Syntheses of (-)-TAN-2483A, (-)-massarilactone B, and the fusidilactone B ring system. Revision of the structures of and syntheses of (±)-Waol A (FD-211) and (±)-Waol B (FD-212)

Article abstract of DOI:10.1021/jo0358628

The structure of waol A has been revised from 1 to 6, the vinylogue of TAN-2483A (5). Aldol reaction of hydroxybutanolides 13b,c with 2,4-hexadienal affords 12b,c, which are subjected to iodoetherification with bis(sym-collidine)IPF₆ to provide

Full text of DOI:10.1021/jo0358628

VOLUME 69, NUMBER 17
AUGUST 20, 2004
© Copyright 2004 by the American Chemical Society
Syn th eses of (-)-TAN-2483A, (-)-Ma ssa r ila cton e B, a n d th e
F u sid ila cton e B Rin g System . Revision of th e Str u ctu r es of a n d
Syn th eses of (()-Wa ol A (F D-211) a n d (()-Wa ol B (F D-212)
Xiaolei Gao and Barry B. Snider*
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received December 22, 2003
The structure of waol A has been revised from 1 to 6, the vinylogue of TAN-2483A (5). Aldol reaction
of hydroxybutanolides 13b,c with 2,4-hexadienal affords 12b,c, which are subjected to iodoetheri-
fication with bis(sym-collidine)IPF6 to provide 11b(c). Treatment with Et3N in CH2Cl2 completes
the three-step syntheses of TAN-2483A (5) and waol A (6). Aldol reaction of hydroxybutanolide 31
with 2,4-hexadienal affords 32, which is subjected to iodoetherification to provide 34, which in
turn is treated with Bu3SnCl, NaBH3CN, and oxygen to provide diol 60. Further elaboration
completes the first syntheses of massarilactone B (7) and the fusidilactone B (9) ring system.
In tr od u ction
A literature search uncovered a 1999 patent reporting
two closely related compounds with this ring system,
TAN-2483B (4) and TAN-2483A (5) (Figure 2), that show
strong c-src kinase inhibitory action and inhibit PTH-
induced bone resorption of a mouse femur.4 The structure
of 5 was assigned crystallographically, the absolute
stereochemistry was assigned by the Mosher ester method,
and the relative stereochemistry of 4 was determined by
NOE experiments.5 The carbonyl groups of 4 and 5
absorb at 1760 cm-1 and the alkene ring hydrogens
absorb at δ 7.12 and 6.90, respectively. H2 and H3 of TAN-
2483B (4) absorb at δ 4.35 and 4.45, while H2 and H3 of
both TAN-2483A (5) and waol A absorb at δ 4.05 and
4.10, respectively. This suggests that waol A might be
the vinylogue of TAN-2483A (5) with structure 6.
Mizoue and co-workers reported the isolation of waol
A (FD-211, 1), which has a broad spectrum of activity
against cultured tumor cell lines, including adriamycin-
resistant HL-60 cells, from the fermentation broth of
Myceliophthora lutea TF-0409 (Figure 1).1 More recently,
they reported the isolation of waol B (FD-212, 2), which
has similar biological activity from the same source.2
Tadano has reported an approach to the synthesis of 1.3
F IGURE 1. Proposed structures of waols A (1) and B (2).
However, the carbonyl group of waol A absorbs at 1767
cm-1,1 which is characteristic of a γ-lactone, rather than
the δ-lactone of 1. The alkene ring hydrogen of waol A
absorbs at δ 6.90,1 while that of 1 would be expected to
absorb between δ 5 and 6. An absorbance at δ 6.90 is
characteristic of CHdCsCdO. Taken together, these
discrepancies suggest that waol A might be a substituted
2,3,7,7a-tetrahydro-5H-furo[3,4-b]pyran-5-one (3).
F IGURE 2. Structures of TAN-2483A (5) and TAN-2483B (4),
and the revised structure of waol A (6).
Other related compounds have since been isolated.
These include the antibacterial massarilactone B (7),
isolated by Gloer from the freshwater aquatic fungus
(1) Nozawa, O.; Okazaki, T.; Sakai, N.; Komurasaki, T.; Hanada,
K.; Morimoto, S.; Chen, Z.-X.; He, B.-M.; Mizoue, K. J . Antibiot. 1995,
48, 113-118.
(2) Nazawa, O.; Okazaki, T.; Morimoto, S.; Chen, Z.-X.; He, B.-M.;
Mizoue, K. J . Antibiot. 2000, 53, 1296-1300.
(3) Suzuki, E.; Takao, K.-i.; Tadano, K.-i. Heterocycles 2000, 52, 519-
523.
(4) Hayashi, K.; Takizawa, M.; Noguchi, K. J apanese Patent
10287679, 1998; Chem. Abstr. 1999, 130, 3122e.
(5) Hayashi, K. Takeda Chemical Industries. Unpublished results.
10.1021/jo0358628 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/04/2004
J . Org. Chem. 2004, 69, 5517-5527
5517

Gao and Snider
Massarina tunicata in 2001,6 and fusidilactones A (8) and
B (9), isolated by Krohn from an endophytic Fusidium
sp. in 2002 (Figure 3).7,8
the side chain alcohol could not be determined by spectral
analysis and was established from the spectra of iodo-
hydrins 17 and 19 (see below). Flash chromatography on
20% AgNO3 on silica gel removes the undesired Z-isomer
giving pure 12a (26%) and 15a (29%). Low-temperature
crystallization has been reported as a means of preparing
pure (2E,4E)-hexadienal.11 This procedure was not very
successful in our hands and equilibration to give a
mixture of (2E,4E)- and (2E,4Z)-2,4-hexadienal occurs
readily.
SCHEME 2
F IGURE 3. Structures of massarilactone B (7) and fusidilac-
tones A (8) and B (9).
Retrosynthetic analysis (Scheme 1) suggested that
TAN-2483A (5) and waol A (6) should be available from
epoxy lactone 10, which should be easily formed from
iodohydrin 11. Iodohydrin 11 should be accessible ste-
reospecifically by iodoetherification of diene diol 12,
which can be prepared by an aldol reaction of the dianion
of hydroxyfuranone 13 with 2,4-hexadienal (14). Aldol
reactions of 13 occur stereospecifically from the face
opposite the hydroxy group, but give mixtures of isomers
at the hydroxy group on the side chain.9,10
Iodoetherification of the desired isomer 12a under a
wide variety of conditions provides <5% iodo alcohol 17,
while iodoetherification of the undesired isomer 15a with
I2 and solid NaHCO3 in CH3CN affords 70% of iodo
alcohol 19 (Scheme 3).12 In 17, J 2.3 ) 10.4 Hz, J 3.4 ) 9.8
Hz, J 4.4a ) 10.4 Hz, and J 4a.7a ) 11.6 Hz indicating that
all the hydrogens on the tetrahydropyran ring are axial
and all the substituents are equatorial. In 19, J 2.3 ) 10.4
Hz, J 3.4 < 1 Hz, J 4.4a < 1 Hz, and J 4a.7a ) 11.6 Hz
indicating that the H4 is equatorial and the hydroxy
group is axial. Isomerization of 19 to the cis-fused isomer
20 occurs easily on heating in the presence of NaHCO3
or on silica gel.
SCHEME 1
SCHEME 3
Resu lts a n d Discu ssion
Mod el Stu d ies. A model study was carried out with
commercially available (S)-dihydro-4-hydroxyfuranone
(13a ) and 2,4-hexadienal (14), which is a 4:1 mixture of
(2E,4E)- and (2E,4Z)-isomers (Scheme 2). Note that
structures 13a , 12a , 15a , 17, and 19-24 are drawn for
clarity with the same absolute stereochemistry as TAN-
2483A, although they are the enantiomers. Treatment of
13a with 2 equiv of LDA in THF and addition of dienal
14 at -42 °C as described by Prestwich9a affords a readily
separable mixture of 12a and 15a , both as a 4:1 mixture
of (2E,4E)- and (2E,4Z)-isomers. The stereochemistry of
(6) Oh, H.; Swenson, D. C.; Gloer, J . B.; Shearer, C. A. Tetrahedron
Lett. 2001, 42, 975-977.
(7) Krohn, K.; Biele, C.; Drogies, K.-H.; Steingro¨ver, K.; Aust, H.-
J .; Draeger, S.; Schulz, B. Eur. J . Org. Chem. 2002, 2331-2336.
(8) Reference 7 provides different structures for fusidilactone B: 9
on p 2331 and 68 on p 2332. Our synthetic studies suggest that
structure 9 on page 2331 is correct.
(9) (a) Shieh, H.-M.; Prestwich, G. D. J . Org. Chem. 1981, 46, 4319-
4321. (b) Chen, S. Y.; J oullie, M. J . Org. Chem. 1984, 49, 2168-2174.
(10) For a preliminary communication on a portion of this work
see: Gao, X.; Nakadai, M.; Snider, B. B. Org. Lett. 2003, 5, 451-454.
We were initially puzzled as to why 15a undergoes
facile iodoetherification to give 19, while 12a fails to give
(11) Albriktsen, P.; Harris, R. K. Acta Chem. Scand. 1973, 27, 3993-
4000.
5518 J . Org. Chem., Vol. 69, No. 17, 2004

TAN-2483A, Massarilactone B, Fusidilactone B, and Waol A and B
the more stable isomer 17 with an equatorial hydroxy
group. Closer examination of the literature revealed that
Chamberlin and Yoshida had made related observations12
and that Chamberlin and Hehre had explained the
origins of these effects.13 Cyclizations in which the
nucleophile is in the R group proceed slowly through the
disfavored π complex 16 with the hydrogen eclipsed with
the double bond and rapidly through the favored π
complex 18 with the hydroxy group eclipsed with the
double bond. The π complex formed from 12a has the
hydrogen eclipsed with the double bond and therefore
cyclizes slowly to give 17. The π complex formed from
15a has the hydroxy group eclipsed with the double bond
and therefore cyclizes rapidly to give 19.
A more reactive iodinating agent is needed to convert
12a to 17 in high yield. Bis(sym-collidine)IPF6 is a very
reactive, but moisture-sensitive, iodinating reagent that
can easily be prepared in situ from bis(sym-collidine)-
AgPF6 and iodine.14 We were delighted to find that
reaction of nonhygroscopic bis(sym-collidine)AgPF6 (1.5
equiv) and iodine (1.2 equiv) in CH2Cl2, addition of 12a ,
and stirring for 1.5 h affords 80% of 17, which can be
purified by flash chromatography on water-deactivated
silica gel (Scheme 4). Partial isomerization to the more
stable cis-fused isomer 21 occurs otherwise. Much lower
yields of 17 were obtained with commercially available
bis(sym-collidine)IPF6.
groups of 17 are in diequatorial arrangement. Formation
of the epoxide requires either that the pyran ring of 17
adopts a boat conformation with these groups anti-
periplanar or that the flexible cis-fused isomer 21 adopts
the chair conformation with the iodide and hydroxy
groups antiperiplanar.
