Model Studies and First Synthesis of the Antifungal and Antibacterial Agent Cladobotryal

Article abstract of DOI:10.1021/jo030284g

The antifungal and antibacterial agent cladobotryal (1) was synthesized by a convergent route from lactone 31 and aldehyde 13, a key step in the elaboration of the pyridinone ring being conversion of a Boc group on nitrogen into a CO₂SiPr-i₃ group. The simple model compounds 9 and 10, representing the core of cladobotryal and of 5, respectively, were prepared as support studies for making the natural product.

Full text of DOI:10.1021/jo030284g

Mod el Stu d ies a n d F ir st Syn th esis of th e An tifu n ga l a n d
An tiba cter ia l Agen t Cla d obotr ya l
Derrick L. J . Clive* and Xiaojun Huang
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
derrick.clive@ualberta.ca
Received September 5, 2003
The antifungal and antibacterial agent cladobotryal (1) was synthesized by a convergent route
from lactone 31 and aldehyde 13, a key step in the elaboration of the pyridinone ring being
conversion of a Boc group on nitrogen into a CO2SiPr-i3 group. The simple model compounds 9 and
10, representing the core of cladobotryal and of 5, respectively, were prepared as support studies
for making the natural product.
In tr od u ction
Cladobotryal (1), which is a metabolite of the fungus
Caldobotrium varium Nees:Fries (CBS 331.95), was first
described1 in 1998 and reported to inhibit the growth of
plant pathogens belonging to Oomyceta. Consequently,
1 may be useful as an agricultural fungicide.2 A more
recent publication3 disclosed another potentially impor-
tant biological property, as the compound was reported
to show moderate activity against some drug-resistant
bacteria such as methicillin-resistant Staphylococcus
aureus. The related dihydrofuro[2,3-b]pyridinones 2-4
were isolated3 from the same organism (C. varium, CL
12284), but the parent heterocyclic system is a rare
structural type and examination of the Beilstein database
shows no other dihydrofuro[2,3-b]pyridinones besides
those that are benzo-fused.4 The compounds 5-8 with
the isomeric and better-known5 dihydrofuro[3,2-c]pyri-
dinone structure were also isolated3 from C. varium (CL
12284). The absolute configuration of these furopyridines
has not been established.
we also describe routes to the model compounds 9 and
10, which represent the core structures of 1 and 5,
respectively; we have previously published7 the synthesis
of 11, a C(2) epimer of (natural) 5.
We give here full details of the first total synthesis of
racemic 16 as well as its naturally occurring congener 2.
Synthetic routes to the heterocyclic system represented
by 1 had not been reported before our own work,6 and
(1) Breinholt, J .; J ensen, H. C.; Kjær, A.; Olsen, C. E.; Rassing, B.
R.; Rosendahl, C. N.; Søtofte, I. Acta Chem. Scand. 1998, 52, 631-
634.
(2) Demuth, H.; Breinholt, J .; Rassing, B. R.; Roemer, B. WO 97/
11076; Chem. Abstr. 1997, 126, 276432.
(3) Sakemi, S.; Bordner, J .; DeCosta, D. L.; Dekker: K. A.; Hirai,
H.; Inagaki, T.; Kim, Y.-J .; Kojima, N.; Sims, J . C.; Sugie, Y.; Sugiura,
A.; Sutcliffe, J . A.; Tachikawa, K.; Truesdell, S. J .; Wong, J . W.;
Yoshikawa, N.; Kojima, Y. J . Antibiot. 2002, 55, 6-18. This publication
assigns hydroxypyridine structures to 1 and 3-8, but for simplicity,
the pyridinone tautomers are used in this manuscript.
(4) E.g.: (a) Kappe, T.; Fritz, P. F.; Ziegler, E. Ber. 1973, 106, 1927-
1942. See also (b) Goodwin, S.; Shoolery, J . N.; J ohnson, L. F. J . Am.
Chem. Soc. 1959, 81, 3065-3069. (c) Goodwin, S.; Smith, A. F.;
Velasquez, A. A.; Horning, E. C. J . Am. Chem. Soc. 1959, 81, 6209-
6213.
(5) E.g., 3,5-Dihydro-2H-furo[3, 2-c]pyridin-4-one (the parent sys-
tem): Clark, B. A. J .; El-Bakoush, M. S.; Parrick, J . J . Chem. Soc.,
Perkin Trans. 1 1974, 1531-1536.
(6) Preliminary communication: Clive, D. L. J .; Huang, X. Chem.
Commun. 2003, 2062-2063.
Syn th esis of m od el com p ou n d s 9 a n d 10. The route
to 9, the core of cladobotryal, is based on the two subunits
γ-butyrolactone (12) and the known8 â-amino aldehyde
13, which we made (Scheme 1) by the sequence 19 f 18
f 13, along lines reported8 in the literature, but with
minor modifications. We found it convenient to prepare
the intermediate 19 by a route different from those
(7) Clive, D. L. J .; Huang, X. Tetrahedron 2002, 58, 10243-10250.
(8) Campestrini, S.; Di Furia, F.; Modena, G. J . Org. Chem. 1990,
55, 3658-3660.
10.1021/jo030284g CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/12/2004
1872
J . Org. Chem. 2004, 69, 1872-1879

Synthesis of the Antifungal and Antibacterial Agent Cladobotryal
SCHEME 1a
SCHEME 2a
a
Key: (i) phthalimide, DEAD, Ph3P, THF, 91%; (ii) N2H4‚H2O,
EtOH, 97%; (iii) Boc2O, NaHCO3, 4:1 acetone-water, 100%; (iv)
Bu4NF, THF, 74%; (v) Dess-Martin periodinane, CH2Cl2, 93%;
(vi) N2H4‚H2O, EtOH, then HCl, 93%; (vii) Boc2O, NaHCO3, 4:1
acetone-water, 96%.
a
previously reported.8,9 The readily available alcohol 1410
was converted (91%) into the phthalimide 15 under
Mitsunobu conditions. Treatment with N2H4‚H2O in
EtOH liberated amine 16 (97%), which was protected
(100%) as its N-Boc derivative (Boc2O, aqueous acetone,
NaHCO3, 16 f 17). Desilylation (Bu4NF, 74%) and Dess-
Martin oxidation (93%) afforded the required aldehyde
13. The same compound was also made by a slightly
shorter route in which phthalimide 15 was treated
successively with N2H4‚H2O and 5% hydrochloric acid to
produce amino alcohol 198,9 (93%), which was easily
converted into 188 (96%) by reaction with Boc2O.
Deprotonation of γ-butyrolactone (12) and condensa-
tion (70%) with aldehyde 13 (Scheme 2) served to link
the two subunits, the product (20) being obtained as a
mixture of stereoisomers. Reduction of the lactone car-
bonyl (DIBALH, 99%, 20 f 21) then set the stage for
the key ring closure (21 f 22a -c). This was accom-
plished efficiently (83%) by exposure to pyridinium
p-toluenesulfonate at room temperature. The cyclization
product was separated into two fractions; one was a
single isomer (22a ) and the other a mixture of two
isomers (22b,c). The stereochemistry of these materials
was not established, and the fractions were individually
subjected to Dess-Martin oxidation so as to produce a
single ketone from each fraction. These ketones (23a ,b)
must differ in stereochemistry at C(5). To introduce the
two double bonds (cf. 9), a mixture of the ketones was
deprotonated with (Me3Si)2NK at 0 °C, treated with
PhSeCl at -78 °C, deprotonated again in situ (0 °C), and
quenched once more at -78 °C with PhSeCl. This
sequence of operations gave bis-selenides 24 (62%), which
were not fully characterized. On oxidation with NaIO4
in aqueous methanolic NaHCO3, double selenoxide frag-
mentation occurred as well as loss of the Boc group,
Key: (i) LDA, THF, HMPA, 70%; (ii) DIBALH, CH2Cl2, 99%;
(iii) TsOH‚pyridine, THF, 83% (36% for 22a , 47% for 22b,c); (iv)
Dess-Martin periodinane, CH2Cl2, 79% for 23a , 82% for 23b; (v)
(Me3Si)2NK, PhSeCl, (Me3Si)2NK, PhSeCl, THF, 62%; (vi) NaIO4,
NaHCO3, MeOH, water, 42%.
affording (42%) the desired core structure of cladobotryal
(24 f 9). We did not establish if the C(3a)-C(7a) double
bond of 9 was formed directly or resulted by isomerization
of an initially formed 3,3a-double bond.11
While the H and 13C NMR spectra of 912 were compat-
1
ible with the assigned structure, they were not, by
themselves, sufficient to exclude structure 10. The latter
was unlikely, of course, when the synthetic route to 9 is
taken into account; nonetheless, we confirmed our as-
signment by synthesizing 10; fortunately, its structure
could be proved by X-ray analysis. We used this indirect
approach, as we were unable to obtain suitable crystals
of 9 to analyze directly.
