Enantioselective synthesis of Aza sugars from amino acids. 2. The 3-hydroxy-2-hydroxymethylpyrrolidines

Full text of DOI:10.1021/jo001736h

J . Org. Chem. 2001, 66, 3621-3626
3621
nucleotides in which the oxygen of the carbohydrate
portion has been replaced by nitrogen or other hetero-
atoms may provide valuable analogues of physiologically
active materials.8
En a n tioselective Syn th esis of Aza Su ga r s
fr om Am in o Acid s. 2.1 Th e
3-Hyd r oxy-2-h yd r oxym eth ylp yr r olid in es2
Linda M. Mascavage,*,† Qing Lu,‡ J essica Vey,‡,§
David R. Dalton,*,‡ and Patrick J . Carroll¶ ,3
Resu lts a n d Discu ssion
As shown in Scheme 1, when the known,9 readily
available 4-(carbomethoxy)-2-phenyl-∆2-oxazolines, L-2
and D-2, derived from, respectively, L- and D-serine
methyl ester, 1, were treated with an excess of DIBAL-H
at low temperature, reduction of each was effected.10
Despite the reports of others,9 our attempts to isolate the
expected aldehydes were unsuccessful. However, an
alcohol quench of the reaction mixture11 followed, in the
same flask, by direct addition of either (+)- or (-)-B-
allyldiisopinocamphenylborane [(+)- or (-)-allyl-Ipc2,
respectively] (freshly prepared from the corresponding
chloroborane and allylmagnesium bromide)12 resulted in
the formation of the specific isomers 3 and 4, i.e., (S,S)-
(+)-4-hydroxy-4-(4,5-dihydro-2-phenyl-4-oxazolyl)-1-
butene and (S,R)-(+)-4-hydroxy-4-(4,5-dihydro-2-phenyl-
4-oxazolyl)-1-butene, respectively, from L-serine and the
respective enantiomeric (+)- and (-)-allyl-Ipc2 isomers.
The formation of the specific isomers 5 and 6, i.e.,
(R,S)-(+)-4-hydroxy-4-(4,5-dihydro-2-phenyl-4-oxazolyl)-
1-butene and (R,R)-(+)-4-hydroxy-4-(4,5-dihydro-2-phen-
yl-4-oxazolyl)-1-butene, respectively, from D-serine and
the respective enantiomeric (+)- and (-)-allyl-Ipc2 iso-
mers is also shown in Scheme 1. The relative stereo-
chemistry of 6 was confirmed by X-ray crystallography.13
Departments of Chemistry, Arcadia University,
Glenside, Pennsylvania 19038, Temple University,
Philadelphia, Pennsylvania 19122, and University of
Pennsylvania, Philadelphia, Pennsylvania 19104
dalton@temple.edu
Received December 13, 2000
In tr od u ction
A number of polyhydroxylated pyrrolidines and pip-
eridines (often called “aminosugars” or “azasugars”) and
related compounds have been found to be potent glycosi-
dase (glycohydrolase) inhibitors.4 Because glycoproteins
mediate cell-cell recognition,5 it is reasoned that inhibi-
tors of glycosidases should have value in the palliation
of viral infections as well as a host of other diseases in
which transmission of information from one cell to
another is important.
In sharp contrast to the substantial body of work on
the synthesis of the eight stereoisomeric 3,4-dihydroxy-
2-hydroxymethylpyrrolidines1 (the physiologically active
“azasugars” formally analogous to the ribosyl fragment
of RNA), relatively little effort has been expended on the
“simpler” four 3-hydroxy-2-hydroxymethylpyrrolidines
(the “azaDNA” analogues). Indeed, despite some indica-
tion of physiological activity reported in the naturally
occurring (2R,3S)-3-hydroxy-2-hydroxymethylpyrrolidine
(13, vide infra) found in Castanospermum australe A.
Cunn,6 most of the synthetic efforts7 resulting in the
formation of these compounds have been directed toward
other ends. Nonetheless, a path to these compounds, as
well as to the corresponding 3,4-dihydroxy-2-hydroxy-
methylpyrrolidines,1 is important since the development
of methods for new types of DNA as well as RNA
* Phone: 215-204-7138. Fax: 215-204-1532.
† Arcadia University.
‡ Temple University.
§ Summer undergraduate research participant.
¶
University of Pennsylvania.
(1) For the first paper in this series, see: Huang, Y.; Dalton, D. R.;
Carroll, P. J . J . Org. Chem. 1997, 62, 372.
(2) Presented, in part, at the 33rd Middle Atlantic Regional Meeting
of the American Chemical Society, Newark, DE, May 2000; ORGN 224.
(3) To whom inquiries concerning the X-ray crystal structure should
be addressed.
Allylation of aldehydes by this method has been
reported to proceed with excellent (g99% ee) enantio-
(4) For leading references, see: (a) Karpas, A.; Fleet, G. W. J .; Dewk,
R. A.; Petrusson, S.; Mangoong, S. K.; Ramsden, J . G.; J acob, G. S.;
Rademacher, T. W. Proc. Nat. Acad. Sci. U.S.A. 1988, 85, 9229. (b)
The Amino Sugars; the Chemistry and Biology of Compounds Contain-
ing Aminosugars; J eanloz, R. W., Balazs, D. A., Eds.; Academic Press:
New York, 1965-1966; Vols. IA, IB, IIA, IIB.
(8) See, for example: Momotake, A.; Mito, J .; Yamaguchi, K.; Togo,
H.; Yokoyama J . Org. Chem. 1998, 63, 7207 and references therein.
