Selective oxidation of hydroxy groups of bafilomycin A1

Full text of DOI:10.1021/jo9607222

J . Org. Chem. 1996, 61, 7185-7188
7185
disclosed.14 Apart from degradative ozonolysis,15 nothing
is reported in the literature about the oxidation of this
macrolide, and we thought it worthwhile to investigate
this reaction with the aim of achieving selective oxidation
of the different hydroxy groups of 1.
Selective Oxid a tion of Hyd r oxy Gr ou p s of
Ba filom ycin A1
Pier Andrea Gatti, Stefania Gagliardi, Alberto Cerri,
Marco Visconti,† and Carlo Farina*
First, a preliminary survey of the behavior of bafilo-
mycin A1 in the presence of several oxidizing agents was
performed: while manganese dioxide or tetrapropylam-
monium perrhutenate (TPAP)16 were ineffective, chro-
mium compounds or Dess-Martin’s periodinane17 were
able to afford several oxidized products. It was observed
that long reaction times, high temperatures, or acidic
conditions resulted in extensive decomposition of the
macrolide. Therefore, all the subsequent reactions were
performed using a large excess of the oxidizing agent, at
low temperatures and in the presence of a buffering agent
when using acidic oxidants. Thus, treatment of 1 with
a 6-fold molar excess of PCC buffered with sodium acetate
in CH2Cl2 afforded a mixture of 7-oxo (6) and 7,21-dioxo
(10) derivatives, while oxidation with excess PDC af-
forded a mixture of 6 and of the 19,20-dehydrated 7,21-
dioxo compound 9 (Scheme 1). When the 21-OH of 1 was
protected by acylation (3-5), the corresponding 7-oxo
derivatives 7 and 8 were smoothly obtained by treatment
with PCC and, as expected, the 19-methoxy group in
compound 4 was easily hydrolyzed during aqueous
workup.
Dess-Martin reagent appeared to be a more eclectic
oxidant, affording different oxidized compounds depend-
ing on the molar excess used. Thus, while in the presence
of stoichiometric amounts no reaction was observed, a
3-fold molar excess of periodinane afforded a quantitative
yield of the dioxo derivative 10 and a 7.5-fold excess
afforded the 19,20-dehydrated trioxo compound 11 in
80% yield.
Rather surprisingly, we were never able to isolate the
monooxidized 21-oxo derivative in any experimental
conditions, using either chromium oxidants or periodi-
nane.
Therefore, to obtain the desired 21-ketone 2, we
exploited the greater reactivity of the 21-hydroxy group
toward electrophilic reagents, as in the case of acylation
or alkylation. Consequently, the Swern reaction,18 en-
tailing an intermediate electrophilic sulfonium ion, proved
successful: treatment of 1 with oxalyl chloride/DMSO at
a temperature between -70 and -40 °C afforded 2 in
good yield (48%).
When pure compound 2 was treated with a large excess
of PCC, a very rapid and quantitative oxidation of the
7-hydroxy group, to give a mixture of 9 and 10 without
any evidence of degradation, was observed, suggesting
that oxidation of the more sterically hindered 7-hydroxy
group is faster than oxidation at 21.
SmithKline Beecham SpA, via Zambeletti, 20021 Baranzate
di Bollate (Milano), Italy
Received April 19, 1996
Bafilomycin A1 (1), a 16-membered antibiotic macrolide
isolated from the fermentation of Streptomyces griseus,1
belongs to the class of so-called “unusual macrolides”.2
This class also comprises the 18-membered concanamycin
A and the C2-symmetric 16-membered elaiophylin3 and
is characterized by the presence of a tetrahydropyran ring
within a long side chain. These macrolides are endowed
with several biological activities, including antitumor,4
antiviral,5 and immunosuppressant6 properties. In par-
ticular, 1 is a specific inhibitor of vacuolar H+-ATPase7
and has also been found to inhibit, in vitro, the release
of â-amyloid8 and the mitogen-induced DNA synthesis.9
Total synthesis of 1 has been recently achieved;10
however, owing to its highly functionalized nature,
selective derivatization of bafilomycin A1 still represents
a challenging target. Little information is available in
the literature about modification of the hydroxy groups
of bafilomycin, and this is limited to alkylation and
acylation.11 Whereas the OH at 19 easily forms a ketal
by reaction with alcohols in the presence of catalytic
amounts of acid, the 21-OH is the most reactive group
toward alkylation and acylation, since the 7-OH is
sterically hindered and the 17-OH is involved in a strong
hydrogen bonding system with the 19-OH and the lactone
carbonyl.12
In the framework of a research program aimed at
studying the pharmacological activity of bafilomycin
derivatives, we became interested in the selective oxida-
tion of the hydroxy groups at positions 7 and 21 of 1.
Although the biological activity of 21-oxobafilomycin (2)
has been previously reported,13 its synthesis was not
† Present address: F.lli Lamberti SpA, Via Piave 18, 21041 Albizzate
(Varese), Italy.
(1) Werner, G.; Hagenmaier, H.; Drautz, H.; Baumgartner, A.;
Za¨hner, H. J . Antibiot. 1984, 37, 110.
(2) Omura, S. Macrolide-like Antibiotics. In Macrolide Antibiotics.
Chemistry, Biology and Practice; Omura, S., Ed.; Academic Press: New
York, 1984; p 510.
(3) Bindseil, K. U.; Zeeck, A. J . Org. Chem. 1993, 58, 5487.
(4) Wilton, J . H.; Hokanson, G. C.; French, J . C. J . Antibiot. 1985,
38, 1449.
(5) Ochiai, H.; Sakai, S.; Hirabayashi, T.; Shimizu, Y.; Terasawa,
K. Antiviral Res. 1995, 27, 425.
(6) Kataoka, T.; Magae, J .; Kasamo, K.; Yamanishi, H.; Endo, A.;
Yamasaki, M.; Nagai, K. J . Antibiot. 1992, 45, 1618.
(7) Bowman, E. M.; Siebers, A.; Altendorf, K. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 7972.
