Enantiospecific syntheses of (R)- and (S)-proline and some derivatives from D-glucono-1,5-lactone

Article abstract of DOI:10.1039/a704915c

Carbohydrate-based enantiospecific syntheses of (R)-proline 1 and (S)-proline 2 from the previously reported D-erythro-hexonate ester 9 are described. Azide-substitution reactions on appropriately activated intermediates derived from ester 9, followed by reductive cyclization (H₂/Pd-C), gave the substituted pyrrolidines 14 and 22, which were converted into their corresponding N-Cbz derivatives 16 and 24 in conventional manner. Mild acidic hydrolysis of these, followed by oxidation (sodium metaperiodate), gave the protected prolinals 3 and 4, which on further oxidation (sodium chlorite), followed by catalytic hydrogenolysis, gave the prolines 1 and 2. The N-Cbz-prolinol derivatives 5 and 6 are also reported.

Full text of DOI:10.1039/a704915c

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Enantiospecific syntheses of (R)- and (S)-proline and some derivatives
from D-glucono-1,5-lactone
Claudio Mazzini,b Letitia Sambri,c Henk Regeling,a Binne Zwanenburga and
Gordon J. F. Chittenden*,a
a Department of Organic Chemistry, NSR Center for Molecular Structure, Design and
Synthesis, The University, Toernooiveld, 6525 ED Nijmegen, The Netherlands
b Groupe ‘Biocatalyse et Chimie Fine,’ Faculté des Sciences de Luminy, Case 901-163,
Avenue de Luminy, 13288 Marseille, France
c Dipartimento di Chimica Organica ‘A Mangini’ Università di Bologna, Viale Risorgimento 4,
40316 Bologna, Italy
Carbohydrate-based enantiospecific syntheses of (R)-proline 1 and (S)-proline 2 from the previously
reported D-erythro-hexonate ester 9 are described. Azide-substitution reactions on appropriately activated
intermediates derived from ester 9, followed by reductive cyclization (H2/Pd–C), gave the substituted
pyrrolidines 14 and 22, which were converted into their corresponding N-Cbz derivatives 16 and 24 in
conventional manner. Mild acidic hydrolysis of these, followed by oxidation (sodium metaperiodate), gave
the protected prolinals 3 and 4, which on further oxidation (sodium chlorite), followed by catalytic
hydrogenolysis, gave the prolines 1 and 2. The N-Cbz-prolinol derivatives 5 and 6 are also reported.
Introduction
Results and discussion
Treatment of the toluene-p-sulfonate ester 103 of compound 9
with sodium azide in N,N-dimethylformamide (DMF) gave the
corresponding -threo-azide 11 as a syrup (91%) which was
characterized by catalytic (palladized charcoal, 10%) reductive
cyclic amination to give the crystalline pyrrolidine-2-one deriv-
ative 12. Reduction of compound 11 in toluene with di-
isobutylaluminium hydride (DIBAL) at Ϫ78 ЊC yielded the
pure, but unstable aldehyde 13. Attempts to form a stable crys-
talline phenylhydrazone, or semicarbazone, of compound 13
were unsuccessful. Catalytic hydrogenation of compound 13
over palladized charcoal (10%) proceeded with concomitant
ring closure to produce the substituted pyrrolidine 14, which on
treatment with toluene-p-sulfonyl chloride (TsCl)–triethylamine
gave the crystalline N-toluene-p-sulfonate 15. Treatment of
compound 14 in aq. ethanol with benzyl chloroformate in the
presence of sodium hydrogen carbonate in the usual manner
gave the corresponding N-benzyloxycarbonyl (N-Cbz) deriv-
ative 16. Hydrolysis (80% aq. acetic acid) of compound 16 gave
the diol 17, which on oxidation with aq. sodium metaperiodate
in methanol gave the protected (R)-prolinal derivative 3. Reduc-
tion of aldehyde 3 with sodium borohydride in methanol pro-
duced the corresponding (R)-prolinol derivative 5.
The stereospecific syntheses of enantiomerically pure com-
pounds, especially those of natural origin, is an active area of
modern organic chemistry. The synthesis of prolines and their
derivatives seems currently of interest, inter alia, in this
respect.1,2 A simple route to (R)-proline 1, (S)-proline 2 and the
related protected aldehydes 3, 4 and alcohols 5, 6, from -
R2
R3
R2
R3
N
R1
N
R1
1 R1 = R3 = H R2 = CO2H
2 R1 = R3 = H, R2 = CO2H
3 R1 = Cbz, R2 = CHO, R3 = H
4 R1 = Cbz, R2 = CHO, R3 = H
5 R1 = Cbz, R2 = CH2OH, R3 = H 6 R1 = Cbz, R2 = CH2OH, R3 = H
7 R1 = Cbz, R2 = CO2H, R3 = H
8 R1 = Cbz, R2 = CO2H, R3 = H
where Cbz = PhCH2OCO
glucono-1,5-lactone via the hexonate ester 9,3 became avail-
able during studies on chiral pyrrolidine derivatives. Early syn-
theses of prolines 1 and 2 produced racemic mixtures which
required resolution.4 Various asymmetric syntheses, including
asymmetric transformations, have been reported,5–14 but with
greater emphasis on the naturally occurring S-isomer 2. Com-
pound 2 is responsible for conformational constraint in certain
proteins and is obtained currently almost exclusively from pro-
tein hydrolysates or by fermentation.15 Recent interest16,17 has
also centred on syntheses designed for the introduction of
specific isotopic labelling into the products. The new route
described here is noteworthy in its flexibility. Both enantiomers
1 and 2 and their related protected derivatives 3–6 are available,
by choice, from one inexpensive source using simple reactions.
