Synthesis of linear and cyclic dimeric ester derivatives from bile acids and glycine

Article abstract of DOI:10.1081/SCC-120015401

Two novel taylor-made linear and cyclic dimers were synthesized from the inexpensive steroid bile acids and amino acid glycine. The structures and stereochemistry of all intermediates and dimers were determined by means of spectroscopic analyses.

Full text of DOI:10.1081/SCC-120015401

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SYNTHESIS OF LINEAR AND CYCLIC DIMERIC ESTER
DERIVATIVES FROM BILE ACIDS AND GLYCINE
a
a
b
Ze Tian , Hong Cui & Yan Wang
a
Institute of Medicinal Plant, Chinese Academy of Medical Science and Peking Union Medical
College, Beijing, 100094, P.R. China
b
Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union
Medical, Beijing, 100050, P.R. China
Published online: 23 Aug 2006.
To cite this article: Ze Tian , Hong Cui & Yan Wang (2002) SYNTHESIS OF LINEAR AND CYCLIC DIMERIC ESTER DERIVATIVES
FROM BILE ACIDS AND GLYCINE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:24, 3821-3829, DOI: 10.1081/SCC-120015401
To link to this article: http://dx.doi.org/10.1081/SCC-120015401
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 24, pp. 3821–3829, 2002
SYNTHESIS OF LINEAR AND CYCLIC
DIMERIC ESTER DERIVATIVES FROM
BILE ACIDS AND GLYCINE
1
,
1
2
Ze Tian, * Hong Cui, and Yan Wang
1
Institute of Medicinal Plant, Chinese Academy of
Medical Science and Peking Union Medical College,
Beijing 100094, P.R. China
2
Institute of Materia Medica, Chinese Academy of
Medical Science and Peking Union Medical,
Beijing 100050, P.R. China
ABSTRACT
Two novel taylor-made linear and cyclic dimers were synthe-
sized from the inexpensive steroid bile acids and amino acid
glycine. The structures and stereochemistry of all intermedi-
ates and dimers were determined by means of spectroscopic
analyses.
The unique features of the bile acids, such as cholic acid 1 (Sch. 1), in
terms of their chiral, rigid framework and chemically different hydroxyl
groups, have made them well-established ‘engineering components’ for
[
1,2]
supramolecular chemistry.
As a result, considerable efforts have been
*
Corresponding author. E-mail: tianze603@sohu.com
821
3
DOI: 10.1081/SCC-120015401
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3
822
TIAN, CUI, AND WANG
2 2 2 3
Scheme 1. Reagents and conditions: i. EEDQ, H NCH CO Et HCl, Et N, EtOAc,
ꢀ
reflux, 24h, 2: 73%; ii. Ac
ꢀ
2
O, pyridine, DMAP, 23 C, 2 h, 3: 86%; iii. 10%
ꢀ
K CO /H O, EtOH, 23 C, 13 h, 4: 93%; iv. NaOEt/EtOH (1.0 M), 23 C, 1 h, 5:
ꢀ
5%; v. LiOCH /H O (0.2 N), THF, 23 C, 6 h, 6: 93%; vi. DCBC, DMAP, toluene,
3 2
2
3
2
7
reflux, 48 h, 7: 57%.
made in recent years towards the synthesis of taylor-made dimeric and
oligomeric steroids.
[3,4]
The macrocyclic polyesters-‘cyclocholates’-formed
by head to tail cyclization of cholic acid derivatives, in general, composed
principally of dimers to pentamers can be prepared by Yamaguchi macro-
[5]
lactonization of 7,12-protected monomeric hydroxy acids using 2,6-
[
6]
dichlorobenzoyl chloride as the coupling reagent. The size of ring
produced was found to depend on both the steric bulk of protecting groups
[
7]
on the 7,12-axial hydroxyl groups and the length of 17-side chain of mono-
[8]
mers. Recently, a steroidal cyclopeptide where two molecules of the
pseudoamino acid (3a-amino-lithocholic acid) form with two or four phenyl-
alanines a cyclopeptide with a lipophilic steroid cavity has been reported.
