The 'triamino-analogue' of methyl cholate; a practical, large-scale synthesis

Article abstract of DOI:10.1055/s-1999-3114

The triamino steroids 2 are in demand as facial amphiphiles and starting materials for supramolecular chemistry. 2 (R = Me)is now available from cholic acid 1 in substantial quantities via a new, high-yielding procedure.

Full text of DOI:10.1055/s-1999-3114

LETTER
991
The “Triamino-analogue” of Methyl Cholate; A Practical, Large-Scale
Synthesis
Anthony P. Davis,* M. Nieves Pérez-Payán
Department of Chemistry, Trinity College, Dublin 2, Ireland
Fax +353(1)6712826; E-mail: adavis@tcd.ie
Received 11 February 1999
The conversion of hydroxyl to amino groups may be
achieved by nucleophilic displacement, or by oxidation
followed by reductive amination. In our initial synthesis
we used the former strategy where possible, to ensure the
correct stereochemical outcome and minimise the need
for potentially difficult separations of diastereomeric
polyamine derivatives. Unfortunately this required that
each secondary hydroxyl be given individual attention, re-
sulting in a synthesis which was “safe” but impractical for
routine preparation of 2. In subsequent work, we have de-
veloped a reductive amination protocol which is reliable,
high-yielding, and shows excellent selectivity for the a-
product at both C7 and C12.8 The application of this
method simultaneously to both positions forms the basis
for the new preparation described herein.9
Abstract: The triamino steroids 2 are in demand as facial am-
phiphiles and starting materials for supramolecular chemistry. 2
(R = Me) is now available from cholic acid 1 in substantial
quantities via a new, high-yielding procedure.
Key words: bile acids, scaffold, supramolecular chemistry, facial
amphiphile, oxime reduction
As part of our programme on cholic acid 1 as a building
block for supramolecular chemistry,1 we have recently be-
come interested in the replacement of -OH with -NH2 at
the steroidal 3, 7 and 12 positions. Amino groups can be
derivatised efficiently in various ways, most of which
give functionality capable of strong and specific non-co-
valent interactions. Aminocholanoates have been used to
synthesize cyclooligomeric hosts,2 and also monomeric
receptors capable of binding inorganic anions,3 amino
acid derivatives4 and DNA.5 They also have potential as
facial amphiphiles,6 and as scaffolds for library synthesis
in combinatorial chemistry.4a,7
The synthetic route to tris-carbamate 11, immediate pre-
cursor of 2 (R = Me), is summarised in the Scheme.
Acetoxydiol 4 was available in 83% yield through a one-
pot esterification and selective 3a-acetylation of 1, em-
ploying MeOAc as source of both methoxy and acetyl
groups.10 Oxidation with potassium chromate gave the
acetoxy-dione 5 in 98% yield.11 Both 4 and 5 could be pu-
rified by crystallisation; alternatively the crystallisation of
4 could be omitted without a drop in overall yield. The
amino groups on C7 and C12 were introduced by
oximation12 to acetoxydioxime 6 (99% yield) followed by
catalytic hydrogenation to give mainly the corresponding
bis-hydroxylamine, and treatment with Zn/AcOH to give
the diamine.8,13 Protection with di-t-butyl dicarbonate,
followed by crystallisation, gave acetoxydicarbamate 7 in
92% yield from 6.13 7 was stereochemically homogeneous
by 1H and 13C NMR,14 and could be prepared in batches of
40 g using normal laboratory equipment.
The “virtues” of aminocholanoates are expressed most
fully in compounds 2, containing the tris-deoxa-tris-aza
analogue of the cholic acid nucleus. 2 (R = Me) has been
used to prepare the unusually potent electroneutral anion-
ophore 3,3 and undoubtedly has many other applications
in supramolecular chemistry. However its value to date
has been limited by a lengthy and somewhat unwieldy
synthesis from 1, requiring 17 steps and proceeding in
≤1.4% overall yield.6a We now report an improved proce-
dure which is shorter, more efficient, and allows multi-
gram production of 2 (R = Me) on a routine basis.
