Substrate control by means of the chiral cavity of prolinamide derivatives of cholic acid in the organocatalyzed Michael addition of cyclohexanone to nitroolefins

Article abstract of DOI:10.1016/j.tetasy.2008.08.018

Different prolinamide and bis-prolinamide derivatives were checked as organocatalysts in the asymmetric Michael addition of cyclohexanone to aromatic nitroolefins, and the derivative bearing a d-prolinamide moiety linked at the 7-position emerged as the m

Full text of DOI:10.1016/j.tetasy.2008.08.018

Tetrahedron: Asymmetry 19 (2008) 2045–2050
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Substrate control by means of the chiral cavity of prolinamide
derivatives of cholic acid in the organocatalyzed Michael addition
of cyclohexanone to nitroolefins
Gian Luigi Puleo a,b, Anna Iuliano b,
*
a Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56126 Pisa, Italy
b Dipartimento di Chimica e Chimica Industriale—Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 June 2008
Accepted 19 August 2008
Different prolinamide and bis-prolinamide derivatives were checked as organocatalysts in the asymmet-
ric Michael addition of cyclohexanone to aromatic nitroolefins, and the derivative bearing a D-prolina-
mide moiety linked at the 7-position emerged as the most efficient, giving the Michael adducts in
satisfactory yield and ees of up to 95%. The corresponding system having a free OH group at the 3-posi-
tion of the cholestanic backbone afforded the opposite enantiomer of the product, suggesting that the
transition state is developed at the inner part of the cholestanic cavity, which is responsible for the sub-
strate control determining the stereochemical outcome of the reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the cholestanic backbone and absolute configuration of the proline
moiety, as well as the presence of free hydroxyl groups, play a sig-
The asymmetric Michael addition of carbon nucleophiles to
nitroolefins has attracted a lot of attention because it allows func-
tionalized products with multiple stereogenic centres to be
obtained in a single step.1 Its organocatalyzed version, pioneered
by List2a and Barbas,2b represents a satisfactory answer to the
demand for environmentally friendly reaction conditions leading
to enantiomerically enriched products.3 Excellent results have
been obtained in the Michael addition of carbonyl compounds to
nitroalkenes using chiral amines as organocatalysts,4 which pro-
mote the reaction via an enamine pathway.5 Among these, proline
derivatives bearing substrate orienting functional groups6 suc-
ceeded in reaching good levels of asymmetric induction. An alter-
native approach to the attainment of high diastereoisomeric and
enantiomeric excesses by means of substrate control can be real-
ized by using a proline derivative where the aminoacid moiety is
a part of a chiral cavity in which the reaction takes place. Following
this idea, we synthesized prolinamide derivatives of bile acids by
linking a proline moiety to the different functionalized positions
of cholic and deoxycholic acids, which were successfully used as
organocatalysts in the direct asymmetric aldol reaction.7 The effec-
tiveness of these systems relies on the cholestanic structure that
forms a functionalized chiral cavity with the appended prolina-
mide groups that were able to exert a good stereochemical control
on the orientation of the substrate.7 Furthermore, both position on
nificant role in determining the stereochemical outcome of the
reaction.7 Since the amine catalyzed Michael addition of ketones
to nitroolefins proceeds via an enamine intermediate, as in the
proline-promoted aldol reaction, we reasoned that this class of
organocatalysts could also succeed in this reaction. To verify this
hypothesis, the prolinamide and bis-prolinamide derivatives of
cholic acid reported in Figure 1 were checked as organocatalysts
in the asymmetric Michael addition of cyclohexanone to aromatic
nitroolefins.
These derivatives possess D- or L-prolinamide moieties linked to
the stereochemically demanding 7 and 12 positions of the cholic
acid and free or protected hydroxyl groups, to check the effect of
these structural features on the outcome of the reaction.
