A convergent preparation of the C1-C13 fragment of amphotericin B from a single chiral precursor

Article abstract of DOI:10.1016/j.tetlet.2004.01.035

A short, highly efficient, stereoconvergent synthesis of the polyolic chain, C1-C13, of the macrolide antibiotic amphotericin B is described. The key features of the synthesis are the use of a single chiral precursor for the establishment of the stereogenic centres in a short synthetic sequence, and the final alkyl lithium addition to the appropriate aldehyde, which showed high diastereoselectivity for the correct stereochemistry at the fifth stereogenic centre.

Full text of DOI:10.1016/j.tetlet.2004.01.035

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2177–2179
A convergent preparation of the C1–C13 fragment of amphotericin
B from a single chiral precursor
Carlo Bonini,* Lucia Chiummiento, Angela Martuscelli and Licia Viggiani
Dipartimento di Chimica, Universitꢀa degli Studi della Basilicata, Via N. Sauro, 85, 85100 Potenza, Italy
Received 18 November 2003; revised 21 December 2003; accepted 9 January 2004
Abstract—A short, highly efficient, stereoconvergent synthesis of the polyolic chain, C1–C13, of the macrolide antibiotic ampho-
tericin B is described. The key features of the synthesis are the use of a single chiral precursor for the establishment of the stereogenic
centres in a short synthetic sequence, and the final alkyl lithium addition to the appropriate aldehyde, which showed high diastereo-
selectivity for the correct stereochemistry at the fifth stereogenic centre.
Ó 2004 Elsevier Ltd. All rights reserved.
Extensive work on the polyene macrolide amphotericin
B, a potent fungicide in clinical use1 produced by
Streptomyces nodosus, has led to three landmark total
syntheses of this antibiotic.2–4 In particular, the polyolic
segment of its aglycon, amphoteronolide B, has been the
target of synthetic organic chemists and several
approaches to different long polyolic chains have been
described.2–5 The C1–C13fragment is particularly useful
since it has been already utilized for two total synthe-
ses2;4 and therefore its improved preparation remains an
intriguing objective.
Amphotericin B
OH
OH
O
37
1
Me
HO
Me
OH
CO H
O
8
12
20
OH OH
O
OH OH
2
Me
H
1
Omycosamine
OH
8
3
13 OTBDMS
BnO
11
O
1
5
9
O
O
O
2
Our retrosynthetic analysis (see Scheme 1) was focused
on the Nicolaou fully protected C1–C13polyol 22 with a
hidden plane of symmetry: this compound 2 could be
derived by the coupling of the two fragments 3 and 4
already possessing four of the five stereogenic centres.
Both 3 and 4 can be eventually derived from a single
chiral precursor such as 5, possessing the 1,3-syn diol
moiety required for both fragments 3 and 4.
H
13
1
3
11
O
9
BnO
5
OTBDMS
7
I
O
+
O
O
O
3
4
1
3
AcO
7
5
OH
O
O
Compound 5 is a polyfunctional seven-carbon tetrol,
which can be easily prepared6 in both optically pure
forms by an optimized eight-step procedure,7 with the
final biocatalytic desymmetrization of the corresponding
meso compound as a key reaction. This desymmetriza-
tion with PSL (Pseudomonas sp. lipase) as catalyst has
5
Scheme 1. Retrosynthetic analysis.
been carried out several times on a multigram scale,
always with quantitative overall yield and with ee6 val-
ues of more than 98%. This chiral synthon 5 has been
already utilized for the preparation of the polyolic chain
of other macrolide antibiotics such as the C1–C108 and
C1–C139 fragments of nystatin A1, as well as for mevinic
acid analogues.6
Keywords: Amphotericin B; Polyols; Asymmetric synthesis; Diastereo-
selective addition.
* Corresponding author. Tel.: +39-0971-202254; fax: +39-0971-202-
223; e-mail: bonini@unibas.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.035