[
9,10]
However, to our knowledge, taylor-made either linear or cyclic dimer system
form with amino acids has not yet been synthesized. We report here a
synthesis of first linear chola-peptide 7 and cyclic cholapeptide 14 where
two molecules of the bile acid form with two molecules of glycine.
Glycine conjugate 2 was obtained by refluxing ethyl glycinate
hydrochloride (1.4eq.), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline
(
EEDQ, 1.4eq.), cholic acid (1 eq.), and triethylamine in ethyl acetate

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LINEAR AND CYCLIC DIMERIC ESTER DERIVATIVES
3823
[
11]
solution overnight (Sch. 1). The triacetylation of compound 2 at 3a-, 7a-
and 12a-positions was carried out in acetic anhydride with pyridine as the
solvent using dimethylaminopyridine (DMAP) a catalyst. The ethyl ester of
compound 3 were selectively hydrolyzed in ethanol and aqueous 10% potas-
sium carbonate for 17 h to obtain compound 4 in 93% yield. Because the
rate of hydrolysis of three acetate groups in decreasing order is
[
12]
3
a ꢀ 7a>12a (vida infra),
selective removal of the 3a-acetoxy group
was achieved using EtONa/THF (1.0 M) in 75% yield after column
chromatography. We also employed lithium methoxide aqueous solution
(0.2 N) regioselectively hydrolyzed both 3a-acetoxy and ethyl ester groups
in compound 3 to obtain compound 6 in 93% yield. The final dimerization
was accomplished from monomers 4 and 5 by Yamaguchi esterification in
57% yield.
[5]
[
8]
The synthesis of cyclic chola-peptide 14, from 24-norcholic acid (8)
with a shorter 17-side chain, is outlined in Sch. 2. The carbonyl group of
ꢀ
Scheme 2. Reagents and conditions: i. BnOH, DCC, DMAP, CH
ꢀ
2
Cl
2
, 23 C, 24h,
H, DCC, DMAP, DMF, 23 C, 15 h, 10: 94% over two steps;
9
; ii. t-BocNHCH
2
CO
2
ꢀ
ꢀ
iii. H , 10% Pd/C, THF, 23 C, 17 h, 11: 965; iv. C F OH, DCC, CH Cl , 23 C, 17 h,
2
6
5
2
2
ꢀ ꢀ
2; v. CH Cl , TFA, 23 C, 1 h, 13; vi. Na HPO , DMAP, CH Cl , 23 C, 5 days, 14:
2 2 2 4 2 2
1
1
7% over three steps.

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3
824
TIAN, CUI, AND WANG
compound 8 was protected as the corresponding benzyl ester via reaction
13]
[
with benzyl alcohol using DCC and DMAP. N-Boc-protected glycine was
easily attached to 9 by same strategy. Cleaving the benzyl group via catalytic
[
14]
hydrogenation
converted to the pentafluorophenolester which cyclized to the cholapeptide
gave compound 11. The free carboxylic acid is then
14 after removal of the t-Boc group.
EXPERIMENTAL
1
13
H NMR and C NMR (proton decoupled) spectra were recorded on
50 MHz and 63 MHz (Bruker), respectively, in CDCl as solvent and with
TMS as internal standard. The following abbreviations indicate signal
2
3
multiplicity, s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, sx ¼ sextet,
1
3
m ¼ multiplet. C NMR assignments in spectra of cholic acid derivatives
[
15,16]
1
In H NMR spectra,
were made by comparison with reference values.
overlapping steroidal backbone resonances are not quoted. Fast atom
bombardment (FAB) mass spectra were obtained using a m-nitrobenzyl
alcohol matrix on a Autospec-Ultima ETOF instrument. Thin layer
chromatography (TLC) was carried out on Fisher 250 micron silica gel G
(
5 Â 20 cm) TLC plates. Visualization was done by either spraying the plates
with 5% phosphomolybdic acid in ethanol and briefly heating or keeping
the plates in an iodine bottle. Flash column chromatography was carried out
using Grade 62 (60–200 mesh) silica gel and eluted by a n-hexane–ethyl
acetate solvent system. Melting points were determined on a Fisher-Johns
melting point apparatus and are uncorrected. Materials were obtained from
commercial suppliers and used without further purification.
