Efficient synthesis of 3-hydroxyprolines and 3-hydroxyprolinols from sugars

Article abstract of DOI:10.1016/S0040-4020(01)01070-5

trans-3-Hydroxy-L-proline 1, trans-3-hydroxy-L-prolinol 2, cis-3-hydroxy-D-proline 3, and cis-3-hydroxy-D-prolinol 4 have been prepared in enantiomerically pure form with chirospecific manner. Key intermediates, 2-amino-3-hydroxy-4-pentenoate 9 and 17, were obtained from D-glucono-δ-lactone and L-gulonic acid γ-lactone via a simultaneous dealkoxyhalogenation.

Full text of DOI:10.1016/S0040-4020(01)01070-5

TETRAHEDRON
Pergamon
Tetrahedron 57 82001) 10071±10076
Ef®cient synthesis of 3-hydroxyprolines and 3-hydroxyprolinols
from sugars
Jin Hwan Lee, Jae Eun Kang, Min Suk Yang, Kyu Young Kang and Ki Hun Parkp
Department of Agricultural Chemistry, Division of Applied Life Science, Gyeongsang National University, Chinju 660-701, South Korea
Received 17 September 2001; accepted 31 October 2001
AbstractÐtrans-3-Hydroxy-l-proline 1, trans-3-hydroxy-l-prolinol 2, cis-3-hydroxy-d-proline 3, and cis-3-hydroxy-d-prolinol 4 have
been prepared in enantiomerically pure form with chirospeci®c manner. Key intermediates, 2-amino-3-hydroxy-4-pentenoate 9 and 17,
were obtained from d-glucono-d-lactone and l-gulonic acid g-lactone via a simultaneous dealkoxyhalogenation. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
2. Results and discussion
As our chiral source, we chose d-glucono-d-lactone and
l-gulonic acid g-lactone, which have two stereocenters as
required for the target molecules 1±4 8Scheme 1). Thus, the
stereochemistry of C2and C3 in d-glucono-d-lactone was
used for compound 1 and 2, while that of C2and C3 in
l-gulonic acid g-lactone was for compound 3 and 4.
3-Hydroxyproline and 3-hydroxyprolinol are an important
component or a chiral synthon for biological active
compounds such as Mucrorin-D,1 Telomycin,2 poly-
hydroxylated alkaloids,3 and detoxinine.4,5 For example,
trans-3-hydroxy-l-proline 1 was isolated from bovine
tendon collagen6 and then found in antibiotic telomycin.2
Several syntheses of 3-hydroxyproline and 3-hydroxypro-
linol have been described, which are based on reductive
cyanation,7,8 Dieckman-type condensation,9 a reductive
amination of a suitable substituted amino aldehyde,10
stereoselective cyclocarbamation,11 diastereoselective ami-
nation,12 and a yeast reduction of pyroglutamate,13 respec-
tively. However, there is no previous report of synthesis of
3-hydroxyproline derivatives using absolute con®gurations
in sugars. This paper describes the transformation of sugars
by homochiral synthetic techniques to obtain optically pure
3-hydroxyprolines 81, 3) and 3-hydroxyprolinols 82, 4).
2.1. trans-3-Hydroxy-l-proline 1 and prolinol 2
The amino group of mannonate 5 was protected with
9-phenyl-9-¯uorenyl 8Pf) group since this protecting group
has been shown to inhibit deprotonation at the a-position of
Our approach to synthesis of 1±4 envisaged the use of the
2-amino-3-hydroxy-4-pentenoate 9 and 17, which can be
easily obtained from sugar via a simultaneous dealkoxy-
halogenation. Generally, Sharpless condition 8SeO2/t-
BuOOH)4 and bislactim ether method14 are accepted to
obtain 2-amino-3-hydroxy-4-pentenoate but these synthetic
route have a limitation in high yield and selectivity. We now
report synthesis optically active 2-amino-3-hydroxy-4-
pentenoate 9 and 17 from sugars, and their application to
the synthesis of enantiomerically pure trans-3-hydroxy-l-
proline 1, trans-3-hydroxy-l-prolinol 2, cis-3-hydroxy-d-
proline 3, and cis-3-hydroxy-d-prolinol 4 8Scheme 1).
Keywords: trans-3-hydroxy-l-proline; trans-3-hydroxy-l-prolinol; cis-3-
hydroxy-d-proline; cis-3-hydroxy-d-prolinol.
Corresponding author. Fax: 182-55-757-0178;
p
Scheme 1. Retrosynthesis of compound 1±4.
e-mail: khpark@gshp.gsnu.ac.kr
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020801)01070-5

10072
J. H. Lee et al. / Tetrahedron 57 +2001) 10071±10076
Scheme 2. Reagents and conditions: 8i) Ref. 16; 8ii) NaIO4, NaBH4, EtOH,
rt, 98%; 8iii) MsCl, Et3N, THF, 08C, 98%; 8iv) LiI, DMF, 808C, 95%; 8v) n-
BuLi, THF, 2408C, 85%; 8vi) TBDMSCl, imidazole, DMF, rt, 98%.
an a-amino ester and stable on an organometallic con-
ditions.15 The diol 5 was synthesized in ®ve high yielding
steps from d-glucono-d-lactone as described;16 the overall
yield for this conversion was 70% 8Scheme 2).
Scheme 4. Reagents and conditions: 8i) Ref. 17; 8ii) MsCl, Et3N, THF, 08C,
98%; 8iii) LiI, DMF, 808C, 90%; 8iv) n-BuLi, THF, 2408C, 90%; 8v)
TBDMSCl, imidazole, DMF, rt, 98%; 8vi) BH38CH3)2S, THF, 08C, 78%;
8vii) MsCl, Et3N, 08C, 90%; 8viii) H2, Pd/C, MeOH, 608C, Dowex 50W-X8,
THF±H2O 82:1), re¯ux, 84%; 8ix) LAH, THF, 08C, H2, Pd/C, MeOH, 608C,
75%.