(9) (a) Tkaczuk, P.; Thornton, E. R. J . Org. Chem. 1981, 46, 4393.
(b) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361.
(10) Polt, R.; Peterson, M. A.; DeYoung, L. J . Org. Chem. 1992, 57,
5469.
(5) Provencher, L.; Steensma, D. H.; Wong, C.-H. Bioorg. Med. Chem.
1994, 2, 1179.
(6) Nash, R. J .; Bell, E. A.; Fleet, G. W. J .; J ones, R. H.; Williams,
M. H. J . Chem. Soc., Chem. Commun. 1988, 738.
(7) For recent syntheses, see, for example: Sundram, H.; Gole-
biowski, A.; Johnson, C. R. Tetrahedron Lett. 1994, 35, 6975. Dell’Uomo,
N.; Di Giovanni, M. D.; Misiti, D.; Zappia, G.; Monache, G. D.
Tetrahedron: Assymtry 1996, 7, 181 and references therein. Full
structural information is not available for all of the materials reported.
(11) As part of another effort, a variety of alcohols were used to
quench the reduction mixture (Mr. M. Kiernan). Although the reaction
between the resulting aldehyde and carbomethoxymethylene tri-
phenylphosphorane1 was studied in that case instead of the one used
here, his results, which produced a variation of the [Z:E] alkene ratio,
also showed that there was no epimerization at C-4 of the oxazoline.
The results here are in concert with his observations.
10.1021/jo001736h CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/18/2001

3622 J . Org. Chem., Vol. 66, No. 10, 2001
Notes
Sch em e 1a
a
(a) DIBAL-H, R-OH quench.
selectivity.14 Reagent control15 as observed under similar
circumstances16 is expected to apply, and small amounts
(ca. 4-8%) of diastereomeric products from the reaction
of the enantiomerically pure aldehydes with each of the
partially purified adducts. The minor isomer is readily
removed by column chromatography. Although optical
rotations for crude material were not examined, the
observation of optical rotations of identical magnitudes
(within experimental error) for the respective purified
enantiomeric pairs (e.g., 3/6 or 4/5) argues that they are
formed in high enantiomeric excess.
The individual secondary alcohols (3-6) were con-
verted to their corresponding acetates and the carbon-
carbon double bonds oxidized with osmium tetroxide and
sodium metaperiodate to produce the corresponding
labile aldehydes. The latter, without isolation, were
reduced to the primary alcohols 7-10 with sodium
borohydride (Scheme 2).
1
allyl-Ipc2 isomers are seen in the H NMR spectra of the
(12) See, for example: Goulet, M. T. In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L., Ed.; J ohn Wiley & Sons: New
York: 1995, Vol. 1, 103 and references therein.
(13) An author (P.J .C.) has deposited atomic coordinates for this
structure with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK. In addition, both active and static views are available at the senior
author’s website (http://astro.temple.edu/∼dalton).
(14) Racherla, U. S.; Brown, H. C. J . Org. Chem. 1991, 56, 401.
(15) Roush, W. R. In Houben-Weyl, Methods of Organic Chemistry;
Veralg, G. Thieme; Stuttgart, Germany: 1995; E21b, 1410ff.
(16) We are grateful for the constructive comments of anonymous
referees who brought refs 10 and 15 to our attention and suggested
we reexamine our data.
As shown in Scheme 3, the individual primary alcohols
(7-10) were converted to the corresponding tosylates and
the oxazoline rings opened hydrolytically in dilute aque-

Notes
J . Org. Chem., Vol. 66, No. 10, 2001 3623
Sch em e 2a
a
(a) Ac2O, triethylamine; (b) OsO4, THF, NaIO4; (c) NaBH4, MeOH.
Sch em e 3a
a
(a) Na-H, p-toluenesulfonyl chloride; (b) aqueous HCl; (c) aqueous NaOH.
ous HCl, whereupon recyclization to the respective pyr-
iminodeoxyribitol] from L- or D-serine methyl ester has
been effected. Having begun with species of known
absolute configuration, no separation of isomers is re-
quired and each can be prepared specifically.
rolidines ensued. A final treatement with aqueous base
served to hydrolyze the acetate and benzoate ester groups
and produce the desired isomeric 3-hydroxy-2-hydroxy-
methylpyrrolidines 11-14.
Exp er im en ta l Section
Con clu sion
Gen er a l Meth od s. Melting points are uncorrected. Satisfac-
tory high-resolution mass spectrometric analyses (The Pennsyl-
vania State University, College Park, PA or Drexel University,
The synthesis of all four isomeric 3-hydroxy-2-hy-
droxymethylpyrrolidines [the isomers of (+)- and (-)-

3624 J . Org. Chem., Vol. 66, No. 10, 2001
Notes
Philadelphia, PA) have been obtained for all new compounds.
1H (300 and 500 MHz) and 13C (75 MHz) NMR spectra were
obtained on GE QE-300 and Omega-500 NMR spectrometers.
Chemical shifts are reported in parts per million (ppm), δ, from
TMS ) 0.00 ppm. NMR spectra of the deoxyazaribitol isomers
11-14, along with the X-ray crystallographic data for the alkene
6, are provided in the Supporting Information. Infrared (FT-
IR) spectra were taken as neat oils (for noncrystalline materials)
or as KBr pellets for crystalline samples on Mattson 4020,
Nicolet 800, or Digilab FTS-40 spectrometers, and those spectra
along with the 1H and 13C NMR spectra of the reported
intermediates can be obtained from http://astro.temple.edu/
∼dalton or by mail from the senior author. Solvents, reactive
reagents, and column materials were purchased from Acros
Chemical, Fisher Scientific, and/or Aldrich Chemical Companies.
