411 008, India
Received November 2, 1998 (Revised Manuscript Received J une
24, 1999 )
In tr od u ction
Tertiary amine N-oxides undergo olefination reactions
at elevated temperature (Cope reaction).1,2 The success
of the reaction depends on the availability of a suitably
located â-hydrogen so that a five-membered transition
state can be easily formed.1b Despite the familiarity with
the general principle of this olefination procedure, no
serious attempt2 has been made to implement, by design,
this methodology in the area of carbohydrates, although
the procedure for accessing the starting materials, i.e.,
the tertiary aminosugars, by opening epoxides of carbo-
hydrates was well documented.3 In the few reported
cases,2b-d (a) the yields of conversion of the N-oxides to
the olefinic products varied between 38% and 76%2b or
between 28% and 51%,2c (b) unwanted side products were
formed,2c and/or (c) deoxygenated starting aminosugars
were recovered2c in up to 60% yields. The inefficiencies
of the above reactions could be attributed to the failure
of the N-oxides of the conformationally flexible carbohy-
drates to form the required five-membered1b cyclic inter-
mediates.
We envisaged that the N-oxides derived from the
conformationally restricted methyl 4,6-O-(phenylmeth-
ylene)-3-deoxy-3-(4-morpholinyl)-D-altro-pyranosides 2,
namely, intermediates 4ra -4rf and 4âa -4âb, would
undergo syn-elimination exclusively, resulting in the
formation of enols 5 (Scheme 1). It is also expected that
the enol ethers 5re and 5rf, derived from the O-allylated
products 3re and 3rf, respectively, would undergo
Claisen rearrangements4 to produce branched-chain sug-
ars. In this paper we report for the first time the
synthesis of three varied classes of important synthons,5
ketoses, enol ethers, and branched-chain sugars, through
a single route starting from a single intermediate.
a
Reagents: (i) morpholine/90-100 °C/9-60 h; (ii) alkylation/
aroylation/allylation; (iii) mCPBA; (iv) pyridine/50-100 °C.
Resu lts a n d Discu ssion
Methyl 4,6-O-(phenylmethylene)-3-deoxy-R-D- and -â-
D-erythro-hexopyranoside-2-ulose (6r and 6â, respec-
tively) have been used extensively in synthetic chem-
istry.5-7 The enolic forms of such ketoses are known to
be important synthetic intermediates,7j,8 although the
syntheses of such compounds are not always straight-
forward. Branched-chain carbohydrates,4,5d,7d-g,k-l,n,9 on
the other hand, constitute an important class of func-
tionalized intermediates,5 useful for further transforma-
tions.
Syn th esis of Ketoses a n d En ol Eth er s. The starting
amino alcohols 2r and 2â were synthesized in high yields,
by reacting the known epoxides 1r10 and 1â,11 respec-
tively, with neat morpholine at elevated temperatures.
In each case, as expected,3 only the 3-deoxy-3-N-mor-
pholino derivative was obtained. Compound 2r was
oxidized with mCPBA, and the crude product was heated
* To whom correspondence should be addressed. E-mail:
pathak@ems.ncl.res.in.
† Dedicated to Dr. S. Rajappa on the occasion of his 65th birthday.
(1) (a) Gesson, J . P.; J acquesy, J . C.; Mondon, M. Synlett 1990, 669.
(b) Albini, A. Synthesis 1993, 263. (c) Chastanet, J .; Roussi, G.; Negron,
G. Carbohydr. Res. 1995, 268, 301.
(5) (a) Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach; Pergamon Press: Oxford, 1983. (b) Inch, T. D.
Tetrahedron 1984, 40, 3161. (c) Cintas, P. Tetrahedron 1991, 47, 6079.
(d) Ferrier, R. J . (Senior Reporter). Carbohydrate Chemistry; The Royal
Society of Chemistry: Cambridge, 1968-1996; Vols. 1-28. (e) Witczak,
Z. J ., Nieforth, K. A., Eds. Carbohydrates in Drug Design; Macel
Dekker Inc.: New York, 1997.
(6) For the synthesis of 6r and 6â, see: (a) Williams, E. H.; Szarek,
W. A.; J ones, J . K. N. Can. J . Chem. 1971, 49, 796. (b) Butterworth:
R. F.; Hanessian, S. Synthesis 1971, 70. (c) Brewer, C. L.; Guthrie, R.
D. J . Chem. Soc., Perkin Trans. 1 1974, 657. (d) Thiem, J .; Rasch, D.;
Paulsen, H. Chem. Ber. 1976, 109, 3588. (e) Tsuchiya, T.; Takahashi,
Y.; Endo, M.; Umezawa, S.; Umezawa, H. J . Carbohydr. Chem. 1985,
4, 587. (f) Horton, D.; Weckerle, W. Carbohydr. Res. 1988, 174, 305.