The diol 5 was oxidized in the presence of NaIO4; this was
followed by sodium borohydride reduction of the resulting
aldehyde, which led to the formation of alcohol 6 in quanti-
tative yield. After mesylation of alcohol 6, the resulting
mesylate was treated with LiI to give 2,3-isopropylidene
iodide 8 in 85% yield. Treatment of 2,3-isopropylidene
iodide 8 with n-BuLi at 2408C gave the 82S,3S)-2-amino-
20
3-hydroxy-4-pentenoate 9 {[a]D ˆ2278.2 8c 1.00, CHCl3)}
in 85% yield through a simultaneous dealkoxyhalogenation.
This is a ®rst report to obtain enantiomerically pure
2-amino-3-hydroxy-4-pentenoic acid derivative. This
useful intermediate could be converted to a variety of bio-
active b-hydroxy-a-amino acid.
The silyl ether 10 was prepared using TBDMSCl in quanti-
tative yield. Following complete hydroboration with
BH38CH3)2S, the resulting organoboranes were oxidized
with alkaline hydrogen peroxide to give 5-hydroxypentano-
ate 11 in 70% yield 8Scheme 3). When the alcohol 11 was
carried out mesylation in THF, intramolecular amination
was occurred simultaneously to produce proline ester 12
in 87% yield. After reduction of Pf group with 10% Pd/C,
the remaining TBDMS and methyl ester group were
completely hydrolyzed with Dowex 50W-X8 in THF±
H2O 82:1). The mixture was ®ltered and the resin was
washed with methanol, then eluted with 3N aqueous NH3
to afford the free base form of trans-3-hydroxy-l-proline 1
876% yield) without further puri®cation. On the other hand,
the treatment of proline methyl ester 12 with LAH gave the
N-protected prolinol 13 in 89% yield. In this step, LAH
removed TBDMS group as well as reduction of ester
group. To remove the remaining Pf group, 13 was treated
with 10% Pd/C in methanol. The free base form of trans-3-
hydroxy-l-prolinol 2 was obtained by ion exchange
chromatography 8Dowex 50W-X8) as an oil and was pure
by NMR and HRMS. 1H and 13C NMR and optical rotation
for 1 and 2 are consistent with those reported.9,18
Scheme 3. Reagents and conditions: 8i) BH38CH3)2S, THF, 08C, 70%;
8ii) MsCl, Et3N, THF, 08C, 87%; 8iii) H2, Pd/C, MeOH, 608C, Dowex
50W-X8, THF±H2O 82:1), re¯ux, 76%; 8iv) LAH,THF, 08C, 89%; 8v) H2,
Pd/C, MeOH, 608C, 93%.

J. H. Lee et al. / Tetrahedron 57 +2001) 10071±10076
10073
2.2. cis-3-Hydroxy-d-proline 3 and prolinol 4
4.1.2. Methyl 2-deoxy-3,4-O-isopropylidene-2-[-9-phenyl-
9-¯uorenyl)-amino]-d-lyxonate 6. To a solution of diol 5
86.00 g, 12.26 mmol) in EtOH±H2O 880:40 mL) was NaIO4
83.15 g, 14.70 mmol) at room temperature. After stirring for
3 h, the mixture was cooled to 08C, and then NaBH4 80.56 g,
14.70 mmol) was added and stirred for 10 min. After
evaporation of EtOH, the mixture was poured into excess
of H2O and extracted with EtOAc 8100 mL£3). After
concentration of combined extracts, the residue was
chromatographed on silica gel [hexane±EtOAc 83:1)] to
give compound 6 85.52g, 98%) as a solid, mp 64±66 8C;
To further demonstrate the versatility of this synthetic
strategy, we have prepared the cis-3-hydroxy-d-proline 3
and prolinol 4. The arabinonate 14 was easily obtained
form l-gulonic acid g-lactone as described;17 the overall
yield for this conversion was 74% 8Scheme 4).
After mesylation of alcohol 14, the mesylate 15 was treated
with LiI at 808C to give 2,3-isopropylidene iodide 16 in 90%
yield. The iodide 16 was treated with n-BuLi in THF at
2408C for 20 min to give the 82R,3S)-2-amino-3-hydroxy-
20
[a]D ˆ2150 8c 1.16, CHCl3); IR 8KBr): 3500, 3050,
4-pentenoate 17{[a]D ˆ1278.9 8c 1.25, CHCl3)}. After
1740 cm21; dH 8500 MHz; CDCl3) 1.09 83H, s), 1.28 83H,
s), 2.63 81H, d, Jˆ8.8 Hz), 3.23 83H, s), 3.35 81H, s, OH),
3.76±3.9284H, m), 7.09±7.73 813H, m, Pf); dC 8125 MHz;
CDCl3) 26.4, 26.8, 51.9, 58.6, 63.8, 72.6, 80.2, 80.3, 109.5,
120.2, 125.5, 125.7, 126.1, 127.4, 127.5, 128.4, 128.5,
128.6, 128.9, 140.4, 141.1, 143.1, 147.9, 174.7 8Found: C,
73.18; H, 6.39; N, 3.02. C28H29NO5 requires C, 73.18; H,
6.36; N, 3.05%).
