4-Substituted prolines as organocatalysts for aldol reactions

Article abstract of DOI:10.1016/j.tet.2005.06.113

A series of 4-substituted prolines were prepared and evaluated as organocatalysts for asymmetric aldol reactions. Using (2S,4R)-4- camphorsulfonyloxy-proline, the aldol products were obtained in much higher enantiomeric excess in comparison to that observ

Full text of DOI:10.1016/j.tet.2005.06.113

Tetrahedron 61 (2005) 8669–8676
4-Substituted prolines as organocatalysts for aldol reactions
*
Evagelos Bellis and George Kokotos
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
Received 11 April 2005; revised 16 June 2005; accepted 30 June 2005
Available online 21 July 2005
Abstract—A series of 4-substituted prolines were prepared and evaluated as organocatalysts for asymmetric aldol reactions. Using (2S,4R)-
4-camphorsulfonyloxy-proline, the aldol products were obtained in much higher enantiomeric excess in comparison to that observed using
proline itself. In addition, the improved solubility of these new catalysts in organic solvents permits their use in lower sub-stoichiometric
amounts compared to proline.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
substituent at the 4-position. The rationale behind the design
was to induce steric hindrance from one side of the
pyrrolidine ring. L-4-Hydroxyproline, which has already
The capability of simple organic molecules from the ‘chiral
pool’ to act like an enzyme represents a remarkable
synthetic alternative to many established asymmetric
transformations. Among the various enantiomerically pure
small organic molecules, amino acids and peptides as well
as cinchona alkaloids are extremely interesting asymmetric
organocatalysts1 demonstrating useful levels of enantio-
selectivity for a wide range of transformations. In particular,
the natural amino acid L-proline acts as an enzyme mimic of
the type I aldolase, catalysing one of the most important
organic asymmetric transformations, the aldol reaction.2 In
addition, proline has shown excellent catalytic activity in
catalysing a wide variety of reactions3 such as Mannich4
and Michael5 reactions, Robinson annulation,6 synthesis of
amino acids,7 a-amination of aldehydes and ketones,8
a-oxidation9 and a-alkylation10 of aldehydes.
2. Results and discussion
As part of our program aimed at developing methodology
for the synthesis of non-natural amino acids and exploring
their applications,11 we synthesized various 4-substituted
prolines. In this article we report our study on their catalytic
effect on the direct asymmetric aldol reaction.12 To develop
improved proline-based catalysts, we decided to maintain
the proline backbone, since both the carboxylic acid group
and the pyrrolidine group are essential for effective
asymmetric induction, and to introduce a chiral bulky
Scheme 1. Reagents and conditions: (a) CCl3C(]NH)OBut, BF3$Et2O,
CH2Cl2/C6H12, 84%; (b) H2, 10% Pd/C, 1,4-dioxane, rt, 24 h, 84%;
(c) (i) (1S)-(K)-camphanic acid or (1R)-(C)-camphanic acid, DCC,
DMAP, CH2Cl2, rt, 24 h, 80% for 4a and 82% for 4d, or (ii) (1R)-(K)-
camphor-10-sulfonyl chloride or (1S)-(C)-camphor-10-sulfonyl chloride,
NMM, THF, 0 8C, 30 min, rt, 24 h, 85% for 4b and 88% for 4e, or (iii) NaH,
THF, 0 8C, then rt, 30 min, and then (K)-menthyl chloroformate or (C)-
menthyl chloroformate, rt, 22 h, 90% for 4c and 93% for 4f; (d) 5 N HCl/
Et2O, rt, 4 h, 94–96%.
Keywords: Aldol reactions; Amino acids; Asymmetric catalysis; Organo-
catalysts; 4-Substituted proline.
*
Corresponding author. Tel.: C30 210 7274462; fax: C30 210 7274761;
e-mail: gkokotos@cc.uoa.gr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.113

8670
E. Bellis, G. Kokotos / Tetrahedron 61 (2005) 8669–8676
Scheme 2. Reagents and conditions: (a) glutaric anhydride, DMAP, CH2Cl2, rt, 36 h, 75%; (b) HCl$H2NCH2COOCH3, EDC, HOBt, Et3N, 0 8C, 1 h, rt, 16 h,
75%; (c) (i) 5 N HCl/Et2O, rt, 1 h, (ii) 6, EDC, HOBt, Et3N, 0 8C, 1 h, rt, 30 h, 70% (overall); (d) 5 N HCl/Et2O, rt, 4 h, 96%.
been used successfully as a catalyst of the aldol reaction,2b
seemed an ideal template. Furthermore, it has been recently
reported that trans-4-tert-butyldimethylsiloxy-L-proline
efficiently catalyses a-aminoxylation of carbonyl com-
pounds, as well as O-nitroso-aldol/Michael, and Mannich
reactions.13
a,g-diaminobutyryl-glycinate using 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide (EDC) in the presence of
1-hydroxybenzotriazole (HOBt) (Scheme 2). Dendron-like
derivative 10 was obtained by deprotection of compound 9.
As depicted in Scheme 3 (1R,3S)-(C)-camphoric acid (11)
was coupled with compound 3, using the DCC/DMAP
method, and deprotected to produce compound 13.
Thus, commercially available (2S,4R)-N-(tert-butoxycarbo-
nyl)-4-benzyloxy-proline (1) was converted into compound
3 (Scheme 1). Compounds 4a,d were prepared by coupling
3 with (1R)-(C)- and (1S)-(K)-camphanic acid using N,N0-
dicyclohexylcarbodiimide (DCC) as coupling agent in the
presence of 4-dimethylamino-pyridine (DMAP).14 Sulfo-
nates 4b,e were prepared by treatment of 3 with the
corresponding sulfonyl chlorides in the presence of
N-methyl-morpholine (NMM) in dry THF and carbonates
4c,f were prepared by treatment of 3 with the corresponding
chloroformates, as depicted in Scheme 1. Deprotected
derivatives 5a–f were prepared by treatment of 4a–f with
5 N HCl/Et2O.
The aldol reaction is one of the most important carbon–
carbon bond-forming reactions in organic synthesis. List
and Barbas have extensively studied the direct asymmetric
aldol reaction of both acyclic and cyclic ketones as aldol
donors with aromatic and aliphatic aldehydes and they have
demonstrated that the most powerful catalysts are L-proline
and 5,50-dimethyl thiazolidinium-4-carboxylate.2b We have
chosen in our preliminary investigations the reaction
between acetone and 4-nitro-benzaldehyde and we have
studied the catalytic effect of derivatives 5a–f, 10 and 13 on
this reaction. The results of our studies are summarized in
Table 1.
