Cyclocholates with 12-Oxo and 7,12-Oxo Groups

Article abstract of DOI:10.1002/(SICI)1099-0690(199804)1998:4<719::AID-EJOC719>3.0.CO;2-F

Syntheses of bile acid cyclooligomers with 12- and 7,12-oxo groups (6a-d, 7a-c, 8a-b) by the Yamaguchi method are described. Cyclotrimerization is the principal reaction route for these cholic acid systems. Conversion of 7- and 12-hydroxy groups in cholic acid (la-b) to oxo groups (4a-c, 5a-c), followed by macrocyclization (6a-d, 7a-c, 8a-b) and selective reduction of the oxo groups back to hydroxy ones without cleaving the 24-carboxylic ester linkages (11) constitutes a new strategy in the synthesis of cyclocholates having unprotected hydroxy groups.

Full text of DOI:10.1002/(SICI)1099-0690(199804)1998:4<719::AID-EJOC719>3.0.CO;2-F

FULL PAPER
Synthesis of Cyclocholates and Derivatives, III[᭛]
Cyclocholates with 12-Oxo and 7,12-Oxo Groups
Hongwu Gao and Jerry Ray Dias*
Department of Chemistry, University of Missouri Ϫ Kansas City,
Kansas City, MO 64110-2499, USA
E-mail: diasgp@cctr.umkc.edu
Received October 7, 1997
Keywords: Steroids / Cyclocholates / Supramolecular chemistry / Sodium borohydride reduction
Syntheses of bile acid cyclooligomers with 12- and 7,12-oxo
groups (6a؊d, 7a؊c, 8a؊b) by the Yamaguchi method are selective reduction of the oxo groups back to hydroxy ones
described. Cyclotrimerization is the principal reaction route without cleaving the 24-carboxylic ester linkages (11) consti-
5a؊c), followed by macrocyclization (6a؊d, 7a؊c, 8a؊b) and
for these cholic acid systems. Conversion of 7- and 12-hy- tutes a new strategy in the synthesis of cyclocholates having
droxy groups in cholic acid (1a؊b) to oxo groups (4a؊c, unprotected hydroxy groups.
Introduction
Results and Discussion
Preparation of Monomers for Dimerization and Cyclization
For more than a century, synthetic chemists have demon-
strated their ability to construct molecules capable of fulfil-
ling a huge variety of requirements. Recently, the synthesis
of taylor-made dimeric and oligomeric steroids has become
of interest because of their possible application as bio-
chemical/cellular membrane models and as components in
molecular engineering.[1][2] Initially, the synthesis of dimeric
steroids occurred as accidental byproducts and then were
produced by design.[2] Of the dimeric steroids with various
inter-steroid linkages, ring AϪring A connections are ob-
served to be the most prevalent whereas ring CϪring C con-
nections are least. For example, Pettit and co-workers[3] iso-
lated a ring AϪring A steroid dimer byproduct during their
total synthesis of bufalitoxin and bufotoxin, and more re-
cently Gouin and Zhu[4] synthesized several ring AϪring A
steroid dimers by design. The synthesis of oligomeric ster-
oids, in general, poses many undefined parameters requir-
ing investigation. Toward defining these parameters, our re-
cent syntheses directed toward evaluating the effect of the
12- and 7,12-oxo groups on macrocyclization reactions of
cholic acid derivatives are described in this paper. Our pre-
vious macrocyclization studies used acetate esters to protect
the 7α-OH and 12α-OH groups. Here we show an alterna-
tive strategy which involves converting these hydroxy
groups in cholic acid monomers to oxo groups and after
macrocyclization these oxo groups are reduced back to
hydroxy groups with NaBH4 without disrupting the 24-car-
boxylic ester linkages. It is well known that NaBH4 re-
duction of the 7-oxo gives 7α-OH[5][6] and reduction of the
12-oxo frequently gives both 12α- and 12β-OH.[7][8] The ef-
fect of cholic acid macrocyclization on NaBH4 reduction of
these oxo groups has been delineated by this study.
Cholic acid and deoxycholic acid (1a, b, Scheme 1) were
methylated in methanol previously treated with acetyl chlo-
ride to give 2a, b. The 3α-hydroxy groups of 2a, b was selec-
tively reacted with excess ethyl chlorocarbonate in pyridine
per the method of Fieser etal.[9][10] affording the 3-car-
bethoxy derivatives 3a, b in good yield. A simple one-pot
selective 3α-acetylation of cholic and deoxycholic acid by
transesterification with acetate esters (ethyl, propyl, or bu-
tyl) in the presence of catalytic amount of p-TsOH and
water was recently reported by Kuhajda and coworkers.[11]
The selective diacetylation of compound 3b at the 3α- and
7α-position[9][10] gives the 3α,7α-diacetoxy-12α-hydroxy
compound 3c. Oxidation of this product with potassium
chromate[9][10] afforded methyl 3α,7α-diacetoxy-12-oxo-5β-
cholan-24-oate (4c). The same oxidation on 3a gave a mix-
ture of 7,12-dioxo (4a) and 7-oxo-12α-hydroxy product.
JonesЈ oxidation gave more satisfactory results. The 3α-car-
bethoxy group and methyl ester were easily removed by re-
fluxing 4a, b with alkali (3  NaOH) under formation of
5a, b. The selective hydrolysis of 3α-OAc and methyl ester
of 4c to 5c was achieved by refluxing with saturated sodium
carbonate in methanol and THF for five hours as described
by our early reports on similar compounds.[12]
Dimerization
The dimerization of 4c with hydrazine and ethylenedi-
amine was first attempted with BortoliniЈs method without
success.[13] In 1982, Chang and Iida reported a procedure
to convert compound 4c into 3α,7α-diacetoxy-12-oxochol-
anoate tosylhydrazone 9 (Scheme 2).[14] Employing equiva-
lent reaction conditions, we obtained the bishydrazone di-
mer 10 with hydrazine but no monomeric hydrazone prod-
Part II: Ref.[18]
.