20
protection of pentenoate 17 with TBDMSCl, vinyl group
in 18 was converted to 5-hydroxypentanoate 19 by
BH38CH3)2S condition. The alcohol 19 was reacted with
MsCl in THF to lead mesylation and cyclization simul-
taneously to obtain proline methyl ester 20 in quantitative
yield. After hydrogenation to remove Pf group in 20, ester
and TBDMS group were hydrolyzed with the same pro-
cedure for compound 1 to yield cis-3-hydroxy-d-proline 3
in 84% yield. The spectroscopic data of 3 is consistent with
those reported.10 The proline methyl ester 20 was treated
with LAH and H2, 10% Pd/C sequentially as same pro-
cedure for compound 2 to give cis-3-hydroxy-d-prolinol 4
4.1.3. Methyl 2-deoxy-3,4-O-isopropylidene-5-O-methane-
sulfonyl-2-[-9-phenyl-9-¯uorenyl)-amino]-d-lyxonate 7.
To a solution of alcohol 6 85.40 g, 11.75 mmol) in THF
858 mL) were added triethylamine 83.26 mL, 23.50 mmol)
and MsCl 81.36 mL, 17.63 mmol) at 08C. The reaction
mixture was stirred for 20 min at room temperature, then
was quenched with saturated aqueous NaHCO3 850 mL).
The organic phase was separated and the aqueous phase
was extracted with CH2Cl2 850 mL£3). After concentration
of combined extracts, the resulting residue was chromato-
20
{[a]D ˆ223.2 8c 0.76, H2O)}.
3. Conclusions
In summary, we report the ®rst chirospeci®c synthesis of
2-amino-3-hydroxy-4-pentenoate 9 and 17 via a simul-
taneous dealkoxyhalogenation. These compounds are an
important precursor for the asymmetric synthesis of bio-
active b-hydroxy-a-amino acids. Additionally, we have
reported the synthesis of enantiomerically pure trans-3-
hydroxy-l-proline 1, trans-3-hydroxy-l-prolinol 2, cis-3-
hydroxy-d-proline 3, and cis-3-hydroxy-d-prolinol 4 with
chirospeci®c manner.
graphed on silica gel [hexane±EtOAc 85:1)] to give com-
ˆ
20
pound 7 86.20 g, 98%) as a solid, mp 155±1588C; [a]D
2204 8c 1.00, CHCl3); IR 8KBr): 3290, 3010, 1715 cm21
H 8500 MHz; CDCl3) 1.10 83H, s), 1.31 83H, s), 2.62 81H,
;
d
dd, Jˆ11.0, 9.0 Hz), 3.1283H, s), 3.24 83H, s,), 3.8281H,
dd, Jˆ8.8, 7.3 Hz), 4.00 81H, m), 4.46 81H, dd, Jˆ10.9,
6.1 Hz), 4.77 81H, dd, Jˆ11.0, 2.4 Hz), 7.11±7.74 813H,
m, Pf); dC 8125 MHz; CDCl3) 26.6, 26.8, 51.9, 58.8, 70.3,
72.6, 78.0, 78.2, 110.6, 120.2, 120.3, 125.1, 125.9, 126.1,
127.5, 128.3, 128.5, 128.6, 128.8, 140.1, 141.3, 143.4,
147.9, 148.2, 174.4 8Found: C, 64.73; H, 5.80; N, 2.59.
C29H31NO7S requires C, 64.79; H, 5.81; N, 2.61%).
4. Experimental
4.1. General
4.1.4. Methyl 2,5-dideoxy-3,4-O-isopropylidene-5-iodo-
2-[-9-phenyl-9-¯uorenyl)-amino]-d-lyxonate 8. To a solu-
tion of mesylate 7 86.10 g, 11.34 mmol) in dried DMF
838 mL) was added LiI 86.17 g, 46.12mmol). After stirring
of the mixture for overnight at 808C, saturated aqueous
NaHCO3 850 mL) was added and the mixture was extracted
with EtOAc 840 mL£3). The extract was evaporated and
the remaining residue was chromatographed on silica gel
[hexane±EtOAc 810:1)] to give compound 8 86.14 g, 95%)
All non-aqueous reaction was carried out under an inert
nitrogen atmosphere. THF was distilled from Na/benzo-
phenone; 2,2-dimethoxypropane, DMF, and methylene
chloride were distilled from CaH2. Column chromatography
was carried out using 230±400 mesh silica gel. Final solu-
tion before evaporation was washed with brine and dried
over anhydrous Na2SO4. Melting points are uncorrected. 1H
and 13C NMR experiments were conducted on Brucker
AW-500 spectrometer. HREIMS were obtained on a
JEOLJMS-700 mass spectrometer. Optical rotations
were measured on a JASCO DIP-1000 polarimeter and
20
as a solid, mp 60±658C; [a]D ˆ2161.8 8c 1.2, CHCl3); IR
8KBr): 3320, 3040, 1735 cm21; dH 8500 MHz; CDCl3) 1.07
83H, s), 1.34 83H, s), 2.63 81H, m), 3.04 81H, d, Jˆ11 Hz),
3.23 83H, s), 3.44 81H, m), 3.67 81H, dd, Jˆ10.2, 3.2 Hz),
7.13±7.71 813H, m, Pf); dC 8125 MHz; CDCl3) 8.8, 27.5,
27.9, 52.2, 59.0, 73.0, 80.0, 82.6, 99.5, 110.6, 120.6, 125.5,
126.3, 126.5, 127.8, 127.9, 128.8, 128.9, 129.0, 129.1,
140.6, 141.6, 144.1, 148.6, 148.7, 174.9 8Found: C, 59.02;
H, 4.97; N, 2.49. C28H28INO4 requires C, 59.06; H, 4.96; N,
2.46%).
[a]D-values are given in units of 1021 deg cm2 g21
.
4.1.1. Methyl 2-deoxy-3,4-O-isopropylidene-2-[-9-phenyl-
9-¯uorenyl)-amino]-d-mannonate 5. This was prepared
from d-glucono-d-lactone as described:16 mp 69±708C
8lit.,16 68±708C).