Syn th esis of TAN-2483A. TAN-2483A precursor (-)-
trans-dihydro-4-hydroxy-5-methyl-2(3H)-furanone (13b)
was prepared by Hatakeyama’s procedure in >90% ee.15
Dihydroxylation of methyl 3Z-pentenoate16 with OsO4
and NMO and treatment of the resulting diol with acid
gives (()-13b. Treatment with Novozyme lipase, vinyl
acetate, and 1,4,8,11-tetrathiacyclotetradecane in diiso-
propyl ether affords (-)-13b and the readily separable
enantiomeric acetate.
We were pleased to find that the selectivity for 12 in
the aldol reaction improves with an alkyl substituent on
furanone 13. Treatment of the dianion of 13b with 14
affords 38% of the desired adduct 12b and only 14% of
15b after AgNO3 chromatography (Scheme 2). Iodoet-
herification of 12b with bis(sym-collidine)AgPF6 and
iodine provides 88% of iodo alcohol 11b, which gives 79%
of TAN-2483A (5) on treatment with Et3N in CH2Cl2 at
1
25 °C for 3 d (Scheme 5). The H and 13C NMR spectra of
5 are identical with those of the natural product. The
optical rotation, [R]D -236, has the same sign, but is
somewhat smaller than that reported, [R]D -292,4 con-
firming the assignment of the absolute stereochemistry.
SCHEME 4
SCHEME 5
Syn th eses of Wa ols A a n d B. Waol A precursor
propenyl lactone 13c was made by modification of
Griengl’s procedure (Scheme 6).17 Reaction of 2E-butenal
with NaCN and HCl18 and silylation19 gives 34% (unop-
timized) of 25. Reaction of 25 with Zn, TMSCl, and
BrCH2CO2Me20 affords 86% of keto ester 26 as a mixture
of keto and enol tautomers. Reduction of 26 with NaBH4
in MeOH at -15 °C gives 97% of 27 as a 5:1 mixture of
isomers. Reduction of 26 with NaBH4 in 49:1 THF/MeOH
Treatment of either 17 or 21 with Et3N in CH2Cl2 for
3 d at 25 °C affords epoxides 22 or 23, which react further
to give 87% of 24, with spectral data similar to those of
TAN-2483A (5) and waol A (6). The iodide and hydroxy
(15) Nishiyama, T.; Nishioka, T.; Esumi, T.; Iwabuchi, Y.; Hatakeya-
ma, S. Heterocycles 2001, 54, 69-72.
(12) (a) Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills, M.
C. J . Am. Chem. Soc. 1983, 105, 5819-5825. (b) Tamaru, Y.; Hojo, M.;
Kawamura, S.-i.; Sawada, S.; Yoshida, Z.-i. J . Org. Chem. 1987, 52,
4062-4072.
(13) Chamberlin, A. R.; Mulholland, R. L., J r.; Kahn, S. D.; Hehre,
W. J . J . Am. Chem. Soc. 1987, 109, 672-677.
(14) (a) Homsi, F.; Robin, S.; Rousseau, G. Org. Synth. 1999, 77,
206-211. (b) Brunel, Y.; Rousseau, G. J . Org. Chem. 1996, 61, 5793-
5800. (c) Evans, R. D.; Magee, J . W.; Schauble, J . H. Synthesis 1988,
862-868.
(16) Krebs, E.-P. Helv. Chim. Acta 1981, 64, 1023-1026.
(17) J ohnson, D. V.; Fischer, R.; Griengl, H. Tetrahedron 2000, 56,
9289-9295.
(18) Anderson, J . R.; Edwards, R. L.; Whalley, A. J . S. J . Chem. Soc.,
Perkin Trans. 1 1982, 215-221.
(19) (a) Brussee, J .; Loos, W. T.; Kruse, C. G.; Van Der Gen, A.
Tetrahedron 1990, 46, 979-986. (b) Warmerdam, E. G. J . C.; van den
Nieuwendijk, A. M. C. H.; Kruse, C. G.; Brussee, J .; van der Gen, A.
Recl. Trav. Chim. Pays-Bas 1996, 115, 20-24.
(20) Hannick, S. M.; Kishi, Y. J . Org. Chem. 1983, 48, 3833-3835.
J . Org. Chem, Vol. 69, No. 17, 2004 5519

Gao and Snider
or THF provides 27 as a 1.5:1 and 1.2:1 mixture of
isomers, respectively. Deprotection of the 5:1 mixture of
isomers of 27 with TBAF in CH3CN and acid-catalyzed
lactonization provides 63% of (()-13c and 13% of (()-
28.21
human disease-oriented 60-cell line, in vitro antitumor
screening protocol. All three compounds showed similar
activity, with GI50 activity values ranging from 10-5 to
10-6 M. Since 5 and 24 have the opposite absolute
stereochemistry and 6 is racemic, the similar activity
observed with all three compounds suggests that the
antitumor activity may result from the ability of these
compounds to act as Michael acceptors, as in the forma-
tion of 30 from 6, rather than from more specific binding.
Ap p r oa ch es to TAN-2483B. We prepared lactone 31
as a potential precursor to TAN-2483B from methyl 3E-
pentenoate by addition of OsO4 and NMO to form (()-31
or AD-mix-R to form (-)-31.23 Addition of 2,4-hexadienal
(14) to the dianion of 31 provides 36% of 32 and 31% of
33. The selectivity for 32 is much lower with cis-lactone
31 than the selectivity for 12b,c with trans-lactones
13b,c. Iodoetherification of 32 affords 92% of 34 (Scheme
8). Treatment of 34 with Et3N in CH2Cl2 at reflux for 3
d provides only 32% of 35 and 61% of recovered 34. As
expected, the spectral data for 35 are different than those
for TAN-2483B (4), which is epimeric to TAN-2483A (5)
at C7a while 35 is epimeric to the enantiomer of 5 at C7.
SCHEME 6
Treatment of the dianion of 13c with 2,4-hexadienal
(14) affords 44% of the desired adduct 12c and 21% of
15c after AgNO3 chromatography (Scheme 2). Iodoet-
herification of 12c with bis(sym-collidine)AgPF6 and
iodine provides 95% of iodo alcohol 11c, which gives 98%
of 6 on treatment with Et3N in CH2Cl2 at reflux overnight
(Scheme 5). The 1H and 13C NMR spectra of 6 are
identical with those of waol A (FD-211) indicating that
the revised structure we proposed is correct.
SCHEME 8
Hydrolysis of 6 with KOH in MeOH/H2O, followed by
acidification and immediate reaction with CH2N2 affords
1
38% of 29 with H and 13C NMR spectral data identical
with those of waol B (FD-212) and 47% of MeOH adduct
30 resulting from conjugate addition of methoxide and
protonation to give the cis-fused ring system (Scheme 7).
SCHEME 7
The conversion of aldol adducts 12b,c to TAN-2483A
(5) and waol A (6) requires only two steps and proceeds
in excellent yield as indicated in Scheme 5. Although the
aldol reaction of the substituted lactones 13b,c is much
more selective for 12b,c than that of the unsubstituted
model lactone 13a , there is still room for improvement
in the selectivity of the aldol reaction. However, initial
attempts at improving the stereoselectivity of the aldol
reaction, e.g., addition of ZnCl2 to make the zinc enolate,22
were not promising.
The formation of 35 from 34 is much slower than the
formation of 5 and 6 from iodohydrins 11b,c. This
suggests that conformations with the iodide and hydroxy
groups antiperiplanar are more strained with the methyl
group cis to the pyran oxygen as in 34 and the epimeric
cis-fused lactone than with the methyl group trans to the
pyran oxygen as in 11b,c and the epimeric cis-fused
lactone. Treatment of 34 with 5 equiv of the stronger base
DBN in CH2Cl2 for 1 h at 0 °C gives 89% of 35, while
Biologica l Stu d ies. Since waol A was reported to
have a broad spectrum of antitumor activity,1 we submit-
ted synthetic (-)-TAN-2483A (5), (()-waol A (6), and (+)-
24 (the enantiomer of the structure shown) to the NCI
(21) Attempted enzymatic resolution of 13c, as successfully carried
out for 13b, gives the opposite enantiomer, (+)-13c, in 18% ee.
Reduction of 26 with NaBH4 and (D)-tartaric acid17 and further
elaboration yields 30% of (+)-13c (38% ee) and 45% of 28.
(22) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H.
D. J . Am. Chem. Soc. 1973, 95, 3310-3324.
(23) (a) Harcken, C.; Bru¨ckner, R.; Rank, E. Chem. Eur. J . 1998, 4,
2342-2352. (b) Harcken, C.; Bru¨ckner, R. New J . Chem. 2001, 25, 40-
54.
5520 J . Org. Chem., Vol. 69, No. 17, 2004

TAN-2483A, Massarilactone B, Fusidilactone B, and Waol A and B
SCHEME 10
treatment of 34 with 5 equiv of DBU in THF for 30 min
at 25 °C affords 86% of 35.
Pyranofuranone 35 has the same relative stereochem-
istry as TAN-2483B (4) at C7 and C7a and the opposite
stereochemistry at C2 and C3. It might be possible to
convert 35 to 4 by oxidation to give enone 36, epimer-
ization to give the â-propenyl group at C2, and reduction
of the enone from the R-face to give the â-alcohol at C3.
Dess-Martin oxidation of 35 provides enone 36 quanti-
tatively. Surprisingly, enone 36 is unstable on silica gel
chromatography, affording only 40-50% of 36 and 40-
50% of butenolide 39. The stereochemistry of the enol of
39 was established by the NOE shown. Presumably,
enone 36 tautomerizes to give dienol 37, which undergoes
electrocyclic ring opening to give 38, which isomerizes
to give the more stable enol 39.
The facile isomerization of 36 to 39 precluded the
epimerization of the propenyl side chain. Nevertheless,
we chose to investigate the stereochemistry of the enone
reduction. Reduction of crude 36 with NaBH4 (1.2 equiv)
and CeCl3‚7H2O at 25 °C affords saturated alcohols 40
(63%) and 41 (10%) (Scheme 9). Preventing reduction of
the double bond in this case is particularly challenging
because 1,4-hydride addition can occur to enone 36 or to
allylic alcohols 42 and 35, which still contain an unsatur-
ated lactone that is very susceptible to conjugate addition
as shown by the formation of 30 during the hydrolysis of
waol A (6) (Scheme 7). Conjugate reduction was avoided
by reducing 39 with only 0.5 equiv of NaBH4 and CeCl3‚
7H2O at 0 °C to give 42 (72%) and 35 (12%). Pyranofura-
none 42 is epimeric to TAN-2483B (4) at C2.
torial propenyl group as required for TAN-2483A (5), but
not TAN-2483B (4). Comparison of the two structures
suggested that they might be biosynthesized by reduction
of a common intermediate 50, which might be formed by
condensation of an aldehyde such as 48, with the common
natural product γ-methyltetronic acid (49)25 as shown in
Figure 4. Initial model studies aimed at developing such
a biomimetic route by condensing tetronic acid with 2,4-
hexadienal (14) and other aldehydes were unsuccessful.