(8) Knops, J .; Suomensaari, S.; Lee, M.; McConlogue, L.; Seubert,
P.; Sinha, S. J . Biol. Chem. 1995, 270, 2419. Haas, C.; Capell, A.;
Citron, M.; Teplow, D. B.; Selkoe, J . J . Biol. Chem. 1995, 270, 6186.
(9) Saurin, A. J .; Hamlett, J .; Clague, M. J .; Pennington, R. Biochem.
J . 1996, 313, 65.
(10) Toshima, K.; J yojima, T., Yamaguchi, H.; Murase, H.; Yoshida,
T.; Matsumura, S.; Nakata, M. Tetrahedron Lett. 1996, 37, 1069.
Toshima, K.; Yamaguchi, H.; J yojima, T.; Noguchi, Y.; Nakata, M.;
Matsumura, S. Tetrahedron Lett. 1996, 37, 1073.
(11) Werner, G.; Hagenmaier, H.; Albert, K.; Kohlshorn, H. Tetra-
hedron Lett. 1983, 24, 5193. Deeg, M.; Hagenmaier, H.; Kretschmer,
A. J . Antibiot. 1987, 11, 320.
Unambiguous identification of the oxidized compounds
1
was done by comparing H-NMR and COSY-90 spectra
(13) Dro¨se, S.; Bindseil, K. U.; Bowman, E. J .; Siebers, A.; Zeeck,
A.; Altendorf, K. Biochemistry 1993, 32, 3902.
(14) A short report on 7- and/or 21-oxobafilomycin derivatives
without any experimental or structural detail has been presented as
a poster communication: Baeden, T. C.; Buckwalter, B. L. Fourteenth
International Congress of Heterocyclic Chemistry, Antwerp, Aug 1-6,
1993; PO1-48.
(15) Meyer, M.; Keller-Schierlein, W.; Drautz, H.; Blank, W.; Za¨nher,
H. Helv. Chim. Acta 1985, 68, 83.
(16) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(12) Baker, G. H.; Brown, P. J .; Dorgan, R. J . J .; Everett, J . R.; Ley,
S. V.; Slawin, A. M. Z.; Williams, D. J . Tetrahedron Lett. 1987, 28,
5565.
(17) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(18) Tidwell, T. T. Synthesis 1990, 857.
S0022-3263(96)00722-0 CCC: $12.00 © 1996 American Chemical Society

7186 J . Org. Chem., Vol. 61, No. 20, 1996
Notes
Sch em e 1
with the corresponding data for 1.19 Essentially, the
disappearance of signals of the hydroxymethine group
and the appearance of downfield protons R to CdO
together with 13C-NMR data were used to determine the
number and position of the formed carbonyl groups. In
compounds 9 and 11 the formation of the R,â-unsaturated
carbonyl group was demonstrated by the presence of a
singlet for an olefinic proton at C-20 at δ 5.42 or 5.45,
respectively, and by the downfield shift of the allylic
hydrogen at position 18 (δ 2.60 or 3.87, respectively).
In compounds 2, 6-8, and 10, the diagnostic hydrogen
bonding system involving 17-OH, 19-OH, and the lactone
carbonyl system is maintained while in compounds 9 and
11 this is, of course, no longer possible owing to the
removal of the 19-hydroxy group.
were recorded with a triple quadrupole mass spectrometer;
experimental conditions were Xe gas, 8 kV, source temperature
50 °C, using diethanolamine matrix in negative-ion mode or
thioglycerol in positive-ion mode. Bafilomycin A1 was isolated
from the mycelium of Streptomyces griseus according to the
reported procedure.19 Reagents and solvent were purchased
from common commercial suppliers and were used as received
or distilled from the appropriate drying agent. Column chro-
matography (CC) was performed with silica gel 0.063-0.200 mm.
TLC was performed on Merck silica gel 60 F254 precoated plates
eluting with solvent A (hexane/AcOEt 3:2) or B (hexane/AcOEt
4:1) and detected by 5% vanillin/H2SO4. Analytical HPLC
method: C-18 column (Vydac RP18), 250 × 4.6 mm i.d., flow
rate 1 mL/min, λ ) 254 nm; mobile phase A, 0.05 M NH4OAc
pH 6.5, B, MeOH, linear gradient indicated. Preparative HPLC
was performed using the same conditions on a Vydac RP18 250
× 22 mm i.d. and a flow rate of 24 mL/min.
21-Deoxy-21-oxoba filom ycin A1 (2) fr om 1. To a solution
of oxalyl chloride (0.26 mL, 2.97 mmol) in CH2Cl2 (20 mL), at
-70 °C under nitrogen was added DMSO (0.45 mL, 6.34 mmol)
dropwise. The solution was stirred for 1 h at -70 °C, and 1
(600 mg, 0.9 mmol) was added. The solution was stirred at -70
°C for 0.5 h. After this time, 1.8 mL of triethylamine was added,
and the mixture was stirred for 5 min at -70 °C, warmed to
-40 °C, and poured into 10% aqueous sodium hydrogensulfate
(60 mL). The layers were separated, and the aqueous phase was
extracted with 3 × 30 mL of dichloromethane. The organic layer
was washed with 90 mL of brine, dried over MgSO4, filtered,
concentrated, and chromatographed (hexane/AcOEt 8:2) to yield
290 mg (52%) of compound 2 as a white powder. Mp: 149-152
In conclusion, the behavior of 1 in the presence of
oxidizing agents has been investigated and selective
oxidation of the different hydroxy groups has been
achieved for the first time. The present work also offers
a convenient and easy entry for further modifications of
bafilomycin A1 useful for the study of the structure
activity relationships of this biologically interesting mac-
rolide.