10074
J. H. Lee et al. / Tetrahedron 57 +2001) 10071±10076
4.1.5. Methyl -2S,3S)-3-hydroxy-2-[-9-phenyl-9-¯uore-
nyl)-amino]-4-pentenoate 9. A solution of iodinated 8
86.00 g, 10.54 mmol) in THF 853 mL) was cooled to
2408C, 2.5 M n-BuLi 816.90 mL, 42.16 mmol, 400
mmol%) was added dropwise over 30 min via syring
pump. The reaction mixture was stirred an additional
20 min at 2408C, then quenched with saturated aqueous
NH4Cl 840 mL). The mixture was extracted with EtOAc
840 mL£3) and combined extracts were concentrated.
The resulting residue was chromatographed on silica gel
[hexane±EtOAc 84:1)] to give compound 9 83.45 g, 85%)
140.4, 141.1, 143.9, 148.3, 148.4, 175.6 8Found: C, 71.88;
H, 7.59; N, 2.75. C31H39NO4Si requires C, 71.92; H, 7.59;
N, 2.71%).
4.1.8. trans-3-O--tert-Butyldimethylsilyl)-1--9-phenyl-9-
¯uorenyl)-l-proline methyl ester 12. To a solution of
alcohol 11 83.00 g, 5.79 mmol) in THF 829 mL) were
added triethylamine 81.57 mL, 11.30 mmol) and MsCl
80.66 mL, 8.46 mmol). The reaction mixture was stirred
for 3 h at 08C, then was quenched with saturated aqueous
NaHCO3 830 mL). The reaction mixture was extracted with
EtOAc 820 mL£3). After concentration of combined
extracts, the resulting residue was chromatographed on
silica gel [hexane±EtOAc 815:1)] to give compound 12
20
as a solid, mp 120±1228C; [a]D ˆ2278.2 8c 1.00, CHCl3);
IR 8KBr): 3480, 3045, 1735 cm21; dH 8500 MHz; CDCl3)
2.77 81H, d, Jˆ5.5 Hz), 3.28 83H, s), 4.01 81H, t, Jˆ5.5 Hz),
4.69 81H, s, NH), 5.15 81H, d, Jˆ10.6 Hz), 5.25 81H, d,
Jˆ14.7 Hz), 5.74 81H, ddd, Jˆ16.3, 10.5, 5.5 Hz), 7.20±
7.67 813H, m, Pf); dC 8125 MHz; CDCl3) 50.4, 58.8, 71.4,
72.0, 115.2, 118.8, 118.9, 124.0, 124.8, 125.1, 126.2, 126.2,
127.0, 127.2, 127.3, 127.5, 135.6, 139.0, 139.9, 142.9,
146.9, 147.3, 172.7 8Found: C, 77.40; H, 6.05; N, 3.60.
C25H23NO3 requires C, 77.90; H, 6.01; N, 3.63%).
20
82.52 g, 87%) as a oil, [a]D ˆ1272.6 8c 2.5, CHCl3); IR
8neat): 3030, 2910, 1725 cm21; dH 8500 MHz; CDCl3)
20.11 83H, s), 0.00 83H, s), 0.8289H, s), 1.73 81H, m),
2.16 81H, m), 2.97 81H, d, Jˆ1.0 Hz), 3.33 81H, m), 3.40
81H, m), 3.44 83H, s), 4.17 81H, m), 7.22±7.85 813H, m, Pf);
dC 8125 MHz; CDCl3) 25.1, 17.7, 25.6, 34.5, 47.0, 51.2,
69.7, 76.0, 119.7, 119.8, 126.9, 127.0, 127.0, 127.2, 127.6,
127.6, 128.1, 128.2, 128.4, 139.4, 141.7, 142.9, 145.9,
148.4, 175.3 8Found: C, 74.54; H, 7.49; N, 2.78.
C31H37NO3Si requires C, 74.51; H, 7.46; N, 2.80%).
4.1.6. Methyl -2S,3S)-3--tert-butyldimethylsilyl)oxy-2-
[-9-phenyl-9-¯uorenyl)-amino]-4-pentenoate 10. To a
solution of compound 9 83.40 g, 8.82mmol) in DMF
830 mL) were added imidazole 81.20 g, 17.64 mmol) and
TBDMSCl 82.66 g, 17.64 mmol) at room temperature.
After stirring of the mixture for 12h, saturated aqueous
NaHCO3 840 mL) was added and the mixture was extracted
with EtOAc 840 mL£3). After concentration of combined
extracts, the remaining residue was chromatographed on
silica gel [hexane±EtOAc 812:1)] to give compound 10
4.1.9. trans-3-Hydroxy-1--9-phenyl-9-¯uorenyl)-l-pro-
linol 13. To an ice-cooled solution of LAH 80.08 g,
2.10 mmol) in THF 87 mL) was added a solution of proline
methyl ester 12 80.70 g, 1.40 mmol) in THF 84 mL). The
reaction mixture was warmed to room temperature, stirred
for 7 h, then quenched by the sequential addition of
water 80.8 mL), 15% aqueous NaOH 80.8 mL), and water
82.4 mL). The mixture was ®ltered and evaporated.
The resulting residue was chromatographed on silica gel
[hexane±EtOAc 82:1)] to give compound 13 80.45 g, 89%)
20
84.32g, 98%) as a solid, mp 95±98 8C; [a]D ˆ2208.0 8c
1.46, CHCl3); IR 8KBr): 3315, 3040, 1740 cm21; dH
8500 MHz; CDCl3) 20.01 83H, s), 0.03 83H, s), 0.81 89H,
s), 2.66 81H, d, Jˆ7.9 Hz), 3.21 83H, s), 4.13 81H, t, Jˆ
7.3 Hz), 5.25 82H, m), 5.74 81H, ddd, Jˆ17.3, 10.3, 7.1 Hz),
7.22±7.71 813H, m, Pf); dC 8125 MHz; CDCl3) 25.2, 24.3,
17.9, 25.6, 51.3, 61.2, 72.7, 76.9, 116.9, 119.9, 119.9, 125.8,
126.1, 126.1, 127.2, 127.3, 127.7, 128.2, 128.3, 128.3,
139.3, 140.2, 141.1, 144.8, 148.5, 148.6, 175.3 8Found: C,
74.54; H, 7.42; N, 2.78. C31H37NO3Si requires C, 74.51; H,
7.46; N, 2.80%).