The substituents at the 4-position have a significant effect on
Derivative 3 was glutarylated and coupled with methyl
Table 1. Direct asymmetric aldol reaction of acetone and 4-nitrobenzalde-
hyde using various proline-based catalysts
Entrya
Catalyst
Catalyst
loading (%)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
5a
5a
5b
5b
5c
5d
5e
5e
5e
5f
10
10
13
13
30
20
30
20
30
30
30
20
10
30
30
15
30
15
20
20
30
62
58
62
60
65
66
61
59
71
65
61
64
60
62
60
63
71
80
73
75
81
77
44
82
84
90
71
68
70
69
71
63
69
70
9
10
11
12
13
14
15
16
17
L-Pro$HCl
L-Prod
L-HyProd
a Reactions carried out for 16–18 h at rt.
b Isolated yields after column chromatography.
c The ee was determined by HPLC on a Daicel Chiralpak AD-RH column.
d In the absence of Et3N.
Scheme 3. Reagents and conditions: (a) 3, DCC, DMAP, CH2Cl2, rt, 36 h,
74%; (b) 5 N HCl/Et2O, rt, 4 h, 98%.

E. Bellis, G. Kokotos / Tetrahedron 61 (2005) 8669–8676
8671
both the enantioselectivity and yield of the reaction. Under
the conditions used (Table 1) the aldol product was obtained
in 69 and 70% ee, when L-proline and L-4-hydroxyproline
were used as catalysts (entries 16 and 17, respectively).
However, when camphanic acid derivative 5a was used ee
values up to 80% were observed (entry 1). A decrease in the
catalyst loading of 5a led to decrease of both chemical yield
and ee value (entry 2). It is interesting to note that (1S)-(K)-
camphanic acid derivative (5a) led to high enantioselec-
tivity, while the (1R)-(C)-camphanic acid derivative (5d)
led to much lower enantioselectivity (entries 1 and 6,
respectively). Menthyl derivatives 5c and 5f (entries 5 and
10, respectively), gave comparable ee values and the result
for 5f was almost similar to those acquired when proline and
L-4-hydroxyproline were used as catalysts. The application
of the camphorsulfonyl derivatives 5b and 5e led to very
interesting results. The camphorsulfonyl derivative 5e
produced the aldol product in high ee (90%) when used in
10 mol% catalyst loading (entry 9). It should be noticed that
although the loading of the catalyst (30 and 20%) did not
considerably influence both the enantioselectivity (82 and
84%, entries 7 and 8, respectively), and the chemical yield
(61 and 59%, entries 7 and 8, respectively), better chemical
yield (71%) was obtained when derivative 5e was employed
in 10 mol% loading (entry 9). Dendron-like derivatives 10
and 13 containing two pyrrolidine rings per molecule led to
chemical yields and ee values almost similar to those
obtained by proline itself, probably because proline residues
act as non interacting moieties and their catalytic potencies
are neither enhanced nor cancelled out by each other.
higher ee value (74%) in comparison to that observed by
using proline itself (64% ee for 20 mol% proline and almost
no aldol product for 10 mol%) and in a comparable
chemical yield (entry 3).
In conclusion, the results of our study indicate that for high
enantioselectivity the catalyst should possess a chiral bulky
group at the 4-position of the pyrrolidine ring in addition to
carboxylic acid and secondary amine groups. In particular,
4-camphorsulfonyloxy-proline derivative 5e, easily syn-
thesized from proline derivative 1, compares favourably to
proline for the direct asymmetric aldol reaction offering:
(a) higher enantioselectivity in comparison to proline and
(b) a decrease of the required amount (10%) in comparison
to proline (20–30%).
3. Experimental
3.1. General
Melting points were determined on a melting point
apparatus and are uncorrected. Specific rotations were
measured on a polarimeter using a 10 cm cell. NMR spectra
were recorded on 200 and 300 MHz Varian spectrometers.
Where applicable, structural assignments were based on
COSY experiments. Where rotamers are apparent peaks for
major and minor rotamers are reported, when resolved. IR
spectra were recorded on a Perkin-Elmer 841 Spectropho-
tometer. Analytical TLC plates (silica gel 60 F254) and silica
gel 60 (70–230 or 230–400 mesh) for column chroma-
tography were purchased from Merck. Visualisation of
spots was effected with UV light and/or phosphomolybdic
acid and/or ninhydrin both in ethanol stain. THF and 1,
4-dioxane were freshly distilled from sodium-benzo-
phenone ketyl radical under an argon atmosphere immedi-
ately prior to use. Et2O was treated with calcium chloride
and stored over Na. DMF was stirred in the presence of P2O5
for 15 h and distilled under reduced pressure. Acetone was
In an attempt to test the efficacy of catalyst 5e, we submitted
4-bromo-benzaldehyde and 2-chloro-benzaldehyde as
acceptor substrates to the aldol process. The results are
presented in Table 2. When proline was used as catalyst in
the reaction between acetone and 4-bromo-benzaldehyde
in 20 mol% loading, the aldol product was obtained in
moderate ee values (62%), whilst in 10 mol% proline
loading practically no aldol product was acquired (entry 2).
However, when catalyst 5e was employed in 10 mol%
catalyst loading, the aldol product was isolated in much
higher enantiomeric excess (80%) (entry 2). In a similar
manner, in the reaction between acetone and 2-chloro-
benzaldehyde, catalyst 5e in 10 mol% loading led to a
˚
dried overnight over 3 A activated molecular sieves (10%
w/v) and then distilled. All other solvents and chemicals
were of reagent grade and used without further purification.
The samples for elemental analyses were dried over P2O5
under high vacuum for 48 h.
Table 2. Comparison between proline and catalyst 5e in the direct asymmetric aldol reaction
Entrya
Substrate Product Proline (10 mol%)
Proline (20 mol%)
5e (10 mol%)
Yield (%)b Ee (%)c
Yield (%)b
ee (%)
Yield (%)b
ee (%)c
1
!5
n.d.d
63
69
71
90
2
3
!5
!5
n.d.d
n.d.d
71
80
62
64
74
78
80
74
a Reactions carried out for 16–18 h at rt.
b Isolated yields after column chromatography.
c The ee was determined by HPLC on a Daicel Chiralpak AD-RH column.
d Not determined.

8672
E. Bellis, G. Kokotos / Tetrahedron 61 (2005) 8669–8676
3.1.1. (2S,4R)-Di-tert-butyl 4-(benzyloxy)pyrrolidine-1,2-
dicarboxylate (2). To a stirred solution of Boc-L-Pro(Bn)–
OH (322 mg, 1.00 mmol) in CH2Cl2 (1 mL), a solution of
tert-butyl-2,2,2-trichloroacetimidate (440 mg, 2.00 mmol)
in C6H12 (2 mL) was added, followed by BF3$Et2O (20 mL).
