Nonracemic α-Fluoro Aldehydes: Asymmetric Synthesis of 4-Deoxy-4-fluoro-D-arabinopyranose

Full text of DOI:10.1021/jo9714829

7546
J . Org. Chem. 1997, 62, 7546-7547
Sch em e 1
Non r a cem ic r-F lu or o Ald eh yd es:
Asym m etr ic Syn th esis of
4-Deoxy-4-flu or o-D-a r a bin op yr a n ose
Franklin A. Davis,* Parimala V. N. Kasu,
Gajendran Sundarababu, and Hongyan Qi
Department of Chemistry, Temple University,
Philadelphia, Pennsylvania 19122
Received August 8, 1997
A well-known method for enhancing the biological and
pharmacological activity of a molecule is the site-specific
introduction of a fluorine atom.1-5 Coupled with the
importance of chirality in bioactive compounds, the
development of new and improved methods for the
enantioselective introduction of fluorine is of significance.
Of particular interest in this regard are fluorinated
carbohydrates because they exhibit significant biological
activity and are useful probes of biochemical mecha-
nisms.6 These target molecules are generally prepared
from carbohydrate substrates via multistep procedures
requiring protection and/or functionalization of the sugar
prior to fluorination.7 In this paper, we describe the first
enantioselective synthesis of epimerizable R-fluoro alde-
hydes and their utility as chiral building blocks by the
asymmetric synthesis of 4-deoxy-4-fluoro-D-arabinopy-
ranose 11.
N2 and described them as “unstable”, decomposing on
standing.9 Similar observations were made by Suga and
Schlosser.10 A sugar-derived R-fluoro aldehyde diaste-
reoisomer has been reported,11 and a nonepimerizable
tertiary R-fluoro aldehyde was prepared in a series of
Nonracemic R-fluoro acids and R-fluoro ketones3,4,8
have been reported, but by contrast R-fluoro aldehydes
are rare.9-13 Purrington et al. prepared racemic R-fluoro
aldehydes by treatment of silyl enol ethers with 5% F2/
steps from (S)-monoethyl 2-fluoro-2-methylmalonate.12
A
potential source of nonracemic R-fluoro aldehydes is the
oxidation of enantiopure 2-fluorohydrins readily available
via reduction of R-fluoro carboximides (Scheme 1).
The requisite R-fluoro carboximide 3 was prepared as
follows: J ones oxidation of 3-(benzyloxy)-1-propanol (1)
gave the corresponding acid in 92% yield. The acid,
treated with SOCl2, gave the acid chloride, which was
not isolated but treated in situ with the lithium salt of
(4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone, gener-
ated by reaction with 1.0 equiv of n-BuLi at -78 °C.
Electrophilic fluorination of the sodium enolate of 2 with
N-fluorobenzenesulfonimide (NFSi)14,15 gave (+)-3 in 78%
yield and in a 97:3 dr.16 Flash chromatography improved
the dr to >99:1. The major diastereoisomer has the (R)-
configuration because, as previously established, the
bulky NFSi reagent approaches the enolate from the
sterically least hindered direction.15,17 Optimum condi-
tions involved addition of the enolate of (+)-2 to NFSi at
-78 °C and quenching after 15-30 min. Longer reaction
times and use of the lithium enolate resulted in the
formation of benzyl 2-fluoro-3-(benzyloxy)propionate ap-
parently formed by decomposition of the enolate.18 Re-
duction of CR-(R)-3 with LiBH4 gave the 2-fluorohydrin
(S)-4 in 93% yield and >97% ee.19
(1) For reviews on biologically active organofluorine compounds
see: (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; J ohn Wiley & Sons: New York, 1991. (b) Welch, J . T.
Tetrahedron 1987, 43, 3123. (c) Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J . R., Welch, J . T., Eds.; ACS
Symposium Series 639; American Chemical Society: Washington, D.C.,
1996.
(2) For recent reviews on selective fluorination see: (a) Wilkinson,
J . A. Chem. Rev. 1992, 92, 505. (b) Mascaretti, O. A. Aldrichim. Acta
1993, 26, 47.
(3) For reviews on the synthesis and properties of chiral organo-
fluorine compounds see: Bravo, P.; Resnati, G. Tetrahedron: Asym-
metry 1990, 1, 661. See also: Yamazaki, T.; Welch, J . T.; Plummer, J .
S.; Gimi, R. H. Tetrahedron Lett. 1991, 32, 4267.
(4) For
a review of R-fluorocarbonyl compounds see: Rozen, S.
Tetrahedron 1985, 41, 1111.
(5) Selective Fluorination in Organic and Bioorganic Chemistry;
Welch, J . T., Ed.; ACS Symposium Series 456; American Chemical
Society: Washington, D.C., 1991.