[᭛]
Eur. J. Org. Chem. 1998, 719Ϫ724
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0404Ϫ0719 $ 17.50ϩ.50/0
719

H. Gao, J. R. Dias
FULL PAPER
Scheme 1
Scheme 2
viously observed in the cyclizations of 7-deoxycholic acid
derivatives.[12][19] The synthesis of the cholaphane cyclodi-
mer of cholic acid with aromatic spacer groups is reported
by Bonar-Law and Davis.[20] The low synthesis yield of
tetramer(6c: 8%, 7c: 10%) is consistent with our cyclization
results of lithocholic acid.[21] Large scale cyclization of 5a
also permitted isolation of some cyclopentamer 6d.
Cmpds.
R1
R2
n
yield (%)
1a؊2a
1b؊2b
3a
Ϫ
Ϫ
OH
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ, 96
Ϫ, 94
80
H
NaBH4 Reduction
EtOCO2
OH
3b
EtOCO2
H
86
In 1958, Wheeler and Mateos reported the reactivity of
ketones at different positions in the steroid nucleus towards
NaBH4.[22][23] They found the following order of reactivi-
ties: ∆5-3-oxo > ∆8(14)-3-oxo > 3-oxo(A,B-cis) > 3-oxo(A,B-
trans) > 6-oxo > 7-oxo > ∆4-3-oxo > 12-oxo > 17-oxo >
20-oxo > 11-oxo. In the 5β-H series reduction of 7-ketocho-
lanic acid gives a 75Ϫ85% of 7α-hydroxy-cholanic acid with
only traces of the 7β-ol.[5][6] When 12-oxocholanoic acids
were reduced by NaBH4, a 12-hydroxy epimeric mixture in
which the 12β/12α ratio of ca. 0.55 was obtained.[7][8] The
tert-butylamineborane reagent reduced 12-oxocholanic ac-
ids to an epimer mixture having a 12β/12α ratio of ca. 3.7.
In this work, the reduction of 7,12-dioxo group in cyclo-
trimer 6b gave mainly cyclotrimer 11 (69% yield) having
7α,12α-dihydroxy groups on each mer (Scheme 3). The con-
figurations of 7,12-dihydroxy groups were established by
3c؊4c
4a
OAc
H, OAc
ϭO
86, 94
81
EtOCO2
4b
EtOCO2
H, H
ϭO
85
5a
Ϫ
؊
؊
Ϫ
Ϫ
Ϫ
92
5b
H, H
H, OAc
ϭO
Ϫ
Ϫ
94
5c
95
6a؊6d
7a؊7c
8a؊8b
2, 3, 4, 5
2, 3, 4
2, 3
5, 38, 8, 3
18, 32, 10
9, 35
H, H
H, OAc
uct. Examination of Dreiding models shows that while both
the s-trans and s-cis conformation have maximum N-N or-
bital overlap, the s-trans has a minimal steric interaction,
whereas s-cis conformation has greater steric repulsion. Al-
though high energy barriers may limit the rotation of NϪN
bond, it is possible that the (ZЈ-Z), (ZЈ-E) and (EЈ-E) iso-
mers are interchangeable through an in-plane conversion
via pseudorotation.[15]
1
the H NMR chemical shifts. With 7α- and 12α-hydroxy
groups, 7β- and 12β-H have chemical shifts around δ ϭ
Cyclization
The cyclooligomers were prepared from appropriately
prepared monomeric hydroxy acids 5a؊c by Yamaguchi
macrolactonization[16][17][18] using 2,6-dichlorobenzoyl
chloride as the coupling agent (Scheme 1). Cyclotrimeri-
zation of 5a؊c is preferred over cyclodimerization and
cyclotetramerization. Because the 7-oxo and 12-oxo groups
exhibit reduced steric effects, cyclodimers (6a: 5%, 7a: 18%,
8a: 9%) were also obtained. The cyclodimers were pre-
Scheme 3
720
Eur. J. Org. Chem. 1998, 719Ϫ724

Synthesis of Cyclocholates and Derivatives, III
FULL PAPER
3.96. With 7β- and 12β-hydroxy groups, 7α- and 12α-H information to gauge the influence of steroid skeleton sub-
would have chemical shifts around δ ϭ 3.40.[8] The prefer- stituents on the remaining proximate carbon positions. For
ence for production the tris-7α,12α-dihydroxy isomer results example, in going from a 12-OAc to a 12-oxo group, C-13
because the NaBH4 attack occurs from the outer perimeter shifted from δ ϭ 45.1 to 53.1. Thus, one should expect C-
of the cyclotrimer for steric reasons. These results should 11 to be shifted by a similar value, namely, approximately
be compared to the 3% yield of 11 obtained by direct mac- 8 ppm; in actuality it was shifted from δ ϭ 25.6 to 37.6 or
rocyclization of cholic acid.[16]
by 12 ppm. Similarly, C-17 shifted from δ ϭ 47.2 to 57.1,
and we determined that C-9 shifted from δ ϭ 28.9 to 35.5.
Comparison of the 13C-NMR spectra of 7,12-diacetyl-[20]
and 7-acetyl-12-oxo-cyclotricholate (8b) showed that all the
respective chemical shift differences, by-and-large, were <1
ppm except for the following: C-11, 25.8 to 37.8; C-12, 75.7
to 213.4; C-13, 45.0 to 53.3; C-14, 44.1 to 45.7; C-17, 46.1
to 57.0; C-18, 12.3 to 11.3; C-21, 17.3 to 18.4. Comparison
of the 13C-NMR spectra of 7-acetyl-12-oxo-cyclotricholate
(8b) and 7,12-dioxo-cyclotricholate (6b) showed that all the
respective chemical shift differences, by-and-large, were <1
ppm except for the following: C-15, 23.71 to 25.06; C-9,
37.59 to 44.37; C-6, 31.83 to 44.92; C-8, 38.03 to 45.17; C-
5, 40.29 to 45.37; C-14, 45.71 to 48.92; C-7, 70.72 to 209.09.