Compound 10 was prepared by the route shown in
Scheme 3. This route is similar to one we had used
previously7 in work that led to 11. Deprotonation of
γ-butyrolactone (12) and condensation with the known
aldehyde 2513 gave 26 as a mixture of two stereoisomers
(77%), and Dess-Martin oxidation then afforded (72%)
the derived ketone 27, which exists largely in the keto
form shown (keto/enol ) ca. 9:1). Treatment with aqueous
ammonia brought about a number of changes that
resulted in isolation of the chromatographically insepa-
rable lactams 28 (44%). These were dehydrated by
heating in the presence of TsOH (28 f 29, 80%). Finally,
dehydrogenation with DDQ in refluxing PhH gave 10
(36%)sthe core of structure 5sand the product (30) of
further dehydrogenation (53%). The two compounds were
(11) Selenoxide elimination generally occurs away from oxygen, but
for nitrogen (the present case) that tendency appears to be weaker:
Clive, D. L. J . Tetrahedron 1978, 34, 1049-1132 (see, especially p
1104).
(9) (a) Testa, E.; Fontanella, L.; Cristiani, G. F.; Mariani, L. Liebigs
Ann. 1961, 639, 166-180. (b) Secor, H. V.; Sanders, E. B. J . Org. Chem.
1978, 43, 2539-2541. (c) Gensler, W. J .; Dheer, S. K. J . Org. Chem.
1981, 46, 4051-4057.
(10) (a) Yuasa, Y.; Fujimaki, N.; Yokomatsu, T.; Ando, J .; Shibuya,
S. J . J . Chem. Soc., Perkin Trans. 1 1998, 3577-3584. (b) Guanti, G.;
Narisano, E.; Podgorski, T.; Thea, S.; Williams, A. Tetrahedron 1990,
46, 7081-7090.
(12) Since some of the expected 13C NMR signals of 9 could not be
detected, we prepared the corresponding O-(tert-butyldimethylsilyl)
derivative, for which all the expected 13C NMR signals could be seen
(see the Supporting Information).
(13) Newman-Evans, R. H.; Simon, R. J .; Carpenter, B. K. J . Org.
Chem. 1990, 55, 695-711. We used the Dess-Martin reagent for the
final oxidation to the aldehyde.
J . Org. Chem, Vol. 69, No. 6, 2004 1873

Clive and Huang
SCHEME 3a
SCHEME 5
Deprotonation of lactone 31 (3 equiv LDA, THF) and
addition of a mixture of aldehyde 13 (1.5 equiv) and
HMPA (1.5 equiv) in THF gave the expected condensation
product 35 as a mixture of isomers in 71% yield [100%
after correction for recovered starting lactone (29%)].
DIBALH reduction generated the corresponding lactols
(35 f 36, ca. 100%), and these could be cyclized in the
required manner (36 f 37) under mildly acidic conditions
(pyridinium p-toluenesulfonate). The product was iso-
lated as two fractions, the chromatographically faster-
moving fraction (37a ) being obtained in 54% yield, and
the slower-moving fraction (37b) in 27% yield. NMR
measurements showed that each fraction was a single
isomer, but the stereochemistry was not determined.
Oxidation to the corresponding ketones was achieved
with the Dess-Martin reagent (96% for 38a ; 85% for
38b). Each ketone was a single isomer differing in
stereochemistry at C(5).
a
Key: (i) LDA, THF, HMPA, 77%; (ii) Dess-Martin periodi-
nane, CH2Cl2, 72%; (iii) NH4OH, NH4Cl, MeOH, 44%; (iv) TsOH,
PhMe, heat, 80%; (v) DDQ, PhH, heat, 36% of 10, 53% of 30, 10%
of 29.
SCHEME 4
Double phenylselenation of 38a (38b was not exam-
ined), as in the model series (cf. Scheme 2, 23a ,b f 24),
was not successful, but introduction of the first of the
required double bonds (38a and 38b f 39) could be
achieved by phenylselenation [(Me3Si)2NK, THF, PhSeCl]
and selenoxide elimination (H2O2, pyridine, CH2Cl2).
However, the product 39 had the unexpected and unwel-
come property of resisting further desaturation to 40.
Phenylselenation of 39 at C(3a) now proved impossible
[LDA or (Me3Si)2NK, followed by PhSeCl], probably
because severe steric crowding blocks access to C(3a).
Phenylselenation of 39 after desilylation also failed, and
introduction of a PhSe group at the eventual C(3a)
position by selenation of lactone 31 before condensation
with 13 was also unsuitable, because lactone reduction
(cf. 35 f 36, Scheme 6) after the condensation was
accompanied by loss of the selenium group. Dehydroge-
nation of 39 using DDQ, Pd/C, MnO2, (NH4)2Ce(NO3)6,14
Ph3CPF6,15 or [PhSe(O)]2O, in some cases,16 under a
variety of conditions, was equally unsuccessful.
At this stage, we considered that removal of the N-Boc
group would provide an alternative method (see below)
for introducing the C(3a)-C(7a) double bond; however,
attempted deprotection of the nitrogen of 39, using CF3-
CO2H or bromocatecholborane, caused decomposition,
and so we were forced to explore several modified
versions of our route.
During these studies, we tried to protect the hydroxy
of 35 as its triisopropylsilyl ether (i-Pr3SiOSO2CF3, 2,6-
lutidine), but found instead that the Boc group was
separated by flash chromatography, and the structure
of 10 was established by single-crystal X-ray analysis,
which showed that the crystalline material exists in the
pyridinone form.
The methods used to make pyridinones 9 and 10
should be applicable to a number of derivatives, especially
those in which the phenyl substituent has been modified,
but we have not tested this possibility.
Syn th esis of Ra cem ic Cla d obotr ya l (1). In explor-
atory work7 leading to 11, we had condensed the substi-
tuted lactone 31 with the simple aldehyde 25 (see Scheme
4). Our route to cladobotryal is also convergent and is
based on the same γ-lactone, which was destined to
provide the dihydrofuran segment of the natural product.
We made many efforts to divert intermediates obtained
from 31 and 25 (and also from 12 and 25) into the
cladobotryal system, but well before we had exhausted
our plans to this end, it had became clear that an
acceptable route would be most easily found by using,
instead of 25, an aldehyde carrying both the phenyl
substituent and a suitably protected nitrogen â to the
carbonyl group. In the event, several such aldehydes had
to be tried before we established through the model
studies described above (see Scheme 2) that 13 is a
satisfactory one.
As described earlier,7 lactone 31 was made by radical
cyclization of 33, and the product 34 was elaborated into
31 (Scheme 5). The radical cyclization 33 f 34 is
stereoselective; the radical approaches the double bond
from the face opposite to the adjacent substituent,
thereby generating the required relative stereochemistry.
(14) Cf. Pfister, J . R. Synthesis 1990, 689-690.
(15) Cf. Shu, C.; Alcudia, A.; Yin, J .; Liebeskind, L. S. J . Am. Chem.
Soc. 2001, 123, 12477-12487.
(16) DDQ, PhH, reflux; Pd/C, xylene, reflux or PhOPh at 220 °C.;
MnO2, xylene, reflux; DDQ, CF3CO2H, PhMe, 80 °C.; (NH4)2Ce(NO3)6,
water-acetone or MeCN.; (NH4)2Ce(NO3)6, 2,6-pyridinedicarboxylic acid
N-oxide, water-MeCN.; Ph3CPF6, CH2Cl2; DDQ, Me3SiOSO2CF3, PhH.;
[PhSe(O)]2O, PhMe, reflux.
1874 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of the Antifungal and Antibacterial Agent Cladobotryal
SCHEME 6a
SCHEME 7a
a
a
Key: (i) 3 equiv of LDA, THF, -78 °C, then room temperature;
Key: (i) i-Pr3SiOSO2CF3, 2,6-lutidine, CH2Cl2, reflux, 100%
then add 13 in THF-HMPA at -78 °C, 71%, recovery of 31 )
29%; (ii) DIBALH, CH2Cl2, -78 °C, ca. 100%; (iii) TsOH‚pyridine,
THF, 45 °C, 54% of 37a , 27% of 37b; (iv) Dess-Martin periodi-
nane, CH2Cl2, 96% for 37a , 85% for 37b; (v) (a) (Me3Si)2NK, THF,
0 °C, then PhSeCl, -78 C, (b) H2O2, pyridine, CH2Cl2, 74% overall
for 38a , 24% (not optimized) for 38b.
for both 38a and 38b; (ii) (a) (Me3Si)2NK, THF, -78 °C, PhSeCl,
-78 C, (b) H2O2, pyridine, CH2Cl2; (iii) Bu4NF, THF, 0 °C, 53%
overall for 41a , 49% for 41b; (iv) (a) t-BuOCl, CH2Cl2, -78 °C, (b)
DBU, PhMe, 71%; (v) Bu4NF, THF, 97%; (vi) Dess-Martin,
CH2Cl2, 97%.
The H and 13C NMR spectra of our racemic materials
matched those reported for the natural products.