The stirring was continued for 24 h at rt. Work-up involved
filtration of the reaction mixture through a pad of Celitew to
remove trichloroacetamide and removal of the solvent under
reduced pressure. The residue was purified by column
chromatography using a mixture of CHCl3/MeOH 95:5 as
eluent to afford 2. Yellowish oil (315 mg, 84%); [a]DK23.9
1.10 (s, 3H, CH3), 1.44 [br, 18H, 2!C(CH3)3], 1.50–2.50
(series of m, 6H, 2!CH2, CH2CHN), 3.40–3.80 (m, 2H,
CH2N), 4.23 (m, 1H, CHN), 5.28 (m, 1H, OCH); 13C NMR
(50 MHz, CDCl3) d 9.5, 16.5, 16.6, 27.8, 28.1, 28.2, 28.7,
29.9, 30.2, 31.9, 32.0, 32.1, 32.6, 35.2, 36.2, 52.0, 54.3,
54.7, 58.1, 73.4, 74.1, 80.1, 80.3, 81.4, 90.6, 153.6, 166.9,
171.2, 178.0; IR [KBr, (cmK1)]: 1795, 1738 and 1704
(C]O); MS (FAB): m/z (%): 468 (5) [MCHC]. Anal.
Calcd for C24H37NO8: C, 61.65; H, 7.98; N, 3.00. Found: C,
61.80; H, 8.32; N, 3.21.
1
(c 1.0, CHCl3); H NMR (200 MHz, CDCl3) d 1.45 [br,
3.2.2. (2S,4R)-Di-tert-butyl 4-[(1R,4S)-4,7,7-trimethyl-3-
oxo-2-oxa-bicyclo[2.2.1]heptane-1-carbonyloxy]pyrro-
lidine-1,2-dicarboxylate (4d). White solid (384 mg, 82%);
mp 153–155 8C; [a]DK18.0 (c 1.0, CHCl3); 1H NMR
(200 MHz, CDCl3) d 0.91 (s, 3H, CH3), 1.01 (s, 3H, CH3),
1.08 (s, 3H, CH3), 1.44 [br, 18H, 2!C(CH3)3], 1.50–2.48
(series of m, 6H, 2!CH2, CH2CHN), 3.49–3.78 (m, 2H,
CH2N), 4.11 (m, 1H, CHN), 5.34 (m, 1H, OCH); 13C NMR
(50 MHz, CDCl3) d 9.5, 16.5, 16.6, 27.8, 28.1, 28.8, 29.9,
30.4, 31.9, 32.0, 32.1, 32.5, 35.2, 36.3, 52.0, 52.1, 54.1,
54.6, 58.2, 73.2, 74.1, 80.3, 81.4, 90.5, 153.5, 166.7, 171.2,
177.8; MS (ESI): m/z (%): 490 (100) [MCNaC]. Anal.
Calcd for C24H37NO8: C, 61.65; H, 7.98; N, 3.00. Found: C,
61.78; H, 8.30; N, 3.26.
18H, 2!C(CH3)3], 2.05 (m, 1H, CHHCHN), 2.35 (m, 1H,
CHHCHN), 3.45–3.75 (m, 2H, CH2N), 4.10–4.38 (m, 2H,
CHN, OCH), 4.42–4.60 (m, 2H, CH2Ph), 7.25–7.42 (m, 5H,
Ph); 13C NMR (50 MHz, CDCl3) d 27.9, 28.3, 35.4, 36.7,
51.2, 51.8, 58.6, 71.1, 75.7, 76.7, 79.7, 79.9, 81.0, 127.6,
127.7, 128.4, 137.7, 154.0, 172.1; IR [film, (cmK1)]: 1730
and 1698 (C]O); MS (ESI): m/z (%): 378 (23) [MCHC],
400 (100) [MCNaC]. Anal. Calcd for C21H31NO5: C,
66.82; H, 8.28; N, 3.71. Found: C, 66.59; H, 8.38; N, 3.68.
3.1.2. (2S,4R)-Di-tert-butyl 4-hydroxypyrrolidine-1,2-
dicarboxylate (3). To a stirred solution of 2 (380 mg,
1.00 mmol) in anhydrous 1,4-dioxane (10 mL), 10% Pd/C
(40 mg) was added. The reaction mixture was stirred under
H2 for 24 h at rt. After filtration through a pad of Celitew, the
solvent was removed and the residue was purified by
column chromatography using EtOAc as eluent to give 3.
Colourless oil (240 mg, 84%); [a]DK68.0 (c 1.0, MeOH);
3.3. General procedure for the preparation of the
sulfonates 4b,e
To a stirred solution of 3 (290 mg, 1.00 mmol) in anhydrous
THF (8 mL) were added NMM (0.14 mL, 1.25 mmol) and
(1R)-(K)-camphor-10-sulfonyl chloride or (1S)-(C)-cam-
phor-10-sulfonyl chloride (315 mg, 1.25 mmol) at 0 8C. The
reaction mixture was stirred at 0 8C for 30 min and at rt for
24 h. The solvent was removed, water (15 mL) was added
and the product was then extracted with EtOAc (3!10 mL).
The combined organic layers were washed consecutively
with 1 M KHSO4 (1!25 mL), H2O (1!30 mL), NaHCO3
10% (1!25 mL), H2O (1!30 mL) and dried over Na2SO4.
The solvent was evaporated and the residue was purified by
column chromatography using initially a mixture of EtOAc/
petroleum ether 40–60 1:1 and finally EtOAc as eluents to
give 4b,e.
[Lit.15 [a]2D1K68.9 (c 1.06, MeOH)]; H NMR (200 MHz,
1
CDCl3) d 1.45 [br, 18H, 2!C(CH3)3], 2.01 (m, 1H,
CHHCHN), 2.25 (m, 1H, CHHCHN), 2.92 (br, 1H, OH),
3.33–3.68 (m, 2H, CH2N), 4.28 (m, 1H, CHN), 4.45 (m, 1H,
OCH); 13C NMR (50 MHz, CDCl3) d 27.9, 28.3, 38.3, 39.1,
54.5, 58.5, 69.1, 70.0, 79.9, 80.2, 81.1, 154.3, 172.2; IR
[film, (cmK1)]: 1745 and 1690 (C]O); MS (FAB): m/z (%):
288 (100) [MCHC]. Anal. Calcd for C14H25NO5: C, 58.52;
H, 8.77; N, 4.87. Found: C, 58.65; H, 7.69; N, 4.88.
3.2. General procedure for the preparation of the
carboxylates 4a,d
To a solution of 3 (290 mg, 1.00 mmol) in dichloromethane
(8 mL) was added (1S)-(K)-camphanic acid or (1R)-(C)-
camphanic acid (200 mg, 1.00 mmol) followed by DCC
(227 mg, 1.10 mmol) and DMAP (12 mg, 0.10 mmol). The
mixture was stirred for 24 h. The dicyclohexylurea was
filtered off, the solvent was removed, water (5 mL) was
added and the product was then extracted with EtOAc (3!
10 mL). The combined organic layers were washed
consecutively with 1 M KHSO4 (1!25 mL), H2O (1!
30 mL), NaHCO3 10% (1!25 mL), H2O (1!30 mL) and
dried over Na2SO4. The solvent was evaporated and the
residue was purified by column chromatography using a
mixture of EtOAc/petroleum ether 40–60 1:1 as eluent to
give 4a,d.
