2-Hydroxy-3-[(S)-prolinamido]pinanes as novel bifunctional organocatalysts for asymmetric aldol reactions in aqueous media

Article abstract of DOI:10.1016/j.tetasy.2011.07.013

Novel (S)-prolinamides with stereoisomeric 2-hydroxy-3-aminopinane units have been synthesized. In the presence of (1R,2R,3S,5R)-2-hydroxy-3-[(S)- prolinamido]pinane (5 mol %) cyclic ketones reacted with (hetero-)aromatic aldehydes in aqueous media to aff

Full text of DOI:10.1016/j.tetasy.2011.07.013

Tetrahedron: Asymmetry 22 (2011) 1320–1324
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
2-Hydroxy-3-[(S)-prolinamido]pinanes as novel bifunctional organocatalysts
for asymmetric aldol reactions in aqueous media
Dmitry E. Siyutkin a, Alexander S. Kucherenko a, Larisa L. Frolova b, Alexander V. Kuchin b, , Sergei G. Zlotin a,
⇑
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prosp., 47, 119991 Moscow, Russian Federation
b Institute of Chemistry Komi SC, Ural Department Russian Academy of Sciences, Pervomayskaya St., Komi Rep., 48, 167610 Syktyvkar, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel (S)-prolinamides with stereoisomeric 2-hydroxy-3-aminopinane units have been synthesized. In
the presence of (1R,2R,3S,5R)-2-hydroxy-3-[(S)-prolinamido]pinane (5 mol %) cyclic ketones reacted with
(hetero-)aromatic aldehydes in aqueous media to afford chiral aldols in high yields. The reaction had
moderate to high diastereo- (dr up to 91/9) and enantioselectivities (up to 83% ee).
Ó 2011 Elsevier Ltd. All rights reserved.
Received 16 May 2011
Accepted 14 July 2011
Available online 11 August 2011
1. Introduction
ries in the asymmetric synthesis of
2-amino-2-phenylethanol,6b
a
-substituted benzylamines,6a
-fluorinated
-aminoacids,6c (S)-dol-
c
a
Asymmetric organocatalysis is a rapidly growing area of mod-
ern organic chemistry.1 One of the most important organocatalytic
transformations is the asymmetric aldol reaction,2a–d which is used
for the synthesis of chiral natural compounds and pharmacologi-
aphenine,6d as well as chiral ligands in catalytic cyclopropanation6e
or hydrogenation reactions.6f However, prolinamides containing
b-hydroxypinane unit have not been reported so far.
cally active substances.2e,f Natural or synthetic
a
-amino acids,3a
their amides,3b b-amino acids,3c–e alkaloid,3f,g 1,2-diaminocyclo-
hexane,3h–j or imidazolidinone3k derivatives and some other chiral
organic compounds3l are suitable catalysts for this reaction. Among
them, prolinamides bearing b-aminoalcohol units provide a high-
level of catalytic activity and selectivity due to the hydroxyl group
being able to generate an additional stereocontrolling hydrogen
bond in the enamine transitional state (bifunctional catalysis).4
Prolinamide derivatives incorporating b-aminoalcohol fragments
of natural origin (e.g., aminocarbohydrate units5a,b) are generally
2. Results and discussion
To verify this hypothesis, we synthesized isomeric 2-hydroxy-
3-aminopinanes 2a–d from 2-hydroxypinan-3-one antipodes (+)-
(1) and (ꢀ)-(1) by known procedures6f,7 and converted them into
the N-protected amides 4a–d via treatment with (S)-Cbz-proline
3 in the presence of a ClCO2Et/Et3N system. The catalytic deprotec-
tion of 4a–d afforded isomeric prolinamides 5a–d with different
orientations of the hydroxy and amido groups (syn- or anti-) and
different absolute configurations of the four stereocenters in the
pinane fragment (Scheme 1).
At first, we compared the catalytic properties of amides 5a–d in
the model reaction between cyclohexanone 6a and 4-nitrobenzal-
dehyde 7a in the presence of water (90 equiv) which has been
widely used over the last decade as an environmentally friendly
medium in an organic synthesis.8 The reactions were carried out
for twenty hours at ambient temperature in the presence of a
catalyst (5 mol %); the molar ratio of the reagents 6a/7a was 3:1.