Compound 3 has not been described previously and its enan-
tiomer 4 is not obtained readily. The prolinols 5 and 6 are usu-
ally prepared by metal hydride reduction of suitably protected
esters of prolines 1 and 2.18 Compounds 1 and 2 and derivatives
thereof, including the alcohols 5 and 6, are useful chiral catalyst
components or auxiliaries for inter alia, enantioselective cata-
lytic reductions18–24 asymmetric intramolecular aldolizations25
and asymmetric induction in conjugated additions,26 self-
condensation of α,β-unsaturated aldehydes,27 Robinson annel-
ation reactions,28 and in the synthesis of some alkaloids.29,30
Oxidation of aldehyde 3 with sodium chlorite, in the presence
of 2-methylbut-2-ene as a chlorine scavenger,31 was rapid and
proceeded smoothly to give the protected (R)-proline derivative
7, which on catalytic hydrogenolysis32 provided pure (R)-
proline 1 (Scheme 1).
Treatment of the bromoester 183 with sodium azide in DMF
did not proceed satisfactorily. Analysis (TLC and GLC) of the
reaction mixture produced after 18 h indicated the presence of
not only the expected azido derivative 19 but also its diastereo-
mer 11 (vide supra), in the ratio 3:2, indicating that epimeri-
zation was occurring during the course of the substitution reac-
tion. This was probably due to nucleophilic attack of bromide
ions, produced during the initial phase of the displacement
reaction, on remaining compound 18, with subsequent and
concurrent replacement of both by azide ions (Scheme 2).
The required compound 19 was obtained successfully by
treatment of bromide 18 with a solution of lithium azide33 in
DMF at room temp. for 7 days. Lithium azide is much more
J. Chem. Soc., Perkin Trans. 1, 1997
3351

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CO2Me
CH2
CH2
OH
O
CO2Me
CH2
CH2
OTs
O
CO2Me
CH2
H
N
O
CH2
iii
ii
i
N3
O
CH3
CH3
CH3
CH3
CH3
CH3
O
O
CH3
CH3
O
O
O
12
9
10
11
iv
CHO
CH2
CH2
Cbz
H
N
Cbz
N
N
vi
iii
v
N3
O
O
O
CH3
CH3
CH3
CH3
OH
OH
17
O
CH3
CH3
O
O
16
14
13
x
vii
Ts
ix
N
iii
3
7
1
viii
5
O
CH3
CH3
O
15
Scheme 1 Reagents and conditions: i, TsCl, pyridine; ii, NaN3, DMF; iii, Pd–C (10%), H2; iv, DIBAL, Ϫ78 ЊC; v, PhCH2OCOCl, NaHCO3; vi, 80%
HOAc–water; vii, NaIO4; viii, NaBH4; ix, NaClO2, 2-methylbut-2-ene; x, TsCl, Et3N
earlier35,36 for compound 4, derived from reduction of esters of
CO2Me
CH2
CO2Me
CH2
CH2
N3
(S)-proline 2. It had been implied36 that amino aldehydes
derived from chiral amino acids could be difficult to obtain
with high optical purity. Compound 3 has not been described
hitherto. The two enantiomeric aldehydes 3 and 4 described
here probably have very high optical purities in view of their
mode of synthesis. These two compounds could be stored
(0 ЊC) for appreciable periods of time (2–3 months) without any
obvious deterioration or racemization.
CH2
i
ii
+
11
9
Br
O
O
CH3
CH3
O
CH3
CH3
O
18
19
Scheme 2 Reagents and conditions: i, Ph3P, CBr4; ii, NaN3, DMF,
100 ЊC
Further oxidation of aldehyde 4 with sodium chlorite in the
same manner as described for its enantiomer 3 (vide supra)
yielded the known, commercially available N-Cbz-(S)-proline 8,
which on catalytic hydrogenation (palladized charcoal, 10%)
yielded (S)-proline 2.
The syntheses described illustrate the useful application of
the ester 9 as a chiral synthon. Further studies on the use of the
aldehydes 4 and 5 as sources of novel chiral ligands is currently
in progress.
soluble (~1 g/10 ml) than sodium azide in this solvent, thereby
enabling the reaction to be conducted at ambient temperature.
Lithium bromide produced during the reaction is also much less
effective as a source of nucleophilic bromide ions under these
conditions. The beneficial use of lithium azide in some nucleo-
philic displacement reactions has been reviewed.34 Compound
19 yielded the crystalline pyrrolidine-2-one derivative 20 on
reductive (Pd/C, H2) cyclization (vide supra).
Reaction of ester 19 with DIBAL in toluene at Ϫ78 ЊC,
followed by reductive (Pd/C, H2) cyclization of the resultant
unstable aldehyde 21 gave the expected pyrrolidine derivative 22
as a syrup, which was characterized as the crystalline N-
toluene-p-sulfonate 23. Compound 22 was also converted into
the corresponding N-Cbz derivative 24 in the usual manner.
Mild acidic hydrolysis of compound 24 gave the free diol 25,
which on treatment with aq. methanolic sodium metaperiodate
yielded the aldehyde 4, reduction of which with sodium boro-
hydride in methanol gave the (S)-prolinol derivative 6 (Scheme
3).
A synthesis of the aldehyde 4 from commercially available
(S)-prolinol, via Swern-type oxidation of the N-benzyloxy-
carbonyl derivative 6, has been described30 relatively recently.