20
as a solid, mp 150±1608C; [a]D ˆ118.6 8c 1.00, CHCl3);
IR 8KBr): 3480, 3040, 2890 cm21; dH 8500 MHz; CDCl3)
1.64 81H, m), 1.9281H, m), 2.3281H, m), 2.51 81H, dd,
Jˆ10.5, 5.6 Hz), 3.05 81H, d, Jˆ10.1 Hz), 3.27 82H, m),
4.03 81H, s), 7.18±7.74 813H, m, Pf); dC 8125 MHz;
CDCl3) 31.7, 47.2, 61.5, 66.3, 75.1, 118.5, 118.7, 124.3,
125.0, 125.9, 125.9, 126.3, 126.4, 126.9, 127.1, 127.4,
137.4, 1405, 141.3, 145.0, 147.4 8Found: C, 80.61; H,
6.51; N, 3.90. C24H23NO2 requires C, 80.64; H, 6.49; N,
3.92%).
4.1.7. Methyl -2S,3S)-3--tert-butyldimethylsilyl)oxy-5-
hydroxy-2-[-9-phenyl-9-¯uorenyl)-amino] pentanoate
11. To a solution of pentenoate 10 84.30 g, 8.60 mmol)
in THF 843 mL) were added BH38CH3)2S 812.90 mL,
25.80 mmol) at 08C. After stirring of the mixture for 10 h
at room temperature, the reaction mixture was quenched
by sequential addition of water 82.6 mL), 3 M sodium
hydroxide 83.25 mL), 30% hydrogen peroxide 85.85 mL).
The mixture was extracted with EtOAc 840 mL£3) and
combined extracts was concentrated. The residue was
chromatographed on silica gel [hexane±EtOAc 84:1)] to
give compound 11 83.12g, 70%) as a solid, mp 64±66 8C;
4.1.10. Methyl 2-deoxy-3,4-O-isopropylidene-2-[-9-phenyl-
9-¯uorenyl)-amino]-d-arabinonate 14. This was prepared
from l-gulonic acid g-lactone as described:17 mp 57±588C
8lit.,17 56±588C).
4.1.11.
Methyl
2-deoxy-3,4-O-isopropylidene-5-O-
methanesulfonyl-2-[-9-phenyl-9-¯uorenyl)-amino]-d-
arabinonate 15. To a solution of alcohol 14 85.40 g,
11.75 mmol) in THF 858 mL) were added triethylamine
83.26 mL, 23.50 mmol) and MsCl 81.42 mL, 17.63 mmol),
at 08C. After stirring of the mixture for 15 min at room
temperature, saturated aqueous NaHCO3 850 mL) was
added and the mixture was extracted with CH2Cl2
860 mL£3). After concentration of combined extracts, the
residue was chromatographed on silica gel [hexane±EtOAc
85:1)] to give compound 15 86.19 g, 98%) as a solid, mp
20
[a]D ˆ281.6 8c 1.73, CHCl3); IR 8KBr): 3530, 3060,
1745 cm21; dH 8500 MHz; CDCl3) 0.00 83H, s), 0.07 83H,
s), 0.80 89H, s), 1.85 81H, m), 2.01 81H, m), 2.72 81H, d,
Jˆ7.7 Hz), 3.21 83H, s), 3.45 82H, m), 3.87 81H, m), 7.15±
7.73 813H, m, Pf); dC 8125 MHz; CDCl3) 25.2, 24.4, 17.7,
25.6, 36.6, 51.5, 59.3, 59.8, 72.7, 74.5, 120.1, 120.2, 125.7,
125.9, 126.1, 127.3, 127.5, 127.9, 128.4, 128.4, 128.7,
20
55±608C; [a]D ˆ1230.2 8c 1.00, CHCl3); IR 8KBr): 3310,

J. H. Lee et al. / Tetrahedron 57 +2001) 10071±10076
10075
3030, 1730 cm21; dH 8500 MHz; CDCl3) 1.35 83H, s), 1.46
83H, s), 2.65 81H, s), 2.99 83H, s), 3.33 83H, s), 3.75 81H, m),
3.87 81H, dd, Jˆ11.5, 5.2Hz), 4.20 81H, dd, Jˆ11.5,
2.7 Hz), 4.47 81H, m), 7.20±7.67 813H, m, Pf); dC
8125 MHz; CDCl3) 27.0, 27.1, 37.7, 51.9, 55.2, 68.4, 72.9,
74.6, 77.6, 110.3, 120.0, 120.2, 125.3, 126.6, 126.7, 127.4,
127.5, 128.1, 128.5, 128.6, 128.8, 140.3, 141.0, 143.7,
147.8, 148.4, 173.5 8Found: C, 64.82; H, 5.80; N, 2.59.
C29H31NO7S requires C, 64.79; H, 5.81; N, 2.61%).