Under these conditions, the reactions ran with a high conversion
(92–98%) affording anti-diastereomeric aldol 8a as the major prod-
uct. The best diastereo- (anti/syn 91:9) and enantioselectivities (ee
anti-8a 78%) were obtained in the presence of prolinamide 5b con-
taining the (1R,2R,3S,5R)-2-hydroxy-3-aminopinane unit (Table 1).
We assumed that catalyst 5b, which has syn-orientated NH– and
OH– groups, had more efficient hydrogen bonding with the alde-
hyde oxygen atom in the transition state than isomeric compounds
5a,c,d, thus lowering its energy.
inferior to their synthetic analogues (e.g., to N-prolyl a,a-diphenyl-
valinole5c) in terms of activity and/or selectivity, which may be
attributed to their conformational flexibility and/or specific solva-
tion affects.5d,5e Some effective N-prolyl-b-hydroxyamine catalysts
have been obtained from chiral a
,b-diols.5f
We assumed that chiral N-prolyl-b-hydroxyamines with a nat-
ural rigid polycyclic skeleton would efficiently catalyze asymmet-
ric aldol reactions. Furthermore, one might expect that their
catalytic properties would depend on the orientation (syn or anti)
of the amido and hydroxy groups in the catalyst. 2-Hydroxyp-
inan-3-ones (+)-1 and (ꢀ)-1 readily available from softwood pitch
may serve as convenient building-blocks for their synthesis. 2-
Hydroxypinan-3-one derivatives have been used as chiral auxilia-
⇑
Corresponding author. Fax: +7 (499) 1355328.
E-mail addresses: kutchin-av@chemi.komisc.ru (A.V. Kuchin), zlotin@ioc.ac.ru
(S.G. Zlotin).
Fax: +7 (8212) 436677.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.013

D. E. Siyutkin et al. / Tetrahedron: Asymmetry 22 (2011) 1320–1324
1321
O
NH2
NH2
NH2
NH2
OH
Me
HO
Me
HO
Me
HO
Me
HO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2b
2d
1
2a
2c
(+)- : (1R,2R,5R)
1
(–)- : (1S,2S,5S)
A
A
A
A
RN
HN
RN
HN
RN
HN
RN
HN
4a d
- , R = Cbz
5a d
- , R = H
O
O
O
O
B
HO
Me
HO
Me
HO
Me
HO
Me
A: Cbz-proline 3, Et3N,
ClCO2Et, THF
B: H2, Pd/C, MeOH
Me
4a, 5a
Me
Me
Me
Me
4c, 5c
Me
Me
Me
4d, 5d
4b, 5b
Scheme 1. Synthesis of 2-hydroxy-3-[(S)-prolinamino]pinanes 5a–d from 2-hydroxypinane-3-ones (+)-1 and (ꢀ)-1.
Table 1
Asymmetric aldol reaction between cyclohexanone 6a and 4-nitrobenzaldehyde 7a in the presence of amides 5a–d in aqueous mediaa
O
O
O
OH
5 (5 mol.%)
+
H2O, RT, 20 h
NO2
NO2
6a
7a
8a
Entry
5
Conv.b (%)
dr (anti/syn)b
ee (anti/syn)c
1
2
3
4
a
b
c
94
98
92
96
84/16
91/9
86/14
85/15
64/30
78/18
57/14
72/38
d
a
b
c
Reactions were carried out on a molar ratio of 3:1 (6a/7a) in the presence of water (0.09 mL, 90 equiv).
1H NMR data for crude 8a.
Chiral HPLC data.
Next, in order to optimize the reaction conditions, we studied
the amide 5b-catalyzed reaction between 6a and 7a at rt in various
solvents (THF, PhMe, DMSO, MeCN, EtOH, CHCl3) and under neat
conditions (Table 2). In most cases, the conversion was close to
complete, however, in DMSO it was only 71%, which was in accor-
dance with the reported data on the lower activity of some prolina-
mides or thioprolinamides in a DMSO solution9 (entry 4). The
highest dr (anti/syn 91:9) and ee values of product 8a (78%) were
obtained in aqueous media (entry 8). Furthermore, we succeeded
in improving the ee value up to 80–83% by carrying out the reac-
tion in the presence of benzoic (entry 10) or 4-nitrobenzoic acid
(entry 11) additives (5 mol %). Reducing the amount of water to
45 or 22 equiv slightly diminished the ee of 8a (entries 12 and 13).
