A short synthesis of methyl 3α, 7α, 12α- triaminocholanoate, the 'triaza-analogue' of methyl cholate

Article abstract of DOI:10.1055/s-2005-865221

Triamine 2a, a facial amphiphile and precursor for anion receptors, has been prepared in just four steps from the inexpensive steroid cholic acid.

Full text of DOI:10.1055/s-2005-865221

LETTER
1319
A Short Synthesis of Methyl 3a,7a,12a-Triaminocholanoate, the ‘Triaza-
Analogue’ of Methyl Cholate
a
a
b
b
c
a
S
V
hor
t
Synthesisof
i
M
ethy
c
3
a
,7
a
,12
a
e
-Triaminoc
n
holanoate te del Amo, Khadga Bhattarai, Maija Nissinen, Kari Rissanen, M. Nieves Pérez-Payán, Anthony P. Davis*
a
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Fax +44(117)9298611; E-mail: anthony.davis@bristol.ac.uk
b
c
University of Jyväskylä, Department of Chemistry, P.O. Box 35, 40351 Jyväskylä, Finland
Department of Chemistry, Trinity College, Dublin 2, Ireland
Received 10 November 2004
what cumbersome for routine use, and we have therefore
sought a shorter and quicker method. We now report such
a synthesis, which gives 2a directly in just four steps from
Abstract: Triamine 2a, a facial amphiphile and precursor for anion
receptors, has been prepared in just four steps from the inexpensive
steroid cholic acid.
1
.
Key words: steroids, hydrogenation, receptors, aminations, stereo-
selectivity
A key transformation in our second, nine-step synthesis of
a was the catalytic hydrogenation of dioxime 3 to di-
2
amine 4 (Equation 1), which proceeded with almost com-
plete stereoselectivity. An analogous reduction of
trioxime 5 to 2a would allow a highly efficient synthesis
of the latter. The conversion requires equatorial attack at
positions 7 and 12, and axial attack at C3. All-equatorial
attack, to give all-axial product 6, might seem more likely
Polyamines derived from the bile acids have been em-
ployed as scaffolds for combinatorial chemistry, ligands
1
2
3
for nucleic acids, agents for gene transfection, antimi-
4
5
crobials, and precursors of synthetic receptors. As the
triaza-analogue’ of cholic acid (1, the principal mamma-
lian bile acid), the system 2 bears special significance
Figure 1). Compounds possess strong facial
amphiphilicity when protonated, and ester 2b has been
shown to promote vesicle fusion and gene transfection.3b
The triaminocholanoate nucleus is also the core structure
‘
(
Figure 2). However, literature precedent, especially from
1
1
the group of Savage, suggested that the reduction
stereochemistry might not be controlled by classical con-
formational effects. We therefore decided to investigate
the hydrogenation of 5.
(
2
6
7
in powerful anion receptors with potential as anion trans-
8
HO
port agents.
N
OMe
O
N
12
OH
OH
O
OAc
H2 (1 atm), PtO2,
AcOH, 6 d,
then Zn, AcOH
7
3
OH
3
OH
OH
1
OMe
OR
O
O
NH2
NH2
NH2
NH2
OAc
4
2
a
R = Me
R = C20H41
NH2
2b
Equation 1
Figure 1
HO
N
OMe
Further applications of 2 can be envisaged in medicinal
chemistry (e.g. as scaffolds for multivalent peptides and
carbohydrates) and materials (e.g. as components of den-
drimers). However, methods are needed for accessing the
triaminocholanoate system rapidly and in useful quanti-
ties. Two syntheses of N-protected 2a have been pub-
O
N
OH
N
HO
5
OMe
O
NH2
H2N
lished; an initial and inefficient sequence (17 steps from 1,
NH2
6
9
≤
1.4% overall yield), followed by a more practical meth-
1
0
od (9 steps, 45% overall yield). Even the latter is some- Figure 2
1
2
13
SYNLETT 2005, No. 8, pp 1319–1321
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-865221; Art ID: D33704ST
1
7.
0
5.
