Use of the potassium ion as a template for the selective derivatization of the antibiotic X-206

Article abstract of DOI:10.1021/jo9903151

The templating effect of potassium ions on the ionophore antibiotic X- 206 (1) ensured that most of the hydroxy, hemiacetal, and ether groups were involved in encapsulation of the metal atom, which allowed a selective derivatization at the unbound C(22) p

Full text of DOI:10.1021/jo9903151

6252
J . Org. Chem. 1999, 64, 6252-6256
Use of th e P ota ssiu m Ion a s a Tem p la te for th e Selective
Der iva tiza tion of th e An tibiotic X-206
Anthony C. O’Sullivan and Fritz Struber*
Novartis AG, 4002 Basel, Switzerland
Steven V. Ley
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, England
Received February 18, 1999
The templating effect of potassium ions on the ionophore antibiotic X-206 (1) ensured that most of
the hydroxy, hemiacetal, and ether groups were involved in encapsulation of the metal atom, which
allowed a selective derivatization at the unbound C(22) position. The mechanism of acylation at
C(22) was investigated and the aquired knowledge used to achieve selective reactions on the benzyl
ester 8 using a similar metal template protection.
In tr od u ction
phore X-206 (1), which has insecticidal and acaricidal
activities in addition to being an antibiotic.10 Unfortu-
When metal ions complex with substrates, they can
influence reactions in various ways. In a monodentate
manner they can increase the rate of a reaction,1 or
through chelation they can hold a substrate in a confor-
mation that encourages a particular stereoselectivity.2
When the complexation is polydentate, the term template
effect is often used. For example, corrins,3 catenanes,4
or peptides5 can be prepared when several components
are held together in a suitable arrangement by a tem-
plating cation. Similarly, polyfunctional long-chain mol-
ecules can be macrocyclized when suitably templated.6
Here we describe the cationic complexation of most of the
polar functionality of the polyether X-206, which protects
it from reaction and allows a selective derivatization of
the C(22) hydroxy group. This work was similar in
concept to that of Isono et al.,7 who described a related
template effect in the reactions of cationomycin, which
in turn was stimulated by the knowledge that the
presence of cations can influence the reactivity of poly-
ethers.8 We describe here: first, the regioselectivity
achieved using the template effect on X-206; second, the
mixed anhydride 6, which is probably an intermediate
in the reaction and is in some cases isolable; and finally,
the mechanism of lactone 7 formation. Knowing this
mechanism, two measures were taken to avoid lactone
formation and achieve clean C(22) derivatization: the use
of acid fluorides rather than other acylating agents,
which made a wide range of esters synthetically acces-
sible, and the derivatization of the benzyl ester 8 in the
presence of lipid-soluble potassium salts.
nately, X-206 is a relative toxic compound, with an LD50
of 17 mg kg-1 in rodents.11 However, we hoped that
derivatization would lead to compounds with increased
insecticidal activity and reduced toxicity.
The polyether antibiotics are ionophores, which com-
plex cations, thus enabling them to diffuse across lipo-
philic cell membranes, thereby affecting the ion gradients
that are vitally important for the cell.9a From the X-ray
structure of X-206 (Figure 1), all of the interactions
involved in its binding to cations are clearly evident.12
Most of the oxygen atoms are in the center of the tertiary
structure of X-206 and either bind to the metal ion or
hydrogen bond to each other, but the C(22) OH is on the
periphery of the tertiary structure and appears to be
uninvolved in any aspect of cation binding. We therefore
chose it as a position suitable for derivatization. Indeed,
it transpired that derivatives at C(22) bound potassium
well and were interesting insecticides, whereas deriva-
tives at C(1), C(9), or C(34) were either very weak or
inactive, either as insecticides or ionophores.13
Resu lts a n d Discu ssion
In addition to their anticoccidial and growth-promoting
antibacterial properties, the polyether antibiotics possess
other interesting activities.9 One example is the iono-
The C(22) derivatives were originally prepared by a
multistep procedure.14 A useful intermediate (2), pro-
(1) Pierre, J L.; Handel, H. Tetrahedron Lett. 1974, 2317-20.
