Total synthesis of cis- and trans-3-hydroxy-D-proline and (+)-detoxinine

Article abstract of DOI:10.1021/jo951444u

The unnatural enantiomer of the amino acid detoxinine and both diastereomeric 3-hydroxy-D-prolines have been prepared from D-mannitol via the O-silylated hydroxyproline 12 as a common key intermediate.

Full text of DOI:10.1021/jo951444u

566
J . Org. Chem. 1996, 61, 566-572
Tota l Syn th esis of cis- a n d tr a n s-3-Hyd r oxy-D-p r olin e a n d
(+)-Detoxin in e†
J ohann Mulzer* and Andreas Meier
Institut fu¨r Organische Chemie der J ohann Wolfgang Goethe Universita¨t, Marie-Curie-Strasse 11,
D-60439 Frankfurt, Germany
J u¨rgen Buschmann and Peter Luger
Institut fu¨r Kristallographie der Freien Universita¨t Berlin, Takustrasse 6, D-14195 Berlin, Germany
Received August 4, 1995X
The unnatural enantiomer of the amino acid detoxinine and both diastereomeric 3-hydroxy-D-
prolines have been prepared from D-mannitol via the O-silylated hydroxyproline 12 as a common
key intermediate.
Peptide structures with proline components have re-
to hydrogen bonding between the hydroxyproline’s hy-
droxyl group and the peptide backbone. The elaboration
of the biological active (â-turn) structure of the polypep-
tide antibiotic telomycin8 (3)sproduced by streptomyces
spp. from florida soilsalso depends on trans-3-hydrox-
yproline, which induces strong preferences for this struc-
tural motif. Telomycin is the only naturally occuring
substance containing the cis isomer of 3-hydroxyproline,
which stabilizes the second one of the two â-turns.9 The
chirality of the amino acids in the central position (i + 1
or i + 2) of a turn have a profound effect on the type of
turn (I, II, I′, or II′) which is formed.10 Several syntheses
of cis- and trans-3-hydroxyproline have been described,11
which among other approaches are based on Dieckmann-
type cyclization,11d a reductive amination of a suitably
substituated amino aldehyde11b and on structural ma-
nipulations of pyroglutamate,11c respectively. In previous
papers,12 we have demonstrated the potential of our
D-mannitol-based SN2-cyclization methodology in the
synthesis of optically pure pyrrolidine-type natural prod-
ucts.
ceived considerable interest over the past few years.1,2
For instance, detoxinine3 (1) is a constituent of the
depsipeptide complex detoxine (2) which is a mixture of
several components and has been isolated from the
fermentation broth of streptomyces caespitosus var. detox-
icus 7072 GC1.
Detoxines are applied as selective antagonists against
the cytotoxic activity of the antibiotic blasticidin S,
without impeding the antibiotic effect.4 So far, 1 has been
prepared in racemic form5 or as the natural enantiomer
((-)-1).6
trans-3-Hydroxy-L-proline has been isolated from med-
iterranean sponge and from collagen hydrolysates of
various sources.7 Hydroxyproline formation in collagen
leads to enhanced stability of the collagen triple helix due
† Dedicated to Professor Helmut Vorbru¨ggen on the occasion of his
65th birthday.
Now we extend this approach to the first synthesis of
the unnatural detoxinine enantiomer ((+)-1) and of the
X Abstract published in Advance ACS Abstracts, J anuary 1, 1996.
(1) (a) Hirschmann, R. Angew. Chem. 1991, 103, 1305-1330. (b)
Giannis, A.; Kolter, T. ibid. 1993, 105, 1303-1326.
(2) Degrado, W. F. Adv. Protein Chem. 1988, 39, 51-118.
(3) (a) Shimazu, A. Experientia 1981, 37, 365. (b) Otake, N.;
Furihata, K.; Yonehara, H. J . Antibiot. 1974, 484.
(8) Sheehan, J . C.; Whitney, J . G. J . Am. Chem. Soc. 1963, 85, 3863-
3865.
(9) Kumar, N. G.; Urry, D. W. Biochemistry 1973, 12, 4392.
(10) Rose, G. D.; Gierasch, L. M.; Smith, J . A. Adv. Protein Chem.
1985, 37, 1-98.
(11) (a) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1989, 54,
1866-1875. (b) J urczak, J .; Prokowicz, P.; Golebiowski, A. Tetrahedron
Lett. 1993, 34, 7107-7110. (c) Cooper, J .; Gallagher, P. T.; Knight, D.
W. J . Chem. Soc., Perkin Trans. 1 1993, 1313-1317. (d) Herdeis, C.;
Hubmann, H. P.; Lotter, H. Asymmetry 1994, 5, 119-128. (e) Sibi, M.
P.; Christensen, F. W. Tetrahedron Lett. 1995, 36, 6213-6216.
(12) (a) Mulzer, J .; Angermann, A. Tetrahedron Lett. 1983, 2843-
2846. (b) Mulzer, J .; Becker, R.; Brunner, E. J . Am. Chem. Soc. 1989,
111, 7500. (c) Mulzer, J .; Sharp, M. Synthesis 1993, 615.
(4) Kakinuma, K.; Otake, N; Yonehara, H. Tetrahedron Lett. 1972,
2509-2512.
(5) Ha¨usler, J . Liebigs Ann. Chem. 1983, 982-992
(6) (a) Ohfune, Y.; Nishio, H. Tetrahedron. Lett. 1984, 25, 4133-
4136. (b) J oullie, M. M.; Ewing, W. R.; Harris, B. D.; Bhat, K. L.
Tetrahedron 1986, 42, 2421-2428. (c) Kogen, H.; Kadokawa, H.;
Kurabayashi, M. J . Chem. Soc., Chem. Commun. 1990, 1240-1241.
For (2S,3R)-3-Hydroxyproline methyl ester, see: Sibi, M. P.; Chris-
tensen, F. W. Tetrahedron Lett. 1995, 36, 6213-6216.
(7) Irreverre, F.; Morita, K.; Robertson, A. V.; Witkop, B. J . Am.
Chem. Soc. 1963, 85, 2824.
0022-3263/96/1961-0566$12.00/0 © 1996 American Chemical Society

Synthesis of cis- and trans-3-Hydroxy-D-proline
J . Org. Chem., Vol. 61, No. 2, 1996 567
Sch em e 1
3-hydroxy-D-prolines 23 and 25, respectively. Retrosyn-
thetic analysis leads to hydroxyproline aldehyde 4 which
in turn is to be prepared from the acyclic amine 5 via
intramolecular SN2-displacement. Amine 5 should be
accessible from the homoallylic alcohol 6 (Scheme 1).
Syn th esis of (+)-Detoxin in e. Known alcohol 6,
easily available in three steps from D-mannitol,12 is
converted into azide 9 via standard reactions. Protection
of the 1-OH function and mesylation of the 2-OH function
generates intermediate 11 with high regioselectivity
(Scheme 2).
Staudinger reaction of the azide with triphenylphos-
phane and base-catalyzed hydrolysis of the phosphine
imine releases the free amine which immediately cyclizes
under inversion of configuration to stereochemically pure
prolinol 12 (Scheme 3). N-BOC-protection and desilyla-
tion of the primary hydroxyl function furnishes alcohol
13 which is oxidized to aldehyde 14 under Swern condi-
tions.13 Aldehyde 14 is configurationally stable despite
its cis-configuration around the five-membered ring and
even maintains its configurational integrity during the
ester enolate addition, furnishing the hydroxy esters 15
and 16 in a ratio of 10:1. Aldehyde 14 has been prepared
by J oullie et al. in racemic form6b and shows spectroscopic
data similar to ours. In the same publication, the
racemic aldehyde was submitted to an aldol addition with
Braun’s HYTRA reagent,14 but the diastereoselection was
only 2:1 in this case.