SCHEME 9
F IGURE 4. Possible biosynthesis of TAN-2483A (5) and TAN-
2483B (4).
Syn th esis of Ma ssa r ila cton e B (7). We now turned
our attention to the synthesis of massarilactone B (7).
We planned to construct the diol by epoxidation of diene
51, which might be available by a double elimination
reaction of either iodohydrin 34 or 52 (Scheme 11). Hsung
has reported the epoxidation of analogous pyranopyra-
nones.26
We then considered a final route to TAN-2483B (4) in
which the pyran ring would be formed by cyclization of
an epoxy alcohol. Directed epoxidation of dienol 33 with
m-CPBA was expected to give mainly threo alcohol 43
(Scheme 10).24 Cyclization of 43 should give pyranofura-
none 46. Conversion of the diol to the â-epoxide and
treatment with base would complete the synthesis of
TAN-2483B (4). However, epoxidation of 33 with m-
CPBA affords 19% of 47, resulting from cyclization of the
erythro epoxide 44, and 39% of a mixture of terminal
epoxides 45. It is conceivable that the lactone alcohol
helps direct epoxidation to the terminal double bond.
All of the sequences involving iodoetherification or
cyclization of an epoxide provide a pyran with an equa-
SCHEME 11
Reaction of 34 with MsCl and Et3N affords mesylate
53 in 99% yield (Scheme 12). Initial attempts at double
(24) Adam, W.; Alsters, P. L.; Neumann, R.; Saha-Mo¨ller, C. R.;
Sloboda-Rozner, D.; Zhang, R. J . Org. Chem. 2003, 68, 1721-1728 and
references therein.
(25) (a) Boll, P. M.; Sørensen, E.; Balieu, E. Acta Chem. Scand. 1968,
22, 3251-3255. (b) Bloomer, J . L.; Kappler, F. E. J . Chem. Soc., Perkin
Trans. 1 1976, 1485-1491.
J . Org. Chem, Vol. 69, No. 17, 2004 5521

Gao and Snider
elimination gave complex mixtures. Eventually we con-
cluded that the iodide liberated in the elimination is
reducing iodo mesylate 53 to form alkene 54. Addition
of sodium iodide makes this the major process; treatment
of 53 with NaI and Et3N in acetone at reflux provides
alkene 54 in 95% yield. The reduction can be suppressed
by use of DBU in DMF. However, these conditions result
in enolization to give 55 and elimination of the iodide to
give cyclopropane 56 in 91% yield. Both the iodide and
mesylate in 53 are equatorial so that the mesylate is not
aligned properly with the enolate to undergo elimination
to give the conjugated lactone, while the iodide is aligned
perfectly with the enolate to give the cyclopropane.27
It should be possible to prepare massarilactone B (7)
by dehydration of dihydromassarilactone B (60), which
will be formed by replacing the iodide of 34 with a
hydroxy group with retention of configuration. Since the
newly introduced hydroxy group of 60 is equatorial, it
should be possible to achieve this transformation by
reducing the iodide of 34 and trapping the resulting
radical with oxygen from the less hindered â-face to give
the more stable equatorial alcohol.29 Treatment of 34
(prepared from (-)-31) with 2 equiv of NaBH3CN, 0.1
equiv of Bu3SnCl, and 0.02 equiv of AIBN in t-BuOH at
65 °C for 5 h under 3 equiv of oxygen affords the desired
diol 60 in 52% yield, none of the axial alcohol isomer 61,
and reduction product 62 in only 3% yield (Scheme 14).
The yield of 60 is quite sensitive to the reaction condi-
tions. Use of excess oxygen leads to recovered starting
material and a low yield of 60, probably due to the
formation of (Bu3Sn)2O.29 A similar reaction in toluene
with Bu3SnH (3 equiv) and AIBN (1 equiv) and with air
bubbling through it, rather than under oxygen, gives 41%
of a 10:1 mixture of 60 and 61 and 32% of reduction
product 62.
SCHEME 12
SCHEME 14
Iodoetherification of minor aldol adduct 33 affords
iodohydrin 52 in 93% yield (Scheme 13). Treatment of
52 with DBN in THF results in equilibration to give 57
with the more stable cis ring fusion. Deprotonation of the
alcohol of 57 forms alkoxide 58, which rearranges to
provide aldehyde 59 in 87% yield.28 These studies indi-
cated that double elimination from 34 or 52 is not
straightforward, so we investigated other approaches to
massarilactone B (7).
SCHEME 13
Protection of the diol of 60 with 2-methoxypropene and
CSA in DMF provides acetonide 63 (99%). Phenylselena-
tion30 with KHMDS and PhSeCl in THF/HMPA affords
cis-fused phenylselenide 64 (95%). Oxidation of 64 with
(26) Zehnder, L. R.; Wei, L.-L.; Hsung, R. P.; Cole, K. P.; McLaugh-
lin, M. J .; Shen, H. C.; Sklenicka, H. M.; Wang, J .; Zificsak, C. A. Org.
Lett. 2001, 3, 2141-2144.
(27) For a similar cyclopropane synthesis see: Arai, Y.; Takeda, K.;
Masuda, K.; Koizumi, T. Chem. Lett. 1985, 1531-1534.
(28) For a similar rearrangement see: Knapp, S.; Naughton, A. J .;
J aramillo, C.; Pipik, B. J . Org. Chem. 1992, 57, 7328-7334.
(29) (a) Mayer, S.; Prandi, J . Tetrahedron Lett. 1996, 37, 3117-3120.
(b) Sawamura, M.; Kawaguchi, Y.; Nakamura, E. Synlett 1997, 801-
802.
(30) For a similar phenylselenation and oxidative elimination see:
Paquette, L. A.; Sivik, M. R. Synth. Commun. 1991, 21, 467-479.
5522 J . Org. Chem., Vol. 69, No. 17, 2004

TAN-2483A, Massarilactone B, Fusidilactone B, and Waol A and B
hydrogen peroxide in aqueous THF for 8 h affords the
desired unsaturated acetonide 65 (31%), the undesired
unsaturated acetonide 66 (39%), and massarilactone B
(7, 24%) resulting from cleavage of the acetonide of 65
under the oxidation conditions. Hydrolysis of 65 in 80%
HOAc for 2 h provides 7 quantitatively, while a similar
hydrolysis of 66 yields hydroxy ketone 67. The prepara-
tion of 7 was most conveniently carried out by oxidation
of phenylselenide 64 with hydrogen peroxide in aqueous
THF for 2.5 d to give 53% of 7 as the sole isolable product.
The acetonides of both 65 and 66 hydrolyze during the
F IGURE 5. Possible structures for fusidilactone B.
longer reaction time. Hydroxy ketone 66 is oxidized
further by hydrogen peroxide to form a complex mixture
of polar products.
allow us to unambiguously establish whether fusidi-
lactone B has structure 9 or 68.
To our surprise, the 1H and 13C NMR spectra of
synthetic massarilactone B (7) do not match those
reported by Gloer.6 We suspected that these differences
result from a concentration dependence of the NMR
spectrum as we have previously noted in erinacine A.31
In dilute solution (1 mg/mL), intramolecular hydrogen
bonding is more important, favoring structure 7a with
all equatorial substituents (Scheme 15). At higher con-
centrations, structure 7b may be more important. Mo-
lecular mechanics calculations suggest that 7a is only 1
kcal/mol more stable than 7b. The NMR spectra of dilute
solutions of synthetic and natural massarilactone B32 are
The trans-fused lactone of 63 is sensitive to hydrolytic
ring opening. It is therefore best to epimerize 63 to the
more stable cis-fused lactone 69 prior to oxidative cleav-
age of the alkene and Wittig reaction. Treatment of 63
with DBN in CH2Cl2 for 10 min at 0 °C provides 69 (95%).
Oxidative cleavage with OsO4 and NMO followed by
addition of NaIO4 affords the unstable aldehyde 70.
Wittig reaction with isobutyltriphenylphosphonium bro-
mide and LHMDS in THF affords the desired cis alkene
71 (40% from 69). Hydrolysis of the acetonide in 80%
AcOH for 3 h provides 99% of the desired model 72. The
1H and 13C NMR spectra of 72 tabulated in the Support-
ing Information correspond very closely to those of
fusidilactone B, except for the expected differences due
to the shorter side chain, thereby establishing that the
natural product has structure 9, not 68. In conclusion,
we have reassigned the structures of waols A and B as 6
and 29, and completed the first syntheses of these
molecules and (-)-TAN-2483A (5) in three steps from
lactones 12 by aldol reaction, iodoetherification, and
elimination. A longer sequence starting from lactone 31
using an aldol reaction, iodoetherification, radical sub-
stitution of the iodide by a hydroxy group, and oxidation
completes the first synthesis of massarilactone B (7).
Finally, we have prepared 72 and shown that it has the
same ring system as fusidilactone B, thereby establishing
that the natural product has structure 9.
1
identical and the H and 13C NMR spectra of a mixture
of the two show that only one compound is present,
thereby establishing that the structures of the natural
and synthetic materials are identical. NMR spectra of a
more concentrated solution of 7 (10 mg/mL) display
spectral data intermediate between that of the dilute
solution and the reported values. For instance, the
coupling pattern of H3 changes from dd, J ) 8.5, 6.1 Hz
in dilute solution, to dd, J ) 7.9, 6.1 Hz in more
concentrated solution, to dd, J ) 6.6, 5.1 Hz in the
reported spectrum.4 A full tabulation of the differences
is provided in the Supporting Information. The optical
rotation of synthetic massarilactone B (7) ([R]22 -96) is
D
similar to that reported for the natural material ([R]28
D
-109) confirming Gloer’s assignment of the absolute
stereochemistry.
SCHEME 16
SCHEME 15
Syn th esis of th e F u sid ila cton e B Rin g System .
There is some question as to whether fusidilactone B has
structure 9 or 68 (Figure 5).7,8 The side chain of fusidi-
lactone B is much longer than the propenyl group of TAN-
2483, massarilactone B, and waol A, with two unassigned
stereocenters and a cis double bond. We thought that
structure 9 was more likely and decided to prepare 72
with a cis double bond as a model for it. Comparison of
the NMR spectra of the natural product and 72 should
Exp er im en ta l Section
(31) Snider, B. B.; Vo, N. H.; O’Neil, S. V. J . Org. Chem. 1998, 63,
4732-4740.