Various cyclic or heterocyclic ketones 6a–d reacted with aro-
matic (heteroaromatic) aldehydes 7a–e under optimal conditions
and generated the respective aldols 8a–f with enantioselectivities
of 62–80% ee (Table 3). In general, the yields of products 8 were
high. 2-Thienylcarboxaldehyde was less active under the
conditions studied and the yield of product 8f after 120 h did not
exceed 54% (entry 6). Six-membered cyclic or heterocyclic ketones
6a,c,d predominantly afforded the anti-diastereomers of the corre-
sponding aldols 8a,b,d,f (anti/syn 78:22–91:9), however, cyclo-
pentanone 6b gave the syn-diastereomer of aldol 8c as the major
product (anti/syn 32/68). In general, aldol reactions in the presence
of catalyst 5b afforded the respective aldols in an aqueous environ-
ment in higher yields but with somewhat lower enantioselectivi-
ties than the corresponding reactions promoted by the most
efficient b-aminoalcohol-derived proline amide catalysts. Proline
itself and the majority bearing carboxyl group water-soluble deriv-
atives efficiently catalyzed the aldol reactions in organic solvents
but exhibited poor catalytic properties in the presence of water.10
3. Conclusion
In conclusion, we have for the first time synthesized (S)-prolina-
mides bearing stereoisomeric 2-hydroxy-3-aminopinane units and
shown that in the presence of (1R,2R,3S,5R)-2-hydroxy-3-[(S)-
prolinamido]pinane 5b cyclic ketones react with (hetero-)aromatic
aldehydes in aqueous media to afford their respective aldols in
high yields. The reaction took place with moderate to high diaste-
reo- and enantioselectivities. Research aimed at novel efficient
organocatalysts and ligands based on plant-derived chiral b-ami-
noalcohols is currently underway in our laboratory.
4. Experimental
4.1. General
The NMR spectra were recorded on a Bruker AM300 NMR spec-
trometer (300.13 MHz for 1H, 75.5 MHz for 13C) in CDCl3. Chemical

1322
D. E. Siyutkin et al. / Tetrahedron: Asymmetry 22 (2011) 1320–1324
Table 2
Influence of solvents and acidic additives on the amide 5b-catalyzed aldol reaction between 6a and 7aa
O
O
O
OH
5b/(additive)
(5 mol.% each)
+
Solvent,
RT, 20 h
NO2
NO2
6a
7a
8a
Entry
Solvent
Additive
Conv.b (%)
dr (anti/syn)b
ee (anti/syn)c
1
2
3
4
5
6
7
8
—
THF
—
—
—
—
—
—
—
—
99
98
99
71
99
97
99
98
97
99
98
99
99
74/26
67/33
75/25
69/31
76/24
73/27
75/25
91/9
90/10
89/11
91/9
91/9
91/9
46/10
60/29
54/22
69/28
56/15
61/22
50/31
78/18
76/48
80/3
PhMe
DMSO
MeCN
EtOH
CHCl3
H2O
9
H2O
AcOH
PhCO2H
4-NO2–C6H4–CO2H
—//—
—//—
10
11
12d
13e
—//—
—//—
—//—
—//—
83/7
81/3
80/1
a
b
c
Reactions were carried out at a molar ratio of 3:1 (6a/7a) in 0.09 mL of the respective solvent (90 equiv for water).
1H NMR data for crude 8a.
Chiral HPLC data.
d
e
45 equiv of water was used.
22 equiv of water was used.