2. Results and discussion
2.1. Synthesis of the organocatalysts
The synthesis of the bis-prolinamide derivatives 3 was per-
formed starting from the 7,12-dioxime derivative of cholic acid
as outlined in Scheme 1. Compound 5 was obtained from cholic
acid in three steps in 85% overall yield, as previously described in
the literature,8 and was eventually reduced, with complete stereo-
selectivity, to the 7,12-diamino derivative 6 by means of catalytic
hydrogenation, followed by reaction with Zn in acetic acid. The
prolinamide derivatives 7 were obtained by reacting the diamine
* Corresponding author. Tel.: +39 0502219231; fax: +39 0502219260.
E-mail address: iuliano@dcci.unipi.it (A. Iuliano).
6 with D-Boc-Proline in the presence of isobutylchloroformate at
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.018

2046
G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 19 (2008) 2045–2050
O
O
O
OMe
OAc
O
O
NH
NH
NH
NH
OMe
OMe
R
NH
R
NH
R
R
O
O
HN
HN
2a (D-Pro)R: OAc
1a R: OAc,D-Pro
1b R: OH,D-Pro
2b
2c
3a R: OAc
3b R: OH
R: OH
(D-Pro)
(L-Pro)R: OAc
Figure 1. Structure of bile acid derived organocatalysts.
O
HO
3 step
85% yield over all
O
OH
O
N
NH2
OH
OMe
OMe
a
OH
O
HO
OH
AcO
N
AcO
NH2
6
5
N
Boc
O
NH
OMe
O
O
NH
NH
OMe
b
c
AcO
NH
H
N
AcO
NH
Boc
N
O
3a
7
O
Scheme 1. Synthesis of bis-prolinamide bile acid derivative 3a. Reagents and conditions: (a) PtO2ꢀxH2O, AcOH, H2 (2 bar), rt, 6 d, then Zn powder, rt, 12 h; (b)
isobutylchloroformate, NMM, CH2Cl2, 0 °C to rt, 26 h; (c) CH2Cl2, TFA, rt 15 min.
D-Boc-Pro,
room temperature7 in 50% yield after chromatographic purifica-
tion. Organocatalyst 3a was obtained in quantitative yield by
removing the Boc protecting group by means of trifluoroacetic acid
in dichloromethane solution. Products 2b and 3b were prepared by
hydrolysis of the corresponding 3-acetate derivatives with HCl in
methanol (Scheme 2).
2.2. Michael addition of cyclohexanone to nitroolefins
Derivatives 1–3 were assayed as organocatalysts in the asym-
metric Michael addition of cyclohexanone to b-nitrostirene, and
the results obtained are reported in Table 1. The reactions were
performed by stirring cyclohexanone and the organocatalyst in
HN
HN
O
OMe
O
OMe
O
NH
O
NH
AcO
NH
HO
NH
3a
a
O
3b
O
HN
HN
O
O
OAc
OA c
OMe
OMe
HO
NH
AcO
NH
2a
2b
O
O
HN
HN
Scheme 2. Synthesis of 3b and 2b. Reagents and conditions: (a) concd HCl., MeOH, 24 h, rt.

G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 19 (2008) 2045–2050
2047
Table 1
Michael addition of cyclohexanone to trans-b-nitrostyrene in the presence of organocatalysts 1–3
O
O
O
cat,48 h, 0°C
NO2
NO2
NO2
+
+
(S,R)
(R,S)
Entrya
Cat.
Cat. loading (mol %)
Solvent
eeb (%)
A.C.c
Conv.d (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1ª
2a
2ª
10
10
5
10
5
DCM
DCM
DCM
PhMe
PhMe
PhMe
i-PrOH
DCM
DCM
PhMe
DCM
DCM
PhMe
THF
41
61
62
70
79
82
23
34
60
75
47
56
50
10
65
27
36
(R,S)
(R,S)
(R,S)
(R,S)
(R,S)
(R,S)
(R,S)
(S,R)
(S,R)
(S,R)
(S,R)
(R,S)
(R,S)
(R,S)
(S,R)
(S,R)
(S,R)
44
94
38
80
28
50
8
65
50
36
68
97
75
31
53
47
19
2a
2a
2a
2a
2c
2b
2b
1b
3a
3a
3a
3b
3a
3a
10e
10
10
10
10
10
5
5
5
5
5
DCM
EtOH
i-PrOH
5
a
Reaction conditions: cyclohexanone (2 equiv), trans-b-nitrostyrene (1 equiv), organocatalyst, solvent (1 mL), 48 h, rt.
