Synthesis of cholaphanes by ring closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2007.02.099

The synthesis of cholaphanes by ring closing metathesis (RCM) of 3α,7α,12α,24-tetraol allyl derivatives, obtained from cholic acid, was attempted. The reactions of tetraol 3,24-diallyl ether or 3,24-diacrylate were not satisfactory. However, diallyl derivatives of disteroidal 3,3′- or 24,24′-ortho-phthalates reacted smoothly affording cyclic dimers in good yields. In all the reactions studied, the E isomers of the macrocycles were obtained in excess.

Full text of DOI:10.1016/j.tetlet.2007.02.099

Tetrahedron Letters 48 (2007) 2851–2855
Synthesis of cholaphanes by ring closing metathesis
Dorota Czajkowska and Jacek W. Morzycki*
Institute of Chemistry, University of Bialystok, al. Pilsudskiego 11/4, 15-443, Poland
Received 12 January 2007; revised 9 February 2007; accepted 22 February 2007
Available online 25 February 2007
Abstract—The synthesis of cholaphanes by ring closing metathesis (RCM) of 3a,7a,12a,24-tetraol allyl derivatives, obtained from
cholic acid, was attempted. The reactions of tetraol 3,24-diallyl ether or 3,24-diacrylate were not satisfactory. However, diallyl deriv-
atives of disteroidal 3,30- or 24,240-ortho-phthalates reacted smoothly affording cyclic dimers in good yields. In all the reactions stud-
ied, the E isomers of the macrocycles were obtained in excess.
Ó 2007 Elsevier Ltd. All rights reserved.
Dimeric steroids with or without spacer groups can be
used as chiral building blocks to construct artificial
receptors and can serve as architectural components
in molecular recognition chemistry.1 The most valuable
steroid unit used for the synthesis of dimers is cholic
acid or its derivatives.2 There are several structural fea-
tures which render cholic acid, an inexpensive natural
product, an ideal building block for artificial enzymes.
One of them is the rigidity of the steroid framework
that insures the formation of a cavity. The cis-junction
of rings A and B imparts a curvature to the ring sys-
tem required for the synthesis of the cyclic dimers: cyc-
locholates or cholaphanes, the latter bearing spacer
groups between the two steroid units. A very impor-
tant feature of cholic acid congeners is that the two
faces of the steroid differ significantly in polarity. The
more polar a face with hydroxyl groups is able to form
hydrogen bonds with a guest molecule, while the b face
is entirely hydrophobic. Therefore, various chola-
phanes have been used as host molecules in biomimetic
chemistry.
3,24-diallyl derivative 3 (Scheme 1). However, this reac-
tion proved rather difficult to perform successfully. The
starting molecule has two ends of similar reactivity and
both head-to-tail and head-to-head connections between
the two steroid units are possible. In addition, larger
rings consisting of three or more units or a linear poly-
mer may be formed. Another problem, common for all
cross metathesis reactions, is the formation of E and Z
isomer mixtures.5
In the first experiment, tetraol 3,24-diallyl 3 ether was
treated with Grubbs’ second generation catalyst, how-
ever, no metathesis products were formed. The reason
was fast isomerization of the allyl ethers to vinyl ethers
under the reaction conditions.6 Apparently, catalysis of
this transformation by the Grubbs II complex is more
efficient than promotion of the metathesis reaction.
Replacement of the catalyst with the much cheaper first
generation Grubbs’ complex proved successful.7 The
reaction afforded a homogenous product by TLC; the
mass spectrum showed a molecular ion corresponding
1
to the cyclic dimer, but H NMR analysis showed that
Cholaphanes have been synthesized by numerous meth-
ods, preferably by macrolactonization3 or macrolacta-
mization.4 However, olefin metathesis, to the best of
our knowledge, has not yet been applied to the synthesis
of cholaphanes. A series of macrocyclic ethers composed
of two steroid units was designed. A synthesis of these
compounds from tetraol 2, obtained by the reduction
of cholic acid 1, was attempted via metathesis of its
the product was a complex mixture of isomers. In order
to reduce the number of isomers, the crude product
was hydrogenated and an inseparable mixture of
head-to-tail and head-to-head cyclic dimers A and B
was obtained.
The metathesis of tetraol 3,24-diacrylate was also briefly
studied. However, the reaction was rather sluggish and
also afforded a complex mixture of products.
*
To avoid the formation of regioisomers, we instead
Corresponding author. Tel.: +48 85 7457585; fax: +48 85 7457581;
e-mail: morzycki@uwb.edu.pl
prepared 3,30-disteroidal ortho-phthalate 8. The tetraol
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.099