ꢁ
Ethyl 3a,7a,12a-triacetoxy-5b-glycocholate (3): To a cooled (0 C)
[11]
solution of 2
8
(13 g, 26.4mmol) in acetic anhydride (21 mL, 222 mmol,
.43 eq.) and pyridine (31 mL), DMAP (1.9 g, 15.5 mmol, 0.6 eq.) was
ꢁ
added. The reaction mixture was stirred at 23 C for 2 h. The solvent was
concentrated in vacuo, the residue was poured into 1.0 M HCl (1000 mL)
aqueous and extracted with ethyl acetate (3 Â 200 mL). The combined
organic layers were washed by NaHCO aqueous solution, brine, dried
3
(
(
(
Na SO ) and concentrated under reduced pressure to afford foamy solid 3
2 4
1
14g, 86%). H NMR (CDCl ): 0.73 (s, 3H, 18-H ); 0.82 (d, 3H, 21-H ); 0.93
3
3
3
s, 3H, 19-H ); 1.40 (t, 3H, CH CH ); 2.06 (s, 3H, 3a-OAc); 2.09 (s, 3H, 7a-
3
2
3
OAc); 2.14(s, 3H, 12 a-OAc); 4.00 (bs, 2H, NHCH COOEt); 4.20 (q, 2H,
2
CH CH ); 4.57 (bs, 1H, 3b-H); 4.90 (s, 1H, 7b-H); 5.09 (s, 1H, 12b-H); 6.44
2
3
þ
þ
(
4
bs, 1H, NHCH COOEt). MS (FAB): 620.3 [Mþ1] , 500.2 [M-2HOAcþ1] ,
2
þ
40.2 [M-3HOAcþ1] , 337.1, 154.0, 136.0, 107.0, 95.0, 69.0, 55.0.

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LINEAR AND CYCLIC DIMERIC ESTER DERIVATIVES
3825
3
pound 3 (14g, 22 mmol) in ethanol (50 mL), 10% K CO (100 mL) aqueous
a,7a,12a-Triacetoxy-5b-glycocholic acid (4): To a solution of com-
2
3
ꢁ
solution was added slowly. The resulted solution was stirred at 23 C for
7 h, neutralized with 1.0 M HCl aqueous solution and extracted with ethyl
acetate. The combined organic layers were washed by NaHCO aqueous
1
3
solution, brine, dried (Na SO ) and concentrated under reduced pressure to
2
4
1
afford foamy solid 4 (12.5 g, 93%) H NMR (CDCl ): 0.73 (s, 3H, 18-H );
3
3
0
7
3
1
4
.81 (d, 3H, 21-H ); 0.93 (s, 3H, 19-H ); 2.06 (s, 3H, 3a-OAc); 2.10 (s, 3H,
3
3
a-OAc); 2.15 (s, 3H, 12a-OAc); 4.03 (bs, 2H, NHCH COOH); 4.57 (bs, 1H,
2
b-H); 4.91 (s, 1H, 7b-H); 5.09 (s, 1H, 12b-H); 6.73 (bs, 1H, NHCH COOH);
2
þ
þ
0.30 (s, 1H, COOH). MS (FAB): 592.2 [Mþ1] , 472.3 [M-2HOAcþ1] ,
þ
40.3, 412.3 [M-3HOAcþ1] .