2
0
0
5
Trioxime 5 was prepared via ester 7 and triketone 8 as
shown in Scheme 1, and subjected to Pt-catalysed hydro-
genation under a range of conditions. The crude products
were treated with Zn/AcOH to cleave any remaining N–O
©
Georg Thieme Verlag Stuttgart · New York

1
320
V. del Amo et al.
LETTER
1
4
bonds, then with (Boc) O to give N-Boc-protected prod-
2
ucts for analysis. The method originally used for 3
(
Equation 1) gave complex mixtures, but increasing the
H pressure yielded cleaner products with all-a isomer 9
2
(
Figure 3) as a major component. Tris-carbamate 9 was
identified by comparison with material from the earlier
1
0
synthesis; moreover, the stereochemistry, previously in-
ferred from NMR data, was confirmed by X-ray crystal-
1
5
lography (Figure 4).
p(H ) = 60 atm, AcOH, PtO (25 mol%), r.t., 5 d], it was
Under optimised conditions
[
2
2
found that further treatment with Zn was unnecessary and
that 9 was the dominant product, comprising at least 40
mol% of the total. Separation of the N-Boc-protected iso-
mers proved impractical; 9 could only be obtained as a
mixture with a second product, possibly the tris-Boc de-
rivative of 6. However, the amines themselves could be
resolved by flash chromatography on silica gel using a po-
lar CHCl –MeOH–NH aqueous system as eluent. Tri-
Figure 4 Molecular structure of 9 in the crystal
–
8
–1 19
for Cl in CHCl = 2.7 ꢀ 10 M . Similar properties
3
may be expected for 10a, and even higher affinities should
be available through use of more electron-poor aryl sub-
stituents.7 Compound 10a thus introduces a family of
electroneutral anion receptors which are powerful, lipo-
philic and readily available in 5 steps from an inexpensive
starting material.
b,8
3
3
1
6
amine 2a was thereby obtained in 32% yield. The full
sequence from cholic acid (1) gave 2a in four steps and
2
7% overall yield.
In conclusion, a short 4-step sequence has been developed
for the conversion of cholic acid (1) to the all-a triamino
ester 2a. The procedure will facilitate the exploration of 2
as a facial amphiphile and as a precursor for synthetic re-
ceptors, especially tris-urea anion receptors such as 10a.
O
OH
OMe
i
1
HO
OH
7
H
Acknowledgment
This research was supported by the EPSRC (GR/R42757) and the
European Commission. Assistance from the EPSRC National Mass
Spectroscopy Service Centre, Swansea, is gratefully acknowledged.
MN wishes to thank the Academy of Finland for financial support.
ii
O
O
OMe
iii
5
References
O
O
8
H
(
1) (a) Cheng, Y. A.; Suenaga, T.; Still, W. C. J. Am. Chem. Soc.
1996, 118, 1813. (b) Kasal, A.; Kohout, L.; Lebl, M. Coll.
Czech. Chem. Commun. 1995, 60, 2147. (c) Zhou, X. T.;
Rehman, A.; Li, C. H.; Savage, P. B. Org. Lett. 2000, 2,
Scheme 1 Reagents and conditions: (i) MeOH, H SO , 95%; (ii)
2
4
Ca(ClO) (aq), AcOH, overnight, 0 °C to r.t., 98%; (iii) H NOH·HCl,
2
2
KOAc, MeOH, 5 h, reflux, 91%
3015. (d) De Muynck, H.; Madder, A.; Farcy, N.; De Clercq,
P. J.; Pérez-Payán, M. N.; Öhberg, L. M.; Davis, A. P.
Angew. Chem. Int. Ed. 2000, 39, 145.
OMe
O
(2) (a) Hsieh, H.-P.; Muller, J. G.; Burrows, C. J. J. Am. Chem.
Soc. 1994, 116, 12077. (b) Geall, A. J.; Al-Hadithi, D.;
Blagbrough, I. S. Bioconjugate Chem. 2002, 13, 481.
NHBoc
NHBoc
NHBoc
9
(
3) (a) Walker, S.; Sofia, M. J.; Kakarla, R.; Kogan, N. A.;
Wierichs, L.; Longley, C. B.; Bruker, K.; Axelrod, H. R.;
Midha, S.; Babu, S.; Kahne, D. Proc. Natl. Acad. Sci. U.S.A.
OR
O
HN
O
O
1996, 93, 1585. (b) Vandenburg, Y. R.; Smith, B. D.; Pérez-
N
H
Payán, M. N.; Davis, A. P. J. Am. Chem. Soc. 2000, 122,
3252.
N
O
N
H
Ph
H
N
H
N
(4) (a) Li, C. H.; Budge, L. P.; Driscoll, C. D.; Willardson, B.
M.; Allman, G. W.; Savage, P. B. J. Am. Chem. Soc. 1999,
121, 931. (b) Savage, P. B. Eur. J. Org. Chem. 2002, 759.