(32) We thank Prof. Gloer for copies of the spectra and a sample of
massarilactone B.
Gen er a l P r oced u r es. NMR spectra were recorded at 400
MHz in CDCl3 unless otherwise indicated. Chemical shifts are
reported in δ, coupling constants in Hz, and IR spectra in cm-1
.
J . Org. Chem, Vol. 69, No. 17, 2004 5523

Gao and Snider
The 20% AgNO3 on silica gel was prepared by suspending 50
g of silica gel in a solution of AgNO3 (10 g) in CH3CN (200
mL). The solvent was removed under reduced pressure and
the 20% AgNO3 on silica gel was stored in a foil-covered flask
in the dark.
concentrated to give a yellow oil. Flash chromatography on
silica gel (4:1 hexanes/EtOAc) gave 5 (47 mg, 79%) as a
colorless oil: [R]22 -236 (c 1.20, CHCl3) {lit.4 [R]23 -293 (c
D
D
0.59, CHCl3)}; 1H NMR 6.88 (dd, 1, J ) 3.7, 2.4, H4), 5.94 (dq,
1, J ) 15.3, 7.0), 5.70 (ddq, 1, J ) 15.3, 6.1, 1.8), 4.34 (dq, 1,
J ) 7.3, 6.1, H7), 4.25 (ddd, 1, J ) 7.3, 2.4, 2.4, H7a), 4.04-
2,5-Did eoxy-2-[(1S,2E,4E)-1-h yd r oxy-2,4-h exa d ien yl]-
L-a r a bin on ic Acid , γ-La ct on e (12b ) a n d 2,5-Did eoxy-2-
[(1R,2E,4E)-1-h ydr oxy-2,4-h exadien yl]-L-ar abin on ic Acid,
γ-La cton e (15b). Lithium diisopropylamide was prepared
from diisopropylamine (292 µL, 2.08 mmol) and n-BuLi (745
µL, 2.79 M in hexanes, 2.08 mmol) in THF (4 mL) at 0 °C.
The solution was cooled to -23 °C and treated with 13b (116
mg, 1 mmol) in THF (1 mL). The mixture was stirred for 15
min, cooled to -42 °C, and treated with a 4:1 mixture of
(2E,4E)- and (2E,4Z)-2,4-hexadienal (14) (110 µL, 1 mmol). The
mixture was stirred at -42 °C for 1 h and saturated aqueous
NH4Cl solution (1 mL) was added to quench the reaction. The
resulting mixture was diluted with ether (80 mL), washed with
brine, dried (Na2SO4), and concentrated to give a yellow oil.
Flash chromatography on silica gel (2:1 hexanes/EtOAc) gave
15b (42 mg, 20%) as a colorless oil, followed by 12b (103 mg,
49%) as a white solid. Both of these compounds are a 4:1
mixture of (2E,4E) and (2E,4Z) isomers. Flash chromatography
of the mixture of 12b isomers on 20% AgNO3 on silica gel (2:1
hexanes/EtOAc) gave (2E,4E)-12b (80 mg, 38%). Similar
chromatography of the mixture of 15b isomers gave (2E,4E)-
15b (30 mg, 14%).
Data for 12b: 1H NMR 6.32 (dd, 1, J ) 15.3, 10.4), 6.07
(ddq, 1, J ) 15.3, 10.4, 1.2), 5.79 (dq, 1, J ) 15.3, 6.7), 5.67
(dd, 1, J ) 15.3, 7.3), 4.53 (ddd, 1, J ) 7.3, 6.7, 3.1), 4.26 (dq,
1, J ) 7.9, 6.1), 3.98 (ddd, 1, J ) 8.5, 7.9, 4.3), 3.18 (d, 1, J )
3.1, OH), 2.85 (dd, 1, J ) 8.5, 6.7), 2.46 (d, 1, J ) 4.3, OH),
1.77 (dd, 3, J ) 6.7, 1.2), 1.46 (d, 3, J ) 6.1); 13C NMR 174.6,
133.7, 132.0, 130.1, 127.7, 80.1, 75.2, 71.3, 54.3, 18.1, 18.0; IR
(KBr) 3401, 1761, 1662; HRMS (CI/NH3) calcd for C11H20NO4
(MNH4+) 230.1392, found 230.1395.
Data for 15b: 1H NMR 6.37 (dd, 1, J ) 15.3, 10.4), 6.07
(dd, 1, J ) 15.3, 10.4), 5.78 (dq, 1, J ) 15.3, 6.1), 5.69 (dd, 1,
J ) 15.3, 6.1), 4.73 (ddd, 1, J ) 6.1, 4.3, 3.7), 4.27 (dq, 1, J )
8.5, 6.1), 4.20 (ddd, 1, J ) 8.5, 7.9, 4.3), 2.79 (dd, 1, J ) 7.9,
3.7), 2.74 (d, 1, J ) 4.3, OH), 2.64 (d, 1, J ) 4.3, OH), 1.77 (d,
3, J ) 6.1), 1.46 (d, 3, J ) 6.1); 13C NMR 174.4, 132.1, 131.4,
130.3, 128.8, 80.1, 74.3, 69.1, 55.0, 18.11, 18.07; IR (KBr) 3430,
1759, 1661.
(2R,3S,4R,4a R,7S,7a R)-Hexa h yd r o-4-h yd r oxy-3-iod o-7-
m eth yl-2-(1E)-1-pr open yl-5H-fu r o[3,4-b]pyr an -5-on e (11b).
Dry bis(sym-collidine)silver(I) hexafluorophosphate (238 mg,
0.48 mmol) was slurried in dry CH2Cl2 (3 mL) with vigorous
stirring, iodine (97 mg, 0.38 mmol) was added in one portion,
and the solution was stirred for 5 min. A yellow precipitate
was produced instantly. Diene diol 12b (68 mg, 0.32 mmol) in
dry CH2Cl2 (1 mL) was added and the resulting mixture was
stirred at room temperature for 1.5 h and filtered through
Celite. The filtrate was washed with 10% aqueous Na2S2O3
solution and saturated aqueous NaHCO3 solution, dried (Na2-
SO4), and concentrated to give a yellow oil. Flash chromatog-
raphy on silica gel (6:1 hexanes/EtOAc) gave 11b (95 mg, 88%)
as a pale yellow solid: 1H NMR 5.92 (dq, 1, J ) 15.3, 6.7),
5.45 (ddq, 1, J ) 15.3, 7.9, 1.2), 4.45 (dq, 1, J ) 8.6, 6.1, H7),
4.25 (dd, 1, J ) 11.0, 7.9, H2), 4.13 (ddd, 1, J ) 10.4, 9.8, 2.4,
H4), 3.59 (dd, 1, J ) 11.0, 9.8, H3), 3.48 (dd, 1, J ) 11.6, 8.6,
4.11 (m, 2, H2,3), 1.78 (br d, 3, J ) 7.0), 1.56 (d, 3, J ) 6.1); 13
C
NMR 166.6, 133.4 (2 C), 131.3, 125.6, 79.9, 79.7, 79.0, 64.1,
18.8, 18.1; IR (neat) 3436, 1773, 1642; HRMS (CI/NH3) calcd
for C11H18NO4 (MNH4+) 228.1236, found 228.1233. The spectral
data are identical with those of the natural product.4
2-(ter t-Bu tyld ip h en ylsilyloxy)-3E-p en ten en itr ile (25).
To a stirred solution of trans-2-butenal (2.8 g, 40 mmol) in
ether (6 mL) at -10 °C was added a precooled (-10 °C) solution
of NaCN (1.96 g, 40 mmol) in H2O (5 mL) over 3 min. A
solution of HCl [36% HCl (2 mL) + H2O (2 mL)] was added
dropwise over 2 h at -10 °C. The mixture was stirred at room
temperature for 3 h, and the ether layer was separated,
washed with water, dried (Na2SO4), and concentrated to give
a yellow oil. Without further purification, the crude cyano-
hydrin was added to a solution of imidazole (3.78 g, 56 mmol)
and tert-butyldiphenylsilyl chloride (7.2 mL, 28 mmol) in dry
DMF (75 mL) at 0 °C. The resulting mixture was stirred
overnight from 0 °C to room temperature and poured into 80
mL of H2O, which was extracted with ether, which was washed
with brine and concentrated to give a yellow oil. Flash
chromatography on silica gel (40:1 hexanes/ether) gave 2519
(4.69 g, 34%) as a colorless oil.
Met h yl 4-(ter t-Bu t yld ip h en ylsilyloxy)-3-oxo-5E-h ep -
ten oa te (26). Powdered zinc was activated by washing
sequentially with 3 M HCl, water, EtOH, and ether and drying
under reduced pressure.20 To a solution of activated zinc dust
(1.06 g, 16.22 mmol) in dry THF (15 mL) was added TMSCl
(189 µL, 1.49 mmol). The solution was stirred for 20 min and
treated with 25 (1.93 g, 5.76 mmol), and the mixture was
heated to reflux. Methyl bromoacetate (1.69 mL, 17.90 mmol)
was added dropwise over 50 min and heating was continued
for 70 min. The mixture was cooled to 5 °C, 3 M HCl (9 mL)
was added, and the resulting solution was stirred at room
temperature for 2 h. The mixture was poured into saturated
aqueous NaHCO3 solution (50 mL) forming an emulsion that
was broken by the addition of water (50 mL). The aqueous
phase was extracted with EtOAc (5 × 80 mL), and the
combined organic layers were dried (Na2SO4) and concentrated
to give a yellow oil. Flash chromatography on silica gel (20:1
hexanes/ether) gave 26 (2.03 g, 86%) as an 87:13 keto/enol
mixture: 1H NMR (keto) 7.59-7.62 (m, 4), 7.36-7.44 (m, 6),
5.62 (ddq, 1, J ) 15.3, 6.7, 1.2), 5.35 (ddq, 1, J ) 15.3, 6.4,
1.8), 4.58 (br d, 1, J ) 6.4), 3.67 (s, 3), 3.57 (s, 2), 1.59 (ddd, 3,
1
J ) 6.7, 1.8, 1.2), 1.10 (s, 9); H NMR (enol) 11.8 (s, 1, OH),
5.44 (s, 1); 13C NMR (keto) 202.6, 167.7, 135.8 (2 C), 135.7 (2
C), 132.9, 132.6, 130.9, 130.1, 129.9, 127.8 (2C), 127.6 (2C),
126.9, 80.5, 52.2, 43.9, 26.9 (3 C), 19.3, 17.8; IR (neat) 2955,
+
1755, 1725; HRMS (DCI/NH3) calcd for C24H34NO4Si (MNH4
428.2257, found 428.2265.