Exp er im en ta l Section
°C. [R]20 ) -12 (c ) 0.33, CHCl3). TLC: (A) Rf 0.70. HPLC:
Gen er a l P r oced u r es. Melting points were determined in
open capillaries and are uncorrected. Optical rotations were
D
gradient 70-75% of B in 40 min, tR 33 min. FAB-MS (nega-
tive): m/ z 619 [M - H]-. 1H-NMR: 6.68 (s, 1H, 3-H); 6.51 (dd,
J ) 15, 11, 1H, 12-H); 5.81 (dd, J ) 11, 1, 1H, 11-H); 5.77 (dd,
J ) 9, 1, 1H, 5-H); 5.67 (d, J ) 3, 1H, 19-OH); 5.16 (dd, J ) 15,
9, 1H, 13-H); 4.95 (dd, J ) 9, 1, 1H, 15-H); 4.72 (d, J ) 4, 1H,
17-OH); 4.16 (ddd, J ) 9, 4, 2, 1H, 17-H); 3.89 (dd, J ) 9, 9, 1H,
14-H); 3.81 (dd, J ) 11, 3, 1H, 23-H); 3.65 (s, 3H, 2-OMe); 3.29
(ddd, J ) 1, 7, 7, 1H, 7-H); 3.25 (s, 3H, 14-OMe); 2.74 (d, J ) 13,
1H, 20-Heq); 2.54 (ddq, J ) 9, 1, 7, 1H, 6-H); 2.34 (dq, J ) 11,7,
1H, 22-H); 2.27 (dd, J ) 13, 3, 1H, 20-Hax); 2.14 (m, 1H, 9-Heq);
2.14 (ddq, J ) 9, 1, 7, 1H, 16-H); 2.00 (m, 1H, 9-Hax); 2.00 (d, J
determined in
a polarimeter with a 100 mm optical cell,
operating at 589 nm (sodium D line) at 20 °C in the solvent
indicated. UV spectra were obtained using a spectrophotometer
in the solvent indicated. NMR were recorded on a 300 MHz
spectrometer in CDCl3 (7.26 ppm and 77.7 ppm) at 303 K.
J
values are given in Hz. Two-dimensional COSY-90 experiments
were carried out using standard software. FAB mass spectra
(19) Everett, J . R.; Baker, G. H.; Brown, P. J .; Dorgan, R. J . J . J .
Chem. Soc., Perkin Trans. 2 1989, 1073.

Notes
J . Org. Chem., Vol. 61, No. 20, 1996 7187
) 1, 3H, 4-Me); 1.94 (d, J ) 1, 3H, 10-Me); 1.90 (m, 1H, 8-H);
1.90 (dq, J ) 2, 7, 1H, 18-H); 1.89 (dqq, J ) 3, 7, 7, 1H, 24-H);
1.53 (d, J ) 7, 1H, 7-OH); 1.07 (d, J ) 7, 3H, 6-Me); 1.05 (d, J
) 7, 3H, 18-Me); 0.97 (d, J ) 7, 3H, 24-Me); 0.97(d, J ) 7, 3H,
22-Me); 0.94 (d, J ) 7, 3H, 8-Me); 0.87 (d, J ) 7, 3H, 24-Me);
0.85 (d, J ) 7, 3H, 16-Me). 13C-NMR: 209.3, 167.9, 143.6, 143.4,
141.7, 134.1, 133.5, 133.4, 127.6, 125.7, 101.6, 82.7, 81.6, 77.6,
77.3, 71.2, 60.4, 56.0, 51.3, 47.8, 42.3, 41.7, 40.5, 37.6, 37.2, 29.2,
gradient 75-90% of B in 40 min, tR 38 min. FAB-MS (posi-
tive): m/ z 765 [MK]+. 1H-NMR: 8.05 (d, J ) 7, 2H, o-PhH);
7.56 (dd, J ) 7, 7, 1H, p-PhH); 7.44 (dd, J ) 7, 7, 2H, m-PhH);
6.69 (s, 1H, 3-H); 6.50 (dd, J ) 13, 11, 1H, 12-H); 5.84 (d br, J
) 11, 1H, 11-H); 5.79 (dd, J ) 9, 1, 1H, 5-H); 5.51 (d, J ) 2, 1H,
19-OH); 5.23 (ddd, J ) 11, 11, 5,1H, 21-H); 5.18 (dd, J ) 13, 9,
1H, 13-H); 4.98 (dd, J ) 9, 1, 1H, 15-H); 4.63 (d, J ) 4, 1H,
17-OH); 4.15 (ddd, J ) 10, 4, 2, 1H, 17H); 3.90 (dd, J ) 9, 9, 1H,
14-H); 3.69 (dd, J ) 9, 2, 1H, 23-H); 3.67 (s, 3H, 2-OMe); 3.30
(dd, J ) 6, 1, 1H, 7-H); 3.27 (s, 3H, 14-OMe); 2.55 (ddq, J ) 9,
6, 7, 1H, 6-H); 2.48 (dd, J ) 11, 5, 1H, 20-Heq); 2.15 (dq br, J )
10, 7, 1H, 16-H); 2.10 (dd, J ) 12, 12, 1H, 9-Heq); 2.00 (d, J ) 1,
3H, 4-Me); 1.95 (m, 1H, 9-Hax); 1.95 (dqq, J ) 2, 7, 7, 1H, 24-H);
1.94 (d, J ) 1, 3H, 10-Me); 1.92 (m, 1H, 8-H); 1.80 (dq, J ) 2, 7,
1H, 18-H); 1.73 (ddq, J ) 11, 9, 7, 1H, 22-H); 1.34 (ddd, J ) 11,
11, 2, 1H, 20-Hax); 1.08 (d, J ) 7, 3H, 6-Me); 1.04 (d, J ) 7, 3H,
18-Me); 0.95 (d, J ) 7, 3H, 8-Me); 0.95 (d, J ) 7, 3H, 24-Me);
0.89 (d, J ) 7, 3H, 22-Me); 0.84 (d, J ) 7, 3H, 16-Me); 0.83 (d,
J ) 7, 3H, 24-Me). 13C-NMR: 168.0, 166.7, 143.7, 143.4, 142.1,
134.1, 133.7, 133.4, 130.9, 130.3, 130.3, 129.2, 129.0, 129.0, 128.0,
126.0, 99.7, 83.0, 81.9, 77.6, 76.4, 75.4, 71.4, 60.7, 56.2, 42.9,
42.0, 40.9, 40.7, 39.1, 37.9, 37.5, 28.7, 22.4, 21.8, 20.8, 18.0, 15.1,
14.7, 13.1, 10.6, 7.8. UV(MeOH) λmax: 237 nm (ꢀ 51 800), 199
(38 300), 282 (21 000).