1
converted into a CO2SiPr-i3 group before the hydroxy
itself was silylated. The analogous conversion of N-Boc
into N-COOSiMe2Bu-t has in fact been observed before,
with t-BuMe2SiOSO2CF3,17 and our own experimental
observation prompted us to treat 38a and 38b with i-Pr3-
SiOSO2CF3. In the event, this was the key reaction that
allowed us to bypass the barriers that had earlier
thwarted introduction of the C(3a)-C(7a) double bond.
Both 38a and 38b were converted quantitatively into the
silyl carbamates 41a and 41b, respectively (Scheme 7).
Each carbamate could be desaturated at C(5)-C(6) by
phenylselenation and selenoxide elimination, under the
conditions we had used to make 39. The crude products
(42) from 41a and 41b were identical, of course, although
not very stable to chromatography over silica or alumina.
The nitrogen protecting group could now be removed
under nonacidic conditions (Bu4NF, THF) to afford 43
(53% overall from 41a , 49% overall from 41b). Compound
43, which was stable to flash chromatography over silica
gel, provided an opportunity to generate an imine that
would be expected to tautomerize spontaneously to 44.
Several methods are available for converting a CH-NH
unit into an imine,18 but the classical procedure18b of
N-chlorination (t-BuOCl)19 and base treatment (DBU),
with which we had had direct experience several years
ago,20 again proved satisfactory (71%), and served to
generate pyridinone 44. Cladobotryal (1) was then easily
reached via the natural product 2 by desilylation (Bu4-
NF, THF, 97%) and Dess-Martin oxidation (2 f 1, 97%).
Con clu sion
Our route to 1 provides the first method for making
this natural product. The approach should also work to
generate simple analogues in which the phenyl group is
substituted, but we have not tried to do this. Replacement
of an N-Boc group by N-CO2SiPr-i3, and related inter-
conversions, may be generally useful where standard
methods for Boc removal do not worksas found in the
present synthesis. We expect that the method we have
used to generate the second double bond of the pyridinone
has general promise in cases where more traditional
methods of dehydrogenation fail.
Exp er im en ta l Section
Hexah ydr o-4-oxo-5-ph en yl-3a,5-bis(ph en ylselan yl)fu r o-
[2,3-b]p yr id in e-7-ca r boxylic Acid ter t-Bu tyl Ester (24).
(Me3Si)2NK (0.5 M in PhMe, 0.430 mL, 0.215 mmol) was added
dropwise to a stirred and cooled (-78 °C) solution of ketones
23a ,b (65.0 mg, 0.205 mmol) in THF (4 mL). After 10 min,
(18) (a) Cf. Dayagi, S.; Degani, Y. In The Chemistry of the Carbon-
Nitrogen Double Bond; Patai, S., Ed.; Interscience: New York, 1970;
pp 117-120. (b) Bachmann, W. E.; Cava, M. P.; Dreiding, A. S. J . Am.
Chem. Soc. 1954, 76, 5554-5555. (c) Cava, M. P.; Vogt, B. R.
Tetrahedron Lett. 1964, 2813-2816. (d) Cornejo, J . J .; Larson, K. D.;
Mendenhall, G. D. J . Org. Chem. 1985, 50, 5382-5383 and references
therein. (e) Reviews: Hoffman, R. V.; Bartsch, R. A.; Cho, B. R. Acc.
Chem. Res. 1989, 22, 211-217. (f) Pawlenko, S. In Methoden der
Organischen Chemie (Houben-Weyl); Georg Thieme Verlag: Stuttgart,
1990; Vol. E14b, pp 226-233.
(17) (a) Sakaitani, M.; Ohfune, Y. J . Org. Chem. 1990, 55, 870-
876. (b) Grieco, P. A.; Perez-Medrano, A. Tetrahedron Lett. 1988, 29,
4225-4228. (c) Busque´, F.; de March, P.; Figueredo, M.; Font, J .;
Gallagher, T.; Mila´n, S. Tetrahedron: Asymmetry 2002, 13, 437-445.
(d) Cf. Brosius, A. D.; Overman, L. E.; Schwink, L. J . Am. Chem. Soc.
1999, 121, 700-709.
(19) (a) Mintz, M. J .; Walling, C. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, pp 184-187. (b) Ha za r d w a r n in g:
Organic Syntheses; Wiley: New York, 1973; Collect. Vol. V, pp 183-
184.
(20) Clive, D. L. J .; Bo, Y.; Tao, Y.; Daigneault, S.; Wu, Y.-J .;
Meignan, G. J . Am. Chem. Soc. 1998, 120, 10332-10349.
J . Org. Chem, Vol. 69, No. 6, 2004 1875

Clive and Huang
the cold bath was replaced by an ice bath, and stirring was
continued for 15 min. The mixture was recooled to -78 °C,
and a solution of PhSeCl (41.0 mg, 0.214 mmol) in THF (2
mL) was injected dropwise. After 15 min at -78 °C, the
mixture was again transferred to an ice bath, and stirring was
continued for 15 min. The mixture was recooled to -78 °C,
and (Me3Si)2NK (0.5 M in PhMe, 0.615 mL, 0.308 mmol) was
then added dropwise. Stirring at -78 °C was continued for 10
min and, as before, at 0 °C for 15 min. Finally, the mixture
was cooled to -78 °C, and a solution of PhSeCl (62.0 mg, 0.324
mmol) in THF (2 mL) was injected dropwise. After 1 h at -78
°C, the mixture was quenched with saturated aqueous NH4Cl
(1 mL), diluted with Et2O (50 mL), and washed with saturated
aqueous NH4Cl (twice) and brine. The organic phase was dried
(Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel (1.5 × 25 cm), using 1:5 EtOAc-hexane, gave
(d, J ) 8.9 Hz, 1 H), 5.41 (d, J ) 1.1 Hz, 1 H), 5.44 (s, 1 H),
7.25-7.37 (m, 3 H), 7.46-7.53 (m, 2 H); 13C NMR (CDCl3, 100.6
MHz) δ 26.1 (t), 43.6 (d), 67.0 (t), 75.8 (d), 117.3 (t), 127.7 (d),
128.0 (d), 128.4 (d), 139.1 (s), 147.8 (s), 179.8 (s); exact mass
m/z calcd for C13H14O3 218.09430, found 218.09471.
Dih ydr o-3-(1-oxo-2-ph en yl-2-pr open yl)fu r an -2-on e (27).
Dess-Martin reagent (444 mg, 1.05 mmol) was added in one
portion to a stirred solution of 26a ,b (mixture of isomers)
(0.176 g, 0.806 mmol) in CH2Cl2 (18 mL). The mixture was
stirred for 1 h, diluted with Et2O (50 mL), washed with 1:1
saturated aqueous NaHCO3-10% aqueous Na2S2O3, and brine,
dried (Na2SO4), and evaporated. Flash chromatography the
residue over silica gel (1.5 × 20 cm), using CH2Cl2, gave 27
(125 mg, 72%) as an oil: FTIR (CH2Cl2, cast) 3057, 2991, 2917,
1767, 1682, 1575 cm-1 1H NMR (CDCl3, 400 MHz) δ 2.41
;
(dddd, J ) 12.8, 9.2, 8.0, 6.3 Hz, 1 H), 2.72 (ddt, J ) 12.8, 8.0,
6.3 Hz, 1 H), 4.27-4.36 (m, 2 H), 4.43 (ddd, J ) 8.8, 8.0, 6.3
Hz, 1 H), 6.16 (s, 1 H), 6.35 (s, 1 H), 7.28-7.39 (m, 5 H); 13C
NMR (CDCl3, 100.6 MHz) δ 26.2 (t), 48.3 (d), 67.5 (t), 128.2
(d), 128.36 (d), 128.4 (d), 128.8 (s), 136.3 (s), 147.9 (t), 172.7
(s), 194.8 (s); exact mass m/z calcd for C13H12O3 216.07864,
found 216.07823.
24 (80 mg, 62%) as
a yellow oil, which was used the
same day: exact mass (electrospray) m/z calcd for C30H31
-
NNaO480Se2 652.04757, found 652.04718.
3,7-Dih yd r o-5-p h en yl-2H-fu r o[2,3-b]p yr id in -4-on e (9).
NaHCO3 (24.0 mg, 0.286 mmol) and NaIO4 (140 mg, 0.655
mmol) were added to a vigorously stirred solution of 24 (90.5
mg, 0.144 mmol) in 6:1 MeOH-water (7 mL). After 5.5 h, the
mixture was diluted with EtOAc (50 mL) and washed with
saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The
aqueous phase was extracted with EtOAc (2 × 20 mL), and
the combined organic extracts were dried (Na2SO4) and
evaporated. Flash chromatography the residue over silica gel
(0.7 × 20 cm), using 1:40 MeOH-CH2Cl2, gave 9 (12.8 mg,
42%) as a white solid: mp 195-198 °C; FTIR (MeOH-acetone,
cast) 2918, 2463, 1646, 1605, 1577, 1550, 1501 cm-1; 1H NMR
(CD3OD, 500 MHz) δ 3.19 (t, J ) 8.7 Hz, 2 H), 4.69 (t, J ) 8.7
Hz, 2 H), 7.27-7.32 (m, 1 H), 7.34-7.41 (m, 2 H), 7.44-7.48
(m, 2 H), 7.54 (s, 1 H), 13C NMR (CD3OD, 100.6 MHz) (four
signals are not observed in this spectrum) δ 26.9 (t), 72.5 (t),
106.3 (s), 128.2 (d), 129.2 (d), 130.4 (d), 136.6 (s); exact mass
m/z calcd for C13H11NO2 213.07898, found 213.07862.