Sch em e 2
The remarkable stereoselectivity in our experiment
may be interpreted via a chelate intermediate 17 formed
from the lithium cation and the aldehyde and amide
oxygens. The silyl protective group prevents any chelate
formation with the 4-oxygen and shields the si-face of
the carbonyl toward the nucleophilic attack.
Sch em e 3
The configuration of 18 is confirmed by an X-ray crystal
structure analysis of the corresponding acetonide 19
(Figure 1), which is, moreover, in the form of the
enantiomer,6a a known compound.
Deprotection of 18 generates free (+)-1, identical with
the enantiomer6b in all spectroscopic data and the abso-
lute value of the optical rotation.
Syn th esis of cis- a n d tr a n s 3-Hyd r oxy-D-p r olin e.
For the synthesis of cis-3-hydroxy-D-proline, the key
intermediate 12 was N-protected with benzyl carbamate
as an acid-resistent protective group. Selective desily-
lation of the TBS ether with aqueous acetic acid leads to
the primary alcohol 20. Under Swern conditions, the
hydroxyl group was smoothly oxidized to aldehyde 21,
A possible epimerization of the stereogenic center R to
the carbonyl group was excluded on the basis of NOE,
H,H-COSY 90, and ROESY (short time NOE) experi-
ments which show that the two observed species are
rotamers with respect to the carbamate CO-N bond.
Interestingly, there is only one set of signals in DMSO-
d6. This demonstrates that the effect is not induced by
a steric effect of the benzyl group. Instead, the hindered
rotation may be due to a dipolar interaction between the
carbamate and the aldehyde. The high polarity of DMSO
could interrupt this interaction and thus enhance the
rotational freedom of the carbamate. With respect to
1
which shows two sets of H-NMR signals in CDCl3 at
room temperature (Figure 2).
(13) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(14) Braun, M.; Devant, R. Tetrahedron Lett. 1984. 25, 5031.

568 J . Org. Chem., Vol. 61, No. 2, 1996
Mulzer et al.
alcohol 6, is available in the form of all four diastereomers
which renders an unusual stereochemical flexibility to
our synthesis.15 Currently, (+)-1 is used in detoxine
structures to test the change in the physiological activi-
ties. Additionally, the incorporation of 23, 25, and (+)-1
in peptidomimetics possibly useful as LHRH antago-
nists16 is also being considered.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed in dried
and purified solvents and monitored by TLC (plates, Merck
5554). Preparative column chromatography was performed
on Merck silica gel 60 F-254, mesh 230-400, with typically
10-30 g of silica gel per gram of substance. NMR spectra were
recorded in CDCl3 with TMS as internal standard. Optical
rotations were determined at 22 °C in CHCl3 (unless otherwise
stated) at 589 nm.
F igu r e 1. Crystal structure of 19.
(2R,3S)-3-O-(ter t-Bu tyld ip h en ylsilyl)-1,2-O-isop r op yli-
d en e-5-h exen e-1,2,3-tr iol (7). To a solution of alcohol 612
(45 g, 0.26 mol), imidazole (75 g, 1.1 mol), and a catalytic
amount of DMAP (0.4 g) in anhydrous DMF (300 mL) was
added tert-butyldiphenylsilyl chloride (80 g, 0.29 mol), and the
mixture was stirred at rt for 24 h. Then the reaction mixture
was treated with H2O (ca. 10 mL) and stirred for 1 h. The
solvents were evaporated, and the residue was partitioned
between H2O (300 mL) and Et2O (600 mL). The aqueous layer
was extracted twice with additional Et2O. The combined
organic layers were washed with brine (300 mL), concentrated
in vacuo, and purified by flash column chromatography
(hexane/EtOAc, 10:1) to give 7 (105 g, 98%) as a colorless
viscous oil: [R]20D ) +1.1 (c ) 1.4, CHCl3); 1H-NMR (250 MHz)
δ ) 1.16 (s, 9H), 1.40 (s, 3H), 1.43 (s, 3H), 2.24 (m, 2H), 3.88
(dd, J ) 8.0, 7.5 Hz, 1H), 4.04 (mc, 2H), 4.20 (dd, J ) 8.3, 7.5
Hz, 1H), 4.96-5.10 (m, 2H), 5.76-5.92 (m, 1H), 7.40-7.54 (m,
6H), 7.76-7.86 (m, 4H); 13C-NMR (63 MHz) δ 19.39, 25.32,
26.46, 27.01, 38.55, 66.14, 73.05, 77.77, 108.69, 117.45, 127.54,
129.70, 133.58, 133.81, 134.00, 135.98; IR (film, KBr) ν 3072
m, 2959 m, 2858 m, 1472 m, 1380 m, 1370 m, 1212 m, 1112 s
Sch em e 4
(br), 998 m, 915 s, 859 s, 822 s, 740 s, 702 vs, 610 s, 510 cm-1
;
Sch em e 5
MS (80 eV, EI, 140 °C) m/z 395 (5.1), 353 (74.9), 295 (100),
225 (64.3), 199 (28.7), 135 (25.3). Anal. Calcd for C25H34O3Si
(410.6273): C, 73.13; H, 8.35. Found: C, 73.32; H, 8.26.
(2R,3S)-3-O-(ter t-Bu tyld ip h en ylsilyl)-1,2-O-isop r op yli-
d en ep en ta n e-1,2,3,5-tetr ol (8). Compound 7 (25 g, 61 mmol)
in technical MeOH (600 mL) was ozonized at -78 °C until a
slightly blue color resulted. Excess ozone was removed by
bubbling oxygen through the mixture. NaBH4 (11.6 g, 0.3 mol)
was added in seven portions, and the mixture was stirred
vigorously until it reached rt. The solvent was removed under
reduced pressure, and the residue was dissolved in H2O (400
mL). After being stirred for 24 h, the mixture was extracted
with Et2O. The combined organic layers were washed with
brine, concentrated in vacuo, and purified by flash column
chromatography (hexane/EtOAc, 6:1) to give 8 (20.5 g, 81%)
as a colorless viscous liquid: [R]20 ) +1.2 (c ) 2.6, CHCl3);
D
potential epimerization of the aldehyde 21, even a high-
temperature 1H-NMR spectrum in DMSO-d6 did not
reveal the appearance of additional signals. There is also
chemical evidence for the configurational stability of 21
as both the oxidation to the carboxylic acid 22 and the
reduction to alcohol 20 gave isomerically pure material.
O- and N-deprotection leads to product 23 in 11 steps
with an overall yield of 46%. Deprotection with TBAF
gave an inseparable mixture of 23 and ammonium salts
(Scheme 4).
The trans isomer 23b was synthesized analogously and
with identical yields from alcohol 7b (Scheme 5) (for data
see the supporting information).