b
Enantiomeric excess of the syn diastereoisomer (de >98%, evaluated by 1H NMR) was determined by enantioselective HPLC: Chiralcel OJ, Hexane/2-propanol 97:3,
220 nm, 1 mL/min.
c
Absolute configuration of the prevailing enantiomer was determined by comparison with the literature data.
d
Determined by 1H NMR.
e
Reaction was performed at 0 °C for 60 h.
the solvent, then adding b-nitrostirene after 1 h, and were inter-
rupted usually after 48 h.
All the reactions proceeded with complete diastereoselectivity
in favour of the syn-diastereoisomer. Derivative 1a, bearing a
induction mechanism. It is conceivable that this could happen only
if the transition state is developed at the inner part of the chiral
cavity, formed by the cholestanic backbone and the appended pro-
linamide moiety, where the 3-OH group is directed. The change of
the asymmetric induction mechanism depending on the presence
of a free 3-OH group is also observed using 1b, which possesses
D
-prolinamide moiety linked to the 12-position, afforded, in dichlo-
romethane at room temperature, the reaction product in 44% yield
and 41% ee (entry 1). Better results were obtained using 2a, which
possesses the same moiety linked at 7-position: under the same
reaction conditions, the Michael adduct was obtained in 94% yield
and 61% ee (entry 2). Lowering the catalyst loading gave rise to a
lower yield, without affecting the extent of asymmetric induction
(entry 3). The use of toluene as a reaction solvent gave a higher
ee (entry 4) that further increased when using lower catalyst load-
ing (entry 5) that, unfortunately, afforded a lower yield of the prod-
uct. On lowering the temperature, the extent of asymmetric
induction increased, and the product was obtained in 50% yield
and 82% ee (entry 6). The use of the protic solvent 2-propanol gave
poor results in terms of both yield and ee (entry 7). Derivative 2c,
a D-prolinamide moiety linked at the 12-position (entry 11), which
gave the opposite prevailing enantiomer with respect to 1a (entries
1 and 11). These results point out the role of the chiral cavity of
these organocatalysts in determining the stereochemical outcome
of the Michael reaction independently of the position of the proli-
namide moiety on the cholestanic backbone. Since 2a gave the best
results in terms of both yield and ee of the product and gave the
same prevailing enantiomer as 1a, we were interested in checking
if two D-prolinamide moieties linked at the 7- and 12-positions
could work in a synergistic manner, affording higher asymmetric
induction. The bis-prolinamide derivative 3a gave the reaction
product in quantitative yield under a 5% catalyst loading and in a
slightly lower ee than that obtained using 2a (entry 12). The higher
reaction rate and the very similar asymmetric induction extent
bearing a
worse results with respect to its diastereoisomer in terms of both
yield and ee (entry 8), suggesting that -prolinamide moiety is in
L-prolinamide moiety at the same position as 2a, gave
D
suggest that the two D-prolinamide moieties of 3a work indepen-
a matched relationship with the cholestanic backbone when linked
at the 7-position. The absolute configuration of the prevailing
enantiomer of the product depends on the absolute configuration
of the prolinamide moiety: as a matter of fact the same prevailing
enantiomer was obtained using 1a and 2a, whereas the sense of
asymmetric induction is inverted when the reaction was promoted
by 2c. It is noteworthy that the same stereoselectivity inversion is
dently as organocatalysts of the reaction. No better results were
obtained by changing reaction solvent (entries 13 and 14). The
sense of asymmetric induction still changes in passing from 3a to
3b, the analogues possessing a free OH group at the 3-position (en-
try 15), and a slight improvement of the ee is also observed. The
same enantioselectivity inversion is observed when polar protic
solvents, such as ethanol or 2-propanol, were used (entries 16
and 17): however, the poor results in terms of both yield and ee
make these reaction conditions scarcely interesting.