(2) Reetz, M. T. Acc. Chem. Res. 1993, 26(9), 462-8.
(3) Pfalz, A.; Bu¨hler, N.; Neier, R.; Hirai, K.; Eschenmoser, A. Helv.
Chim. Acta 1977, 60, 2653.
(9) (a) Polyether Antibiotics, Vols 1 & 2; Westley, J . W., Ed.; Marcel
Dekker: New York, 1983. (b) Dutton, C. J .; Banks, B. J .; Copper, C.
B. Nat. Prod. Rep. 1995, 12, 165-181.
(10) Chugai Pharmaceutical Co., Ltd.; J 56118-08; Chem. Abstr.
1982, 96, 29972).
(4) Amabilino, D. M.; Stoddart, J . F. Chem. Rev. 1995, 95, 2725.
(5) Kraatz, H.-B. In Organic Synthesis Highlights Vol 3: Mulzer,
J ., Waldmann, H., Eds.; Wiley-VCH: Weinheim, 1998; pp 192-197.
(6) Mandolini, L. Adv. Phys. Org. Chem. 1986, 22, 1-111.
(7) Ubukata, M.; Hamazaki, Y.; Isono, K. Agric. Biol. Chem. 1986,
50, 1153-60. Ubukata, M.; Hamazaki, Y.; Isono, K. Agric. Biol. Chem.
1988, 52, 1637-41.
(11) Westley, J . W. Adv. Appl. Microbiol. 1977, 22, 176-223.
(12) Blount, J . F.; Westley, J . W. J . Chem. Soc., Chem. Commun.
1975, 533. Van Roey, P.; Duax, W. L.; Strong, P. D.; Smith, G. D. Isr.
J . Chem. 1984, 24, 283-289.
(13) Fiebich, K.; Hoermann, A.; Mutz, M.; O’Sullivan, A. C.; Rindlis-
bacher, A.; Struber, F. Pestic. Sci. 1999, 55, 379.
(8) Private communication, Bernard J . Banks, Pfizer, Kent, England.
(14) O’Sullivan, A. C.; Struber, F. Helv. Chim. Acta 1998, 81, 812.
10.1021/jo9903151 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/04/1999

Selective Derivatisation of the Antibiotic X-206
J . Org. Chem., Vol. 64, No. 17, 1999 6253
F igu r e 1. X-ray structure of X-206 sodium salt.
Sch em e 1
tected by hydrogenolytically cleavable groups, was used
to synthesize a number of C(22) derivatives. These
compounds turned out to be promising insecticides,
particularly the C(22) esters, some of which were much
better insecticides than X-206 itself.13 As greater num-
bers and larger amounts of derivatives were required, a
simpler route to their preparation was sought. This goal
was achieved by exploiting the templating effect of
potassium ions to prepare the desired C(22) esters in a
single step as described below.
Sch em e 2
It was thought that potassium ion binding would
protect the internal oxygen atoms from attack, allowing
the C(22) OH group to be selectively derivatized. This
turned out to be true, although the matter was more
complex than we first imagined, as shown later. Thus,
treatment of the potassium salt 3 with Ac2O and pyridine
led in a seemingly straighforward manner to 4a in high
yield, whereas a corresponding treatment of the free acid
1 gave a mixture of products from which 4a was isolated
in only 5% yield (Scheme 1). Isono et al. have described
a similar acetylation of cationomycin at C(2) using the
templating effect of sodium ions to achieve selectivity.7
Having demonstrated the effectiveness of the potas-
sium ion as a protective template, 3 was treated with a
variety of anhydrides, and indeed the straight chain
aliphatic anhydrides yielded the desired esters (see
Scheme 2 and Table 1). However, mixtures of compounds
were obtained with other anhydrides, including benzoyl,
phenyl acetyl, pivaloyl, chloroacetyl, and methacroyl
anhydrides among others. As the anhydrides were only
moderately successful, a number of other acylating
agents were screened, using the benzoyl ester 4o as a
target. Treatment of 3 with BzCl in pyridine, Bz2O in
pyridine, or BzOH activated with 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride led to the lac-
tone 7, but fortunately benzoyl fluoride gave the desired
ester 4o, albeit in low yield. Pleasingly, however, when
a series of other acid fluorides were examined under these
conditions, the esters were formed in all cases, although
again the yields were often only moderate. The acid
fluorides 5 were prepared by simply treating the acids
with 1 equiv of diethylaminosulfur trifluoride15 and were
used without further purification.