The observed optical rotations for these two derivatives were in
good overall agreement with the values reported here, and also
with the numerical values for their enantiomeric counterparts,
compound 3 and 5. The current value for compound 4, [α]D
Ϫ76.5† is marginally higher than the most recently cited30
value, [α]D Ϫ63.7, and both are much greater than those cited
Experimental
Optical rotations were determined with a Perkin-Elmer model
241 automatic polarimeter on 1% solutions in chloroform at
25 ЊC, unless indicated otherwise. TLC on pre-coated plates of
silica gel (Merck) was performed with light petroleum–ethyl
acetate (1:1). Detection was affected by spraying with 0.1 
K2Cr2O7 in 0.05  H2SO4 and heating at 140 ЊC. Column chro-
matography and flash-column chromatography were per-
formed on silica gel 60 and 60 H with the solvent mixtures
indicated. GLC was performed with a Hewlett-Packard 5890
gas chromatograph; a fused-silica capillary column (25 m)
coated with HP-1 cross-linked methyl silicone gumphase oper-
ating at 100–150 ЊC (t = 0 min, 100 ЊC isothermal; t = 5 min,
5 ЊC minϪ1) and nitrogen as the carrier gas at 2 ml minϪ1 was
1
used. H NMR spectra were recorded with a Bruker AC 100
(100 MHz) or Bruker AC 300 (300 MHz) spectrometer on
solutions in CDCl3 (internal Me4Si) or D2O or as indicated.
J-Values are given in Hz. 13C NMR spectra were recorded with
Bruker AC 100, AC 300 or AM 400 spectrometers operating at
25, 75 and 100.6 MHz respectively on solutions in CDCl3
(internal Me4Si) or D2O (external 1,4-dioxane at δC 67.8). Mass
spectra were recorded using a double-focusing VG 7070E
† [α]D-Values are given in units of 10Ϫ1 deg cm2 gϪ1
.
3352
J. Chem. Soc., Perkin Trans. 1, 1997

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CHO
CH2
CH2
H3C
H3C
H3C
H3C
O
O
O
O
H
N
Ts
N
iv
ii
iii
i
19
18
N3
O
O
CH3
CH3
iii
22
23
H3C
H3C
O
O
21
H
N
O
20
HO
HO
H3C
H3C
O
O
Cbz
Cbz
vii
viii
ix
N
N
vi
6
4
iii
2
8
25
24
Scheme 3 Reagents and conditions: i, LiN3, DMF, 20 ЊC; ii, DIBAL, Ϫ78 ЊC; iii, Pd–C (10%), H2; iv, TsCl, KOH; v, PhCH2OCOCl, NaHCO3; vi,
80% HOAc–water; vii, NaIO4; viii, NaBH4; ix, NaClO2, 2-methylbut-2-ene
spectrometer or a Varian Saturn 2 GC-MS ion-trap system. IR
spectra were determined on a Perkin-Elmer 298 spectrometer
as indicated. DIBAL was purchased as a 1  solution in hex-
ane. Light petroleum is the fraction distilled between 60–
80 ЊC.
the same temperature, treated with sodium sulfate decahydrate
(1.5 g), diluted with dichloromethane (25 ml) and stirred at
room temp. for 1 h. The mixture was then treated with
anhydrous sodium sulfate, and filtered, the inorganic material
was washed with dichloromethane, and the combined filtrate
and washings were washed with water (2 × 20 ml), dried
(NaSO4), and concentrated in vacuo. Column chromatography
(light petroleum–ethyl acetate, 1:1) of the resultant material
gave aldehyde 13 (1.04 g, 82%) as an oil, [α]D ϩ10.4;
δH(CDCl3) 9.81 (s, 1 H, CHO), 4.10 (m, 2 H, H-5, Ha-6), 3.82
(dd, J 6 and 8, 1 H, Hb-6), 3.27 (m, 1 H, H-4), 2.68 (m, 2 H,
H2-2), 1.84–1.70 (m, 2 H, H2-3) and 1.47 and 1.38 (2 s, each 3
H, CMe2); δC(CDCl3) 200.73, 110.12, 78.53, 66.33, 62.71,
40.22, 26.32, 25.13 and 23.01; m/z 186 (Mϩ ϩ 1 Ϫ 28, 2.8%),
101 (100), 82 (44), 55 (12) and 43 (97); νmax(neat)/cmϪ1 2880,
2710, 2100 and 1710.
Methyl 4-azido-2,3,4-trideoxy-5,6-O-isopropylidene-D-threo-
hexonate [(4R,5S)-methyl 4-azido-5,6-(isopropylidenedioxy)-
hexanoate] 11
A stirred mixture of compound 103 (2.4 g, 6.45 mmol) and
sodium azide (1.28 g, 19.7 mmol) in DMF (50 ml) was heated
for 12 h at 100 ЊC, cooled and then treated with ice–water
(200 ml). The mixture was extracted with diethyl ether
(2 × 150 ml) and the combined extracts were washed succes-
sively with saturated aq. sodium chloride (2 × 20 ml) and
water (2 × 20 ml), dried (MgSO4), and concentrated in vacuo.
Column chromatography (ethyl acetate–light petroleum, 3:1)
of the residue yielded compound 11 (1.43 g, 91%) as a pure
(TLC and GLC) syrup, [α]D ϩ14.4; δH(CDCl3) 4.09 (m, 2 H,
H-5, Ha-6), 3.82 (dd, J 8 and 6, 1 H, Hb-6), 3.70 (s, 3 H,
OCH3), 3.28 (m, 1 H, H-4), 2.50 (m, 2 H, H2-2), 1.78 (m, 2 H,
H2-3) and 1.48 and 1.37 (2 s, each 3 H, CMe2); δC(CDCl3)
173.08, 78.49, 66.37, 62.73, 51.78, 30.32, 26.34, 25.9 and
25.17; m/z 228 (Mϩ Ϫ 15, 11%), 216 (3.7), 130 (11.7), 101
(81), 87 (13), 59 (21) and 43 (100); νmax(neat)/cmϪ1 2980, 2110
and 1730.