Except for minor variation in 13C-NMR assignments, the
NMR spectra of 7b agree with previously published
ones.[24]
1H-NMR Spectra
The C20-methyl group shows a doublet because of spin-
spin coupling with a hydrogen at 20-carbon. After oxi-
dation of 12α-OH to the 12-oxo group, C18-H and C19-H
became deshielded from δ ϭ 0.68 to 1.03 and δ ϭ 0.90 to
1.03, respectively; the C21-H shifts upfield from δ ϭ 0.97 to
0.85 because the conformation of the 17-sidechain places
these protons within the shielding zone of the 12-carbonyl
group. After the 12-oxo in 5c is transformed to a 12-hydra-
zone moiety in 9, the 18-methyl and 19-methyl groups un-
dergo an upfield shift from δ ϭ 1.03 to 0.80 and δ ϭ 1.03
to 0.95, respectively, and the 21-methyl becomes further
shielded (δ ϭ 0.85 shifts to 0.62) because of the added effect
of diamagnetic anisotropy of the aromatic ring-current.
This ring-current effect is absent in 10. The C11 α-carbonyl
protons are coupled to the C9 axial proton and appear as a
doublet of doublet near δ ϭ 2.5. After regeneration of 12α-
OH, C18-H, and C19-H are shielded from δ ϭ 1.08 to 0.70
and δ ϭ 1.08 to 0.85, respectively. Upon hydrolysis of the
3α-carbethoxy, the geminal 3β-hydrogen becomes shifted
upfield from δ ϭ 4.53Ϫ4.56 to 3.61Ϫ3.69. After hydrolysis
of 3α-OAc, the geminal 3β-hydrogen shifts upfield from δ ϭ
4.58 to 3.48. Generally, the chemical shifts of the same func-
tional groups on two different monomers overlap. This can
be demonstrated by integrations. Compared with cholic
acid system, the same functional groups of deoxycholic acid
system shift to the lower field.
Table 1. 13C NMR (CDCl3) of 3α-hydroxy-7α-acetoxy-12-oxo-5β-
cholan-24-oic acid derivatives
Assignment
4c
10
8a
8b
C-18
11.52
18.56
21.41
21.41
22.14
23.78
26.57
27.39
30.50
31.24
31.36
34.57
34.92
34.92
35.54
35.54
37.60
37.89
40.52
46.39
53.13
57.13
51.49
70.54
73.57
170.19
170.67
174.60
213.98
12.44
19.96
21.42
21.67
22.38
23.90
27.29
27.60
30.87
31.56
31.99
34.98
34.98
35.61
35.85
36.21
36.21
38.09
40.94
47.32
51.67
53.78
51.59
70.96
73.99
169.94
170.37
174.49
184.56
11.28
20.81
21.81
Ϫ
11.34
18.44
21.29
Ϫ
C-21
CH3CO (ax.)
CH3CO (eq.)
C-19
23.47
23.47
25.58
26.87
29.89
31.35
31.35
33.84
34.81
35.54
37.42
37.42
37.89
38.04
40.26
43.12
52.67
56.35
Ϫ
22.03
23.71
26.38
27.71
30.69
31.19
31.83
34.49
34.82
34.82
35.84
37.59
37.76
38.03
40.29
45.71
53.31
56.99
Ϫ
C-15
C-2
C-16
C-23
C-22
C-6
C-10
13C-NMR Spectra
C-1
C-4
Within a steroid family, a given substituent produces
similar effects on the 13C-NMR chemical shifts of carbons
at and near the site of substitution. Thus, a very useful ap-
C-20
C-9
C-11
C-8
proach in spectral assignments is through comparison of C-5
C-14
closely related compounds. Previously we have noted that
C-13
the 13C-NMR chemical shifts for C-20 of most cholanes
C-17
were least variable and occurred around δ ϭ 35±1.[21] Ad-
OCH3
C-7
71.06
72.47
Ϫ
170.36
174.01
211.55
70.72
72.92
Ϫ
169.83
173.70
213.38
ditionally, since the 17-sidechain of cyclocholates undergoes
C-3
a major change in flexibility and molecular tension as the
cycle size goes from cyclodimer to cyclotetramer, the largest
13C-NMR chemical shift differences with changes in cycle
size occur in the C-17 and C-20 to C-24 carbons.[21] In com-
parison of the 13C NMR, significant deshielding of the C-
20 and C-21 carbons occurred in the cyclodimer 8a relative
to the cyclotrimer 8b and 10. The 12-carbonyl has a strong
deshielding effect on C-9, C-11, C-12, C-13, and C-17. Be-
C2H5CO (eq.)
C2H5CO (ax.)
C-24
C-12
Mass Spectra
All these spectra have the peaks for loss of 3α-functional
cause the high field chemical shifts for C-18, C-21, and C- groups and the 17-sidechain. For all the intermediates, the
19 and the chemical shifts for C-14, C-13, and C-17 are 17-sidechain can be lost before or after the 3α-functional
well separated from the other 13C-NMR peaks, their peak group is lost; while the 3α-OH is always lost after 7α-OH,
assignment is more easily done and allows one to use this the 3α-carbethoxy can be lost before or after the 7α-OH
Eur. J. Org. Chem. 1998, 719Ϫ724
721

H. Gao, J. R. Dias
FULL PAPER
Table 2. 13C NMR (CDCl3) of 3α-hydroxy-12-oxo-5β-cholan-24-
Conclusion
oic acid derivatives
Nine bile acid cyclooligomer analogs with 12-oxo and
7,12-dioxo have been synthesized by Yamaguchi Method
and characterized by 1H NMR, 13C NMR, MS spec-
troscopy. Under Yamaguchi reaction conditions, the 12-oxo
and 7,12-dioxo derivatives of cholic acid give mainly cyclic
trimer products. A new synthetic strategy for the pro-
duction of cyclotricholates with unprotected 7α,12α-di-
hydroxy groups has been demonstrated.