Table 3
Amide 5b-catalyzed aldol reactions between cyclic ketones 6a–d and (hetero-)aromatic aldehydes 7a–e in the presence of watera
O
O
X
OH
5b/4-NO2-C6H4-CO2H
O
(5 mol.% each)
R
+
R
H2O, RT
X
6a-d
7a-e
8b-f
Entry
1
6 (X)
7 (R)
8
a
Time (h)
Yield (%)
dr (anti/syn)b
ee (%) (anti/syn)c
a (–CH2–)
a (4-NO2–C6H4–)
20
95
91/9
78/18
(72)d
(20–48)e
(24)f
(24–48)g
40
(85)d
(69–85)e
(89)f
(65)g
81
(90/10)d
(87:13)e
(99/1)f
(63/37)g
85/15
(92/nd)d
(91/nd)e
(96/nd)f
(89/67)g
79/16
2
3
4
5
6
a (–CH2–)
b (–)
c (–O–)
d (–S–)
a (–CH2–)
b (4-MeO2C–C6H4–)
a (4-NO2–C6H4–)
c (4-CN–C6H4–)
d (4-F–C6H4–)
b
c
d
e
f
16
16
40
120
96
71
80
54
32/68
85/15
89/11
78/22
76/34
80/6
62/14
62/3
e (2-thienyl)
a
Reactions were carried out at a molar ratio of 3:1 (6a/7a) in the presence of water (0.09 mL, 90 equiv). Reported data for respective reactions promoted by other catalysts
in aqueous medium are given in brackets.
b
1H NMR data for isolated products 8a–f.
c
Chiral HPLC data.
d
Catalyst: N-(S)-prolyl-chitosan.5b
Catalyst: N-(S)-prolyl-
Catalyst: N-(S)-prolyl-
a
a
,a
-diphenyl-b-phenylglycinol.4a
e
f
,b-diphenyl-b-aminoethanol.11a
g
Catalyst: (S)-proline, DMSO as the solvent.11b
shifts are given in ppm and referenced to an internal TMS standard
for 1H and CDCl3 for 13C. Elemental analyses were conducted on a
Perkin–Elmer 2400 microanalyser. High resolution mass spectra
(HRMS) were measured on a Bruker microTOF II instrument using
electrospray ionization (ESI).12 The measurements were carried out
in a positive ion mode (interface capillary voltage 4500 V); mass
range from m/z 50 to m/z 3000 Da; external or internal calibration
was done with Electrospray Calibrant Solution (Fluka). A syringe
injection was used for a solution in methanol (flow rate 3 mL/
min). Nitrogen was applied as a dry gas; interface temperature
was set at 180 °C. The IR spectra (KBr pellets) were recorded with
ꢂ
a Specord M82. Specific optical rotations ½a Dt;
ꢁ
C were measured with
a Jasco DIP-360 polarimeter at 589 nm. Compounds 8a,13a 8b,13a
8c,13a 8d,13b 10e,13c and 10f13d were identified by comparing the
NMR spectra with literature data. The dr values of the aldols were
evaluated by 1H NMR spectra and diastereomer signals were as-
3
signed in accordance with JH(1),H(2) values: J < 3 Hz (d = 5.51–
5.59 ppm) for syn- and J = 6.6–9.5 Hz (d = 5.02–5.24 ppm) for the
anti-diastereomer. Enantiomeric excess values (ee) of the aldols
were determined by HPLC on a Stayer chromatograph with the

D. E. Siyutkin et al. / Tetrahedron: Asymmetry 22 (2011) 1320–1324
1323
chiral phase Chiralcel OD-H, OJ-H, or Chiralpak AD-H. Racemic
forms of the corresponding aldols were obtained with racemic pro-
line in the ketone medium. Silica gels 0.060–0.200 and 0.035–
0.070 nm (Acros) were used for column chromatography. Solvents
were purified by standard methods.
N, 6.94. HRMS(ESI) m/z calcd for
C
23H32N2O4 ([M+Na]+):
423.2254, found: 423.2256. IR (KBr, cmꢀ1): 3424, 3307, 2917,
1708, 1658, 1542, 1418, 1355, 1119, 752, 697.