(2R,4ЈS)-2-(2Ј,2Ј-Dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)pyrrolidine 14
A solution of compound 13 (0.442 g, 2.07 mmol) in methanol
(25 ml) was treated with palladized charcoal (10%; 45 mg) and
was then hydrogenated (1 atm) at room temp. for 7 h. The
inorganic material was removed by filtration and washed with
methanol (10 ml). The combined filtrate and washings were
concentrated in vacuo at <25 ЊC to give the pyrrolidine 14 (0.34
g, 96%). A portion of the product (172 mg) was distilled in
vacuo (Kügelrohr, 80 ЊC/0.25 mbar‡) to give pure compound 14
(130 mg, 76%), [α]D ϩ9 (Found: C, 62.84; H, 10.41; N, 7.96.
C9H17NO2 requires C, 63.12; H, 10.01; N, 8.18%); δH(CDCl3)
3.99 (m, 2 H, H2-5), 3.64 (m, 1 H, H-4Ј), 3.09–2.89 (m, 3 H),
2.10 (br s, 1 H, NH), 1.85–1.67 (m, 3 H) and 1.42 and 1.36 (2 s,
each 3 H, CMe2); δC(CDCl3) 109.13, 79.40, 67.11, 60.95, 46.30,
27.43, 26.77, 25.37 and 25.24; m/z 172 (Mϩ ϩ 1, 8.4%), 156
(3.3), 70 (100) and 43 (31); νmax(film)/cmϪ1 3330, 2940, 2850 and
1690.
A portion of the above material (98.4 mg, 0.575 mmol) in
methanol (2 ml) containing trimethylamine (0.163 ml, 1.17
mmol) was treated with TsCl (134 mg, 0.702 mmol), set aside
at room temp. for 4 h, and processed in the usual manner.
Recrystallization (light petroleum) of the resultant crude crys-
talline material (151 mg) gave the N-toluene-p-sulfonate 15 (125
mg, 67%), mp 95–97 ЊC; [α]D Ϫ86 (Found: C, 58.67; H, 6.83; N,
4.31; S, 9.78. C16H23NO4S requires C, 59.05; H, 7.12; N, 4.30; S,
9.85%); δH(CDCl3) 7.72 and 7.32 (2 d, each J 8.2, each 2 H,
ArH), 4.21 (q, J 6.3, 1 H, H-4Ј), 4.13 (dd, J 8.5 and 6.3, 1 H, Ha-
5Ј), 3.98 (dd, J 8.5 and 6.3, 1 H, Hb-5Ј), 3.72 (m, 1 H, H-2), 3.41
(m, 1 H, Ha-5), 3.18 (m, 1 H, Hb-5), 2.43 (s, 3 H, C6H4Me), 1.90
(5R,4ЈS)-5-(2Ј,2Ј-Dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)pyrrolidin-2-
one 12
A solution of compound 11 (0.604 g, 2.49 mmol) in methanol
(20 ml) was treated with palladized charcoal (10%; 60 mg) and
was then hydrogenated (1 atm) at room temp. The inorganic
material was removed by filtration and washed with methanol
(20 ml), and the combined filtrate and washings were concen-
trated in vacuo to give an oil which crystallized on storage (48
h). Recrystallization (diisopropyl ether–dichloromethane) gave
pure lactam 12 (0.23 g, 63%), mp 102–104 ЊC; [α]D Ϫ54 (Found:
C, 58.27; H, 8.11; N, 7.45. C9H15NO3 requires C, 58.36; H, 8.16;
N, 7.56%); δH(100 MHz; CDCl3) 6.48 (br s, 1 H, NH), 4.03–3.67
(m, 4 H, H-4Ј, -5 and H2-5Ј), 2.3–1.95 (m, 4 H, H2-3 and -4)
and 1.42 and 1.33 (2 s, each 3 H, CMe2); νmax(KBr)/cmϪ1 3260,
1690 and 1650.
(4R,5S)-4-Azido-5,6-(isopropylidenedioxy)hexanal 13
A solution of DIBAL (7.1 ml) was added dropwise to a
stirred, cooled (Ϫ78 ЊC) solution of compound 11 (1.44 g, 5.9
mmol) in light petroleum–toluene (25 ml; 1:1) maintained
under nitrogen. The mixture was stirred for a further 1 h at
‡ 1 bar = 105 Pa.
J. Chem. Soc., Perkin Trans. 1, 1997
3353

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(m, 2 H), 1.55 (m, 1 H), 1.43 and 1.39 (2 s, each 3 H, CMe2)
and 1.35 (m, 1 H); δC(CDCl3) 143.57, 134.61, 129.73, 127.59,
109.40, 77.41, 67.56, 62.05, 49.17, 29.95, 26.52, 25.15, 24.06
and 21.52.
ml) was hydrogenated (1 atm) in the presence of palladized
charcoal (10%; 60 mg) for 6 h and was then processed as
described above. Distillation in vacuo (Kügelrohr, 80 ЊC/0.5
mbar) of the material gave pure compound 22 (0.322 g,
62.5%), [α]D ϩ16 (Found: C, 63.4; H, 9.86; N, 8.01. C9H17NO2
requires C, 63.12; H, 10.01; N, 8.18%); δH(CDCl3) 4.04 (m,
2 H, H2-5Ј), 3.76 (dd, J 8 and 6, 1 H, H-4Ј), 3.15 (m, 1 H,
H-2), 2.92 (m, 2 H, H2-5), 1.96 (br s, 1 H, NH), 1.95–1.54
(m, 4 H, H2-3 and -4) and 1.42 and 1.35 (2 s, each 3 H,
CMe2); δC(CDCl3) 108.97, 78.86, 67.59, 60.53, 46.98, 28.19,
26.65, 25.71 and 25.26; m/z 172 (Mϩ ϩ 1, 3.25%), 156 (4.08),
96 (15.37), 70 (100) and 43 (32.51); νmax(neat)/cmϪ1 3340, 2920
and 1690.