22.1, 21.4, 20.6, 17.7, 14.6, 14.4, 10.2, 9.3, 7.3; UV(CHCl3) λmax
249 nm (ꢀ 43 800), 287 (22 300)
:
21-O-Acetylba filom ycin A1 (3) fr om 1. To a solution of 1
(1 g, 1.6 mmol) and DMAP (103 mg, 0.8 mmol) in dry pyridine
(15 mL) was added acetyl chloride (0.3 mL) dropwise. The
mixture was stirred under nitrogen at room temperature for 2.5
h, diluted with AcOEt (150 mL), and washed with 5% citric acid,
a saturated solution of NaHCO3, and brine. After being dried
over MgSO4, evaporation of the solvent afforded the crude
product that was purified by CC, eluting with hexane/AcOEt
4:1, obtaining 513 mg (48%) of 3 as a white powder. Mp: 68-
69 °C. [R]20 ) -23 (c ) 0.31; MeOH). TLC (B): Rf ) 0.32.
D
HPLC: gradient 75-90% of B in 40 min, tR 24.8 min. FAB-MS
(negative): m/ z 663 [M - H]-. 1H-NMR: 6.67 (s, 1H, 3-H); 6.50
(dd, J ) 15, 11, 1H, 12-H); 5.81 (dd, J ) 11, 1, 1H, 11-H); 5.76
(dd, J ) 9, 1, 1H, 5-H); 5.46 (d, J ) 2, 1H, 19-OH); 5.16 (dd, J
) 15, 9, 1H, 13-H); 4.96 (ddd, J ) 11, 11, 5, 1H, 21-H); 4.95 (dd,
J ) 9, 1, 1H, 15-H); 4.60 (d, J ) 3, 1H, 17-OH); 4.12 (ddd, J )
10, 3, 2, 1H, 17-H); 3.87 (dd, J ) 9, 9, 1H, 14-H); 3.64 (s, 3H,
2-OMe); 3.60 (dd, J ) 11, 2, 1H, 23-H); 3.30 (s br, 1H, 7-H); 3.24
(s, 3H, 14-OMe); 2.54 (ddq, J ) 9, 1, 7, 1H, 6-H); 2.34 (dd, J )
11, 5, 1H, 20-Heq); 2.15 (m, 1H, 9-Heq); 2.12 (ddq, J ) 10, 1, 7,
1H, 16-H); 2.02 (s, 3H, 21-OAc); 2.00 (d, J ) 1, 3H, 4-Me); 1.95
(m, 1H, 9-Hax); 1.92 (m, 1H, 8-H); 1.92 (d, J ) 1, 3H, 10-Me);
1.90 (dqq, J ) 2, 7, 7, 1H, 24-H); 1.75 (dq, J ) 2, 7, 1H, 18-H);
1.53 (ddq, J ) 11, 11, 7, 1H, 22-H); 1.17 (ddd, J ) 11, 11, 2, 1H,
20-Hax); 1.07 (d, J ) 7, 3H, 6-Me); 1.03 (d, J ) 7, 3H, 18-Me);
0.94 (d, J ) 7, 3H, 8-Me); 0.91 (d, J ) 7, 3H, 24-Me); 0.83 (d, J
) 7, 3H, 16-Me); 0.82 (d, J ) 7, 3H, 22-Me); 0.77 (d, J ) 7, 3H,
24-Me). 13C-NMR: 171.1, 168.0, 143.7, 143.4, 142.1, 134.1, 133.7,
133.7, 128.0, 126.0, 99.5, 83.0, 82.0, 77.6, 76.3, 74.7, 71.3, 60.6,
56.2, 42.8, 42.0, 40.9, 40.7, 38.9, 37.9, 37.4, 28.7, 22.4, 21.9, 21.7,
20.8, 18.0, 15.0, 14.7, 13.0, 10.5, 7.7. UV(MeOH) λmax: 247 nm
(ꢀ 28 900), 285 (12 200).
7-Deoxy-7-oxoba filom ycin A1 (6) fr om 1. To a solution of
1 (600 mg, 0.96 mmol) in CH2Cl2 (120 mL), at 0 °C under
nitrogen, were added AcONa (468 mg, 5.7 mmol) and PCC (1.3
g, 6 mmol). The mixture was stirred at 0 °C for 2 h, diluted
with Et2O (60 mL), and filtered on Florisil. The crude product
was purified by CC eluting with hexane/AcOEt 8:2 obtaining
118 mg of 6 (20%) as a white powder. Mp: 126-132 °C. [R]20
D
) -88 (c ) 0.29; MeOH). TLC (A): Rf ) 0.55. HPLC (gradient
70-75% of B in 40 min, tR 36 min). FAB-MS (negative): m/ z
619 [M - H]-. 1H-NMR: 6.51 (s, 1H, 3-H); 6.49 (dd, J ) 16, 11,
1H, 12-H); 5.84 (dd, J ) 11, 1, 1H, 11-H); 5.47 (d, J ) 2, 1H,
19-OH); 5.25 (d br,J ) 10, 1H, 5-H); 5.22 (dd, J ) 16, 10, 1H,
13-H); 4.95 (dd, J ) 10, 1, 1H, 15-H); 4.57 (dd, J ) 3, 1, 1H,
17-OH); 4.14 (ddd, J ) 11, 3, 2, 1H, 17-H); 3.87 (dd, J ) 10, 10,
1H, 14-H); 3.70 (ddd, J ) 12, 10, 6, 1H, 21-H); 3.67 (s, 3H,
2-OMe); 3.50 (dd, J ) 10, 3, 1H, 23-H); 3.43 (dq, J ) 10, 7, 1H,
6-H); 3.25 (s, 3H, 14-OMe); 2.81 (ddq, J ) 4, 1, 7, 1H, 8-H); 2.31
(dd, J ) 13, 1, 1H, 9-Heq); 2.28 (dd, J ) 12, 6, 1H, 20-Heq); 2.24
(ddq, J ) 11, 1, 7, 1H, 16-H); 2.15 (dd br, J ) 13,4, 1H, 9-Hax);
2.09 (d, J ) 1, 3H, 4-Me); 1.89 (dqq, J ) 3, 7, 7, 1H, 24-H); 1.78
(ddq, J ) 2, 1, 7, 1H, 18-H); 1.74 (d, J ) 1, 3H, 10-Me); 1.34
(ddq, J ) 10, 10, 6, 1H, 22-H); 1.16 (ddd, J ) 12, 12, 2, 1H, 20-
21-O-Acetyl-19-O-m eth ylba filom ycin A1 (4) fr om 3.
