Chemoselectivity in the reduction of (2S,4S)-4-Amino-5-oxoproline derivatives with borane complexes

Article abstract of DOI:10.1002/ejoc.201100049

Reduction of the carbonyl groups in N-protected (2S,4S)-4-amino-5-oxo-1- phenylprolinates with BH₃ complexes resulted in (2S,4S)-4- aminoproline or (2S,4S)-4-aminoprolinol derivatives depending on the reaction conditions and the type of protect

Full text of DOI:10.1002/ejoc.201100049

FULL PAPER
DOI: 10.1002/ejoc.201100049
Chemoselectivity in the Reduction of (2S,4S)-4-Amino-5-oxoproline Derivatives
with Borane Complexes
Alexey Yu. Vigorov,[a] Irina A. Nizova,[a] Liliya Sh. Sadretdinova,[a] Marina A. Ezhikova,[a]
Mikhail I. Kodess,[a] Iliya N. Ganebnykh,[a] and Victor P. Krasnov*[a]
Keywords: Amino acids / Protecting groups / Lactams / Reduction / Chemoselectivity
Reduction of the carbonyl groups in N-protected (2S,4S)-4-
derivatives depending on the reaction conditions and the
amino-5-oxo-1-phenylprolinates with BH3 complexes re- type of protecting groups used.
sulted in (2S,4S)-4-aminoproline or (2S,4S)-4-aminoprolinol
Introduction
Results and Discussion
Optically active prolines including 4-aminoproline deriv-
atives have been widely used in organic synthesis as chiral
synthons,[1] fragments of conformationally constrained pep-
tides,[2] substrates of glutamate neuroreceptors,[3] and the
components of catalysts for asymmetric synthesis.[4] One of
the efficient synthetic approaches for producing various
substituted prolines involves the reduction of the lactam
carbonyl in the appropriate 5-oxoproline derivatives. BH3
complexes have been used for selective reduction of N-Boc
protected 5-oxoprolinates.[5]
In the present work we explored the reduction of various
N- and C-protected derivatives of (2S,4S)-4-amino-5-oxo-1-
phenylproline[6] (1) with BH3 complexes (Figure 1). 5-Oxo-
1-phenylprolines were chosen as the substrates for our study
because their reduction results in chiral 1-phenylprolines
and 1-phenylprolinols. It should be noted that 1-arylprol-
ines are of special interest for preparing catalysts for asym-
metric synthesis,[7] and they are also promising biologically
active compounds.[8] The probable reduction mechanism in-
volves the coordination of the borane with the carbonyl
oxygen atom.[9] Accordingly, we consider that the number
and type of protecting groups used can influence the spatial
accessibility and the reactivity of the different carbonyl
groups to thereby influence the chemoselectivity of the re-
duction of the lactam and ester groups.
N-Protected derivatives of 4-amino-5-oxo-1-phenylpro-
line (1), such as 4-tosylamino- (2), 4-phthalimido- (3), and
4-Boc-amino- (4) (2S,4S)-5-oxo-1-phenylprolines were pre-
pared as described previously.[6]
Methyl esters 5 and 6 were prepared in high yields ac-
cording to the standard procedure of treating N-tosylated 2
and N-phthaloyl-protected 3 with MeOH and thionyl chlo-
ride, respectively (Scheme 1). tert-Butyl ester 7 was obtained
by the action of Boc2O/DMAP on N-Boc derivative 4 in
tBuOH. When we used Boc2O in tBuOH for esterification
of compound 2, we obtained the tert-butyl ester of N-dipro-
Figure 1. (2S,4S)-4-Amino-5-oxo-1-phenylproline.
[a] I. Ya. Postovsky Institute of Organic Synthesis of RAS,
22/20, S. Kovalevskoy/Akademicheskaya St., 620990 Ekaterin-
burg, Russian Federation
Scheme 1. Synthesis of alkyl esters of N-protected 4-amino-5-oxo-
1-phenylprolines.
Fax: +7-343-3741189
E-mail: ca@ios.uran.ru
2562
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2562–2569

Chemoselective Reduction of (2S,4S)-4-Amino-5-oxoproline Derivatives
tected 4-amino-5-oxo-1-phenylproline (8) in a low yield due
Each reaction was quenched by addition of MeOH. Af-
to the formation of the byproduct 4-tosyl-5-phenyl-2,5-di- ter evaporation to dryness under reduced pressure each resi-
azabicyclo[2.2.1]heptan-3,6-dione (9) obtained by intermo- due was separated by flash column chromatography on sil-
lecular cyclization as described previously.[6] Thus, we first ica gel, and the major reaction products were isolated. The
prepared tert-butyl ester 10 by esterification of N-tosyl de- structures of the isolated compounds were confirmed by 1H
rivative 2 with 2-methylpropene[10] in dichloromethane in and 13C NMR spectroscopy, elemental analysis, and LC–
the presence of sulfuric acid. We then introduced N-Boc MS data.
protection using Boc2O/DMAP in tBuOH to obtain com-
pound 8 in 81% overall yield. The structure of compound
8 was confirmed by X-ray crystallographic analysis (Fig-
ure 2).
The composition of the mixtures of the reaction products
was quantitatively estimated based on isolated yields
(Table 1). When we failed to separate the reaction products
1
we applied H NMR spectroscopy and HPLC data.
It was found that reaction of N-tosyl compounds 5 and
10 with 4 equiv. of BH3 complex led to reduction of not
only the lactam carbonyl groups affording esters 11 and 12
but also the ester carbonyl groups affording ethers 14 and
15, prolinol 13, and aldehyde 16 (Scheme 2). Decreasing the
amount of reducing agent did not result in a considerable
increase in the chemoselectivity, but diminished the conver-
sion of the starting compounds.
In the case of the reduction of compound 5, conducting
the reaction at low temperature (–5 °C) made it possible to
increase the yield of ester 11 to 44% (Table 1, Entry 2),
whereas when the reaction was carried out at 40 °C the
major product of reduction with BH3·Me2S was prolinol 13
(Table 1, Entry 9; 72% yield). The structure of compound
13 was established on the basis of X-ray crystallographic
data (Figure 3).
Figure 2. X-ray crystal structure of compound 8.
Reduction of compounds 5–8 and 10 was carried out
using borane complexes, such as BH3·Me2S and BH3·THF
in THF under an atmosphere of argon at various tempera-
In the case of tert-butyl ester 10, together with the lactam
tures (Scheme 2). We used different amounts of reducing carbonyl, the ester carbonyl group also underwent signifi-
agent, from 1.5 to 4 equiv. relative to the substrate. The du- cant reduction. Thus, when the reduction was carried out
ration of the reduction was varied from 3 to 35 d.
at –5 °C for 12 d the major reduction products included not
Scheme 2. Reduction of compounds 5–8 and 10.
Eur. J. Org. Chem. 2011, 2562–2569
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2563

V. P. Krasnov et al.
FULL PAPER
Table 1. Reaction conditions and the results of reduction of compounds 5–8 and 10.
Entry
Reaction conditions
Reduction products
Substrate
Temp.
[°C]
Borane
(equiv.)
Time
[d]
Ester
Yield[a] Prolinol Yield[a]
[%]
Ether
Yield[a]
[%]
Other
products
Yield[a]
[%]
[%]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
–5
–5
–5
BH3·Me2S (2)
BH3·Me2S (4)
BH3·Me2S (4)
BH3·Me2S (4)
BH3·Me2S (2)
BH3·Me2S (4)
BH3·THF (1.5)
BH3·THF (4)
BH3·Me2S (4)
BH3·THF (4)
BH3·Me2S (4)
BH3·Me2S (4)
BH3·Me2S (4)
BH3·Me2S (4)
BH3·Me2S (4)
BH3·Me2S (4)
BH3·THF (1.5)
BH3·Me2S (4)
3
3
12
35
7
7
5
8
7
7
3
7
12
35
7
35
7
11
11
11
11
11
38
44
20
7
13
13
13
13
13
13
8
16
16
16
16
3
4
5
8
22
59
70
63
72
–5
14
14
2
2
+25
+25
+25
+25
+40
+40
–5
–5
–5
–5
+25
–5
4
16
3
11
21
13
13
13
13
13
13
13
52
72
55
9
12
14
23
37
11
20
10
14
14
14
12
4
20
9
10
11
12
13
14
15
16
17
18
5
10
10
10
10
10
6
12
12
12
12
43
48
42
21
16
16
16
16
16
19
11
14
20
25
12
22
15
15
15
15
2
3
8
13
38
17
17
17
24
21
26
18[b]
18[b]
18[b]
6
6
+25
+25
7
19
20
28
11
19
20
21
7
7
8
–5
+25
+25
BH3·Me2S (4)
BH3·Me2S (4)
BH3·Me2S (4)
35
7
35
21
21
77
43
23
23
11
48
24[b]
10
13
18
2
14
22
8
+40
BH3·Me2S (4)
22
22[b]
12
[a] Isolated yield. [b] Compounds 18, 22, and 24 were not isolated in pure form; yields were determined on the basis of 1H NMR
spectroscopy.