Treatment of a portion (100 mg) of compound 22 in the
manner described above for compound 14 gave the N-toluene-
p-sulfonate 23 (109 mg, 57%), mp 71.5–72.5 ЊC (from light pet-
roleum); [α]D ϩ95.3 (Found: C, 59.23; H, 7.04; N, 4.33; S, 9.90.
C16H23NO4NS requires C, 59.05; H, 7.12; N, 4.30; S, 9.85%);
δH(CDCl3) 7.73 and 7.32 (2 d, J 8.5 and 6.3, each 1 H, ArH),
4.54 (dt, J 6.6 and 4.0, 1 H, H-4Ј), 4.10 (dd, J 9 and 6.8, 1 H, Ha-
5Ј), 3.98 (dd, J 9 and 6.4, 1 H, Hb-5Ј), 3.82 (quintet, J 4.2, H-2),
3.35 (m, 2 H, H2-5), 2.43 (s, 3 H, C6H4Me), 1.89–1.60 (m, 3 H),
1.42 and 1.35 (2 s, each 3 H, CMe2) and 1.33 (m, 1 H);
δC(CDCl3) 143.66, 134.10, 129.71, 127.70, 109.26, 77.51, 65.61,
50.24, 27.29, 26.17, 24.99, 24.44 and 21.53.
(2R,4ЈS)-N-Benzyloxycarbonyl-2-(2Ј,2Ј-dimethyl-1Ј,3Ј-
dioxolan-4Ј-yl)pyrrolidine 16
Treatment of a stirred solution of free amine 14 (336 mg, 1.97
mmol) in 50% aq. ethanol (25 ml), containing sodium hydrogen
carbonate (336 mg), with benzyl chloroformate (0.45 ml, 3.2
mmol) followed by processing in the usual manner and column
chromatography (hexane–ethyl acetate, 3:1) of the resulting
material gave compound 16 (491 mg, 82%), [α]D ϩ59;
δH(CDCl3) 7.33 (m, 5 H, Ph), 5.13 (qAB, J 15.6 and 12.4, 2 H,
PhCH2), 4.41 (m, 1 H), 4.13 (m, 1 H), 3.9 (m, 1 H), 3.84 (m, 1
H), 3.61 (m, 1 H), 3.36 (m, 1 H), 2.00–1.78 (m, 4 H, H2-3 and
-4) and 1.37 and 1.33 (2 s, each 3 H, CMe2); δC(CDCl3) 155.52,
136.64, 128.33, 127.83, 127.74, 108.77, 77.48, 66.80, 65.81,
57.75, 47.39, 27.66, 26.08, 25.19 and 23.89; m/z 290 (Mϩ Ϫ 15,
1.95%), 160 (40.21), 91 (100) and 43 (18.21); νmax(film)/cmϪ1
3030, 2960, 2880, 1820 and 1680.
Methyl 4-azido-2,3,4-trideoxy-5,6-O-isopropylidene-D-erythro-
hexonate [(4S,5S)-methyl 4-azido-5,6-(isopropylidenedioxy)-
hexanoate] 19
A stirred solution of compound 183 (2.85 g, 10.2 mmol) in dry
DMF (24 ml) was treated with lithium azide33 (2.45 g, 50 mmol)
and then was set aside at room temp. for 7 days. The mixture
was treated with a mixture of diethyl ether (100 ml) and water
(100 ml). The separated aqueous layer was extracted with a
further portion of diethyl ether (100 ml) and the combined
ether layers were washed successively with saturated aq. sodium
chloride and water, dried (Na2SO4), and concentrated in vacuo.
Flash column chromatography (hexane–ethyl acetate, 3:1) of
the resultant residue gave pure (GLC) compound 19 (1.58 g,
65%) as an oil, [α]D Ϫ45; δH(CDCl3) 4.07 (m, 2 H, H-5, Ha-6),
3.89 (dd, J 8 and 6, 1 H, Hb-6), 3.70 (s, 3 H, OCH3), 3.59 (m, 1
H, H-4), 2.50 (m, 2 H, H2-2), 1.96 (m, 1 H, Ha-3), 1.60 (m, 1 H,
Hb-3) and 1.47 and 1.36 (2 s, each 3 H, CMe2); δC(CDCl3)
173.06, 109.79, 77.73, 65.80, 62.72, 51.74, 30.44, 26.17, 26.05
and 25.09; m/z 228 (Mϩ Ϫ 15, 10%), 216 (3.7), 130 (3.2), 101
(57), 98 (22), 83 (16.5), 59 (20) and 43 (100); νmax(film)/cmϪ1
2980, 2110, 1730, 1240 and 1060.
