Enantioselective allyltitanation. Efficient synthesis of the C1-C14 polyol subunit of amphotericin B

Article abstract of DOI:10.1021/ol0063914

(Matrix presented) An efficient synthesis of the C₁-C₁₄ fragment of amphotericin B is described. This synthesis is based on the formation of syn-1,3-diols from enantioselective allyltitanation of unprotected β-hydroxyaldehydes.

Full text of DOI:10.1021/ol0063914

ORGANIC
LETTERS
2000
Vol. 2, No. 25
3975-3977
Enantioselective Allyltitanation. Efficient
Synthesis of the C1−C14 Polyol Subunit
of Amphotericin B
Samir BouzBouz* and Janine Cossy*
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received July 28, 2000
ABSTRACT
An efficient synthesis of the C −C fragment of amphotericin B is described. This synthesis is based on the formation of syn-1,3-diols from
1
14
enantioselective allyltitanation of unprotected â-hydroxyaldehydes.
The polyene macrolide antibiotics have received considerable
attention as a result of their selective cytotoxic properties.1
Several of these compounds, most notably amphotericin B,
have gained clinical prominence for treatment of systemic
fungal infections.2,3 As a consequence of the interest in the
structural and biological features of the polyene macrolide
antibiotics, they have become appealing targets for synthetic
studies. Accordingly, a conspicuous synthetic challenge is
found in the 1,3-polyol regions that are ubiquitous to this
family of compounds. A feature of the polyol segment of
amphotericin B compared to other macrolides is that it
possesses a varied disposition of hydroxyl substituents (1,3-
diols, 1,4-diols, and 1,2-diols). The only member of this
family of macrolides that contains a similar pattern of
hydroxyl substitution is surgumycin. The C2-C13 segment
of amphotericin compares to the C18-C29 segment of
surgumycin, and this could be a common fragment for their
synthesis if the relative stereochemistry of the hydroxy
groups is identical (Figure 1).
Figure 1.
Amphotericin B and its aglycon, amphoteronolide B,
represent important synthetic targets, providing unique
opportunities for the development of both new and existing
synthetic technologies.4,5 Recently, we described a direct
method for obtaining 1,3-diols with excellent diastereomeric
(1) (a) Omura, S. Macrolide Antibiotics: Chemistry, Biology, Practice;
Academic Press: New York, 1984. (b) Rychnovsky, S. D. Chem. ReV. 1995,
95, 2021. (c) Hunter, P. A. Drug DiscoV. Today 1996, 1, 227.
(2) Sarosi, G. A. Postgrad. Med. 1990, 88, 151.
(3) Sabra, R.; Branch, R. A. Drug Safety 1990, 5, 94.
10.1021/ol0063914 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/15/2000