Several pieces of evidence indicated that the reaction
proceeds via an intermediate mixed anhydride 6 (Scheme
3). First, an intermediate was seen during the reactions
by TLC, which was isolated and characterized in the case
of the mixed anhydride 6r . Also, the lactone 7 is presum-
ably formed by cyclization of such a mixed anhydride. It
is interesting that certain acylating agents yield the
lactone 7, whereas others form the desired C(22) esters
selectively. Some information relating to this question
(15) Mukherjee, J . J . Fluorine Chem. 1990, 49, 151-4.

6254 J . Org. Chem., Vol. 64, No. 17, 1999
O’Sullivan et al.
Ta ble 1. Acyla tion of th e P ota ssiu m Sa lt 3
rothionoformate in pyridine in the presence of potassium
tetrakis(4-chlorophenyl)-borate, albeit in only 10% yield
(Scheme 5). After radical reduction of 11 and deprotec-
tion, the deoxygenated compound 13 was formed, and its
ionophoric properties were determined. From its log Kc
value of 4.5, it is evident that the C(22) OH group does
not contribute significantly to K+ binding.
R
method
product
yield (%)
CH3
C2H5
anhydride
anhydride
anhydride
anhydride
anhydride
anhydride
anhydride
anhydride
anhydride
anhydride
anhydride
anhydride
anhydride
anhydride
fluoride
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
80
79
58
51
32
45
77
45
50
55
82
59
84
73
19
15
41
19a
22
54
C
C
C
C
11H23
17H3
17H33 (oleate)
17H31 (linolate)
(CH2)2COOH
(CH2)3COOH
i-Bu
Con clu sion
The determination of C(22) in X-206 as a position that
can be modified without loss of activity is important and
useful for a number of reasons. First, it led to the
synthesis of compounds with greatly improved insecti-
cidal activity, although sadly their toxicological profile
prohibited practical use.13 Furthermore, with this meth-
odology, a functionally active ionophoric X-206 may now
be covalently attached to fluorescent or radioactive
markers, photoaffinity labels, proteins, and solid phases.
Because of the large number of functional groups in
ionophores, the means of reacting selectively and extra-
peripherally is all important. Using the templating ability
of metal ions, which is inherent to the natural function
of ionophores, this goal was achieved.
n-Bu
n-Pr
i-Pr
n-pentyl
MeOCO
Ph
Bn
fluoride
fluoride
fluoride
fluoride
PhOCH2
3-pentyl
cyclopropyl
2-methyl cyclopropyl
4s
4t
fluoride
a
Plus 16% 7.
can be obtained from the X-ray structure12 of X-206 Na
salt (Figure 1). As the C(22) OH is far away from C(1),
the mixed anhydride 6 must conformationally twist away
from its cation-binding tertiary structure for it to be able
to cyclize to 7. We assume, therefore, that cyclization
takes place in uncomplexed 6, which is more conforma-
tionally mobile. It then follows that fluoride as counterion
serves to keep K+ complexed to 6, in a manner which we
do not fully understand.