(2S,4ЈS)-N-Benzyloxycarbonyl-2-(2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-
4Ј-yl)pyrrolidine 24
Treatment of a portion of compound 22 (260 mg, 1.52 mmol)
with benzyl chloroformate (0.23 ml, 1.52 mmol) followed by
processing in the usual manner, and column chromatography
(hexane–ethyl acetate, 3:1), gave compound 24 (302 mg,
65%), [α]D Ϫ39; δH(400 MHz; 61 ЊC; CDCl3) 7.52 (m, 5 H,
Ph), 5.13 (qAB, J 19.6 and 12.5, 2 H, PhCH2), 4.26 (m, 1 H),
3.99 (m, 1 H), 3.76 (m, 1 H), 3.49 (m, 2 H), 2.02 (m, 2 H),
1.85 (m, 2 H) and 1.40 and 1.31 (2 s, each 3 H, CMe2);
δC(61 ЊC; CDCl3) 155.29, 137.00, 128.50 and 127.91 (2×),
127.56, 109.10, 76.67, 67.69, 66.86, 55.54, 47.06, 26.36 (2×),
25.20 and 23.82; m/z 306 (Mϩ ϩ 1, 0.18%), 290 (1.5), 160
(35.34), 91 (100) and 43 (16.49); νmax(film)/cmϪ1 3430, 3020,
2960, 2800 and 1690.
(2R,1ЈS)-N-Benzyloxycarbonyl-2-(1,2-dihydroxyethyl)pyrroli-
dine 17
(5S,4ЈS)-5-(2Ј,2Ј-Dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)pyrrolidin-2-one
20
A solution of compound 16 (491 mg) in 80% aq. acetic acid (10
ml) was set aside at room temperature for 5 days and was then
concentrated in vacuo. Water (5 ml), followed by toluene (3 × 10
ml) was distilled in vacuo from the residue to give diol 17 (403
mg, 95%) as an oil, [α]D ϩ66; δH(CDCl3) 7.36 (m, 5 H, Ph), 5.15
(s, 2 H, PhCH2), 4.05 (m, 1 H, H-2), 3.60 (m, 1 H), 3.37 (m, 1 H)
and 2.09–1.73 (m, 4 H, H2-3 and -4); δC 157.90, 136.15, 128.14,
128.14, 128.03, 127.80, 75.64, 67.45, 64.04, 59.99, 47.31, 28.48
and 24.12; m/z 266 (Mϩ ϩ 1, 0.16%), 204 (40.24), 160 (45.83),
114 (7.79), 91 (100), 70 (17.04), 65 (14.85), 43 (10.32), 41
(15.28), 39 (13.27), 31 (8.33) and 28 (19.73); νmax(KBr)/cmϪ1
3400, 3030, 2940, 2885 and 1665.
Reductive cyclization of compound 19 (0.458 g, 1.89 mmol) in
the manner described above for compound 11 gave the lactam
20 (0.206 g, 59%), mp 125–126 ЊC (from diisopropyl ether–
dichloromethane); [α]D ϩ28.2 (Found: C, 58.40; H, 7.91; N,
7.53. C9H15NO3 requires C, 58.36; H, 8.16; N, 7.56%); δH(100
MHz; CDCl3) 6.60 (br s, 1 H, NH), 4.06–3.77 (m, 4 H, H-4Ј, -5
and H2-5Ј), 2.45–1.75 (m, 4 H, H2-3 and -4) and 1.43 and 1.35
(2 s, each 3 H, CMe2); νmax(film)/cmϪ1 3430, 1690 and 1650.
(4S,5S)-4-Azido-5,6-(isopropylidenedioxy)hexanal 21
A solution of compound 19 (1.26 g, 5.19 mmol) was treated
with DIBAL (6.23 ml) and processed as described above. Col-
umn chromatography (light petroleum–ethyl acetate, 3:1) of
the resulting material gave the aldehyde 21 (0.85 g, 77%), [α]D
ϩ46, as an oil; δH(CDCl3) 9.81 (s, 1 H, CHO), 4.08 (m, 2 H, H-
5, Ha-6), 3.91 (dd, 1 H, J 8 and 5, Hb-6), 3.55 (quintet, J 5, 1 H,
H-4), 2.65 (m, 2 H, H2-2), 1.97 (m, 1 H, Ha-3), 1.60 (m, 1 H, Hb-
3) and 1.47 and 1.36 (2 s, each 3 H, CMe2); δC(CDCl3) 200.76,
109.85, 77.69, 65.86, 62.70, 40.29, 26.19, 25.07 and 23.24; m/z
186 (Mϩ ϩ 1 Ϫ 28, 0.45%), 101 (44.49), 82 (16.35), 55 (11.06)
and 43 (100); νmax/cmϪ1 2980, 2890, 2720, 2120 and 1700.
(2S,1ЈS)-N-Benzyloxycarbonyl-2-(1,2-dihydroxyethyl)pyrroli-
dine 25
Treatment of compound 24 (302 mg) with 80% aq. acetic acid
(15 ml), followed by processing in the above manner, yielded
compound 25 (235 mg, 90%), [α]D Ϫ20; δH(CDCl3) 7.35 (m, 5
H, Ph), 5.14 (qAB, J 12.7 and 12.7, 2 H), 3.92 (1 H, m, H-2),
3.59 (br s, 1 H, H-4Ј), 3.46 (m, 3 H), 2.09 (m, 1 H) and 1.91
(m, 3 H); δC(CDCl3) 158.8, 136.3, 128.51, 128.1, 127.81, 72.62,
67.41, 62.73, 59.32, 47.18, 27.62 and 23.31; m/z 266 (Mϩ ϩ 1,
0.16%), 204 (40.24), 160 (45.83), 114 (4.34), 91 (100), 70
(13.74), 65 (27.77), 43 (28.04), 41 (21.55), 39 (18.89), 31
(19.97) and 28 (13.94); νmax(KBr)/cmϪ1 3380, 3020, 2950, 2880
and 1660.