(2) For N-oxides derived from carbohydrates, see: (a) Guthrie, R,
D.; Prior, A, M. Carbohydr. Res. 1971, 18, 373. (b) Banaszek, A.;
Zamojski, A. Carbohydr. Res. 1972, 25, 453. (c) Mieczkowski, J .;
Zamojski, A. Carbohydr. Res. 1977, 55, 177. (d) Carret, G.; Abou-Assali,
M.; Cottin, M.; Et. Heneri-Pacheco, D. A. Carbohydr. Res. 1986, 152,
292. (e) Chastanet, J .; Fathallah, H.; Negron, G.; Roussi, G. Hetero-
cycles 1992, 34, 1565.
(3) Willams, N. R. Adv. Carbohydr. Chem. Biochem. 1970, 25, 109.
(4) (a) Martin, S. F.; Tu, C.-Y. J . Org. Chem. 1981, 46, 3764. (b)
Furuichi, K.; Hashimoto, H.; Miwa, T. Carbohydr. Res. 1991, 220, 63.
10.1021/jo982199s CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/01/1999

9716 J . Org. Chem., Vol. 64, No. 26, 1999
Notes
Sch em e 2a
in pyridine at 90-100 °C. The only carbohydrate-based
product that could be isolated on purification was the
ketose derivative 6r. The formation of this product
validated our envision regarding the preferential in-
tramolecular abstraction of the C-2 equatorial proton
from the N-oxide intermediate 4ra as discussed above.
To broaden the scope of this reaction, compounds 3rb,
3rc, and 3rd were synthesized from the single interme-
diate 2r by methylation, benzylation, and benzoylation,
respectively (see the Experimental Section). Each of these
compounds was oxidized and heated in pyridine as
described for the synthesis of compound 6r. Compounds
3rb, 3rc, and 3rd produced 5rb, 5rc, and 5rd , respec-
tively, in high yields. The â-isomers 6â6,7 and 5âb were
obtained from compounds 2â and 3âb in similar fashion
(Scheme 1).
Syn th esis of Br a n ch ed -Ch a in Der iva tives. Com-
pound 2r on allylation with allyl bromide or 2-methylallyl
chloride produced 3re and 3rf, respectively. Compound
3re on oxidation followed by heating afforded the enolic
form 5re (Scheme 1). Compound 5re rearranged4 in situ
to a mixture of isomers 7re at C-3. The mixture, however,
was converted to the single compound 7re by brief
treatment with silica gel (Scheme 2).4b Similarly, 3rf was
converted to 7rf via 5rf.
Compounds 5, 6, and 7 have so far been synthesized
through completely unrelated routes. Each preparation
required the synthesis of different starting materials and
separate sets of reaction conditions. For example, 6r was
synthesized by regioselective (C-3) opening of epoxide 1r
by hydride followed by oxidation of the C-2 hydroxyl
group.6c The best method for the synthesis of 6â, however,
used the chlorination at C-3 of methyl 4,6-O-(phenyl-
methylene)-â-D-gluco-pyranoside by SO2Cl2 as the key
a
Reagents: (i) pyridine/80-90 °C/3 h; (ii) pyridine/silica gel/
80-90 °C/8-20 h.
step.6e Interestingly, this methodology was only ap-
plicable to â-glycosides because R-glycosides did not form
chloro derivatives due to steric reasons.12 We have
synthesized 6r from 1r in 72% and 6â from 1â in 79%
overall yields. According to the only report8b on the
synthesis of 5rb, methyl 4,6-O-benzylidene-2,3-di-O-
methyl-R-D-hexopyranosides with D-gluco, D-altro, D-allo,
and D-manno configurations were treated with n-butyl-
lithium to produce the desired compound in 30%, 45%,
55%, and 0% yields, respectively. The D-allo derivative
gave the best yield, but D-allose is one of the most
expensive carbohydrates and normally accessed from
D-glucose. In our case, the overall yield of 5rb from 1r
is 61%. The related benzyl derivative 5rc has been
obtained8k from methyl 2-O-benzyl-3-O-trifluoromethane
sulfonyl-4,6-O-(phenylmethylene)-R-D-gluco-pyranoside in
51% yield along with a side product (21%). Although 5rc
has been obtained8k from methyl 2-O-benzyl-3-O-tri-
fluromethane sulfonyl-4,6-O-(phenylmethylene)-R-D-allo-
pyranoside in 91% yield, accessing the starting material
from expensive D-allose (or D-glucose) will certainly make
the overall yield drop to a much lower value. By our
method, 5rc was synthesized in 71% overall yield from
1r. The reported4b yield of 7re from 1r was 55%; in our
case the overall yield is 61%. The versatility of the
method has been demonstrated further by synthesizing
hitherto unknown benzoyl derivative 5r d , methyl de-
rivative 5âb, and methylallyl derivative 7rf.