The acetoxy group on C3 was easily removed with
sodium carbonate to yield 8 in quantitative yield. The
third amino group was then introduced through double
nucleophilic displacement. A Mitsunobu reaction with
methanesulfonate as nucleophile, employing a modifica-
tion of conditions published earlier from our laboratory,15
gave mesylate 9.16 Treatment of 9 with NaN3 gave azide
10 in 72% yield from 8.16 Finally, reduction/N-protection
with H2/Pd/(Boc)2O17 gave tris-carbamate 11 in 85% crys-
talline yield, 45% overall from cholic acid. Although
chromatography was required for the purification of 9 and
10, the preparation of 11 could be conducted in 8 gram
batches without inconvenience. Deprotection of 11 with
Synlett 1999, S1, 991–993 ISSN 0936-5214 © Thieme Stuttgart · New York

992
A. P. Davis, M. N. Pérez-Payán
LETTER
Scheme
Reagents and conditions: (i) p-TsOH, AcOMe, 23 h, reflux; (ii) K2CrO4, AcOH, 48 h, rt; (iii) H2NOH·HCl, AcONa, MeOH, 4.5 h, reflux; (iv)
H2, PtO2·xH2O, AcOH, 6 d, rt; (v) Zn, AcOH, 12 h, rt; (vi) (Boc)2O, NaHCO3 aq., THF, 3 d, rt; (vii) Na2CO3, MeOH, 12 h, rt; (viii) Ph3P, Et3N,
MeSO3H, DEAD, THF, 1 d, 45 oC; (ix) NaN3, DMF, 2 d, 45 oC; (x) H2, Pd/C (10%), (Boc)2O, EtOH, 24 h, rt.
TFA in dichloromethane occurs cleanly to give 2 (R =
Me), as its tris-TFA salt, in apparently quantitative yield.
Oxford, 1996; Vol. 4, p 257. See also: (c) Walliman, P.; Marti,
T.; Furer, A.; Diederich, F. Chem. Rev. 1997, 97, 1567; (d) Li,
Y. X.; Dias, J. R. Chem. Rev. 1997, 97, 283.
In conclusion, we have presented a new route to the “tria-
za-analogue” of the cholic acid nucleus. This new synthe-
sis is high-yielding and can be performed on a multigram
scale with normal laboratory equipment. Ready access to
2 will allow us to explore further applications in the de-
sign and synthesis of receptors, facial amphiphiles, and
scaffolds for combinatorial chemistry. Intermediate 7,
moreover, is exceptionally convenient to prepare, and
may itself find uses in these areas.
(2) (a) Davis, A. P.; Walsh, J. J. Chem. Commun. 1996, 449.
(b) Davis, A. P.; Menzer, S.; Walsh, J. J.; Williams, D. J.
Chem. Commun. 1996, 453. (c) Albert, D.; Feigel, M.
Tetrahedron Lett. 1994, 35, 565. (d) Albert, D.; Feigel, M.;
Benet-Buchholz, J.; Boese, R. Angew. Chem., Int. Ed. Engl.
1998, 37, 2727.
(3) Davis, A. P.; Perry, J. J.; Williams, R. P. J. Am. Chem. Soc.
1997, 119, 1793.
(4) (a) Cheng, Y. A.; Suenaga, T.; Still, W. C. J. Am. Chem. Soc.
1996, 118, 1813. (b) Davis, A. P.; Lawless, L. J. Chem.
Commun. 1999, 9.
(5) Hsieh, H.-P.; Muller, J. G.; Burrows, C. J. J. Am. Chem. Soc.
1994, 116, 12077.
Acknowledgement
(6) (a) Broderick, S.; Davis, A. P.; Williams, R. P. Tetrahedron
Lett. 1998, 39, 6083. For a general leading reference to facial
amphiphiles, see: (b) McQuade, D. T.; Barrett, D. G.; Desper,
J. M.; Hayashi, R. K.; Gellman, S. H. J. Am. Chem. Soc. 1995,
117, 4862.
(7) Kasal, A.; Kohout, L.; Lebl, M. Coll. Czech. Chem. Comm.
1995, 60, 2147.