The conditions giving the best results in the asymmetric
Michael addition of cyclohexanone and b-nitrostirene, that is,
10% of 2a as an organocatalyst in toluene at 0 °C, were used to test
the reaction with other aromatic nitroolefins, and the results are
reported in Table 2.
observed using 2b (entry 9), which possesses a D-prolinamide moi-
ety linked at the 7-position, as 2a, but has a free hydroxyl group at
the 3-position. In addition, this organocatalyst gave better results
in terms of asymmetric induction with respect to 2c, which further
improved using toluene as a solvent (entry 10). These results sug-
gest that the free OH on the cholestanic backbone enters the tran-
sition state leading to the product, changing the asymmetric

2048
G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 19 (2008) 2045–2050
Table 2
moieties in determining the stereochemical outcome of the reac-
tion. As a matter of fact, the presence of a free hydroxyl group,
which can interact with the substrate only in a transition state
developed at the inner part of the cavity, gives rise to the change
of the sense of asymmetric induction, with respect to the corre-
sponding systems having a protected hydroxyl group. This result
also has a practical implication given that deprotection of the OH
group is easily realized, so that it is possible to obtain both enanti-
omers of the Michael adducts starting from the same chiral
architecture.
Michael addition of cyclohexanone to aromatic nitroolefins 8 in the presence of
organocatalyst 2a
O
Ar
O
2a (10mol%),
NO2
NO2
+
Ar
72h, 0°C
Toluene
8
8a Ar:p-NO2C6H4
8b Ar:p-MeOC6H4
8c Ar:o-NO2C6H4
8d Ar:p-BrC6H4
8e Ar:2-furyl
8f Ar:p-MeC6H4
8g Ar:2-naphthyl
8h Ar:1,3-benzodioxoane-5-yl
Entrya
Ar
deb (%)
Conv.b (%)
eec (%)
4. Experimental
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
98
98
98
62
61
70
71
98
64
55
59
65
68
66
65
26
93d
55e
49f
80g
82h
79i
75j
95k
4.1. General procedures and materials
1H and 13C NMR spectra were recorded in CDCl3 on a Varian
Gemini-300 300 MHz NMR spectrometer, using TMS as external
standard. The following abbreviations are used: s = singlet,
d = doublet, dd = double doublet, t = triplet, m = multiplet and
br = broad. HPLC analyses were performed on a JASCO PU-980
intelligent HPLC pump equipped with a JASCO UV-975 detector.
Optical rotations were measured with a JASCO DIP-360 digital
polarimeter. Melting points were taken using a Kopfler Reichert-
Jung apparatus, and are uncorrect. IR spectra were recorded on a
Perkin-Elmer 1710 spectrophotometer.
TLC analyses were performed on silica gel 60 sheets; flash chro-
matography separations were carried out on columns using silica
gel 60 (230–400 mesh). Toluene was refluxed over sodium and
distilled before use. THF was refluxed over Na/K alloy and distilled
before use. CH2Cl2 and N-methylmorpholine were refluxed over
CaH2 and distilled before use. Zn powder was washed with concen-
trated HCl, water, acetone and diethylether before use. Glacial acetic
acid was used. Unless otherwise specified, the reagents were used
8g
8h
a
Reaction conditions: cyclohexanone (2 equiv), nitroolefin (1 equiv), organocat-
alyst (10 mol %) and toluene, 0 °C, 72 h.
Determined by 1H NMR.
Enantiomeric excess of the syn prevailing diastereoisomer was determined by
b
c
enantioselective HPLC.
d
Chiralcel OJ, 238 nm, 1 mL/min, Isoct/Ipa 80:20.
Chiralpack AD, 238 nm, 1 mL/min, Hex/Ipa 95:5.
Chiralpack AD, 254 nm, 0.5 mL/min, Hex/Ipa 90:10.
Chiralpack AS, 238 nm, 1 mL/min, Hex/Ipa 90:10.