Ethyl 7a,12a-diacetoxy-3a-hydroxy-5b-glycocholate (5): To a solution
of compound 3 (23 g, 37 mmol) in THF (400 mL), EtONa (1.0 M in EtOH,
50 mL) was added. The resulted solution was stirred at 23 C for 2 h and the
solvent was concentrated in vacuo. The residue was poured into 1.0 M HCl
ꢁ
(
bined organic layers were washed by NaHCO aqueous solution, brine,
1000 mL) aqueous and extracted with ethyl acetate (3 Â 300 mL). The com-
3
dried (Na SO ) and concentrated under reduced pressure. The residue
2
4
was flash chromatographed on a silica gel column to afford foamy solid 5
1
(
16 g, 75%). H NMR (CDCl ): 0.73 (s, 3H, 18-H ); 0.82 (d, 3H, 21-H );
3 3 3
0
.91 (s, 3H, 19-H ); 1.29 (t, 3H, CH CH ); 2.09 (s, 3H, 7a-OAc); 2.13
3
2
3
(
s, 3H, 12a-OAc); 3.50 (bs, 1H, 3b-H); 4.03 (bs, 2H, NHCH COOEt);
2
4
1
4
.22 (q, 2H, CH CH ); 4.90 (s, 1H, 7b-H); 5.10 (s, 1H, 12b-H); 6.34(bs,
2
3
þ
H, NHCH COOEt). MS (EI) m/z (rel intensity): 577.4[M] (8), 440.2 (25),
12.2 (10), 337.2 (19), 253.1 (27), 227.1 (15), 136.0 (33), 107.0 (42), 104.0
2
(
48), 95.0 (53), 81.0 (57), 69.0 (68), 55 (100).
7
compound 3 (4.5 g, 7.8 mmol) in THF (155 mL) at 23 C, LiOCH (0.2 N,
a,12a-Diacetoxy-3a-hydroxy-5b-glycocholic acid (6): To a solution of
ꢁ
3
155 mL) aqueous solution was added. The resulted solution was continued
to stirred at the same temperature for 6 h, neutralized with 1.0 M HCl aqu-
eous solution and extracted with ethyl acetate (3 Â 100 mL). The combined
organic layers were washed by NaHCO aqueous solution, brine, dried
3
(
6
0
Na SO ) and concentrated under reduced pressure to afford foamy solid
2 4
1
(3.98 g, 93%). H NMR (CDCl ): 0.72 (s, 3H, 18-H ); 0.81 (d, 3H, 21-H );
3 3 3
.91 (s, 3H, 19-H ); 2.09 (s, 3H, 7a-OAc); 2.13 (s, 3H, 12a-OAc); 3.53
3
(
bs, 1H, 3b-H); 4.02 (bs, 2H, NHCH COOH); 4.89 (s, 1H, 7b-H); 5.08
2
(
s, 1H, 12b-H); 6.68 (bs, 1H, NHCH COOH); 7.64(s, 1H, COOH).
2
þ
þ
þ
MS (FAB): 550.3 [Mþ1] , 548.3 [Mꢂ1] , 430.3 [M-2HOAcþ1] , 412.3
þ
[M-2HOAc-H Oþ1] .
2
Dimerization of compound 4 and 5: A mixture of monomers 4 (6.7 g,
1.3 mmol), 5 (6.5 g, 11.3 mmol), 2,6-dichlorobenzoyl chloride (2 mL,
1

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3
826
TIAN, CUI, AND WANG
1
(
4mmol, 1.2 eq.), DMAP (5.5 g, 45 mmol, 3.98 eq.) and anhydrous toluene
366 mL) was refluxed for 48 h. The solvent was concentrated under reduced
pressure, the residue was flash chromatographed on a silica gel column and
ꢁ
1
crystalized to afford dimer 7. M.p. 128–130 C, yield: 57%. H NMR
CDCl ): 0.73 (s, 6H, 18-CH ), 0.82 (d, 6H, 21-CH ), 0.93 (s, 6H, 19-CH ),
3 3 3 3
(
1
4
2
.28 (t, 3H, CH CH ), 2.05–2.14(m, 15H, 3 a-OAc, 7a-OAc, 12a-OAc),
2
3
.00, 4.02 (d, 4H, NHCH COO), 4.20 (q, 2H, CH CH ), 4.57, 4.62 (db,
H, 3b-H), 4.91 (bs, 2H, 7b-H), 5.10 (bs, 2H, 12b-H), 6.35 (bs, 2H,
2
2
3
1
3
NHCH COO). C NMR (CDCl ): 34.66 (C-1), 26.78 (C-2), 74.02 (C-3),
2
3
3
(
2
4.66 (C-4), 40.84 (C-5), 31.13 (C-6), 70.57, 70.65 (C-7), 37.61 (C-8), 28.80
C-9), 34.24 (C-10), 25.50 (C-11), 75.34 (C-12), 44.99 (C-13), 43.32 (C-14),
2.75 (C-15), 27.17 (C-16), 47.40 (C-17), 12.19 (C-18), 22.48 (C-19), 34.47
(
(
C-20), 17.51 (C-21), 31.33 (C-22), 32.96 (C-23), 169.67 (C-24), 41.26, 41.50
CH COO), 173.59 (CH COO), 14.13 (CH CH ), 61.37 (CH CH ), 21.43,
2
2
2
3
2
3
2
1.62 (CH COO), 170.06, 170.41, 170.52 (CH COO). MS (FAB): 1151.3
3 3
þ
[Mþ1] , 662.2, 578.3, 557.2, 529.25, 440.3, 391.3, 373.3.