In earlier separate experiments, the individual isomers of
26 each gave 27, under the above conditions, but in lower yield
(ca 65%).
Hexa h yd r o-7a -h yd r oxy-7-p h en ylfu r o[3,2-c]p yr id in -4-
on e (28). NH4Cl (890 mg, 16.6 mmol) and concentrated (28-
30% w/w) ammonia solution (13 mL) were added successively
to a stirred solution of 27 (420 mg, 1.94 mmol) in MeOH (50
mL), and stirring was continued for 1 h. The mixture was then
placed in a preheated oil bath set at 50 °C, and stirring was
continued for 1 h. The mixture was cooled to room temperature
and evaporated. Flash chromatography of the residue over
silica gel (2 × 25 cm), using 1:25 MeOH-CH2Cl2, gave 28 (200
mg, 44%) as an oil, which was a mixture of two isomers: FTIR
(CH2Cl2, cast) 3304, 2891, 1660 cm-1; the 1H NMR spectrum
was too complex to be of diagnostic value; 13C NMR (CDCl3,
50.3 MHz) (signals for both isomers) δ 28.8 (t), 29.2 (t), 42.4
(t), 43.7 (t), 48.5 (d), 50.3 (d), 51.2 (d), 51.5 (d), 66.7 (t), 67.3
(t), 103.5 (s), 104.4 (s), 128.0 (d), 128.2 (d), 128.7 (d), 128.8 (d),
129.0 (d), 129.9 (d), 135.2 (s), 135.7 (s), 173.2 (s), 173.5 (s);
exact mass m/z calcd for C13H15NO3 233.10519, found 233.10471.
To obtain a 13C NMR spectrum showing all the expected
signals, compound 9 was silylated on oxygen, as described in
the next experiment.
Dih yd r o-3-(1-h yd r oxy-2-p h en yl-2-p r op en yl)fu r a n -2-
on e (26a ,b). BuLi (2.5 M in hexanes, 4.0 mL, 10 mmol) was
added dropwise to a stirred and cooled (0 °C) solution of i-Pr2-
NH (1.4 mL, 10 mmol) in THF (20 mL). Stirring at 0 °C was
continued for 15 min, and the solution was then cooled to -78
°C. A solution of 12 (0.75 mL, 0.98 mmol) in THF (12 mL) was
then added dropwise. The mixture was stirred at -78 °C for
90 min, and freshly made aldehyde 2513 (435 mg, 3.28 mmol)
in THF (12 mL) was added dropwise. Stirring at -78 °C was
continued for 1 h, and saturated aqueous NH4Cl (10 mL) was
added, followed by EtOAc (100 mL). The cooling bath was
removed, and stirring was continued for 30 min. The mixture
was washed with saturated aqueous NH4Cl and brine, and the
organic extract was dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (2 × 30 cm), using
2:5 EtOAc-hexane, gave 26 as two isomers: isomer 26a (less
polar, 35 mg, 5%) was obtained as a liquid and isomer 26b
(more polar, 515 mg, 72%) as a solid.
Isomer 26a : FTIR (CH2Cl2, cast) 3455, 3055, 2989, 2915,
1758, 1634, 1598, 1574; 1H NMR (CDCl3, 400 MHz) δ 1.90
(dddd, J ) 12.8, 9.6, 7.5, 3.3 Hz, 1 H), 2.34 (dq, J ) 12.8, 9.6
Hz, 1 H), 2.39 (d, J ) 4.0 Hz, 1 H), 2.64 (dt, J ) 2.4, 9.6 Hz,
1 H), 4.11 (dt, J ) 7.5, 8.9 Hz, 1 H), 4.33 (dt, J ) 3.3, 8.9 Hz,
1 H); 5.34 (br s, 1 H), 5.39 (t, J ) 1.3 Hz, 1 H), 5.51 (t, J ) 1.5
Hz, 1 H), 7.27-7.38 (m, 5 H); 13C NMR (CDCl3, 100.6 MHz) δ
21.0 (t), 43.8 (d), 67.2 (t), 70.0 (d), 113.3 (t), 126.6 (d), 128.2
(d), 128.7 (d), 138.9 (s), 148.7 (s), 178.6 (s); exact mass m/z
calcd for C13H14O3 218.09430, found 218.09472.
3,5,6,7-Tet r a h yd r o-7-p h en yl-2H -fu r o[3,2-c]p yr id in -4-
on e (29). TsOH‚H2O (24.0 mg, 0.139 mmol) was added to a
stirred solution of 28 (mixture of isomers) (65.0 mg, 0.279
mmol) in PhMe (30 mL), and the mixture was stirred at 115
°C (oil bath) for 5 h, cooled and evaporated. Flash chromatog-
raphy the residue over silica gel (1.5 × 15 cm), using 1:30
MeOH-CH2Cl2, gave 29 (48 mg, 80%) as a white solid: mp
165-166 °C; FTIR (CDCl3, cast) 3216, 3062, 2870, 1671, 1637
1
cm-1; H NMR (CDCl3, 400 MHz) δ 2.88-3.06 (m, 2 H), 3.45
(dd, J ) 14.0, 8.8 Hz, 1 H), 3.73-3.81 (m, 2 H), 4.51-4.63 (m,
2 H), 5.62 (br s, 1 H), 7.21-7.37 (m, 5 H); 13C NMR (CDCl3,
100.6 MHz) δ 26.8 (t), 40.4 (d), 47.3 (t), 73.1 (t), 106.0 (s), 127.8
(d), 127.9 (d), 128.9 (d), 137.2 (s), 168.0 (s), 170.0 (s); exact
mass m/z calcd for C13H13NO2 215.09464, found 215.09507.
3,5-Dih yd r o-7-p h en yl-2H-fu r o[3,2-c]p yr id in -4-on e (10)
a n d 7-P h en yl-5H-fu r o[3,2-c]p yr id in -4-on e (30). DDQ (75.0
mg, 0.330 mmol) was added to a stirred solution of 29 (48.0
mg, 0.223 mmol) in PhH (40 mL). The mixture was lowered
into a preheated oil bath set at 85 °C, stirred for 3 days, cooled
to room temperature, and evaporated. The residue was dis-
solved in EtOAc (100 mL), and the solution was washed with
5% NaOH (20 mL) and brine (20 mL). The aqueous phase was
extracted with EtOAc (3 × 40 mL). All the organic extracts
were combined, dried (Na2SO4) and evaporated. Flash chro-
matography the residue over silica gel (1.5 × 35 cm), using
1:30 to 1:10 MeOH-CH2Cl2, gave 10 (17 mg, 36%), 30 (25 mg,
53%) and starting material (29) (5 mg, 10%).
Isomer 26b: mp 77-79 °C; FTIR (CH2Cl2, cast) 3477, 2988,
2914, 1749 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.77-2.04 (m,
2 H), 2.67 (dt, J ) 11.2, 9.0 Hz, 1 H), 4.06 (ddd, J ) 10.2, 9.0,
6.7 Hz, 1 H), 4.27 (dt, J ) 2.2, 8.9 Hz, 1 H), 4.39 (s, 1 H), 4.65
Compound 10: mp 242-244 °C; FTIR (CH2Cl2 cast) 2927,
2850, 1655, 1597, 1576, 1566, 1502 cm-1 1H NMR (CD2Cl2,
;
400 MHz) δ 3.15 (t, J ) 9.2 Hz, 2 H), 4.74 (t, J ) 9.2 Hz, 2 H),
1876 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of the Antifungal and Antibacterial Agent Cladobotryal
7.28-7.34 (m, 1 H), 7.36-7.43 (m, 2 H), 7.45 (s, 1 H), 7.49-
7.54 (m, 2 H); 13C NMR (CD2Cl2, 100.6 MHz) δ 27.0 (t), 73.6
(t), 109.8 (s), 111.1 (s), 127.7 (d), 127.9 (d), 128.9 (d), 133.7 (s),
an oil bath set at 45 °C, and stirring was continued for 15 h.
The mixture was cooled to room temperature, diluted with
Et2O (100 mL), washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), and evaporated. Flash chromatography
of the residue over silica gel (1.5 × 40 cm), using 1:6 to 1:4
EtOAc-hexane, gave 37 as two fractions: fraction A (less
polar, 150 mg, 54%) and fraction B (more polar, 76 mg, 27%).