Solvents were distilled under argon prior to use. Optical rota-
tions were taken as noted in a Perkin-Elmer 341 polarimeter.
(S,S)-, (S,R)-, (R,S)-, a n d (R,R)-4-Hyd r oxy-4-(4,5-d ih yd r o-
2-p h en yl-4-oxa zolyl)-1-bu ten es (3, 4, 5, a n d 6). The oxazoline
methyl ester 21 (215 mg, 1.05 mmol) in dry toluene was cooled
to -78 °C in an atmosphere of Ar, and with stirring, DIBAL-H
(1.5 M, 1.3 mL. 1.9 mmol) in toluene was added slowly. The
reaction mixture was stirred at -78 °C for an additional 3 h
and then quenched with precooled MeOH (1 mL); after 0.5 h,
the temperature was allowed to rise to -20 °C where it was held
for an additional 1 h. In the meantime, under an atmosphere of
Ar, one of the enantiomers of diisopinocamphenylborane chloride
(DIP-chloride) (617 mg, 2.039 mmol) in dry Et2O (5 mL) was
cooled to -78 °C and, with stirring, allylmagnesium bromide in
Et2O (2.1 mL of a 1 M solution, 2.1 mmol) was added dropwise.
After stirring at -78 °C for an additional 15 min, the reaction
mixture was allowed to warm to room temperature and 1 h later
recooled to -78 °C. Then, the aldehyde solution prepared above
was transferred, via cannula, over a few minutes into the
allylborane solution. Stirring was continued at -78 °C for an
additional 1 h after which the reaction mixture was allowed to
warm to room temperature over 1 h. When at room temperature,
the reaction mixture was treated with 0.2 mL (5 mmol) of 2.5 N
aqueous NaOH and 0.4 mL (3 mmol) of 30% H2O2. Then, with
stirring, the basic solution was heated to reflux for 0.5 h before
the solution was cooled to room temperature. The organic phase
was separated and washed with water and brine and dried over
MgSO4 and the solvent removed at reduced pressure. The
alkenols were purified by silica gel flash chromatography and
obtained in 89-91% (purified) yields (eluting with hexane:ether
[6:1]). For (S,S)-4-hydroxy-4-(4,5-dihydro-2-phenyl-4-oxazolyl)-
7.72 (d, 2H); 7.39-7.44 (t, 1H); 7.25-7.30 (t, 2H); 5.88-6.02 (m,
1H); 5.14-5.22 (m, 1H); 4.47-4.52 (t, 2H); 4.35-4.42 (m, 2H);
4.28-4.32 (m, 1H); 4.18-4.23 (m, 1H); 2.24-2.43 (m, 2H). 13C
NMR (CDCl3) δ 165.15, 134.61, 131.22, 128.16, 128.07, 126.92,
117.63, 70.73, 70.69, 67.34, 38.38. IR (KBr, cm-1) 3223.8, 3066.0,
1633.3, 1450.1, 1360.7, 1092.3, 962.9, 694.0. HRMS calcd for
[C13H15NO2 + H] 218.1181, found [M + H]+ 218.1174.
(S,S)-, (S,R)-, (R,S)-, a n d (R,R)-4-Hyd r oxy-4-(4,5-d ih yd r o-
2-p h en yl-4-oxa zolyl)-1-b u t en e Acet a t es (3-OAc, 4-OAc,
5-OAc, a n d 6-OAc). A hydroxyalkene (2.9 g, 13.4 mmol) was
dissolved in methylene chloride (100 mL), and triethylamine
(26.7 mmol, 3.73 mL) and acetic anhydride (26.7 mmol, 2.5 mL)
were sequentially added at room temperature. After permitting
the reaction mixture to stir overnight, it was quenched with
water, and the organic phase was separated, washed with water
and brine, and dried over magnesium sulfate. The solvent was
removed at reduced pressure and the residue purified by flash
chromatography on silica gel. The esters (93-96% yield) were
eluted with hexanes-ether (6:4). For (S,S)-4-hydroxy-4-(4,5-
dihydro-2-phenyl-4-oxazolyl)-1-butene acetate (3-OAc), [R]20
)
D
+33.4 (c ) 0.011, CHCl3). 1H NMR (CDCl3) δ 7.89-7.92 (d, 2H);
7.27-7.40 (m, 3H); 5.67-5.80 (m, 3H); 4.99-5.10 (m, 1H); 4.38-
4.45 (m, 1H); 4.25-4.32 (t, 1H); 4.09-4.14 (t, 1H); 2.39-2.45
(m, 2H); 1.93 (s, 3H). 13C NMR (CDCl3) δ 170.45, 164.65, 133.49,
131.34, 128.27, 128.19, 127.48, 117.88, 73.35, 68.69, 68.26, 35.12,
20.83. IR (neat oil, cm-1) 3076.3, 2897.5, 1738.3, 1650.1, 1369.8,
1237.1, 1026.3, 698.5. HRMS calcd for [C15H17NO3 + H] 260.1287,
found [M + H]+ 260.1294. The enantiomer, (R,R)-4-hydroxy-4-
(4,5-dihydro-2-phenyl-4-oxazolyl)-1-butene acetate (6-OAc), [R]20
D
) -33.2 (c ) 0.011, CHCl3). 1H NMR (CDCl3) δ 7.85-7.88 (d,
2H); 7.25-7.36 (m, 3H); 5.62-5.76 (m, 3H); 4.95-5.06 (m, 1H);
4.34-4.41 (m, 1H); 4.22-4.28 (t, 1H); 4.05-4.10 (t, 1H); 2.35-
2.41 (m, 2H); 1.89 (s, 3H). 13C NMR (CDCl3) δ 170.42, 164.62,
133.44, 131.30, 128.24, 128.15, 127.44, 117.85, 73.31, 68.65,
68.21, 35.07, 20.80. IR (neat oil, cm-1) 3076.3, 2897.5, 1738.3,
1651.7, 1369.8, 1237.5, 1026.3, 698.7. HRMS calcd for [C15H17
-
NO3 + H] 260.1287, found [M + H]+ 260.1239. For (S,R)-4-
hydroxy-4-(4,5-dihydro-2-phenyl-4-oxazol-yl)-1-butene acetate (4-
OAc), [R]20 ) +59.6 (c ) 0.015, CHCl3). 1H NMR (CDCl3) δ
D
7.87-7.89 (m, 2H); 7.29-7.42 (m, 3H); 5.67-5.83 (m, 1H); 5.01-
5.09 (m, 3H); 4.22-4.38 (m, 3H); 2.35-2.45 (m, 2H); 1.92 (s, 3H).