A
solution of compound 3 (489 mg, 0.7 mmol) in MeOH (50 mL)
was treated with acetic acid (0.1 mL) and heated at 60 °C for 8
h. After cooling, an excess of solid NaHCO3 was added. The
mixture was concentrated under vacuum, diluted with AcOEt,
and washed with water. The organic layer was dried over
MgSO4 and evaporated to give 412 mg of 4 (87%) as an
amorphous white solid. TLC (B): Rf ) 0.34. HPLC: gradient
75-90% of B in 40 min, tR 29.9 min. FAB-MS (positive): m/ z
717 [MK]+. 1H-NMR: 6.63 (s, 1H, 3-H); 6.49 (dd, J ) 14, 10,
1H, 12-H); 5.81 (d br, J ) 10, 1H, 11-H); 5.74 (d br, J ) 9, 1H,
5-H); 5.20 (dd, J ) 14, 9, 1H, 13-H); 5.09 (dd, J ) 9, 1, 1H, 15-
H); 4.93 (ddd, J ) 11, 11, 5, 1H, 21-H); 3.88 (dd, J ) 9, 9, 1H,
14-H); 3.82 (d br, J ) 2, 1H, 17-OH); 3.71 (s, 3H, 2-OMe); 3.47
(d br, J ) 9, 1H, 17-H); 3.30 (d br, J ) 6, 1H, 7-H); 3.24 (s, 3H,
14-OMe); 3.16 (dd, J ) 10, 2, 1H, 23-H); 3.05 (s, 3H, 19-OMe);
2.53 (ddq, J ) 9, 2, 7, 1H, 6-H); 2.22 (dd, J ) 13, 5, 1H, 20-Heq);
2.10 (dd, J ) 13, 13, 1H, 9-Heq); 2.05 (s, 3H, 21-OAc); 2.00 (m,
1H, 9-Hax); 2.00 (m, 1H, 16-H); 2.00 (m, 1H, 18-H); 1.98 (d, J )
1, 3H, 4-Me); 1.95 (m, 1H, 8-H); 1.95 (dqq, J ) 2, 7, 7, 1H, 24-
H); 1.93 (d, J ) 1, 3H, 10-Me); 1.60 (dd, J ) 13, 11, 1H, 20-Hax);
1.54 (ddq, J ) 11, 10, 7, 1H, 22-H); 1.07 (d, J ) 7, 3H, 6-Me);
1.03 (d, J ) 7, 3H, 8-Me); 0.99 (d, J ) 7, 3H, 18-Me); 0.94 (d, J
) 7, 3H, 24-Me); 0.91 (d, J ) 7, 3H, 16-Me); 0.89 (d, J ) 7, 3H,
24-Me); 0.80 (d, J ) 7, 3H, 22-Me).
H
ax); 1.09 (d, J ) 7, 3H, 6-Me); 1.05 (d, J ) 7, 3H, 18-Me); 1.03
(d, J ) 7, 3H, 8-Me); 0.95 (d, J ) 6, 3H, 22-Me); 0.91 (d, J ) 7,
3H, 24-Me); 0.84 (d, J ) 7, 3H, 16-Me); 0.78 (d, J ) 7, 3H, 24-
Me). 13C-NMR: 214.9, 167.2, 143.1, 141.0, 138.2, 135.3, 133.7,
132.0, 129.3,127.0, 99.4, 82.2, 77.0, 76.3, 71.4, 71.0, 60.2, 56.3,
47.0, 46.0, 44.0, 43.5, 42.7, 41.5, 36.7, 28.4, 21.7, 19.8, 19.7, 14.8,
14.4, 14.0, 12.6, 10.0, 7.5; UV(MeOH) λmax: 245 (37 000), 280
nm (ꢀ 12 700).