Figure 3. X-ray crystal structure of compound 13.
only ester 12 (42% yield), but prolinol 13 (14% yield) and
Figure 4. X-ray crystal structure of compound 21.
aldehyde 16 (20% yield) (Table 1, Entry 13) as well.
Treatment of N-phthaloyl derivative 6 with borane com-
plexes resulted not only in the reduction of the lactam and
The reduction of sterically constrained compound 8 with
ester carbonyl groups affording ester 17 and prolinol 18 but both N-Boc and N-tosyl groups at the same nitrogen atom
also in the partial reduction of the phthalimido group af- proceeded more slowly. When the reaction was carried out
fording compounds 19 and 20. The amount of 19 and 20 with BH3·Me2S at +25 °C for 35 d the conversion was 46%
produced decreased when the reaction temperature was and the composition of reduction products was distinctive
lowered, as did the conversion of starting compound 6 (Scheme 2). The product mixtures at both +40 and +25 °C
(Table 1, Entries 16–18). The yield of prolinol 18, the prod- contained alcohol 22, whose structure was assigned on the
1
uct of reduction of the ester carbonyl in N-phthaloyl com- basis of H NMR spectroscopy and LC–MS data, ether 23
pound 6, was lower than the yield of prolinol 13, the prod- with the lactam carbonyl reduced, and ether 24, in which
uct of N-tosyl-protected 5 (Table 1 Entries 3–8 and 16–18). the lactam carbonyl was untouched. The relative configura-
The only isolated reduction product for N-Boc derivative tion of cis-23 was confirmed by X-ray crystallographic data
7 with BH3·Me2S was ester 21, whose structure was con- (Figure 5) and a 2D NOESY spectrum, in which cross-
firmed by X-ray crystallographic data (Figure 4). When re- peaks between 3-HA and both 2-H and 4-H were observed.
ductions was carried out at –5 °C for 35 d or at +25 °C for Compounds 10 and 13 without the N-Boc group were also
7 d the yield of compound 21 was 77 or 43%, respectively detected among the reaction products. Thus, an increase in
(Table 1, Entries 19 and 20).
the steric hindrance caused by the presence of both N-tosyl
2564
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2562–2569

Chemoselective Reduction of (2S,4S)-4-Amino-5-oxoproline Derivatives
(Q-array) and CDL were used in scan mode according to the auto-
tuning parameters. LC separation was performed using ODS col-
umns made by Phenomenex [Luna C18(2), 150ϫ2.0 mm, 3 μm] or
Supelco (Supelcosil LC-18 250ϫ4.6 mm, 5 μm) at 60 °C. MeCN/
H2O or MeOH/H2O mixtures were used as solvents.
and N-Boc protecting groups at C-4 led to an increase in
the number of the reduction products.
Methyl (2S,4S)-4-(4-Methylbenzenesulfonyl)amino-5-oxo-1-phenyl-
prolinate (5): SOCl2 (0.50 mL, 6.88 mmol) was added dropwise to
a stirred solution of compound 2 (1.00 g, 2.67 mmol) in dry MeOH
(20 mL) at –5 °C. The reaction mixture was kept for 0.5 h at that
temperature and for 1 d at r.t. and then evaporated to dryness un-
der reduced pressure. The residue was recrystallized from benzene
and dried at 80 °C in vacuo to give compound 5 (0.920 g, 89%) as
1
Figure 5. X-ray crystal structure of compound 23.
a white solid. M.p. 190–193 °C. [α]D = –2.7 (c = 1.0, CHCl3). H
NMR (400 MHz, CDCl3): δ = 2.22 (ddd, J = 13.1, 8.8, 8.0 Hz, 1
H, 3-HB), 2.42 (s, 3 H, Me-Ts), 2.98 (ddd, J = 13.1, 8.6, 7.2 Hz, 1
H, 3-HA), 3.67 (s, 3 H, OMe), 3.94 (td, J = 8.6, 3.9 Hz, 1 H, 4-H),
4.71 (dd, J = 8.0, 7.2 Hz, 1 H, 2-H), 5.47 (d, J = 3.9 Hz, 1 H, NH),
7.20 (m, 1 H, Hp-Ph), 7.31–7.37 (m, 6 H, Ph, Ts), 7.81 (m, 2 H,
Ts) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.53 (Me-Ts), 32.22
(C-3), 52.93, 53.74 (OMe, C-4), 58.58 (C-2), 121.71 (Co-Ph), 126.43
(Cp-Ph), 127.36 (Co-Ts), 129.11 and 129.86 (Cm-Ts, Cm-Ph),
135.89 and 137.00 (Ci-Ph, Ci-Ts), 144.02 (Cp-Ts), 169.78 and
170.84 (C-5, CO2Me) ppm. C19H20N2O5S (388.44): calcd. C 58.75,
H 5.19, N 7.21, S 8.26; found C 58.79, H 5.14, N 7.10, S 8.18.
HPLC (A/B, 40:1): tR = 21.2 min.
Thus, it has been found that the chemoselectivity of re-
duction of N-protected (2S,4S)-4-amino-5-oxo-1-phenyl-
prolinates is determined to a large degree by the nature of
the protecting groups, and to a smaller degree on the type
of borane complex and the reagent ratios used (Table 1).
Conclusions
In sum, it has been shown that, depending on the reac-
tion conditions and the type of protecting groups attached
to the substrate, one can obtain both (2S,4S)-4-aminopro-
line and (2S,4S)-4-aminoprolinol derivatives as a result of
the borane-mediated reduction of the carbonyl moieties in
N-protected (2S,4S)-4-amino-5-oxo-1-phenylprolinates. In
particular, we obtained certain (2S,4S)-4-amino-1-phenyl-
proline and (2S,4S)-4-amino-1-phenylprolinol derivatives in
approximately 70% yields.
Methyl (2S,4S)-5-Oxo-1-phenyl-4-phthalimidoprolinate (6): SOCl2
(0.25 mL, 3.4 mmol) was added dropwise to a stirred suspension of
compound 3 (0.500 g, 1.43 mmol) in dry MeOH (10 mL) at 0 °C.
The reaction mixture was kept for 0.5 h at that temperature and
for 1 d at r.t. and then evaporated to dryness under reduced pres-
sure. The residue was recrystallized from MeOH to give compound
6 (0.50 g, 96%) as white crystals. M.p. 175–177 °C. [α]D = +30.7 (c
1
= 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 2.65 (ddd, J =
12.5, 10.5, 8.9 Hz, 1 H, 3-HB), 2.93 (ddd, J = 12.5, 9.5, 7.6 Hz, 1
H, 3-HA), 3.67 (s, 3 H, OMe), 4.92 (dd, J = 8.9, 7.6 Hz, 1 H, 2-H),
5.14 (dd, J = 10.5, 9.5 Hz, 1 H, 4-H), 7.22 (m, 1 H, Hp-Ph), 7.39
(m, 2 H, Hm-Ph), 7.48 (m, 2 H, Ho-Ph), 7.75 (m, 2 H, Phth), 7.88
(m, 2 H, Phth) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.54 (C-
3), 49.49 (C-4), 52.73 (OMe), 57.94 (C-2), 122.24 (Co-Ph), 123.62
(Co-Phth), 126.19 (Cp-Ph), 128.96 (Cm-Ph), 131.82 (Cm-Phth),
134.32 (Ci-Phth), 137.61 (Ci-Ph), 167.20 (CO-Phth), 168.29 (C-5),
170.32 (CO2Me) ppm. C20H16N2O5 (364.36): calcd. C 65.93, H
4.43, N 7.69; found C 65.84, H 4.31, N 7.52. HPLC (A/B, 20:1):
tR = 26.4 min.