Exp er im en ta l P r oced u r es
Gen er a l. X-206 was obtained from Gra¨fe and Schlegel of
the Hans Kno¨ll Institute in Germany.17 Most of the common
procedures and instrumentation have been previously de-
scribed, as has the preparation of 4a .14 The metal binding
constants Kc were determined calorimetrically. Solutions of the
derivatives in tetrabutylammonium hydroxide (1.2 mM) were
titrated automatically with KCl or NaCl in MeOH at 25 °C.16
Implicit in the above mechanistic rationale is the
ability of the mixed anhydride 6 to complex potassium
ions, even though it is no longer anionic. We obtained
evidence for this supposition by measuring calorimetri-
cally the complexing ability of the benzyl ester 8. It has
a log Kc value of 2.8, which is less than that of X-206
(4.9) but is nevertheless significant, particularly when
compared with derivatives at C(9) and C(34), which show
no sign of cation binding.16 The ion-binding abilites of 8
were further demonstrated by its selective acylation at
the C(22) OH in the presence of potassium ions. This
selectivity was not only of mechanistic interest, but it
also opened a new route to C(22) derivatives, some of
which were unattainable from other approaches. For K+
ions to alter the course of the acylation of 8, they have
to be soluble in organic solvents, which is only the case
when they are accompanied by large lipophilic anions.
For example, potassium dodecyl sulfate was not soluble
enough to alter the course of the acetylation of 8, and
therefore 10 was formed exclusively. However, addition
of potassium tetrakis(4-chlorophenyl)-borate to the acety-
lation reaction led to the selective acetylation of 8 at
C(22), yielding the ester 9 in 58% yield (Scheme 4).
The ionophoric properties of the 22-desoxy compound
13 illuminate the role of the C(22) O atom in cation
binding. As our derivatization strategy rested wholly on
the premise that this atom is uninvolved in binding,
considerable effort was put into the synthesis of 13. Only
mixtures were obtained when 2 was treated with phenyl
chlorothionoformate under various conditions, and only
the lactone 7 was isolated from the K+ salt of 3 under
similar conditions. However, the desired thionocarbonate
11 was obtained when 8 was treated with phenyl chlo-
1
The H NMR signals were assigned mainly according to their
appearance, which for most protons is very similar throughout
the series of compounds described here. This is of course a
subjective assignment based on our experience, so we relegate
the NMR data to the Supporting Information.
X-206-22-P r op ion a te (4b). A 100 mg (110 µmol) portion
of 3 and 2.7 mg (22 µmol) of DMAP in 1 mL of pyridine were
treated with 71 µL (550 µmol) of propionic anhydride. After
2.5 days the reaction mixture was treated dropwise with water
to the point of turbidity. After 5 min the mixture was shaken
between 1 M HCl and 50% EtOAc/hexane (3×). The organic
phase was washed with water, dried with MgSO4, and
evaporated. The crude product was chromatographed with
5-10-15-20% MeCN/toluene to yield 80.2 mg (79%) of 4b
after freeze-drying. IR (KBr) 3389 (br), 2967, 2937, 1738, 1461,
1381, 1188, 1083, 1065, 1037, 992 cm-1; m/z (Cs-FAB, NBA)
neg. 925 (M - H)-, pos. 949 (M + Na)+, 799. Anal. Calcd for
C
50H86O15‚H2O: C, 63.53; H, 9.38. Found: C, 63.84; H, 9.24.
X-206-22-Meth oxa la te (4n ). A solution of 200 mg (220
µmol) of 3 and 44 µL (550 µmol) of pyridine in 1 mL CH2Cl2 at
0 °C under argon was treated dropwise with 440 µL 1 M
methoxalic anhydride18 in CH2Cl2. After 30 min the mixture
was diluted with CH2Cl2, washed with 0.5 M HCl (1×) and
H2O (3×), dried with MgSO4, and evaporated. The crude
product was chromatographed with 5-15-25-30-35% DME/
hexane to yield 152.9 mg (73%) of 4n after freeze-drying. IR
(KBr) 3390 (br), 2966, 2937, 1772, 1744, 1459, 1381, 1313,
1202, 1166, 1102, 1037, 992 cm-1; m/z (Xe-FAB, NBA) neg.