2178
C. Bonini et al. / Tetrahedron Letters 45 (2004) 2177–2179
5
OH
BnO
a
OTBDMS
8
3 +
4
a,b
70%
O
O
O
O
HO
OTBDMS
2
de > 90%
O
O
6 (93%)
Scheme 3. Coupling reaction between 3 and 4. Reagents and condi-
tions: (a) t-BuLi, Et2O, )78 °C, 30 min, MgBr2, CuI, )78 °C, 2 h.
c
f
OTBDMS
BnO
BnO
o-NO2C6H4Se
OTBDMS
OTBDMS
After several attempts to prepare different organome-
tallic reagents in different solvents, the Li-derived frag-
ment 3 (see Scheme 3) was successfully added, in the
presence of MgBr2 and CuI, to the aldehyde 4 to give12
O
O
O
O
O
7 (95%)
9 (90%)
g
d
the single diastereoisomer 2. Compound 2 showed an
25
D
identical 1H NMR spectrum and ½aŠ +6.3° (c 0.30,
OH
CHCl3) to the reported C1–C13fragment (by Nicolaou
et al.).2a
O
O
O
10 (73%)
8 (90%)
The success of the diastereoselective addition of 3–4,
could have been anticipated by considering the reaction
conditions. In fact, it has already been reported in cases
with a similar polyfunctional structure, for example,
glyceraldehyde acetonide,13 that the chelation of the
Mg2þ between the carbonyl and an a-alkoxyl group
allows an easier approach for the incoming nucleophile
on one side of the C@O. As shown in Figure 1, the
probable role of the Mg2þ is in chelating the aldehyde
function and the protected hydroxy group in compound
3, allowing the preferred approach of the alkylcopper
complex to afford the required syn-diastereoisomer.
e
h
3 (70%)
4 (80%)
Scheme 2. Preparation of the synthons 3 and 4. Reagents and condi-
tions: (a) imid., TBSCI, DMAP, CH2Cl2, 0 °C, 20 h; (b) Na, CH3OH,
rt, 4 h; (c) BnBr, NaH, THF, rt, 48 h; (d) TBAF, THF, rt, 3h; (e) I 2,
Ph3P, imid., toluene, 70 °C, 2 h; (f) o-(NO2)C6H4SeNC, n-Bu3P, THF,
rt, 3h; (g) H 2O2, THF, rt, 4 h; (h) OsO4, NMO/NaIO4, THF/H2O, rt,
12 h.
With a large quantity of the starting synthon 5 available,
the synthetic sequences (see Scheme 2) were accom-
plished.
This synthesis of the C1–C13fragment of amphotericin
B, represents the shortest route to this key polyol, with a
total of 17 steps starting from commercially available
starting materials and with the use of simple reactions
and easily available and cheap reagents. Furthermore
four of the five stereogenic centres can be introduced via
a well researched biocatalytic reaction to 5. Finally the
fifth stereogenic centre has been successfully introduced
via a metal-chelated addition of the two fragments with
a high diastereoselection in favor of the correct frag-
ment 2.
Firstly compound 5 was transformed in two steps
(TBDMS introduction and then deacetylation) into the
more conveniently functionalized compound 610 in an
overall 93% yield. This compound was then subjected to
two different synthetic sequences to obtain the fragments
3 and 4.
In the first sequence, 6 (see Scheme 2) was benzylated to
compound 7. Desilylation to compound 8 was followed
by the introduction of the required iodine functional-
ization to give compound 3, with an overall 66% yield
(from 6) and in 13steps starting from commercially
available compounds.6;7 Compound 3 is the same syn-
thon already prepared in the McGarvey total synthesis4
by a longer sequence of steps compared to ours.
The further application of this chemistry to other related
polyol fragments of complex molecules is under inves-
tigation.
Experimental procedure for the coupling reaction between
3 and 4. To a stirred solution of 3 (0.100 g, 0.24 mmol) in
ether (5 mL) at )78 °C under argon was added dropwise
a
solution 1.5 M in ether of t-BuLi (0.24 mL,
In the other sequence, the one-carbon shortening of
compound 6 was achieved via a selenium oxide prepa-
ration (compound 9) and then syn elimination to the
olefin 10 (two steps with an overall 65% yield). The final
six-carbon fragment 4 was then obtained via double
bond oxidation to the required aldehyde: the aldehyde 4
0.36 mmol). The resulting mixture was stirred for
30 min. After this period the mixture was cannulated
into a solution of CuI (0.055 g, 0.29 mmol) in ether
O
O
Mg
O
is the same as the fragment prepared by Carreira and
5e
O
€
Kruger.
Cu
OBn
O
H
H
With the two fragments 3 and 4 in hand, we faced the
coupling to give the desired target 2, possibly with the
direct introduction of the correct configuration at C-8.11
TBDMSO
Figure 1.