Ph
H
Ph
1
0a R = Me
1
0b R = C20H41
(
c) Ronsin, G.; Kirby, A. J.; Rittenhouse, S.; Woodnutt, G.;
Figure 3
Camilleri, P. J. Chem. Soc., Perkin Trans. 2 2002, 1302.
5) Davis, A. P.; Joos, J.-B. Coord. Chem. Rev. 2003, 240, 143.
6) McQuade, D. T.; Barrett, D. G.; Desper, J. M.; Hayashi, R.
K.; Gellman, S. H. J. Am. Chem. Soc. 1995, 117, 4862.
(7) (a) Davis, A. P.; Perry, J. J.; Williams, R. P. J. Am. Chem.
Soc. 1997, 119, 1793. (b) Ayling, A. J.; Pérez-Payán, M. N.;
Davis, A. P. J. Am. Chem. Soc. 2001, 123, 12716.
(
(
To illustrate the value of this procedure, 2a was further
converted into the anion receptor 10a by treatment with
1
8
phenyl isocyanate. Measurements on close analogue
0b (prepared via a 14-step sequence) have revealed high
1
binding constants to a number of anions; for example, Ka
Synlett 2005, No. 8, 1319–1321 © Thieme Stuttgart · New York

LETTER
Short Synthesis of Methyl 3a,7a,12a-Triaminocholanoate
1321
(
8) Koulov, A. V.; Lambert, T. N.; Shukla, R.; Jain, M.; Boon,
CHCl –i-PrOH (9:1). The combined organic layers were
3
J. M.; Smith, B. D.; Li, H. Y.; Sheppard, D. N.; Joos, J. B.;
dried (MgSO ), filtered, and evaporated. Flash
4
Clare, J. P.; Davis, A. P. Angew. Chem. Int. Ed. 2003, 42,
chromatography on silica gel, eluting with CHCl –MeOH–
3
4
931.
NH aq (28% NH in H O; 85:10:5) afforded 2a (413 mg,
3
3
2
1
7 1
(
9) Broderick, S.; Davis, A. P.; Williams, R. P. Tetrahedron
Lett. 1998, 39, 6083.
32%) as an off-white solid; R = 0.16. H NMR (400 MHz,
f
CDCl ): d = 0.78 (s, 3 H, 18-CH3), 0.93 (s, 3 H, 19-CH ),
3
3
(
(
10) Davis, A. P.; Pérez-Payán, M. N. Synlett 1999, 991.
11) (a) Li, C. H.; Rehman, A.; Dalley, N. K.; Savage, P. B.
Tetrahedron Lett. 1999, 40, 1861. (b) Zhou, X. T.; Rehman,
A.; Li, C. H.; Savage, P. B. Org. Lett. 2000, 2, 3015.
0.99 (d, J = 5.4 Hz, 3 H, 21-CH ), 3.05 (m, 1 H, 3b-H), 3.30
3
(br s, 1 H, 3b-H), 3.30 (br s, 1 H, 7b-H), 3.47 (s, 3 H,
CO CH ), 3.50 (s, 1 H, 12b-H). For characterisation as 9,
2
3
triamine 2a (300 mg, 0.71 mmol) was dissolved in MeOH (7
(c) The former describes the reduction of oxime and ester
mL), Et N (400 mL, 290 mg, 2.9 mmol) and di-tert-
3
groups in 5 using NaBH /TiCl . The major hydroxytriamine
butyldicarbonate (624 mg, 2.86 mmol) were added and the
mixture was stirred overnight at 50 °C. Evaporation,
dissolution in CH Cl –EtOAc (98:2) and filtration through a
4
4
product has the all-a stereochemistry. The latter describes
the hydrogenation of a 3,7-dioxime, again to give mainly the
all-a product.
2
2
plug of silica gave tricarbamate 9 (480 mg, 94%) as a white
(
(
(
12) Fieser, L. F.; Rajagopalan, S. J. Am. Chem. Soc. 1949, 71,
solid. The product was identical (NMR, TLC) to material
prepared using the method in ref.
(17) The major side-products, presumably stereoisomers of 2a,
1
0
3935.
13) Pearson, A. J.; Chen, J.-S.; Han, G. R.; Hsu, S.-Y.; Ray, T.
J. Chem. Soc., Perkin Trans. 1 1985, 267.
possess R ≥0.26 in this solvent system.
f
14) Two sets of conditions were used: (i) THF, NaHCO aq, r.t.,
(18) Triurea 10a.