(7) For the applications of 6r and 6â in organic synthesis, see: (a)
Hicks, D. R.; Fraser-Reid, B. J . Chem. Soc., Chem. Commun. 1976,
869. (b) Garegg, P. J .; Gotthammar, B. Carbohydr. Res. 1977, 58, 345.
(c) Brimacombe, J . S.; Hanna, R.; Marther, A. M.; Weakley, T. J . R. J .
Chem. Soc., Perkin Trans. 1 1980, 273. (d) J arosz, S.; Hicks, D. R.;
Fraser-Reid, B. J . Org. Chem. 1982, 47, 935. (e) Tulshian, D. B.; Tsang,
R.; Fraser-Reid, B. J . Org. Chem. 1984, 49, 2347. (f) Csuk, R.; Furstner,
A.; Weidmann, H. J . Carbohydr. Chem. 1986, 5, 77. (g) Krohn, K.;
Broser, E.; Heins, H. Carbohydr. Res. 1987, 164, 59. (h) Rocherolle,
V.; Lopez, J . C.; Olesker, A.; Lukacs, G. J . Chem. Soc., Chem. Commun.
1988, 513. (i) Thang, T. T.; Laborde, M. de los A.; Olesker, A.; Lukacs,
G. J . Chem. Soc., Chem. Commun. 1988, 1581. (j) Csuk, R.; Furstner,
A.; Weidmann, H. J . Carbohydr. Chem. 1986, 5, 271. (k) Peseke, K.;
Feist, H.; Cuny, E. Carbohydr. Res. 1992, 230, 319. (l) Feist, H.; Peseke,
K.; Koll, P. Carbohydr. Res. 1993, 247, 315. (m) Marschner, C.;
Baumgartner, J .; Griengl, H. Liebigs Ann. Chem. 1994, 999. (n)
Schmeichel, M.; Redlich, H. Synthesis 1996, 1002. (o) Alves, R. J .;
Castillon, S.; Dessinges, A.; Herczegh, P.; Lopez, J . C.; Lukacs, G.;
Olesker, A.; Thang, T. T. J . Org. Chem. 1988, 53, 4616.
(8) For the synthesis, biological importance, and synthetic applica-
tions of carbohydrate enol ethers, see: (a) Ferrier, R. J .; Prasad, N.;
Sankey, G. H. J . Chem. Soc. C 1969, 587. (b) Kelmer, A.; Rodemeyer,
G. Chem. Ber. 1975, 108, 1896. (c) Blattner, R.; Ferrier, R. J .; Prasit,
P. J . Chem. Soc., Chem. Commun. 1980, 944. (d) Koll, P.; Steinweg,
E.; Meyer, B.; Metzger, J . Liebigs Ann. Chem. 1982, 1039. (e) Kong,
F.; Su, B. Carbohydr. Res. 1985, 142, 152. (f) Haradahira, T.; Maeda,
M.; Kai, Y.; Omae, H.; Kojima, M. Chem. Pharm. Bull. 1985, 33, 165.
(g) Varela, O.; de Fina, G. M.; de Lederkermer, R. M. Carbohydr. Res.
1987, 167, 187 (h) Lichtenthaler, F. W.; Ronninger, S.; J arglis, P.
Liebigs Ann. Chem. 1989, 1153. (i) Sigurskjold, B. W.; Duss, B.; Bock,
K. Acta Chem. Scand. 1991, 45, 1032. (j) Anastasia, M.; Allevi, P.;
Ciuffreda, P.; Fiecchi, A.; Scala, A. J . Org. Chem. 1991, 56, 3054. (k)
El Nemr, A.; Tsuchiya, T. Tetrahedron Lett. 1995, 36, 7665. (l)
Ichikawa, Y.; Kobayashi, C.; Isobe, M. J . Chem. Soc., Perkin Trans. 1
1996, 377.
Con clu sion
We have reported for the first time a single methodol-
ogy for the preparation of synthetically and biologically
important carbohydrate molecules, such as ketoses, enol
ethers, and branched-chain sugars, from a single amino
alcohol intermediate prepared from D-glucose. The N-
oxides derived from the conformationally restricted amino
alcohols or various ethers and esters undergo syn-
elimination exclusively to produce the aforementioned
products.
(9) (a) Thorn, S. N.; Gallagher, T. Synlett 1996, 856. (b) Holzapfel,
C. W.; Engelbrecht, G. J .; Marais, L.; Toerien, F. Tetrahedron 1997,
53, 3957. (c) Marco-Contelles, J . J . Org. Chem. 1996, 61, 7666. (d)
Nguefack, J .-F.; Bolitt, V.; Sinou, D. J . Org. Chem. 1997, 62, 1341.
(10) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203.