In conclusion, we have prepared the unnatural enan-
tiomer of detoxinine ((+)-1) from 6 in 11 steps and an
overall yield of 25%. The route has also opened an access
to the 3-hydroxy-D-prolines 23 and 25 in optically and
diastereomerically pure form. The starting material,
1H-NMR (250 MHz) δ 1.04 (s, 9H), 1.28 (s, 3H), 1.30 (s, 3H),
1.76-1.84 (m, 2H), 2.24 (t(br), J ) 5.0 Hz, 1H), 3.58 (mc, 2H),
3.64 (dd, J ) 8.5, 7.0 Hz, 1H), 3.82 (dd, J ) 11.3, 6.3 Hz, 1H),
3.98 J ) 8.3, 6 Hz, 1H), 4.08-4.18 (m, 1H), 7.32-7.44 (m, 6H),
7.64-7.70 (m, 4H); 13C-NMR (63 MHz) δ 19.32, 25.28, 26.29,
26.90, 37.55, 58.95, 67.68, 73.18, 78.52, 109.23, 127.63, 129.85,
13.22, 133.56, 135.83; IR (film, KBr) ν 3445 s (br), 3071 m,
2932 m, 2890 m, 1473 m, 1428 s, 1259 s (br), 1112 s (br), 1074
s (br), 822 s, 703 vs, 611 s, 508 cm-1; MS (80 eV, EI, 250 °C)
m/z 399 (2.7), 357 (1.7), 313 (7.5), 299 (12.2), 269 (48.1), 221
(100), 199 (71.1), 177 (17.8), 135 (20.7). Anal. Calcd for
C24H34O4Si (414.6157): C, 69.53; H, 8.27. Found: C, 69.25;
H, 8.01.
(15) (a) Rao, A. V.; Reddy, E. R.; J oshi, B. V.; Yadar, J . S. Terahedron
Lett. 1987, 28, 4697. (b) Roush, W. R.; Walts, A. E.; Hoong, L. K. J .
Am. Chem. 1985, 107, 8186-8190. (c) Hubschwerlen, C. Synthesis
1986, 962-964.
(16) (a) Ljunqvist, A.; Feng, D.; Bowers, C.; Hook, W. A.; Folkers,
K. Tetrahedron 1990, 46, 3297. (b) Allen, R. C. Annual Reports in
Medical Chemistry 1988, 23, 210.

Synthesis of cis- and trans-3-Hydroxy-D-proline
J . Org. Chem., Vol. 61, No. 2, 1996 569
F igu r e 2. 1H-NMR-spectra of 21 in CDCl3 (A) and DMSO-d6 (B).
(2R,3S)-5-Azid o-3-O-(ter t-bu tyld ip h en ylsilyl)-1,2-O-iso-
p r op ylid en ep en ta n e-1,2,3-tr iol (9). Alcohol 8 (20 g, 48
mmol) in pyridine (100 mL) was treated with methanesulfonyl
chloride (7.2 g, 63 mmol) at 0 °C and strirred at rt for 9 h. The
mixture was quenched with H2O (10 mL) and stirred for 1 h.
The solvents were removed under reduced pressure, and the
residue was filtered through silica gel. The resulting crude
product was dissolved in DMF (250 mL), treated with NaN3
(15.6 g, 240 mmol), and stirred vigorously for 12 h at 65 °C.
After the mixture was cooled to rt, H2O was added and the
solution was extracted with ether (4 × 250 mL). The combined
organic layers were washed with brine, concentrated in vacuo,
and purified by flash column chromatography (hexane/EtOAc,
(51.8), 267 (14.6), 252 (43.9), 225 (38.1), 218 (20.6), 199 (100),
183 (50.3), 135 (35.7). Anal. Calcd for C24H33N3O3Si (439.6285):
C, 65.57; H, 7.57; N, 9.56. Found: C, 65.78; H, 7.26; N, 9.41.
(2R,3S)-5-Azid o-1-O-(ter t-bu tyld im eth ylsilyl)-3-O-(ter t-
bu tyld ip h en ylsilyl)p en ta n e-1,2,3-tr iol (10). Compound 9
(30 g, 68 mmol) was hydrolyzed with a mixture of HOAc/H2O
6:1 at rt for 24 h. The solvents were removed under reduced
pressure, and the residue was dried in vacuo at 40 °C for 6 h
to give (2R,3S)-5-azido-3-O-(tert-butyldiphenylsilyl)pentane-
1,2,3-triol (26.1 g, 96%) as a waxy solid: [R]20 ) +26.9 (c )
D
3.2, CHCl3); 1H-NMR (250 MHz) δ 1.10 (s, 9H), 1.60-1.76 (m,
1H), 1.84 (mc, 1H), 3.12-3.28 (m, 1H), 3.30-3.42 (m, 1H),
3.48-3.62 (m, 2H), 3.68 (mc, 1H), 3.86 (dt, J ) 6, 5 Hz, 1H),
4-5 (s (br), D2O-exchange position: 2H), 7.38-7.52 (m, 6 H),
7.66-7.76 (m, 4H); 13C-NMR (63 MHz) δ 19.34, 20.59, 26.95,
31.71, 47.33, 63.14, 71.84, 74.21, 127.75, 127.79, 129.99,
132.86, 133.15, 135.74, 135.76; IR (film, KBr) ν 3405 vs (br),
3072 m, 3050 m, 29.57 m, 2933 m, 2892 m, 2096 vs, 1713 s,
1589 w, 1473 m, 1462 m, 1428 s, 1262 s (br), 1112 vs (br), 823
s, 740 s, 703 vs, 612 cm-1; MS (80 eV, EI, 150 °C) m/z 384
(1.3), 338 (5.5), 296 (20.5), 225 (9.2), 218 (12.0), 199 (100), 183
(17.8), 163 (30.9), 135 (21.4), 91 (13.9). Anal. Calcd for
C21H29N3O3Si (399.5639): C, 63.13; H, 7.32; N, 10.52. Found:
C, 63.44; H, 7.39; N, 10.27. To a solution of the diol (25 g, 63
mmol), imidazole (12.9 g, 190 mmol), and a catalytic amount
10:1) to give 9 (19.6 g, 93%) as a colorless oil: [R]20 ) +15.2
D
1
(c ) 3.0, CHCl3); H-NMR (250 MHz) δ 1.06 (s, 9H), 1.30 (s,
6H), 1.70-1.94 (m, 2H), 3.32 (dt, J ) 7.5, 2.5 Hz, 2H), 3.58
(dd, J ) 8, 6.5 Hz, 1H), 3.76 (dd, J ) 11.3, 6.3 Hz, 1H), 3.92
(dd, J ) 8, 7 Hz, 1H), 4.06 (t, J ) 6.3 Hz, 1H), 7.36-7.50 (m,
6H), 7.66-7.76 (m, 4H); 13C-NMR (63 MHz) δ 19.38, 25.19,
26.37, 26.95, 33.02, 47.23, 67.40, 71.96, 78.31, 109.20, 127.65,
127.73, 129.87, 129.94, 133.20, 133.33, 135.79, 135.85; IR (film,
KBr) ν 2985 m, 2958 m, 2891 m, 2859 m, 2096 vs, 1590 w,
1473 m, 1428 s, 1380 m, 1370 m, 1262 m, 1112 s, 1075 s (br),
822 s, 741 s, 703 vs, 612 s, 508 s cm-1; MS (80 eV, EI, 120 °C):
m/z 424 (2.9), 396 (1.3), 382 (82.0), 338 (7.3), 317 (11.9), 296

570 J . Org. Chem., Vol. 61, No. 2, 1996
Mulzer et al.