Fraction A (37a ): mp 77-80 °C; FTIR (CH2Cl2, cast) 3517,
3070, 2962, 2930, 2889, 2858, 1703, 1589 cm-1; 1H NMR (CD2-
Cl2, 400 MHz) δ 1.10 (s, 9 H), 1.45 (s, 3 H), 1.47 (s, 12 H), 1.50
(d, J ) 6.8 Hz, 3 H), 2.26 (d, J ) 7.9 Hz, 1 H), 2.34 (s, 1 H),
2.78 (dd, J ) 12.2, 3.2 Hz, 1 H), 3.22 [d (formally part of AB
q), J ) 10.3 Hz, 1 H], 3.42-3.74 (m containing part of AB q,
2 H), 3.84-4.14 (m, 2 H), 4.34 (s, 1 H), 5.49 (q, J ) 6.8 Hz, 1
H), 5.61-5.87 (m, 1 H), 7.25-7.50 (m, 11 H), 7.62-7.69 (m, 4
H); 13C NMR (CD2Cl2, 100.6 MHz) δ 12.8 (q), 14.3 (q), 18.1 (q),
19.6 (s), 27.2 (q), 28.4 (q), 37.7 (t), 45.9 (d), 47.0 (d), 49.7 (s),
68.0 (t), 69.3 (d), 80.7 (s), 82.5 (d), 88.2 (d), 119.8 (d), 127.3
(d), 128.08 (d), 128.12 (d), 128.4 (d), 128.9 (d), 130.1 (d), 130.2
(d), 133.4 (s), 133.9 (s), 134.0 (s), 135.98 (d), 136.02 (d), 141.4
134.3 (d), 163.1 (s), 167.8 (s); exact mass m/z calcd for C13H11
-
NO2 213.07898, found 213.07930. The structure was confirmed
by single-crystal X-ray analysis.
Compound 30: mp 195-197 °C; FTIR (CDCl3, cast) 3106,
3050, 1665, 1598, 1556, 1523 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 7.09 (d, J ) 2.1 Hz, 1 H), 7.33-7.50 (m, 3 H), 7.52 (s, 1 H),
7.62 (d, J ) 2.1 Hz, 1 H), 7.64-7.71 (m, 2 H); 13C NMR (CDCl3,
125.7 MHz) δ 106.9 (d), 112.2 (s), 116.1 (s), 127.5 (d), 127.9
(d), 128.3 (d), 128.9 (d), 132.5 (s), 143.8 (d), 158.9 (s), 161.6
(s); exact mass m/z calcd for C13H9NO2 211.06332, found
211.06346.
[3-[(4R*,5S*)-4-[(ter t-Bu tyld ip h en ylsila n yl)oxym eth yl]-
tetr a h yd r o-4-m eth yl-5-[(1E)-1-m eth yl-1-p r op en yl]-2-oxo-
fu r an -3-yl]-3-h ydr oxy-2-ph en ylpr opyl]car bam ic Acid ter t-
Bu tyl Ester (35). BuLi (2.5 M in hexanes, 1.6 mL, 4.0 mmol)
was added dropwise to a stirred and cooled (0 °C) solution of
i-Pr2NH (0.55 mL, 3.9 mmol) in THF (16 mL). Stirring at 0 °C
was continued for 15 min, and the solution was then cooled to
-78 °C. A solution of 31 (0.5520 g, 1.306 mmol) in THF (16
mL) was added dropwise to the LDA solution. The mixture
was stirred at -78 °C for 30 min, the dry ice-acetone bath was
changed to an ice bath, and stirring was continued for 40 min.
The mixture was recooled to -78 °C and a solution of 13 (0.490
g, 1.97 mmol) and HMPA (0.34 mL, 2.0 mmol) in THF (10 mL)
was added dropwise. Stirring at -78 °C was continued for 90
min, and saturated aqueous NH4Cl (5 mL) was added, followed
by Et2O (100 mL). The cooling bath was removed, and stirring
was continued for 30 min. The mixture was washed with
saturated aqueous NH4Cl (twice) and brine, dried (Na2SO4)
and evaporated. Flash chromatography the residue over silica
gel (1.8 × 40 cm), using 1:8 to 1:5 EtOAc-hexane, gave
starting lactone 31 (0.160 g, 29%) and 35 (0627 g, 71%) as a
mixture of isomers: FTIR (CDCl3, cast) 3355, 2965, 2931, 2859,
1763, 1711, 1689, 1589, 1511 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 0.82-1.58 (m, 27 H), 2.53 (s, 0.7 H), 2.96-4.30 (m, 3.5 H),
3.09 (AB q, J ) 10.1 Hz, ∆νAB ) 84.4 Hz, 1.4 H), 3.58 (dt, J )
10.7, 3.2 Hz, 0.7 H), 4.16 (d, J ) 10.7 Hz, 0.7 H), 4.70-4.83
(m, 1.1 H), 4.91 (s, 0.7 H), 4.98-5.06 (m, 0.2 H), 5.31-5.42
(m, 0.1 H), 5.47 (q, J ) 6.7 Hz, 0.7 H), 5.52-5.61 (m, 0.2 H),
7.14-7.65 (m, 16 H); 13C NMR (CDCl3, 100.6 MHz, major
isomer only) δ 12.7 (q), 13.7 (q), 16.1 (q), 19.0 (s), 26.7 (q), 28.3
(q), 42.6 (t), 47.0 (s), 48.7 (d), 48.8 (d), 67.9 (t), 67.7 (d), 80.4
(s), 89.7 (d), 122.1 (d), 127.0 (d), 127.5 (d), 127.8 (d), 128.4 (d),
129.0 (d), 129.2 (s), 129.5 (d), 132.8 (s), 133.0 (s), 135.5 (d),
135.6 (d), 140.8 (s), 158.0 (s), 176.4 (s); exact mass (electro-
(s), 155.4 (s); exact mass (electrospray) m/z calcd for C40H53
-
NNaO5Si 678.359072, found 678.358975.
Fraction B (37b): mp 54-56 °C; FTIR (CH2Cl2, cast) 3465,
3070, 2963, 2930, 2858, 1703, 1602, 1589 cm-1; 1H NMR (CD2-
Cl2, 400 MHz) δ 1.01 (s, 9 H), 1.29 (s, 3 H), 1.39 (s, 9 H), 1.46
(s, 3 H), 1.54 (d, J ) 6.8 Hz, 3 H), 2.48-2.58 (m, 1 H), 3.22 (d,
J ) 4.8 Hz, 1 H), 3.39 (dd, J ) 13.2, 4.0 Hz, 1 H), 3.42 (AB q,
J ) 10.1 Hz, ∆νAB ) 156.3 Hz, 2 H), 4.02-4.16 (m, 2 H), 4.25
(s, 1 H), 5.49 (q, J ) 6.8 Hz, 1 H), 6.03 (br s, 1 H), 7.24-7.49
(m, 12 H), 7.57-7.65 (m, 4 H); 13C NMR (CD2Cl2, 100.6 MHz)
δ 13.1 (q), 14.0 (q), 19.1 (q), 19.6 (s), 27.1 (q), 28.3 (q), 42.6 (t),
45.1 (d), 46.7 (d), 51.1 (s), 67.6 (t), 68.5 (d), 80.5 (s), 83.5 (d),
88.1 (d), 121.5 (d), 127.5 (d), 128.0 (d), 128.1 (d), 128.9 (d), 129.9
(d), 130.0 (d), 130.2 (d), 132.5 (s), 133.8 (s), 134.0 (s), 136.0
(d), 139.5 (s), 155.3 (s); exact mass (electrospray) m/z calcd for
C
40H53NNaO5Si 678.359072, found 678.358885.
(2R*,3S*)-3-[(ter t-Bu t yld ip h en ylsila n yl)oxym et h yl]-
h exa h yd r o-3-m eth yl-2-[(1E)-1-m eth yl-1-p r op en yl]-4-oxo-
5-p h en ylfu r o[2,3-b]p yr id in e-7-ca r boxylic Acid ter t-Bu tyl
Ester (38a ). Dess-Martin reagent (128 mg, 0.302 mmol) was
added in one portion to a stirred solution of 37a (less polar
isomer) (132 mg, 0.201 mmol) in CH2Cl2 (18 mL). After 30 min,
another portion of Dess-Martin reagent (128 mg, 0.302 mmol)
was added. Stirring was continued for 2 h, and the mixture
was diluted with Et2O (100 mL), washed with 1:1 saturated
aqueous NaHCO3-10% aqueous Na2S2O3, and brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (1.5 × 40 cm), using 1:9 EtOAc-hexane, gave
38a (126 mg, 96%) as a solid: mp 57-59 °C; FTIR (CH2Cl2,
cast) 3070, 2964, 2931, 2858, 1704, 1589 cm-1; 1H NMR (CD2-
Cl2, 400 MHz) δ 1.39 (s, 9 H), 1.41 (s, 3 H), 1.79 (s, 12 H), 1.84
(d, J ) 6.8 Hz, 3 H), 3.66 (d, J ) 7.3 Hz, 1 H), 3.71 (AB q, J )
10.0 Hz, ∆νAB ) 120.6 Hz, 2 H), 3.81-4.09 (m, 2 H), 4.63 (s, 1
H), 4.60-4.77 (m, 1 H), 5.84 (q, J ) 6.8 Hz, 1 H), 6.60 (br s, 1
H), 7.44-7.52 (m, 2 H), 7.56-7.78 (m, 9 H), 7.91-7.98 (m, 4
H); 13C NMR (CD2Cl2, 75.5 MHz) δ 13.2 (q), 14.0 (q), 19.7 (s),
20.0 (q), 27.2 (q), 28.5 (q), 43.2 (t), 53.9 (s), 54.8 (d), 56.1 (d),
68.3 (t), 81.3 (s), 84.4 (d), 91.5 (d), 122.8 (d), 127.8 (d), 128.10
(d), 128.13 (d), 129.0 (d), 129.2 (d), 130.2 (d), 131.6 (s), 133.8
(s), 133.9 (s), 136.08 (d), 136.10 (d), 136.8 (s), 154.4 (s), 207.7
(s); exact mass (electrospray) m/z calcd for C40H51NNaO5Si
676.343422, found 676.343928.