Assignment
4b
7a
7b
7c
C-18
CH3CH2O
C-21
C-19
C-15
C-16
C-7
C-2
C-6
C-23
C-22
C-4
11.71
14.31
18.62
22.75
24.38
26.02
26.38
27.00
27.54
30.57
31.31
32.15
34.89
35.36
35.68
(35.68)
38.09
41.42
44.03
46.52
57.50
58.60
51.43
63.62
76.66
154.63
174.60
214.31
11.39
Ϫ
11.51
Ϫ
11.68
Ϫ
19.57
22.78
24.10
26.01
26.53
27.21
27.81
28.36
30.18
32.00
35.15
35.52
35.94
(35.94)
37.95
41.10
43.40
43.89
57.17
58.69
Ϫ
18.53
22.72
24.28
25.99
26.36
26.91
27.69
30.17
30.85
32.19
34.98
35.33
(35.33)
35.64
38.06
41.33
43.95
45.22
57.40
58.68
Ϫ
18.54
22.72
24.39
26.01
26.32
26.92
27.75
30.89
(30.89)
32.17
34.95
35.34
35.68
(35.68)
38.07
41.22
44.07
45.22
57.48
58.87
Ϫ
We gratefully thank the Nebraska Center for determining Mass
Spectrometry.
Experimental Section
C-10
C-8
C-1
Column chromatography was carried out using Grade 62
(60Ϫ200 mesh) silica gel and eluted by hexane/ethyl acetate solvent
system. Melting points were determined on a Fisher-Johns melting-
C-20
C-11
C-9
1
point apparatus and are uncorrected. Ϫ H-NMR and 13C-NMR
spectra were measured at 250 MHz and 63 MHz (Bruker) in CDCl3
as solvent and TMS as internal standard. Ϫ Mass spectra were
recorded on a VG20-253 or VGZAB-HS Spectrometer. Ϫ All new
products were homogeneous by TLC, NMR, and mass spec-
troscopy.
C-5
C-13
C-17
C-14
OCH3
CH3CH2O
C-3
Ϫ
74.35
Ϫ
176.47
214.38
Ϫ
73.36
Ϫ
173.98
214.19
Ϫ
73.36
Ϫ
173.56
214.25
Methyl 3-Carbethoxy-7Ͱ,12Ͱ-dihydroxy-5β-cholan-24-oate (3a):
Methyl cholate 2a was prepared by published method[10]. Yield:
96%, m.p. 153Ϫ155°C (ref.[10] m.p. 156Ϫ157°C). Ϫ 1H NMR
(CDCl3): 0.67 (s, 3 H, 18-H3); 0.88 (s, 3 H, 19-H3); 0.99 (d, 3 H,
21-H3); 3.43 (broad, 1 H, 3β-H); 3.66 (s, 3 H, COOCH3); 3.82 (s,
1 H, 7β-H); 3.94 (s, 1 H, 12β-H).
EtOCO
C-24
C-12
Table 3. 13C NMR (CDCl3) of 3α-hydroxy-7,12-dioxo-5β-cholan-
Compound 3a was prepared by esterification of 2a with ethyl
chloroformate in pyridine[10]. Yield: 80.4%, m.p. 175Ϫ177°C
24-oic acid derivatives
1
(ref.[10] m.p. 176Ϫ177°C). Ϫ H NMR (CDCl3): 0.68 (s, 3 H, 18-
Assignment
4a
6a
6b
6c
6d
H3); 0.90 (s, 3 H, 19-H3); 0.97 (d, 3 H, 21-H3); 3.66 (s, 3 H, CO-
OCH3); 3.85 (s, 1 H, 7β-H); 3.98 (s, 1 H, 12β-H); 4.14 (q, 2 H, 3-
EtOCOO); 4.41 (broad, 1 H, 3β-H). Ϫ MS (EI): 494.3 [M]ϩ· (2),
476.3 [M Ϫ H2O]ϩ· (3), 458.3 [M Ϫ 2 H2O]ϩ·, 404.3 [M Ϫ
C3H6O3]ϩ· (5), 386.2 [M Ϫ H2O Ϫ C3H6O3]ϩ· (29), 368.2 [M Ϫ 2
H2O Ϫ C3H6O3]ϩ· (42), 253 [M Ϫ 2 H2O Ϫ C9H17O5]ϩ (100).
C-18
CH3CH2O
C-21
C-19
C-15
C-2
11.80
14.23
18.59
22.36
25.14
25.75
27.63
30.47
31.27
33.05
33.64
35.52
35.75
38.30
44.86
45.15
45.39
45.58
48.86
51.77
56.81
51.41
63.78
75.97
155.17
174.46
208.92
212.19
11.41
Ϫ
11.62
Ϫ
11.74
Ϫ
11.83
Ϫ
20.87
22.26
25.05
25.10
27.16
29.72
30.14
32.94
33.90
34.94
35.67
38.09
42.21
44.99
(44.99)
45.37
49.07
51.13
56.41
Ϫ
18.53
22.41
25.06
25.77
27.93
30.12
31.01
33.10
33.80
35.40
35.70
38.34
44.37
44.92
45.17
45.37
48.92
51.78
56.74
Ϫ
18.60
22.42
25.08
25.81
27.82
30.66
31.64
33.21
33.81
35.46
35.76
38.36
44.92
45.04
45.22
45.34
48.92
51.77
56.80
Ϫ
18.68
22.46
25.12
25.86
27.60
30.61
31.85
33.21
33.79
35.36
35.85
38.35
44.96
45.25
45.44
(45.44)
48.95
51.79
56.89
Ϫ
C-16
C-23
C-22
C-10
C-1
Methyl 3Ͱ,12Ͱ-Dihydroxy-5β-cholan-24-oate (2b) was prepared
in similar fashion, m.p. 90Ϫ92°C (ref.[10] m.p. 75Ϫ86°C) (93.9%).
1
Ϫ H NMR (CDCl3): 0.67 (s, 3 H, C-18); 0.90 (s, 3 H, C-19); 0.96
(d, 3 H, C-21); 3.60 (broad, 1 H, 3β-H); 3.66 (s, 3 H, COOCH3);
3.98 (s, 1 H, 12β-H).
C-4
C-20
C-11
C-9
Methyl 12Ͱ-Hydroxy-3Ͱ-carbethoxy-5β-cholan-24-oate (3b) was
prepared in similar fashion, m.p. 135Ϫ137°C (ref.[10] m.p.