4.3.3. (S)-Benzyl 2-((1S,2S,3S,5S)-2-hydroxy-2,6,6-trimethylbi
cyclo[3.1.1]heptan-3-ylcarbamoyl)-pyrrolidine-1-carboxylate
4c
4.2. General procedure for the aldol reaction
White solid, mp 53–55 °C, ½a D23
ꢁ
¼ ꢀ79:85 (c 1.0, CHCl3). 1H NMR
Ketone 6 (0.3 mmol) and aldehyde 7 (0.1 mmol) were added to
a solution or suspension of catalyst 5 (0.005 mmol, 1.3 mg) in the
corresponding media (0.09 mL by default or specified otherwise
in Table 2). The reaction mixture was stirred for 16 h or the period
given in Table 3. Aldols 8a–f and the remaining starting materials
were extracted with Et2O (2 ꢃ 3 mL). The combined extracts were
filtered through a silica gel pad (1 g) and the residue was washed
with Et2O (2 mL). The resulting solution was evaporated under re-
duced pressure (15 Torr) to afford crude product 8. Aldols 8a–f
were isolated by column chromatography (Silica Gel Acros, 60A,
0.035–0.070 mm, eluent: hexane–EtOAc 3:1).
(CDCl3): d 0.84 (s, 3H), 1.18 (s, 3H), 1.26 (s, 3H), 1.37–1.51 (m, 1H),
1.64–1.75 (m, 2H), 1.87–2.06 (m, 4H), 2.12–2.30 (m, 2H), 2.33–2.46
(m, 1H), 3.41–3.64 (m, 2H), 4.08–4.48 (m, 2H), 5.11–5.27 (m, 2H),
7.28–7.43 (m, 5H) ppm. 13C NMR (CDCl3): d 23.1, 24.4, 25.1, 25.2,
27.6, 28.6, 30.8, 38.5, 39.8, 47.0, 53.2, 55.2, 60.0, 67.3, 76.5,
127.3, 127.9, 128.4, 136.8, 154.8, 174.0 ppm. Anal. Cacld for
C
23H32N2O4: C, 68.97; H, 8.05; N, 6.99. Found: C, 69.03; H, 8.18;
N, 6.92. HRMS(ESI) m/z calcd for
C
23H32N2O4 ([M+Na]+):
423.2254, found: 423.2258. IR (KBr, cmꢀ1): 3424, 3307, 2917,
1708, 1658, 1542, 1418, 1355, 1119, 752, 697.
4.3.4. (S)-Benzyl 2-((1R,2R,3R,5R)-2-hydroxy-2,6,6-trimethylbi
4.3. General procedure for the synthesis of compounds 4a–d
cyclo[3.1.1]heptan-3-ylcarbamoyl)-pyrrolidine-1-carboxylate
4d
A
solution of ethylchloroformate (0.34 mL, 3.55 mmol) in
White solid, mp 108–110 °C, ½a D24
ꢁ
¼ ꢀ54:35 (c 2.0, CHCl3). 1H
THF (10 mL) was added over 10 min to a stirred solution of
N-Cbz-proline 2 (0.88 g, 3.55 mmol) and Et3N (0.50 mL, 3.55 mmol)
in THF (15 mL) at 0–5 °C. After 20 min a solution of corresponding
b-hydroxyamine 3a–d (0.60 g, 3.55 mmol) in THF (10 mL) was
added dropwise over 10 min. The resulting mixture was stirred
for 1 h at 0–5 °C, then for 2 h at ambient temperature and then
was refluxed for 30 min. After cooling to room temperature, the
reaction mixture was filtered off. The precipitate was washed with
THF (20 mL). The combined organic extracts were evaporated, after
which the residue was dissolved in EtOAc and the organic solution
was successively washed with aqueous solutions of K2CO3 (20%)
and 1 M HCl and then with water. The organic layer was separated,
dried over anhydrous Na2SO4, and evaporated. The residue was
washed with hexane (2 ꢃ 20 mL) and dried in vacuo (0.5 Torr) for
2 h to afford 4a–d (0.93 g, 66% / 1.00 g, 71% 1.13 g, 80% 1.17 g,
83%) as white solid.