Chiralpack AD, 254,nm, 0.7 mL/min, Hex/Ipa 90:10.
Chiralcel OJ, 220 nm, 1 mL/min, Hex/Ipa 97:3.
Chiralpack AS, 254 nm, 0.7 mL/min, Hex/Ipa 55:45.
Chiralpack AS, 214 nm, 1 mL/min, Hex/Ipa 97:3.
e
f
g
h
i
j
k
All the reactions were stopped after 72 h for comparative pur-
poses. Conversions ranging from 55% to 68% were obtained, with
the only exception of substrate 8h which gave a poor yield of the
Michael adduct (entry 8), probably because the presence of an
electron rich aromatic ring slows down the addition to a greater
extent. The reaction is diastereoselective in favour of the syn dia-
stereoisomer with all the substrates, but the extent depends on
the nature of the nitroolefin. A general trend depending on the
electronic character or the substitution pattern of the aromatic ring
cannot be found: as a matter of fact, complete diastereoselectivity
was obtained with both electron-poor and electron-rich substrates
(entries 1 and 2) or with substrates bearing substituents on differ-
ent positions of the aromatic ring (entries 1, 3 and 8). The same
considerations can be made with regard to the substrates giving
lower diastereoisomeric excesses (entries 4–7). The ees are moder-
ate only for substrates 8b and 8c (entries 2 and 3). The other nitro-
olefins gave the Michael adducts with ees ranging from 75% to 95%.
Again, a trend depending on electronic characteristics or substitu-
tion of the aromatic rings cannot be found, and there is no correla-
tion between diastereoselectivity and enantioselectivity. In fact,
starting from olefin 8b a Michael adduct with high diastereo-
isomeric excess but moderate ee was obtained (entry 2), whereas
substrate 8e afforded a product with moderate diastereoselectivity
and good ee (entry 5).
without any purification. Methyl 3
5b-cholan-24-oate 5,8 methyl
noyl)amino-5b-cholan-24-oate 1a,7b methyl
12 -(
-prolinoyl)amino-5b-cholan-24-oate 1b,7b methyl 3
diacetyloxy-7 -(
-prolinoyl)amino-5b-cholan-24-oate 2a,7b and
methyl ,12 -diacetyloxy-7
a
a
-acetyloxy-12
,7 -diacetyloxy-12
,7 -dihydroxy-
,12
a
,7
a
a
-dioxime-
-(D-proli-
3
a
3
a a
a
D
a
a-
a
a
D
3a
a-(L-prolinoyl)amino-5b-cholan-24-
oate 2c7b were obtained as previously described, and matched the
reported characteristics.
4.2. Synthesis of organocatalysts
4.2.1. Methyl 3a-acetyloxy-12a,7a-diamino-5b-cholan-24-oate 6
Hydrated PtO2 (120 mg, 12,5 mol %) was added to a solution of
dioxime 5 (2.07 g, 4.22 mmol) in glacial acetic acid (9 mL), and the
mixture was stirred under H2 (2 bar) at room temperature for six
days. The solid was filtered off and powdered Zn (4.5 g,
33.72 mmol) was added to the solution, concentrated under vac-
uum to 2 mL. The mixture was stirred at room temperature for
12 h, then the solid was filtered off and washed with acetic acid.
After concentration under reduced pressure, water was added
and the aqueous solution was made basic with KOH pellets. The
organic product was extracted with ethyl acetate and the organic
extracts were dried (Na2SO4). The solvent was evaporated under
vacuum affording pure amine. Yield 1.11 g, 57%. Mp 94–95 °C.