137Ϫ140°C) (86%). Ϫ 1H NMR (CDCl3): 0.67 (s, 3 H, 18-H3);
0.90 (s, 3 H, 19-H3); 0.98 (d, 3 H, 21-H3); 3.66 (s, 3 H, COOCH3);
3.99 (s, 1 H, 12β-H); 4.16 (q, 2 H, 3-EtOCOO); 4.43 (broad, 1 H,
3β-H). Ϫ MS (EI): 478.3 [M]ϩ· (2), 460 [M Ϫ H2O]ϩ· (5), 388 [M
Ϫ C3H5O3]ϩ· (5), 370 [M Ϫ H2O Ϫ C3H6O3]ϩ· (31), 255 [M Ϫ
H2O Ϫ C9H17O5]ϩ (100).
C-6
C-8
C-5
C-14
C-13
C-17
OCH3
CH3CH2O
C-3
Ϫ
71.75
Ϫ
174.18
208.46
210.69
Ϫ
72.04
Ϫ
173.67
209.09
211.89
Ϫ
72.10
Ϫ
173.56
208.88
212.13
Ϫ
72.18
Ϫ
173.59
209.13
212.34
Methyl 3Ͱ,7Ͱ-Diacetoxy-12Ͱ-hydroxy-5β-cholan-24-oate (3c):
Compound 3c was prepared by esterification of 2a with acetic an-
hydride[10]. Yield: 86%, m.p. 183Ϫ185°C (ref.[10] m.p. 187Ϫ188°C).
EtOCO
C-24
C-7
1H NMR (CDCl3): 0.68 (s, 3 H, 18-H3); 0.92 (s, 3 H, 19-H3);
C-12
Ϫ
0.97 (d, 3 H, 21-H3); 2.02 (s, 3 H, 3-OAc); 2.03 (s, 3 H, 7-OAc);
2.3 (m, 2 H, 23-H2); 3.66 (s, 3 H, COOCH3); 3.99 (s, 1 H, 12β-H);
4.58 (broad, 1 H, 3β-H); 4.89 (s, 1 H, 7β-H). Ϫ MS (EI): 506 [M]ϩ·
(1), 446 [M Ϫ HOAc]ϩ· (3), 428 [M Ϫ HOAc Ϫ H2O]ϩ· (11), 386
[M Ϫ 2 HOAc]ϩ· (10), 368 [M Ϫ 2 HOAc Ϫ H2O]ϩ· (38), 253 [M
Ϫ 2 HOAc Ϫ H2O Ϫ C6H11O2]ϩ (100).
and 12α-OH. Three kinds of FAB mass spectral peaks
[MNa ϩ NaI]ϩ, [MNa]ϩ, [M ϩ H]ϩ were present in all
spectra.
722
Eur. J. Org. Chem. 1998, 719Ϫ724

Synthesis of Cyclocholates and Derivatives, III
FULL PAPER
Methyl 3Ͱ-Carbethoxy-7,12-dioxo-5β-cholan-24-oate (4a):
A
Cyclodimer 6a: m.p. 305Ϫ307°C, yield: 5%. Ϫ 1H NMR
solution of 3a (25 g, 50.6 mmol) in acetone (300 ml) was treated (CDCl3): 0.87 (d, 6 H, 21-H3, 21Ј-H3); 1.01 (s, 12 H, 18-H3, 18Ј-
with JonesЈ reagent (27 ml) as it was being magnetically stirred and H3; 19-H3, 19Ј-H3); 2.33 (m, 4 H, 11-H2, 11Ј-H2); 2.74 (dd, 4 H, 6-
chilled on an ice bath. After complete addition of the JonesЈ re-
H2, 6Ј-H2); 2.88 (m, 2 H, 8-H, 8Ј-H); 4.80 (m, 2 H, 3β-H, 3Јβ-
agent, the ice bath was removed and stirring continued at rt for 10 H). Ϫ FAB/MS (3-NBA): 773.3 [Mϩ1]ϩ, 755.4 [M ϩ 1 Ϫ H2O]ϩ,
min and then it was quenched with 2-propanol (30 ml). The solu-
tion was concentrated and diluted with water and extracted with
ethyl acetate. The ethyl acetate was washed with NaHCO3 and
NaCl solutions, dried with Na2SO4, and concentrated under re-
duced pressure to afford 4a (20 g, 80.6%): m.p. 135Ϫ137°C (ref.[10]
m.p. 137Ϫ138°C). Ϫ 1H NMR (CDCl3): 0.83 (d, 3 H, 21-H3); 1.03
(s, 6 H, 18-H3; 19-H3); 2.36 (m, 2 H, 11-H2); 2.71 (dd, 2 H, 6-H2);
2.90 (m, 1 H, 8-H); 3.66 (s, 3 H, COOCH3); 4.14 (q, 2 H, 3-EtO-
COO); 4.53 (broad, 1 H, 3β-H). Ϫ MS (EI): 490.3 [M]ϩ· (19), 472.3
[M Ϫ H2O]ϩ· (19), 400.3 [M Ϫ C3H6O3]ϩ· (15), 359.3 (25), 269.2
(78), 245 (100).
739.3, 723.4.
Cyclotrimer 6b: m.p. 320Ϫ322°C, yield: 38%. 1H NMR (CDCl3):
0.84 (d, 9 H, 21-H3, 21Ј-H3, 21ЈЈ-H3); 1.03 (s, 18 H, 18-H3, 18Ј-H3,
18ЈЈ-H3; 19-H3, 19Ј-H3, 19ЈЈ-H3); 2.30 (m, 6 H, 11-H2, 11Ј-H2, 11ЈЈ-
H2); 2.75 (dd, 6 H, 6-H2, 6Ј-H2, 6ЈЈ-H2); 2.84 (m, 3 H, 8-H, 8Ј-H,
8ЈЈ-H); 4.70 (m, 3 H, 3β-H, 3Јβ-H, 3ЈЈβ-H). FAB/MS (3-NBA ϩ
NaI): 1331.3 [MNa ϩ NaI]ϩ, 1181.6 [MNa]ϩ, 1042.5, 846.7, 469.3.