98%) as a oil, [a]D ˆ2109.28 c 3.00, CHCl3); IR 8neat):
3340, 3040, 1730 cm21; dH 8500 MHz; CDCl3) 20.06 83H,
s), 0.00 83H, s), 0.91 89H, s), 2.84 81H, s), 3.11 81H, s), 3.32
83H, s), 4.20 81H, m), 5.25 81H, dt, Jˆ10.4, 1.3 Hz), 5.31
81H, dt, Jˆ17.2, 1.6 Hz), 6.03 81H, ddd, Jˆ17.0, 10.4,
6.4 Hz), 7.31±7.79 813H, m, Pf); dC 8125 MHz; CDCl3)
24.8, 24.5, 18.4, 26.1, 51.5, 61.1, 73.2, 76.5, 116.6,
120.2, 120.3, 125.8, 126.6, 126.8, 127.5, 127.7, 128.2,
128.6, 128.7, 137.9, 140.7, 141.4, 145.0, 149.2, 149.5,
174.4 8Found: C, 74.48; H, 7.49; N, 2.76. C31H37NO3Si
requires C, 74.51;H, 7.46; N, 2.80%).
20
4.1.12. Methyl 2,5-dideoxy-3,4-O-isopropylidene-5-iodo-
2-[-9-phenyl-9-¯uorenyl)-amino]-d-arabinonate 16. To a
solution of mesylate 15 86.00 g, 11.16 mmol) in DMF
840 mL) was added LiI 86.17 g, 46.12mmol). After stirring
of the mixture for overnight at 808C, saturated aqueous
NaHCO3 850 mL) was added, and the mixture was extracted
with EtOAc 850 mL£3). After evaporation of combined
extracts, the resulting residue was chromatographed on
silica gel [hexane±EtOAc 810:1)] to give compound 16
4.1.15. Methyl -2R,3S)-3--tert-butyldimethylsilyl)oxy-5-
hydroxy-2-[-9-phenyl-9-¯uorenyl)-amino] pentanoate
19. To a solution of compound 18 84.00 g, 8.00 mmol) in
THF 841 mL) were added BH38CH3)2S 812.00 mL,
24.00 mmol) at 08C. After stirring of the mixture for 10 h
at room temperature, the reaction mixture was quenched
by sequential addition of water 82.5 mL), 3 M sodium
hydroxide 83.15 mL), 30% hydrogen peroxide 85.35 mL).
The mixture was extracted with EtOAc 840 mL£3). After
evaporation of combined extracts, the residue was chro-
matographed on silica gel [hexane±EtOAc 84:1)] to give
compound 19 83.23 g, 78%) as a solid, mp 117±1208C;
20
85.72g, 90%) as a solid, mp 59±64 8C; [a]D ˆ1200.7 8c
1.25, CHCl3); IR 8KBr): 3340, 3020, 1730 cm21; dH
8500 MHz; CDCl3) 1.37 83H, s), 1.50 83H, s), 2.64 81H,
m), 2.89 81H, dd, Jˆ10.8, 5.8 Hz), 3.01 81H, dd, Jˆ10.8,
4.0 Hz), 3.33 81H, s), 3.60 81H, dd, Jˆ7.6, 3.0 Hz), 4.13
81H, m), 7.21±7.69 813H, m, Pf); dC 8125 MHz; CDCl3)
5.9, 27.2, 51.8, 55.3, 72.8, 75.4, 81.8, 109.7, 119.9, 120.1,
125.4, 126.1, 126.9, 127.3, 127.4, 128.1, 128.3, 128.4,
128.5, 128.7, 140.2, 141.1, 143.9, 147.8, 148.6, 173.6
8Found: C, 59.02; H, 4.99; N, 2.47. C28H28INO4 requires
C, 59.06; H, 4.96; N, 2.46%).
20
[a]D ˆ1381.0 8c 1.26, CHCl3); IR 8KBr): 3490, 3030,
1720 cm21; dH 8500 MHz; CDCl3) 20.25 83H, s), 0.00
83H, s), 0.91 89H, s), 1.76 81H, m), 2.24 81H, m), 2.82
81H, d, Jˆ4.6 Hz), 3.44 83H, s), 3.77 82H, m), 3.90 81H,
m), 7.29±7.85 813H, m, Pf); dC 8125 MHz; CDCl3) 25.3,
25.2, 17.8, 25.7, 34.8, 51.3, 59.1, 59.8, 60.0, 73.0, 119.9,
120.1, 125.4, 126.1, 126.2, 127.3, 127.5, 128.0, 128.4,
128.6, 128.7, 140.4, 141.4, 144.0, 148.6, 149.1, 174.6
8Found: C, 71.88; H, 76.2; N, 2.73. C31H39NO4Si requires
C, 71.92; H, 7.59; N, 2.71%).
4.1.13. Methyl -2R,3S)-3-hydroxy-2-[-9-phenyl-9-¯uor-
enyl)-amino]-4-pentenoate 17. A solution of iodinated 16
85.30 g, 9.31 mmol) in THF 850 mL) was cooled to 2408C,
2.5 M n-BuLi 814.90 mL, 37.24 mmol, 400 mmol%) was
added dropwise over 30 min via syring pump. The reaction
mixture was stirred an additional 20 min at 2408C, then
quenched with saturated aqueous NH4Cl 840 mL). The
mixture was extracted with EtOAc 850 mL£3) and
combined extracts were concentrated. The remaining resi-
due was chromatographed on silica gel [hexane±EtOAc
84:1)] to give compound 17 83.23 g, 90%) as a solid, mp
4.1.16. cis-3-O--tert-Butyldimethylsilyl)-1--9-phenyl-9-
¯uorenyl)-d-proline methyl ester 20. To a solution of
alcohol 19 82.40 g, 4.63 mmol) in THF 823 mL) were
added triethylamine 81.29 mL, 9.26 mmol) and MsCl
80.54 mL, 7.0 mmol). The reaction mixture was stirred for
3 h at 08C, then was quenched with saturated aqueous
NaHCO3 830 mL). The organic phase was separated, and
the aqueous phase was treated with EtOAc 840 mL£3).