3. Conclusion
½
a 2D2
ꢁ
¼ þ35:0 (c 1.00, CH2Cl2). 1H NMR (200 MHz, CDCl3, d): 0,73
(s, 3H, CH3), 0,92 (s, 3H, CH3), 0,97 (d, 3H, 21-CH3), 1,00–2,60 (m,
28H, steroidal CH and CH2), 2.01 (s, 3H, CH3CO), 3.10 (br t, 1H,
12-CH), 3.16 (br t, 1H, 7-CH), 3.67 (s, 3H, OMe), 4.56 (m, 1H, 3-
CH). 13C NMR (40 MHz, CDCl3, d): 13.68, 17.31, 21.56, 22.81,
23.67, 26.03, 26.83, 27.72, 28.36, 31.01, 31.21, 34.76, 35.06,
35.13, 35.26, 36.05, 39.66, 41.72, 41.99, 46.23, 47.67, 47.90,
Screening of different prolinamide and bis-prolinamide deriva-
tives of cholic acid as organocatalysts in the asymmetric Michael
addition of cyclohexanone not only allowed us to find a chiral sys-
tem that is able to afford satisfactory yields of the products and ees
up to 95%, but also pointed out the role of the chiral cavity consti-
tuted by the cholestanic backbone and the appended prolinamide

G. L. Puleo, A. Iuliano / Tetrahedron: Asymmetry 19 (2008) 2045–2050
2049
51.61, 54.03, 74.47, 170.89 (acetate C@O), 174.63 (24 C@O). IR
(KBr, cmꢂ1): 2961, 1735, 1654, 1636, 1560, 1458, 1382, 1261,
1164, 1096, 1033, 804. Anal. Calcd for C27H46N2O4: C, 70.09; H,
10.02; N, 6.05; O, 13.83. Found: C, 70.13; H, 10.01; N, 6.04.
cally 0.2 mL) and stirred at rt for 24 h. A 5% solution of NaHCO3
was added to remove the excess of acid, and the product was
extracted with CH2Cl2 (3 ꢃ 30 mL). The organic phase was then
washed with brine (3 ꢃ 50 mL) and dried over anhydrous Na2SO4.
The solvent was evaporated under vacuum affording chemical pure
product.
4.2.2. Methyl 3
5b-cholan-24-oate 7
To a solution of N-Boc protected
in anhydrous CH2Cl2, N-methylmorpholine (290
was added and the mixture was cooled to ꢂ20 °C, then isobutyl-
chloroformate (340 L, 2.38 mmol) was added. The reaction tem-
a-acetyloxy-7a,12a-bis(D-Boc-Prolinoyl)amino-
D-proline (512 mg, 2.38 mmol)
4.3.1. Methyl 3a-hydroxy-12a,7a-bis(d-prolinoyl)amino-5b-
l
L, 2.63 mmol)
cholan-24-oate 3b
Yield 90 mg, quantitative. Mp 133–135 °C. ½a D22
¼ þ112:7 (c
ꢁ
l
1.00, CH2Cl2). 1H NMR (200 MHz, CDCl3, d): 0,79 (s, 3H, CH3),
0,85 (d, 3H, 21-CH3), 0.92 (s, 3H, CH3), 1.00–2.40 (m, 28H, steroidal
CH e CH2 and 8H 30 and 40-CH2 of Pro), 3.03 (br m, 1H, 20-CH of 7-
Pro), 3.46 (br m, 4H, 30-CH2 of 7 and 12-Pro) 3.63 (s, 3H, OMe), 3.82
(br m, 1H, 20-CH of 12-Pro), 3.85 (br d, 1H, 12-CH), 4.22 (br d, 1H, 7-
CH), 4.36 (br d, 1H, 3-CH), 8.08 (br d, 1H, NH amide) 8.28 (br d, 1H,
NH amide). 13C NMR (40 MHz, CDCl3, d): 13.60, 17.75, 22.72, 23.08,
23.22, 26.56, 25.02, 26.17, 26.44, 26.87, 27.47, 29.45, 29.90, 30.57,
31.20, 31.70, 32.13, 34.76, 35.13, 35.96, 36.88, 37.09, 38.65, 39.88,
41.68, 41.94, 44.82, 45.47, 46.09, 46.82, 47.40, 47.75, 51.34, 51.69,
59.80, 60.81, 61.29, 61.99, 70.52, 71.81, 72.54, 172,54 (amide
C@O), 173.55 (amide C@O), 174.83 (24 C@O). IR (KBr, cmꢂ1):
2937, 2862, 1737, 1669, 1538, 1458, 1433, 1371, 1340, 1309,
1247, 1197, 1167, 1089, 1068, 1012, 919, 820. Anal. Calcd for
perature was maintained at ꢂ20 °C for 5 min, then a CH2Cl2
solution of diamine 6 (500 mg, 1.08 mmol) was added dropwise
over 15 min at 0 °C. The reaction mixture was stirred for 26 h.