Cyclotetramer 6c: m.p. 315Ϫ317°C, yield: 8%. 1H NMR
(CDCl3): 0.84 (d, 12 H, 21-H3, 21Ј-H3, 21ЈЈ-H3, 21ЈЈЈ-H3); 1.03 (s,
24 H, 18-H3, 18Ј-H3, 18ЈЈ-H3, 18ЈЈЈ-H3; 19-H3, 19Ј-H3, 19ЈЈ-H3,
19ЈЈЈ-H3); 2.28 (m, 8 H, 11-H2, 11Ј-H2, 11ЈЈ-H2, 11ЈЈЈ-H2); 2.75 (dd,
8 H, 6-H2, 6Ј-H2, 6ЈЈ-H2, 6ЈЈЈ-H2); 2.85 (m, 4 H, 8-H, 8Ј-H, 8ЈЈ-H,
8ЈЈЈ-H); 4.70 (m, 4 H, 3β-H, 3Јβ-H, 3ЈЈβ-H, 3ЈЈЈβ-H). FAB/MS (3-
NBA ϩ NaI): 1718.4 [MNa ϩ NaI]ϩ, 1568.6 [MNa]ϩ, 1425.9,
1181.7, 1039.7, 873.3, 619.1, 469.3, 325.9.
Methyl 3Ͱ-Carbethoxy-12-oxo-5β-cholan-24-oate (4b) was pre-
pared in similar fashion, m.p. 152Ϫ154°C (ref.[10] m.p. 157Ϫ158°C)
(85%). Ϫ 1H NMR (CDCl3): 0.84 (d, 3 H, 21-H3); 1.02 (s, 6 H, 18-
H3; 19-H3); 2.40 (m, 2 H, 11-H2); 3.66 (s, 3 H, COOCH3); 4.16 (q,
2 H, 3-EtOCOO); 4.56 (broad, 1 H, 3β-H). Ϫ MS (EI): 476.3 [M]ϩ·
(33), 458.3 [M Ϫ H2O]ϩ· (3), 386.3 [M Ϫ C3H5O3]ϩ· (69), 231.2
(100).
Cyclopentamer 6d: m.p. 260Ϫ262°C, yield: 3%. Ϫ 1H NMR
(CDCl3): 0.84 (d, 15 H, 21-H3, 21Ј-H3, 21ЈЈ-H3, 21ЈЈЈ-H3, 21ЈЈЈЈ-
H3); 1.03 (s, 30 H, 18-H3, 18Ј-H3, 18ЈЈ-H3, 18ЈЈЈ-H3, 18ЈЈЈЈ-H3; 19-
H3, 19Ј-H3, 19ЈЈ-H3, 19ЈЈЈ-H3, 19ЈЈЈЈ-H3); 2.28 (m, 10 H, 11-H2,
11Ј-H2, 11ЈЈ-H2, 11ЈЈЈ-H2, 11ЈЈЈЈ-H2); 2.75 (dd, 10 H, 6-H2, 6Ј-H2,
6ЈЈ-H2, 6ЈЈЈ-H2, 6ЈЈЈЈ-H2); 2.85 (m, 5 H, 8-H, 8Ј-H, 8ЈЈ-H, 8ЈЈЈ-H,
8ЈЈЈЈ-H); 4.70 (m, 5 H, 3β-H, 3Јβ-H, 3ЈЈβ-H, 3ЈЈЈβ-H, 3ЈЈЈЈβ-H). Ϫ
FAB/MS (3-NBA): 1932.9 [M ϩ 1]ϩ, 1142.9, 755.6, 613.3, 550.7,
419.4, 307.1.
Methyl 3Ͱ,7Ͱ-Diacetoxy-12-oxo-5β-cholan-24-oate (4c): Com-
pound 4c was prepared by oxidation of 3c with potassium chro-
mate[10]. Yield: 94%, m.p. 179Ϫ181°C (ref.[10] m.p. 177Ϫ179°C). Ϫ
1H NMR (CDCl3): 0.85 (d, 3 H, 21-H3); 1.03 (s, 6 H, 18-H3; 19-
H3); 2.02 (s, 3 H, 3-OAc); 2.03 (s, 3 H, 7-OAc); 2.32 (m, 2 H, 23-
H2); 2.5 (dd, 2 H, 11-H2); 3.66 (s, 3 H, COOCH3); 4.58 (broad, 1
H, 3β-H); 4.99 (s, 1 H, 7β-H). Ϫ MS (EI): 504 [M]ϩ· (4), 444 [M
Ϫ HOAc]ϩ· (56), 384 [M Ϫ 2 HOAc]ϩ· (22), 269 [M Ϫ 2 HOAc Ϫ
C6H11O2]ϩ (76), 229 (100).
Cyclodimer 7a: m.p. 145Ϫ147°C, yield: 18%. Ϫ 1H NMR
(CDCl3): 0.93 (d, 6 H, 21-H3, 21Ј-H3); 1.05 (s, 12 H, 18-H3, 18Ј-
H3; 19-H3, 19Ј-H3); 2.49 (m, 4 H, 11-H2, 11Ј-H2); 4.72 (m, 2 H,
3β-H, 3Јβ-H). Ϫ FAB/MS (3-NBA): 745.5 [M ϩ 1]ϩ, 447.3,
355.3, 307.1.
3Ͱ-Hydroxy-7,12-dioxo-5β-cholan-24-oic Acid (5a): To a solution
of 4a (10 g, 20.4 mmol) in CH3OH (120 ml) and THF (120 ml),
NaOH (3 , 180 ml) was added. The solution was refluxed for 10
h. The extra base was neutralized by conc HCl, extracted with ethyl
acetate. The organic layer was washed by NaCl soln., dried with
Na2SO4 and concentrated under reduced pressure to afford 5a (7.6
Cyclotrimer 7b: m.p. 350Ϫ352°C, yield: 32%. Ϫ 1H NMR
(CDCl3): 0.92 (d, 9 H, 21-H3, 21Ј-H3, 21ЈЈ-H3); 1.08 (s, 18 H, 18-
H3, 18Ј-H3, 18ЈЈ-H3; 19-H3, 19Ј-H3, 19ЈЈ-H3); 2.49 (m, 6 H, 11-H2,
11Ј-H2, 11ЈЈ-H2); 4.78 (m, 3 H, 3β-H, 3Јβ-H, 3ЈЈβ-H).[24] Ϫ FAB/
MS (3-NBA): 1117.7 [M ϩ 1]ϩ, 745.5 [2/3M ϩ 1]ϩ, 447.3, 355.3,
289.1.