Experimental Section
General:
(2S,4S)-4-[(4-Methylbenzenesulfonyl)amino]-5-oxo-1-
phenylproline (2), (2S,4S)-5-oxo-1-phenyl-4-phthalimidoproline
(3), and (2S,4S)-4-(tert-butyloxycarbonyl)amino-5-oxo-1-phenyl-
proline (4) were prepared as described previously.[6] 2-Methylpro-
pene was obtained according to a literature procedure[10] and was
used as such in the subsequent step. All other reagents were of
commercial quality. Solvents were dried and purified by standard
methods. Routine monitoring of reaction mixtures was carried out
by using Sorbfil UV 254 (Russia) TLC aluminum-plated silica gel.
Silica gel 60 (230–400 mesh) was used for flash chromatography.
tert-Butyl (2S,4S)-4-(tert-Butyloxycarbonyl)amino-5-oxo-1-phenyl-
prolinate (7): Py (0.25 mL, 3.11 mmol), DMAP (0.038 g,
0.31 mmol) and Boc2O (1.06 g, 4.83 mmol) were added to a stirred
suspension of compound 4 (1.00 g, 3.12 mmol) in tBuOH (25 mL).
The reaction mixture was stirred for 12 h at r.t., poured into cooled
water (125 mL), and kept for 0.5 h at 10 °C. Filtration of the pre-
cipitate gave compound 7 (1.02 g, 87%) as colorless crystals. M.p.
171.5–172.5 °C (subl.) [α]D = –14.9 (c = 1.0, CHCl3). 1H NMR
(400 MHz, [D6]DMSO): δ = 1.25 (s, 9 H, tBu), 1.41 (s, 9 H, tBu),
1.89 (ddd, J = 11.5, 11.0, 9.6 Hz, 1 H, 3-HB), 2.68 (ddd, J = 11.5,
8.8, 7.0 Hz, 1 H, 3-HA), 4.42 (ddd, J = 11.0, 8.9, 8.8 Hz, 1 H, 4-
H), 4.81 (dd, J = 9.6, 7.0 Hz, 1 H, 2-H), 7.17 (m, 1 H, Hp-Ph),
7.34 (d, J = 8.9 Hz, 1 H, NH), 7.36–7.40 (m, 4 H, Ph) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 27.25 and 28.15 (both Me-tBu),
29.43 (C-3), 51.20 (C-4), 57.31 (C-2), 78.16 and 81.42 (both C-tBu),
121.36 (Co-Ph), 124.95 (Cp-Ph), 128.44 (Cm-Ph), 138.47 (Ci-Ph),
155.29 (NCO2-tBu), 169.65 and 171.46 (CO2-tBu, C-5) ppm.
C20H28N2O5 (376.45): calcd. C 63.81, H 7.50, N 7.44; found C
63.52, H 7.60, N 7.35. HPLC (A/B, 40:1): tR = 14.0 min.
Analytical HPLC was performed with
a LiChrosorb Si-60
(4ϫ250 mm, 5 μm) column, with a flow rate of 1 mL/min, and by
using a tuneable UV detector set at 230 nm. Mixtures of hexane
(solvent A) and iPrOH (solvent B) were used as the mobile phases.
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, using TMS as a reference. The assignment of chemical
1H and 13C shifts for compounds 11, 13, and 23 was based on
standard 2D NMR techniques (COSY, 1H–1H NOESY, 1H–13C
HSQC, and HMBC). Optical rotation values were measured with
a Perkin–Elmer M 341 polarimeter. All optical rotations were ob-
tained at room temperature. LC–MS data were collected by LCMS
solution software with a LCMS-2010 instrument (Shimadzu) op-
erating in positive and negative ion mode with ESI or APCI probe
installed at N2 flow rate of 4.5 or 2.5 L/min, correspondingly. The
probe voltage was set to 4.5 kV, and the APCI probe temperature
was set to 400 °C. The curved desolvation line (CDL) and block
heater were set at 250 and 200 °C, respectively. Quadrupole array
Eur. J. Org. Chem. 2011, 2562–2569
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2565

V. P. Krasnov et al.
FULL PAPER
1
tert-Butyl (2S,4S)-4-(4-Methylbenzenesulfonyl)amino-5-oxo-1-phen-
ylprolinate (10): Concentrated H2SO4 (0.1 mL) was added to a
stirred suspension of compound 2 (0.75 g, 2.0 mmol) in dry CH2Cl2
(6.5 mL). The reaction mixture was cooled to –18 °C. Freshly pre-
pared 2-methylpropene was bubbled into the reaction mixture. The
reaction bottle was tightly sealed, and the reaction mixture was
stirred for 1 d until the solution clarified. The reaction mixture was
then poured into a 1:1 mixture of EtOAc and 5% aqueous Na2CO3
(140 mL). The organic layer was separated, washed with aqueous
Na2CO3 (5%) and brine to neutral pH, dried with Na2SO4, and
then evaporated to dryness under reduced pressure. The residue
was reprecipitated from EtOAc solution with hexane to give com-
pound 10 (0.76 g, 88%) as colorless crystals. M.p. 179–183 °C (de-
comp.). [α]D = +1.4 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 1.28 (s, 9 H, tBu), 2.19 (ddd, J = 13.0, 9.0, 8.3 Hz, 1 H, 3-HB),
[α]D = –65.6 (c = 2.0, CHCl3). H NMR (400 MHz, CDCl3): δ =
1.96 (ddd, J = 14.0, 2.8, 1.6 Hz, 1 H, 3-HB), 2.38 (ddd, J = 14.0,
9.9, 6.3 Hz, 1 H, 3-HA), 2.44 (s, 3 H, Me-Ts), 3.39 (ddd, J = 10.2,
2.2, 1.2 Hz, 1 H, 5-HB), 3.43 (dd, J = 10.2, 5.0 Hz, 1 H, 5-HA),
3.79 (s, 3 H, OMe), 4.14 (dd, J = 9.9, 1.6 Hz, 1 H, 2-H), 4.19 (m,
1 H, 4-H), 6.06 (d, J = 10.2 Hz, 1 H, NH), 6.43 (dd, 3J = 8.8,
3
1.0 Hz, 2 H, Ho-Ph), 6.77 (tt, J = 7.3, 1.0 Hz, 1 H, Cp-Ph), 7.21
(dd, 3J = 8.8, 7.3 Hz, 2 H, Hm-Ph), 7.31 (d, J = 8.3, Hz, 2 H, Hm-
Ts), 7.77 (d, J = 8.1 Hz, 2 H, Ho-Ts) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.53 (Me-Ts), 36.42 (C-3), 52.79 (C-4 and CO2Me),
55.18 (C-5), 59.73 (C-2), 112.30 (Co-Ph), 117.95 (Cp-Ph), 126.95
(Co-Ts), 129.38 (Cm-Ph), 129.79 (Cm-Ts), 138.21 (Ci-Ts), 143.46
(Cp-Ts), 145.94 (Ci-Ph), 175.77 (CO2Me) ppm. C19H22N2O4S
(374.46): calcd. C 60.94, H 5.92, N 7.48; found C 61.30, H 6.19, N
7.34. RP-HPLC–MS [Supelcosil LC-18; MeCN/H2O, 1:1; 1.0 mL/
2.41 (s, 3 H, Me-Ts), 2.97 (ddd, J = 13.0, 8.3, 7.0 Hz, 1 H, 3-HA), min; tR = 11.6 min; APCI]: m/z (%) = 375 (100) [M + H]+; 373
3.89 (ddd, J = 9.0, 8.3, 3.8 Hz, 1 H, 4-H), 4.57 (dd, J = 8.3, 7.0 Hz,
1 H, 2-H), 5.45 (d, J = 3.8 Hz, 1 H, NH), 7.19 (m, 1 H, Hp-Ph),
7.30–7.38 (m, 6 H, Ph, Ts), 7.82 (m, 2 H, Ts) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.52 (Me-Ts), 27.57 (Me-tBu), 32.32 (C-
3), 53.85 (C-4), 59.59 (C-2), 83.22 (C-tBu), 121.69 (Co-Ph), 126.19
(Cp-Ph), 127.38 (Co-Ts), 128.92 (Cm-Ph), 129.86 (Cm-Ts), 135.82
and 137.25 (Ci-Ts, Ci-Ph), 143.99 (Cp-Ts), 169.19 and 169.64 (C-
5, CO2-tBu) ppm. C22H26N2O5S (430.52): calcd. C 61.38, H 6.09,
N 6.51, S 7.45; found C 60.97, H 5.97, N 6.19, S 7.51. HPLC (A/
B, 40:1): tR = 8.9 min.