Finally the reaction mixture was treated with HCl acq. and NaHCO3
acq. and NaCl acq. then dried over Na2SO4. The organic phases were
concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (AcOEt/Hex 1:1) affording the pure
product. Yield 500 mg, 54%. Mp 66–67 °C. ½a D22
¼ þ79:5 (c 1.00,
ꢁ
CH2Cl2). 1H NMR (200 MHz, CDCl3, d): 0,77 (s, 3H, CH3), 0.90 (d,
3H, 21-CH3), 0.94 (s, 3H, CH3), 1.00–2.40 (m, 28H, steroidal CH
and CH2 and 8H 30 and 40-CH2 of Boc-Pro), 1.46 (s, 18H, Boc
6CH3) 2.03 (s, 3H, CH3CO), 3.35 (br m, 1H, 20-CH of 7-Boc-Pro),
3.37 (br m, 4H, 30-CH2 of 7 and 12-Boc-Pro) 3.66 (s, 3H, OMe),
4.01 (br m, 1H, 20-CH of 12-Boc-Pro), 4.27 (br d, 1H, 12-CH), 4.37
(br d, 1H, 7-CH), 4.56 (m, 1H, 3-CH), 7.60 (br d, 1H, 7 and 12-NH
amide). 13C NMR (40 MHz, CDCl3, d): 13.65, 14.29, 16.99, 21.65,
23.15, 23.44, 24.51, 24.74, 26.92, 27.09, 27.39, 28.56 (3C, Boc),
28.63 (3C, Boc), 29.43, 30.98, 31.43, 31.92, 34.84, 35.01, 35.54,
37.10, 41.53, 44.79, 45.03, 46.07, 47.16, 47.31, 48.41, 51.51,
51.87, 59.91, 60.25, 60.48, 74.62, 79.85, 80.38, 170.44 (acetate
C@O), 171.03 (7 and 12 Boc C@O), 171.50 (7 and 12 amide C@O),
174.58 (24 C@O). IR (KBr, cmꢂ1): 2962, 2874, 1739, 1679, 1528,
1401, 1365, 1260, 1164, 1120, 1088, 1026, 802. Anal. Calcd for
C35H58N4O5: C, 68.37; H, 9.51; N, 9.11 O, 13.01. Found: C, 68.38;
H, 9.52; N, 9.09.
4.3.2. Methyl 3
a
-hydroxy-12
a
-acetyloxy-7
a-(
D
-prolinoyl)-
amino-5b-cholan-24-oate 2b
Yield 92 mg, quantitative. Mp 92–93 °C. ½a D22
ꢁ
¼ þ132:6 (c 1.00,
CH2Cl2). 1H NMR (300 MHz, CDCl3, d): 0.76 (s, 3H, CH3), 0.84 (d,
3H, 21-CH3), 0.96 (s, 3H, CH3), 0.90–2.40 (m, 28H, steroidal CH
and CH2), 2.14 (s, 3H, 12-CH3CO), 3.04 (br m, 2H, 30-CH2 of 7-
Pro), 3.49 (br s, 1H, 7-CH), 3.67 (s, 3H, CH3OCO), 3.77 (br s, 1H,
20-CH of Boc-Pro), 5.13 (br s, 1H, 12-CH) 3.99 (m, 1H, 3-CH), 8.20
ppm (br s, NH amide). 13C NMR (75 MHz, CDCl3, d): 12.39, 17.61,
21.58, 22.74, 22.99, 25.79, 26.98, 27.24, 28.58, 29.30, 30.81,
31.02, 34.63, 34.79, 36.63, 41.35, 43.90, 45.32, 46.60, 47.35,
47.61, 51.61, 74.20, 75.40, 80.42, 170.37, 170.70, 171.18, 174.60,
198.11 ppm. IR (KBr, cmꢂ1): 2960, 2871, 1738 (br C@O), 1703
(C@O), 1679, 1654, 1526, 1506, 1457, 1437, 1398, 1368, 1245,
1162, 1118, 1083, 1022, 960, 887. Anal. Calcd for C32H52N2O6: C,
68.54; H, 9.35; N, 5.00 O, 17.12. Found: C, 68.56; H, 9.34; N,
5.00.