13C NMR (CDCl3) δ 170.19, 164.88, 133.12, 131.41, 128.23,
127.32, 118.05, 74.26, 68.99, 68.81, 35.87, 20.87. IR (neat oil,
cm-1) 1739.8, 1648.8, 1371.8, 1234.9. HRMS calcd for [C15H17
-
NO3 + H] 260.1287, found [M + H]+ 260.1294. The enantiomer,
(R,S)-4-hydroxy-4-(4,5-dihydro-2-phenyl-4-oxazolyl)-1-butene ac-
etate (5-OAc), [R]20 ) -58.1 (c ) 0.019, CHCl3). 1H NMR
1-butene (3) [from (-)-DIP-Cl], mp 94-95 °C, [R]20 ) +91.8 (c
D
D
) 0.101, CHCl3). 1H NMR (CDCl3) δ 7.94-7.96 (d, 2H); 7.45-
7.48 (d, 1H); 7.37-7.42 (t, 2H); 5.89-6.03 (m, 1H); 5.12-5.21
(t, 2H); 4.39-4.45 (t, 1H); 4.29-4.35 (m, 1H); 4.20-4.27 (m, 1H);
3.63-3.69 (m, 1H); 3.54 (s, 1H); 2.37-2.42 (m, 2H). 13C NMR
(CDCl3) δ 165.10, 134.67, 131.50, 128.38, 128.25, 127.39, 117.54,
73.16, 70.93, 69.49, 38.35. IR (KBr, cm-1) 3159.3, 3073.9, 1638.9,
1378.2, 1091.9, 687.5. HRMS calcd for [C13H15NO2 + H] 218.1181,
found [M + H]+ 218.1176. The enantiomer, (R,R)-4-hydroxy-4-
(4,5-dihydro-2-phenyl-4-oxazolyl)-1-butene (6) [from (+)-DIP-Cl],
(CDCl3) δ 7.87-7.89 (m, 2H); 7.30-7.43 (m, 3H); 5.68-5.81 (m,
1H); 5.01-5.09 (m, 3H); 4.21-4.41 (m, 3H); 2.33-2.49 (m, 2H);
1.92 (s, 3H). 13C NMR (CDCl3) δ 170.17, 164.85, 133.13, 131.41,
128.22, 127.32, 118.04, 74.25, 68.98, 68.80, 35.84, 20.85. IR (neat
oil, cm-1) 1740.1, 1648.9, 1371.5, 1235.3. HRMS calcd for [C15H17
-
NO3 + H] 260.1287, found [M + H]+ 260.1287.
(S,S)-, (S,R)-, (R,S)-, a n d (R,R)-3-(4,5-Dih yd r o-2-p h en yl-
4-oxa zolyl)-3-a cetoxy-1-p r op a n ols (7, 8, 9, a n d 10). An
acetoxyalkene (2.0 g, 7.7 mmol) was dissolved in dry THF (30
mL) and water (10 mL), and osmium tetroxide (31.6 mg, 0.124
mmol) was added. The reaction mixture was stirred at room
temperature for 5 min, and then sodium periodate (a total of
3.24 g, 15.4 mmol) was added in portions over 0.5 h while the
temperature of the reaction mixture was maintained at room
temperature. The slurry was stirred for an additional 1.5 h and
quenched in water (10 mL). The reaction mixture was extracted
with chloroform (3 × 25 mL), and the organic phases were
combined, washed with brine, and dried over magnesium sulfate.
After removal of the solvent at reduced pressure, the residue
was dissolved in methanol and cooled to 0 °C. Then, with cooling
and stirring, sodium borohydride (300 mg, 7.93 mmol) was added
in portions over 1 h. Stirring was continued for an additional
0.5 h, and the solution was neutralized by dropwise addition of
aqueous 1 N HCl. The solvents were removed at reduced
pressure, and the residue was purified by flash chromatography
on silica gel (eluting with acetone/hexane; 3:1) to produce the
desired primary alcohols (58-62% yield). For (S,S)-3-(4,5-
mp 95-96 °C, [R]20 ) -91.7 (c ) 0.101, CHCl3). 1H NMR
D
(CDCl3) δ 7.96-7.99 (d, 2H); 7.49-7.451 (d, 1H); 7.40-7.45 (t,
2H); 5.90-6.04 (m, 1H); 5.15-5.23 (t, 2H); 4.44-4.50 (t, 1H);
4.32-4.438 (m, 1H); 4.23-4.31 (m, 1H); 3.66-3.72 (m, 1H); 3.31
(s, 1H); 2.39-2.44 (m, 2H). 13C NMR (CDCl3) δ 161.13, 134.54,
131.54, 128.37, 128.29, 127.37, 117.70, 73.22, 70.91, 69.54, 38.42.