(100) [M – H]–. HPLC (A/B, 40:1): tR = 7.9 min.
tert-Butyl (2S,4S)-4-(4-Methylbenzenesulfonyl)amino-1-phenylpro-
linate (12): BH3·Me2S (0.18 mL, 1.87 mmol) was added to a solu-
tion of compound 10 (200 mg, 0.46 mmol) in dry THF (2 mL). The
reaction mixture was kept for 7 d at –5 °C. Column flash
chromatography gave a 96:4 mixture (100 mg) of ester 12 and ether
15, respectively, according to 1H NMR spectroscopy and HPLC
data. Column flash chromatography (hexane/EtOAc) of that mix-
ture gave compound 12 (80 mg, 43%) as a colorless amorphous
solid. [α]D = –66.8 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 1.48 (s, 9 H, tBu), 1.90 (dm, J = 14.0 Hz, 1 H, 3-HB), 2.34
(ddd, J = 14.0, 9.9, 6.3 Hz, 1 H, 3-HA), 2.44 (s, 3 H, Me-Ts), 3.37
and 3.40 (ABX system, JAB = 10.1 Hz, JAX = 4.4 Hz, JBX = 2.6 Hz,
2 H, 5-HB and 5-HA), 3.98 (dd, J = 9.9, 1.6 Hz, 1 H, 2-H), 4.17
(m, 1 H, 4-H), 6.29 (d, J = 10.4 Hz, 1 H, NH), 6.45 (dd, J = 8.8,
tert-Butyl (2S,4S)-4-[(tert-Butyloxycarbonyl)(4-methylbenzenesulfo-
nyl)amino]-5-oxo-1-phenylprolinate (8): Py (0.12 mL, 1.49 mmol),
DMAP (10 mg, 0.08 mmol), and Boc2O (300 mg, 1.38 mmol) were
added to a stirred solution of compound 10 (352 mg, 0.82 mmol)
in tBuOH (9 mL). The reaction mixture was stirred for 18 h at r.t.,
poured into water (40 mL), and kept for 2 h at 0 °C. Filtration of
the precipitate gave compound 8 (398 mg, 92%) as colorless crys-
tals. M.p. 166–172 °C (decomp.). [α]D = –45.4 (c = 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.29 (s, 9 H, tBu), 1.37 (s, 9 H, tBu),
2.42 (s, 3 H, Me-Ts), 2.63 (ddd, J = 11.8, 11.0, 9.6 Hz, 1 H, 3-HB),
2.95 (ddd, J = 11.8, 9.0, 7.4 Hz, 1 H, 3-HA), 4.70 (dd, J = 9.6,
7.4 Hz, 1 H, 2-H), 5.33 (dd, J = 11.0, 9.0 Hz, 1 H, 4-H), 7.19 (m,
1 H, Hp-Ph), 7.31 (m, 2 H, Ho-Ph), 7.35–7.43 (m, 4 H, Hm-Ph, Ts),
8.02 (d, J = 8.1 Hz, 2 H, Ts) ppm. 13C NMR (100 MHz, CDCl3): δ
= 21.63 (Me-Ts), 27.62 and 27.95 (both Me-tBu), 28.95 (C-3), 57.28
and 58.05 (C-4, C-2), 82.59 and 85.45 (both C-tBu), 121.87 (Co-
Ph), 125.76 (Cp-Ph), 128.16 (Co-Ts), 128.79 (Cm-Ph), 129.31 (Cm-
Ts), 136.77 and 137.98 (Ci-Ts, Ci-Ph), 144.26 (Cp-Ts), 149.57
(NCO2-tBu), 168.69 and 169.14 (CO2-tBu, C-5) ppm.
C27H34N2O7S (530.64): calcd. C 61.11, H 6.46, N 5.28, S 6.04;
3
1.0 Hz, 2 H, Ho-Ph), 6.75 (tt, J = 7.3, 1.0 Hz, 1 H, Hp-Ph), 7.20
(dd, J = 8.8, 7.3 Hz, 2 H, Hm-Ph), 7.30 (d, J = 8.4 Hz, 2 H, Hm-
Ts), 7.76 (d, J = 8.4 Hz, 2 H, Ho-Ts) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.51 (Me), 27.88 (Me-tBu), 36.39 (C-3), 52.81 (C-4),
55.29 (C-5), 60.99 (C-2), 82.96 (C-tBu), 112.29 (Co-Ph), 117.71
(Cp-Ph), 126.94 (Co-Ts), 129.27 and 129.77 (Cm-Ts, Cm-Ph),
138.32 (Ci-Ts), 143.33 (Cp-Ts), 146.09 (Ci-Ph), 174.66 (CO2-tBu)
ppm. C22H28N2O4S (416.54): calcd. C 63.44, H 6.78, N 6.72; found
C 63.56, H 6.88, N 6.76. RP-HPLC–MS [Luna C18(2); MeCN/
H2O, 75:25; 0.25 mL/min; tR = 3.9 min; ESI]: m/z (%) = 439 (45)
[M + Na]+, 417 (100) [M + H]+, 361 (89) [M – tBu + 2H]+; 415
(100) [M – H]–. HPLC (A/B, 120:1): tR = 8.1 min.
(2S,4S)-2-Hydroxymethyl-4-(4-methylbenzenesulfonyl)amino-1-phen-
ylpyrrolidine (13): BH3·Me2S (0.68 mL, 7.21 mmol) was added to a
solution of compound 5 (0.70 g, 1.80 mmol) in dry THF (10 mL).
The reaction mixture was kept for 7 d at 40 °C. Column flash
chromatography gave compound 13 (0.45 g, 72%) as colorless crys-
tals. M.p. 142–144 °C. [α]D = –73.8 (c = 1.0, acetone). 1H NMR
(400 MHz, CDCl3): δ = 1.72 (ddd, J = 13.9, 2.6, 1.3 Hz, 1 H, 3-
HB), 2.23 (br. m, 1 H, OH), 2.33 (ddd, J = 13.9, 9.9, 7.3 Hz, 1 H,
3-HA), 2.44 (s, 3 H, Me-Ts), 3.36 (dd, J = 10.3, 6.0 Hz, 1 H, 5-HB),
3.48 (dd, J = 10.3, 1.2 Hz, 1 H, 5-HA), 3.50 (dm, J = 11.3 Hz, 1
H, 6-HB), 3.85 (dm, J = 9.9, Hz, 1 H, 2-H), 4.03 (m, 1 H, 4-H),
4.12 (dt, J = 11.3, 2.4 Hz, 1 H, 6-HA), 6.54 (d, J = 8.7 Hz, 2 H,
Ho-Ph), 6.74 (t, J = 7.3 Hz, 1 H, Hp-Ph), 6.76 (d, J = 9.4 Hz, 1 H,
NH), 7.21 (dd, 3J = 8.7, 7.3 Hz, 2 H, Hm-Ph), 7.31 (d, J = 8.1 Hz,
2 H, Hm-Ts), 7.78 (d, J = 8.1 Hz, 2 H, Ho-Ts) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.52 (Me-Ts), 35.85 (C-3), 51.68 (C-4),
57.40 (C-5), 58.74 (C-2), 62.62 (C-6), 112.73 (Co-Ph), 117.34 (Cp-
Ph), 126.96 (Co-Ts), 129.37 (Cm-Ph), 129.75 (Cm-Ts), 138.35 (Ci-
Ts), 143.24 (Cp-Ts), 146.90 (Ci-Ph) ppm. C18H22N2O3S (346.45):
found C 61.17, H 6.63, N 4.74, S 6.21. HPLC (A/B, 80:1): tR
6.90 min.