(11) Kim, K. S.; Vyas, D. M.; Szarek, W. A. Carbohydr. Res. 1979,
72, 25.
(12) (a) J ennings, H. J .; J ones, J . K. N. Can. J . Chem. 1965, 43,
2372. (b) Arita, H.; Fukukawa, K.; Matsushima, Y. Bull. Chem. Soc.
J pn. 1972, 45, 3614.

Notes
J . Org. Chem., Vol. 64, No. 26, 1999 9717
Calcd for C19H27NO6: C, 62.44; H. 7.45; N, 3.83. Found: C, 62.46;
H, 7.49; N, 3.50.
Exp er im en ta l Section
Compound 3rb (1.0 g, 2.74 mmol) was converted to a colorless
solid, 5rb (0.61 g, 80%), following the general procedure. Mp:
142-143 °C, lit.8b 147 °C. 1H NMR (CDCl3): δ 3.54 (s, 3H), 3.64
(s, 3H), 3.92 (m, 2H), 4.34 (m, 2H), 4.77 (s, 1H), 5.02 (d, J ) 1.3
Hz, 1H), 5.59 (s, 1H), 7.35-7.57 (m, 5H). Anal. Calcd for
C15H18O5: C, 64.73; H, 6.52. Found: C, 65.14; H, 6.78.
Meth yl 4,6-O-(P h en ylm eth ylen e)-3-d eoxy-2-O-m eth yl-â-
D-er yth r o-h ex-2-en op yr a n osid e (5âb). The procedure for the
synthesis of 3rb was used for the conversion of 2â (0.7 g, 1.9
mmol) to syrupy methyl 4,6-O-(phenylmethylene)-3-deoxy-2-O-
methyl-3-(4-morpholinyl)-â-D-altro-pyranoside (3âb) (0.59 g, 83%).
Gen er a l Meth od s. Melting points were determined in open-
end capillary tubes and are uncorrected. Carbohydrates were
obtained from commercial suppliers and were used without
purification. Pyridine was dried over CaH2. TLC was carried out
on precoated plates (Merck silica gel 60, f254), and the spots were
visualized under UV or by using I2 as the developing agent.
Column chromatography was performed on silica gel (silica gel
1
60, 230-400 mesh). H NMR spectra were recorded at 200 and
300 MHz in CDCl3 using the residual CHCl3 or TMS as the
standard. 13C NMR spectra were recorded at 50.3 and 75 MHz
in CDCl3 using the triplet centered at δ 77.0 as the standard.
Optical rotation was recorded at 589 nm.
[R]32 -33.4° (c 1.5, CHCl3). 1H NMR (CDCl3): δ 2.69 (m, 2H),
D
2.97 (m, 3H), 3.50 (s, 6H), 3.75 (m, 6H), 4.00-4.39 (m, 3H), 4.90
(s, 1H), 5.45 (s, 1H), 7.35-7.55 (m, 5H). 13C NMR (CDCl3): δ
52.2 (CH2), 56.6, 59.5, 62.3, 63.5, 66.8 (CH2), 69.2 (CH2), 76.9,
77.3, 99.3, 102.1, 125.7, 127.8, 128.5, 137.4. MS EI: m/z (%) 365
(M+, 20), 334 (M+ - OCH3, 2). Anal. Calcd for C19H27NO6: C,
62.44; H, 7.45; N, 3.83. Found: C, 62.07; H, 7.44; N, 3.61.
Compound 3âb (0.39 g, 1.07 mmol) was converted to a
Meth yl 4,6-O-(P h en ylm eth ylen e)-3-d eoxy-3-(4-m or p h oli-
n yl)-r-D-a ltr o-p yr a n osid e (2r). A solution of methyl 2,3-
anhydro-4,6-O-(phenylmethylene)-R-D-mannopyranoside (1r) (1.65
g, 6.25 mmol) in neat morpholine (5-7 mL) was heated for 10 h
at 90-100 °C. Morpholine was coevaporated with toluene under
reduced pressure. The resulting syrup was purified over silica
gel to yield a colorless solid, 2r (1.95 g, 89%). Mp: 149-150 °C.
colorless solid, 5âb (0.23 g, 78%), following the general proce-
1
[R]28.5 +96.3° (c 0.56, CH2Cl2). H NMR (CDCl3): δ 1.88 (br s,
D
1
dure. Mp: 143-144 °C. [R]26 -26.9° (c 1.13, CHCl3). H NMR
D
1H), 2.81 (m, 2H), 3.03 (m, 3H), 3.42 (s, 3H), 3.71 (m, 5H), 4.23
(m, 4H), 4.58 (d, J ) 1.9 Hz, 1H), 5.5 (s, 1H), 7.35-7.46 (m, 5H).