The extract was concentrated and the resulting residue
was chromatographed on silica gel [hexane±EtOAc
815:1)] to give compound 20 82.08 g, 90%) as a oil,
20
117±1208C; [a]D ˆ1278.9 8c 1.25, CHCl3); IR 8KBr):
3490, 3020, 1720 cm21; dH 8500 MHz; CDCl3) 2.51 81H,
d, Jˆ7.8 Hz), 3.20 83H, s), 3.89 81H, dd, Jˆ7.7, 6.9 Hz),
5.04 81H, dt, Jˆ10.4, 1.1 Hz), 5.16 81H, dt, Jˆ17.1, 1.3 Hz),
5.49 81H, m), 7.23±7.39 813H, m, Pf); dC 8125 MHz;
CDCl3) 51.5, 61.0, 72.5, 74.3, 117.7, 120.1, 120.1, 125.3,
125.9, 126.2, 127.4, 127.5, 128.4, 128.5, 128.6, 128.7,
136.1, 140.1, 141.2, 143.8, 148.1, 148.1, 174.3 8Found: C,
77.88; H, 6.03; N, 3.60. C25H23NO3 requires C, 77.90;H,
6.01; N, 3.63%).
20
[a]D ˆ2248.7 8c 1.73, CHCl3); IR 8neat): 3020, 2910,
1730 cm21; dH 8500 MHz; CDCl3) 0.00 83H, s), 0.04 83H,
s), 0.88 89H, s), 1.91 81H, m), 2.17 81H, m), 2.84 81H, m),
3.37 82H, m), 3.51 83H, s), 4.14 81H, m), 7.20±7.81 813H,
m, Pf); dC 8125 MHz; CDCl3) 24.9, 17.9, 25.6, 33.1, 46.1,
50.9, 65.0, 73.6, 76.5, 119.8, 120.0, 126.3, 126.6, 127.3,
127.3, 127.5, 127.6, 128.3, 128.3, 128.4, 140.0, 141.2,
142.8, 146.8, 148.2, 173.7 8Found: C, 74.47; H, 7.49; N,
2.79. C31H37NO3Si requires C, 74.51; H, 7.46; N, 2.80%).
4.1.14. Methyl -2R,3S)-3--tert-butyldimethylsilyl)oxy-2-
[-9-phenyl-9-¯uorenyl)-amino]-4-pentenoate 18. To a
solution of pentenoate 17 83.20 g, 8.30 mmol) in DMF
828 mL) were added imidazole 81.13 g, 16.60 mmol) and
TBDMSCl 82.50 g, 16.60 mmol) at room temperature.
After stirring of the mixture for 12h, saturated aqueous
NaHCO3 840 mL) was added and the mixture was extracted
with EtOAc 850 mL£3). After concentration of combined
extracts, the residue was chromatographed on silica gel
[hexane±EtOAc 810:1)] to give compound 18 84.06 g,
4.1.17. trans-3-Hydroxy-l-proline 1. The protected proline
12 80.70 g, 1.40 mmol) and 10% Pd/C 80.07 g) were stirred
in CH3OH 814 mL) under an atmosphere of hydrogen at
608C for 3 h. The reaction mixture was ®ltered through
Celite, and the ®ltrate was concentrated. A solution of
remaining residue and Dowex 50W-X8 80.18 g) in THF±
H2O 84:2mL) was re¯uxed for overnight, cooled to room

10076
J. H. Lee et al. / Tetrahedron 57 +2001) 10071±10076
temperature. The mixture was ®ltered, and then the
insoluble material was washed with CH3OH 850 mL). The
remaining residue was eluted with 3N NH4OH. The ammo-
niacal solution was evaporated, then co-evaporation with
toluene to give the compound 1 80.14 g, 76%) as a solid,
the ®ltrate was concentrated. The remaining oil was
subjected to ion-exchange chromatography 8Dowex 50W-
X8, eluting with 3N NH3 in water), and free base 4 was
20
obtained as an oil in 75% yield, [a]D ˆ223.2 8c 0.76,
H2O); IR 8neat): 3310, 2890 cm21; dH 8500 MHz; D2O)
1.93 81H, m), 2.14 81H, m), 3.14 81H, m), 3.30 82H, m),
3.78 81H, m), 3.38 81H, dd, Jˆ11.7, 5.5 Hz), 4.46 81H, s);
dC 8125 MHz; D2O) 33.8, 43.5, 59.3, 64.8, 71.2; MS: m/z
117 8M1); [Found 8HRMS): 8M1), 117.0804. Calcd for
C5H11NO2: 117.0790].
20
mp 231±2348C 8decomp.); [a]D ˆ223.3 8c 0.92, H2O);
{lit.,9 [a]D ˆ218.8 8c 0.14, H2O), mp 2328C}; IR 8KBr):
20
3410, 2920 cm21; dH 8500 MHz; D2O) 2.04 82H, m), 3.48
81H, m), 3.58 81H, m), 4.06 81H, s), 4.67 81H, m); dC
8125 MHz; D2O) 30.1, 42.8, 67.6, 72.5, 170.2; MS: m/z
131 8M1); [found 8HRMS): 8M1), 131.0567. Calcd for
C5H9NO3: 131.0582].
Acknowledgements
4.1.18. trans-3-Hydroxy-l-prolinol 2. The N-protected
prolinol 13 80.30 g, 0.84 mmol) and 10% Pd/C 80.03 g)
were stirred in CH3OH 84 mL) under an atmosphere of
hydrogen at 608C for 3 h. The reaction mixture was ®ltered
through Celite, and the ®ltrate was concentrated. The
remaining oil was subjected to ion-exchange chroma-
tography 8Dowex 50W-X8, eluting with 3N NH3 in
water), and free base 2 was obtained as an oil in 93%
This work was supported by a grant form High-tech-
nology Development Project for Agriculture, Forestry and
Fisheries.