2852
D. Czajkowska, J. W. Morzycki / Tetrahedron Letters 48 (2007) 2851–2855
HO
HO
OH
O
LiAlH4
85%
NaH
cholic acid
allyl bromide
46%
1
HO
OH
O
OH
H
H
3
2
OH
OH
OH
OH
OH
O
+
O
O
O
O
O
O
1. Grubbs I
(8 mol%)
2. H2, Pd/C
60%
O
OH
OH
OH
dimer A
dimer B
Scheme 1.
O
O
HO
HO
OMe
OMe
TBDMS-Cl
imidazole
MeOH/H+
95%
1
92%
HO
OH
TBDMS-O
OH
H
H
4
5
HO
HO
OH
O
1. NaH,
allyl bromide, 62%
LiAlH4
87%
TBDMS-O
2. n-Bu4N+ F-, 85%
OH
HO
OH
H
H
7
6
O
O
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
O
Grubbs I
O
O
O
(25 mol%)
72%
DCC
DMAP
66%
O
O
OH
OH
OH
8
C:8:1 E/Z
Scheme 2.
24-monoallyl derivative 7 was obtained as outlined in
was obtained with the E isomer predominating
Scheme 2.
(E:Z = 8:1).
The 1,3-dicyclohexylcarbodiimide (DCC) method was
used for regioselective esterification with phthalic anhy-
dride at the 3a-OH. The RCM was promoted by the first
generation Grubbs’ catalyst and the reaction was very
efficient. However, a mixture of geometric isomers (C)
This result was rather unexpected since molecular mod-
eling studies showed a slight preference for the Z isomer
(Table 1). It is also evident from calculations that for the
smaller macrocycles (prepared from the nor- or bis-
nortetraol, vide infra) the difference in the steric energies