IR (KBr, cm-1) 3172.7, 3074.0, 1638.7, 1377.9, 1091.9, 687.5.
HRMS calcd for [C13H15NO2 + H] 218.1181, found [M + H]+
218.1186. The X-ray crystal structure of 6 is provided in the
Supporting Information.12 For (S,R)-4-hydroxy-4-(4,5-dihydro-
2-phenyl-4-oxazolyl)-1-butene (4) [from (+)-DIP-Cl], [R]20
)
D
+42.6 (c ) 0.010, CHCl3). 1H NMR (CDCl3) δ 7.69-7.72 (d, 2H);
7.39-7.44 (t, 1H); 7.25-7.30 (t, 2H); 5.88-6.02 (m, 1H); 5.14-
5.22 (m, 1H); 4.46-4.52 (t, 2H); 4.31-4.42 (m, 2H); 4.18-4.23
(m, 1H); 2.24-2.43 (m, 2H). 13C NMR (CDCl3) δ 165.14, 134.61,
131.22, 128.16, 128.07, 126.93, 117.63, 70.79, 70.69, 67.35, 38.38.
IR (KBr, cm-1) 3223.8, 3077.4, 1633.3, 1450.1, 1360.7, 1092.3,
962.9, 694.0. HRMS calcd for [C13H15NO2 + H] 218.1181, found
[M + H]+ 218.1180. The enantiomer, (R,S)-4-hydroxy-4-(4,5-
dihydro-2-phenyl-4-oxazolyl)-1-butene (5) [from (-)-DIP-Cl],
dihydro-2-phenyl-4-oxazolyl)-3-acetoxy-1-propanol (7) [R]20
)
D
+50.0 (c ) 0.004, CHCl3). 1H NMR (CDCl3) δ 7.87-7.90 (m, 2H);
[R]20 ) -40.9 (c ) 0.010, CHCl3). 1H NMR (CDCl3) δ 7.69-
7.42-7.47 (m, 1H); 7.33-7.38 (m, 2H); 4.40-4.44 (m, 2H); 4.19-
D

Notes
J . Org. Chem., Vol. 66, No. 10, 2001 3625
4.29 (m, 1H); 3.65-3.67 (m, 1H); 3.53-3.61 (m, 1H); 2.01 (s, 3H);
1.83-1.89 (m 2H). 13C NMR (CDCl3) δ 171.13, 165.31, 131.55,
128.26, 127.20, 71.21, 70.28, 69.39, 61.32, 32.78, 20.90. IR (KBr,
cm-1) 3163.4, 1726.2, 1635.5, 1380.3, 1254.8. HRMS calcd for
[C14H17NO4 + H] 264.1236, found [M + H]+ 264.1227. The
enantiomer, (R,R)-3-(4,5-dihydro-2-phenyl-4-oxazolyl)-3-acetoxy-
29.59, 21.54, 20.81. IR (KBr, cm-1) 2965.33, 1739.9, 1646.9,
1363.0, 1176.0. HRMS calcd for [C21H23NSO6 + H] 418.1324,
found [M + H]+ 418.1319. The enantiomer, (R,S)-3-(4,5-dihydro-
2-phenyl-4-oxazolyl)-3-acetoxy-1-propyl tosylate (9-OTs) [R]20
D
) -30.6 (c ) 0.01, CHCl3). 1H NMR (CDCl3) δ 7.72-7.75 (d, J
) 9.0 Hz, 2H); 7.64-7.67 (d, J ) 9.0 Hz, 2H); 7.42-7.47 (m,
1H); 7.31-7.36 (m, 2H); 7.07-7.09 (d, J ) 8.1 Hz, 2H); 4.85-
4.91 (m, 1H); 4.29-4.47 (m, 3H); 4.07-4.21 (m, 1H); 2.27 (s, 3H),
2.04-2.12 (m, 2H); 2.01 (s, 3H). 13C NMR (CDCl3) δ 170.65,
165.33, 149.57, 144.58, 133.69, 131.54, 129.59, 128.32, 127.50,
126.92, 80.91, 69.28, 68.58, 59.98, 31.41, 21.53, 20.81. IR (KBr,
cm-1) 2966.23, 1740.2, 1652.6, 1362.9, 1176.0. HRMS calcd for
[C21H23NSO6 + H] 418.1324, found [M + H]+ 418.1322.
1-propanol (10) [R]20 ) -53.2 (c ) 0.007, CHCl3). 1H NMR
D
(CDCl3) δ 7.85-7.87 (m, 2H); 7.39-7.44 (m, 1H); 7.30-7.35 (m,
2H); 4.34-4.41 (m, 2H); 4.19-4.25 (m, 1H); 3.63-3.66 (m, 1H);
3.53-3.61 (m, 1H); 1.98 (s, 3H); 1.83-1.89 (m 2H). 13C NMR
(CDCl3) δ 171.10, 165.26, 131.52, 128.26, 128.22, 127.21, 71.22,
70.19, 69.35, 61.34, 32.71, 20.88. IR (KBr, cm-1) 3161.4, 1726.2,
1639.7, 1380.4, 1255.4. HRMS calcd for [C14H17NO4 + H]
264.1236, found [M + H]+ 264.1238. For (S,R)-3-(4,5-dihydro-
(S,S)-, (S,R)-, (R,S)-, a n d (R,R)-3-H yd r oxy-2-h yd r oxy-
m eth ylp yr r olid in e Acetoxy Ben zoa tes [11 (-OAc, -OBz), 12
(-OAc, -OBz), 13 (-OAc, -OBz) a n d 14 (-OAc, -OBz)]. A
tosylate (823 mg, 1.98 mmol) was dissolved in methanol (30 mL),
water (2 mL), and aqueous hydrochloric acid (1 M, 2.98 mL).