13C NMR (CDCl3): δ 52.8 (CH2), 54.9, 59.4, 64.8, 67.2 (CH2), 68.3,
69.4 (CH2), 78.2, 101.1, 102.3, 125.9, 128.1, 128.8, 137.4. MS
EI: m/z (%) 351 (M+, 20), 320 (M+ - OCH3, 4). Anal. Calcd for
C18H25NO6: C, 61.52; H, 7.17; N, 3.99. Found: C, 61.15; H, 6.62;
N, 3.94.
(CDCl3): δ 3.49 (s, 3H), 3.62 (s, 3H), 3.54-3.71 (m, 1H), 3.89 (t,
J ) 10.2 Hz, 1H), 4.40 (m, 2H), 5.12 (s, 1H), 5.23 (d, J ) 1.8 Hz,
1H), 5.62 (s, 1H), 7.35-7.54 (m, 5H). 13C NMR (CDCl3): 54.2,
54.9, 68.5 (CH2), 70.1, 74.6, 98.0, 98.6, 101.3, 125.9, 127.9, 128.7,
137.1, 152.8. MS EI: m/z (%) 278 (M+, 18), 247 (M+ - OCH3, 8).
Anal. Calcd for C15H18O5: C, 64.73; H, 6.52. Found: C, 64.93;
H, 6.28.
Meth yl 4,6-O-(P h en ylm eth ylen e)-3-d eoxy-3-(4-m or p h oli-
n yl)-â-D-a ltr o-p yr a n osid e (2â). A solution of methyl 2,3-
anhydro-4,6-O-(phenylmethylene)-â-D-mannopyranoside (1â) (0.65
g, 2.46 mmol) in neat morpholine (3-5 mL) was heated for 60 h
at 90-100 °C. Morpholine was coevaporated with toluene. The
resulting syrup was purified over silica gel to yield syrupy 2â
Meth yl 4,6-O-(P h en ylm eth ylen e)-3-d eoxy-2-O-ben zyl-r-
D-er yth r o-h ex-2-en op yr a n osid e (5rc).8k To a suspension of
NaH (80% dispersion in oil, 0.103 g, 3.58 mmol) in anhydrous
DMF (10 mL) was added 2â (0.42 g, 1.19 mmol) in anhydrous
DMF (10 mL). The reaction mixture was stirred under nitrogen
atmosphere for 0.5 h at ambient temperature. Benzyl bromide
(1.42 mL, 11.96 mmol) was added dropwise to the reaction
mixture, and the mixture was stirred for a further 4.5 h at
ambient temperature. After the usual workup as described for
3rb the residue was purified over silica gel to yield syrupy
methyl 4,6-O-(phenylmethylene)-3-deoxy-2-O-benzyl-3-(4-mor-
(0.81 g, 94%). [R]29 - 23.5° (c 0.2, CH2Cl2). 1H NMR (CDCl3):
D
δ 2.70 (m, 3H), 3.00 (m, 3H), 3.56 (s, 3H), 3.72 (m, 5H), 4.08 (m,
2H), 4.32 (m, 2H), 4.81 (s, 1H), 5.49 (s, 1H), 7.35-7.57 (m, 5H).
13C NMR (CDCl3) δ 52.3 (CH2), 56.4, 63.3, 63.5, 66.8 (CH2), 68.0,
69.3 (CH2), 77.3, 98.6, 102.1, 125.8, 127.9. 128.6, 137.2. MS EI:
m/z (%) 351 (M+, 11). Anal. Calcd for C18H25NO6: C, 61.52; H,
7.17; N, 3.99. Found: C, 60.80; H, 7.08; N, 3.69.
pholinyl)-R-D-altro-pyranoside (3rc) (0.5 g, 94%). [R]31 +60.0°
D
(c 0.33, CHCl3). 1H NMR (CDCl3): 2.69 (m, 2H), 2.95 (m, 2H),
3.04 (s, 1H), 3.36 (s, 3H), 3.59-3.80 (m, 5H), 3.86 (s, 1H), 4.17-
4.39 (m, 3H), 4.62-4.64 (m, 2H), 4.68 (s, 1H), 5.49 (s, 1H), 7.29-
7.47 (m, 10H). 13C NMR (CDCl3): δ 52.9 (CH2), 54.5, 58.9, 62.5,
66.9 (CH2), 69.3 (CH2), 72.3 (CH2), 75.2, 78.2, 99.1, 102.2, 125.8,
126.5, 127.6, 127.9, 128.1, 128.6, 137.2, 137.5. MS EI: m/z (%)
441 (M+, 11), 351 (M+ - CH2Ph, 28).