=
General Procedure for Reduction of Compounds 5–8 and 10: BH3
complex was added dropwise to a stirred solution of substrate 5–8
or 10 in THF at 0 °C under an atmosphere of argon. The reaction
mixture was kept for 0.5 h at 0 °C under an argon atmosphere, then
for 3–35 d at the appropriate temperature. MeOH was then added
dropwise to the reaction mixture until foaming stopped. The reac-
tion mixture was evaporated to dryness. The residue was subjected
to column flash chromatography (benzene/EtOAc) to isolate the
reaction products.
Methyl (2S,4S)-4-(4-Methylbenzenesulfonyl)amino-1-phenylprolin-
ate (11): BH3·Me2S (0.2 mL, 2.09 mmol) was added to a solution of
compound 5 (200 mg, 0.52 mmol) in dry THF (2 mL). The reaction
mixture was kept for 3 d at –5 °C. Column flash chromatography
gave compound 11 (85 mg, 44%) as a colorless amorphous solid.
2566
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2562–2569

Chemoselective Reduction of (2S,4S)-4-Amino-5-oxoproline Derivatives
calcd. C 62.40, H 6.40, N 8.09, S 9.26; found C 62.42, H 6.47, N
7.94, S 9.52. HPLC (A/B, 40:1): tR = 16.5 min.
(C-5), 65.71 (C-2), 112.39 (Co-Ph), 118.17 (Cp-Ph), 127.10 (Co-Ts),
129.44 and 129.90 (Cm-Ph, Cm-Ts), 136.87 (Ci-Ts), 143.88 (Cp-Ts),
146.39 (Ci-Ph), 203.24 (CHO) ppm. C18H20N2O3S (344.43): calcd.
C 62.77, H 5.85, N 8.13; found C 62.78, H 6.21, N 7.75. HPLC
(A/B, 40:1): tR = 8.2 min.
(2S,4S)-2-Methoxymethyl-4-(4-methylbenzenesulfonyl)amino-1-phen-
ylpyrrolidine (14): A 1 m solution (1.0 mL) of BH3 in THF was
added to a solution of compound 5 (100 mg, 0.26 mmol) in dry
THF (1 mL). The reaction mixture was kept for 8 d at 25 °C. Col-
umn flash chromatography gave compound 14 (11 mg, 12%) as a
pale-yellow amorphous solid. [α]D = –56.5 (c = 1.0, acetone). 1H
NMR (400 MHz, CDCl3): δ = 1.72 (dm, J = 13.9 Hz, 1 H, 3-HB),
2.30 (ddd, J = 13.9, 10.1, 7.3 Hz, 1 H, 3-HA), 2.44 (s, 3 H, Me-Ts),
3.30 (dd, J = 10.3, 6.1 Hz, 1 H, 5-HB), 3.36 (dd, J = 9.8, 2.1 Hz, 1
H, 6-HB), 3.39 (s, 3 H, OMe), 3.41 (dt, J = 10.3, 1.4 Hz, 1 H, 5-
HA), 3.80 (dd, J = 9.8, 2.4 Hz, 1 H, 6-HA), 3.87 (dm, J = 10.1 Hz,
1 H, 2-H), 4.05 (dddt, J = 9.9, 7.3, 6.1, 1.4 Hz, 1 H, 4-H), 6.55 (d,
J = 8.7 Hz, 2 H, Ho-Ph), 6.75 (t, J = 7.3 Hz, 1 H, Hp-Ph), 6.78 (d,
J = 9.9 Hz, 1 H, NH), 7.22 (dd, J = 8.7, 7.3 Hz, 2 H, Hm-Ph), 7.32
(d, J = 8.3, Hz, 2 H, Hm-Ts), 7.77 (d, J = 8.3 Hz, 2 H, Ho-Ts)
ppm. 13C NMR (100 MHz, CDCl3): δ = 21.50 (Me-Ts), 35.41 (C-
3), 51.67 (C-4), 56.94, 57.94 and 59.28 (OMe, C-5, C-2), 72.86 (C-
6), 112.70 (Co-Ph), 117.20 (Cp-Ph), 126.93 (Co-Ts), 129.28 and
129.68 (Cm-Ph, Cm-Ts), 138.55 (Ci-Ts), 143.10 (Cp-Ts), 146.71 (Ci-
Ph) ppm. MS [direct liquid introduction; MeOH, 0.25 mL/min.
ESI]: m/z (%) = 383 (100) [M + Na]+, 329 (14) [M – OMe]–, 359
Methyl (2S,4S)-1-Phenyl-4-phthalimidoprolinate (17), (2S,4S)-2-
Hydroxymethyl-1-phenyl-4-phthalimidopyrrolidine (18), Methyl
(2S,4S)-4-(2,3-Dihydro-3-oxo-1H-isoindol-2-yl)-1-phenylprolinate
(19), and (2S,4S)-4-(2,3-Dihydro-3-oxo-1H-isoindol-2-yl)-2-hy-
droxymethyl-1-phenylpyrrolidine (20): BH3·Me2S (0.49 mL,
5.17 mmol) was added to a solution of compound 6 (0.47 g,
1.29 mmol) in dry THF (10 mL). The reaction mixture was kept
for 7 d at 25 °C. Column flash chromatography gave ester 17
1
(118 mg, 26%), a 26:74 (according to H NMR spectroscopy and
HPLC and LCMS data, 163 mg) mixture of prolinol 18 and ester
19, and compound 20 (44 mg, 11%).
Methyl (2S,4S)-1-Phenyl-4-phthalimidoprolinate (17): Pale-yellow
crystals. M.p. 122–124 °C. [α]D = –40.3 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 2.73 (dt, J = 12.6, 8.3, Hz, 1 H, 3-HB),
2.99 (ddd, J = 12.6, 9.9, 7.5 Hz, 1 H, 3-HA), 3.74 (s, 3 H, CO2Me),
3.78 (dd, J = 8.6, 8.3 Hz, 1 H, 5-HB), 4.02 (dd, J = 9.0, 8.6 Hz, 1
H, 5-HA), 4.51 (dd, J = 8.2, 7.5 Hz, 1 H, 2-H), 4.94 (ddt, J = 9.9,
9.0, 8.3 Hz, 1 H, 4-H), 6.57 (dd, J = 8.8, 1.0 Hz, 2 H, Ho-Ph), 6.76
(tt, J = 7.3, 1.0 Hz, 1 H, Hp-Ph), 7.23 (dd, J = 8.8, 7.3 Hz, 2 H,
Hm-Ph), 7.74 (m, 2 H, Phth), 7.86 (m, 2 H, Phth) ppm. 13C NMR
(100 MHz, CDCl3): δ = 32.17 (C-3), 47.81 and 49.58 (C-4, C-5),
52.30 (CO2Me), 59.51 (C-2), 112.33 (Co-Ph), 117.58 (Cp-Ph),
123.36 (Co-Phth), 129.21 (Cm-Ph), 131.74 (Cm-Phth), 134.21 (Ci-
Phth), 146.25 (Ci-Ph), 167.96 (CO-Phth), 173.68 (CO2Me) ppm.
RP-HPLC–MS [Supelcosil LC-18; MeOH/H2O, 6:4; 1.0 mL/min;
tR = 12.3 min; APCI]: m/z (%) = 351 (100) [M + H]+, 367 (100)
[M – H + H2O]–. C20H18N2O4 (350.37): calcd. C 68.56, H 5.18,
(100) [M – H]–. C19H24N2O3S (360.48). HPLC (A/B, 40:1): tR
=
7.1 min.