The resulting solution was stirred at room temperature over-
night and then neutralized by addition of solid sodium bicarbon-
ate. The solvent was removed at reduced pressure and the
residue purified by silica gel flash column chromatography
[eluting with hexane-ethyl acetate (3:7)] to yield the respective
acetoxybenzoates (68-72% yield). For (S,S)-3-acetoxy-2-hy-
2-phenyl-4-oxazolyl)-3-acetoxy-1-propanol (8) [R]20 ) +29.6 (c
D
) 0.005, CHCl3). 1H NMR (CDCl3) δ 7.74-7.76 (m, 2H); 7.39-
7.44 (m, 1H); 7.27-7.32 (t, 2H); 4.39-4.46 (m, 1H); 4.23-4.36
(m, 2H); 4.06-4.09 (m, 1H); 2.05 (s, 3H); 1.81-1.86 (m 2H);
1.66-1 76 (m, 2H). 13C NMR (CDCl3) δ 171.21, 165.32, 131.43,
128.17, 126.87, 71.20, 68.58, 67.74, 61.53, 32.59, 20.93. IR (KBr,
cm-1) 3226.0, 2916.5, 1723.7, 1637.6, 1374.4, 1248.0, 1031.6
HRMS calcd for [C14H17NO4 + H] 264.1236, found [M + H]+
264.1238. The enantiomer, (R,S)-3-(4,5-dihydro-2-phenyl-4-ox-
azolyl)-3-acetoxy-1-propanol (9) [R]20 ) -28.5 (c ) 0.006,
D
CHCl3). 1H NMR (CDCl3) δ 7.66-7.69 (m, 2H); 7.34-7.39 (m,
1H); 7.21-7.27 (t, 2H); 4.32-4.44 (m, 1H); 4.22-4.29 (m, 2H);
4.03-4.10 (m, 1H); 2.02 (s, 3H); 1.77-1.86 (m 2H); 1.64-1 74
(m, 2H). 13C NMR (CDCl3) δ 171.14, 165.22, 131.32, 128.10,
droxymethylpyrrolidine benzoate (11, -OAc, -OBz) [R]20
)
D
-26.8 (c ) 0.5, CHCl3). 1H NMR (CDCl3) δ 8.04-8.07 (m, 2H);
7.54-7.57 (m, 1H); 7.41-7.46 (m, 2H); 4.34 (dd, J ) 6.9 Hz, 12.0
Hz, 2H); 4.24 (m, 2H); 2.54 (q, J ) 6.0 Hz, 1H), 2.28 (q, J ) 6.0
Hz, 1H), 2.06 (s, 3H); 1.67-1.88 (m, 2H). 13C NMR (CDCl3) δ
170.99, 166.44, 133.02, 129.89, 129.59, 128.33, 64.59, 62.75,
31.98, 31.52, 28.33, 20.92. IR (neat oil, cm-1) 3318.3, 1737.2,
1721.7, 1273.7, 1112.6. HRMS calcd for [C14H17NO4 + H]
264.1236, found [M + H]+ 264.1239. The enantiomer, (R,R)-3-
acetoxy-2-hydroxymethylpyrrolidine benzoate (14, -OAc, -OBz)
126.83, 71.23, 68.40, 67.59, 61.55, 32.59, 20.88. IR (KBr, cm-1
)
3224.6, 2911.9, 1722.6, 1637.6, 1374.4, 1249.9, 1062. HRMS calcd
for [C14H17NO4 + H] 264.1236, found [M + H]+ 264.1227.