(2R*,3S*)-3-[(ter t-Bu t yld ip h en ylsila n yl)oxym et h yl]-
h exa h yd r o-3-m eth yl-2-[(1E)-1-m eth yl-1-p r op en yl]-4-oxo-
5-p h en ylfu r o[2,3-b]p yr id in e-7-ca r boxylic Acid ter t-Bu tyl
Ester (38b). Dess-Martin reagent (146 mg, 0.344 mmol) was
added in one portion to a stirred solution of 37b (more polar
isomer) (105 mg, 0.160 mmol) in CH2Cl2 (15 mL). Stirring was
continued for 3 h, and the mixture was diluted with Et2O (40
mL), washed with 1:1 saturated aqueous NaHCO3-10% aque-
ous Na2S2O3 and brine, dried (Na2SO4),and evaporated. Flash
chromatography of the residue over silica gel (1.5 × 30 cm),
spray) m/z calcd for
C40H53NNaO6Si 694.353987, found
694.353635.
[3-[(4R*,5S*)-4-[(ter t-Bu tyld ip h en ylsila n yl)oxym eth yl]-
t et r a h yd r o-2-h yd r oxy-4-m et h yl-5-[(1E)-1-m et h yl-1-p r o-
p en yl]fu r a n -3-yl]-3-h yd r oxy-2-p h en ylp r op yl]ca r b a m ic
Acid ter t-Bu tyl Ester (36). DIBALH (1.0 M in hexane, 2.4
mL, 2.4 mmol) was added dropwise to a stirred and cooled (-78
°C) solution of 35 (284 mg, 0.423 mmol) in CH2Cl2 (19 mL).
Stirring at -78 °C was continued for 2.5 h, and 3:1 MeOH-
water (4 mL) was added dropwise. The cooling bath was
removed and stirring was continued for 1 h. The mixture was
filtered through a pad of Celite (3 × 3 cm), using EtOAc (80
mL) as a rinse, and the filtrate was dried (Na2SO4) and
evaporated. The residue was kept under oil pump vacuum for
4 h to afford crude 36 (286 mg, 100%), which was a mixture of
isomers and was used without further purification: exact mass
(electrospray) m/z calcd for C40H55NNaO6Si 696.369637, found
696.369017.
(2R*,3S*)-3-[(ter t-Bu t yld ip h en ylsila n yl)oxym et h yl]-
h exa h yd r o-4-h yd r oxy-3-m et h yl-2-[(1E)-1-m et h yl-1-p r o-
pen yl]-5-ph en ylfu r o[2,3-b]pyr idin e-7-car boxylic Acid ter t-
Bu tyl Ester (37a ,b). TsOH‚pyridine (148 mg, 0.589 mmol)
was added in one portion to a stirred solution of 36 (286 mg,
0.423 mmol) in THF (30 mL). The mixture was lowered into
J . Org. Chem, Vol. 69, No. 6, 2004 1877

Clive and Huang
using 1:9 EtOAc-hexane, gave 38b (89 mg, 85%) as an oil:
J ) 10.2 Hz, 1 H], 3.37 (d, J ) 4.9 Hz, 1 H), 3.51 [d (broad
signal, formally part of AB q), J ) 8.4 Hz, 1 H], 3.99-4.16 (m,
3 H), 4.42 (s, 1 H), 5.56 (br s, 1 H), 6.14-6.45 (m, 1 H), 7.11-
7.44 (m, 11 H), 7.55-7.61 (m, 4 H); 13C NMR (CDCl3, 125.7
MHz) (major rotamer only) δ 12.0 (d), 12.3 (q), 12.9 (q), 17.8
(q), 19.4 (s), 19.8 (q), 26.9 (q), 47.5 (t), 52.4 (s), 53.5 (d), 67.0
(t), 86.0 (d), 121.9 (d), 127.7 (d), 128.7 (d), 129.8 (d), 131.0 (s),
133.2 (s), 135.6 (d), 135.7 (d), 154.1 (s), 206.7 (s); exact mass
(electrospray) m/z calcd for C45H63NNaO5Si2 776.414251, found
776.414651.
When the 1H NMR spectrum was run at 45 °C many signals
coalesced: 1H NMR (CDCl3, 400 MHz) δ 1.00-1.14 (m, 30 H),
1.30 (septet J ) 7.4 Hz, 3 H), 1.44 (s, 3 H), 1.51 (d, J ) 6.6 Hz,
3 H), 3.36 (AB q, J ) 10.3 Hz, ∆νAB ) 130.3 Hz, 2 H), 3.37 (d,
J ) 6.1 Hz, 1 H), 3.99-4.15 (m, 3 H), 4.41 (s, 1 H), 5.50-5.62
(m, 1 H), 6.29 (br s, 1 H), 7.17 (d, J ) 7.1 Hz, 2 H), 7.23-7.44
(m, 9 H), 7.55-7.62 (m, 4 H). At -60 °C (and at -20 °C) well-
separated sets of signals appeared (values for -60 °C): 1H
NMR (CDCl3, 400 MHz) δ 0.84-1.04 (m, 30 H), 1.21 (septet,
J ) 7.5 Hz, 3 H), 1.34 (s, 3 H), 1.41-1.48 (m, 3 H), 3.02-3.11
(m, 1 H), 3.28-3.44 (m, 2 H), 3.77-3.92 (m, 1 H), 3.95-4.06
(m, 1 H), 4.12-4.23 (m, 1 H), 4.36 (s, 0.5 H), 4.38 (s, 0.5 H),
5.49 (q, J ) 7.0 Hz, 0.5 H), 5.61 (q, J ) 7.0 Hz, 0.5 H), 6.17 (d,
J ) 5.7 Hz, 0.5 H), 6.30 (d, J ) 6.0 Hz, 0.5 H), 7.08-7.14 (m,
2 H), 7.23-7.43 (m, 9 H), 7.47-7.55 (m, 4 H).
(2R*,3S*)-3-[(ter t-Bu t yld ip h en ylsila n yl)oxym et h yl]-
2,3,3a ,7a -tetr a h yd r o-3-m eth yl-2-(1-m eth yl-1-p r op en yl)-4-
oxo-5-p h en yl-4H-fu r o[2,3-b]p yr id in e-7-ca r boxylic Acid
Tr iisop r op ylsilyl Ester (42). (Me3Si)2NK (0.5 M in PhMe,
0.60 mL, 0.30 mmol) was added dropwise to a stirred and
cooled (-78 °C) solution of ketone 41a (208 mg, 0.275 mmol)
in THF (10 mL), and stirring at -78 °C was continued for 90
min. A solution of PhSeCl (58.5 mg, 0.305 mmol) in THF (5
mL) was added dropwise. After 45 min at -78 °C, the mixture
was quenched with saturated aqueous NH4Cl (5 mL), diluted
with Et2O (100 mL), and washed with saturated aqueous NH4-
Cl and brine. The organic phase was dried (Na2SO4) and
evaporated to give the crude selenide (266 mg), which was used
directly for the next step.
Pyridine (0.15 mL, 1.9 mmol) and H2O2 (30%, 0.24 mL, 2.1
mmol) were added to a vigorously stirred and cooled (0 °C)
solution of the crude selenide (266 mg, ca. 0.175 mmol) in CH2-
Cl2 (30 mL). The cooling bath was removed and stirring was
continued for 35 min. The mixture was diluted with EtOAc
(80 mL), washed successively with water, saturated aqueous
CuSO4, water, and brine, dried (Na2SO4), and evaporated. The
residue was kept under oil pump vacuum for 30 min to afford
the crude material (200 mg), which was used directly for next
step without purification.