3.3.1. (2S,4R)-Di-tert-butyl 4-{[(1R,4S)-7,7-dimethyl-2-
oxobicyclo[2.2.1]heptan-1-yl]methylsulfonyloxy}pyrro-
lidine-1,2-dicarboxylate (4b). Colourless oil (426 mg,
85%); [a]DK44.0 (c 1.0, CHCl3); 1H NMR (200 MHz,
CDCl3) d 0.80–2.56 (series of m, 35H, 2!CH3, 2!
C(CH3)3, 3!CH2, CH, CH2CHN, CH2SO2) 3.40–3.80 (m,
2H, CH2N), 4.30 (m, 1H, CHN), 5.29 (m, 1H, OCH); 13C
NMR (50 MHz, CDCl3) d 19.6, 19.7, 25.2, 26.8, 27.9, 28.0,
28.3, 33.1, 35.5, 36.6, 42.3, 42.7, 51.9, 52.1, 58.4, 64.2,
71.9, 72.8, 80.1, 80.3, 81.4, 153.8, 171.6, 172.3, 212.8; MS
(ESI): m/z (%): 524 (100) [MCNaC]. Anal. Calcd for
C24H39NO8S: C, 57.46; H, 7.84; N, 2.79. Found: C, 57.70;
H, 7.55; N, 2.76.
3.2.1. (2S,4R)-Di-tert-butyl 4-[(1S,4R)-4,7,7-trimethyl-3-
oxo-2-oxa-bicyclo[2.2.1]heptane-1-carbonylox]pyrro-
lidine-1,2-dicarboxylate (4a). Pale yellow solid (374 mg,
80%); mp 173–175 8C; [a]DK61.0 (c 1.0, CHCl3); 1H NMR
(200 MHz, CDCl3) d 0.90 (s, 3H, CH3), 1.03 (s, 3H, CH3),
3.3.2. (2S,4R)-Di-tert-butyl 4-{[(1S,4R)-7,7-dimethyl-2-
oxobicyclo[2.2.1]heptan-1-yl]methylsulfonyloxy}pyrro-
lidine-1,2-dicarboxylate (4e). White solid (442 mg, 88%);
mp 93–95 8C; [a]DK10.6 (c 1.0, CHCl3); 1H NMR
(200 MHz, CDCl3) d 0.76 (s, 3H, CH3), 0.96 (s, 3H, CH3),

E. Bellis, G. Kokotos / Tetrahedron 61 (2005) 8669–8676
8673
1.37 [br, 18H, 2!C(CH3)3], 1.40–2.60 (series of m, 9H, 3!
CH2, CH, CH2CHN), 2.91 (d, JZ14.9 Hz, 1H, CHHSO2),
3.40–3.83 (m, 3H, CH2N, CHHSO2), 4.16 (m, 1H, CHN),
5.17 (m, 1H, OCH); 13C NMR (50 MHz, CDCl3) d 19.2,
19.3, 24.5, 24.6, 26.5, 27.6, 27.9, 35.9, 37.2, 42.1, 42.3,
47.7, 52.1, 52.4, 57.6, 57.7, 57.8, 78.2, 78.9, 80.0, 81.2,
153.2, 170.8, 170.9, 213.8; IR [KBr, (cmK1)]: 1749, 1728
and 1700 (C]O), 1365 and 1160 (S]O); MS (ESI): m/z
(%): 524 (100) [MCNaC]. Anal. Calcd for C24H39NO8S: C,
57.46; H, 7.84; N, 2.79. Found: C, 57.71; H, 7.60; N, 2.74.
stirring was continued for 36 h at rt. The solvent was then
removed under reduced pressure, water (8 mL) was added
and the product was extracted with EtOAc (3!8 mL). The
combined organic layers were washed consecutively with
1 M KHSO4 (1!20 mL) and H2O (1!25 mL) and dried
over Na2SO4. The solvent was evaporated and the residue
was purified by column chromatography using EtOAc as
eluent to give 6. Light yellowish oil (300 mg, 75%); [a]DK
37.3 (c 1.1, CHCl3); 1H NMR (200 MHz, CDCl3) d 1.47 [br,
18H, 2!C(CH3)3], 1.92–2.08 (m, 2H, CH2CH2CH2), 2.17
(m, 1H, CHHCHN), 2.27–2.51 (m, 5H, CHHCHN, CH2-
CH2CH2), 3.40–3.78 (m, 2H, CH2N), 4.25 (m, 1H, CHN),
5.27 (m, 1H, OCH); 13C NMR (50 MHz, CDCl3) d 19.6,
27.8, 27.9, 28.2, 29.6, 32.8, 33.1, 35.5, 36.5, 51.9, 52.1,
58.4, 71.9, 72.8, 80.3, 80.5, 81.5, 153.9, 171.6, 172.3, 177.9;
IR [film, (cmK1)]: 1738 and 1705 (C]O); MS (FAB): m/z
(%): 402 (10) [MCHC], 424 (2.5) [MCNaC]. Anal. Calcd
for C19H31NO8: C, 56.84; H, 7.78; N, 3.49. Found: C, 56.65;
H, 7.69; N, 3.48.
3.4. General procedure for the preparation of the
carbonates 4c,f
To an ice-cold solution of 3 (290 mg, 1.00 mmol) in dry
THF (5 mL), NaH (24 mg, 1.00 mmol) was added. The
mixture was warmed up to rt and stirred for 30 min, after
which (K)- or (C)-menthyl chloroformate (240 mg,
235 mL, 1.10 mmol) was added. The stirring was continued
at rt for 22 h. The solvent was removed under reduced
pressure, water (7 mL) was added and the product was then
extracted with EtOAc (3!6 mL). The combined organic
layers were washed consecutively with 1 M KHSO4 (1!
20 mL), H2O (1!25 mL), NaHCO3 10% (1!20 mL), H2O
(1!25 mL) and dried over Na2SO4. The solvent was
evaporated and the residue was purified by column
chromatography using a mixture of EtOAc/petroleum
ether 40–60 1:1 as eluent to give 4c,f.
3.4.4. (S)-Methyl 2-[2,4-bis(tert-butoxycarbonyl)butana-
mido]acetate (8). To a stirred solution of (S)-2,4-bis(tert-
butoxycarbonyl)butanoic acid (7) (318 mg, 1.00 mmol) in
CH2Cl2 (10 mL) were added methyl glycinate hydro-
chloride (126 mg, 1.00 mmol), 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (211 mg,
1.10 mmol), 1-hydroxybenzotriazole (135 mg, 1.00 mmol)
and Et3N (0.16 mL, 1.10 mmol). The reaction mixture
was stirred for 1 h at 0 8C and for 16 h at rt. The solvent was
removed, water (8 mL) was added and the product was
extracted with EtOAc (3!8 mL). The combined organic
layers were washed consecutively with 1 M KHSO4 (1!
10 mL), H2O (1!10 mL), 5% aqueous NaHCO3 (1!