C. Bonini et al. / Tetrahedron Letters 45 (2004) 2177–2179
2179
4. McGarvey, G. J.; Mathys, J. A.; Wilson, K. J. Org. Chem.
1996, 61, 5704–5705.
5. For the synthesis of the polyolic fragment see for C1–C12:
(a) Masamune, S.; Ma, P.; Okumoto, H.; Ellingboe, J. W.;
(3mL) and stirred for 10 min. A solution of 4 (0.048 g,
0.16 mmol) and MgBr2 etherate (0.082 g, 0.32 mmol) in
ether (2 mL) was cannulated therein and the reaction
mixture was heated to room temperature for 2 h and
quenched with aqueous NH4Cl. The layers were sepa-
rated and the aqueous layer was extract with ether. The
combined organic layers were washed with brine, dried
over Na2SO4 and evaporated under reduced pressure.
The residue was purified by chromatography (petroleum
ether/EtOAc 7:3) on silica gel to provide the alcohol 2
(0.065 g, 70%) as an oil: ½aŠ +6.3° (c 0.30, CHCl3); H
NMR (300 MHz, CDCl3) dD¼ 7.40–7.30 (m, 5H), 4.51 (s,
2H), 4.10–3.36 (m, 9H), 2.70 (br s, 1H), 1.80–1.15 (m,
12H), 1.45 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H), 1.39 (s,
3H), 0.90 (s, 9H), 0.05 (s, 6H). Anal. calcd for
C32H56O7Si (580.87): C, 66.17; H, 9.72. Found: C, 66.34;
H, 9.66.
ꢁ
Ito, Y. J. Org. Chem. 1984, 49, 2837–2838; (b) Solladie,
G.; Hutt, J. Tetrahedron Lett. 1987, 28, 797–800; For C2–
C12: (c) Hanessian, S.; Sahoo, S. P.; Botta, M. Tetrahe-
dron Lett. 1987, 28, 1143–1146; For C1–C13: (d) McGar-
vey, G. J.; Mathys, J. A.; Wilson, K. J.; Overly, K. R.;
Buonora, P. T.; Spoors, G. P. J. Org. Chem. 1995, 60,
€
7778–7790; (e) Kruger, J.; Carreira, E. M. Tetrahedron
25
1
Lett. 1998, 39, 7013–7016; For C1–C14: (f) BouzBouz, S.;
Cossy, J. Org. Lett. 2000, 2, 3975–3977.
6. (a) Bonini, C.; Racioppi, R.; Righi, G.; Viggiani, L. J.
Org. Chem. 1993, 58, 802–803; (b) Bonini, C.; Racioppi,
R.; Viggiani, L.; Righi, G.; Rossi, L. Tetrahedron:
Asymmetry 1993, 4, 793–805.
7. Compound 5 was prepared in eight steps (47% overall
yield) according to our previous report6 with an increase in
the yield of the corresponding c-hydroxy-b-keto ester
(above 70%), that was directly reduced to the 1,3-syn diol
without any purification.
8. Bonini, C.; Giugliano, A.; Racioppi, R.; Righi, G.
Tetrahedron Lett. 1996, 37, 2487–2490.
Acknowledgements
ꢁ
9. Solladie, G.; Wilb, N.; Bauder, C.; Bonini, C.; Viggiani,
Thanks are due to the University of Basilicata and the
MIUR (FIRB-Progettazione, preparazione e valutazi-
one biologica e farmacologica di nuove molecole or-
ganiche quali potenziali farmaci innovativi grant) for
financial supports. A.M. thanks CINMPIS for a fel-
lowship.
L.; Chiummiento, L. J. Org. Chem. 1999, 64, 5447–5452.
10. The choice of the protecting groups was determined in
order to obtain the known polyol fragment 2 for compar-
ison with the reported data. The use of another protecting
group sequence, leading to a differently protected C1–C13
fragment, would allow
sequence.
a shortcut of the synthetic
11. In all the described syntheses of the C1–C13fragment of
amphotericin B,2a;4 the direct introduction of the OH
group on the C-8, always gave an unsatisfactory diaste-
reomeric ratio. Therefore all syntheses follow the Nicolaou
original approach with the diastereoselective reduction of
the corresponding ketone.
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Practice; Academic: New York, 1984; (b) Cohen, B. E. Int.
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Papahatjis, D. P.; Chakraborty, T. K. J. Am. Chem. Soc.
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12. The diastereoisomeric ratio was determined, as reported in
1
Ref. 2a, via H NMR analysis on the acetyl derivative of
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