3
1
0
4
8 h (as described in ref. ), and (ii) MeOH, Et N, 50 °C, 12
Triamine 2a (300 mg, 0.71 mmol), DMAP (88 mg, 0.72
3
h. The latter method proved more convenient and effective.
Details are given in ref. below.
mmol) and Et N (396 mL, 287 mg, 2.84 mmol) were
3
1
6
dissolved in dry THF (7 mL). Phenyl isocyanate (309 mL,
338 mg, 2.84 mmol) was added and the mixture was refluxed
for 6 h under a nitrogen atmosphere. The solvent was
(
15) Crystal data for 9: C H N O 0.5 CH Cl , M = 762.45,
4
0
69
3
8·
2
2
a = 14.9131 (4), b = 20.251 (1), c = 32.299 (1) Å,
3
V = 9754.5 (6) Å , orthorhombic, C222 (No. 20), Z = 8,
evaporated and the residue was redissolved in CHCl and
1
3
–
3
–1
D = 1.038 g·cm , m(MoK ) = 0.124 mm , F(000) = 3320,
washed with H O. The organic phase was dried (MgSO ),
c
a
2
4
colourless crystal of size 0.20 ꢀ 0.20 ꢀ 0.30 mm, T = 173 ±
.1 K. 19433 reflections collected, 8525 unique
Rint = 0.074), 5049 reflections (I > 2sI) were used in
filtered, and evaporated. Flash chromatography, eluting with
CH Cl –MeOH (97:3), and crystallisation (MeOH–CHCl )
0
(
2
2
3
afforded the triurea 10a (405 mg, 72%); mp 197–199 °C. IR
(solid state): nmax = 3330, 2935, 2871, 1734, 1656, 1596,
refinement. R1 = 0.0930 and wR2 = 0.2161 for data I > 2sI
and 500 parameters and R1 = 0.1607and wR2 = 0.2508 for
all data. Absolute structure parameter refined –0.3 (3),
–
1 1
1544, 1498, 1439, 1235, 1223, 751, 691 cm . H NMR (400
MHz, MeOH-d ): d = 0.89 (m, 3 H, 18-CH ), 0.93 (d, J = 6.4
4
3
2
Goodness of fit on F = 1.109. CCDC-250336 contains the
Hz, 3 H, 21-CH ), 1.03 (s, 3 H, 19-CH ), 2.04–2.10 (m, 1 H),
3
3
supplementary crystallographic data for this paper. These
data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; fax: (internat.) +44 (1223)336033; email:
deposit@ccdc.cam.ac.uk].
2.19–2.27 (m, 1 H), 2.31–2.39 (m, 1 H), 3.27 (m, 1 H, 3b-H),
3.61 (s, 3 H, CO CH ), 3.90 (br s, 1 H, 7b-H), 4.10 (s, 1 H,
2
3
12b-H), 6.91–7.00 (m, 3 H, ArH), 7.17–7.28 (m, 8 H, ArH),
1
3
7.35–7.39 (m, 4 H, ArH). C NMR (100 MHz, MeOH-d ):
4
d = 14.99 (CH ), 18.68 (CH ), 24.47 (CH ), 25.23 (CH ),
3
3
3
2
28.57 (CH ), 29.10 (CH ), 30.01 (CH ), 31.06 (CH ), 32.85
2
2
2
2
(
16) Hydrogenation of Trioxime 5.
(CH ), 34.45 (C), 36.88 (CH), 39.48 (CH), 44.36 (CH),
2
Trioxime 5 (1.4 g, 3.03 mmol), PtO ·H O (186 mg, 0.76
46.99 (C), 52.83 (CO CH ), 55.25 (CH), 121.30 (ArCH),
2
2
2
3
mmol) and AcOH (31 mL) were stirred vigorously for 5 d
under 60 atmospheres of hydrogen. The solution was filtered
under reduced pressure and evaporated. The residue was
dissolved in CHCl –i-PrOH (9:1) and washed with Na CO
121.34 (ArCH), 121.36 (ArCH), 124.37 (ArCH), 124.46
(ArCH), 124.50 (ArCH), 130.62 (ArCH), 158.40
(NHCONHAr), 158.43 (2 ꢀ NHCONHAr), 177.22
+
+
(CO CH ). MS (ES ): m/z (%) = 777 (100) [M] .
3
2
3
2
3
(aq sat.). The aqueous phase was extracted with 3 portions of
(19) Clare, J. PhD Thesis; University of Bristol: UK, 2004.
Synlett 2005, No. 8, 1319–1321 © Thieme Stuttgart · New York