10 mL), H2O (1!10 mL), dried (Na2SO4), and the solvent
was evaporated to give 8. White solid (292 mg, 75%); mp
100–101 8C; [a]DK29.4 (c 1.0, CHCl3); 1H NMR
(200 MHz, CDCl3) d 1.40 [br, 18H, 2!C(CH3)3], 1.70–
2.00 (m, 2H, CHCH2), 3.05 (m, 1H, CHHNHOCO), 3.45
(m, 1H, CHHNHOCO), 3.69 (s, 3H, OCH3), 3.85–4.35 (m,
3H, CH, CH2COOCH3), 5.22 (m, 1H, CH2NHOCO), 5.50
(d, JZ8 Hz, 1H, CHNHOCO), 8.64 (m, 1H, NHCO); 13C
NMR (50 MHz, CDCl3) d 28.2, 28.3, 34.2, 36.7, 41.1, 51.6,
52.2, 79.5, 79.9, 155.6, 156.7, 170.1, 172.1; IR[KBr, (cmK1)]:
3331 (N–H), 1754, 1705 and 1689 (C]O), 1519 (N–H);
MS (ESI): m/z (%): 389 (25) [MC]. Anal. Calcd for
C17H31N3O7: C, 52.43; H, 8.02; N, 10.79. Found: C, 52.56;
H, 7.98; N, 10.80.
3.4.1. (2S,4R)-Di-tert-butyl 4-{[(1R,2S,5R)-2-isopropyl-5-
methylcyclohexyloxy]carbonyloxy}pyrrolidine-1,2-
dicarboxylate (4c). Pale yellow oil (423 mg, 90%); [a]DK
1
66.0 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) d 0.70–
2.50 (series of m, 38H, 3!CH3, 2!C(CH3)3, 3!CH2, 3!
CH, CH2CHN), 3.50–3.80 (m, 2H, CH2N), 4.22 (m, 1H,
CHN), 4.48 (m, 1H, CHCHO), 5.17 (m, 1H, OCH); 13C
NMR (50 MHz, CDCl3) d 16.1, 20.6, 21.8, 23.1, 25.9, 27.8,
27.9, 28.2, 31.3, 33.9, 35.4, 36.5, 40.6, 46.8, 51.9, 58.2,
75.0, 75.8, 78.8, 80.0, 80.2, 81.3, 153.5, 154.0, 171.5; MS
(ESI): m/z (%): 470 (45) [MCHC], 492 (100) [MCNaC].
Anal. Calcd for C25H43NO7: C, 63.94; H, 9.23; N, 2.98.
Found: C, 64.10; H, 9.45; N, 2.79.
3.4.2. (2S,4R)-Di-tert-butyl 4-{[(1S,2R,5S)-2-isopropyl-5-
methylcyclohexyloxy]carbonyloxy}pyrrolidine-1,2-
dicarboxylate (4f). Pale yellow oil (437 mg, 95%); [a]DC
1
25.0 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) d 0.68–
2.53 (series of m, 38H, 3!CH3, 2!C(CH3)3, 3!CH2, 3!
CH, CH2CHN), 3.50–3.77 (m, 2H, CH2N), 4.25 (m, 1H,
CHN), 4.50 (m, 1H, CHCHO), 5.12 (m, 1H, OCH); 13C
NMR (50 MHz, CDCl3) d 16.1, 20.6, 21.8, 23.1, 25.9, 27.8,
28.2, 31.3, 33.9, 35.4, 36.5, 40.6, 46.9, 51.8, 52.0, 58.1,
74.9, 75.8, 78.7, 79.9, 80.1, 81.2, 153.5, 154.0, 171.4, 171.5;
IR [film, (cmK1)]: 1742 and 1709 (C]O); MS (ESI): m/z
(%): 470 (40) [MCHC], 492 (100) [MCNaC]. Anal. Calcd
for C25H43NO7: C, 63.94; H, 9.23; N, 2.98. Found: C, 64.08;
H, 9.45; N, 2.76.
3.4.5. (2S,4R)-Di-tert-butyl 4-(5-((S)-3-(5-((3R,5S)-1,5-
bis(tert-butoxycarbonyl)pyrrolidin-3-yloxy)-5-oxopenta-
namido)-4-(2-methoxy-2-oxoethylamino)-4-oxobutyl-
amino)-5-oxopentanoyloxy)pyrrolidine-1,2-dicarboxyl-
ate (9). The tert-butoxycarbonyl groups of 8 (390 mg,
1.00 mmol) were removed by treatment with 5 N HCl in
Et2O (14 mL) for 1 h at rt. After evaporation, Et2O was
added and the product was filtered and recrystallised from
MeOH/Et2O. The product was suspended in CH2Cl2 (8 mL)
and to the solution were added 6 (802 mg, 2.00 mmol), EDC
(422 mg, 2.20 mmol), HOBt (270 mg, 2.00 mmol) and Et3N
(0.70 mL, 5.00 mmol). The reaction mixture was stirred for
1 h at 0 8C and for 30 h at rt. The solvent was removed,
water (15 mL) was added and the product was extracted
with EtOAc (3!10 mL). The combined organic layers were
3.4.3. 5-[(3R,5S)-1,5-Bis(tert-butoxycarbonyl)pyrrolidin-
3-yloxy]-5-oxopentanoic acid (6). To a stirred solution of 3
(287 mg, 1.00 mmol) in CH2Cl2 (7 mL), a solution of
glutaric anhydride (224 mg, 2.00 mmol) in CH2Cl2 (3 mL)
was added, followed by DMAP (16 mg, 0.13 mmol). The

8674
E. Bellis, G. Kokotos / Tetrahedron 61 (2005) 8669–8676
washed consecutively with 1 M KHSO4 (1!25 mL), H2O
(1!30 mL), 5% aqueous NaHCO3 (1!25 mL), H2O (1!
30 mL), dried (Na2SO4), and the solvent was evaporated to
give a residue, which was further purified by column
chromatography using initially CHCl3 and finally CHCl3/
MeOH 95:5 as eluents to give 9. Colourless oil (670 mg,
70%); [a]DK48.0 (c 1.0, CHCl3); 1H NMR (200 MHz,
CDCl3) d 1.48 [br, 36H, 4!C(CH3)3], 1.68–2.75 (m, 18H,
2!CH2CH2CH2, CHCH2CH2, 2!OCHCH2CHN), 2.92
(m, 1H, CHCH2CHH), 3.40–4.08 (m, 9H, CHCH2CHH,
2!CH2N, OCH3, CHHCOOCH3), 4.10–4.35 (m, 3H,
CHHCOOCH3, 2!OCHCH2CHN), 4.47 (m, 1H, CHCH2-
CH2), 5.17–5.35 (m, 2H, 2!OCH), 6.68–7.00 (m, 2H, 2!