of DMAP (0.2 g) in anhydrous THF (750 mL) was added
dropwise a solution of tert-butyldimethylsilyl chloride (9.9 g,
66 mmol) in THF (220 mL) at 0 °C for 3 h. The reaction
mixture was stirred for 24 h until rt was reached. The solution
was worked up as described for preparation of compound 7
and purified by flash column chromatography (hexane/EtOAc,
2H), 4.08 (mc, 1H), 4.20 (mc, 1H), 4.36-4.48 (m, 1H), 7.36-
7.52 (m, 6H), 7.64-7.72 (m, 4H); 13C-NMR (63 MHz) δ -5.62,
14.11, 18.02, 19.18, 22.59, 25.82, 26.84, 32.55, 43.72, 59.22,
60.48, 66.44, 71.33, 72.71, 127.72, 128.32, 129.73, 133.34,
135.63, 154.44; IR (film, KBr) ν 3437 s (br), 3071 m, 2960 m,
2931 m, 2891 s, 2858 s, 1697 vs (br), 1674 vs (br), 1367 s, 1255
m, 1174 vs, 1112 vs, 1041 s, 822 s, 740 s, 702 vs, 610 s, 509 s
cm-1; MS (80 eV, EI, 250 °C) m/z 454 (0.1), 424 (0.1), 398 (0.5),
382 (2.9), 342 (100), 324 (6.0), 290 (6.1), 199 (25.0), 135 (5.8),
91 (4.1), 57 (9.0). Anal. Calcd for C26H37NO4Si (455.67): C,
68.53; H, 8.18; N, 3.07. Found: C, 68.22; H, 7.78; N, 2.88.
(3R)- a n d (3S)-ter t-Bu tyl 3-h yd r oxy-3-((2S,3S)-3-(ter t-
b u t yld ip h en ylsiloxy)-N-(ter t-b u t oxyca r b on yl)-2-p yr r o-
lid in yl)p r op ion a te (15) a n d (16). A cold (-78 °C), well-
stirred solution of DMSO (5.6 g, 72 mmol) in CH2Cl2 (250 mL)
was treated dropwise with oxalyl chloride (3.82 g, 30 mmol).
After 30 min, compound 13 was added, and the mixture was
stirred for 45 min at -78 °C. NEt3 (15 g, 150 mmol) was
added, and the solution was stirred until rt was reached. The
solvents were removed under reduced pressure, and the
residue was extracted with Et2O (3 × 300 mL)-H2O (1 × 200
mL), dried with MgSO4, and concentrated in vacuo (bath
temperature maximum 30 °C). The resulting aldehyde was
added dropwise without further purification to a cold (-100
°C) solution of tert-butyl acetate (5.8 g, 50 mmol) and LDA
(60 mmol) in ether (200 mL). The reaction mixture was stirred
at -100 °C for 6 h and at rt for 4 h. The solvents were
evaporated in vacuo, and the residue was purified by flash
column chromatography (hexane/EtOAc, 6:1) to give 15 (6.7
6:1) to give 10 (28.8 g, 89%) as a colorless viscous oil: [R]20
)
D
-9.4 (c ) 2.4, CHCl3); 1H-NMR (270 MHz) δ 0.00 (s, 3H), 0.02
(s, 3H), 0.86 (s, 9H), 1.10 (s, 9H), 1.70-1.84 (m, 1H), 1.86-
2.00 (m, 1H), 2.46 (d, J ) 2.5 Hz, D2O-exchange position: 1H),
3.20-3.48 (m, 3H), 3.56-3.72 (m, 2H), 3.86 (mc, 1H), 7.36-
7.48 (m, 6H), 7.66-7.76 (m, 4H); 13C-NMR (68 MHz) δ -5.57,
-5.52, 19.40, 25.76, 26.98, 31.56, 47.46, 64.04, 71.52, 73.83,
127.67, 129.85, 135.78, 135.80; MS (80 eV, EI, 120 °C) m/z 498
(0.3), 470 (0.8), 456 (32.1), 428 (12.2), 410 (9.2), 378 (7.6), 350
(17.9), 306 (15.5), 296 (29.0), 235 (13.1), 225 (17.5), 199 (100),
195 (30.0), 183 (15.9), 135 (62.8), 73 (76.0). Anal. Calcd for
C27H43N3O3Si2 (513.820): C, 63.11; H, 8.43; N, 8.18. Found:
C, 62.96; H, 8.29; N, 8.41.
(2R,3S)-5-Azid o-1-O-(ter t-bu tyld im eth ylsilyl)-3-O-(ter t-
b u t yld ip h en ylsilyl)-2-O-(m et h ylsu lfon yl)p en t a n e-1,2,3-
tr iol (11). Compound 10 (28 g, 54 mmol) in pyridine (175 mL)
was mesylated as described for compound 9 to give 11 (31.3 g,
98%) as a colorless viscous oil after flash chromatography
(hexane/EtOAc, 6:1): [R]20D ) +21.3 (c ) 2.8, CHCl3); 1H-NMR
(250 MHz) δ 0.08 (s, 3H), 0.10 (s, 3H), 0.88 (s, 9H), 1.12 (s,
9H), 1.24-1.36 (m, 1H), 1.80 (mc, 2H), 3.00 (s, 3H), 3.12-3.24
(m, 1H), 3.82-3.94 (m, 2H), 4.12 (mc, 1H), 4.70 (m, 1H), 7.38-
7.54 (m, 6H), 7.66-7.80 (m, 4H); 13C-NMR (63 MHz) δ -5.54,
18.19, 19.40, 25.76, 26.92, 32.46, 38.48, 47.40, 61.85, 70.93,
85.45, 127.74, 127.79, 129.97, 130.09, 132.18, 133.28, 135.73,
136.07; MS (80 eV, EI, 200 °C) m/z 548 (1.0), 534 (1.6), 506
(80.7), 410 (19.4), 351 (9.6), 331 (11.3), 296 (13.4), 277 (100),
240 (10.1), 209 (16.9), 199 (37.4), 135 (50.6), 89 (27.7), 37 (38.7).
Anal. Calcd for C28H45N3O5SSi2 (591.9176): C, 56.82; H, 7.66;
N, 7.10. Found: C, 57.22; H, 8.03; N, 6.99.