)
Meth yl 4-(ter t-Bu tyld ip h en ylsilyloxy)-3-h yd r oxy-5E-
h ep ten oa te (27). To a stirred solution of 26 (1 g, 2.43 mmol)
in MeOH (10 mL) at -15 °C was added NaBH4 (111 mg, 2.92
mmol) in portions. The solution was stirred for 5 min and 10%
aqueous HCl was added to quench the reaction. After concen-
tration to remove the MeOH, the aqueous phase was extracted
with EtOAc (3 × 80 mL), which was washed with saturated
aqueous NaHCO3 solution and brine, dried (Na2SO4), and
concentrated to give a yellow oil. Flash chromatography on
silica gel (4:1 hexanes/ether) gave 970 mg (97%) of an
inseparable 5:1 mixture of 27a and 27b.
H
7a), 3.07 (d, 1, J ) 2.4, OH), 2.47 (dd, 1, J ) 11.6, 10.4, H4a),
1.80 (dd, 3, J ) 6.7, 1.2), 1.51 (d, 3, J ) 6.1); 13C NMR 169.9,
134.2, 127.6, 84.9, 80.6, 78.3, 73.2, 51.6, 38.6, 17.74, 17.71; IR
(KBr) 3469, 1784.
(2R,3R,7S,7a R)-2,3,7,7a -Tetr a h yd r o-3-h yd r oxy-7-m eth -
yl-2-(1E)-1-p r op en yl-5H-fu r o[3,4-b]p yr a n -5-on e [(-)-TAN-
2483A, 5]. To a solution of 11b (95 mg, 0.28 mmol) in dry
CH2Cl2 (3 mL) was added Et3N (2 mL). The resulting mixture
was stirred at room temperature for 3 days and diluted with
CH2Cl2 (80 mL), washed with 10% aqueous HCl, saturated
aqueous NaHCO3 solution, and brine, dried (Na2SO4), and
Partial data for 27a were determined from the mixture: 1H
NMR 3.656 (s, 3), 2.65 (d, 1, J ) 3.7, OH), 2.48 (dd, 1, J )
15.9, 4.3), 2.45 (dd, 1, J ) 15.9, 7.9).
Partial data for 27b were determined from the mixture: 1H
NMR 3.663 (s, 3), 2.78 (d, 1, J ) 4.3, OH), 2.52 (dd, 1, J )
15.2, 3.7), 2.36 (dd, 1, J ) 15.2, 8.5).
5524 J . Org. Chem., Vol. 69, No. 17, 2004

TAN-2483A, Massarilactone B, Fusidilactone B, and Waol A and B
(4R,5S)-r el- a n d (4R,5R)-r el-Dih yd r o-4-h yd r oxy-5-(1E)-
1-p r op en yl-2(3H)-fu r a n on e (13c a n d 28). To a cooled solu-
tion (5 °C) of the 5:1 mixture of 27a and 27b (890 mg, 2.16
mmol) in THF (20 mL) was added TBAF (6.8 mL, 0.7 M in
CH3CN, 4.76 mmol) dropwise. The reaction was stirred for 48
h at room temperature and treated with 10% aqueous HCl (2
mL). The solution was stirred for 1 h. Ethyl acetate and solid
NaCl were added. The layers were separated and the organic
layer was washed with saturated aqueous NaHCO3 solution
and brine, dried (Na2SO4), and concentrated to give a yellow
oil. Flash chromatography on silica gel (1:1 hexanes/EtOAc)
gave 13c (193 mg, 63%) as a colorless oil, followed by 28 (40
mg, 13%) also as a colorless oil.
Data for 13c: 1H NMR 5.88 (dq, 1, J ) 15.3, 6.7), 5.46 (dd,
1, J ) 15.3, 6.7), 4.77 (dd, 1, J ) 6.7, 1.8), 4.33 (m, 1), 2.89 (br,
1, OH), 2.81 (dd, 1, J ) 17.7, 6.7), 2.51 (dd, 1, J ) 17.7, 4.3),
1.75 (d, 3, J ) 6.7); 13C NMR 175.4, 131.2, 125.7, 87.7, 72.1,
37.0, 17.8; IR (neat) 3432, 1778, 1672; HRMS (CI/NH3) calcd
for C7H14NO3 (MNH4+) 160.0974, found 160.0969.
in dry CH2Cl2 (2 mL) was added. The resulting mixture was
stirred at room temperature for 2 h and filtered through Celite.
The filtrate was washed with 10% aqueous Na2S2O3 solution
and saturated aqueous NaHCO3 solution, dried (Na2SO4), and
concentrated to give a yellow oil. Flash chromatography on
silica gel (3:1 hexanes/ether) gave 11c (118 mg, 95%) as a pale
1
yellow solid: mp 125-127 °C; H NMR 6.01 (dq, 1, J ) 15.3,
6.7), 5.90 (dq, 1, J ) 15.3, 6.7), 5.49 (ddq, 1, J ) 15.3, 7.9,
1.2), 5.43 (ddq, 1, J ) 15.3, 7.9, 1.2), 4.71 (dd, 1, J ) 8.6, 7.9,
H7), 4.24 (dd, 1, J ) 10.4, 7.9, H2), 4.14 (dd, 1, J ) 10.4, 9.8,
H4), 3.61 (dd, 1, J ) 11.6, 8.6, H7a), 3.60 (dd, 1, J ) 10.4, 9.8,
H3), 3.17 (br, 1, OH), 2.48 (dd, 1, J ) 11.6, 10.4, H4a), 1.79 (dd,
3, J ) 6.7, 1.2), 1.78 (dd, 3, J ) 6.7, 1.2); 13C NMR 169.7, 135.0,
134.2, 127.5, 124.9, 84.9, 82.3, 79.2, 73.1, 51.3, 38.6 18.0, 17.7;
IR (KBr) 3449, 1768, 1677.
(2R,3R,7S,7a R)-r el-2,3,7,7a -Tetr a h yd r o-3-h yd r oxy-2,7-
d i-(1E)-1-p r op en yl-5H-fu r o[3,4-b]p yr a n -5-on e [(()-Wa ol
A, 6]. To a solution of 11c (90 mg, 0.25 mmol) in dry CH2Cl2
(10 mL) was added Et3N (2 mL). The resulting mixture was
stirred at reflux overnight, diluted with CH2Cl2 (125 mL),
washed with 10% aqueous HCl, saturated aqueous NaHCO3
solution, and brine, dried (Na2SO4), and concentrated to give
a yellow oil. Flash chromatography on silica gel (1:1 hexanes/
ether) gave 6 (57 mg, 98%) as a colorless oil: 1H NMR 6.89
(dd, 1, J ) 3.7, 2.4, H4), 6.01 (dq, 1, J ) 15.3, 6.7), 5.92 (dq, 1,
J ) 15.3, 6.7), 5.71 (ddq, 1, J ) 15.3, 6.7, 1.2), 5.61 (ddq, 1, J
) 15.3, 7.9, 1.2), 4.60 (dd, 1, J ) 7.9, 7.9, H7), 4.38 (ddd, 1, J
) 7.9, 2.4, 1.8, H7a), 4.04-4.08 (m, 2, H2,3), 2.07 (br d, 1, J )
7.9, OH), 1.79 (dd, 6, J ) 6.7, 1.2); 13C NMR 166.4, 134.0, 133.6,
132.9, 131.3, 125.9, 125.7, 82.9, 79.8, 78.5, 64.1, 18.1, 17.9; IR
(neat) 3440, 1762, 1674; HRMS (CI/NH3) calcd for C13H20NO4
(MNH4+) 254.1392, found 254.1381. The spectral data are
identical with those of natural waol A.1
Meth yl (2S,5S,6S)-r el-5,6-Dih ydr o-5-h ydr oxy-2-[(1R,2E)-
1-h yd r oxy-2-bu ten yl]-6-(1E)-1-p r op en yl-2H-p yr a n -3-ca r -
boxyla te [(()-Wa ol B, 29] a n d (2R,3R,4S,4a S,7S,7a R)-r el-
Hexa h yd r o-3-h yd r oxy-4-m eth oxy-2,7-d i-(1E)-1-p r op en yl-
5H-fu r o[3,4-b]p yr a n -5-on e (30). A solution of 6 (20 mg, 0.08
mmol) in 5 mL of 1:1 MeOH/H2O containing 142 mg of KOH
was stirred for 1 h. The MeOH was removed by concentration
and the resulting aqueous solution was acidified with 0.5 M
HCl to pH 3 and extracted with Et2O (3 × 15 mL). The
combined extracts were washed with H2O and dried (Na2SO4).
A solution of diazomethane in ether was added dropwise to
the Et2O solution at 0 °C. Concentration afforded an oil that
was purified by flash chromatography on silica gel (3:1
hexanes/EtOAc) to give 30 (10.6 mg, 47%) as a colorless oil,
followed by 29 (8.6 mg, 38%) as a colorless oil.
Data for 28: 1H NMR 6.01 (dq, 1, J ) 15.3, 6.7), 5.63 (ddq,1,
J ) 15.3, 6.7, 1.8), 4.86 (dd, 1, J ) 6.7, 3.7), 4.48 (m, 1), 2.78
(dd, 1, J ) 17.7, 5.7), 2.62 (dd, 1, J ) 17.7, 1.8), 2.12 (d, 1, J
) 3.1, OH), 1.82 (br d, 3, J ) 6.7); 13C NMR 175.7, 133.6, 122.8,
84.9, 69.7, 38.7, 18.0; IR (neat) 3432, 1765.
(3S,4S,5R)-r el-Dih yd r o-4-h yd r oxy-3-[(1R,2E,4E)-1-h y-
d r oxy-2,4-h e xa d ie n yl]-5-(1E )-1-p r op e n yl-2(3H )-fu r a -
n on e (12c) a n d (3R,4R,5S)-r el-Dih yd r o-4-h yd r oxy-3-[(1R-
2E,4E)-1-h ydr oxy-2,4-h exadien yl]-5-(1E)-1-pr open yl-2(3H)-
fu r a n on e (15c). Lithium diisopropylamide was prepared from
diisopropylamine (493 µL, 3.52 mmol) and n-BuLi (1.41 mL,
2.5 M in hexanes, 3.52 mmol) in THF (10 mL) at 0 °C. This
solution was cooled to -42 °C and treated with 13c (200 mg,
1.41 mmol) in THF (1 mL). The solution was stirred for 15
min and a 4:1 mixture of (2E,4E)- and (2E,4Z)-2,4-hexadienal
(14) (156 µL, 1.42 mmol) was added. The mixture was stirred
at -42 °C for 1 h and saturated aqueous NH4Cl solution (1
mL) was added to quench the reaction. The resulting mixture
was diluted with ether (125 mL), washed with brine, dried
(Na2SO4), and concentrated to give a yellow oil. Flash chro-
matography on silica gel (1:1 hexanes/ether) gave 15c (90 mg,
27%) followed by 12c (188 mg, 56%). Both of these compounds
are a 4:1 mixture of (2E,4E) and (2E,4Z) isomers. Flash
chromatography of the mixture of 12c isomers on 20% AgNO3
on silica gel (1:1 hexanes/EtOAc) gave (2E,4E)-12c (147 mg,
44%) as a white solid. Similar chromatography of the mixture
of 15c isomers gave (2E,4E)-15c as a white solid (71 mg, 21%).