(2S,4ЈS)-2-(2Ј,2Ј-Dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)pyrrolidine 22
A solution of compound 21 (0.64 g, 3.0 mmol) in methanol (20
3354
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
(2R)-N-(Benzyloxycarbonyl)pyrrolidine-2-carbaldehyde 3
A stirred solution of compound 17 (403 mg, 1.52 mmol) in a
mixture of water (12 ml) and methanol (8 ml) was treated with
sodium metaperiodate (325 mg, 1.52 mmol) and set aside in the
dark for 2 h. The mixture was extracted with dichloromethane
(2 × 20 ml) and the combined extracts were washed with water
(20 ml), dried (Na2SO4) and concentrated in vacuo. Column
chromatography (light petroleum–ethyl acetate, 3:1) of the
residue gave the aldehyde 3 (280 mg, 79%), [α]D ϩ 83;
δH(CDCl3) 9.59 (d, 0.5 H, J 1.6, CHO), 9.49 (d, J Ϫ2.3, 0.5 H,
CHO), 7.32 (m, 5 H, Ph), 5.16 (m, 2 H, PhCH2), 4.30 (m, 0.5 H,
H-2), 4.20 (m, 0.5 H, H-2), 3.56 (m, 2 H, H2-5), 2.05 (m,
2 H, H2-3) and 1.92 (m, 2 H, H2-4); δC(CDCl3) 199.98,
155.23 ϩ 154.37 (1 C), 136.35 ϩ 136.12 (1 C), 128.85, 128.39,
127.99, 67.13, 65.15 ϩ 64.76 (1 C), 47.12 ϩ 46.59 (1 C),
27.67 ϩ 26.47 (1 C) and 24.37 ϩ 23.60 (1 C); m/z 204 (Mϩ Ϫ 29,
3.15%), 160 (18.92), 91 (100) and 65 (12.60); νmax(neat)/cmϪ1
2978, 2880, 1735 and 1694.
aside at room temperature for a further 1 h. The mixture was
concentrated in vacuo, the residue was dissolved in water (10
ml), the pH was adjusted to 7–8 with dil. aq. sodium hydroxide,
and the mixture was extracted with hexane (2 × 20 ml). The
aqueous phase was then adjusted to pH 3 by addition of 10%
aq. -tartaric acid, extracted with diethyl ether (3 × 10 ml) and
the combined extracts were dried (Na2SO4), and concentrated
in vacuo to give compound 7 (131 mg, 88%), mp 74–75 ЊC; [α]D
ϩ69.7 {lit.,37 mp 76–77 ЊC; [α]D ϩ61.2 (AcOH)}; δH(CDCl3)
9.10 (br s, 1 H, CO2H), 7.34 (m, 5 H, Ph), 5.16 (m, 2 H, PhCH2),
4.42 (m, 1 H, H-2), 3.52 (m, 2 H, H2-5), 2.19 (m, 2 H, H2-3)
and 1.96 (m, 2 H, H2-4); δC(CDCl3) 178.01 ϩ 175.59 (1 C),
156.15 ϩ 154.34 (1 C), 136.46 ϩ 136.17 (1 C), 128.51, 128.39,
128.17, 127.96, 127.89 ϩ 127.67 (1 C), 67.64 ϩ 67.10 (1 C),
59.37 ϩ 58.56 (1 C), 46.90 ϩ 46.71 (1 C), 30.98 ϩ 29.04 (1 C)
and 24.30 ϩ 23.45 (1 C); m/z 249 (Mϩ, 1.84%), 160 (13.82), 114
(32.49), 91 (100), 70 (12.45), 65 (12.40) and 39 (5.19); νmax(KBr)/
cmϪ1 3010, 2980, 2885 and 1750.
(2S)-N-(Benzyloxycarbonyl)pyrrolidine-2-carbaldehyde 4
Treatment of compound 25 (234 mg, 0.83 mmol) with sodium
metaperiodate (189 mg, 0.83 mmol) as described above yielded
aldehyde 4 (165 mg, 80%), [α]D Ϫ76.5 {lit.,30 [α]D20 Ϫ63.7
(MeOH)}; δH(CDCl3) 9.58 (d, J 1.7, 0.5 H, CHO), 9.48 (d, 0.5
H, J 2.3, CHO), 7.32 (m, 5 H, Ph), 5.16 (m, 2 H, PhCH2), 4.28
(m, 0.5 H, H-2), 4.19 (m, 0.5 H, H-2), 3.55 (m, 2 H, H2-5),
2.05 (m, 2 H, H2-3) and 1.91 (m, 2 H, H2-4); δC(CDCl3)
199.88, 155.24 ϩ 154.37 (1 C), 136.37, 128.40, 127.93, 67.14,
65.17 ϩ 64.77 (1 C), 47.20 ϩ 46.67 (1 C), 27.70 ϩ 26.49 (1 C)
and 24.39 ϩ 23.62 (1 C); m/z 204 (Mϩ Ϫ 29, 3.67%), 160
(19.80), 91 (100) and 65 (12.62); νmax(neat)/cmϪ1 2980, 2860,
1720 and 1690.
(R)-Proline 1
A solution of compound 7 (131 mg, 0.53 mmol) in methanol
(10 ml) was treated with palladium on charcoal (10%; 13 mg)
and the mixture was hydrogenated (1 atm) for 5 h. The insol-
uble material was removed by filtration, then washed with
methanol, and the combined filtrate and washings were concen-
trated in vacuo to give compound 1 (61 mg, 96%), mp 220 ЊC
(from EtOH); [α]D ϩ80 (water) {lit.,38 mp 215–222 ЊC;
[α]D ϩ81.5}; δH(D2O) 3.91 (m, 1 H, H-2), 3.16 (m, 2 H, H2-5)
and 2.30–1.7 (m, 4 H, H2-3 and -4); δC(D2O) 177.41, 63.95,
48.82, 31.76 and 26.51; νmax(KBr)/cmϪ1 3080, 2980, 2935, 2860,
2510, 1650, 1417 and 1365.