(2S,4S)-2-tert-Butyloxymethyl-4-(4-methylbenzenesulfonyl)amino-1-
phenylpyrrolidine (15): BH3·Me2S (0.17 mL, 1.83 mmol) was added
to a solution of compound 10 (197 mg, 0.46 mmol) in dry THF
(2 mL). The reaction mixture was kept for 7 d at 25 °C. Column
flash chromatography gave compound 15 (70 mg, 38%) as a color-
less amorphous solid. [α]578 = –46.5 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.19 (s, 9 H, tBu), 1.70 (dm, J = 14.0 Hz,
1 H, 3-HB), 2.30 (ddd, J = 14.0, 10.1, 7.7 Hz, 1 H, 3-HA), 2.44 (s,
3 H, Me-Ts), 3.26–3.30 (m, 2 H, 5-HB, 6-HB), 3.36 (dm, J =
10.4 Hz, 1 H, 5-HA), 3.86–3.93 (m, 2 H, 2-H, 6-HA), 4.06 (m, 1 H,
4-H), 6.49 (dd, J = 8.8, 1.0 Hz, 2 H, Ho-Ph), 6.70 (tt, J = 7.3,
1.0 Hz, 1 H, Hp-Ph), 7.19 (dd, J = 8.8, 7.3 Hz, 2 H, Hm-Ph), 7.27
(d, J = 9.7 Hz, 1 H, NH), 7.31 (d, J = 8.4 Hz, 2 H, Hm-Ts), 7.77
(d, J = 8.4 Hz, 2 H, Ho-Ts) ppm. 13C NMR (100 MHz, CDCl3): δ
= 21.52 (Me-Ts), 27.40 (Me-tBu), 35.67 (C-3), 51.66 (C-4), 57.03
and 57.90 (C-5, C-2), 61.75 (C-6), 74.72 (C-tBu), 112.45 (Co-Ph),
116.66 (Cp-Ph), 126.90 (Co-Ts), 129.24 and 129.68 (Cm-Ph, Cm-
Ts), 139.01 (Ci-Ts), 142.94 (Cp-Ts), 146.95 (Ci-Ph) ppm.
C22H30N2O3S (402.56): calcd. C 65.64, H 7.51, N 6.96; found C
65.84, H 7.54, N 6.92. RP-HPLC–MS [Luna C18(2); MeCN/H2O,
75:25; 0.25 mL/min; tR = 4.6 min; ESI]: m/z (%) = 403 (100) [M +
H]+, 347 (16) [M – tBu + 2H]+, 401 (100) [M – H]–. HPLC (A/B,
120:1): tR = 5.9 min.
N 7.99; found C 68.34, H 5.06, N 7.79. HPLC (A/B, 20:1): tR
=
5.5 min.
(2S,4S)-2-Hydroxymethyl-1-phenyl-4-phthalimidopyrrolidine (18):
1H NMR (400 MHz, CDCl3): δ = 2.11 (br. m, 1 H, OH), 2.50 (ddd,
J = 12.7, 9.0, 7.4 Hz, 1 H, 3-HB), 2.86 (ddd, J = 12.7, 10.0, 7.3 Hz,
1 H, 3-HA), 3.67 (t, J = 9.0 Hz, 1 H, 5-HB), 3.76–3.79 (m, 1 H, 6-
HB), 3.99–4.03 (m, 2 H, 6-HA), 4.01 (t, J = 9.0 Hz, 1 H, 5-HA),
4.16 (m, 1 H, 2-H), 4.92 (m, 1 H, 4-H), 6.71 (d, J = 8.7 Hz, 2 H,
Ho-Ph), 6.76 (t, J = 7.4 Hz, 1 H, Hp-Ph), 7.24 (dd, J = 8.7, 7.4 Hz
2 H, Hm-Ph), 7.74 (m, 2 H, Phth), 7.86 (m, 2 H, Phth) ppm. RP-
HPLC–MS [Supelcosil LC-18; MeOH/H2O, 7:3; 1.0 mL/min; tR
=
5.8 min; APCI]: m/z (%) = 323 (100) [M + H]+, 339 (100) [M – H
+ H2O]–. HPLC (A/B, 20:1): tR = 13.0 min.
Methyl
(2S,4S)-4-(2,3-Dihydro-3-oxo-1H-isoindol-2-yl)-1-phenyl-
prolinate (19): 3 m NaOH (0.05 mL) was added to a solution of a
mixture of compounds 18 and 19 (163 mg) in acetone (1 mL). The
(2S,4S)-4-(4-Methylbenzenesulfonyl)amino-1-phenylpyrrolidine-2-car- reaction mixture was kept for 1 h at 5 °C and diluted with water.
baldehyde (16): BH3·Me2S (0.18 mL, 1.89 mmol) was added to a
solution of compound 10 (200 mg, 0.47 mmol) in dry THF (2 mL).
The reaction mixture was kept for 35 d at –5 °C. Column flash
chromatography gave compound 16 (41 mg, 25%) as an amorph-
ous solid. [α]D = –122.7 (c = 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 2.11 (dt, J = 13.6, 4.1 Hz, 1 H, 3-HB), 2.31 (ddd, J =
The precipitate was filtered off, washed with water, dried, and re-
precipitated from EtOAc solution with hexane to give compound
19 (79 mg, 28%) as colorless needles. M.p. 160–162 °C. [α]D = –31.2
(c = 0.8, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.37 (ddd, J =
13.4, 6.6, 5.8 Hz, 1 H, 3-HB), 2.85 (ddd, J = 13.4, 9.1, 7.8 Hz, 1 H,
3-HA), 3.70 (s, 3 H, CO2Me), 3.74 (dd, J = 9.8, 6.5 Hz, 1 H, 5-HB),
13.6, 9.4, 5.8 Hz, 1 H, 3-HA), 2.44 (s, 3 H, Me), 3.47 (d, J = 4.5 Hz, 3.77 (dd, J = 9.8, 7.0 Hz, 1 H, 5-HA), 4.38 (dd, J = 9.1, 5.8 Hz, 1
2 H, 5-H), 3.97 (m, 1 H, 4-H), 4.07 (ddd, J = 9.4, 4.1, 2.5 Hz, 1 H,
2-H), 5.08 (d, J = 6.4 Hz, 1 H, NH), 6.47 (d, J = 7.8 Hz, 2 H, Ho-
Ph), 6.79 (t, J = 7.4 Hz, 1 H, Hp-Ph), 7.21 (dd, J = 8.7, 7.4 Hz, 2
H, Hm-Ph), 7.32 (d, J = 8.4 Hz, 2 H, Hm-Ts), 7.76 (d, J = 8.4 Hz,
H, 2-H), 4.50 (d, J = 17.0 Hz, 1 H, CHB-Ar), 4.58 (d, J = 17.0 Hz,
1 H, CHA-Ar), 5.18 (dddd, J = 7.8, 7.0, 6.6, 6.4 Hz, 1 H, 4-H),
6.59 (dd, J = 8.8, 1.0 Hz, 2 H, Ho-Ph), 6.80 (tt, J = 7.4, 1.0 Hz, 1
H, Hp-Ph), 7.25 (dd, J = 8.8, 7.4 Hz, 2 H, Hm-Ph), 7.47 (m, 2 H,
2 H, Ho-Ts), 9.59 (d, J = 2.5 Hz, 1 H, CHO) ppm. 13C NMR Ar), 7.55 (m, 1 H, Ar), 7.86 (m, 1 H, 4Ј-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.51 (Me), 34.42 (C-3), 52.19 (C-4), 54.92 (100 MHz, CDCl3): δ = 34.85 (C-3), 46.68 and 49.62 (C-4, C-5),
Eur. J. Org. Chem. 2011, 2562–2569
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2567

V. P. Krasnov et al.
FULL PAPER
51.31 and 52.31 (CO2Me, CH2-Ar), 59.83 (C-2), 112.76 (Co-Ph), 8.7 Hz, 1 H, 6-HB), 3.62 (t, J = 8.6 Hz, 1 H, 5-HB), 3.78 (dd, J =
118.07 (Cp-Ph), 122.84, 123.61 and 128.07 (Ar), 129.31 (Cm-Ph),
8.6, 3.6 Hz, 1 H, 6-HA), 3.88 (t, J = 8.9 Hz, 1 H, 5-HA), 4.01 (dddd,
131.55, 132.35 and 141.29 (Ar), 146.40 (Ci-Ph), 168.91 (CO-Ar), J = 8.9, 7.8, 6.9, 3.6 Hz, 1 H, 2-H), 5.08 (dq, J = 10.4, 8.9 Hz, 1
174.22 (CO2Me) ppm. RP-HPLC–MS [Supelcosil LC–18, MeCN/ H, 4-H), 6.67 (d, J = 8.6 Hz, 2 H, Ho-Ph), 6.71 (t, J = 7.3 Hz, 1
H2O, 97:3, 1.2 mL/min; tR = 2.5 min; APCI]: m/z (%) = 337 (100) H, Hp-Ph), 7.23 (dd, J = 8.6, 7.3 Hz, 2 H, Hm-Ph), 7.33 (d, J =
[M + H]+, 303 (100) [M – H – MeOH]–, 335 (7) [M – H]–. 8.1 Hz, 2 H, Hm-Ts), 7.76 (d, J = 8.1 Hz, 2 H, Ho-Ts) ppm. 13C
C20H20N2O3 (336.39): calcd. C 71.41, H 5.99, N 8.33; found C
71.42, H 5.84, N 8.52. HPLC (A/B, 20:1): tR = 15.2 min.