NHCO), 8.26 (m, 1H, NHCO); 13C NMR (50 MHz, CDCl3)
d 20.4, 20.8, 28.0, 28.3, 33.3, 33.5, 34.2, 35.2, 35.3, 35.5,
35.7, 36.3, 36.5, 41.1, 49.9, 51.8, 52.0, 52.1, 52.3, 58.4,
71.7, 72.0, 72.7, 80.4, 81.5, 153.9, 170.1, 171.6, 171.7,
171.9, 172.5, 172.9, 173.7; IR [film, (cmK1)]: 3315 (N–H),
1735, 1696, 1683 and 1650 (C]O), 1535 (N–H); MS
(FAB): m/z (%): 956 (47) [MCHC]. Anal. Calcd for
C45H73N5O17: C, 56.53; H, 7.70; N, 7.33. Found: C, 56.55;
H, 7.71; N, 7.35.
oxylic acid hydrochloride (5a). White solid (334 mg,
96%); mp 219–221 8C; [a]DK6.4 (c 1.0, DMF); H NMR
1
(200 MHz, CD3OD) d 0.97 (s, 3H, CH3), 1.10 (s, 3H, CH3),
1.12 (s, 3H, CH3), 1.57–2.75 (series of m, 6H, 2!CH2,
CH2CHN), 3.58 (m, 1H, CHHN), 3.83 (dd, JZ5.0, 13.6 Hz,
1H, CHHN), 4.63 (m, 1H, CHN), 5.67 (m, 1H, OCH); 13C
NMR (50 MHz, CD3OD) d 9.9, 17.0, 17.2, 28.1, 29.8, 31.6,
35.9, 52.2, 55.6, 56.1, 59.7, 75.3, 92.4, 167.9, 170.2, 179.9;
MS (ESI): m/z (%): 312 (100) [MCHC]. Anal. Calcd for
C15H21NO6$HCl: C, 51.80; H, 6.38; N, 4.03. Found: C,
52.01; H, 6.47; N, 4.11.
3.5.2. (2S,4R)-4-{[(1R,4S)-7,7-Dimethyl-2-oxobicyclo-
[2.2.1]heptan-1-yl]methylsulfonyloxy}pyrrolidine-2-
carboxylic acid hydrochloride (5b). White solid (363 mg,
95%); mp 164–166 8C; [a]DK26.2 (c 1.0, MeOH); 1H NMR
(200 MHz, CD3OD) d 0.91 (s, 3H, CH3), 1.10 (s, 3H, CH3),
1.47–2.90 (series of m, 9H, 3!CH2, CH2CHN, CH), 3.35
(m, 1H, CHHSO2), 3.62–3.87 (m, 3H, CH2N, CHHSO2),
4.64 (m, 1H, CHN), 5.59 (m, 1H, OCH); 13C NMR
(50 MHz, CD3OD) d 19.7, 19.9, 26.3, 27.7, 37.0, 43.4,
44.1, 49.1, 53.0, 59.2, 59.4, 80.8, 170.3, 216.6; MS (ESI):
m/z (%): 346 (100) [MCHC]. Anal. Calcd for C15H23NO6-
S$HCl: C, 47.18; H, 6.33; N, 3.67. Found: C, 47.02; H, 6.48;
N, 3.85.
3.4.6. Compound 12. To a solution of 3 (575 mg,
2.00 mmol), in dichloromethane (10 mL), (1R,3S)-(C)-
camphoric acid (200 mg, 1.00 mmol) was added, followed
by DCC (454 mg, 2.20 mmol) and DMAP (24 mg,
0.20 mmol). The mixture was stirred for 36 h at rt. The
dicyclohexylurea was filtered off, the solvent was removed,
water (12 mL) was added and the product was then
extracted with EtOAc (3!10 mL). The combined organic
layers were washed consecutively with 1 M KHSO4 (1!
25 mL), H2O (1!30 mL), NaHCO3 10% (1!25 mL), H2O
(1!30 mL) and dried over Na2SO4. The solvent was
evaporated and the residue was purified by column
chromatography using a mixture of EtOAc/petroleum
ether 40–60 1:1 as eluent to give 12. Colourless oil
(547 mg, 74%); [a]DK32.8 (c 1.0, CHCl3); 1H NMR
(200 MHz, CDCl3) d 0.92 (s, 3H, CH3), 1.03 (s, 3H, CH3),
1.18 (s, 3H, CH3), 1.38 [br, 36H, 4!C(CH3)3], 1.75–2.40
(series of m, 8H, 2!CH2, 2!CH2CHN), 2.75 (m, 1H,
CHCO), 3.30–3.70 (m, 4H, 2!CH2N), 4.10–4.26 (m, 2H,
2!CHN), 5.10–5.25 (m, 2H, 2!OCH); 13C NMR
(50 MHz, CDCl3) d 13.9, 19.5, 19.9, 20.5, 24.2, 27.6,
27.7, 28.0, 28.1, 32.8, 33.2, 35.2, 36.3, 43.4, 51.7, 51.9,
54.0, 58.1, 71.7, 72.5, 79.8, 80.0, 81.1, 153.6, 153.8, 171.2,
171.3, 172.0; IR [film, (cmK1)]: 1806, 1762, 1741 and 1703
(C]O); MS (ESI): m/z (%): 739 (15) [MCHC]. Anal.
Calcd for C38H62N2O12: C, 61.77; H, 8.46; N, 3.79. Found:
C, 61.90; H, 8.50; N, 3.82.
3.5.3. (2S,4R)-4-{[(1R,2S,5R)-2-Isopropyl-5-methylcyclo-
hexyloxy]carbonyloxy}pyrrolidine-2-carboxylic acid
hydrochloride (5c). White solid (330 mg, 94%); mp 195–
197 8C (dec); [a]DK22.0 (c 1.0, H2O); 1H NMR (200 MHz,
CD3OD) d 0.75–2.15 (series of m, 18H, 3!CH3, 3!CH2,
2!CH, CHHCHN), 2.35–2.72 (m, 2H, CH, CHHCHN),
3.58 (m, 1H, CHHN), 3.74 (dd, JZ4.4, 13.6 Hz, 1H,
CHHN), 4.45–4.66 (m, 2H, CHN, CHCHO), 5.37 (m, 1H,
OCH); 13C NMR (50 MHz, CD3OD) d 16.7, 21.0, 22.4,
24.4, 27.4, 32.6, 35.2, 35.8, 41.8, 48.4, 52.3, 59.5, 77.1,
80.3, 155.1, 170.4; MS (ESI): m/z (%): 314 (100) [MCHC].
Anal. Calcd for C16H27NO5$HCl: C, 54.93; H, 8.07; N,
4.00. Found: C, 54.80; H, 8.15; N, 4.15.
3.5.4. (2S,4R)-4-[(1R,4S)-4,7,7-Trimethyl-3-oxo-2-oxa-
bicyclo[2.2.1]heptane-1-carbonyloxy]pyrrolidine-2-
carboxylic acid hydrochloride (5d). White solid (330 mg,
1
95%); mp 234–235 8C (dec); [a]DK15.0 (c 1.0, DMF); H
NMR (200 MHz, CD3OD) d 0.96 (s, 3H, CH3), 1.09 (s, 3H,
CH3), 1.11 (s, 3H, CH3), 1.58–2.70 (series of m, 6H, 2!