C47H76N4O10: C, 65.86; H, 8.94; N, 6.54; O, 18.67. Found: C,
65.88; H, 8.93; N, 6.55.
4.2.3. Methyl 3
a-acetyloxy-12a,7a-bis(D-prolinoyl)amino-5b-
cholan-24-oate 8
A solution of amide in CH2Cl2 (5 mL) was reacted with a large ex-
cess of TFA (5 mL) and stirred at rt for 30 min. The resulted mixture
was washed with NaHCO3 5% to remove the excess of acid and ex-
tracted with CH2Cl2 (typically 3 ꢃ 30 mL). Organic phase was then
washed with brine (3 ꢃ 50 mL) and dried over anhydrous Na2SO4.
The solvent was evaporated under vacuum affording chemical pure
product. Yield 435 mg, quantitative. Mp 102–103 °C. ½a D22
ꢁ
¼ þ43:4
4.4. General procedure for the Michael reaction
(c 1.00, CH2Cl2). 1H NMR (200 MHz, CDCl3, d): 0.82 (s, 3H, CH3),
0.84 (d, 3H, 21-CH3), 0.96 (s, 3H, CH3), 1.00–2.60 (m, 28H, steroidal
CH and CH2 and 8H 30 and 40-CH2 of Pro), 1.99 (s, 3H, CH3CO), 2.99
(br m, 1H, 20-CH of 7-Pro), 3.09 (br m, 4H, 30-CH2 of 7 and 12-Pro)
3.66 (s, 3H, OMe), 3.78 (br m, 1H, 20-CH of 12-Pro), 3.88 (br d, 1H,
12-CH), 4.24 (br d, 1H, 7-CH), 4.55 (m, 1H, 3-CH), 8.18 (br d, 1H, 7
and 12-NH amide). 13C NMR (40 MHz, CDCl3, d): 13.61, 17.48,
21.42, 23.09, 23.22, 26.25, 26.49, 26.99, 27.43, 29.25, 30.73, 30.86,
31.05, 31.79, 34.68, 34.94, 35.83, 37.05, 41.25, 44.57, 45.29, 45.57,
47.35, 47.68, 48.89, 51.04, 51.64, 60.77, 61.13, 74.07, 170.34 (ace-
tate C@O), 173.58 (7 and 12 amide C@O), 174.68 (24 C@O). IR
(KBr, cmꢂ1): 2961, 2871, 1735, 1654, 1648, 1560, 1541, 1508,
1458, 1448, 1381, 1364, 1260, 1170, 1098, 1025, 801. Anal. Calcd
for C37H60N4O6: C, 67.65; H, 9.21; N, 8.53; O, 14.61. Found: C,
67.66; H, 9.20; N, 8.55.
The organocatalyst (5 or 10 mol %) was stirred in the solvent
with cyclohexanone (0.5 mmol) for 1 h. trans-b-Nitrostyrene
(0.25 mmol) was added and the mixture was stirred at the desired
temperature, monitoring the reaction by TLC (SiO2 ethyl acetate/
hexane 30:70). The reaction was stopped by evaporating the
solvent, and the crude product was analyzed by HPLC on a chiral
stationary phase and 1H NMR (see Tables).
Acknowledgements
The work was supported by the University of Pisa and Scuola
Normale Superiore of Pisa.
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