g, 47%) and 16 (0.68, 4.8%) as colorless viscous oils: 15: [R]20
D
1
) -19.2 (c ) 0.9, CHCl3); H-NMR (270 MHz) δ 1.08 (s, 9H),
1.42 (s, 9H), 1.48 (s, 9H), 1.66-1.82 (m, 1H), 2.02-2.12 (m,
1H), 2.48 (t(br), J ) 12.5 Hz, 1H), 2.56-2.74 (m, 1H), 3.06-
3.26 (m, 2H), 3.34 (dt, J ) 11.5, 2 Hz, 1H), 3.80 (mc, 1H), 4.36
(dt, J ) 10, 8.7 Hz, 1H), 4.43 (mc, 1H), 7.34-7.48 (m, 6H),
7.60-7.70 (m, 4H); 13C-NMR (68 MHz) δ -5.32, 18.75, 26.65,
31.81, 43.34, 58.36, 61.15, 65.68, 72.05, 127.77, 128.27, 129.88,
132.83, 133.34, 135.18, 137.00, 154.25, 171.21; IR (film, KBr)
ν 3435 s (br), 3069 m, 2961 m, 2931 m, 2891 s, 2858 s, 1695
vs, 1674 vs, 1472 s, 1427 s, 1407 vs, 1367 s, 1255 m, 1174 vs,
1112 vs, 822 s, 740 s, 700 vs, 607 m cm-1; MS (80 eV, EI; 130
°C) m/z 570 (0.1), 569 (0.1), 551 (1.7), 512 (0.4), 496 (1.5), 465
(9.2), 440 (20.9), 412 (10.1), 400 (35.8), 368 (32.0), 356 (57.4),
324 (48.6), 290 (67.3), 278 (17.5), 199 (64.4), 169 (26.6), 135
(25.7), 113 (38.7), 57 (100). Anal. Calcd for C32H47NO6Si
(2S,3S)-2-[(ter t-Bu t yld im et h ylsiloxy)m et h yl]-3-(ter t-
bu tyld ip h en ylsiloxy)p yr r olid in e (12). To a solution of 11
(13 g, 25 mmol) in anhydrous THF (200 mL) was added
triphenylphosphine (7.9 g, 30 mmol) in eight portions (atten-
tion: vigorous N2 evolution). The mixture was stirred at rt
for 7 h and then treated with aqueous 1 M NaOH (2.5 mL)
and refluxed for 36 h. The solvents were removed under
reduced pressure, and the residue was purified by flash column
chromatography (CH2Cl2/MeOH/NH4OH, 95:5:0.5) to give 12
(10.8 g, 92%) as colorless viscous liquid: [R]20 ) -4.0 (c )
(569.81): C, 67.45; H, 8.31; N, 2.56. Found: C, 67.32; H, 8.26;
D
1
N, 2.41. 16: [R]20 ) -14.8 (c ) 1.1, CHCl3); H-NMR (270
1
2.3, CHCl3); H-NMR (250 MHz) δ 0.06 (s, 6H), 0.88 (s, 9 H),
D
MHz) δ 1.14 (s, 9H), 142 (s, 9H), 1.48 (s, 9H), 1.68-1.78 (m,
1H), 1.88-2.02 (m, 1H), 2.36-2.50 (m, 1H), 2.60-2.70 (m, 1H),
3.08 (t, J ) 10 Hz, 2H), 3.72-3.84 (m, 1H), 4.10 (mc, 1H), 4.40
(q, J ) 7.5 Hz, 1H), 4.60 (mc, 1H), 7.34-7.48 (m, 6H), 7.60-
7.70 (m, 4H); IR (film, KBr) ν 3437 s (br), 3068 m, 2960 m,
2931 m, 2891 s, 2858 s, 1695 vs, 1674 vs, 1472 s, 1427 s, 1407
vs, 1367 s, 1255 m, 1174 vs, 1112 vs, 821 s, 738 s, 702 vs, 605
m cm-1; MS (80 eV, EI, 150 °C) m/z 551 (1.3), 496 (1.7), 465
(12.3), 440 (20.1), 412 (11.3), 400 (38.3), 368 (39.4), 3567 (61.3),
324 (57.3), 290 (73.0), 199 (84.9), 169 (46.7), 135 (27.6), 113
(43.7), 57 (100). Anal. Calcd: C, 67.45; H, 8.31; N, 2.56.
Found: C, 66.62; H, 8.16; N, 2.81.
1.06 (s, 9H), 1.68 (mc, 2H), 2.70 (s(br), 1H), 2.72-2.82 (m, 1H),
2.96 (dt, J ) 8, 5.5 Hz, 1H), 3.12 (mc, 1H), 3.80 (mc, 2H), 4.44
(dt, J ) 5.4, 3.5 Hz, 1H), 7.28-7.46 (m, 6H), 7.62-7.72 (m,
4H); 13C-NMR (63 MHz) δ -5.52, 14.01, 18.03, 19.19, 22.62,
25.84, 26.80, 31.63, 32.25, 43.91, 59.29, 60.22, 66.38, 66.49,
71.92, 72.50, 127.58, 128.41, 129.32, 129.78, 133.36; IR (film,
KBr) ν ) 3071 w, 2955 m, 2930 m, 2857 s, 1472 m, 1428 m,
1390 w, 1361 w, 1256 s, 1112 s, 1090 s (br), 837 s, 776 m, 740
m, 701 vs, 612 m, 506 s cm-1; MS (80 eV, EI, 100 °C) m/z 470
(0.5), 469 (1.1), 454 (2.9), 412 (21.9), 324 (100), 295 (5.6), 262
(13.0), 199 (5.6), 183 (8.1), 135 (10.5). Anal. Calcd for C27H43
-
NO2Si2 (469.8072): C, 69.03; H, 9.23; N, 2.98. Found: C,
69.12; H, 9.09; N, 2.86.
(2S,3S,2′R)-N-(ter t-Bu toxyca r bon yl)-3-h yd r oxy-2-[1-h y-
d r oxy-2-(ter t-bu toxyca r bon yl)eth yl]p yr r olid in e (18). Al-
cohol 15 (6.5 g, 11 mmol) in THF (100 mL) was treated with
TBAF (4.3 g, 16.7 mmol) and stirred at rt for 16 h. The
reaction was quenched by adding H2O (5 mL). The resulting
solution was concentrated in vacuo, and the residue was
purified by flash column chromatography (hexane/EtOAc, 1:1)
(2S,3S)-N-(ter t-Bu toxyca r bon yl)-3-(ter t-bu tyld ip h en yl-
siloxy)-2-(h yd r oxym eth yl)p yr r olid in e (13). To an ice-cold
solution of 12 (8.5 g, 18 mmol) in 1 M aqueous NaOH/THF
1:3 (500 mL) was added di-tert-butyl dicarbonate (11.8 g, 54
mmol) with vigorous stirring for 12 h. The mixture was
concentrated in vacuo and partitioned between Et2O (3 × 250
mL) and H2O (200 mL), and the combined organic layers were
concentrated in vacuo. Excess di-tert-butyl dicarbonate was
recovered by distillation in vacuo (bp(15torr) 70-73 °C). The
crude product was dissolved in acetic acid/H2O (15:1-15:5, 200
mL) and stirred at rt for 9 h. The solvents were removed under
reduced pressure, and the residue was purified by flash column
chromatography (hexane/EtOAc, 6:1) to give 13 (7.6 g, 95%)
to give 18 (3.6 g, 99%) as colorless powder: [R]20 ) +1.8 (c )
D
1
1.4, CHCl3); H-NMR (500 MHz, DMSO-d6, 80 °C) δ 1.43 (s,
18H; tert-butyl groups), 1.58-1.90 (m, 1H; H-4), 1.91-1.99 (m,
1H; H-4), 2.38 (dd, J ) 15, 8.7 Hz, 1H; H-2′′), 2.53 (dd, J ) 15,
4.5 Hz, 1H; H-2′′), 3.31 (ddd, J ) 11.3, 8.7, 5 Hz, 1H; H-5),
3.37 (dt, J ) 11.3, 7.5 Hz, 1H; H-5), 3.73 (dd, J ) 7, 4.5 Hz,
1H; H-2), 4.07 (s(br), 1H; D2O-exchange position, 3-OH), 4.32
(mc, 2H; H-2′ and H-3), 4.68 (s(br), 1H; D2O-exchange position,
2′′-OH), determination verified by COSY-experiments; 13C-
NMR (68 MHz) δ 27.96, 28.28, 33.00, 39.85, 44.55, 62.07, 68.63,
as a colorless oil: [R]20 ) -11.1 (c ) 2.7, CHCl3); 1H-NMR
D
(250 MHz) δ 1.08 (s, 9H), 1.46 (s, 9H), 1.62-1.76 (m, 1H), 1.78-
1.94 (m, 1H), 3.04-3.22 (m, 1H), 3.36 (mc, 1H), 3.76-3.96 (m,

Synthesis of cis- and trans-3-Hydroxy-D-proline
J . Org. Chem., Vol. 61, No. 2, 1996 571
71.84, 79.93, 81.02, 82.59, 172.73; IR (film, KBr) ν 3362 m,
2979 m, 2936 m, 2894 w, 1738 s, 1720 s, 1702 vs, 1477 m,
1455 m, 1383 s, 1365 s, 1159 s, 1104 m, 1061 m, 1030 m, 975
m, 894 w, 857 w, 773 w cm-1; MS (80 eV, EI, 100 °C) m/z 331
(0.2), 215 (0.9), 312 (4.5), 202 (28.9), 186 (12.4), 160 (11.6), 130
(91.6), 113 (36.6), 86 (100), 71 (30.2), 57 (53.1), 43 (35.5). Anal.