NMR (CDCl3): d 0.78 (s, 3H), 1.06 (s, 3H), 1.26 (s, 3H), 1.62–1.75
(m, 2H), 1.83–1.45 (m, 4H), 1.90–2.03 (m, 2H), 2.14–2.24 (m,
2H), 3.41–3.66 (m, 2H), 4.05–4.30 (m, 1H), 4.38–4.50 (m, 1H),
5.08–5.28 (m, 2H), 7.29–7.40 (m, 5H) ppm. 13C NMR (CDCl3):
23.1, 24.9, 25.0, 27.7, 29.9, 30.9, 34.5, 38.4, 39.8, 46.9, 53.2, 55.0,
59.8, 67.2, 76.5, 127.7, 128.0, 128.4, 136.3, 154.2, 172.3 ppm. Anal.
Cacld for C23H32N2O4: C, 68.97; H, 8.05; N, 6.99. Found: C, 69.18; H,
8.12; N, 6.94. HRMS(ESI) m/z calcd for C23H32N2O4 ([M+Na]+):
423.2254, found: 423.2256. IR (KBr, cmꢀ1): 3424, 3307, 2917,
1708, 1658, 1542, 1418, 1355, 1119, 752, 697.
4.4. General procedure for the synthesis of compounds 5a–d
A mixture of 4a–d (0.80 g, 2.00 mmol/0.88 g, 2.20 mmol/1.00 g,
2.50 mmol/1.00 g, 2.50 mmol) and Pd/C (5%, 0.08 g/0.09 g/0.10 g/
0.10 g) in dry CH3OH (25 mL) was stirred under H2 (760 Torr) at
ambient temperature for 3 h. The resulting precipitate was filtered
off and then washed with CH3OH (10 mL). The combined organic
phases were evaporated, and the residue was dried under reduced
pressure (0.5 Torr) for 2 h to afford 5a–d (0.53 g, 99%/0.58 g, 98%/
0.65 g, 97%/0.66 g, 99%) as white solids.
4.3.1. (S)-Benzyl 2-((1S,2S,3R,5S)-2-hydroxy-2,6,6-trimethylbicy
clo[3.1.1]heptan-3-ylcarbamoyl)-pyrrolidine-1-carboxylate 4a
White solid, mp 99–101 °C, ½a D23
ꢁ
¼ ꢀ24:25 (c 1.0, CHCl3). 1H
NMR (CDCl3): d 1.02 (s, 3H), 1.19 (s, 3H), 1.25 (s, 3H), 1.08–1.30
(m, 2H), 1.37–1.50 (m, 1H), 1.79–1.99 (m, 3H), 2.00–2.26 (m,
3H), 2.33–2.47 (m, 1H), 3.42–3.64 (m, 2H), 4.05–4.19 (m, 1H),
4.34–4.48 (m, 1H), 5.01–5.26 (m, 2H), 6.56 (br, 1H), 7.21–7.38
(m, 5H) ppm. 13C NMR (CDCl3): d 23.6, 24.7, 28.1, 28.6, 29.3,
29.9, 35.6, 38.6, 40.5, 47.0, 48.0, 54.2, 61.1, 67.2, 74.9, 127.3,
127.9, 128.4, 136.5, 155.2, 171.8 ppm. Anal. Cacld for
4.4.1. (S)-N-((1S,2S,3R,5S)-2-Hydroxy-2,6,6-trimethylbicyclo
[3.1.1]heptan-3-yl)-pyrrolidine-2-carboxamide 5a
White solid, mp 167–169 °C, ½a D24
ꢁ
¼ ꢀ32:25 (c 1.0, CHCl3). 1H
NMR (CDCl3): d 1.07 (s, 3H), 1.27 (s, 3H), 1.29 (s, 3H), 1.39–1.57
(m, 2H), 1.64–1.80 (m, 2H), 1.86–2.04 (m, 3H), 2.06–2.29 (m,
2H), 2.40–2.56 (m, 1H), 2.90–3.09 (m, 2H), 3.75 (dd, J = 5.3,
8.9 Hz, 1H), 4.30 (q, J = 8.7 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H) ppm.
13C NMR (CDCl3): d 23.6, 26.0, 28.2, 28.7, 29.8, 31.0, 36.0, 38.7,
40.6, 47.2, 47.8, 54.7, 60.9, 74.1, 174.6 ppm. Anal. Calcd for
C
23H32N2O4: C, 68.97; H, 8.05; N, 6.99. Found: C, 69.20; H, 8.09;
N, 6.96. HRMS(ESI) m/z calcd for
C
23H32N2O4 ([M+Na]+):
423.2254, found: 423.2255. IR (KBr, cmꢀ1): 3424, 3307, 2917,
1708, 1658, 1542, 1418, 1355, 1119, 752, 697.