(2S)-N-(Benzyloxycarbonyl)proline 8
(2R)-N-Benzyloxycarbonyl-2-(hydroxymethyl)pyrrolidine [(R)-
N-(benzyloxycarbonyl)prolinol] 5
Treatment of the aldehyde 4 (150 mg, 0.64 mmol) in the manner
described above for compound 3 yielded the acid 8 (144 mg,
90.5%), mp 75 ЊC (from diethyl ether–hexane), [α]D Ϫ69.7
{lit.,37 mp 76–77 ЊC; [α]D Ϫ61.7 (AcOH)}; δH(CDCl3) 8.95 (br s,
1 H, CO2H), 7.33 (m, 5 H, ArH), 5.16 (m, 2 H, PhCH2), 4.40
(m, 1 H, H-2), 3.52 (m, 2 H, H2-5), 2.20 (m, 2 H, H2-3) and 1.96
(m, 2 H, H2-4); δC(D2O) 178.09 ϩ 175.93 (1 C), 156.00 ϩ 154.36
(1 C), 136.45 ϩ 136.21 (1 C), 128.50, 128.38, 128.14, 127.94,
127.87 ϩ 127.66 (1 C), 67.57 ϩ 67.14 (1 C), 59.32 ϩ 58.57 (1 C),
46.89 ϩ 46.67 (1 C), 30.87 ϩ 29.15 (1 C) and 24.27 ϩ 23.43 (1
C); m/z 249 (Mϩ, 2.67%), 160 (18.25), 114 (36.77), 91 (100), 70
(17.48), 65 (17.10) and 39 (12.37); νmax(KBr)/cmϪ1 3020, 2960,
2880 and 1730.
A stirred solution of compound 3 (148 mg, 0.63 mmol) in
methanol (10 ml) was treated portionwise with sodium borohy-
dride (60 mg, 1.9 mmol), and then was stirred for a further 30
min when analysis (TLC) indicated complete reaction. The
stirred mixture was treated cautiously with water (50 ml),
extracted with dichloromethane (2 × 20 ml) and the combined
extracts were dried (Na2SO4), and concentrated in vacuo. Col-
umn chromatography (hexane–ethyl acetate, 1:1) of the residue
gave compound 5 (130 mg, 88%), [α]D ϩ40 as an oil; δH(CDCl3)
7.34 (m, 5 H, Ph), 5.13 (qAB, J 12.5 and 14.2, 2 H, PhCH2), 4.46
(br s, 1 H, OH), 3.98 (m, 1 H, H-2), 3.63 (d, J 5.6, 2 H, H2-1Ј),
3.51–3.38 (m, 2 H, H2-5) and 2.04–1.58 (m, 4 H, H2-3 and -4);
δC 156.71, 136.34, 128.30, 127.84, 127.68, 66.97, 66.18, 60.35,
47.08, 28.26 and 23.78; m/z 235 (Mϩ, 0.55%), 204 (26.65), 160
(23.87), 91 (100), 65 (12.32) and 41 (9.42); νmax(KBr)/cmϪ1 2960,
2885 and 1690.
(S)-Proline 2
Hydrogenolysis of compound 8 (131 mg, 0.53 mmol) in the
presence of palladized charcoal (10%; 13 mg) as described
above for compound 7 gave title compound 2 (66 mg, 98%), mp
224 ЊC (from EtOH); [α]D Ϫ83.4 (water) {lit.,13 mp 227–229 ЊC;
[α]D Ϫ83 (water)}; δH(D2O) 3.89 (m, 1 H, H-2), 3.16 (m, 2 H,
H2-5) and 2.30–1.96 (m, 4 H, H2-3 and -4); δC(D2O) 177.35,
63.97, 48.81, 31.72 and 26.58; νmax(KBr)/cmϪ1 3080, 2985, 2940,
2860, 2515, 2480, 1655, 1420 and 1362.
(2S)-N-Benzyloxycarbonyl-2-(hydroxymethyl)pyrrolidine [(S)-
N-(benzyloxycarbonyl)prolinol] 6
Treatment of compound 4 (100 mg) in the above manner gave
compound 6 (77 mg, 88%), [α]D Ϫ41 (lit.,30 [α]D Ϫ41.4);
δH(CDCl3) 7.36 (m, 5 H, ArH), 5.14 (qAB, J 12.5 and 13.9, 2 H,
PhCH2), 4.43 (br s, 1 H, OH), 3.99 (m, 1 H, H-2), 3.64 (d, 2 H, J
6.3, H2-1Ј), 3.54 (m, 1 H), 3.39 (m, 1 H), 2.05–1.57 (m, 4 H, H2-3
and -4); δC(CDCl3) 156.94, 136.38, 128.39, 127.94, 127.78,
67.10, 66.63, 60.54, 47.19, 28.42 and 23.99; m/z 235 (Mϩ,
0.81%), 204 (36.59), 160 (32.53), 91 (100), 65 (18.65) and 41
(15.10); νmax(KBr)/cmϪ1 3030, 2960, 2880 and 1680.
Acknowledgements
Claudio Mazzini and Letitia Sambri are grateful to the
ERASMUS programme for providing the opportunity to con-
duct parts of the described work at the University of Nijmegen.
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Paper 7/04915C
Received 9th July 1997
Accepted 17th July 1997
3356
J. Chem. Soc., Perkin Trans. 1, 1997