Calcd for C16H29NO6 (331.41): C, 57.99; H, 8.82; N, 4.23.
Found: C, 57.82; H, 8.76; N, 4.45.
The combined organic layers were washed with brine (30 mL),
concentrated in vacuo, and purified by flash column chroma-
tography (hexane/EtOAc, 10:1) to give (2S,3S)-N-(benzyloxy-
carbonyl)-2-[(tert-butyldimethylsiloxy)methyl]-3-(tert-butyl-
diphenylsiloxy)pyrrolidine (7.3 g, 95%) as a colorless viscous
1
liquid: [R]20 ) -3.1 (c ) 2.9, CHCl3); H-NMR (270 MHz) δ
D
0.00 + 0.04 + 0.06 (three s, all in all 6H), 0.92 + 0.95 (two s,
all in all 9H), 1.12 (s, 9H), 1.32 (mc, 1H), 1.74 (mc, 1H), 2.16-
2.32 (m, 1H), 3.2 (quint, J ) 9.5 Hz, 1H), 3.48 (t, J ) 10 Hz,
1H), 3.46 + 3.76 (two mc, all in all 1H), 3.92-4.00 (m, 1H),
4.08 (mc, 1H), 4.36 (mc, 1H), 5.12 (s (br), 2H), 7.28-7.48 (m,
11H), 7.68-7.76 (m, 4H). (rotameric signal split); 13C-NMR
(63 MHz) δ -5.65, 14.07, 18.07, 19.17, 22.59, 25.81, 26.81,
31.37, 31.52, 32.20, 43.71, 43.93, 59.26, 60.10, 60.16, 60.48,
66.35, 66.48, 71.90, 72.51, 127.57, 127.85, 127.98, 128.32,
129.77, 133.36, 133.77, 135.56, 135.68, 136.99, 154.57; MS (80
eV, EI, 150 °C) m/z 604 (0.2), 603 (0.3), 588 (2.1), 546 (100),
502 (8.6), 410 (5.2), 378 (8.1), 195 (5.9), 91 (67.9). Anal. Calcd
for C35H49NO4Si2 (603.9474): C, 69.61; H, 8.18; N, 2.32.
Found: C, 68.98; H, 8.05; N, 2.55. The fully protected amino
alcohol (7.0 g, 11.6 mmol) was dissolved in acetic acid/H2O (15:
1-15:5, 200 mL) and stirred at rt for 36 h. The solvents were
removed under reduced pressure, and the residue was purified
by flash column chromatography (hexane/EtOAc, 6:1) to give
(1S,5R,6R)-N-(ter t-Bu toxycar bon yl)-3,3-dim eth yl-5-(ter t-
bu toxyca r bon yl)m eth yl-2,4-d ioxa -7-a za bicyclo[4.3.0]n o-
n a n e (19). To a solution of 18 (2.5 g, 7.5 mmol) and
dimethoxypropane (3.1 g, 30 mmol) in CH2Cl2 (200 mL) was
added trifluoroacetic acid (2-3 drops). The solution was
stirred for 12 h at rt, and the solvents were evaporated in
vacuo. The residue was partitioned between ether (3 × 200
mL) and aqueous phosphate buffer (NaH2PO4/Na2HPO4, 1:1).
The combined organic layers were washed with brine and
concentrated in vacuo. The crude product was purified by
flash column chromatography (hexane/EtOAc, 6:1) and recrys-
tallized with methanol to give 19 (2.6 g, 94%) as colorless
needles: Mp 91 °C; [R]20 ) +99.6 (c ) 1.4, CHCl3) (lit.6a for
D
(-)-19: mp 90-91 °C, [R]20 ) -100.0 (c ) 1.8, CHCl3); H-
1
D
NMR (500 HHz, DMSO-d6, 130 °C) δ 1.29 (s, 3H; CH3-3), 1.39
(s, 3H; CH3-3), 1.42 (s, 18H; tert-butyl group), 1.74-1.80 (m,
1H; H-9), 1.81-1.87 (m, 1H; H-9), 2.27 (dd, J ) 15, 10 Hz,
1H; H-5′), 2.62 (dd, J ) 15, 3.8 Hz, 1H; H-5), 3.30 (dt, J ) 10,
6.3 Hz, 1H; H-8), 3.64 (ddd, J ) 11.3, 7.5, 2.5 Hz, 1H; H-8),
3.78 (dd, J ) 5, 4.5 Hz, 1H; H-6), 4.50 (dt, J ) 10, 3.8 Hz, 1H;
H-5), 4.58 (ddd, J ) 5, 5, 2.5 Hz, 1H; H-1); H,H-COSY-90 (500
HHz, DMSO-d6, 130 °C) crosspeaks: δx/δy ) 1.74-1.80/3.30,
1.74-1.80/3.64, 1.74-1.80/4.58, 1.81-1.87/3.30, 1.81-1.87/
3.64, 1.81-1.87/4.58, 2.27/2.62, 2.27/4.50, 2.62/4.50, 3.30/3.64,
3.78/4.50, 3.78/4.58; 13C-NMR (DMSO-d6, 126 MHz, 130 °C) δ
20.80, 27.46, 27.63, 29.19, 31.74, 38.80, 46.13, 55.42, 67.33,
70.44, 78.70, 79.05, 96.92, 155.25, 169.50; IR (film, KBr) ν
29.86 s, 2835 m, 2900 m, 1720 vs, 1689 vs, 1451 m, 1379 vs,
1365 vs, 1303 s, 1262 s, 1213 s, 1159 vs, 1122 s, 1031 s, 982 s,
954 s, 845 s, 777 m, 547 m cm-1; MS (80 eV, EI, 100 °C) m/z
371 (3.9), 356 (2.8), 313 (1.6), 271 (2.9), 244 (12.3), 213 (3.3),
198 (1.5), 184 (5.1), 169 (16.5), 157 (6.1), 122 (2.1), 113 (100),
69 (43.5), 57 (49.7). Anal. Calcd for C19H33NO6 (371.47): C,
61.43; H, 8.94; N, 3.77. Found: C, 61.24; H, 8.96; N, 3.81.
The author 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.