(8) Barry, J. F.; Davis, A. P.; Pérez-Payán, M. N.; Elsegood, M.
R. J.; Jackson, R. F. W.; Gennari, C.; Piarulli, U.; Gude, M.
Tetrahedron Lett. 1999, 40, 2849.
Financial support for this work was provided through a Marie Curie
Fellowship (to MNP) and a Network Contract under the EU Trai-
ning and Mobility for Researchers (TMR) Programme, with addi-
tional funds from Forbairt, the Irish Science and Technology
Agency. We are grateful to Freedom Chemical Diamalt GmbH for
generous gifts of cholic acid, and Dr. A. P. Dominey for assistance
in preparing the manuscript.
References and Notes
(9) Simultaneous reductive aminations have been used
independently by Savage and co-workers in a synthesis of
3a,7a,12a-triaminocholan-24-ol: Li, C.; Rehman, A.; Dalley,
(1) (a) Davis, A. P. Chem. Soc. Rev. 1993, 22, 243; (b) Davis, A.
P.; Bonar-Law, R. P.; Sanders, J. K. M. in Comprehensive
Supramolecular Chemistry; Murakami, Y., Ed.; Pergamon:
Synlett 1999, S1, 991–993 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
N. K.; Savage, P. B. Tetrahedron Lett. 1999, 40, 1861. We
Synthesis of the “Triamino-analogue” of Methyl Cholate
993
their NCH chemical shifts and coupling patterns. The
thank Prof. Savage for informing us of this work prior to
publication.
(10) Kuhaida, K.; Kandrac, J.; Cirin-Novta, V.; Miljkovic, D.,
Coll. Czech. Chem. Comm. 1996, 61, 1073.
configurations at C7 and C12 (and also C3) were further
confirmed through the identity of 11, as prepared in this work,
with that synthesised using the earlier procedure.6a
(15) (a) Davis, A. P.; Dresen, S.; Lawless, L. J. Tetrahedron Lett.
1997, 38, 4305. See also: (b) Anderson, N. G.; Lust, D. A.;
Colapret, K. A.; Simpson, J. H.; Malley, M. F.; Gougoutas, J.
Z. J. Org. Chem. 1996, 61, 7955.
(11) Fieser, L. F.; Rajagolapan, J. Am. Chem. Soc. 1950, 72, 5530.
(12) Williams, R. P., Ph. D. Thesis, University of Dublin, 1995.
(13) The diketone 5 (17.6 g, 38 mmol), sodium acetate (35 g, 430
mmol) and hydroxylamine hydrochloride (9.8 g, 140 mmol)
were dissolved in methanol (350 ml) and heated under reflux
for 4.5 hours. The reaction mixture was evaporated under
reduced pressure, redissolved in DCM, washed with water,
dried (MgSO4), and evaporated under reduced pressure. The
residue was crystallised from chloroform-hexane and filtered
to obtain dioxime 6 (18.4 g, 99%) as a white solid.
(16) To a solution of compound 8 (4.06 g, 6.54 mmol) and
triphenyl phosphine (5.7 g, 21.7 mmol) in dry THF (40 ml) at
0 oC was added triethylamine (1.9 ml, 13 mmol) and
methanesulfonic acid (0.90 ml, 13 mmol). The mixture was
warmed to 45 oC, and DEAD (3.1 ml, 20 mmol) was added
dropwise with stirring. Stirring was maintained for 24 hours,
after which the solvent was removed under reduced pressure
and the residue partially purified by flash chromatography
(hexane-EtOAc, 3:1) to give compound 9 contaminated with
DEAD residues. This material was redissolved in DMF (32
ml), sodium azide (2.76 g, 42 mmol) was added with stirring,
and stirring was continued for 48 hours at ca. 45 oC. Water
was added and the resulting mixture extracted with EtOAc.
The extract was dried (MgSO4) and evaporated under reduced
pressure. The residue was purified by flash chromatography
(hexane-EtOAc, 4:1) and crystallisation from DCM-hexane to
give 10 as a white powder (3.0 g, 72%).