21-O-Acetyl-7-d eoxy-7-oxoba filom ycin A1 (7) fr om 4. To
a solution of 4 (382 mg, 0.56 mmol) in CH2Cl2 (100 mL), at 0 °C
and under nitrogen, were added AcONa (650 mg, 8 mmol) and
PCC (1.4 g, 6.6 mmol). The reaction mixture was stirred at 0
°C for 3 h and at room temperature for 4 h, diluted with Et2O
(150 mL), and filtered on Florisil. After evaporation of the
solvent, the crude product was purified by CC, eluting with CH2-
Cl2/MeOH 98:2, to obtain 190 mg (51%) of 7 as an amorphous
white solid. [R]20 ) -131 (c ) 0.07; MeOH). HPLC: gradient
D
75-90% of B in 40 min, tR 28.6 min. FAB-MS (negative): m/ z
661 [M - H]-. 1H-NMR: 6.50 (s, 1H, 3-H); 6.49 (dd, J ) 15, 11,
1H, 12-H); 5.84 (dd, J ) 11, 1, 1H, 11-H); 5.45 (d, J ) 2, 1H,
19-OH); 5.24 (dd, J ) 11, 1, 5-H); 5.22 (dd, J ) 15, 9, 1H, 13-H);
4.97 (ddd, J ) 11, 11, 4, 1H, 21-H); 4.94 (dd, J ) 9, 1, 1H, 15-
H); 4.55 (d, J ) 3, 1H, 17-OH); 4.12 (ddd, J ) 9, 3, 2, 1H, 17-H);
3.85 (dd, J ) 9, 9, 1H, 14-H); 3.66 (s, 3H, 2-OMe); 3.60 (dd, J )
10, 3, 1H, 23-H); 3.41 (dq, J ) 11, 7, 1H, 6-H); 3.25 (s, 3H, 14-
OMe); 2.80 (ddq, J ) 6, 2, 7, 1H, 8-H); 2.35 (dd, J ) 11, 4, 1H,
20-Heq); 2.27 (dd, J ) 6, 6, 1H, 9-Heq); 2.17 (ddq, J ) 9, 1, 7, 1H,
16-H); 2.15 (dd, J ) 6, 2, 1H, 9-Hax); 2.08 (d, J ) 1, 3H, 4-Me);
2.05 (s, 3H, 21-OAc); 1.90 (dqq, J ) 3, 7, 7, 1H, 24-H); 1.73 (dq,
J ) 2, 7, 1H, 18-H); 1.73 (d, J ) 1, 3H, 10-Me); 1.55 (ddq, J )
11, 10, 7, 1H, 22-H); 1.20 (ddd, J ) 11, 11, 2, 1H, 20-Hax); 1.08
(d, J ) 7, 3H, 6-Me); 1.03 (d, J ) 7, 3H, 8-Me); 1.03 (d, J ) 7,
21-O-Ben zoylba filom ycin A1 (5) fr om 1. To a solution of
1 (400 mg, 0.64 mmol) and DMAP (44 mg, 0.36 mmol) in dry
pyridine (4 mL) was added benzoyl chloride (0.2 mL) dropwise.
The mixture was stirred under nitrogen at room temperature
for 3 h and then poured into 5% citric acid (50 mL) and extracted
with CH2Cl2. The organic layer was then washed with a
saturated solution of Na2CO3 and brine. After the organic layer
was dried over MgSO4, the solvent was removed and the crude
product was purified by CC, eluting with hexane/AcOEt 9:1, to
obtain 165 mg of 5 (35%) as a white powder. Mp: 98-101 °C.
[R]20 ) -30 (c ) 0.27; MeOH). TLC (A): Rf ) 0.70. HPLC:
D

7188 J . Org. Chem., Vol. 61, No. 20, 1996
Notes
3H, 18-Me); 0.91 (d, J ) 7, 3H, 24-Me); 0.83 (d, J ) 7, 3H, 16-
Me); 0.82 (d, J ) 7, 3H, 22-Me); 0.78 (d, J ) 7, 3H, 24-Me). 13C-
NMR: 215.2, 171.5, 167.5, 143.3, 141.3, 138.5, 135.6, 133.9, 132.3,
129.6, 127.3, 99.7, 82.5, 77.3, 76.4, 74.7, 71.2, 60.4, 56.6, 47.3,
46.3, 43.8, 43.0, 40.9, 38.9, 37.0, 28.7, 21.9, 21.8, 20.1, 20.0, 15.0,
14.7, 14.3, 13.0, 10.3, 7.7. UV(MeOH) λmax: 244 nm (ꢀ 40 000),
278 (16 000).
separated, washed with a saturated solution of NaHCO3, brine,
dried over MgSO4, filtered, and concentrated to yield 600 mg
(100%) of 10 as a white foam. [R]20 ) -119 (c ) 0.32; MeOH).
D
HPLC: gradient 70-75% of B in 40 min, tR 40.5 min. FAB-MS
(negative): m/ z 617 [M - H]-. 1H-NMR: 6.54 (s, 1H, 3-H); 6.50
(dd, J ) 15, 11, 1H, 12-H); 5.85 (dd, J ) 11, 1, 1H, 11-H); 5.66
(d, J ) 3, 1H, 19-OH); 5.25 (dd, J ) 11, 1, 1H, 5-H) 5.22 (dd, J
) 15, 9, 1H, 13-H); 4.94 (dd, J ) 9, 2, 1H, 15-H); 4.69 (d br, J )
4, 1H, 17-OH); 4.16 (ddd, J ) 11, 4, 2, 1H, 17-H); 3.88 (dd, J )
9, 9, 1H, 14-H); 3.82 (dd, J ) 10, 3, 1H, 23-H); 3.68 (s, 3H, 2-
OMe); 3.44 (dq, J ) 11, 7, 1H, 6-H); 3.26 (s, 3H, 14-OMe); 2.90
(dqq, J ) 3, 7, 7, 1H, 24-H); 2.82 (ddq, J ) 6, 3, 7, 1H, 8-H); 2.74
(d, J ) 13, 1H, 20-Heq); 2.35 (dq, J ) 10, 7, 1H, 22-H); 2.31 (dd,
J ) 13, 6, 1H, 9-Heq); 2.28 (dd, J ) 13, 3, 1H, 20-Hax); 2.25 (ddq,
J ) 11, 2, 7, 1H, 16-H); 2.15 (dd, J ) 13, 3, 1H, 9-Hax); 2.10 (d,
J ) 1, 3H, 4-Me); 1.96 (dq br, J ) 2, 7, 1H, 18-H); 1.74 (d, J )
1, 3H, 18-Me); 1.09 (d, J ) 7, 3H, 6-Me); 1.03 (d, J ) 7, 3H,
8-Me); 1.03 (d, J ) 7, 3H, 18-Me); 0.98 (d, J ) 7, 3H, 22-Me);
0.97 (d, J ) 7, 3H, 24-Me); 0.88 (d, J ) 7, 3H, 24-Me); 0.87 (d,
J ) 7, 3H, 16-Me). 13C-NMR: 214.9, 209.2, 167.3, 143.0, 141.1,
138.4, 135.2, 133.8, 132.3, 129.2, 127.0, 101.6, 82.2, 77.6, 77.0,
71.1, 60.3, 56.3, 51.3, 47.8, 47.0, 46.0, 43.5, 42.4, 36.7, 29.2, 21.5,
19.9, 19.7, 14.6, 14.4, 14.1, 10.0, 9.3, 7.3. UV (MeOH) λmax: 245
nm (ꢀ 39 500), 280 (13 400).