Data for 12c: mp 83-84 °C; 1H NMR 6.32 (dd, 1, J ) 15.3,
11.0), 6.07 (ddq, 1, J ) 15.3, 11.0, 1.8), 5.97 (dq, 1, J ) 15.3,
6.7), 5.79 (dq, 1, J ) 15.3, 6.7), 5.67 (dd, 1, J ) 15.3, 7.3), 5.49
(ddq, 1, J ) 15.3, 6.9, 1.8), 4.49-4.53 (m, 2), 4.08 (ddd, 1, J )
11.6, 9.2, 3.7), 3.11 (d, 1, J ) 3.1, OH), 2.84 (dd, 1, J ) 9.2,
6.7), 2.34 (d, 1, J ) 3.7, OH), 1.77 (dd, 6, J ) 6.7, 1.8); 13C
NMR 174.2, 133.8, 133.6, 132.2, 130.1, 127.7, 125.9, 84.1, 74.1,
71.6, 53.6, 18.2, 17.9; IR (KBr) 3397, 1733, 1672; HRMS
(CI/NH3) calcd for C13H22NO4 (MNH4+) 256.1549, found
256.1553.
Data for 15c: mp 95-98 °C; 1H NMR 6.36 (dd, 1, J ) 15.3,
10.4), 6.08 (ddq, 1, J ) 15.3, 10.4, 1.8), 5.96 (dq, 1, J ) 15.3,
6.7), 5.77 (dq, 1, J ) 15.3, 6.7), 5.71 (dd, 1, J ) 15.3, 6.1), 5.52
(ddq, 1, J ) 15.3, 7.9, 1.8), 4.74 (ddd, 1, J ) 6.1, 4.3, 3.7), 4.49
(dd, 1, J ) 7.9, 7.9), 4.31 (ddd, 1, J ) 10.4, 7.9, 4.3), 2.82 (d, 1,
J ) 3.7, OH), 2.80 (d, 1, J ) 4.3, OH), 2.46 (dd, 1, J ) 10.4,
4.3), 1.77 (br d, 6, J ) 6.7); 13C NMR 173.9, 133.4, 132.2, 131.4,
130.2, 128.6, 126.2, 84.3, 73.1, 69.2, 54.2, 18.1, 17.9; IR (KBr)
3337, 1767, 1676.
(2R,3S,4R,4aR,7S,7aR)-r el-Hexah ydr o-4-h ydr oxy-3-iodo-
2,7-d i-(1E)-1-p r op en yl-5H-fu r o[3,4-b]p yr a n -5-on e (11c).
Dry bis(sym-collidine)silver(I) hexafluorophosphate (255 mg,
0.52 mmol) was slurried in dry CH2Cl2 (3 mL) with vigorous
stirring and iodine (104 mg, 0.41 mmol) was added in one
portion forming a yellow precipitate instantly. The solution
was stirred for 5 min and diene diol 12c (81 mg, 0.34 mmol)
Data for 29: 1H NMR 7.13 (dd, 1, J ) 6.4, 2.0, H4), 5.84
(dq, 1, J ) 15.3, 6.7), 5.62-5.71 (m, 2), 5.44 (ddq, 1, 15.3, 6.7,
1.8), 4.76 (br s, 1), 4.59-4.63 (m, 1), 3.91-3.97 (m, 2), 3.76 (s,
3), 2.55 (d, 1, J ) 8.5, OH), 1.90 (d, 1, J ) 10.4, OH), 1.77 (d,
3, J ) 6.7), 1.68 (dd, 3, J ) 6.7, 1.2); 13C NMR 165.7, 137.9,
132.7, 130.3, 128.9, 128.5, 126.7, 77.2, 76.8, 72.7, 64.3, 52.0,
18.1, 17.8; IR (neat) 3415, 1717; HRMS (CI/NH3) calcd for
C
14H24NO5 (MNH4+) 286.1654, found 286.1656. The spectral
data are identical with those of natural waol B.2
Data for 30: 1H NMR 5.81-5.94 (m, 2), 5.54 (ddq, 1, J )
15.3, 6.7, 1.8), 5.42 (ddq, 1, J ) 15.3, 5.5, 1.8), 4.98 (d, 1, J )
5.5, H7), 4.28 (d, 1, J ) 4.9, H7a), 4.16 (dd, 1, J ) 6.7, 1.2, H2),
3.99 (dd, 1, J ) 2.4, 1.8, H4), 3.65 (dd, 1, J ) 4.8, 2.4, H3), 3.47
(s, 3), 2.74 (dd, 1, J ) 4.9, 1.8, H4a), 1.83 (d, 1, J ) 4.8, OH),
1.72-1.76 (m, 6); 13C NMR 174.4, 130.2, 130.0, 126.7, 124.4,
84.2, 76.0, 75.6, 72.8. 66.8, 57.9, 39.9, 18.0, 17.8; IR (neat) 3477,
1770; HRMS (CI/NH3) calcd for C14H24NO5 (MNH4+) 286.1654,
found 286.1656.
2,5-Did eoxy-2-[(1R,2E,4E)-1-h yd r oxy-2,4-h exa d ien yl]-
L-xylon ic Acid , γ-La cton e (32) a n d 2,5-Did eoxy-2-[(1S,-
2E,4E)-1-h yd r oxy-2,4-h exa d ien yl]-L-xylon ic a cid , γ-La c-
ton e (33). Lithium diisopropylamide was prepared from
diisopropylamine (1.43 mL, 10.18 mmol) and n-BuLi (6.37 mL,
1.6 M in hexanes, 10.18 mmol) in THF (12 mL) at 0 °C. The
J . Org. Chem, Vol. 69, No. 17, 2004 5525

Gao and Snider
solution was cooled to -42 °C and treated with (-)-31 (568
mg, 4.90 mmol) in THF (4 mL). The mixture was stirred for
15 min, and treated with a 4:1 mixture of (2E,4E)- and (2E,4Z)-
2,4-hexadienal (14) (595 µL, 5.39 mmol). The mixture was
stirred at -42 °C for 1.2 h and 10% HCl solution (7 mL) was
added to quench the reaction. The organic layer was separated
and the aqueous layer was extracted with ether (3 × 50 mL).
The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated to give a yellow oil. Flash chro-
matography on silica gel (2:1 hexanes/EtOAc) gave 33 (405 mg,
39%) as a colorless oil, followed by 32 (467 mg, 45%) as a
colorless oil. Both of these compounds are a 4:1 mixture of
(2E,4E) and (2E,4Z) isomers. Flash chromatography of the
mixture of 32 isomers on 20% AgNO3 on silica gel (2:1 hexanes/
EtOAc) gave (2E,4E)-32 (374 mg, 36%). Similar chromatog-
raphy of the mixture of 33 isomers gave (2E,4E)-33 (324 mg,
31%).
mg, 3%) as a colorless oil followed by diol 60 (175 mg, 52%) as
a white solid.
A flask was charged with a solution of iodohydrin 34 (125
mg, 0.37 mmol) in toluene (2 mL) with air bubbling in it at 65
°C, to which a solution of Bu3SnH (298 µL, 1.11 mmol) and
AIBN (61 mg, 0.37 mmol) in toluene (3 mL) was added in 3
portions over 12 h. The solvent was evaporated and 10 mL of
hexanes and 10 mL of CH3CN were added to the residue. The
resulting two-phased mixture was stirred vigorously for 5 min.
The CH3CN layer was separated and the hexanes layer was
extracted with CH3CN (3 × 30 mL). The combined CH3CN
layers were washed with hexanes (3 × 10 mL) and concen-
trated to give a yellow oil. Flash chromatography on silica gel
(1:1 hexanes/EtOAc) gave alcohol 62 (25 mg, 32%) as a
colorless oil followed by a 10:1 mixture of diols 60 and 61 (34
mg, 41%) as a white solid. Yields vary in the other runs. Diols
60 and 61 cannot be separated via flash chromatography on
silica gel, but after the two hydroxyl groups were protected,
the two acetonides can be separated easily via flash chroma-
tography on silica gel.
Data for 32: [R]22D -65 (c 1.2, MeOH); 1H NMR 6.30 (dd, 1,
J ) 15.3, 10.4), 6.06 (ddq, 1, J ) 15.3, 10.4, 1.3), 5.79 (dq, 1,
J ) 15.3, 6.7), 5.68 (dd, 1, J ) 15.3, 7.3), 4.70 (dq, 1, J ) 6.7,
6.7), 4.53 (ddd, 1, J ) 7.3, 6.5, 3.1), 4.45 (br dd, 1, J ) 6.7,
6.7), 3.03 (d, 1, J ) 3.1, OH), 2.81 (dd, 1, J ) 6.7, 6.5), 2.65 (d,
Data for 60: [R]22 -55 (c 1.30, MeOH); mp 149-151 °C;
D
1H NMR 5.93 (dq, 1, J ) 15.3, 6.7), 5.55 (ddq, 1, J ) 15.3, 7.9,
1.2), 4.77 (dq, 1, J ) 7.3, 6.7), 4.00 (dd, 1, J ) 12.2, 7.3), 3.96
(dd, 1, J ) 10.4, 8.6), 3.84 (dd, 1, J ) 9.4, 7.9), 3.67 (br s, 1,
OH), 3.30 (ddd, 1, J ) 9.4, 8.6, 3.1), 2.88 (d, 1, J ) 3.1, OH),
2.62 (dd, 1, J ) 12.2, 10.4), 1.78 (dd, 3, J ) 6.7, 1.2), 1.40 (d,
3, J ) 6.7); 13C NMR 171.9, 132.7, 127.4, 83.1, 76.1, 75.8, 75.4,
71.9, 44.7, 18.0, 13.5; IR (neat) 3428, 1782; HRMS (EI, 20 EV)
calcd for C11H16O5 (M+) 228.0998, found 228.1006.
1, J ) 4.9, OH), 1.77 (br d, 3, J ) 6.7), 1.38 (d, 3, J ) 6.7); 13
C
NMR 175.5, 133.6, 132.1, 130.1, 127.7, 78.8, 71.5, 70.7, 53.6,
18.2, 14.2; IR (neat) 3374, 1736; HRMS (DCI/NH3) calcd for
+
C
11H18NO3 (M + NH4 - H2O) 212.1287, found 212.1291.