excess by the allyltitanation6 of unprotected â-hydroxy-
with aqueous osmium tetroxide/sodium periodate to afford
the stable aldehyde 49 in 90% yield (Scheme 3).
aldehydes7 (Scheme 1). This strategy was exploited to good
Scheme 3
Scheme 1
advantage in our recently reported synthesis of lactone units
of mevinolin and compactin.8 Herein, we report an applica-
tion of this approach for the construction of the C1-C14
fragment of amphotericin B.
As shown in the retrosynthetic analysis of the C1-C14
fragment (acetonide) of amphotericin B, we envisioned the
introduction of the desired C3, C5, C9, and C11 stereogenic
centers through asymmetric allyltitanation starting from
aldehyde 4. The requisite aldehyde would be potentially
available from (S)-glycidol or R-alkoxyaldehyde 1a (Scheme
2).
With the intermediate 4 available in enantiopure form and
in high overall yield (60%), we turned our attention to the
elaboration of the C1-C14 fragment of amphotericin B
(Scheme 4). Enantioselective allyltitanation of aldehyde 4
with cyclopentadienyldialkoxyallyltitanium complex (R,R)-I
gave homoallylic alcohol 5 in high yield (92%). The
transfomation of this alcohol to the corresponding â-hy-
droxyaldehyde was achieved by the use of sodium periodate
in the presence of 1.8 mol % of osmium tetroxide. This
â-hydroxyaldehyde was immediately treated with allyltita-
nium complex (R,R)-I to deliver homoallylic 1,3-diol 610
(4) (a) Nicolaou, K. C.; Daines, R. A.; Uenishi, J.; Li, W. S.; Papahatjis,
D. P.; Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, 4672. (b) Nicolaou,
K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y. J. Am. Chem. Soc.
1988, 110, 4685. (c) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.;
Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, 4696. (d) Masamune, S.;
Ma, P.; Okumoto, H.; Ellingboe, J. W.; Ito, Y. J. Org. Chem. 1984, 49,
2837.
Scheme 2
(5) (a) McGarvey, G. J.; Mathys, J. A.; Wilson, K. J.; Overly, K. R.;
Buonora, P. T.; Spoors, P. G. J. Org. Chem. 1995, 60, 7778. (b) McGarvey,
G. J.; Mathys, J. A.; Wilson, K. J. J. Org. Chem. 1996, 61, 5704. (c) Kru¨ger,
J.; Carreira, E. M. Tetrahedron Lett. 1998, 39, 7013.
(6) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, J.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(7) BouzBouz, S.; Cossy, J. Org. Lett. 2000, 2, 501.
(8) BouzBouz, S.; Cossy, J. Tetrahedron Lett. 2000, 41, 3363.
(9) Aldehyde 4 was prepared by an alternative method from the protected
R-alkoxyaldehyde 1a in high overall yield (69%):
(S)-Glycidol 1 was transformed to the corresponding
p-methoxybenzyl (PMP) derivative 2 (80%) by the Mit-
sunobu procedure. The epoxide ring of 2 was opened with
allylmagnesium chloride in THF, and the resulting secondary
alcohol was protected with methoxymethyl chloride to afford
diether 3 (84% for two steps). The double bond was oxidized
(10) Synthesis of 6. A solution of 5 (0.124 g, 0.4 mmol, 1 equiv),
N-methylmorpholine N-oxide hydrate (0.132 g, 0.68 mmol, 1.7 equiv), and
OsO4 (2.5% in t-BuOH, 0.07 mL, 7.23 10-3 mmol) in acetone (3 mL) and
H2O (1 mL) was vigourously stirred at 25 °C. After 20 min (TLC analysis
showed complete consumption of the starting alkene), a solution of NaIO4
(0.352 g, 2 mmol, 2 equiv) in H2O (10 mL) was added, and stirring was
continued for 30 min. The mixture was diluted with water and extracted
with EtOAc (3 × 10 mL), and the combined organic phases were washed
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Org. Lett., Vol. 2, No. 25, 2000