Gen er a l P r oced u r e for th e Oxid a tion a n d Th er m a l
Degr a d a tion of 2 a n d 3. To a solution of 2 or 3 in dichlo-
romethane (10 mL/mmol) was added mCPBA (50-60%, 2.5
equiv). The reaction mixture was stirred for 0.5 h at ambient
temperature. Dichloromethane was evaporated under reduced
pressure. The resulting crude N-oxide was dissolved in anhy-
drous pyridine (10 mL/mmol) and heated at 80-100 °C for 2-8
h (TLC). Pyridine was evaporated and coevaporated with toluene
under reduced pressure. The resulting residue was dissolved in
EtOAc and washed successively with saturated aqueous NaH-
CO3 solution and water. The organic layer was dried over
anhydrous Na2SO4, filtered, and evaporated to dryness under
reduced pressure. The resulting residue was purified over silica
gel.
Compound 3rc (0.33 g, 0.75 mmol) was converted to a
colorless solid, 5rc (0.41 g, 85%), following the general proce-
dure. Mp: 128-130 °C. [R]26 +84.1° (c 2.0, CHCl3). 1H NMR
D
(CDCl3): δ 3.50 (s, 3H), 3.82 (t, J ) 7.3 Hz, 1H), 4.05 (m, 1H),
4.28 (m, 2H), 4.82 (m, 3H), 5.08 (s, 1H), 5.59 (s, 1H), 7.28-7.57
(m, 10H). 13C NMR (CDCl3): δ 56.2, 65.2, 69.3 (CH2), 69.8 (CH2),
77.9, 97.0, 98.5, 102.1, 126.5, 127.7, 128.2, 128.4, 128.6, 129.4,
136.3, 137.7, 153.2. MS EI: m/z (%) 263 (M+ - CH2Ph, 5). Anal.
Calcd for C21H22O5: C, 71.17; H, 6.26. Found: C, 71.63; H, 6.11.
Meth yl 4,6-O-(P h en ylm eth ylen e)-3-d eoxy-2-O-ben zoyl-
r-D-er yth r o-h ex-2-en op yr a n osid e (5rd ). To a solution of 2r
(0.47 g, 1.34 mmol) in anhydrous pyridine (10 mL) at 0 to -5 °C
was added benzoyl chloride (0.49 mL, 4.28 mmol) in anhydrous
pyridine (5 mL) dropwise. The reaction mixture was stirred for
2 h at 0 °C. After the usual workup the residue was purified
over silica gel to give syrupy methyl 4,6-O-(phenylmethylene)-
Meth yl 4,6-O-(P h en ylm eth ylen e)-3-d eoxy-2-O-m eth yl-r-
D-er yth r o-h ex-2-en op yr a n osid e (5rb).8b To a suspension of
NaH (80% dispersion in oil, 0.42 g, 14.67 mmol) in anhydrous
dioxane (10 mL) was added 2r (1.72 g, 4.89 mmol) in anhydrous
dioxane (15 mL). The reaction mixture was stirred under
nitrogen atmosphere for 0.5 h at ambient temperature. Iodo-
methane (3.0 mL, 48.9 mmol) was added dropwise to the reaction
mixture and stirred for a further 26 h at ambient temperature.
The reaction mixture was poured into saturated aqueous NH4-
Cl solution (50 mL) and extracted with dichloromethane (3 ×
30 mL). The organic layer was dried over anhydrous Na2SO4,
filtered, and evaporated under reduced pressure. The resulting
residue was purified over silica gel to yield syrupy methyl 4,6-
O-(phenylmethylene)-3-deoxy-2-O-methyl-3-(4-morpholinyl)-R-D-
altro-pyranoside 3rb (1.53 g, 86%). [R]30D +99.1° (c 2.2, CHCl3).
1H NMR (CDCl3): δ 2.75 (m, 2H), 3.01 (m, 3H), 3.39 (s, 3H),
3.46 (s, 3H), 3.69 (m, 6H), 4.10 (dd, J ) 4.0, 9.6 Hz, 1H), 4.30
(m, 2H), 4.61 (s, 1H), 5.48 (s, 1H), 7.33-7.47 (m, 5H). 13C NMR
(CDCl3): δ 53.3 (CH2), 54.9, 58.4, 59.1, 62.1, 67.3 (CH2), 69.5
(CH2), 78.4, 78.6, 99.0, 102.4, 126.1, 128.2, 128.9, 137.9. Anal.
3-deoxy-2-O-benzoyl-3-(4-morpholinyl)-R-D-altro-pyranoside (3rd)
1
(0.51 g, 84%). [R]31 +3.0° (c 0.67, CHCl3). H NMR (CDCl3): δ
D
2.86 (m, 2H), 3.01 (m, 3H), 3.44 (s, 3H), 3.78 (m, 5H), 4.20 (dd,
J ) 4.3, 9.7 Hz, 1H), 4.43-4.60 (m, 2H), 4.67 (s, 1H), 5.55 (s,
2H), 7.36-7.63 (m, 8H), 8.09 (dd, J ) 1.4, 8.3 Hz, 2H). 13C NMR
(CDCl3): δ 52.9 (CH2), 55.0, 58.9, 62.5, 67.1 (CH2), 69.4 (CH2),
70.5, 78.7, 98.6, 102.3, 125.9, 128.0, 128.3, 128.7, 129.5, 133.2,
137.5, 164.8.