Benzyl 3a-hydroxy-7a,12a-diacetoxy-24-nor-5b-cholan-23-oate (9):
DCC (6.5 g, 31.5 mmol, 1.2 equiv.) was added to a stirred solution of the
acid 8 (12.75 g, 26.7 mmol, 1 equiv.), benzyl alcohol (3.8 mL, 36.7 mmol,
1.37 equiv.) and DMAP (0.9 g, 7.37 mmol, 0.28 equiv.) in anhydrous
CH Cl (150 mL) at 23 C. After being stirred at same temperature for 24h,
ꢁ
2
2
the mixture was diluted with CH Cl and filtered. The filtrate was washed
2
2
with 5% aq. HCl, satd. NaHCO , brine, dried (MgSO ) and evaporated
3
4
to dryness. The residue was purified by column chromatography to give
1
foamy solid 9 in a quantitative yield. H NMR (CDCl ): 0.75 (s, 3H,
3
1
8-H ); 0.86 (d, 3H, 21-H ); 0.89 (s, 3H, 19-H ); 2.07 (s, 3H, 7a-OAc);
3
3
3
2
.09 (s, 3H, 12a-OAc); 2.42 (d, 2H, 22-H ); 3.40 (bs, 1H, 3b-H); 4.65
2
(
(
bs, 1H, 7b-H); 4.87 (bs, 1H, 12b-H); 5.10 (s, 2H, CH Ph); 7.33, 7.35
2
þ
þ
bs, 5H, CH Ph). MS (FAB): 591.2 [MþNa] , 549.4 [M-H O-1] , 449.2
2
2
þ
[
8
Mꢂ2HOAcþ1] , 306.2, 225.1, 207.1, 176.0, 154.0, 136.0, 107.0, 95.0, 91.0,
1.0, 55.0.
Benzyl 7a,12a-diacetoxy-3a-{N-[(tert-butoxy)carbonyl]-glycyl}-24-nor-
b-cholan-23-oate (10): A solution of 9 (7.4g, 13 mmol, 1 equiv.) and t-Boc-
5
glycine (2.7 g, 15.4mmol, 1.2 equiv.) in anhydrous DMF was treated with
DMAP (0.64g, 5.2 mmol, 0.4equiv.) and DCC (3.2 g, 15.5 mmol,
ꢁ
1
.2 equiv.) at 23 C. The mixture was stirred 24h at the same temperature
and the solvent was removed in vacuo. The residue was taken up in ethyl
acetate (400 mL). The solution was extracted with 1.0 M HCl, saturated aqu-
eous NaHCO , brine, dried (Na SO ) and evaporated to dryness. The crude
3
2
4
product was purified by column chromatography to afford 10 as a white solid
ꢁ
8.9 g, 94%). M.p. 98–100 C. H NMR (CDCl ); 0.76 (s, 3H, 18-H ); 0.87 (d,
3 3
1
(
3
H, 21-H ); 0.92 (s, 3H, 19-H ); 1.44 (s, 9H, (CH ) C); 2.08 (s, 3H, 7a-OAc);
3
3
3 3

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LINEAR AND CYCLIC DIMERIC ESTER DERIVATIVES
3827
2
.11 (s, 3H, 12a-OAc); 3.97 (d, 2H, t-BocNHCH COO); 4.63 (m, 1H, 3b-H);
2
4
.90 (bs, 1H, 7b-H); 5.10 (s, 2H, CH Ph); 5.16 (s, 1H, 12b-H); 7.34(bs, 5H,
2
þ
CH Ph); 7.58 (t, 1H, t-BocNHCH COO). MS (FAB): 724.2 [Mꢂ1] , 551.1,
2
2
þ
50.1 [M-t-BocNHCH COOH] , 540.2, 483.1, 201.0, 157.0, 91.0, 57.0.