NMR (100 MHz, CDCl3): δ = 21.58 (Me-Ts), 27.54 (Me-tBu),
27.84 (Me-Boc), 33.44 (C-3), 50.68 (C-5), 54.67 (C-4), 56.70 (C-2),
63.08 (C-6), 73.02 (C-tBu), 84.69 (C-Boc), 113.05 (Co-Ph), 116.60
(Cp-Ph), 127.45 (Co-Ts), 129.20 (Cm-Ph), 129.37 (Cm-Ts), 137.65
(Ci-Ts), 144.10 (Cp-Ts), 146.99 (Ci-Ph), 150.14 (CO-Boc) ppm. RP-
(2S,4S)-4-(2,3-Dihydro-3-oxo-1H-isoindol-2-yl)-2-hydroxymethyl-1-
phenylpyrrolidine (20): Pale-yellow amorphous solid. 1H NMR
(400 MHz, CDCl3): δ = 1.89 (br. s, 1 H, OH), 2.50 (dd, J = 8.9,
7.4 Hz, 2 H, 3-H), 3.59 (dd, J = 9.5, 8.6 Hz, 1 H, 5-HB), 3.67 (dm,
J = 11.3, Hz, 1 H, 6-HB), 3.76 (dd, J = 9.5, 7.9 Hz, 1 H, 5-HA),
4.02 (dd, J = 11.3, 4.4 Hz, 1 H, 6-HA), 4.09 (tdd, J = 7.4, 4.4,
2.2 Hz, 1 H, 2-H), 4.50 (d, J = 16.8 Hz, 1 H, CHB-Ar), 4.56 (d, J
= 16.8 Hz, 1 H, CHA-Ar), 4.97 (tdd, J = 8.9, 8.6, 7.9 Hz, 1 H, 4-
H), 6.71 (d, J = 8.7 Hz, 2 H, Ho-Ph), 6.77 (t, J = 7.4 Hz, 1 H, Hp-
Ph), 7.25 (dd, J = 8.7, 7.4 Hz, 2 H, Hm-Ph), 7.45–7.50 (m, 2 H,
Ar), 7.56 (m, 1 H, Ar), 7.86 (m, 1 H, Ar) ppm. RP-HPLC–MS
[Supelcosil LC-18; MeCN/H2O, 8:2; 1.0 mL/min; tR = 3.1 min;
HPLC–MS [Luna C18(2); MeOH/H2O, 8:2; 0.25 mL/min; tR
=
13.6 min; ESI]: m/z (%) = 525 (5) [M + Na]+, 503 (100) [M + H]+,
447 (5) [M – Boc + 2Na]+, 425 (1) [M – Boc + H + Na]+, 403 (10)
[M – Boc + 2H]+, 347 (18) [M – Ts]+. HPLC (A/B, 80:1): tR
=
3.3 min.
(2S,4S)-4-[(tert-Butyloxycarbonyl)(4-methylbenzenesulfonyl)amino]-
2-tert-butyloxymethyl-5-oxo-1-phenylpyrrolidine (24): BH3·Me2S
(0.12 mL, 1.31 mmol) was added to a solution of compound 8
(173 mg, 0.33 mmol) in dry THF (2 mL). The reaction mixture was
kept for 35 d at 25 °C. After evaporation to dryness under reduced
pressure the residue was subjected to column flash chromatography
(hexane/iBuOH) to give 0.65:1 mixture (49 mg) of compounds 8
APCI]: m/z (%) = 309 (100) [M + H]+. HPLC (A/B, 20:3): tR
=
11.3 min.
tert-Butyl (2S,4S)-4-(tert-Butyloxycarbonyl)amino-1-phenylprolinate
(21): BH3·Me2S (0.5 mL, 5.31 mmol) was added to a solution of
compound 7 (0.5 g, 1.33 mmol) in dry THF (5 mL). The reaction
mixture was kept for 35 d at –5 °C. Column flash chromatography
gave compound 21 (370 mg, 77%) as colorless crystals. M.p. 112–
114 °C. [α]578 = –84.7 (c = 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.44 (s, 9 H, tBu), 1.49 (s, 9 H, tBu), 2.08 (dq, J =
13.8, 1.5 Hz, 1 H, 3-HB), 2.51 (ddd, J = 13.8, 10.0, 6.3 Hz, 1 H, 3-
HA), 3.47 (dt, J = 9.8, 1.4 Hz, 1 H, 5-HB), 3.57 (dd, J = 9.8, 5.5 Hz,
1 H, 5-HA), 4.08 (dd, J = 10.0, 1.5 Hz, 1 H, 2-H), 4.46 (m, 1 H, 4-
H), 5.77 (d, J = 9.4 Hz, 1 H, NH), 6.54 (dd, J = 8.7, 1.0 Hz, 2 H,
Ho-Ph), 6.76 (tt, J = 7.3, 1.0 Hz, 1 H, Hp-Ph), 7.23 (dd, J = 8.7,
7.3 Hz, 2 H, Hm-Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.86
and 28.40 (both Me-tBu), 37.20 (C-3), 49.77 (C-4), 55.61 (C-5),
61.28 (C-2), 79.31 and 82.26 (both C-tBu), 112.30 (Co-Ph), 117.38
(Cp-Ph), 129.24 (Cm-Ph), 146.52 (Ci-Ph), 155.39 (NCO2-tBu),
174.25 (CO2-tBu) ppm. C20H30N2O4 (362.47): calcd. C 66.27, H
8.34, N 7.73; found C 66.20, H 8.57, N 7.45. HPLC (A/B, 40:1):
tR = 3.5 min.
1
and 24. H NMR (400 MHz, CDCl3): δ = 1.03 (s, 9 H, tBu), 1.33
(s, 9 H, Me-Boc), 2.38 (m, 1 H, 3-HB), 2.41 (s, 3 H, Me-Ts), 2.80
(ddd, J = 12.3, 9.8, 7.2 Hz, 1 H, 3-HA), 3.34 (dd, J = 8.9, 7.2 Hz,
1 H, 6-HB), 3.55 (dd, J = 8.9, 4.3 Hz, 1 H, 6-HA), 4.29 (m, 1 H, 2-
H), 5.33 (dd, J = 10.2, 9.8 Hz, 1 H, 4-H), 7.22–7.39 (m, 7 H, Ph,
Ts), 8.06 (d, J = 7.7 Hz, 2 H, Ts) ppm. RP-HPLC–MS [Luna
C18(2), MeOH/H2O, 8:2, 0.25 mL/min; tR = 4.6 min; APCI]: m/z
(%) = 517 (6) [M + H]+, 417 (69) [M – Boc]+, 361 (100) [M –
Ts]+. HPLC (A/B, 80:1): tR = 6.4 min.
X-ray Analysis: Data for compounds 8, 13, 21, and 23 were col-
lected with an XCALIBUR-3 diffractometer (CCD) by using
graphite-monochromated Mo-Kα radiation. Absorption and anom-
alous dispersion effects were not taken into consideration due to
its insignificance. The structures were solved by direct methods and
expanded by using Fourier techniques. Refinement of the structure
was accomplished with the SHELXL-97 program. Non-hydrogen
atoms were refined anisotropically. Hydrogen atoms involved in hy-
drogen bonding were located in electron density maps. The remain-
der of the hydrogen atoms were placed in idealized positions and
allowed to ride on the C atoms to which they are bonded. CCDC-
803760 (for 8), -803761 (for 13), -803762 (for 21), and -803763 (for
23) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(2S,4S)-4-[(tert-Butyloxycarbonyl)(4-methylbenzenesulfonyl)amino]-
2-hydroxymethyl-1-phenylpyrrolidine (22) and (2S,4S)-4-[(tert-Bu-
tyloxycarbonyl)(4-methylbenzenesulfonyl)amino]-2-tert-butyloxyme-
thyl-1-phenylpyrrolidine (23): BH3·Me2S (0.13 mL, 1.41 mmol) was
added to a solution of compound 8 (188 mg, 0.35 mmol) in dry
THF (2 mL). The reaction mixture was kept for 24 d at 40 °C. After
evaporation to dryness under reduced pressure the residue was sub-
jected to column flash chromatography (hexane/iBuOH) to give
compound 23 (85 mg, 48%), a 4:1 (according to 1H NMR spec-
troscopy) mixture of compounds 22 and 13 (23 mg), and com-
pound 13 (10 mg, 14%).