References
1. Tschesche, R.; Samuel, T. D.; Uhlendorf, J.; Fehlaber, H. W.
Chem. Ber. 1972, 105, 3106±3114.
20
20
yield, [a]D ˆ145.8 8c 0.5, H2O); {lit.,18 [a]D ˆ146.5
8c 1.0, H2O)}; IR 8neat): 3450, 2895 cm21; dH 8500 MHz;
D2O) 1.78 81H, m), 2.02 81H, m), 3.03 83H, m), 3.55 81H,
m), 3.64 81H, m), 4.14 81H, m); dC 8125 MHz; D2O) 34.0,
44.3, 62.2, 67.4, 73.6; MS: m/z 117 8M1); [Found 8HRMS):
8M1), 117.0792. Calcd for C5H11NO2: 117.0790].
2. Sheeban, J. C.; Mania, D.; Nakamura, S.; Stock, J. A.; Maeda,
K. J. Am. Chem. Soc. 1968, 90, 462±470.
3. 8a) Fleet, G. W. J.; Son, J. C. Tetrahedron 1998, 44, 2637±
2647. 8b) Fleet, G. W. J.; Witty, D. R. Tetrahedron:
Asymmetry 1990, 1, 119±136. 8c) Sardina, F. J.; Rapoport,
H. Chem. Rev. 1996, 96, 1825±1872.
4.1.19. cis-3-Hydroxy-d-proline 3. The protected proline
20 80.70 g, 1.40 mmol) and 10% Pd/C 80.07 g) were in
CH3OH 814 mL) under an atmosphere of hydrogen at
608C 3 h. The reaction mixture was ®ltered through Celite,
and the ®ltrate concentrated. A solution of remaining
residue and Dowex 50W-X8 80.17 g) in THF±H2O
84:2mL) was re¯uxed for overnight, cooled to room
temperature. The mixture was ®ltered, and then the
insoluble material was washed with CH3OH 850 mL). The
remaining residue was eluted with 3N NH4OH. The ammo-
niacal solution was evaporated, then co-evaporation with
toluene to give the compound 3 80.15 g, 84%) as a solid,
4. Ohfune, Y.; Nishio, H. Tetrahedron Lett. 1984, 25, 4133±
4136.
5. Mulzer, J.; Meier, A.; Buschmann, J.; Luger, P. J. Org. Chem.
1996, 61, 566±572.
6. Ogle, J.; Arlinghaus, R.; Logan, M. Arch. Biochem. Biophys.
1961, 94, 85±93.
7. Kubo, A.; Nakai, T.; Koizumi, Y.; Kitahara, Y.; Saito, N.;
Micami, Y.; Yazawa, K.; Uno, J. Heterocycles 1996, 42,
195±211.
Ã
8. Durand, J.-O.; Larcheveque, M.; Petit, Y. Tetrahedron Lett.
1998, 39, 5743±5746.
9. Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron:
Asymmetry 1994, 5, 119±128.
20
mp 210±2178C 8decomp.); [a]D ˆ196.3 8c 0.92, H2O);
20
{lit.,10 [a]D ˆ189.0} 8c 0.7, H2O), mp 225±2358C
10. Jurczak, J.; Prokowicz, P.; Golebiowski, A. Tetrahedron Lett.
1993, 34, 7107±7110.
8decomp.)}; IR 8KBr): 3400, 2910 cm21; dH 8500 MHz;
D2O) 2.12 81H, m), 2.21 81H, m), 3.47 81H, m), 3.57 81H,
m), 4.13 81H, d, Jˆ4.1 Hz), 4.7281H, m); dC 8125 MHz;
D2O) 32.3, 42.9, 66.7, 70.0, 169.7; MS: m/z 131 8M1);
[Found 8HRMS): 8M1), 131.0580. Calcd for C5H9NO3:
131.0582].
11. Dell'Uomo, N.; Cristina Di Giovanni, M.; Misiti, D.; Zappia,
G.; Delle Monache, G. Tetrahedron: Asymmetry 1996, 7,
181±188.
Ã
12. Poupardin, O.; Greck, C.; Genet, J.-P. Synlett 1998, 1279±
1281.
13. Cooper, J.; Gallagher, P. T.; Knight, D. W. J. Chem. Soc.,
Perkin Trans. 1 1993, 1313±1317.
4.1.20. cis-3-Hydroxy-d-prolinol 4. To an ice-cooled solu-
tion of LAH 80.08 g, 2.10 mmol) in THF 87 mL) was added
a solution of proline 20 80.70 g, 1.40 mmol) in THF
810 mL). The reaction mixture was warmed to room
temperature, stirred for 7 h and then quenched by sequential
addition of water 80.8 mL), 15% aqueous NaOH 80.8 mL),
and water 82.4 mL). The mixture was ®ltered, and the ®ltrate
was concentrated. The residue was chromatographed on
silica gel [hexane±EtOAc 82:1)] to give compound. The
N-protected prolinol and 10% Pd/C 80.03 g) were stirred
in CH3OH 84 mL) under an atmosphere of hydrogen at
608C for 3 h. The mixture was ®ltered through Celite, and
È
14. Schollkopf, U.; Bardenhagen, J. Liebigs Ann. Chem. 1987,
393±397.
15. Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109,
236±239.
16. Kim, J. H.; Lee, W. S.; Yang, M. S.; Park, K. H. J. Chem. Soc.,
Perkin Trans. 1 1998, 2877±2880.
17. Lee, B. W.; Jeong, I. Y.; Yang, M. S.; Choi, S. U.; Park, K. H.
Synthesis 2000, 9, 1305±1309.
18. Nash, R. J.; Bell, E. A.; Fleet, G. W. J.; Jones, R. H.; Williams,
J. M. J. Chem. Soc. Chem. Commun. 1985, 738±740.