Data for 33: 1H NMR 6.32 (dd, 1, J ) 15.3, 10.4), 6.07 (ddq,
1, J ) 15.3, 10.4, 1.2), 5.77 (dq, 1, J ) 15.3, 6.7), 5.65 (dd, 1,
J ) 15.3, 6.1), 4.65-4.73 (m, 2), 4.51 (br dd, 1, J ) 9.8, 4.9),
3.02 (d, 1, J ) 4.9, OH), 2.96 (d, 1, J ) 4.9, OH), 2.72 (dd, 1,
J ) 4.3, 3.7), 1.77 (br d, 3, J ) 6.7), 1.37 (d, 3, J ) 6.7); 13C
NMR 176.8, 132.2, 131.3, 130.3, 128.9, 79.9, 70.2, 69.7, 55.0,
18.1, 14.1; IR (neat) 3416, 1744.
1
Data for 62: H NMR 5.80 (dq, 1, J ) 15.3, 6.7), 5.53 (ddq,
1, J ) 15.3, 7.3, 1.2), 4.79 (dq, 1, J ) 7.3, 6.7), 4.02-4.13 (m,
2), 3.81 (dd, 1, J ) 12.2, 7.3), 2.91 (d, 1, J ) 2.4, OH), 2.40
(dd, 1, J ) 12.2, 9.7), 2.09 (ddd, 1, J ) 13.3, 4.9, 2.4), 1.74 (dd,
3, J ) 6.7, 1.2), 1.41 (d, 3, J ) 6.7), 1.40 (ddd, 1, J ) 13.3,
11.6, 10.4); 13C NMR 173.0, 129.5, 129.4, 79.5, 76.6, 75.5, 67.1,
46.4, 40.0, 17.8, 13.6; IR (neat) 3448, 1774; HRMS (EI, 20 EV)
calcd for C11H16O4 (M+) 212.1049, found 212.1041.
(2S,3R,4S,4a S,7S,7a S)-Hexa h yd r o-4-h yd r oxy-3-iod o-7-
m eth yl-2-(1E)-1-p r op en yl-5H-fu r o[3,4-b]p yr a n -5-on e (34).
Dry bis(sym-collidine)silver(I) hexafluorophosphate (294 mg,
0.59 mmol) was slurried in dry CH2Cl2 (10 mL) with vigorous
stirring, iodine (121 mg, 0.48 mmol) was added in one portion,
and the solution was stirred for 5 min. A yellow precipitate
was produced instantly. Diene diol 32 (84 mg, 0.40 mmol) in
dry CH2Cl2 (2 mL) was added. The resulting mixture was
stirred at 25 °C for 2.5 h and filtered through Celite. The Celite
was washed with CH2Cl2 (60 mL) and the combined filtrate
was washed with 10% aqueous Na2S2O3 solution, 10% HCl
solution, and saturated aqueous NaHCO3 solution, dried (Na2-
SO4), and concentrated to give a yellow oil. Flash chromatog-
raphy on silica gel (6:1 hexanes/EtOAc) gave iodohydrin 34
Aceton id e 63. A mixture of diol 60 (169 mg, 0.74 mmol)
and D-(+)-camphor-10-sulfonic acid (26 mg, 0.11 mmol) in dry
DMF (1 mL) was prepared and added to a solution of
2-methoxypropene (1.42 mL, 14.80 mmol) in dry DMF (3 mL)
at 25 °C. The resulting mixture was stirred at 25 °C for 1.5 h,
diluted with EtOAc (120 mL), washed with saturated aqueous
NaHCO3 solution, H2O, and brine, dried (MgSO4), and con-
centrated to give a yellow oil. Flash chromatography on silica
gel (10:1 hexanes/EtOAc) gave acetonide 63 (197 mg, 99%) as
1
a colorless oil: [R]22 -51 (c 1.20, MeOH); H NMR 5.82 (dq,
D
1, J ) 15.3, 6.7), 5.56 (ddq, 1, J ) 15.3, 7.3, 1.8), 4.83 (dq, 1,
J ) 7.3, 6.7), 4.09 (dd, 1, J ) 9.7, 7.3), 3.93 (dd, 1, J ) 11.6,
7.3), 3.74 (dd, 1, J ) 10.4, 8.5), 3.18 (dd, 1, J ) 9.7, 8.5), 2.86
(dd, 1, J ) 11.6, 10.4), 1.79 (dd, 3, J ) 6.7, 1.8), 1.50 (s, 3),
1.49 (s, 3), 1.43 (d, 3, J ) 6.7); 13C NMR 169.9, 132.6, 126.6,
112.1, 81.5, 80.9, 76.7, 76.4, 76.3, 44.9, 26.6, 26.5, 18.1, 13.8;
IR (neat) 1786; HRMS (EI, 20 EV) calcd for C14H20O5 (M+)
268.1311, found 268.1315.
(121 mg, 91%) as a pale yellow oil: [R]22 -9.3 (c 1.1, MeOH);
D
1H NMR 5.91 (dq, 1, J ) 15.3, 6.7), 5.47 (ddq, 1, J ) 15.3, 7.9,
1.2), 4.81 (dq, 1, J ) 7.3, 6.7, H7), 4.27 (dd, 1, J ) 10.4, 7.9,
H2), 4.14 (ddd, 1, J ) 10.4, 10.4, 2.4, H4), 4.00 (dd, 1, J ) 12.2,
7.3, H7a), 3.58 (dd, 1, J ) 10.4, 10.4, H3), 3.16 (d, 1, J ) 2.4,
OH), 2.53 (dd, 1, J ) 12.2, 10.4, H4a), 1.80 (dd, 3, J ) 6.7, 1.2),
1.41 (d, 3, J ) 6.7); 13C NMR 170.3, 133.8, 127.7, 84.9, 76.2,
75.6, 73.6, 46.5, 38.7, 17.7, 13.5; IR (neat) 3474, 1781.
The cis acetonide was obtained as a minor product of the
protection of the 10:1 mixture of diols 60 and 61: 1H NMR
5.90 (dq, 1, J ) 15.3, 7.1), 5.76 (ddq, 1, J ) 15.3, 7.9, 1.2), 4.77
(dq, 1, J ) 6.7, 6.1), 4.41 (dd, 1, J ) 9.1, 4.9), 4.25 (dd, 1, J )
7.9, 2.4), 4.05 (dd, 1, J ) 4.9, 2.4), 3.78 (dd, 1, J ) 12.2, 6.7),
2.65 (dd, 1, J ) 12.2, 9.1), 1.79 (br d, 3, J ) 7.1), 1.56 (s, 3),
1.40 (d, 3, J ) 6.1), 1.37 (s, 3); 13C NMR 172.3, 131.5, 126.0,
110.0, 80.4, 75.8, 74.9, 74.5, 72.3, 42.5, 28.7, 26.1, 17.9, 13.7;
IR (neat) 1786.
P h en ylselen id e 64. To a solution of potassium bis(tri-
methylsilyl)amide (840 µL, 0.42 mmol, 0.5 M in toluene) in
dry THF (3 mL) was added a solution of acetonide 63 (94 mg,
0.35 mmol) in dry THF (2 mL) at -78 °C over 30 min. This
mixture was stirred at -78 °C for 15 min and treated with a
solution of phenylselenyl chloride (80 mg, 0.42 mmol) and
HMPA (70 µL, 0.39 mmol) in dry THF (1 mL). The resulting
mixture was stirred for 3 h from -78 to 25 °C, diluted with
(2S,3R,4S,4aS,7S,7aS)-Hexah ydr o-3,4-dih ydr oxy-7-m eth -
yl-2-(1E)-1-pr open yl-5H-fu r o[3,4-b]pyr an -5-on e (60). AIBN
(5 mg, 0.03 mmol), NaBH3CN (192 mg, 2.96 mmol), Bu3SnCl
(20 µL, 0.07 mmol), and iodohydrin 34 (500 mg, 1.48 mmol) in
t-BuOH (6 mL) were placed in a 100-mL round-bottomed flask
that was connected to an empty thick-walled natural latex
rubber balloon. After being degassed under reduced pressure,
the flask was filled with O2. The resulting mixture was stirred
at 65 °C for 2.5 h and another portion of Bu3SnCl (20 µL, 0.07
mmol) was added to the mixture. The reaction mixture was
stirred for another 2.5 h and poured into water (6 mL), which
was extracted with ether (3 × 50 mL) and CH2Cl2 (3 × 50 mL).
The combined extracts were dried (MgSO4) and concentrated
to give a yellow oil. Flash chromatography on silica gel (1:1
hexanes/EtOAc) gave (2R,4R,4aS,7S,7aS)-hexahydro-4-hydroxy-
7-methyl-2-(1E)-1-propenyl-5H-furo[3,4-b]pyran-5-one (62) (9
5526 J . Org. Chem., Vol. 69, No. 17, 2004

TAN-2483A, Massarilactone B, Fusidilactone B, and Waol A and B
ether, washed with brine, dried (MgSO4), and concentrated to
P r otected F u sid ila cton e B Rin g System 71. To a stirred
give a yellow oil. Flash chromatography on silica gel (10:1
solution of acetonide 69 (25 mg, 0.09 mmol) in acetone (1 mL)
and H2O (1 mL) was added NMO (33 mg, 0.28 mmol) at 0 °C
followed by 2.5 wt % of OsO4 in t-BuOH (122 µL, 10 mmol %).
The reaction mixture was warmed to 25 °C then stirred for
12 h and NaIO4 (50 mg, 0.23 mmol) was added. The resulting
mixture was stirred for another 4 h, diluted with CH2Cl2 (30
mL), and washed with saturated aqueous NH4Cl solution. The
aqueous phase was extracted with CH2Cl2 (3 × 20 mL) and
the combined organic layers were dried (MgSO4) and concen-
trated to give aldehyde 70 (25 mg) as a colorless residue, which
was used in the next step without further purification.