2
5
7a,12a-Diacetoxy-3a-{N-[(tert-butoxy)carbonyl]-glycyl}-24-nor-5b-cho-
lan-23-oic acid (11): To a solution of 10 (3.3 g, 4.55 mmol, 1 equiv.) in THF
(
atmosphere for 20 h at 23 C. The catalyst was filtered and the filtrate was
50 mL), 10% Pd-C (500 mg) was added. The mixture was stirred in a H
ꢁ
2
evaporated in vacuo to yield compound 11 as a foamy solid (2.78 g, 96%).
1
H NMR (CDCl ): 0.78 (s, 3H, 18-H ); 0.93 (bs, 6H, 19-H , 21-H ); 1.45 (s,
3
3
3
3
9
H, (CH ) C); 2.10 (s, 3H, 7a-OAc); 2.15 (s, 3H, 12a-OAc); 3.98 (d, 2H,
3
3
t-BocNHCH COO): 4.63 (bs, 1H, 3b-H); 4.92 (bs, 1H, 7b-H); 5.10 (s, 1H,
2
þ
1
5
2
2b-H); 7.58 (t, 1H, t-BocNHCH COO). MS (FAB): 635.5 [M] , 539.4,
14.2 [M-2HOAc-1] , 460.3 [M-t-BocNHCH COOH] , 382.4, 326.3,
58.2, 201.2, 183.2, 157.2, 98.1.
2
þ
þ
2
Pentafluorophenyl
glycyl}-24-nor-5b-cholan-23-oate (12): Compound 11 (7.8 g, 12.3 mmol,
equiv.) was dissolved in anhydrous CH Cl (150 mL) with pentafluorophe-
7a,12a-Diacetoxy-3a-{N-[(tert-butoxy)carbonyl]-
1
2
2
ꢁ
nol (3.4g, 18.4mmol, 1.5 equiv.) and cooled to 0 C under an inert atmos-
phere. DCC (3.8 g, 18.5 mmol, 1.5 equiv.) was added in one portion. The
mixture was left stirring overnight and filtered. The filtrate was extracted
with aqueous NaHCO , 1.0 M HCl, brine and dried over Na SO . The sol-
3
2
4
vent was removed in vacuo to give compound 12 as a glass in a quantitative
1
crude yield. This product was used without further purification. H NMR
(
CDCl ): 0.81 (s, 3H, 18-H ); 0.94(s, 3Hbs, 19-H ); 1.15 (d, 3H, 21-H );
3 3 3 3
2
4
1
.10 (s, 3H, 7a-OAc); 2.15 (s, 3H, 12a-OAc); 4.00 (d, 2H, NHCH COO);
2
.92 (bs, 1H, 3b-H); 5.11 (bs, 1H, 7b-H); 5.44 (s, 1H, 12b-H); 7.51 (t,
þ
H, t-BocNHCH COO). MS (FAB): 824.2 [MþNa] , 626.1 [M-t-
2
ꢂ
þ
BocNHCH COOH] , 507.1 [M-t-BocNHCH COOH-2HOAcþ1] , 431.3,
2
2
4
04.2, 382.2, 326.2, 307.0, 225.2, 201.1, 154.0, 136.0, 95.1, 83.1, 69.1, 57.1.