(S,S)-, (S,R)-, (R,S)-, a n d (R,R)-3-(4,5-Dih yd r o-2-p h en yl-
4-oxa zolyl)-3-a cetoxy-1-p r op yl Tosyla tes (7-OTs, 8-OTs,
9-OTs, a n d 10-OTs). A primary alcohol (1.0 g, 3.8 mmol) was
dissolved in dry THF (10 mL), and a solution of toluenesulfonyl
chloride (876.6 mg, 4.59 mmol) in the same solvent (10 mL) was
also prepared. The two solutions were then added simulta-
neously to a suspension of sodium hydride (729.6 mg, 30.4 mmol)
in dry THF (30 mL) with stirring. The resulting mixture was
heated to 40 °C for 5 h and allowed to cool, and water was added
to destroy the excess sodium hydride. The reaction mixture was
extracted with ethyl acetate (3 × 25 mL), and the combined
organic layers were washed with brine and dried over magne-
sium sulfate. The solvent was removed at reduced pressure, and
the tosylates were purified (58-62% yield) by silica gel flash
column chromatography (eluting with hexanes-ethyl acetate
(1:1). For (S,S)-3-(4,5-dihydro-2-phenyl-4-oxazolyl)-3-acetoxy-1-
[R]20 ) +25.1 (c ) 1.6, CHCl3). 1H NMR (CDCl3) δ 8.05-8.08
D
(m, 2H); 7.55-7.63 (m, 1H); 7.44-7.49 (m, 2H); 4.35 (dd, J )
6.9 Hz, 12.0 Hz, 2H); 4.26 (m, 2H); 2.54 (q, J ) 6.0 Hz, 1H),
2.27 (q, J ) 6.0 Hz, 1H), 2.07 (s, 3H); 1.67-1.88 (m, 2H). 13C
NMR (CDCl3) δ 170.99, 166.44, 133.63, 133.02, 129.04, 128.61,
128.33, 62.80, 60.55, 53.82, 28.63, 28.32, 20.89. IR (neat oil, cm-1
3318.1, 1737.2, 1720.7, 1273.6, 1247.9. HRMS calcd for [C14H17
)
-
NO4 + H] 264.1236, found [M + H]+ 264.1224. For (S,R)-3-
acetoxy-2-hydroxymethylpyrrolidine benzoate (12, -OAc, -OBz)
[R]20 ) -35.9 (c ) 1.1 CHCl3). 1H NMR (CDCl3) δ 8.03-8.06
D
(m, 2H); 7.55-7.59 (m, 1H); 7.42-7.47 (m, 2H); 4.47 (dd, J )
4.8 Hz, 12.0 Hz, 1H); 4.15-4.25 (m, 3H); 2.17-2.21 (m, 1H); 2.04
(s, 3H); 2.01-2.06 (m, 1H); 1.73-1.86 (m, 2H). 13C NMR (CDCl3)
δ 170.97, 166.49, 133.10, 129.60, 128.35, 67.11, 62.49, 34.93,
32.78, 20.85. IR (neat oil, cm-1) 3296.5, 2927.8, 1717.3, 1451.6,
1273.4, 1111.9. HRMS calcd for [C14H17NO4 + H] 264.1236,
found [M + H]+ 264.1239. The enantiomer, (R,S)-3-acetoxy-2-
propyl tosylate (7-OTs) [R]20 ) +15.2 (c ) 0.009, CHCl3). 1H
D
NMR (CDCl3) δ 7.86-7.88 (d, J ) 7.5 Hz, 2H); 7.78-7.81 (d, J
) 7.8 Hz, 2H); 7.45-7.49 (t, J ) 7.2 Hz, 1H); 7.36-7.41 (t, J )
7.5 Hz, 2H); 7.29-7.32 (d, J ) 7.8 Hz, 2H); 4.91-4.97 (m, 1H);
4.65-4.71 (m, 1H); 4.35-4.49 (m, 2H); 4.04-4.13 (m, 1H); 3.81-
3.91 (m, 1H); 2.42 (s, 3H); 1.95 (s, 3H); 1.90-1.95 (m, 2H). 13C
NMR (CDCl3) δ 170.55, 165.63, 145.03, 133.37, 131.71, 129.82,
128.31, 127.78, 127.09, 78.89, 68.13, 59.98, 28.57, 21.59, 20.73.
IR (KBr, cm-1) 2968.3, 1740.2, 1647.3, 1365.68, 1242.4, 1176.2.
HRMS calcd for [C21H23NSO6 + H] 418.1324: Found [M + H]+
418.1319. The enantiomer, (R,R)-3-(4,5-dihydro-2-phenyl-4-ox-
azolyl)-3-acetoxy-1-propyl tosylate (10-OTs) [R]20D ) -16.1 (c )
0.011, CHCl3). 1H NMR (CDCl3) δ 7.85-7.88 (d, J ) 7.5 Hz, 2H);
7.76-7.79 (d, J ) 7.8 Hz, 2H); 7.44-7.49 (t, J ) 7.2 Hz, 1H);
7.35-7.39 (t, J ) 7.5 Hz, 2H); 7.28-7.31 (d, J ) 7.8 Hz, 2H);
4.90-4.96 (m, 1H); 4.64-4.71 (m, 1H); 4.35-4.49 (m, 2H); 4.04-
4.11 (m, 1H); 3.82-3.90 (m, 1H); 2.40 (s, 3H); 1.95 (s, 3H); 1.90-
1.95 (m, 2H). 13C NMR (CDCl3) δ 170.55, 165.63, 145.06, 133.44,
131.78, 129.83, 128.32, 128.36, 127.76, 112.86, 78.91, 68.22,
68.04, 59.97, 28.63, 21.58, 20.73. IR (KBr, cm-1) 2963.3, 1740.7,
1648.9, 1366.4, 1243.6, 1175.9. HRMS calcd for [C21H23NSO6 +
H] 418.1324, found [M + H]+ 418.1316. For (S,R)-3-(4,5-dihydro-
hydroxymethylpyrrolidine benzoate (13, -OAc, -OBz) [R]20
)
D
+37.1 (c ) 1.0, CHCl3). 1H NMR (CDCl3) δ 8.01-8.04 (m, 2H);
7.53-7.58 (m, 1H); 7.40-7.45 (m, 2H); 4.44 (dd, J ) 4.8 Hz, 12.0
Hz, 1H); 4.13-4.25 (m, 3H); 2.17-2.21 (m, 1H); 2.02 (s, 3H);
2.01-2.06 (m, 1H); 1.69-1.86 (m, 2H). 13C NMR (CDCl3) δ
170.96, 166.46, 133.55, 133.09, 129.58, 128.54, 128.34, 67.13,
65.18, 62.49, 58.85, 56.29, 34.92, 33.86, 32.76, 20.83. IR (neat
oil, cm-1) 3296.4, 2957.3, 1732.3, 1451.6, 1271.0, 1112.0. HRMS
calcd for [C14H17NO4 + H] 264.1236, found [M + H]+ 264.1239.