C
15H26N2O2: C, 67.63; H, 9.84; N, 10.52. Found: C, 67.80; H, 9.91;
4.3.2. (S)-Benzyl 2-((1R,2R,3S,5R)-2-hydroxy-2,6,6-trimethylbi
cyclo[3.1.1]heptan-3-ylcarbamoyl)-pyrrolidine-1-carboxylate
4b
N, 10.48. HRMS(ESI) m/z calcd for C
15H26N2O2 ([M+Na]+):
289.1886, found: 289.1876. IR (KBr, cmꢀ1): 3444, 3349, 2962,
2925, 2867, 1642, 1520, 1464, 1382, 1299, 1121, 1073, 899.
White solid, mp 102–104 °C, ½a D24
ꢁ
¼ ꢀ86:95 (c 1.0, CHCl3). 1H
NMR (CDCl3): d 1.06 (s, 3H), 1.28 (s, 6H), 1.12–1.50 (m, 2H),
1.80–2.06 (m, 4H), 2.08–2.30 (m, 3H), 2.38–2.52 (m, 1H), 3.43–
3.70 (m, 2H), 4.19–4.51 (m, 2H), 5.08–5.28 (m, 2H), 6.73 (br, 1H),
7.22–7.44 (m, 5H) ppm. 13C NMR (CDCl3): d 23.6, 24.4, 28.1, 28.7,
29.4, 29.7, 36.0, 38.7, 40.5, 47.2, 47.8, 54.3, 61.3, 67.3, 74.5,
128.0, 128.1, 128.5, 136.3, 155.1, 171.3 ppm. Anal. Cacld for
4.4.2. (S)-N-((1R,2R,3S,5R)-2-Hydroxy-2,6,6-trimethylbi
cyclo[3.1.1]heptan-3-yl)-pyrrolidine-2-carboxamide 5b
White solid, mp 150–152 °C, ½a D24
ꢁ
¼ ꢀ39:45 (c 1.0, CHCl3). 1H
NMR (CDCl3): d 1.05 (s, 3H), 1.26 (s, 33H), 1.27 (s, 3H), 11.36–
1.46 (m, 1H), 1.61–1.77 (m, 2H), 1.79–2.03 (m, 4H), 2.05–2.27
(m, 2H), 2.40–2.52 (m, 1H), 2.85–3.05 (m, 2H), 3.74 (dd, J = 5.3,
9.0 Hz, 1H), 4.29 (q, J = 8.6 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H) ppm.
C
23H32N2O4: C, 68.97; H, 8.05; N, 6.99. Found: C, 69.16; H, 8.11;

1324
D. E. Siyutkin et al. / Tetrahedron: Asymmetry 22 (2011) 1320–1324
13C NMR (CDCl3): d 23.6, 26.0, 28.1, 28.6, 29.9, 30.9, 36.3, 38.7, 40.5,
47.1, 47.6, 54.6, 60.8, 74.2, 174.7 ppm. Anal. Calcd for C15H26N2O2:
C, 67.63; H, 9.84; N, 10.52. Found: C, 67.78; H, 9.90; N, 10.49.
HRMS(ESI) m/z calcd for C15H26N2O2 ([M+Na]+): 289.1886, found:
289.1882. IR (KBr, cmꢀ1): 3444, 3349, 2962, 2925, 2867, 1642,
1520, 1464, 1382, 1299, 1121, 1073, 899.