Compound 3rd (0.34 g, 0.747 mmol) was converted to a
colorless solid, 5rd (0.22 g, 80%), following the general proce-
1
dure. Mp: 134-135 °C. [R]27 +67.9° (c 0.99, CHCl3). H NMR
D
(CDCl3): δ 3.45 (s, 3H), 3.86 (t, J ) 10.2 Hz, 1H), 4.02 (m, 1H),

9718 J . Org. Chem., Vol. 64, No. 26, 1999
Notes
4.38 (m, 2H), 5.14 (s, 1H), 5.59 (s, 1H), 6.02 (s, 1H), 7.23-7.62
(m, 8H), 8.07 (dd, J ) 1.4, 7.1 Hz, 2H). 13C NMR (CDCl3): δ
56.0, 64.2, 68.9 (CH2), 74.8, 95.5, 101.8, 117.3, 126.1, 128.0,
128.3, 128.9, 129.9, 133.4, 137.1, 145.2, 164.1. Anal. Calcd for
C21H20O6: C, 68.47; H, 5.47. Found: C, 68.56; H, 5.45.
1H), 7.35-7.47 (m, 5H). 13C NMR (CDCl3): δ 53.5 (CH2), 55.2,
59.4, 63.0, 67.6 (CH2), 69.8 (CH2), 71.9 (CH2), 75.8, 79.0, 99.8,
102.6, 118.0 (CH2), 126.4, 128.4, 129.1, 134.5, 138.2.
Compound 3re (0.38 g, 0.97 mmol) was converted to a white
solid, 7re (0.24 g, 81%), following the general procedure. Mp:
97-98 °C, lit.4b 100-101 °C. IR: νmax (CHCl3) 1738 cm-1 1H
.
Met h yl 4,6-O-(P h en ylm et h ylen e)-3-d eoxy-r-D-er yth r o-
h exop yr a n osid e-2-u lose (6r).6c Compound 1r (1.0 g, 3.78
mmol) was converted to 2r as described above. The crude syrup
was oxidized directly, and the N-oxide was heated in pyridine.
The usual workup and purification produced 6r (0.72 g, 72%).
NMR (CDCl3): δ 2.53 (m, 2H), 3.12 (m, 1H), 3.50 (s, 3H), 3.57-
3.83 (m, 2H), 4.25 (m, 1H), 4.40 (m, 1H), 4.61 (s, 1H), 5.15-5.20
(m, 2H), 5.50 (s, 1H), 5.87 (m, 1H), 7.38-7.53 (m, 5H). Anal.
Calcd for C17H20O5: C, 67.09; H, 6.62. Found: C, 67.02; H, 6.76.
1
Mp: 112-114 °C, lit.6c 114 °C. IR: νmax (CHCl3) 1737 cm-1. H
Meth yl 3-C-(2-Meth yla llyl)-4,6-O-(p h en ylm eth ylen e)-r-
D-a r a bin o-h exop yr a n osid -2-u lose (7rf). Compound 2r (0.4
g, 1.2 mmol) was allylated with 2-methylallyl chloride using a
method described for the synthesis of 3re to obtain syrupy
methyl 4,6-O-(phenylmethylene)-3-deoxy-2-O-2-methylallyl-3-(4-
NMR (CDCl3): δ 2.92 (m, 2H), 3.52 (s, 3H), 3.84 (m, 2H), 4.18
(m, 1H), 4.42 (m, 1H), 4.61 (s, 1H), 5.57 (s, 1H), 7.36-7.54 (m,
5H). Anal. Calcd for C14H16O5: C, 63.62; H, 6.10. Found: C,
63.37; H, 6.30.
Met h yl 4,6-O-(P h en ylm et h ylen e)-3-d eoxy-â-D-er yth r o-
h exop yr a n osid e-2-u lose (6â).6e Compound 1â was converted
to a white solid 6â following a procedure similar to that described
for the synthesis of 6R. Yield: 0.41 g, 84%. Mp: 165 °C, lit.6e
morpholinyl)-R-D-altro-pyranoside (3rf) (0.43 g, 84%). [R]31
D
+72.9° (c 0.11, CHCl3). 1H NMR (CDCl3): δ 1.79 (s, 3H), 2.77
(m, 2H), 2.98 (m, 3H), 3.35 (s, 4H), 3.47-4.34 (m, 10H), 4.56 (s,
1H), 4.95 (m, 2H), 5.46 (s, 1H), 7.24-7.43 (m, 5H). 13C NMR
(CDCl3): δ 19.5, 53.3 (CH2), 55.0, 59.1, 62.8 (CH2), 67.0 (CH2),
69.6 (CH2), 74.5, 75.0, 78.4, 99.2, 102.5, 113.3 (CH2), 126.1, 128.2,
153-155 °C. IR: νmax (CHCl3) 1744 cm-1 1H NMR (CDCl3): δ
.