(S,S)-, (S,R)-, (R,S)-, a n d (R,R)-3-H yd r oxy-2-h yd r oxy-
m eth ylp yr r olid in es (11, 12, 13 a n d 14). A solution of sodium
hydroxide (106 mg, 2.65 mmol) in methanol (14.7 mL) was added
to each of the individually purified benzoates (100 mg, 0.379
mmol). The reaction mixture was stirred for 1 h at room
temperature and the solvent removed at reduced pressure. The
residue was triturated with methylene chloride and the meth-
ylene chloride extract purified by silica gel column chromatog-
raphy, eluting with a 10:5:1 mixture of methanol:methylene
chloride:ammonium hydroxide to yield the free bases directly
2-phenyl-4-oxazolyl)-3-acetoxy-1-propyl tosylate (8-OTs) [R]20
D
1
) +32.7 (c ) 0.009, CHCl3). H NMR (CDCl3) δ 7.73-7.76 (d, J
(68-72% yield). For (S,S)-3-hydroxy-2-hydroxymethylpyrrolidine
1
) 9.0 Hz, 2H); 7.65-7.68 (d, J ) 9.0 Hz, 2H); 7.43-7.49 (m,
1H); 7.32-7.37 (m, 2H); 7.10-7.08 (d, J ) 8.1 Hz, 2H); 4.85-
4.91 (m, 1H); 4.30-4.45 (m, 3H); 4.08-4.20 (m, 1H); 2.29 (s, 3H),
2.05-2.13 (m, 2H); 2.02 (s, 3H). 13C NMR (CDCl3) δ 170.66,
165.35, 149.55, 144.58, 133.70, 135.90, 133.70, 131.54, 129.60,
128.32, 128.11, 127.51, 126.94, 80.90, 69.29, 68.61, 59.98, 31.43,
(11) [R]20 ) 24.7 (c ) 1.4, CH3OH). H NMR (CD3OD) δ 3.66-
D
3.78 (m, 3H); 3.47-3.54 (dd, J ) 6.9 Hz, 11.7 Hz, 1H); 2.24-
2.35 (m, 2H); 1.67-1.73 (q, J ) 6.0 Hz, 2H). 13C NMR (CDCl3)
δ 61.08, 58.87, 35.75, 31.68, 29.97. IR (neat oil, cm-1) 3344.9,
1734.4, 1600.7, 1558.6, 1436.8, 1053.2. HRMS calcd for [C5H11
-
NO2 + Na] 140.0687, found [M + Na]+ 140.0686. The enanti-

3626 J . Org. Chem., Vol. 66, No. 10, 2001
Notes
omer, (R,R)-3-hydroxy-2-hydroxymethylpyrrolidine (14) [R]20
)
31.99. IR (neat oil, cm-1) 3415.47, 1599.2, 1560.1, 1452.4. HRMS
D
1
-23.7 (c ) 1.5, CHCl3). H NMR (CD3OD) δ 3.66-3.76 (m, 3H);
3.48-3.54 (dd, J ) 6.9 Hz, 11.7 Hz, 1H); 2.22-2.31 (m, 2H);
1.65-1.71 (q, J ) 6.0 Hz, 2H). 13C NMR (CD3OD) δ 61.28, 59.80,
34.77, 31.63, 30.57. IR (neat oil, cm-1) 3295.0, 1732.8, 1596.2,
1548.5, 1411.5, 1057.2. HRMS calcd for [C5H11NO2 + Na]
140.0687, found [M + Na]+ 140.0686. For (S,R)-3-hydroxy-2-
hydroxymethylpyrrolidine (12) [R]20D ) -43.4 (c ) 1.5, CH3OH).
1H NMR (CD3OD) δ 3.63-3.76 (m, 2H); 3.63 (dd, J ) 4.5 Hz,
12.0 H, 1H); 3.58 (dd, J ) 5.1 Hz, 11.7 Hz, 1H); 1.93-1.99 (m,
2H); 1.62-1.74 (m, 2H). 13C NMR (CD3OD) δ 63.09, 60.39, 39.11,
36.43, 32.68. IR (neat oil, cm-1) 3415.02, 1599.9, 1561.3, 1451.5.
HRMS calcd for [C5H11NO2 + H] 118.0868, found [M + H]+
118.0869. The enantiomer, (R,S)-3-hydroxy-2-hydroxymethylpyr-
calcd for [C5H11NO2 + H] 118.0868, found [M + H]+ 118.0866.
Ack n ow led gm en t. L.M.M. gratefully acknowledges
partial financial support through an Arcadia University
Faculty Development Grant. We also thank Drs. F.
Davis, D. Hill, and P. Sonnet for fruitful discussions and
the former for use of a micropolarimeter.
Su p p or tin g In for m a tion Ava ila ble: The X-ray crystal
structure data for the hydroxyoxazoline 6, 1H NMR spectra
for all of the compounds reported, and 13C NMR spectra for
the isomers 11 and 12 (which are similar to those of 14 and
13, respectively). This material is available free of charge via
the Internet at http://pubs.acs.org.
rolidine (13) [R]20 ) +45.3 (c ) 1.3, CH3OH). 1H NMR (CD3-
D
OD) δ 3.68-3.74 (m, 2H); 3.65 (dd, J ) 4.5 Hz, 12.0 H, 1H);
3.55 (dd, J ) 5.1 Hz, 11.7 Hz, 1H); 1.97-2.03 (m, 2H); 1.62-
1.74 (m, 2H). 13C NMR (CD3OD) δ 62.39, 59.54, 37.81, 35.26,
J O001736H