(2R*,3S*)-3-[(ter t-Bu tyld ip h en ylsila n yl)oxym eth yl]-3,-
3a,7,7a-tetr ah ydr o-3-m eth yl-2-[(1E)-1-m eth yl-1-pr open yl]-
5-p h en yl-2H-fu r o[2,3-b]p yr id in e-4-on e (43). Bu4NF (1.0 M
in THF, 0.20 mL, 0.20 mmol) was added dropwise to a stirred
and cooled (0 °C) solution of crude 42 (200 mg) in THF (20
mL). After 5 min, the mixture was quenched with saturated
aqueous NH4Cl (5 mL), diluted with EtOAc (60 mL), washed
with saturated aqueous NH4Cl and brine, dried (Na2SO4) and
evaporated. Flash chromatography of the residue over silica
gel (1.5 × 25 cm), using 1:3 EtOAc-hexane, gave 43 (79.8 mg,
53% from 41a ) as a colorless oil: FTIR (CH2Cl2 cast) 3247,
3049, 2960, 2930, 2858, 1826, 1602, 1584 cm-1; 1H NMR (CD2-
Cl2, 500 MHz) δ 1.08 (s, 9 H), 1.17 (s, 3 H), 1.62 (d, J ) 6.7
Hz, 3 H), 1.66 (s, 3 H), 2.99 (d, J ) 7.9 Hz, 1 H), 3.55 (AB q,
J ) 10.2 Hz, ∆νAB ) 18.1 Hz, 2 H), 4.36 (s, 1 H), 5.42 (d, J )
6.3 Hz, 1 H), 5.60 (q, J ) 6.7 Hz, 1 H), 5.66 (d, J ) 7.9 Hz, 1
H), 7.16-7.48 (m, 12 H), 7.61-7.72 (m, 4 H); 13C NMR (CD2-
Cl2, 125.7 MHz) δ 13.3 (q), 14.5 (q), 19.6 (s), 19.7 (q), 27.2 (q),
52.4 (s), 55.2 (d), 68.4 (t), 86.6 (d), 90.9 (d), 111.4 (s), 122.4 (d),
126.2 (d), 127.96 (d), 127.97 (d), 128.3 (d), 128.4 (d), 129.9 (d),
130.0 (d), 132.6 (s), 133.89 (s), 133.94 (s), 136.2 (d), 136.4 (s),
148.4 (d), 189.7 (s); exact mass (electrospray) m/z calcd for
FTIR (CH2Cl2, cast) 3361, 2974, 2931, 2859, 1746, 1708, 1589
1
cm-1; H NMR (CD2Cl2, 500 MHz) δ 1.08 (s, 3 H), 1.09 (s, 9
H), 1.43 (s, 9 H), 1.50 (s, 3 H), 1.55 (d, J ) 6.8 Hz, 3 H), 3.33
(d, J ) 6.4 Hz, 1 H), 3.39 (AB q, J ) 10.2 Hz, ∆νAB ) 152.1
Hz, 2 H), 3.92-4.02 (m, 2 H), 4.07 (dd, J ) 9.0, 7.0 Hz, 1 H),
4.44 (s, 1 H), 5.57 (q, J ) 6.8 Hz, 1 H), 6.23 (d, J ) 5.1 Hz, 1
H), 7.16-7.22 (m, 2 H), 7.29-7.49 (m, 9 H), 7.61-7.68 (m, 4
H); 13C NMR (CD2Cl2, 100.6 MHz) δ 13.1 (q), 14.1 (q), 19.6 (s),
20.0 (q), 27.1 (q), 28.3 (q), 47.7 (t), 52.8 (s), 53.9 (d), 56.6 (d),
66.7 (t), 81.1 (s), 85.5 (d), 89.8 (d), 122.2 (d), 127.8 (d), 128.07
(d), 128.13 (d), 128.8 (d), 129.3 (d), 130.1 (d), 130.2 (d), 131.6
(s), 133.6 (s), 133.7 (s), 136.0 (d), 136.1 (d), 137.1 (s), 154.8 (s),
207.3 (s); exact mass (electrospray) m/z calcd for C40H51NNaO5-
Si 676.343422, found 676.343733.
(2R*,3S*)-3-[(ter t-Bu t yld ip h en ylsila n yl)oxym et h yl]-
h exa h yd r o-3-m eth yl-2-[(1E)-1-m eth yl-1-p r op en yl]-4-oxo-
5-p h en ylfu r o[2,3-b]p yr id in e-7-ca r b oxylic Acid Tr iiso-
p r op ylsilyl Ester (41a ). 2,6-Lutidine (0.34 mL, 2.9 mmol)
and i-Pr3SiOSO2CF3 (0.63 mL, 2.3 mmol) were added succes-
sively to a stirred solution of 38a (less polar isomer) (189 mg,
0.289 mmol) in CH2Cl2 (25 mL). After 15 min, the mixture was
lowered into a preheated oil bath set at 45 °C, and stirring
was continued for 60 h. The mixture was cooled, diluted with
Et2O (100 mL), washed with saturated aqueous NH4Cl and
brine, dried (Na2SO4), and evaporated. Flash chromatography
of the residue over silica gel (1.5 × 35 cm), using 1:25 EtOAc-
hexane, gave 41a (218 mg, 100%) as a colorless oil: FTIR (CH2-
Cl2, cast) 3070, 2944, 2866, 1692, 1589 cm-1; 1H NMR (CDCl3,
500 MHz) δ 0.99-1.12 (m, 30 H), 1.32 (septet, J ) 7.5 Hz, 3
H), 1.43 (s, 3 H), 1.50 (d, J ) 6.4 Hz, 3 H), 3.31-3.92 (m, 3 H),
3.35 (AB q, J ) 10.0 Hz, ∆νAB ) 161.8 Hz, 2 H), 4.20-4.60 (m,
2 H), 5.40-5.60 (m, 1 H), 6.20-6.50 (m, 1 H), 7.10-7.44 (m,
11 H), 7.56-7.62 (m, 4 H); 13C NMR (CDCl3, 125.7 MHz, major
rotamer only) δ 12.1 (d), 12.3 (q), 12.9 (q), 17.8 (q), 19.4 (s),
19.6 (q), 27.0 (q), 43.2 (s), 53.5 (t), 54.2 (d), 55.6 (d), 67.7 (t),
84.9 (d), 90.7 (d), 122.2 (d), 127.6 (d), 127.7 (d), 128.6 (d), 129.7
(d), 129.8 (d), 131.0 (s), 133.3 (s), 133.4 (s), 135.6 (d), 135.7
(d), 153.8 (s), 207.2 (s); exact mass (electrospray) m/z calcd for
C
45H63NNaO5Si2 776.41370, found 776.41333.
When the 1H NMR spectrum was run at 45 °C many signals
coalesced: 1H NMR (CDCl3, 400 MHz) δ 0.99-1.12 (m, 30 H),
1.30 (septet, J ) 7.5 Hz, 3 H), 1.41 (s, 3 H), 1.48 (d, J ) 6.6
Hz, 3 H), 3.34 (d, J ) 7.0 Hz, 1 H), 3.35 (AB q, J ) 10.0 Hz,
∆νAB ) 130.1 Hz, 2 H), 3.54 (br s, 1 H), 3.71 (br s, 1 H), 4.26
(s, 1 H), 4.42 (br s, 1 H), 5.39-5.53 (m, 1 H), 6.31 (br s, 1 H),
7.11 (d, J ) 7.3 Hz, 2 H), 7.21-7.41 (m, 9 H), 7.57 (d, J ) 7.0
Hz, 4 H). At -60 °C (and at -20 °C) well-separated sets of
signals appeared (values for -60 °C): 1H NMR (CDCl3, 400
MHz) δ 0.89-1.12 (m, 30 H), 1.24 (septet, J ) 7.3 Hz, 3 H),
1.35 (s, 1.5 H), 1.36 (s, 1.5 H), 1.45 (d, J ) 6.7 Hz, 3 H), 3.02-
3.13 (m, 1 H), 3.30-3.82 (m, 4 H), 4.22-4.34 (m, 1.5 H), 4.40-
4.50 (m, 0.5 H), 5.43 (q, J ) 6.7 Hz, 0.5 H), 5.53 (q, J ) 6.7
Hz, 0.5 H), 6.26 (d, J ) 7.0 Hz, 0.5 H), 6.40 (d, J ) 7.7 Hz, 0.5
H), 7.02-7.09 (m, 2 H), 7.20-7.42 (m, 9 H), 7.48-7.55 (m, 4
H).
(2R*,3S*)-3-[(ter t-Bu t yld ip h en ylsila n yl)oxym et h yl]-
h exa h yd r o-3-m eth yl-2-[(1E)-1-m eth yl-1-p r op en yl]-4-oxo-
5-p h en ylfu r o[2,3-b]p yr id in e-7-ca r b oxylic Acid Tr iiso-
p r op ylsilyl Ester (41b). 2,6-Lutidine (0.045 mL, 0.39 mmol)
and i-Pr3SiOSO2CF3 (0.075 mL, 0.28 mmol) were added
successively to a stirred solution of 38b (28.0 mg, 0.0428 mmol)
in CH2Cl2 (3 mL). After 15 min, the mixture was lowered into
a preheated oil bath set at 45 °C, and stirring was continued
for 2 days. The mixture was cooled, diluted with Et2O (20 mL),
washed with saturated aqueous NH4Cl and brine, dried (Na2-
SO4), and evaporated. Flash chromatography of the residue
over silica gel, using 1:20 EtOAc-hexane, gave 41b (32.3 mg,
100%) as a colorless oil: FTIR (CDCl3, cast) 3070, 2944, 2892,
2866, 1723, 1692, 1589 cm-1 1H NMR (CDCl3, 500 MHz) δ
;
0.98-1.13 (m, 30 H), 1.29 (septet, J ) 7.4 Hz, 3 H), 1.44 (s, 3
H), 1.50 (d, J ) 6.7 Hz, 3 H), 3.18 [d (formally part of AB q),
C
35H41NNaO3Si 574.275343, found 574.275410.