955 (M - H)-, pos. 979 (M + Na)+. Anal. Calcd for C50H84O17
0.5 H2O: C, 62.15; H, 8.87. Found: C, 62.28; H, 8.82.
‚
The other esters were prepared analogously to 4b using
either the anhydrides or the acid fluorides according to the
Tables 2 and 3. Concentrated extracts of 4c and 4d were cooled
in an ice bath before chromatography. The fatty acids that
(17) Graefe, U.; Stengel, C.; Schlegel, R.; Wiesner, J .; Ihn, W.; Fleck,
W. DD 298428 A5 920220.
(16) Struber, F. PhD Thesis, Graz, 1996.
(18) Oppenauer, R. V. Monatsh. Chem. 1966, 97, 67-76.

Selective Derivatisation of the Antibiotic X-206
J . Org. Chem., Vol. 64, No. 17, 1999 6255
Sch em e 3
Sch em e 4
Sch em e 5
crystallized were not applied to the column. The 1H NMR
spectra of the esters are almost superimposable with that of
4a , with the exception of the ester peaks.
2-Eth yl-bu tyr yl F lu or id e (5r ). A 2.2 mL (2.69 g, 16.7
mmol) portion of diethylaminosulfur trifluoride was added to
a solution of 2 mL (1.84 g, 15.9 mmol) of 2-ethyl-butyric acid
in 10 mL of CH2Cl2 at -60 °C. After stirring for 15 min at 0
°C, the mixture was shaken between pentane and water (2×).
The pentane was dried with MgSO4 and evaporated under
water pump pressure to yield 1.65 g (88%) of 2-ethyl-butyryl
fluoride, which according to 1H NMR was pure apart from
small amounts of CH2Cl2 and pentane. The other acid fluorides
were prepared analogously according to a literature proce-
dure15 and used for the acylation of 3 without purification
(Table 4).
X-206-22-Eth yl-bu tyr yl a n h yd r id e (6r ). A 100 mg (110
µmol) portion of 3 in 0.5 mL of pyridine was treated with 65
mg (550 µmol) of 2-ethyl-butyryl fluoride. After 3 days at room
temperature the reaction mixture was worked up as usual.
The crude mixture was chromatographed with 5-10-15-20%
MeCN/toluene to yield 21 mg of crude 6r and 47 mg of
recovered X-206. The crude 6r was rechromatographed under
the same conditions to yield 5 mg (5%) of pure 6r . m/z (Xe-
FAB, NBA) neg. 1121 (M + NBA)-, 967 (M - H)-, pos. 991 (M
+ Na)+.
Ta ble 2. Syn th eses of X-206-22-Ester s fr om Acid
An h yd r id es
equiv
equiv
compd
anhydride
DMAP
temp
time
18 h
2.5 d
3.5 d
3.5 d
5 d
5 d
4 d
4 d
4 h
yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
10
5
5
5
5
0.2
0.2
0.2
0.2
0.2
0.2
1
1
1
1
0.2
1
rt
rt
rt
50 °C
rt
80
79
58
51
32
45
77
45
50
55
82
59
84
73
5
rt
10
10
8
10
5
10
5
2.5
60 °C
60 °C
rt
rt
rt
50 °C
rt
0 °C
4j
4k
4l
4 h
5 d
5 d
5 d
4m
4n
0.2
0
30 min
reaction mixture was worked up as usual to yield 379 mg of a
crude mixture, which was chromatographed with 10-20-40%
MeCN/toluene to yield 39 mg (36%) of the lactone 7 after
freeze-drying from benzene. The lactone 7 was isolated in 37%
X-206-22-La cton e (7). Benzoyl chloride (128 µL, 154 mg,
1.1 mmol) was added to a solution of 3 (100 mg, 110 µmol) in
pyridine (0.5 mL). After 30 min at room temperature, the

6256 J . Org. Chem., Vol. 64, No. 17, 1999
O’Sullivan et al.
Ta ble 3. Syn th eses of X-206-22-Ester s fr om Acid
F lu or id es
of 8, 2.5 mg (21 µmol) of DMAP, and 258 mg (521 µmol) of
potassium tetrakis(4-chlorophenyl)-borate in 2 mL of pyridine.