2.67 (dd, J ) 15.5, 11.8 Hz, 1H), 3.05 (dd, J ) 5.48, 10.3 Hz,
1H), 3.56 (s, 3H), 3.81 (m, 2H), 4.07 (m, 1H), 4.48 (m, 1H), 4.73
(s, 1H), 5.55 (s, 1H), 7.23-7.57 (m, 5H). MS EI: m/z (%) 264
(M+, 2).
128.9, 137.8, 141.5. MS EI: m/z (%) 405 (M+, 5), 374 (M+
OCH3, 5), 350 (M+ - methylallyl, 28).
-
Compound 3rf (0.49 g, 1.21 mmol) was converted to a white
Gen er a l P r oced u r e for th e Syn th esis of 7re a n d 7rf. To
a solution of 3re and 3rf in dichloromethane (10 mL/mmol) was
added mCPBA (50-60%, 2.5 equiv). The reaction mixture was
stirred for 0.5 h at ambient temperature. Dichloromethane was
evaporated under reduced pressure. The crude N-oxide was
dissolved in anhydrous pyridine (10 mL/mmol), and the solution
was heated at 80-90 °C for 3 h. Silica gel (1.5 g/mmol) was added
to the solution, and the mixture was heated further for 8-20 h
at the same temperature. Pyridine was evaporated and coevapo-
rated with toluene. The resulting residue was purified over silica
gel to obtain 7re and 7rf.
solid, 7rf (0.30 g, 78%), following the general procedure. Mp:
76-77 °C. [R]27 +56.9° (c 1.2, CHCl3). IR: νmax (CHCl3) 1733
D
cm-1. 1H NMR (CDCl3; 1H-1H COSY): δ 1.72 (s, 3H, CH3), 2.47
(m, 2H, methylallyl CH2), 3.23 (m, 1H, H-3), 3.47 (s, 4H, OCH3
and H-4), 3.74 (t, J ) 10.3 Hz, 1H, H-6), 4.22 (m, 1H, H-5), 4.36
(m, 1H, H-6), 4.60 (s, 1H, H-1), 4.67 (s, 1H, dCH2), 4.75 (s, 1H,
dCH2), 5.48 (s, 1H, PhCH), 7.24-7.48 (m, 5H, aromatic). 13C
NMR (CDCl3): δ 23.3, 31.1 (CH2), 49.9, 55.6, 64.6, 69.0 (CH2),
81.2, 101.1, 101.2, 111.6 (CH2), 126.1, 128.3, 129.1, 137.3, 143.0,
199.7. MS EI: m/z (%) 318 (M+, 6). Anal. Calcd for C18H22O5:
C, 67.91; H, 6.97. Found: C, 67.40; H, 6.80.
Meth yl 3-C-Allyl-4,6-O-(p h en ylm eth ylen e)-r-D-a r a bin o-
h exop yr a n osid -2-u lose (7re).4b To a suspension of NaH (80%
dispersion in oil, 0.103 g, 3.58 mmol) in anhydrous DMF (10
mL) was added 2r (0.42 g, 1.19 mmol) in anhydrous DMF (10
mL). The reaction mixture was stirred under nitrogen atmo-
sphere for 0.5 h at ambient temperature. Allyl bromide (1.04
mL, 11.96 mmol) was added dropwise to the reaction mixture,
and the mixture was stirred for a further 4.5 h at ambient
temperature. After the usual workup as described for 3rb the
residue was purified over silica gel to yield syrupy methyl 4,6-
O-(phenylmethylene)-3-deoxy-2-O-allyl-3-(4-morpholinyl)-R-D-al-
tro-pyranoside (3re) (0.41 g, 85%). [R]31D +48.1° (c 0.09, CH2Cl2).
1H NMR (CDCl3): δ 2.75 (m, 2H), 2.99 (m, 3H), 3.38 (s, 3H),
3.69-3.83 (m, 6H), 4.09-4.30 (m, 3H), 4.34 (m, 2H), 4.59 (s, 1H),
5.22 (d, J ) 1.1 Hz, 1H), 5.28 (m, 1H), 5.49 (s, 1H), 5.91 (m,
Ack n ow led gm en t. B.R. thanks the Council for
Scientific and Industrial Research, New Delhi, India,
for a fellowship. This work was supported by the
Department of Science and Technology, New Delhi,
India.
Su p p or tin g In for m a tion Ava ila ble: Copies of both 1H
and 13C NMR spectra of 2r, 2â, 5âb, 5rd , and 7rf. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O982199S