To a suspension of isobutyltriphenylphosphonium bromide
(56 mg, 0.14 mmol) in dry THF (1 mL) was added LHMDS
(140 µL, 1.0 M in THF) at 0 °C. The mixture was stirred for 5
min and treated dropwise with aldehyde 70 (25 mg) in dry
THF (1 mL). The resulting mixture was stirred from 0 to 25
°C for 3 h and poured into saturated aqueous NH4Cl solution
(2 mL). The aqueous phase was extracted with EtOAc (3 × 30
mL) and the organic layers were washed with brine, dried
(MgSO4), and concentrated to give a yellow oil. Flash chro-
matography on silica gel (4:1 hexanes/EtOAc) gave 71 (11 mg,
40% for two steps) as a colorless oil: 1H NMR 5.55 (dd, 1, J )
11.0, 10.4), 5.29 (dd, 1, J ) 11.0, 8.5), 4.55 (dq, 1, J ) 3.0,
6.7), 4.27 (dd, 1, J ) 9.2, 8.5), 4.22 (dd, 1, J ) 3.6, 3.0), 3.85
(dd, 1, J ) 9.2, 5.5), 3.39 (dd, 1, J ) 5.5, 3.6), 3.36 (dd, 1, J )
9.2, 9.2), 2.56-2.66 (m, 1), 1.51 (s, 3), 1.46 (s, 3), 1.44 (d, 3, J
) 6.7), 1.00 (d, 6, J ) 6.7); 13C NMR 171.6, 143.6, 122.9, 111.0,
78.2, 76.2, 76.0, 75.6, 74.7, 46.8, 27.8, 26.5, 26.4, 23.1, 23.0,
13.7; IR (neat) 1777, 1664; HRMS (DCI/NH3) calcd for C16H25O5
(MH+) 297.1702, found 297.1708.
(2R,3S,4R,4a S,7R,7a R)-r el-Hexa h yd r o-3,4-d ih yd r oxy-
2-[(1Z)-3-m eth yl-1-bu ten yl]-7-m eth yl-5H-fu r o[3,4-b]pyr an -
5-on e (72). Acetonide 71 (5.4 mg, 0.02 mmol) in 80% AcOH
(1 mL) was stirred at 25 °C for 3 h. Removal of the solvent
under reduced pressure with heating gave 72 (4.6 mg, 99%)
as a white solid: 1H NMR (acetone-d6) 5.42 (dd, 1, J ) 11.0,
10.4), 5.26 (dd, 1, J ) 11.0, 7.9), 4.67 (dq, 1, J ) 3.0, 6.7), 4.37
(dd, 1, J ) 3.0, 3.0), 4.21 (d, 1, J ) 3.7, OH), 4.05 (d, 1, J )
9.8, OH), 3.97 (dd, 1, J ) 9.2, 7.9), 3.86 (ddd, 1, J ) 9.8, 9.2,
6.7), 3.37 (dd, 1, J ) 6.7, 3.0), 3.15 (ddd, 1, J ) 9.2, 9.2, 3.7),
2.65-2.75 (m, 1), 1.35 (d, 3, J ) 6.7), 0.96 (d, 3, J ) 6.7), 0.95
(d, 3, J ) 6.7); 13C NMR (acetone-d6) 178.0, 143.1, 125.7, 79.8,
76.7, 75.4, 74.6, 72.5, 47.8, 28.4, 23.5, 23.3, 13.8; IR (neat) 3459,
1780; HRMS (DCI/NH3) calcd for C13H21O5 (MH+) 257.1389,
found 257.1387. The spectral data of 72 fit very well to those
of natural fusidilactone B (9),7 except for the expected differ-
ences due to the side chain.
hexanes/ethyl ether) gave 64 (141 mg, 95%) as a colorless oil:
1
[R]22 -53 (c 1.3, MeOH); H NMR 7.77 (dd, 2, J ) 8.0, 1.2),
D
7.47 (ddd, 1, J ) 7.3, 7.3, 1.2), 7.37 (dd, 2, J ) 8.0, 7.3), 5.82
(dq, 1, J ) 15.3, 6.7), 5.44 (ddq, 1, J ) 15.3, 6.7, 1.2), 5.01 (dq,
1, J ) 2.4, 6.7), 3.91 (d, 1, J ) 2.4), 3.71 (dd, 1, J ) 9.2, 6.7),
3.50 (d, 1, J ) 9.2), 3.38 (dd, 1, J ) 9.2, 9.2), 1.72 (dd, 3, J )
6.7, 1.2), 1.52 (s, 3), 1.43 (s, 3), 1.41 (d, 3, J ) 6.7); 13C NMR
170.5, 138.6 (2 C), 130.9, 130.4, 129.4 (2 C), 126.8, 123.5, 110.8,
80.9, 78.7, 78.5, 76.8, 76.3, 52.3, 26.5, 26.3, 18.0, 13.7; IR (neat)
1767; HRMS (DCI/NH3) calcd for C20H25O5Se (MH+) 425.0867,
found 425.0861.
(2S,3R,4S,7S)-2,3,4,7-Tetr ah ydr o-3,4-dih ydr oxy-7-m eth -
yl-2-(1E)-1-p r op en yl-5H-fu r o[3,4-b]p yr a n -5-on e (Ma ssa -
r ila cton e B, 7). To a stirred solution of 64 (50 mg, 0.12 mmol)
in THF (2 mL) at 0 °C was added 30% H2O2 (300 µL) dropwise.
The resulting mixture was stirred from 0 to 25 °C for 2.5 d,
diluted with ether (100 mL), and washed with saturated
aqueous Na2CO3 solution. The aqueous phase was extracted
with ether (3 × 30 mL) and CH2Cl2 (3 × 30 mL). The combined
organic layers were dried (MgSO4) and concentrated to give a
yellow oil. Flash chromatography on silica gel (1:2 hexanes/
EtOAc) gave 7 (14 mg, 53%) as a colorless oil: [R]22 -96 (c
D
1
0.70, MeOH) {lit.6 [R]28 -109 (c 2.2, MeOH)}; H NMR 5.99
D
(dq, 1, J ) 15.3, 6.7), 5.68 (ddq, 1, J ) 15.3, 7.9, 1.2), 4.86 (dq,
1, J ) 1.2, 6.7), 4.63 (dd, 1, J ) 7.9, 7.9), 4.55 (br d, 1, J )
6.1), 3.81 (dd, 1, J ) 7.9, 6.1), 3.65 (br s, 1, OH), 3.13 (br s, 1,
OH), 1.81 (dd, 3, J ) 6.7, 1.2), 1.48 (d, 3, J ) 6.7); 13C NMR
177.3, 171.4, 134.7, 124.8, 100.7, 84.1, 74.0, 71.9, 65.3, 18.0,
17.2; IR (neat) 3418, 1738, 1664; HRMS (DCI/NH3) calcd for
C
11H15O5 (MH+) 227.0919, found 227.0916.
To a stirred solution of 64 (13 mg, 0.03 mmol) in THF (1
mL) at 0 °C was added 30% H2O2 (78 µL) dropwise. The
resulting mixture was stirred from 0 to 25 °C for 8 h, diluted
with ether (30 mL), and washed with saturated aqueous Na2-
CO3 solution. The aqueous phase was extracted with ether (3
× 15 mL) and CH2Cl2 (3 × 15 mL). The combined organic
layers were dried (MgSO4) and concentrated to give a yellow
oil. Flash chromatography on silica gel (4:1 to 1:2 hexanes/
EtOAc) gave acetonide 66 (3.2 mg, 39%), followed by acetonide
65 (2.5 mg, 31%) and 7 (1.7 mg, 24%).
1
Data for 65: H NMR 6.11 (dq, 1, J ) 15.3, 6.7), 5.64 (ddq,
1, J ) 15.3, 7.9, 1.2), 4.95 (dd, 1, J ) 10.4, 7.9), 4.82 (dq, 1, J
) 1.8, 6.7), 4.44 (dd, 1, J ) 8.0, 1.8), 3.65 (dd, 1, J ) 10.4, 8.0),
1.85 (dd, 3, J ) 6.7, 1.2), 1.54 (s, 3), 1.53 (s, 3), 1.47 (d, 3, J )
6.7); IR (neat) 1760, 1638.
1
Data for 66: H NMR 5.98 (dq, 1, J ) 15.3, 6.7), 5.62 (ddq,
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM-50151) for financial support. We
thank Dr. Kozo Hayashi (Takeda Chemical Industries)
for information about the structures of and copies of the
spectra of TAN-2483A and TAN-2483B, Dr. Kazutoshi
Mizoue (Taisho Pharmaceutical Co.) for copies of the
spectra of waols A and B, Prof. J ames Gloer (University
of Iowa) for spectra and a sample of massarilactone B,
and Prof. Krohn (Universita¨t Padeborn) for helpful
discussions regarding the stereochemistry of fusidilac-
tone B. We thank Dr. Masakazu Nakadai for carrying
out preliminary experiments. We thank Ms. Carol
Palmer for preparing the cover art and Prof. Carol A.
Shearer, University of Illinois, for a photograph of
Massarina tunicata.
1, J ) 15.3, 6.7, 1.8), 4.91 (dd, 1, J ) 6.7, 3.0), 4.78 (dq, 1, J )
6.7, 6.1), 4.41 (dd, 1, J ) 9.2, 3.0), 4.22 (dd, 1, J ) 9.2, 6.7),
1.81 (br d, 3, J ) 6.7), 1.68 (s, 3), 1.60 (s, 3), 1.26 (d, 3, J )
6.1); 13C NMR 164.0, 154.0, 132.4, 126.8, 118.4, 90.5, 79.2, 76.7,
76.2, 75.2, 26.8, 23.7, 18.0, 14.6; IR (neat) 1758, 1721.
Acetonide 65 (2.5 mg, 0.009 mmol) in 80% AcOH (0.5 mL)
was stirred at 25 °C for 2 h. Removal of the solvent under
reduced pressure with heating gave 7 (2.1 mg, 100%) as a pale
yellow oil.
Cis-F u sed Aceton id e 69. To a stirred solution of acetonide
63 (120 mg, 0.45 mmol) in dry CH2Cl2 (6 mL) was added DBN
(138 µL, 1.12 mmol) dropwise at 0 °C under N2. The mixture
was stirred at 0 °C for 10 min, diluted with CH2Cl2 (120 mL),
washed with H2O and brine, dried (MgSO4), and concentrated
to give a yellow oil. Flash chromatography on silica gel (4:1
hexanes/EtOAc) gave 69 (114 mg, 95%) as a white solid: 1H
NMR 5.89 (dq, 1, J ) 15.3, 6.7), 5.53 (ddq, 1, J ) 15.3, 6.7,
1.2), 4.57 (dq, 1, J ) 3.0, 6.7), 4.22 (dd, 1, J ) 3.7, 3.0), 3.92
(dd, 1, J ) 9.2, 6.7), 3.84 (dd, 1, J ) 9.8, 4.5), 3.40 (dd, 1, J )
4.5, 3.7), 3.36 (dd, 1, J ) 9.8, 9.2), 1.76 (dd, 3, J ) 6.7, 1.2),
1.52 (s, 3), 1.48 (s, 3), 1.45 (d, 3, J ) 6.7); 13C NMR 171.6,
130.6, 127.0, 110.9, 78.6, 78.2, 76.3, 75.9, 75.4, 46.6, 26.4, 26.3,
17.9, 13.6; IR (KBr) 1781.
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental procedures, analysis of the concentration dependence
of the spectra of 7, comparison of the spectra of 9 and 72, and
1
copies of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0358628
J . Org. Chem, Vol. 69, No. 17, 2004 5527