After 33 h ice was added, and after a few minutes the mixture
was shaken between H2O and 25% EtOAc/hexane (3×). The
organic phase was washed with 0.5 M HCl, H2O, 0.5 M
NaHCO3, H2O, and brine and dried with MgSO4. Most of the
borate salt was precipitated from a DME solution of the crude
product by addition of hexane. The mother liquors were
evaporated and chromatographed to yield 67 mg (64%) of 9.
equiv
equiv
compd
RCOF
DMAP
temp
time
yield (%)
4o
4p
4q
4r
4s
4t
10
10
2.4
15
20
18
0
1
0
1
1
1
80 °C
rt
0 °C
rt
rt
rt
30 min
15 min
15 min
16 h
2 h
2 h
19
15
41
19a
22
1
According to 500 MHz H NMR the material was identical to
54
that prepared previously.14 It contained approximately 10%
a
1
Plus 16% lactone 7. When 5 equiv of RCOF were used in
pyridine without DMAP, 6r (5%) was isolated.
of the diacetate 7 according to H NMR.
X-206-Ben zyl Ester -22-p h en ylth ion oca r bon a te (11). A
1.8 mL (13.3 mmol) portion of phenyl chlorothionoformate was
added dropwise to a solution of 1.00 g (1.04 mmol) of 8, 4.13 g
(8.32 mmol) of potassium tetrakis(4-chlorophenyl)-borate, and
26 mg (0.21 mmol) of DMAP in 10 mL of pyridine. After 2 h
ice was added, and the mixture was extracted with 25% EtOAc/
hexane (3×). The organic phase was washed with 1 M HCl,
H2O, 0.5 M NaHCO3, H2O, and brine and dried with MgSO4.
The crude material was chromatographed with 10-20-30%
EtOAc/hexane, again with 10-15-20-25% EtOAc/hexane,
and yet again with 10-20-25% DME/hexane to yield 108.4
mg (10%) of 11 as a white foam. IR (KBr) 3385 (br), 2965, 2936,
1739, 1457, 1381, 1278, 1201, 1064, 1038 cm-1; m/z (Xe-FAB,
NBA) neg. 1249 (M + NBA), 1095 (M - H)-, 1005 (M - Bn)-,
941 (M - C(S)OPh - H2O)-. Anal. Calcd for C61H92O15S‚
0.5H2O: C, 66.21; H, 8.47. Found: C, 66.20; H, 8.82.
Ta ble 4. Syn th eses of th e Acid F lu or id es RCOF (5)
compd
R
yield (%)
purchasable
Ph
Bn
PhOCH2
3-pentyl
cyclopropyl
2-methyl
5p
5q
5r
5s
5t
79
60
88
45
100
yield on treatment of 3 with 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride and benzoic acid in pyridine.
It was also isolated in 71% yield on treatment of 3 with p-tolyl
chlorothionoformate and DMAP in CH2Cl2. The confirmation
of this structure through alternative synthesis is described in
the Supporting Information. IR (KBr) 3501, 2935, 1742, 1458,
1379, 1162, 1101, 1057, 1009 cm-1; m/z (Cs-FAB, THG) neg.
851 (M - H)-. Anal. Calcd for C47H80O13: C, 66.17; H, 9.45.
Found: C, 66.19; H, 9.24.
22-Desoxy-X-206-ben zyl Ester (12). A solution of 60 mg
(54.7 µmol) of 11, 84 µL (273.5 µmol) of tris(trimethylsilyl)-
silane, and 9 mg (54.7 µmol) of R,R′-azoisobutyronitrile in 1.5
mL of toluene was heated under argon for 1.5 h at 80 °C. The
solvent was evaporated, and the mixture was chromato-
praphed (5-10-15-20% DME/hexane) to yield 38.5 mg of 12
(75%) as a white foam. IR (KBr) 3380 (br), 2933, 1739, 1457,
1380, 1166, 1088, 1050, 981 cm-1; m/z (Xe-FAB, NBA) neg.