1
g, 92%): m.p. 185Ϫ187°C (ref.[25] m.p. 192Ϫ193.5°C). Ϫ H NMR
(CDCl3): 0.85 (d, 3 H, 21-H3); 1.03 (s, 6 H, 18-H3; 19-H3); 2.35 (m,
2 H, 11-H2); 2.75 (dd, 2 H, 6-H2); 2.88 (m, 1 H, 8-H); 3.61 (m, 1
H, 3β-H). Ϫ FAB/MS (3-NBA): 405.2 [M ϩ 1]ϩ, 387.2 [M ϩ 1 Ϫ
H2O]ϩ, 369.2 [M ϩ 1 Ϫ 2 H2O]ϩ, 353.2, 307.
Cyclotetramer 7c: m.p. 245Ϫ247°C, yield: 10%. Ϫ 1H NMR
(CDCl3): 0.92 (d, 12 H, 21-H3, 21Ј-H3, 21ЈЈ-H3, 21ЈЈЈ-H3); 1.08 (s,
24 H, 18-H3, 18Ј-H3, 18ЈЈ-H3, 18ЈЈЈ-H3; 19-H3, 19Ј-H3, 19ЈЈ-H3,
19ЈЈЈ-H3); 2.49 (m, 8 H, 11-H2, 11Ј-H2, 11ЈЈ-H2, 11ЈЈЈ-H2); 4.77 (m,
4 H, 3β-H, 3Јβ-H, 3ЈЈβ-H, 3ЈЈЈβ-H). Ϫ FAB/MS (3-NBA): 1490 [M
ϩ 1]ϩ, 1117.8 [3/4M ϩ 1]ϩ, 822.7, 745.5 [1/2M ϩ 1]ϩ, 682.6.
3Ͱ-Hydroxy-12-oxo-5β-cholan-24-oic Acid (5b): was prepared in
similar fashion, m.p. 163Ϫ165°C (94%). Ϫ 1H NMR (CDCl3): 0.91
(d, 3 H, 21-H3); 1.07 (s, 6 H, 18-H3; 19-H3); 2.48 (m, 2 H, 11-H2);
3.69 (s, 1 H, 3β-H). Ϫ MS (EI): 390.3 [M]ϩ· (100), 372.3 [M Ϫ
H2O]ϩ· (39.10), 354.3 [M Ϫ 2 H2O]ϩ· (3), 289.3 [M Ϫ C5H9O2]ϩ·
(12.65), 249.2 (43.23), 231.2 (70.45).
Cyclodimer 8a: m.p. 220Ϫ222°C, yield: 9%. Ϫ 1H NMR
(CDCl3): 0.81 (d, 6 H, 21-H3, 21Ј-H3); 0.97 (s, 12 H, 18-H3, 18Ј-
H3; 19-H3, 19Ј-H3); 2.10 (s, 6 H, 7-OAc, 7Ј-OAc); 2.24 (m, 4 H, 23-
H2, 23Ј-H2); 2.4 (dd, 4 H, 11-H2, 11Ј-H2); 4.60 (m, 2 H, 3β-H, 3Јβ-
H); 5.03 (s, 2 H, 7β-H, 7Јβ-H). Ϫ FAB/MS (3-NBA): 861.4 [M ϩ
1]ϩ, 800.4 [M Ϫ HOAc]ϩ, 447.3, 369.2 [1/2M Ϫ HOAc]ϩ, 353.2,
307, 273. Ϫ C52H76O10 (860): Calcd: C 72.56, H 8.84. Found: C
72.26, H 9.36.
3Ͱ-Hydroxy-7Ͱ-acetoxy-12-oxo-5β-cholan-24-oic Acid (5c): The
[12]
acid 5c was prepared by saponification of 4c with satd Na2CO3
.
1
Yield: 95%, m.p. 240Ϫ242°C. Ϫ H NMR (CDCl3): 0.85 (d, 3 H,
21-H3); 1.03 (s, 6 H, 18-H3; 19-H3); 2.03 (s, 3 H, 7-OAc); 2.3 (m, 2
H, 23-H2); 2.49 (dd, 2 H, 11-H2); 3.48 (broad, 1 H, 3β-H); 4.7
(hump, OHs); 4.98 (s, 1 H, 7β-H). Ϫ MS (EI): 448 [M]ϩ· (6), 388
[M Ϫ HOAc]ϩ· (9), 370 [M Ϫ HOAc Ϫ H2O]ϩ· (41), 205 (100).
General Procedure of Cyclization: A mixture of monomer (3.4
Cyclotrimer 8b: m.p. 310Ϫ312°C, yield: 35%. Ϫ 1H NMR
mmol), 2,6-dichlorobenzoyl chloride (0.53 ml, 3.7 mmol), DMAP (CDCl3): 0.86 (d, 9 H, 21-H3, 21Ј-H3, 21ЈЈ-H3); 1.03 (s, 18 H, 18-
(1.6 g, 13 mmol) and sodium-dried toluene (800 ml) were refluxed H3, 18Ј-H3, 18ЈЈ-H3; 19-H3, 19Ј-H3, 19ЈЈ-H3); 1.98 (s, 9 H, 7-OAc,
for 48 h. The solvent was concentrated under reduced pressure, 7Ј-OAc, 7ЈЈ-OAc); 2.34 (m, 6 H, 23-H2, 23Ј-H2, 23ЈЈ-H2); 2.5 (dd,
the residue was flash chromatographed on a silica gel column and
crystallized to afford cyclooligomers.