D. Czajkowska, J. W. Morzycki / Tetrahedron Letters 48 (2007) 2851–2855
Table 1. Calculated steric energies (kcal/mol) of dimersa
2853
Ozonolysis of the double bond followed by LiAlH4
reduction afforded 23,24-bisnortetraol 18. This com-
pound was regioselectively allylated at 22-OH and then
treated with 0.5 equiv of phthalic anhydride to give 20.
The RCM of ortho-phthalate 20 using Grubbs I catalyst
yielded the desired macrocycle. However, even in this
case the reaction was not stereoselective. The E isomer
once again dominated in the mixture of cyclic dimers
E (E:Z = 2.8:1).
Macrocycle size
E
Z
DG (E ꢀ Z)
38-Membered (normal)
36-Membered (nor)
34-Membered (bisnor)
38-Membered
115.55
114.79
113.80
116.19
115.10
113.30
111.12
117.61
0.45
1.49
2.68
ꢀ1.42
(side-chain ortho-phthalate)
a HyperChem for Windows, Release 7.5, from Hypercube, Inc.; mini-
mizations employed the MM+ force field and the Polak-Ribiere
˚
algorithm with RMS gradient 0.001 kcal/A mol.
In all the RCM reactions the less thermodynamically
stable E isomers were formed in excess. It seems that
metathetic macrocyclization is not reversible and the
reaction is under kinetic control.
between the E and Z isomers increases. Therefore, the Z
stereochemistry would be expected for the RCM reac-
tions leading to macrocycles of smaller size.
We also attempted the RCM of 24,240-disteroidal ortho-
phthalate 23 with allyl groups attached to the ring A
oxygen atoms. The synthesis of 23 (Scheme 5) consisted
of selective protection of the side chain hydroxyl group
followed by allylation at the 3a position. The protecting
group was removed and 24,240-disteroidal ortho-phtha-
late 23 was prepared using the same method as described
above. The RCM reaction proceeded smoothly leading
to E and Z cyclic dimers F in the ratio 5:3. Molecular
modeling studies also showed preference for the E iso-
mer in this case. The difference in steric energies
amounted to 1.4 kcal/mol.
Triacetoxy-24-norcholic acid 11a was prepared from
cholic acid by the known Barbier–Wieland procedure.8
Its LiAlH4 reduction afforded 24-nortetraol 12, which
was regioselectively allylated at 23-OH. Next, the corre-
sponding 3,30-disteroidal ortho-phthalate 14 was pre-
pared and subjected to RCM with the Grubbs I
catalyst (Scheme 3). The reaction proceeded smoothly
to afford an E,Z isomeric mixture of cyclic dimers D
in the ratio 3:1.
23,24-Bisnortetraol 18 was obtained by LiAlH4 reduc-
tion of triacetoxy-23,24-bisnorcholic acid 11b prepared
by a double Barbier–Wieland approach. Alternately,
cholic acid was subjected to a decarboxylation/dehydro-
genation procedure leading to 22-olefin 16 (Scheme 4).9
The constrained disteroidal ortho-phthalate systems
readily undergo RCM promoted by the Grubbs’ first
generation catalyst. The 34–38 membered cyclic dimers
Ph
Ph
n
OH
HO
AcO
AcO
O
Ph
Ph
OH
PhMgBr
Ac2O
CrO3
4
AcOH
AcO
OAc
HO
OH
AcO
OAc
H
H
H
9
11a (n = 1)
b (n = 0)
10
HO
HO
O
OH
t
-BuOK
LiAlH4
allyl bromide
58%
HO
OH
HO
OH
H
H
12 (30% from 4)
13
O
OH
OH
O
O
OH
OH
O
O
OH
OH
O
O
O
O
Grubbs I
O
O
O
(25 mol%)
O
77%
DCC
DMAP
63%
O
O
OH
OH
14
D: 3:1 E/Z
Scheme 3.

2854
D. Czajkowska, J. W. Morzycki / Tetrahedron Letters 48 (2007) 2851–2855
O
O
H
O
H
O
OH
O
C
O
C
O
C
H
O
Pb(OAc)4
Cu(OAc)2
HCOOH
68%
1. O3
1
cat. Py
83%
2. Me2S
47%
O
H
O
H
O
H
O
H
O
H
O
H
O
O
C
O
O
C
C
O
O
C
C
C
H
H
H
15
16
17
HO
HO
O
OH
LiAlH4
73%
t
-BuOK
allyl bromide
49%
HO
OH
HO
OH
H
H
18
19
O
OH
OH
OH
OH
O
O
OH
O
O
O
OH
O
O
O
Grubbs I
O
O
O
O
(25 mol%)
O
82%
DCC
DMAP
60%
O
OH
OH
20
E: 2.8:1 E/Z
Scheme 4.
HO
HO
O-TIPS
OH
TIPS-Cl
imidazole
1.
t
-BuOK,
allyl bromide, 43%
2
2. n-Bu4N+ F-, 81%
DMAP
52%
HO
OH
O
OH
H
H
21
22
O
OH
OH
OH
OH
OH
OH
O
O
O
O
O
O
Grubbs I
O
O
O
O
O
(25 mol%)
O
75%
DCC
DMAP
74%
O
O
OH
OH
23
F: 5:3 E/Z
Scheme 5.
were obtained in good yields. It is likely that hydrogen
bonds between the hydroxyl groups of the two steroid
units of the ortho-phthalates allow them to attain the
suitable conformation for cyclization. However, a seri-
ous drawback of the method is the formation of E and
Z isomeric mixtures. In all the cases studied the E iso-
mers predominated as in the cross metathesis reactions.
The problem of formation of isomers can be, of course,
overcome by hydrogenation of the newly formed double
bond.
Acknowledgment
This work was supported by the Polish State Committee
for Scientific Research (Grant No. 3 T09A 013 27).

D. Czajkowska, J. W. Morzycki / Tetrahedron Letters 48 (2007) 2851–2855
2855
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