1097 (M + NBA), 1079 (M + NBA - H2O), 943 (M - H)-, 853
X-206-Ben zyl Ester (8). A 5.40 mL (45.3 mmol) portion of
benzyl bromide was added dropwise to a solution of 10.0 g (11.3
mmol) of X-206 (1) and 9.60 mL (56.3 mmol) of N-ethyldiiso-
propylamine in 100 mL of acetonitrile. After 18 h the solvent
was evaporated, and the residue was shaken between 75 mL
of water and 250 mL of ether (3×). The combined etheral phase
was washed with 0.5 M HCl (1×) and water (2×), dried with
MgSO4, and evaporated. Chromatography (35% EtOAc/hexane)
afforded 9.56 g (88%) of the benzyl ester 8 as a white foam. IR
(M - Bn)-. Anal. Calcd for C54H88O13
Found: C, 68.23; H, 9.42.
: C, 68.61; H, 9.38.
22-Desoxy-X-206 (13). A solution of 38 mg (40.3 µmol) of
12 in 4 mL of THF containing 4 mg of Pd/C (5%) was
hydrogenated at room temperature and normal pressure for
16 h. The catalyst was filtered off with Celite, and the crude
product was chromatographed (15-25% DME/hexane) to yield
29.1 mg (85%) of 13 after freeze-drying. IR (KBr) 3368 (br),
2966, 2936, 1737, 1460, 1381, 1158, 1086, 1049, 979 cm-1; m/z
(Xe-FAB, NBA): neg. 853 (M - H)-, pos. 877 (M + Na)+, 893
(M + K)+. Anal. Calcd for C47H82O13‚H2O: C, 64.65; H, 9.70.
Found: C, 64.79; H, 9.76.
(KBr) 3398 (br), 2964, 2935, 1740, 1458, 1381, 1065, 1042 cm-1
;
m/z (Xe-FAB, THG) neg. 959 (M - H2O - H)-, 869 (M - H2O
- Bn)-. Anal. Calcd for C54H88O14‚H2O: C, 66.23; H, 9.26.
Found: C, 66.46; H, 9.34.
X-206-Ben zyl Ester -9,22-d ia ceta te (10). A 300 mg (0,312
mmol) portion of benzyl ester 8 and 7.5 mg of DMAP (62 µmol)
were dissolved in 6 mL of pyridine and treated with 0.6 mL of
acetic anhydride. HPTLC showed the formation of approxi-
mately equal amounts of the monoacetates, which did not
accumulate but were further converted to the diacetate 10,
before 8 was consumed. After 6.5 h ice was added and after
some time the mixture was shaken between H2O and 75%
EtOAc/hexane (3×). The organic phase was washed with 1 M
HCl, H2O, 0.5 M NaHCO3, H2O, and brine and dried with
MgSO4. The crude product was chromatographed (5-10-15-
20% DME/hexane) to give 181 mg (56%) of 10 as a white foam.
Ack n ow led gm en t. We thank Dr. K. Fiebich, Dr. A.
Ho¨rmann, and Dr. M. Mutz, analytical department of
Novartis AG, Basel, for the determination of the iono-
phoric properties.
Su p p or tin g In for m a tion Ava ila ble: NMR data of the
compounds and structure confirmation of the lactone 7 through
alternative synthesis. This material is available free of charge
via the Internet at http://pubs/acs/org.
IR (KBr) 3412 (br), 2937, 1738, 1458, 1377, 1240, 1063 cm-1
;
m/z (Cs-FAB, THG) neg. 1043 (M - H)-, 953 (M - Bn)-. Anal.
Calcd for C58H92O16: C, 66.64; H, 8.87. Found: C, 66.4; H, 8.8.
X-206-Ben zyl Ester -22-a ceta te (9). A 0.2 mL portion of
acetic anhydride was added to a solution of 100 mg (104 µmol)
J O9903151