21-O-Ben zoyl-7-d eoxy-7-oxob a filom ycin A1 (8) fr om 5.
To a solution of 5 (750 mg, 1 mmol) in CH2Cl2 (150 mL), at room
temperature and under nitrogen, were added AcONa (1.3 g, 16
mmol) and PCC (2.8 g, 13 mmol). The reaction mixture was
stirred for 5 h, diluted with Et2O (300 mL), and filtered on
Florisil. After evaporation of the solvent, the crude product was
purified by CC, eluting with CH2Cl2/MeOH 98:2, and then
crystallized from MeOH to give 174.3 mg (24%) of 8. Mp: 186-
187 °C. [R]20 ) -140 (c ) 0.28; CHCl3). HPLC: gradient 75-
D
90% of B in 40 min, tR 41.5 min. FAB-MS (negative): m/ z 723
[M - H]-. 1H-NMR: 8.04 (d, J ) 8, 2H, o-PhH); 7.55 (dd, J )
8, 8, 1H, p-PhH); 7.42 (dd, J ) 8, 8, 2H, m-PhH); 6.50 (s, 1H,
3-H); 6.49 (dd, J ) 15, 11, 1H, 12-H); 5.85 (d br, J ) 11, 1H,
11-H); 5.49 (d, J ) 3, 1H, 9-OH); 5.24 (d br, J ) 11, 1H, 5-H);
5.22 (dd, J ) 15, 9, 1H, 13-H); 5.22 (ddd, J ) 11, 11, 5, 1H, 21-
H); 4.95 (dd, J ) 9, 2, 1H, 15-H); 4.57 (d, J ) 4, 1H, 17-OH);
4.15 (ddd, J ) 11, 4, 2, 1H, 17-H); 3.86 (dd, J ) 9, 9, 1H, 14-H);
3.68 (dd, J ) 11, 3, 1H, 23-H); 3.66 (s, 3H, 2-OMe); 3.42 (dq, J
) 11, 7, 1H, 6-H); 3.25 (s, 3H, 14-OMe); 2.80 (ddq, J ) 12, 4, 7,
1H, 8-H); 2.48 (dd, J ) 11, 5, 1H, 20-Heq); 2.29 (dd, J ) 12, 12,
1H, 9-Heq); 2.25 (ddq, J ) 7, 2, 11, 1H, 16-H); 2.15 (dd, J ) 12,
4, 1H, 9-Hax); 2.10 (d, J ) 1, 3H, 4-Me); 1.93 (dqq, J ) 3, 7, 7,
1H, 24-H); 1.80 (dq, J ) 2, 7, 1H, 18-H); 1.74 (d, J ) 1, 3H,
10-Me); 1.70 (ddq, J ) 11, 11, 7, 1H, 22-H); 1.33 (ddd, J ) 11,
11, 3, 1H, 20-Hax); 1.08 (d, J ) 7, 3H, 6-Me); 1.03 (d, J ) 7, 3H,
18-Me); 1.02 (d, J ) 7, 3H, 8-Me); 0.94 (d, J ) 7, 3H, 24-Me);
0.89 (d, J ) 7, 3H, 22-Me); 0.83 (d, J ) 7, 3H, 16-Me); 0.82 (d,
J ) 7, 3H, 24-Me). 13C-NMR: 215.2, 167.4, 166.6, 143.4, 141.2,
138.5, 135.6, 133.9, 133.4, 132.2, 131.6, 130.3, 130.3, 129.6, 129.0,
129.0, 127.3, 99.7, 82.5, 77.3, 76.4, 75.4, 71.3, 60.5, 56.6, 47.3,
46.2, 43.8, 43.0, 41.0, 39.1, 37.0, 28.7, 21.9, 20.1, 20.0, 15.1, 14.7,
14.3, 13.1, 10.3, 7.7. UV(CHCl3) λmax: 249 nm (ꢀ 38 000), 282
(14 400).
19,20-Did eh yd r o-7,17,19,21-tetr a d eoxy-7,17,21-tr ioxoba -
filom ycin A1 (11) fr om 1. To a solution of Dess-Martin
reagent (509 mg, 1.2 mmol) in CH2Cl2 (20 mL), at room
temperature, was added 1 (100 mg, 0.16 mmol). The solution
was stirred at room temperature for 3.5 h, diluted with Et2O
(80 mL), and poured into a solution of 1 g of sodium thiosulfate
in a saturated solution of NaHCO3 (40 mL). The mixture was
stirred for 15 min. The organic layer was separated, washed
with a saturated solution of NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated. The crude product was
purified by CC, eluting with CH2Cl2/MeOH 99:1, to obtain 76.4
mg (79%) of 11. Mp: 63-65 °C. [R]20D ) -30 (c ) 0.27; MeOH).