Crystal Data for 8: Mr = 530.62; 0.34ϫ0.21ϫ0.06 mm; colorless
plate; T = 295 K; orthorhombic; space group P212121; Z = 4; a =
10.5475(7) Å, b = 12.1445(9) Å, c = 22.4485(13) Å, α = β = γ =
90.00°, V = 2875.5(3) Å3; ρcalcd. = 1.226 gcm–3; Θmax = 26.38°; R1
= 3.79% [IϾσ(I)], wR2 = 4.54%, S = 0.984.
(2S,4S)-4-[(tert-Butyloxycarbonyl)(4-methylbenzenesulfonyl)amino]-
2-hydroxymethyl-1-phenylpyrrolidine (22): RP-HPLC–MS [Luna
C18(2); MeCN/H2O, 7:3; 0.3 mL/min; tR = 3.5 min; ESI]: m/z (%)
= 469 (3.6) [M + Na]+, 447 (100) [M + H]+, 391 (4.9) [M – tBu +
2H]+, 347 (39) [M – Boc + 2H]+. HPLC (A/B, 40:1): tR = 10.4 min.
Crystal Data for 13: Mr = 346.44; 0.38ϫ0.18ϫ0.07 mm; colorless
needle; T = 295 K; monoclinic, space group P21; Z = 2; a =
9.718(3) Å, b = 7.974(3) Å, c = 11.531(3) Å, α = γ = 90.0° β =
104.19(2)°, V = 866.3(4) Å3; ρcalcd. = 1.328 gcm–3; Θmax = 26.39°;
R1 = 4.18% [IϾσ(I)], wR2 = 2.61%, S = 0.813.
(2S,4S)-4-[(tert-Butyloxycarbonyl)(4-methylbenzenesulfonyl)amino]-
2-tert-butyloxymethyl-1-phenylpyrrolidine
(23):
1H
NMR
(400 MHz, CDCl3): δ = 1.16 (s, 9 H, tBu), 1.37 (s, 9 H, Me-Boc),
2.45 (s, 3 H, Me-Ts), 2.51 (ddd, J = 12.3, 10.4, 6.9 Hz, 1 H, 3-HB),
2.58 (ddd, J = 12.3, 8.9, 7.8 Hz, 1 H, 3-HA), 3.23 (dd, J = 8.9,
Crystal Data for 21: Mr = 362.46; 0.43ϫ0.27ϫ0.14 mm; colorless
prism; T = 295 K; orthorhombic, space group P212121; Z = 4; a =
6.3189(4) Å, b = 9.0566(5) Å, c = 35.412(2) Å, α = β = γ = 90.0°,
2568
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2562–2569

Chemoselective Reduction of (2S,4S)-4-Amino-5-oxoproline Derivatives
V = 2026.5(2) Å3; ρcalcd. = 1.188 gcm–3; Θmax = 26.36°; R1 = 3.05%
[IϾσ(I)], wR2 = 2.90%, S = 1.006.
[3] a) M. G. Moloney, Nat. Prod. Rep. 2002, 19, 597–616; b) D. D.
Schoepp, B. G. Johnson, C. R. Salhoff, M. J. Valli, M. A. De-
sai, J. P. Burnett, N. G. Mayne, J. A. Monn, Neuropharmacol-
ogy 1995, 34, 843–850; c) V. Bruno, G. Battaglia, A. Copani,
M. DЈOnofrio, P. Di Iorio, A. De Blasi, D. Melchiorri, P. J.
Flor, F. Nicoletti, J. Cerebral Blood Flow Metabol. 2001, 21,
1013–1033.
[4] a) T. E. Kristensen, T. Hansen, Eur. J. Org. Chem. 2010, 3179–
3204; b) S. B. Tsogoeva, S. B. Jagtap, Z. A. Ardemasova, Tetra-
hedron: Asymmetry 2006, 17, 989–992; c) S. G. Zlotin, A. S.
Kucherenko, I. P. Beletskaya, Russ. Chem. Rev. 2009, 78, 737–
784.
Crystal Data for 23: Mr = 502.65; 0.34ϫ0.18ϫ0.09 mm; colorless
prism; T = 120 K; monoclinic, space group P21; Z = 4; a =
10.5799(8) Å, b = 10.0648(9) Å, c = 25.178(2) Å, α = γ = 90.0°, β
= 90.146(6)°, V = 2681.1(4) Å3; ρcalcd. = 1.245 gcm–3; Θmax
26.37°; R1 = 3.95% [IϾσ(I)], wR2 = 3.43%, S = 0.849.
=
Acknowledgments
[5] a) C. Nájera, M. Yus, Tetrahedron: Asymmetry 1999, 10, 2245–
2303; b) S. K. Panday, J. Prasad, D. K. Dikshit, Tetrahedron:
Asymmetry 2009, 20, 1581–1632; c) F. Lenda, F. Guenoun, J.
Martinez, F. Lamaty, Tetrahedron Lett. 2007, 48, 805–808.
[6] V. P. Krasnov, I. A. Nizova, A. Yu. Vigorov, T. V. Matveeva,
G. L. Levit, P. A. Slepukhin, M. A. Ezhikova, M. I. Kodess,
Eur. J. Org. Chem. 2008, 1802–1810.
The work was financially supported by the Ural Division of the
Russian Academy of Sciences (Ural Div. of RAS), grants 09-P-3-
2001 and 09-I-3-2001, the State Program for Supporting of Leading
Scientific Schools of the Russian Federation (Grant NSh
65261.2010.3), and the Russian Foundation for Basic Research
(Grant 11-03-00548). The authors thank the Ural Div. of RAS for
financial support for A.Yu.V. The authors thank Dr. P. Slepukhin
for performing X-ray crystallography analyses.
[7] B. Jiang, Z.-G. Huang, K.-J. Cheng, Tetrahedron: Asymmetry
2006, 17, 942–951 and references cited therein.
[8] a) T. Hosokami, M. Kuretani, K. Higashi, M. Asano, K. Ohya,
N. Takasugi, E. Mafune, T. Miki, Chem. Pharm. Bull. 1992,
40, 2712–2719; b) T. M. Kamenecka, T. Lanza Jr., S. E.
de Laszlo, B. Li, E. D. McCauley, G. Van Riper, L. A. Egger,
U. Kidambi, R. A. Mumford, S. Tong, M. MacCoss, J. A.
Schmidt, W. K. Hagmann, Bioorg. Med. Chem. Lett. 2002, 12,
2205–2208.
[9] A. F. C. Alcântara, H. S. Barroso, D. Piló-Veloso, Quim. Nova
2002, 25, 300–311.
[10] P. Sieber, B. Iselin, Helv. Chim. Acta 1969, 52, 1525–1531.
[1] a) M. I. Calaza, C. Cativiela, Eur. J. Org. Chem. 2008, 3427–
3448; b) H. Sakashita, F. Akahoshi, H. Kitajima, R. Tsutsumi-
uchi, Y. Hayashi, Bioorg. Med. Chem. 2006, 14, 3662–3671; c)
C. E. Schafmeister, Z. Z. Brown, S. Gupta, Acc. Chem. Res.
2008, 41, 1387–1398.
[2] a) D. Torino, A. Mollica, F. Pinnen, F. Feliciani, S. Spisani, G.
Lucente, Bioorg. Med. Chem. 2009, 17, 251–259; b) S. Flemer,
A. Wurthmann, A. Mamai, J. S. Madalengoitia, J. Org. Chem.
2008, 73, 7593–7602; c) A. Flores-Ortega, J. Casanovas, X.
Assfeld, C. Alemán, J. Org. Chem. 2009, 74, 3101–3108.
Received: January 13, 2011
Published Online: March 22, 2011
Eur. J. Org. Chem. 2011, 2562–2569
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2569