20 (5.45 g, 96%) as a colorless visocus oil: [R]20 ) -11.2 (c )
D
1
1.3, CHCl3); H-NMR (DMSO-d6, 250 M Hz, 60 °C) δ 1.08 (s,
9H), 1.78 (mc, 1H), 1.92-2.10 (m, 1H), 3.16-3.28 (m, 1H),
3.32-3.44 (dt, J 1 ) 10 Hz, J 2 ) 3.5 Hz, 1H), 3.68-3.76 (m,
1H), 3.84 (mc, 2H), 4.08 (mc, 1H), 4.44 (dt, J 1 ) 8 Hz, J 2 ) 7.5
Hz, 1H), 5.06 (s, 2H), 7.24-7.48 (m, 11H), 7.64-7.72 (m, 4H);
13C-NMR (DMSO-d6, 63 MHz) δ 18.75, 26.65, 31.83, 43.34,
58.36, 61.15, 65.68, 72.05, 127.77, 128.27, 129.88, 132.83,
133.34, 135.18, 137.00, 154.25; IR (film, KBr) ν 3431 m (br),
3071 m, 3050 m, 2959 s, 2931 s, 2892 s, 2858 s, 1696 vs, 1674
vs, 1589 w, 1473 m, 1405 vs (br), 1256 m, 1173 s, 1113 vs,
1086 s, 007 m, 822 s, 703 vs, 612 s, 505 s cm-1; MS (80 eV, EI,
150 °C) m/z 424 (0.5), 382 (1.9), 368 (6.8), 342 (21.6), 324 (15.6),
290 (15.5), 264 (86.5), 220 (34.6), 199 (36.4), 135 (16.6), 57
(100). Anal. Calcd for C29H35NO4Si (489.6853): C, 71.13; H,
7.20; N, 2.86. Found: C, 71.43; H, 7.02; N, 3.23.
(2R,3S)-N-(Ben zyloxyca r bon yl)-2-for m yl-3-(ter t-bu tyl-
d ip h en ylsiloxy)p yr r olid in e (21). Alcohol 20 (1.0 g, 2.1
mmol) was oxidized as desribed for 13 to give aldehyde 21 as
a colorless oil: [R]20 ) +71.2 (c ) 1.6, CHCl3); 1H-NMR (500
D
MHz) δ 1.04 (s, 9 H; C(CH3)3), 1.72 (mc, 2 H; 4-H), 3.42+3.51
(two dt, J 1 ) 8 Hz, J 2 ) 6 Hz, 1 H; 5-Ha), 3.70 + 3.76 (jeein dt,
J 1 ) 10 Hz, J 2 ) 6 Hz, 1 H; 5-Hb), 4.12 + 4.24 (two dd, J 1 ) 6
Hz, J 2 ) 3.5 Hz, 1 H; 2-H), 4.70 (mc, 1 H; 3-H), 5.10-5.22 (m,
2 H, benzyl-CH2), 7.22-7.48 (m, 11 H; aromatic-H), 7.60-7.70
(m, 4 H; aromatic-H), 9.65 + 9.75 (two d, J ) 3.5 Hz, 1 H;
aldehyde-H); H,H-COSY-90 (500 MHz) crosspeaks δx/δy 1.72/
3.42, 1.72/3.51, 1.72/3.70, 1.72/3.76, 1.72/4.70, 3.42/3.70, 3.51/
3.76, 4.12/4.70, 4.12/9.65, 4.24/4.70, 4.24/9.75; 1H-NMR (DMSO-
d6, 250 MHz, 60 °C) δ 1.02 (s, 9 H; C(CH3)3), 1.80 (mc, 2 H;
4-H), 3.44 (mc, 1 H; 5-H), 3.60 (mc, 1 H; 5-H), 4.26 (dd, J 1 ) 6
Hz, J 2 ) 2 Hz, 1 H; 2-H), 4.82 (dt, J 1 ) 6.3 Hz, J 2 ) 6 Hz, 1 H;
3-H), 5.08 (s, 2 H; -CH2Ph), 7.24-7.52 (m, 11 H; aromatic-
H), 7.60-7.68 (m, 4 H; aromatic-H), 9.66 (d, J ) 2 Hz, 1 H;
aldehyde-H); 13C-NMR (DMSO-d6, 63 MHz) δ 18.64, 26.46,
32.34, 33.11, 44.04, 44.50, 66.23, 67.64, 68.06, 74.57, 75.46,
127.25, 127.85, 128.27, 130.07, 131.89, 132.78, 135.17, 136.41,
136.52, 153.65, 154.38; H,H-COSY-90 (DMSO-d6, 250 MHz)
crosspeaks δx/δy 1.80/3.44, 1.80/3.60, 1.80/4.82, 4.26/4.82, 4.26/
9.66; IR (film, KBr) ν 3436 s (br), 3070 m, 3047 m, 3032 m,
2954 s, 2931 s, 2891 s, 2858 s, 1700 vs, 1681 vs, 1588 w, 1471
m, 1427 vs, 1359 s, 1112 vs, 823 m, 740 s, 701 vs, 615 s, 505
s cm-1; MS (80 eV, EI, 150 °C) m/z 472 (3.9), 446 (23.9), 428
(9.3), 402 (6.3), 338 (2.9), 278 (2.9), 250 (3.0), 234 (11.3), 199
(3S)-3-Hydr oxy-3[(2S,3R)-3-h ydr oxy-2-pyr r olidin yl]pr o-
p a n oic Acid ((+)-1). 18 (0.7 g, 2.2 mmol) in CH2Cl2 (100 mL)
was treated with a catalytic amount of camphor-10-sulfonic
acid and refluxed for 45 min. The resulting mixture was
concentrated, filtered through silica gel with CH2Cl2/MeOH
94:6 as the eluent, and treated with trifluoracetic acid in
MeOH (10%, 100 mL) at rt for 6 h. After being evaporated to
dryness, the residue was treated several times with ion
exchange resin (Dowex 50W × 4). After removal of the solvent,
(+)-1 (300 mg, 80%) was isolated as colorless powder (mp:
224-227 °C, dec): [R]20 ) +4.7 (c ) 1.3, H2O) (lit.6a [R]20
)
D
D
-4.8 (c ) 0.5, H2O); lit.6b [R]20 ) -4.1 (c ) 0.5, H2O) for (-)-
D
1
1); H-NMR (250 MHz, D2O) δ 2.14 (ddt, J ) 13.5, 7.5, 3 Hz,
1H), 2.26 (ddt, J ) 13.5, 10.5, 3.5 Hz, 1H), 2.44 (dd, J ) 15.5,
8 Hz, 1H), 2.65 (dd, J ) 15.5, 3.5 Hz, 1H), 3.40-3.58 (m, 3H),
4.32 (mc, 1H), 4.50 (dt, J ) 3.5, 1.5 Hz, 1H); IR (film, KBr) ν
) 3300 vs (br), 2800 s (br), 1640 vs, 1545 m, 1412 s, 1342 s,
1140 m, 1020 m, 843 w, 760 s, 620 s cm-1; MS (80 eV, EI, 120
°C) m/z 175 (0.9), 157 (32.7), 139 (12.3), 131 (43.2), 113 (23.2),
95 (5.3), 71 (44.2), 44 (100). Anal. Calcd for C7H13NO4
(175.18): C, 47.99; H, 7.48; N, 8.00. Found: C, 48.04; H, 7.39;
N, 7.84.
(5.1), 183 (3.5), 135 (5.0), 91 (100). Anal. Calcd for C29H33
-
NO4Si (487.6695): C, 71.42; H, 6.82; N, 2.87. Found: C, 71.44;
H, 6.79; N, 2.92.
(2S,3S)-N-(Ben zyloxyca r bon yl)-2-(h yd r oxym et h yl)-3-
(ter t-bu tyld ip h en ylsiloxy)p yr r olid in e (20). 12 (6 g, 12.8
mmol) and potassium carbonate (8.9 g, 64 mmol) were dis-
solved in THF/H2O (3:1, 200 mL) and treated with benzyloxy-
carbonyl chloride (4.4 g, 26 mmol) at 0 °C under vigorous
stirring for 2 h. The reaction mixture was concentrated and
partitioned between H2O (200 mL) and ether (3 × 200 mL).