1878 J . Org. Chem., Vol. 69, No. 6, 2004

Synthesis of the Antifungal and Antibacterial Agent Cladobotryal
(2R*,3S*)-3-[(ter t-Bu t yld ip h en ylsila n yl)oxym et h yl]-
3,3a ,7,7a -tetr a h yd r o-3-m eth yl-2-(1-m eth yl-1-p r op en yl)-5-
p h en yl-2H-fu r o[2,3-b]p yr id in -4-on e (43). (Me3Si)2NK (0.5
M in PhMe, 0.10 mL, 0.050 mmol) was added dropwise to a
stirred and cooled (-78 °C) solution of 41b (32.0 mg, 0.0428
mmol) in THF (2 mL), and stirring at -78 °C was continued
for 90 min. A solution of PhSeCl (10 mg, 0.052 mmol) in THF
(1 mL) was added dropwise. After 45 min at -78 °C, the
mixture was quenched with saturated aqueous NH4Cl (1 mL),
diluted with Et2O (20 mL), washed with saturated aqueous
NH4Cl and brine, dried (Na2SO4), and evaporated to give the
crude selenide (44.4 mg), which was used directly for the next
step.
Pyridine (0.030 mL, 0.37 mmol) and H2O2 (30%, 0.050 mL,
0.44 mmol) were added to a vigorously stirred and cooled (0
°C) solution of the crude selenide (44.4 mg) in CH2Cl2 (6 mL).
The cooling bath was removed, and stirring was continued for
45 min. The mixture was diluted with EtOAc (20 mL), washed
successively with water, saturated aqueous CuSO4, water, and
brine, dried (Na2SO4), and evaporated. Flash chromatography
of the residue over Al2O3 (Grade III), using 1:20 to 1:5 EtOAc-
hexane, gave 43 (11.5 mg, 49% from 41b), which had the same
spectral characteristics as material from the less polar series.
(2R*,3S*)-3-[(ter t-Bu t yld ip h en ylsila n yl)oxym et h yl]-
3,7-dih ydr o-3-m eth yl-2-[(1E)-1-m eth yl-1-pr open yl]-5-ph en -
yl-2H-fu r o[2,3-b]p yr id in -4-on e (44). All steps in this ex-
periment were done with protection from light.
was added dropwise to a stirred solution of 44 (21.5 mg, 0.0391
mmol) in THF (7 mL). Stirring was continued for 15 min, and
then saturated aqueous NH4Cl (10 mL) was added. The
mixture was extracted with EtOAc (2 × 10 mL) and the
combined organic extracts were dried (Na2SO4) and evapo-
rated. Flash chromatography the residue over silica gel (0.9
× 20 cm), using 1:1 EtOAc-hexane, gave 2 (11.8 mg, 97%) as
a colorless solid: mp 213-214 °C; FTIR (CH2Cl2, cast) 3057,
1
2926, 2860, 2742, 1695, 1598, 1502 cm-1; H NMR (acetone-
d6, 400 MHz) δ 1.51 (s, 3 H), 1.54 (s, 3 H), 1.63 (d, J ) 6.8 Hz,
3 H), 3.76 (AB q, J ) 10.1 Hz, ∆νAB ) 13.6 Hz, 2 H), 4.84 (s,
1 H), 5.63 (q, J ) 6.8 Hz, 1 H), 7.25-7.31 (m, 1 H), 7.34-7.41
(m, 2 H), 7.50-7.56 (m, 2 H), 7.82 (s, 1 H); 13C NMR (acetone-
d6, 100.6 MHz) δ 13.4 (q), 13.5 (q), 25.7 (q), 50.5 (s), 67.3 (t),
95.3 (d), 111.8 (s), 125.3 (d), 128.0 (d), 129.3 (d), 130.6 (d), 133.7
(s), 137.3 (s); exact mass m/z calcd for C19H21NO3 311.15213,
found 311.15171.
(2R*,3R*)-2,3,4,7-Tetr a h yd r o-3-m eth yl-2-[(1E)-1-m eth -
yl-1-p r op en yl]-4-oxo-5-p h en ylfu r o[2,3-b]p yr id in e-3-ca r -
ba ld eh yd e (Cla d obotr ya l) (1). Dess-Martin reagent (30.0
mg, 0.0708 mmol) was added in one portion to a stirred
solution of 2 (11.0 mg, 0.0353 mmol) in CH2Cl2 (6 mL). After
15 min, saturated aqueous NaHCO3 (10 mL) and 10% aqueous
Na2S2O3 (5 mL) were added. The mixture was extracted with
EtOAc (2 × 10 mL), and the combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated. Flash
chromatography of the residue over silica gel (0.9 × 25 cm),
using 2:3 EtOAc-hexane, gave aldehyde 1 (10.6 mg, 97%) as
a solid: mp 95-97 °C; FTIR (CDCl3, cast) 2923, 2859, 2721,
Freshly prepared t-BuOCl19 (0.1 M in CH2Cl2, 1.4 mL, 0.14
mmol) was added dropwise to a stirred and cooled (-78 °C)
solution of 43 (31.0 mg, 0.0562 mmol) in CH2Cl2, the mixture
being protected from light by alumina foil. After 15 min at
-78 °C, the solvent was evaporated and the residue was kept
under oil pump vacuum for 15 min.
1
1727, 1648, 1595, 1555, 1501 cm-1; H NMR (acetone-d6, 400
MHz) δ 1.57 (s, 3 H), 1.63 (s, 3 H), 1.65 (d, J ) 6.8 Hz, 3 H),
5.01 (s, 1 H), 5.82 (q, J ) 6.8 Hz, 1 H), 5.30-5.49 (m, 5 H),
7.78 (s, 1 H), 9.61 (s, 1 H); 13C NMR (acetone-d6, 100.6 MHz)
δ 13.5 (q), 20.7 (q), 59.2 (s), 107.8 (s), 125.5 (d), 128.8 (d), 129.9
(d), 130.8 (d), 131.8 (s), 136.1 (s), 201.2 (d); exact mass m/z
calcd for C19H19NO3 309.13651, found 309.13632.
PhMe (5 mL) was injected into the reaction flask (protection
from light), followed by DBU (0.080 mL, 0.53 mmol). Stirring
was continued for 1 h at room temperature, and the solvent
was evaporated. Flash chromatography of the residue over
silica gel (0.7 × 20 cm), using 1:3 EtOAc-hexane, gave 44 (22
mg, 71%) as a white solid: mp 99-101 °C; FTIR (CH2Cl2, cast)
3050, 2960, 2930, 2858, 1827, 1647, 1595, 1556 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 1.10 (s, 9 H), 1.35 (s, 3 H), 1.41 (d, J )
Ack n ow led gm en t. We thank NSERC and Cromp-
ton Co. (Elmira, Ontario) for financial support and Dr.
R. McDonald (X-ray Crystallography Laboratory) for the
crystal structure determination. X.H. holds a Graduate
Research Assistantship.
6.7 Hz, 3 H), 1.48 (s, 3 H), 3.57 (AB q, J ) 10.0 Hz, ∆νAB
)
144.3 Hz, 2 H), 4.64 (s, 1 H), 5.34 (q, J ) 6.7 Hz, 1 H), 7.28-
7.67 (m, 15 H), 7.95 (s, 1 H), 9.34 (s, 1 H); 13C NMR (CDCl3,
125.7 MHz) δ 12.8 (q), 12.9 (q), 19.2 (s), 24.7 (q), 26.9 (q), 49.0
(s), 69.4 (t), 94.1 (d), 110.0 (s), 120.9 (s), 124.2 (d), 126.9 (d),
127.98 (d), 128.01 (d), 128.2 (d), 129.3 (d), 130.3 (d), 130.5 (d),
131.2 (s), 131.3 (s), 131.5 (s), 135.3 (s), 135.5 (d), 135.9 (d),
149.1 (d), 158.5 (s), 167.9 (s); exact mass (electrospray) m/z
calcd for C35H40NO3Si 550.27720, found 550.27768.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
compounds, except 21, 24, 36, and 42, X-ray data for 10, and
experimental procedures for 9 f silylated derivative, 13, 15,
16, 17, 17 f 18, 19, 19 f 18, 20, 21, 22a , 22b,c, 23a , 23b,
38a f 39, and 38b f 39. This material is available free of
charge via the Internet at http://pubs.acs.org.
(2R*,3S*)-3,7-Dih yd r o-3-h yd r oxym et h yl-3-m et h yl-2-
[(1E)-1-m eth yl-1-p r op en yl]-5-p h en yl-2H-fu r o[2,3-b]p yr i-
d in -4-on e (2). Bu4NF (1.0 M in THF, 0.12 mL, 0.12 mmol)
J O030284G
J . Org. Chem, Vol. 69, No. 6, 2004 1879