A mixture of 6 (37.6 g, 70.4 mmol), obtained as above, and
platinum oxide hydrate (4.05 g) in glacial AcOH (150 ml) was
stirred under H2 atmosphere for 6 days. The reaction mixture
was filtered, washing with glacial acetic acid. The filtrates
were concentrated under reduced pressure to ca. 200 ml. Zinc
powder (75 g) was added. The resulting mixture was stirred
overnight at r.t., filtered (washing with glacial AcOH),
evaporated under reduced pressure, then redissolved in THF
(560 ml) and sat. aq. NaHCO3 (280 ml). Di-t-butyl
dicarbonate (40 g, 0.18 mol) was added, and the solution
stirred for 3 days. The mixture was evaporated under reduced
pressure, redissolved in DCM, washed with dilute aq. HCl,
dried (MgSO4) and evaporated under reduced pressure. The
white foamy crude product crystallised from DCM-hexane to
give 7 (46.8 g, 92%) as a white solid.
Selected data for 10: 1H NMR [400 MHz, CDCl3] d 0.80 (s,
3H, 18-Me), 0.93 (d, 3H, J 5.5, 21-Me), 0.95 (s, 3H, 19-Me),
1.42 (s, 9H, CMe3), 1.43 (s, 9H, CMe3), 3.26 (broad m, 1H,
3b-H), 3.65 (broad s, 1H, 7b-H), 3.73 (s, 3H, CO2CH3), 3.99
(broad m, 1H, 12b-H), 5.24 (broad s, 1H, 7a-NH), 5.43 (broad
s, 1H, 12a-NH); 13C NMR [CDCl3] d 13.7 (C-18), 17.4 (C-
21), 22.96, 23.02 (C-19), 26.9, 27.0, 27.6, 28.51 (C(CH3)3),
28.53 (C(CH3)3), 28.9, 30.7, 31.7, 31.8, 34.8, 35.2, 35.4, 35.5,
37.0, 41.8, 44.6, 44.7, 47.2 (C-7), 49.2, 52.1 (CO2CH3), 53.2
(C-12), 61.7 (C-3), 78.9 (C(CH3)3), 79.0 (C(CH3)3), 155.5 (2
x NCO), 174.9 (CO2CH3).
Selected data for 7: 1H NMR [400 MHz, CDCl3] d 0.81 (s, 3H,
18-Me), 0.92 (d, 3H, J 6.0, 21-Me), 0.95 (s, 3H, 19-Me), 1.46
(s, 18H, 2 x CMe3), 2.04 (s, 3H, CH3COO), 3.70 (broad s, 4H,
CO2CH3/7b-H), 3.97 (broad m, 1H, 12b-H), 4.58 (broad m,
1H, 3b-H), 4.94 (broad s, 1H, 7a-NH), 5.12 (broad s, 1H, 12a-
NH); 13C NMR [CDCl3] d 13.5 (C-18), 17.5 (C-21), 21.3
(CH3COO), 22.8 (C-19), 22.9 , 26.7, 27.1, 27.8, 28.5 (2 x
C(CH3)3), 30.5, 31.8, 32.2, 34.8, 34.9, 35.8, 37.1, 41.4, 44.3,
44.7, 47.2 (C-7), 49.5, 52.3 (CO2CH3), 53.3 (12-C), 74.4 (3-
C), 155.0 (NCO), 155.5 (NCO), 170.1 (OCOCH3), 174.7
(CO2CH3); nmax (Nujol, cm-1) 3386 (NH), 3370 (NH), 1709
(CO), 1246, 1167. Anal. Found: C, 67.19; H, 9.43; N 3.95.
C37H62N2O8 requires C, 67.04; H, 9.43; N 4.23%.
(17) Saito S.; Nakajima, H.; Inaba, M.; Moriwake, T., Tetrahedron
Lett. 1989, 30, 837.
Article Identifier:
1437-2096,E;1999,0,S1,0991,0993,ftx,en;W07599ST.pdf
(14) Previous work has shown that the stereoisomers of N-Boc
aminocholanoate derivatives can be distinguished through
Synlett 1999, S1, 991–993 ISSN 0936-5214 © Thieme Stuttgart · New York