Scheme 4a
a (a) (R,R)-I, ether, -78 °C, 4 h; (b) (1) OsO4, NMO, acetone/H2O, NaIO4, 25 °C, (2) (R,R)-I, ether, -78 °C, 4 h; (c) MOMCl, iPr2NEt,
CH2Cl2, 25 °C; (d) OsO4, NMO, acetone/H2O, NaIO4, 25 °C; (e) NaBH4, MeOH, 0 °C; (f) PivCl, pyridine, 25 °C; (g) CAN, CH3CN/H2O,
30 min, 0 °C; (h) (COCl)2, DMSO, CH2Cl2, -78 °C, Et3N, 25 °C; (i) (S,S)-II, ether, -78 °C, 4 h; (j) (1) OsO4, NMO, acetone/H2O, NaIO4,
25 °C, (2) (S,S)-II, ether, -78 °C, 4 h; (k) DMP/acetone, CSA, 25 °C.
(70%) with high diastereoselectivity (dr ) 97/3). The relative
stereochemistry of the syn-1,3-diol 6 was determined by
converting it to the corresponding acetonide 7 and by
analyzing the 13C NMR chemical shifts11 (Scheme 5). As
the acetonide of compound 7 is sensitive to ceric ammonium
nitrate (CAN), compound 6 was transformed to 7a, which
was obtained by protection of diol 6 with MOMCl in the
presence of Hunig’s base in high yield (90%).
NaIO4), reduction of the aldehyde with sodium borohydride
in the presence of methanol at 0 °C, and protection of the
alcohol with pivaloyl chloride in the presence of pyridine
(72%, three steps).
Treatment of 8 with CAN in a biphasic mixture (CH3CN/
H2O), followed by Swern oxidation, afforded the aldehyde
9 (81%). This compound was immediately treated with
allyltitanium complex (S,S)-II to provide the secondary
alcohol 10 (89%). Similarly, the transformation of homo-
allylic alcohol 10 to the corresponding â-hydroxyaldehyde
and immediate treatment of the aldehyde with allyltitanium
complex (S,S)-II gave the diol 11 (73%). The relative
stereochemistry of the syn-1,3-diol was confirmed by 13C
NMR analysis of the acetonide 12.11,12
Scheme 5
In conclusion, we have described an efficient and stereo-
selective synthesis of the C1-C14 polyol fragment of
amphotericin B that utilizes a versatile and rapid method for
the formation of syn-1,3,-diol from â-hydroxy aldehydes,
without any protective or deprotective steps.
The double bond of 7a was then transformed to the
protected ether 8 by oxidative cleavage (OsO4, NMO;
Acknowledgment. The authors are indebted to Dr. R.
O. Duthaler for a generous gift of chiral cyclopentadienyl-
dialkoxytitanium chloride complexes and C. Ferroud and A.
Falguie`res for HPLC analysis.
with brine, dried with MgSO4, and concentrated under vacuum to furnished
the crude hydroxyaldehyde (0.112 g). The crude hydroxyaldehyde was used
immediately for the preparation of diol 6. Allylmagnesium chloride in THF
(0.195 mL of a 2 M solution, 0.388 mmol) was added dropwise over 5 min
at 0 °C to a solution of (R,R)-I (0.285 g, 0.46 mmol) in ether (8 mL). After
stirring for 90 min at 0 °C, the slightly orange suspension was cooled at
-78 °C, and the crude aldehyde dissolved in ether (3 mL) was added
dropwise over a period of 5 min. Stirring at -78 °C was continued for 4
h. The reaction mixture was then treated with water (10 mL), stirred for 14
h at 25 °C, filtered through Celite, and extracted twice with Et2O (2 × 20
mL) and then with EtOAc (10 mL). The combined organic phases were
washed with brine, dried over MgSO4, and concentrated. Purification of
the residue by silica gel chromatography (EtOAc/hexane 2/8) furnished
0.089 g of diol 6 (70% yield, calculated from the aldehyde). The Taddol
ligand was recovered (75%).
OL0063914
(12) Data for acetonide 12: 1H NMR (CDCl3, 300 MHz) 5.90-5.70
(m, 1H), 5.17-5.07 (m, 2H), 4.80-4.61 (m, 6H), 4.20-4.13 (m, 2H), 4.02-
3.51 (m, 5H), 3.45 (3s, 9H), 2.41-2.10 (m, 2H), 2.02-1.40 (m, 10H), 1.47
(s, 3H), 1.37 (s, 3H), 1.20 (s, 9 H); 13C NMR (75 MHz, CDCl3) 178.3 (s),
134.1 (d), 117.1(t), 98.5 (s), 96.9 (t), 95.6 (t), 95.5 (t), 79.8 (d), 74.5 (d),
71.9 (d), 70.9 (d), 68.5 (d), 61.0 (t), 55.7 (3q), 40.9 (t), 39.8 (t), 38.5 (s),
33.6 (t), 31.5 (t), 30.4 (t), 30.0 (q), 27.2 (q, t-Bu), 25.2 (t), 19.7 (q); MS
(IE) m/z 534 (M+), 533 (3), 427 (2), 353 (10), 323 (4), 287 (46), 257 (11),
155 (100), 97 (86), 79 (20), 57 (23).
(11) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945.
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