CH2, CH2CHN), 3.56 (m, 1H, CHHN), 3.80 (dd, JZ4.8,
13.6 Hz, 1H, CHHN), 4.53 (m, 1H, CHN), 5.62 (m, 1H,
OCH); 13C NMR (50 MHz, CD3OD) d 9.8, 17.0, 17.1, 28.1,
29.8, 31.6, 36.0, 52.2, 55.7, 56.1, 60.2, 75.3, 92.4, 168.0,
168.3, 179.9; MS (FAB): m/z (%): 312 (97) [MCHC]. Anal.
Calcd for C15H21NO6$HCl: C, 51.80; H, 6.38; N, 4.03.
Found: C, 52.08; H, 6.50; N, 4.09.
3.5. General procedure for the removal of Boc and But
protecting groups
Boc and But groups of 4a–f, 9, 12 (1.00 mmol) were
removed by treatment with 5 N HCl in Et2O (14 mL,
70 mmol) for 4 h at rt. After evaporation under reduced
pressure to a small volume (1 mL), anhydrous Et2O was
added (5 mL) and the precipitated product was afforded
through decantation.
3.5.5. (2S,4R)-4-{[(1S,4R)-7,7-Dimethyl-2-oxobicyclo-
[2.2.1]heptan-1-yl]methylsulfonyloxy}pyrrolidine-2-carb-
oxylic acid hydrochloride (5e). White solid (363 mg,
95%); mp 184–186 8C; [a]DC15.2 (c 1.0, DMF); 1H NMR
(200 MHz, CD3OD) d 0.91 (s, 3H, CH3), 1.11 (s, 3H, CH3),
1.42–2.87 (series of m, 9H, 3!CH2, CH2CHN, CH), 3.35
(m, 1H, CHHSO2), 3.64–3.83 (m, 3H, CHHSO2, CH2N),
4.65 (m, 1H, CHN), 5.59 (m, 1H, OCH); 13C NMR
(50 MHz, CD3OD) d 19.7, 19.9, 26.4, 27.7, 36.7, 43.4,
3.5.1. (2S,4R)-4-[(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-
bicyclo[2.2.1]heptane-1-carbonyloxy]pyrrolidine-2-carb-

E. Bellis, G. Kokotos / Tetrahedron 61 (2005) 8669–8676
8675
44.1, 49.2, 53.1, 59.3, 59.4, 80.7, 170.3, 216.4; MS
(FAB): m/z (%): 346 (100) [MCHC]. Anal. Calcd for
C15H23NO6S$HCl: C, 47.18; H, 6.33; N, 3.67. Found: C,
46.98; H, 6.42; N, 3.81.
3.6.1. (4R)-(4-Nitrophenyl)-4-hydroxy-2-butanone2b (14)
1H NMR (200 MHz, CDCl3) d 2.21 (s, 3H, CH3), 2.83 (m,
2H, CH2), 3.56 (d, JZ3.2 Hz, 1H, OH), 5.25 (m, 1H, CH),
7.52 (d, JZ7.0 Hz, 2H, C6H4), 8.20 (d, JZ7.0 Hz, 2H,
C6H4); HPLC (Daicel Chiralpak AD-RH, CH3CN/H2O
30:70, flow rate 0.5 mL/min, lZ254 nm): tR (major)Z
16.58 min, tR (minor)Z20.26 min.
3.5.6. (2S,4R)-4-{[(1S,2R,5S)-2-Isopropyl-5-methylcyclo-
hexyloxy]carbonyloxy}pyrrolidine-2-carboxylic acid
hydrochloride (5f). White solid (333 mg, 95%); mp 120–
122 8C; [a]DK22.0 (c 1.0, H2O); 1H NMR (200 MHz,
CD3OD) d 0.70–2.15 (series of m, 18H, 3!CH3, 3!CH2,
2!CH, CHHCHN), 2.35–2.74 (m, 2H, CH, CHHCHN),
3.53 (m, 1H, CHHN), 3.74 (dd, JZ4.4, 13.6 Hz, 1H,
CHHN), 4.44–4.65 (m, 2H, CHN, CHCHO), 5.38 (m, 1H,
OCH); 13C NMR (50 MHz, CD3OD) d 16.6, 21.1, 22.4,
24.3, 27.2, 32.6, 35.2, 35.9, 41.7, 48.4, 52.3, 59.6, 77.1,
80.3, 155.1, 170.6; MS (FAB): m/z (%): 314 (60) [MCHC].
Anal. Calcd for C16H27NO5$HCl: C, 54.93; H, 8.07; N,
4.00. Found: C, 54.83; H, 8.17; N, 4.19.
3.6.2. (4R)-(4-Bromophenyl)-4-hydroxy-2-butanone2b
(15) 1H NMR (300 MHz, CDCl3) d 2.20 (s, 3H, CH3),
2.82 (m, 2H, CH2), 3.40 (d, JZ3.0 Hz, 1H, OH), 5.12 (m,
1H, CH), 7.24 (d, JZ8.4 Hz, 2H, C6H4), 7.47 (d, JZ8.4 Hz,
2H, C6H4); HPLC (Daicel Chiralpak AD-RH, CH3CN/H2O
30:70, flow rate 0.5 mL/min, lZ254 nm): tR (major)Z
27.31 min, tR (minor)Z30.77 min.
3.6.3. (4R)-(2-Chlorophenyl)-4-hydroxy-2-butanone2b
(16) 1H NMR (300 MHz, CDCl3) d 2.22 (s, 3H, CH3),
2.64–3.03 (m, 2H, CH2), 3.61 (br, 1H, OH), 5.56 (m, 1H,
CH), 7.19–7.34 (m, 3H, C6H4), 7.64 (d, JZ7.7 Hz, 1H,
C6H4); HPLC (Daicel Chiralpak AD-RH, CH3CN/H2O
30:70, flow rate 0.5 mL/min, lZ254 nm): tR (major)Z
15.63 min, tR (minor)Z18.07 min.
3.5.7. (2S,4R)-4-(5-((S)-3-(5-((3R,5S)-5-Carboxypyrroli-
din-3-yloxy)-5-oxopentanamido)-4-(2-methoxy-2-oxo-
ethylamino)-4-oxobutylamino)-5-oxopentanoyloxy)pyr-
rolidine-2-carboxylic acid dihydrochloride (10).
Colourless viscous oil (690 mg, 96%); [a]DK24.5 (c 1.0,
H2O); 1H NMR (200 MHz, D2O) d 1.75–2.10 (m, 6H,
2!CH2CH2CH2, CH2CH2CH), 2.17–2.50 (m, 10H, 2!
CH2CH2CH2, 2!OCHCHHCHN), 2.50–2.74 (m, 2H, 2!
OCHCHHCHN), 3.20–3.75 (series of m, 9H, CH2CH2CH,
CH3O, 2!OCHCH2N), 3.94–4.05 (m, 2H, CH2COOCH3),
4.35 (m, 1H, CH2CH2CH), 4.49–4.65 (m, 2H, 2!