(6) For reviews on fluorinated carbohydrates see: (a) Tsuchiya, T.
Adv. Carbohydr. Chem. Biochem. 1990, 48, 91. (b) Penglis, A. A. E.
Adv. Carbohydr. Chem. Biochem. 1981, 38, 195. (c) Welch, J . T.
Tetrahedron 1987, 43, 3123. (d) Mann, J . Chem. Soc. Rev. 1987, 16,
381. (e) Curd, P. J . J . Carbohydr. Chem. 1985, 4, 451.
(7) (a) Albano, E. L.; Tolman, R. L.; Robins, R. K. Carbohydr. Res.
1971, 19, 63. (b) Butchard, C. G.; Kent, P. W. Tetrahedron 1971, 27,
3457. (c) Wright, J . A.; Fox, J . J . Carbohydr. Res. 1970, 13, 297. (d)
Reichman, U.; Watanabe, K. A.; Fox, J . J . Carbohydr. Res. 1975, 42,
233e. (e) Su, T.-S.; Klein, R. S.; Fox, J . J . J . Org. Chem. 1981, 46, 1790.
(f) Lundt, K.; Pedersen, C. Mikrochem. Acta Suppl. 1966, 126. (g) Dax,
K.; Gla¨nzer, B. I. Carbohydr. Res. 1987, 162, 13. (h) Bols, M.; Lundt,
I. Acta Chem. Scand. 1990, 44, 252.
The oxidations of the fluorohydrin (S)-4 and (R)-2-
(14) Davis, F. A.; Han, W.; Murphy, C. K. J . Org. Chem. 1995, 60,
4730.
(8) Davis, F. A.; Zhou, P.; Murphy, C. K. Tetrahedron Lett. 1993,
34, 3971.
(9) Purrington, S. T.; Lazaridis, N. V.; Bumgardner, C. L. Tetrahe-
dron Lett. 1986, 27, 2715.
(10) Suga, H.; Schlosser, M. Tetrahedron 1990, 46, 4261.
(11) Szarek, W. A.; Hay, G. W.; Perlmutter, M. M. J . Chem. Soc.,
Chem. Commun. 1982, 1253.
(12) Yamazaki, T.; Yamamoto, T.; Kitazume, T. J . Org. Chem. 1989,
54, 83.
(15) Davis, F. A.; Qi, H. Tetrahedron Lett. 1996, 37, 4345.
(16) Selected properties: (+)-2, gum, [R]20 +25.1 (c 1.95, CHCl3);
D
(R)-(+)-3, gum, [R]20 +27.9 (c 0.98, CHCl3); (S)-(+)-4, oil, [R]20 +5.7
D
D
(c 1.13, MeOH); (R)-(+)-5, oil, [R]20 +9.3 (c 2.14, CHCl3); (R)-(-)-6, oil,
D
[R]20D -34.28 (c 0.7, CHCl3); (S-)-(-)-7, oil, [R]20D -21.80 (c 1.99, CHCl3);
(2S,3S,4R)-(+)-8, mp 70-3 °C, [R]20 +10.2 (c 1.08, CHCl3); (+)-9, oil,
D
[R]20 +14.33 (c 2.12, CHCl3); (+)-10, oil, [R]20 +7.64 (c 3.86, MeOH);
D
D
11, oil.
(17) Davis, F. A.; Han, W. Tetrahedron Lett. 1992, 33, 1153.
(18) This compound gave satisfactory elemental analysis and had
spectral properties consistent with its structure.
(13) Patrick, T. B.; Hosseini, S.; Bains, S. Tetrahedron Lett. 1990,
31, 179.
S0022-3263(97)01482-5 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 22, 1997 7547
Ta ble 1. Selective Oxid a tion of F lu or oh yd r in s to
Sch em e 2
r-F lu or o Ald eh yd es 5 a n d 6
a
Determined by 19F NMR on the corresponding imine of (R)-
(+)-R-methylbenzylamine (ref 22). b Isolated yield of crude product.
c C5H5N‚SO3/DMSO/Et3N, see ref 20.
phenyl-2-fluoroethanol17 to R-fluoro aldehydes 5 and 6
was accomplished by treatment with an equivalent
amount of the oxidizing reagent (Table 1). The Swern
oxidation gave racemic material under a variety of
conditions as did a modified Moffatt oxidation procedure
(Table 1, entry 6).20 PCC gave uncharacterizable materi-
als (Table 1, entry 2). The only reagent to give satisfac-
tory yields and ee’s was the Dess-Martin periodinane21
reagent in CH2Cl2 at rt (Table 1, entries 3-5). The
oxidation time proved to be critical, and much lower ee’s
were observed on longer reaction times (Table 1, entry
3). Attempts to purify the R-fluoro aldehydes 5 and 6 by
flash chromatography on silica gel resulted in decomposi-
tion so they were used in crude form in subsequent
reactions (Scheme 2). R-Fluoro aldehydes 5 and 6 exhibit
we had shown that the adjacent fluorine atom in com-
pounds related to 7 have little, if any, stereodirecting
effects in OsO4-catalyzed dihydroxylation.15 If the AD-
mix-â reagents were added separately using K2OsO4‚2H2O,
the reaction was complete within 30 min, affording 8 in
96% yield with no change in the dr. Crystallization from
Et2O/hexane afforded 8 as a single diastereoisomer.