HPLC: gradient 70-75% of B in 40 min, tR 32.7 min. FAB-MS
(negative): m/ z 597 [M - H]-. 1H-NMR: 6.49 (dd, J ) 15, 11,
1H, 12-H); 6.32 (s, 1H, 3-H); 5.86 (dd, J ) 11, 1, 1H, 11-H); 5.45
(s, 1H, 20-H); 5.20 (dd, J ) 9, 1, 1H, 5-H); 5.20 (dd, J ) 15, 9,
1H, 13-H); 5.07 (dd, J ) 9, 4, 1H, 15-H); 3.88 (dd, J ) 13, 3, 1H,
23-H); 3.87 (q, J ) 7, 1H, 18-H); 3.79 (dd, J ) 9, 9, 1H, 14-H);
3.62 (s, 3H, 2-OMe); 3.40 (dq, J ) 4, 7, 1H, 16-H); 3.38 (dq, J )
9, 7, 1H, 6-H); 3.22 (s, 3H, 14-OMe); 2.80 (ddq, J ) 11, 4, 7, 1H,
8-H); 2.46 (dq, J ) 13, 7, 1H, 22-H); 2.31 (dd, J ) 11, 11, 1H,
9-Heq); 2.14 (dd, J ) 11, 4, 1H, 9-Hax); 2.05 (d, J ) 1, 3H, 4-Me);
2.00 (dqq, J ) 3, 7, 7, 1H, 24-H); 1.74 (d, J ) 1, 3H, 10-Me);
1.33 (d, J ) 7, 3H, 18-Me); 1.11 (d, J ) 7, 3H, 24-Me); 1.09 (d,
J ) 7, 3H, 16-Me); 1.09 (d, J ) 7, 3H, 22-Me); 1.08 (d, J ) 7,
3H, 6-Me); 1.02 (d, J ) 7, 3H, 8-Me); 0.96 (d, J ) 7, 3H, 24-Me).
13C-NMR: 215.1, 206.6, 195.9, 174.3, 164.4, 143.3, 141.4, 137.1,
135.3, 134.1, 130.2, 128.4, 126.8, 104.8, 88.8, 83.3, 75.4, 59.9,
56.3, 51.3, 47.0, 46.3, 45.8, 43.9, 41.4, 29.2, 20.0, 19.8, 19.7, 15.1,
14.4, 14.1, 14.1, 10.3, 10.3. UV (MeOH) λmax: 249 nm (ꢀ 17 600).
19,20-Did eh yd r o-7,19,21-t r id eoxy-7,21-d ioxob a filom y-
cin A1 (9) fr om 1. To a solution of 1 (200 mg, 0.32 mmol) in
CH2Cl2 (20 mL), at 0 °C and under nitrogen, were added PDC
(120 mg, 0.32 mmol) and molecular sieves (4 Å, 500 mg). The
mixture was stirred at 0 °C for 3 h and then at room temperature
overnight. After this time an additional mole of PDC was added.
After 6 h, the reaction mixture was diluted with Et2O (50 mL)
and filtered on Florisil. The crude product was obtained by
evaporation of the solvent. Purification by CC eluting with
hexane/AcOEt 4:1 afforded 13 mg (7%) of 9 (Rf ) 0.65) as a white
foam and 22 mg (11%) of 6 as a more polar fraction (Rf ) 0.32
TLC (B)). FAB-MS (positive): m/ z 639 [MK]+. 1H-NMR: 6.47
(s, 1H, 3-H); 6.46 (dd, J ) 15, 11, 1H, 12-H); 5.82 (dd, J ) 11, 1,
1H, 11-H); 5.42 (s, 1H, 20-H); 5.22 (dd, J ) 11, 1, 1H, 5-H); 5.21
(dd, J ) 15, 9, 1H, 13-H); 5.02 (dd, J ) 9, 1, 1H, 15-H); 3.84 (dd,
J ) 13, 3, 1H, 23-H); 3.80 (dd, J ) 9, 9, 1H, 14-H); 3.67 (s, 3H,
2-OMe); 3.59 (ddd, J ) 10, 6, 4, 1H, 17-H); 3.48 (d, J ) 6, 1H,
17-OH); 3.41 (dq, J ) 11, 7, 1H, 6-H); 3.22 (s, 3H, 14-OMe); 2.80
(ddq, J ) 12, 3, 7, 1H, 8-H); 2.60 (dq, J ) 4, 7, 1H, 18-H); 2.42
(dq, J ) 13, 7, 1H, 22-H); 2.29 (dd, J ) 12, 12, 1H, 9-Heq); 2.20
(ddq, J ) 10, 1, 7, 1H, 16-H); 2.17 (dd, J ) 12, 3, 1H, 9-Hax);
2.07 (d, J ) 1, 3H, 4-Me); 2.00 (dqq, J ) 3, 7, 7, 1H, 24-H); 1.73
(d, J ) 1, 3H, 10-Me); 1.17 (d, J ) 7, 3H, 18-Me); 1.08 (d, J ) 7,
3H, 6-Me); 1.07 (d, J ) 7, 3H, 22-Me); 1.06 (d, J ) 7, 3H, 24-
Me); 1.02 (d, J ) 7, 3H, 8-Me); 0.96 (d, J ) 7, 3H, 24-Me); 0.95
(d, J ) 7, 3H, 16-Me). 13C-NMR: 214.9, 196.3, 179.2, 166.6,
143.2, 140.9, 138.0, 135.2, 133.6, 131.6, 129.3, 127.0, 103.9, 88.2,
82.8, 76.8, 73.4, 60.2, 56.3, 47.0, 46.0, 43.6, 41.8, 41.5, 37.8, 29.1,
20.2, 19.8, 19.7, 15.1, 14.4, 14.0, 10.9, 10.8, 10.3.
Ack n ow led gm en t. The authors gratefully acknowl-
edge R. Imrie and M. Verrall for the supply of bafilo-
mycin A1, Professor B. Danieli (University of Milan) for
valuable discussions and assistance in elucidating NMR
and MS data, and Professor C. Fuganti (Polytechnic of
Milan) and V. Vecchietti for helpful advice.
Su p p or tin g In for m a tion Ava ila ble: 1H (300 MHz), 13C
(75 MHz), and 1H,1H COSY spectra of compounds 2, 3, 5-11
and 1H (300 MHz) and 1H,1H COSY spectra of 4 (29 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
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7,21-Did eoxy-7,21-d ioxoba filom ycin A1 (10) fr om 1. To
a solution of Dess-Martin reagent (1.23 g, 2.9 mmol) in CH2Cl2
(60 mL), at room temperature, was added 1 (600 mg, 0.96 mmol).
The solution was stirred at room temperature for 2.5 h, diluted
with Et2O (250 mL), and poured into a solution of 3 g of sodium
thiosulfate in a saturated solution of NaHCO3 (120 mL). The
mixture was stirred for 15 min, and the organic layer was
J O9607222