OCHCH2CHN), 5.44–5.50 (m, 2H, 2!OCH); 13C NMR
(50 MHz, D2O) d 22.9, 23.1, 33.1, 35.5, 37.0, 37.3, 37.5,
38.3, 39.7, 43.8, 53.7, 54.0, 56.0, 61.5, 72.4, 76.1, 174.3,
175.7, 177.0, 177.1, 178.6, 178.8. Anal. Calcd for
C27H41N5O13$2HCl: C, 45.26; H, 6.05; N, 9.77. Found: C,
45.27; H, 6.12; N, 9.80.
Acknowledgements
This research was supported by Herakleitos EPEAEK
programme.
References and notes
¨
1. For reviews see: (a) Groger, H.; Wilken, J. Angew. Chem., Int.
3.5.8. Compound 13. White solid (490 mg, 98%); mp 115–
117 8C; [a]DK4.1 (c 1.0, MeOH); 1H NMR (200 MHz,
CD3OD) d 1.03 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.24 (s, 3H,
CH3), 1.70–2.90 (series of m, 9H, 2!CH2, 2!CH2CHN,
CHCO), 3.50–3.75 (m, 4H, 2!CH2N), 4.60 (m, 2H, 2!
CHN), 5.45 (m, 2H, 2!OCH); 13C NMR (50 MHz,
CD3OD) d 14.4, 20.3, 20.6, 20.8, 25.3, 33.8, 34.6, 34.7,
35.8, 52.3, 55.6, 59.7, 74.1, 170.7, 173.7; MS (FAB): m/z
(%): 411 (100) [MCKCH3]. Anal. Calcd for C20H30N2-
O8$2HCl: C, 48.10; H, 6.46; N, 5.61. Found: C, 47.99; H,
6.52; N, 5.81.
Ed. 2001, 40, 529–532. (b) Javro, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481–2495. (c) Yoon, T. P.; Jacobsen,
E. N. Science 2003, 299, 1691–1693. (d) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2001, 40, 3726–3748. (e) Dalko, P.
I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175.
2. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc.
2000, 122, 2395–2396. (b) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260–5267.
(c) List, B.; Pojarlief, P.; Castello, C. Org. Lett. 2001, 3,
´
573–575. (d) Cordova, A.; Notz, W.; Barbas, C. F., III Chem.
Commun. 2002, 3024–3025. (e) Northrup, A. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799.
3. For reviews see: (a) List, B. Synlett 2001, 1675–1686. (b) List,
B. Tetrahedron 2002, 58, 5573–5590. (c) Paraskar, A. S.
Synlett 2003, 582–583.
3.6. General procedure for the preparation of aldol
products
To a mixture of anhydrous DMF (1.60 mL) and anhydrous
acetone (0.40 mL) was added the corresponding aldehyde
(0.20 mmol) followed by the catalysts 5a–f or 10 or 13
(10–30 mol%) and an equivalent amount of Et3N. The
resulting mixture was stirred at rt for 18–24 h. Following
aqueous workup with saturated ammonium chloride
solution and extraction several times with EtOAc, the
combined organic layers were dried (Na2SO4), and the
solvent was evaporated. The pure aldol products were
obtained by column chromatography using a mixture of
EtOAc/petroleum ether 40–60 1:1 as eluent.
4. (a) List, B.; Pojarlief, P.; Biller, W. T.; Martin, H. J. J. Am.
´
Chem. Soc. 2002, 124, 827–833. (b) Cordova, A.; Barbas, C. F.,
III Tetrahedron Lett. 2003, 44, 1923–1926. (c) Hayashi, Y.;
Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003,
´
125, 11208–11209. (d) Cordova, A. Chem. Eur. J. 2004, 10,
´
1987. For a review see: (e) Cordova, A. Acc. Chem. Res. 2004,
37, 102–112.
5. (a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975–2978.
(b) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3,
2423–2425. (c) Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Barbas, C. F., III Tetrahedron Lett.

8676
E. Bellis, G. Kokotos / Tetrahedron 61 (2005) 8669–8676
2001, 42, 4441–4444. (d) Enders, D.; Seki, A. Synlett 2002,
26–28.
6. Bui, T.; Barbas, C. F., III Tetrahedron Lett. 2000, 41,
11. (a) Kokotos, G.; Padron, J. M.; Noula, C.; Gibbons, W. A.;
Martin, V. S. Tetrahedron: Asymmetry 1996, 7, 857–866.
(b) Kokotos, G.; Padron, J. M.; Martin, V. S. J. Org. Chem.
1998, 63, 3741–3744. (c) Padron, J. M.; Kokotos, G.; Martin,
T.; Markidis, T.; Gibbons, W. A.; Martin, V. S. Tetrahedron:
Asymmetry 1998, 9, 3381–3394. (d) Markidis, T.; Kokotos, G.
J. Org. Chem. 2002, 67, 1685–1688. (e) Kokotos, G.;
Kotsovolou, S.; Six, D. A.; Constantinou-Kokotou, V.;
Beltzner, C. C.; Dennis, E. A. J. Med. Chem. 2002, 45,
2891–2893. (f) Bellis, E.; Markidis, T.; Kokotos, G. Synthesis
2002, 1359–1364. (g) Kokotos, G.; Six, D. A.; Loukas, V.;
Smith, T.; Constantinou-Kokotou, V.; Hadjipavlou-Litina, D.;
Kotsovolou, S.; Chiou, A.; Beltzner, C. C.; Dennis, E. A.
6951–6954.
´
7. (a) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.;
Barbas, C. F. J. Am. Chem. Soc. 2002, 124, 1842–1843.
´
(b) Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas,
C. F. J. Am. Chem. Soc. 2002, 124, 1866–1867.
8. (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657.
(b) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig,
A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254–6255.
(c) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790–1793.
For a review see: (d) Duthaler, R. O. Angew. Chem., Int. Ed.
2003, 42, 975–978.
´
J. Med. Chem. 2004, 47, 3615–3628. (h) Mu¨ller, E.; Peczely,
¨
G.; Skoda-Foldes, R.; Takaks, E.; Kokotos, G.; Bellis, E.;
´
9. (a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2003, 125, 10808–10809. (b) Zhong, G.
Angew. Chem., Int. Ed. 2003, 42, 4247–4250. (c) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003,
44, 8293–8296. (d) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.;
Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112–1115.
´
Kollar, L. Tetrahedron 2005, 61, 797–802.
12. Presented in part at the ‘1st Hellenic Symposium on Organic
Synthesis’, Athens, 4–6 November; 2004.
13. Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.;
Urushima, T.; Shoji, M.; Hashizume, D.; Koshino, H. Adv.
Synth. Catal. 2004, 346, 1435–1439.
´ ´
(e) Cordova, A.; Sunden, H.; Bøgevig, A.; Johansson, M.;
Himo, F. Chem. Eur. J. 2004, 10, 3673–3684. (f) Bøgevig, A.;
14. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978,
17, 522–524.
´ ´
Sunden, H.; Cordova, A. Angew. Chem., Int. Ed. 2004, 43,
1109–1112.
10. Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450–451.
15. Tanaka, K.; Sawanishi, H. Tetrahedron: Asymmetry 1998, 9,
71–77.