(2R,3S)-N-(Ben zyloxyca r bon yl)-3-(ter t-bu tyld ip h en yl-
siloxy)p yr r olid in e-2-ca r boxylic Acid (22). Alcohol 20 (5.2
g, 10.6 mmol) dissolved in acetone (100 mL) was treated
dropwise with J ones reagent (freshly prepared from CrO3 (1
g), H2SO4 (1.4 g) and H2O (6 mL)) under vigorous stirring at

572 J . Org. Chem., Vol. 61, No. 2, 1996
Mulzer et al.
0 °C until a lasting orange color was obtained. 2-Propanol (1
mL) was added, and the mixture was filtered through Celite
and washed with acetone/HOAc 20:1. The solvents were
evaporated, and the residue was purified by flash column
chromatography (CH2Cl2/ MeOH/HOAc 94:5:1) to give 22 (4.9
129.39, 137.49, 157.08, 176.68; IR (film, KBr) ν 3392 vs (br),
3093 m, 3037 m, 2983 m, 2960 m, 1685 vs (br), 1600 vs (br),
1433 vs, 1363 s, 1209 s, 1138 s, 973 m, 914 m, 837 m, 800 m,
721 s, 697 s cm-1; MS (80 eV, EI, 250 °C) m/z 249 (1.3), 221
(3.4), 219 (6.3), 159 (11.5), 149 (7.3), 108 (70.6), 91 (100), 79
(35.4), 77 (25.0), 65 (12.6), 51 (12.2), 44 (66.5). Anal. Calcd
for C13H15NO5 (265.2652): C, 48.86; H, 5.70; N, 5.28. Found:
C, 58.82; H, 5.72; N, 5.32. (2R,3S)-N-(Benzyloxycarbonyl)-3-
hydroxypyrrolidine-2-carboxylic acid (0.4 g 1.5 mmol) was
dissolved in MeOH/H2O 3:1 (50 mL), and a catalytic amount
of Pd-C (10%) was added. The mixture was treated with H2
(1 atm) with vigorous stirring for 3 h at rt. The solvents were
removed under reduced pressure, and the residue was filtered
through Celite and washed with MeOH/H2O 3:1. The solvents
were evaporated and the residual solid was crystallized from
aqueous ethanol to give 23 (170 mg, 91%) as a colorless
g, 92%) as colorless brittle foam: [R]20 ) -35.9 (c ) 1.8,
D
CHCl3); 1H-NMR (250 MHz) δ 0.96 (s, 9H), 1.70 (mc, 1H), 1.92-
2.08 (m, 1H), 3.16 (dd, J 1 ) 17.5 Hz, J 2 ) 10 Hz, 1H), 3.60
(mc, 1H), 4.22-4.48 (m, 2H), 4.86-5.10 (m, 2H), 7.12-7.40 (m,
11H), 7.56-7.70 (m, 4H), 9.72 (s (br), 1H); 13C-NMR (63 MHz)
δ 18.99, 26.71, 31.27, 32.07, 43.82, 44.03, 62.43, 62.76, 67.11,
72.63, 73.43, 127.51, 127.73, 127.78, 128.37, 129.98, 132.47,
133.26, 133.44, 135.71, 135.83, 136.35, 154.35, 154.78, 175.16,
175.61; IR (film, KBr) ν 3441 m (br), 3070 m, 3056 s, 3032 m,
2932 s, 2894 s, 2858 s, 1712 vs (br), 1428 vs, 1361 s, 1194 m,
1113 s, 1054 s, 999 m, 920 m, 855 m, 823 m, 724 s, 703 vs,
612 s, 503 s cm-1; MS (EI, 80 eV, 200 °C) m/z 684 (1.2), 472
(0.5), 446 (15.9), 418 (4.1), 402 (22.7), 374 (7.0), 338 (3.9), 310
(3.6), 278 (6.2), 266 (2.9), 234 (4.8), 199 (18.0), 135 (4.8), 91
(100), 65 (1.3). Anal. Calcd for C29H33NO5Si (503.6689): C,
69.16; H, 6.60; N, 2.78. Found: C, 69.47; H, 6.41; N, 2.69.
cis-(2R,3S)-3-Hyd r oxyp r olin e (23). Acid 22 (2.5 g, 5
mmol) was dissolved in CH2Cl2/CF3CO2H 100:1 (130 mL) and
refluxed for 36-48 h. The solvents were removed under
reduced pressure, and the residue was purified by flash column
chromatography (CH2Cl2/MeOH/HOAc; 85:15:1) to give (2R,3S)-
N-(benzyloxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid
powder: mp 242-253 °C dec (lit.11d, mp 245-255 °C); [R]20
D
) +93.4 (c ) 1.3, H2O) (lit.11b, [R]20 +89.0 (c ) 0.7, H2O));
D
1H-NMR (D2O, 500 MHz) δ 2.02-2.10 (m, 1H), 2.14-2.24 (m,
1H), 3.34 (dt, J ) 11.5, 2.9 Hz, 1H), 3.49 (dt, J ) 10.6, 7.8 Hz,
1H), 4.00 (d, J ) 4.0 Hz, 1H), 4.63 (m, 1 H), 13C-NMR (D2O,
126 MHz) δ 36.34, 46.54, 70.55, 74.41, 171.84; IR (film, KBr)
ν 3250 s, 3080 m, 2849 m, 1630 vs, 1580 s, 1469 s, 1410 m,
1380 m, 1290 m, 1109 m, 870 s cm-1; MS (80 eV, EI, 250 °C)
m/z 86 (100), 74 (14.3), 69 (41.2), 57 (6.6). Anal. Calcd for
C5H9NO3 (131.0582): C, 45.80; H, 6.92; N, 10.68. Found: C,
45.47; H, 6.52; N, 10.45.
(1.2 g, 92%) as a colorless brittle foam: [R]20 ) +31.5 (c )
D
1
1.1, MeOH); H-NMR (D2O/CD3OD, 500 MHz, 90 °C) δ 2.55
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR, 13C-NMR,
IR, optical rotation data, mass spectral data, and elemental
analyses of 7b, 9b, 10b, 11b, 13b, 24, and 25 and preparation
procedures of 24 and 25 (4 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
ACS; see any current masthead page for ordering information.
(mc, 1 H; 4-Ha), 2.67 (mc, 1H; 4-Hb), 4.07-4.12 (m, 1H; 5-Ha),
4.18-4.24 (m, 1H; 5-Hb), 4.89 (d, J ) 10 Hz, 1H; 2-H), 5.15 (q,
J ) 10 Hz, 1H; 3-H), 5.73 (s (br), 2 H; benzyl-CH2), 7.94-8.06
(m, 5 H; aromatic-H); H,H-COSY-90 (D2O/CD3OD, 500 MHz,
90 °C) crosspeaks δx/δy 2.55/2.67, 2.55/4.07-4.12, 2.55/4.18-
4.24, 2.55/5.15, 2.67/4.07-4.12, 2.55/4.18-4.24, 2.67/5.15,
4.07-4.12/4.14-4.24, 4.89/5.15; 13C-NMR (D2O/CD3OD, 126
MHz, 90 °C) δ 32.71, 45.25, 66.38, 68.00, 72.08, 128.33, 128.88,
J O951444U