6 H, 11-H2, 11Ј-H2, 11ЈЈ-H2); 4.60 (m, 3 H, 3β-H, 3Јβ-H, 3ЈЈβ-H);
4.97 (broad s, 3 H, 7β-H, 7Јβ-H, 7ЈЈβ-H). Ϫ FAB/MS (3-NBA):
Eur. J. Org. Chem. 1998, 719Ϫ724
723

H. Gao, J. R. Dias
FULL PAPER
1291.3 [M ϩ 1]ϩ, 1231.5 [M ϩ 1 Ϫ HOAc]ϩ, 1171.6 [M ϩ 1 Ϫ 2 3.85 (s, 3 H, 7β-H, 7Јβ-H, 7ЈЈβ-H); 3.96 (s, 3 H, 12β-H, 12Јβ-H,
HOAc]ϩ, 1111.7 [M ϩ 1 Ϫ 3 HOAc]ϩ, 1093.7 [M ϩ 1 Ϫ 3 HOAc 12ЈЈβ-H); 4.70 (m, 3 H, 3β-H, 3Јβ-H, 3ЈЈβ-H). Ϫ 13C NMR
Ϫ H2O]ϩ·. Ϫ C78H114O15 (1290): Calcd: C 72.56, H 8.84. Found: (CDCl3): 12.46 (C-18), 17.34 (C-21), 22.58 (C-19), 23.09 (C-15),
C 72.59, H 9.01.
26.63 (C-9), 26.87 (C-16), 27.47 (C-11), 28.45 (C-2), 30.20 (C-22),
30.45 (C-23), 34.14 (C-6), 34.46 (C-10), 34.63 (C-1), 34.92 (C-20),
35.21 (C-4), 39.65 (C-8), 41.13 (C-14), 42.22 (C-5), 45.77 (C-13),
46.46 (C-17), 68.23 (C-7), 72.78 (C-3), 73.81 (C-12), 173.90 (C-24).
Ϫ FAB/MS (3-NBA ϩ NaI): 1344.0 [MNa ϩ NaI]ϩ, 1193.9
[MNa]ϩ, 326.0, 176.1.
Methyl 3Ͱ,7Ͱ-Diacetoxy-12-oxocholanate Tosylhydrazone (9):
Compound 9 was prepared by published method[14]. Yield: 71%,
m.p. 147Ϫ149°C (ref.[14] m.p. 146Ϫ147°C). Ϫ H NMR (CDCl3):
1
0.62 (d, 3 H, 21-H3); 0.80 (s, 3 H, 18-H3); 0.95 (s, 3 H, 19-H3); 2.03
(s, 3 H, 3-OAc); 2.04 (s, 3 H, 7-OAc); 2.45 (s, 3 H, Ar-CH3); 3.67
(s, 3 H, COOCH3); 4.53 (broad, 1 H, 3β-H); 4.90 (s, 1 H, 7β-H); 6.0
(broad, 1 H, -SO2NHNϭ); 7.33 (dd, 2 H, Ar); 7.85 (dd, 2 H, Ar).
[1]
A. P. Davis, Chem. Soc. Rev. 1993, 243.
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Y. X. Li, J. R. Dias, Chem. Rev. 1997, 97, 283.
Dimerization of 4c to Bishydrazone 10: To a stirred solution of
4c (1 g, 2 mmol) in acetic acid (15 ml) was added slowly anhydrous
hydrazine (0.065 ml, 2.1 mmol) while chilling in an ice bath. After
stirring at rt for 24 h, the solution was poured in water (50 ml) and
extracted with ethyl acetate. The combined ethyl acetate was
washed with satd Na2CO3 soln., NaCl soln., dried with Na2SO4,
and evaporated to afforded a residue from which 10 (0.68 g, 68%)
was obtained by chromatography (n-hexane/ethyl acetate, 1:10):
[3]
G. R. Pettit, Y. Kamano, P. Drasar, M. Inoue, J. Knight, J. Org.
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L. F. Fieser, S. Rajagopalan, E. Wilson, M. Tishler, J. Am.
1
Chem. Soc. 1951, 73, 4133.
m.p. 125Ϫ127°C. Ϫ H NMR (CDCl3): 0.96 (d, 6 H, 21-H3, 21Ј-
[10]
L. F. Fieser, S. Rajagopalan, J. Am. Chem. Soc. 1950, 72, 5530.
H3); 0.97 (s, 6 H, 18-H3, 18Ј-H3); 1.04 (s, 6 H, 19-H3, 19Ј-H3); 2.00
(s, 6 H, 3-OAc, 3Ј-OAc); 2.04 (s, 6 H, 7-OAc, 7Ј-OAc); 3.66 (s, 6
H, COOCH3, COOCH3Ј); 4.62 (m, 2 H, 3β-H, 3Јβ-H); 4.99 (broad
s, 2 H, 7β-H, 7Јβ-H). Ϫ FAB/MS (3-NBA): 1005.6 [M ϩ 1]ϩ, 945.5
[M ϩ 1 Ϫ HOAc]ϩ, 885.4 [M ϩ 1 Ϫ 2 HOAc]ϩ, 849.4, 789.4,
502.2 [M/2]ϩ, 442 [M/2 Ϫ HOAc]ϩ, 382.2 [M/2 Ϫ 2 HOAc]ϩ·. Ϫ
C58H88N2O12 (1004): Calcd: C 69.32, H 8.76, N 2.79. Found: C
70.03, H 9.20, N 2.59.
[11]
K. Kuhajda, J. Kandrac, V. Cirin-Novta, D. Miljkovic, Collect.
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H. W. Gao, J. R. Dias, Synth. Commun. 1997, 27, 757.
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[17]
J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi,
Preparation of 11 by Reduction Cyclotrimer 6b: To a stirred solu-
tion of compound 6b (0.1 g, 0.086 mmol) in CH3OH (20 ml) was
added NaBH4 (0.06 g, 1.59 mmol) at 0°C. After the solution was
stirred for 24 h at 0°C, dilute HCl were added to acidify the solu-
tion, the solvent was removed. The residue was dissolved in CHCl3
and washed with water, brine, dried and finally evaporated to dry-
ness. The crude product was purified by column chromatography
to yield 11 (0.07 g, 69%) as a colorless solid: m.p. 258Ϫ260°C. Ϫ
1H NMR (CDCl3): 0.70 (s, 9 H, 18-H3, 18Ј-H3, 18ЈЈ-H3); 0.85 (s, 9
H, 19-H3, 19Ј-H3, 19ЈЈ-H3); 0.90 (d, 9 H, 21-H3, 21Ј-H3, 21ЈЈ-H3);
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
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H. W. Gao, J. R. Dias, New J. Chem., in press.
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Steroids from Steraloids Inc. 11th, 85 (1992).
[97300]
724
Eur. J. Org. Chem. 1998, 719Ϫ724