78, 737–784; (c) Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20,
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4.4.3. (S)-N-((1S,2S,3S,5S)-2-Hydroxy-2,6,6-trimethylbicy
clo[3.1.1]heptan-3-yl)-pyrrolidine-2-carboxamide 5c
White solid, mp 62–64 °C, ½a D25
ꢁ
¼ ꢀ62:4 (c 1.0, CHCl3). 1H NMR
(CDCl3): d 0.87 (s, 3H), 1.17 (s, 3H), 1.28 (s, 3H), 1.57 (dd, J = 9.6,
12.8 Hz, 1H), 1.66–1.82 (m, 2H), 1.86–2.06 (m, 4H), 2.10–2.26 (m,
2H), 2.26–2.39 (m, 1H), 2.86–3.11 (m, 2H), 3.83 (dd, J = 5.2,
9.1 Hz, 1H), 4.19 (q, J = 8.4 Hz, 1H), 7.65 (br, 1H) ppm. 13C NMR
(CDCl3): d 23.1, 25.0, 25.1, 26.1, 27.6, 30.3, 30.8, 38.5, 39.8, 47.1,
53.2, 54.5, 59.9, 76.2, 177.2 ppm. Anal. Calcd for C15H26N2O2: C,
67.63; H, 9.84; N, 10.52. Found: C, 67.69; H, 9.97; N, 10.45.
HRMS(ESI) m/z calcd for C15H26N2O2 ([M+Na]+): 289.1886, found:
289.1874. IR (KBr, cmꢀ1): 3444, 3349, 2962, 2925, 2867, 1642,
1520, 1464, 1382, 1299, 1121, 1073, 899.
4. (a) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593–2595; (b) Liu, X.; Lin,
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Park, S. E.; Bae, H. Y.; Song, C. E. Org. Biomol. Chem. 2010, 8, 3918–3922; (f) Tang,
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6. (a) Chen, Y.; Mi, A.-Q.; Xiao, X.; Jiang, Y. Synth. Commun. 1989, 19, 1423–1430;
(b) Mi, A.-Q.; Wang, J.; Chen, Y.; Yang, G.; Jiang, Y. Synth. Commun. 1989, 19,
3337–3342; (c) Laue, K. W.; Kroger, S.; Wegelius, E.; Haufe, G. Eur. J. Org. Chem.
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12731–12744; (e) Dvornikova, I. A.; Frolova, L. L.; Churakov, A. V.; Kuchin, A. V.
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4.4.4. (S)-N-((1R,2R,3R,5R)-2-Hydroxy-2,6,6-trimethylbicy
clo[3.1.1]heptan-3-yl)-pyrrolidine-2-carboxamide 5d
White solid, mp 185–187 °C, ½a D25
ꢁ
¼ ꢀ8:9 (c 2.0, CHCl3). 1H NMR
(CDCl3): d 0.87 (s, 3H), 1.14 (s, 3H), 1.28 (s, 3H), 1.51–1.61 (m, 1H),
1.65–1.82 (m, 2H), 1.85–2.45 (m, 2H), 1.89–2.06 (m, 2H), 2.10–2.25
(m, 2H), 2.25–2.39 (m, 1H), 2.86–3.10 (m, 2H), 3.71–3.82 (m, 1H),
4.11–4.24 (m, 1H) ppm. 13C NMR (CDCl3): d 23.2, 25.0, 25.1, 26.1,
27.7, 30.8, 30.9, 38.5, 40.0, 47.2, 53.3, 54.4, 60.1, 76.3, 177.5 ppm.
Anal. Calcd for C15H26N2O2: C, 67.63; H, 9.84; N, 10.52. Found: C,
67.81; H, 9.93; N, 10.46. HRMS(ESI) m/z calcd for C15H26N2O2
([M+Na]+): 289.1886, found: 289.1880. IR (KBr, cmꢀ1): 3444,
3349, 2962, 2925, 2867, 1642, 1520, 1464, 1382, 1299, 1121,
1073, 899.
7. Masui, M.; Shioiri, T. Tetrahedron 1995, 51, 8363–8370.
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Acknowledgment
This work was supported by the Russian Foundation of Basic
Research (Grant No. 09-03-00384).
12. Belyakov, P. A.; Kadentsev, V. I.; Chizhov, A. O.; Kolotyrkina, N. G.; Shashkov, A.
S.; Ananikov, V. P. Mendeleev Commun. 2010, 20, 125–131.
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III J. Am. Chem. Soc. 2006, 128, 734–735; (b) Raj, M.; Parashari, G. S.; Singh, V. K.
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