Pentafluorophenyl 7a,12a-Diacetoxy-3a-glycyl-24-nor-5b-cholan-23-oate
13). Crude compound 12 (assumed 12.3 mmol, 1 equiv.) was dissolved in
(
CH Cl (100 mL) followed by addition of trifluoroacetic acid (15 mL). The
2
2
ꢁ
mixture was stirred at 23 C for 1 h and evaporated to dryness. The residue
was take up in CH Cl (200 mL), washed with NaHCO aqueous solution,
brine, dried (Na SO ) and evaporated to yield 13 of sufficient purity for
2
2
3
2
4
further elaboration. A portion of the crude product (0.1 g) was purified by
flash chromatography using CHCl -MeOH (9:1) as eluent to yield pure 13
3
1
0.07 g). H NMR (CDCl ): 0.76 (s, 3H, 18-H ); 0.92 (s, 6H, 19-H , 21-H );
(
3
3
3
3
2
4
.02 (s, 3H, 7a-OAc); 2.07 (s, 3H, 12a-OAc); 3.97 (s, 2H, NH CH COO);
.64 (bs, 1H, 3b-H); 4.81 (bs, 1H, 7b-H); 5.01 (s, 1H, 12b-H); 8.21 (bs, 2H,
2
2
NH CH COO).
2
2

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3
828
TIAN, CUI, AND WANG
Dimerization of compound 13: To a solution of compound 13 (assumed
12.3 mmol), in CH Cl (3075 mL) was added DMAP (3.0 g, 24.6 mmol,
2 2
2
equiv.), and Na HPO (7.0 g, 49.3 mmol, 4 equiv.). After 5 days of stirring
2
4
ꢁ
at 23 C, the mixture was filtered and evaporated to dryness. The residue was
purified by chromatography on silica gel (CH Cl –MeOH: 9 : 1) to afford
1
compound 14 as a foamy solid (1.07 g, 17% over three steps). H NMR
2
2
(
CDCl ): 0.77 (s, 6H, 18-CH ), 0.85 d, 6H, 21-CH ), 0.94(s, 6H, 19-CH ),
3 3 3 3
2
4
.09 (s, 6H, 7a-OAc), 2.13 (s, 6H, 12a-OAc), 4.07 (s, 4H, NHCH COO),
2
.66 (s, 2H, 3b-H), 4.91 (bs, 2H, 7b-H), 5.10 (bs, 2H, 12b-H), 8.08 (bs, 2H,
1
3
NHCH COO). C NMR (CDCl ): 34.43 (C-1), 26.67 (C-2), 75.30 (C-3),
2
3
3
3
4.24 (C-4), 41.61 (C-5), 31.17 (C-6), 70.69 (C-7), 37.69 (C-8), 28.76 (C-9),
4.24 (C-10), 25.27 (C-11), 75.81 (C-12), 45.14 (C-13), 43.94 (C-14), 22.79
(
1
C-15), 27.33 (C-16), 48.21 (C-17), 12.27 (C-18), 22.44 (C-19), 32.33 (C-20),
8.40 (C-21), 40.80 (C-22), 167.73 (C-23), 43.32, 43.94 (CH COO), 170.56
2
(
1
1
CH COO), 21.04, 21.27, 21.47 (CH COO), 171.84(CH COO). MS (FAB):
2 3 3
þ
056.4[M þNa-1] , 929.3, 892.3, 851.3, 768.3, 711.2, 656.2, 599.2, 169.9,
51.9, 124.9.
ACKNOWLEDGMENTS
The authors are grateful to the financial support from National
Science Council of China.
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2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
LINEAR AND CYCLIC DIMERIC ESTER DERIVATIVES
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2. Gao, H.; Dias, J.R. Org. Prep. Proc. Int. 1999, 31, 4 5.
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Received in the USA December 9, 2001

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2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.