Protection with 2,2-dimethoxypropane (DMP) gave ace-
tonide 9 (87%) followed by deprotection (H2/Pd/C) af-
forded 10 in 97% yield. DIBAL-H reduction presumably
gave an intermediate aldehyde or prealdehyde that could
not be isolated.26
Consequently, the crude reaction mixture was treated
in situ with 1% H2SO4 at 60 °C to remove the acetonide
and acetylated with Ac2O/pyridine to give 1,2,3-tri-O-
acetyl-4-deoxy-4-fluoro-D-arabinopyranose (11) as a 1:1
mixture of anomers that could not be separated by flash
chromatography. The combined yield for the 3 steps was
79%. The structure of 11 is supported by satisfactory
elemental analysis and the similarity of its spectral
properties to the related sugar 1-methyl-4-deoxy-4-fluoro-
L-arabinopyranoside.27
1
resonance absorption in the H NMR at δ 9.76 and 9.81
ppm for the aldehydic proton and at δ -204.8 and -192.5
ppm, respectively, in the 19F NMR. Treatment of 5 and
6 with (R)-(+)-R-methylbenzylamine in CDCl3 gave the
diastereomeric imines within a few minutes and was used
to evaluate the enantiomeric purity by 19F NMR (Table
1).22
Because of the enhanced acidity of the R-fluoro carbon
proton R-fluoro carbonyl compounds are extremely sensi-
tive to base-catalyzed epimerization.17,23 Consequently,
there was considerable concern about whether R-fluoro
aldehydes 5 and 6 would be useful nonracemic building
blocks. Horner-Wadsworth-Emmons reaction of (R)-5
with NaH/triethylphosphonoacetate at -78 °C afforded
a 92:8 E/Z mixture of the allyl fluoride 7, which on
purification by flash chromatography gave pure (E)-7 in
71% yield. Significantly, no epimerization of the R-fluoro
stereogenic center in 7 was detected, which was deter-
mined to be >97% ee by deprotection, reduction (H2/Pd/
C), and formation of the Mosher ester of the resulting
saturated alcohol. Sharpless AD of 7 using AD-mix-â
(MeSO2NH2 in t-BuOH/H2O) for 2 days at rt gave the
dihydroxy compound (2S,3S,4R)-8 as a 97:3 mixture of
diastereomers based on the Sharpless model.24,25 Earlier
In summary, the first examples of chiral nonracemic,
epimerizable R-fluoro aldehydes were prepared, and their
utility was demonstrated by the noncarbohydrate syn-
thesis of 4-deoxy-4-fluoro-D-arabinopyranose 11.
Ack n ow led gm en t. We thank Mr. George Kemmer-
er, Director of NMR facilities at Temple University, for
help with the 19F experiments. This work was sup-
ported by the National Science Foundation.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data (17 pages).
J O9714829
(19) For low yield (4-5%) syntheses of racemic 4 see: Muehlbacher,
M.; Poulter, C. D. J . Org. Chem. 1988, 53, 1026. Landini, D.; Albanese,
D.; Penso, M. Tetrahedron 1992, 48, 4163.
(24) Crispino, G. A.; J eong, J .-S.; Kolbe, H. C.; Wang, Z.-H.; Xu, W.
D.; Sharpless, K. B. J . Org. Chem. 1993, 58, 3785.
(25) For reviews on Sharpless AD see: Cha, J . K.; Kim, N.-S. Chem.
Rev. 1995, 95, 1761. Kolb, H. C.; VanNiewwenhz, M. S.; Sharpless, K.
B. Chem. Rev. 1994, 94, 2483.
(26) An absorption for the aldehyde proton could not be detected by
1H NMR and may be the hemiacetal that forms the aldehyde on acid
hydrolysis.
(20) Evans, D. A.; Bartroli, J . Tetrahedron Lett. 1982, 23, 807.
(21) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(22) The possibility that R-methylbenzylamine could cause some
epimerization of the fluoroaldehyde cannot be ruled out, and the ee’s
are probably minimum values.
(23) Davis, F. A.; Zhou, P.; Murphy, C. K. Tetrahedron Lett. 1993,
34, 3971.
(27) Card, P. J .; Reddy, G. S. J . Org. Chem. 1983, 48, 4734.