Synthesis of (-)-TAN-2483A. Revision of the structures and syntheses of (±)-FD-211 (waol A)and (±)-FD-212 (waol B)

Article abstract of DOI:10.1021/ol0273405

(Matrix presented) The structure of waol A has been revised from 1 to 6, the vinylogue of TAN-2483 A (5). Aldol reaction of 10b(c) with 2,4-hexadienal (11) affords 9b(c), which is subjected to iodoetherification with bis(sym-collidine)IPF₆ to p

Full text of DOI:10.1021/ol0273405

ORGANIC
LETTERS
2
003
Vol. 5, No. 4
51-454
Synthesis of (−)-TAN-2483A. Revision of
the Structures and Syntheses of
4
(
±)-FD-211 (Waol A) and (±)-FD-212
(Waol B)
Xiaolei Gao, Masakazu Nakadai, and Barry B. Snider*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received November 22, 2002
ABSTRACT
The structure of waol A has been revised from 1 to 6, the vinylogue of TAN-2483 A (5). Aldol reaction of 10b(c) with 2,4-hexadienal (11) affords
b(c), which is subjected to iodoetherification with bis(sym-collidine)IPF to provide 8b(c). Treatment with Et Nin CH Cl completes three-step
9
6
3
2
2
syntheses of TAN-2483A (5) and waol A (6).
Mizoue and co-workers reported the isolation of waol A (FD-
However, the carbonyl group of waol A absorbs at 1767
-
1 1
2
11, 1), which has a broad spectrum of activity against
cultured tumor cell lines, including adriamycin-resistant HL-
0 cells, from the fermentation broth of Myceliophthora lutea
cm , which is characteristic of a γ-lactone, rather than the
δ-lactone of 1. The alkene ring hydrogen of waol A absorbs
1
6
at δ 6.90, while that of 1 would be expected to absorb
1
TF-0409 (Figure 1). More recently, they reported the
between δ 5 and 6. An absorbance at δ 6.90 is characteristic
of CHdC-CdO. Taken together, these discrepancies sug-
gest that waol A might be a substituted 2,3,7,7a-tetrahydro-
5
H-furo[3,4-b]pyran-5-one (3).
A literature search uncovered two compounds with this
ring system, TAN-2483B (4) and TAN-2483A (5) (Figure
), which show strong c-src kinase inhibitory action and
2
4
inhibit PTH-induced bone resorption of a mouse femur. 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
Figure 1. Proposed structures of waol A and waol B.
(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,
1
13.
2) Nazawa, O.; Okazaki, T.; Morimoto, S.; Chen, Z.-X.; He, B.-M.;
Mizoue, K. J. Antibiot. 2000, 53, 1296.
(
isolation of waol B (FD-212, 2), which has similar biological
activity, from the same source. Tadano has reported an
approach to the synthesis of 1.3
(
3) Suzuki, E.; Takao, K.-i.; Tadano, K.-i. Heterocycles 2000, 52, 519.
2
(4) Hayashi, K.; Takizawa, M.; Noguchi, K. Jpn. Patent 10287679, 1998;
Chem. Abstr. 1999, 130, 3122e.
1
0.1021/ol0273405 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/30/2003

Scheme 2
Figure 2. Structures of TAN-2483A and TAN-2483B and revised
structure of waol A.
5
experiments. The carbonyl groups of 4 and 5 absorb at 1760
a readily separable mixture of 9a and 12a, both as a 4:1
mixture of (2E,4E)- and (2E,4Z)-isomers. Flash chromatog-
-
1
cm , and the alkene ring hydrogens absorb at δ 7.12 and
.90, respectively. H and H of TAN-2483B (4) absorb at
δ 4.35 and 4.45, and H and H 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
with structure 6.
6
2
3
3
raphy on 20% AgNO on silica gel gives pure 9a (26%) and
2
3
1
2a (29%). The stereochemistry of the side chain alcohol
could not be determined by spectral analysis and was
established from the spectra of iodohydrins 14 and 16 (see
below).
Iodoetherification of the desired isomer 9a under a wide
variety of conditions provides <5% iodo alcohol 14, while
Retrosynthetic analysis (Scheme 1) suggested that TAN-
483A (5) and waol A (6) should be available from epoxy
2
iodoetherification of the undesired isomer 12a with I
2
and
solid NaHCO in CH CN affords 70% of iodo alcohol 16
3
3
7
Scheme 1. Retrosynthetic Analysis
(Scheme 3). In 14, J2.3 ) 10.4 Hz, J3.4 ) 9.8 Hz, J4.4a
)
Scheme 3
lactone 7, which should be easily formed from iodohydrin
. Iodohydrin 8 should be accessible stereospecifically by
8
iodoetherification of diene diol 9, which can be prepared by
an aldol reaction of the dianion of hydroxyfuranone 10 with
2,4-hexadienal (11). Aldol reactions of 10 occur stereospe-
cifically from the face opposite the hydroxy group, but give
6
mixtures of isomers at the hydroxy group on the side chain.
A model study was carried out with commercially avail-
able (S)-dihydro-4-hydroxyfuranone (10a) and 2,4-hexadienal
(
(
2
11), which is a 4:1 mixture of (2E,4E)- and (2E,4Z)-isomers
Scheme 2). Note that structures 10a, 9a, 12a, 14, and 16-
1 are drawn for clarity with the same absolute stereochem-
1
0.4 Hz, and J4a.7a ) 11.6 Hz, indicating that all of the
hydrogens on the tetrahydropyran ring are axial and all of
the substituents are equatorial. In 16, J2.3 ) 10.4 Hz, J3.4
Hz, J4.4a < 1 Hz, and J4a.7a ) 11.6 Hz, indicating that the
<
istry as TAN-2483A, although they are the enantiomers.
Treatment of 10a with 2 equiv of LDA in THF and addition
of dienal 11 at -42 °C as described by Prestwich affords
1
6
a
H is equatorial and the hydroxy group is axial. Isomerization
4
(
5) Hayashi, K. Takeda Chemical Industries. Unpublished results.
(7) (a) Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills, M. C. J.
Am. Chem. Soc. 1983, 105, 5819. (b) Tamaru, Y.; Hojo, M.; Kawamura,
S.-i.; Sawada, S.; Yoshida, Z.-i. J. Org. Chem. 1987, 52, 4062.
(6) (a) Shieh, H.-M.; Prestwich, G. D. J. Org. Chem. 1981, 46, 4319.
(
b) Chen, S. Y.; Joullie, M. J. Org. Chem. 1984, 49, 2168.
452
Org. Lett., Vol. 5, No. 4, 2003

of 16 to the cis-fused isomer 17 occurs easily on heating in
the presence of NaHCO or on silica gel.
with spectral data similar to those of TAN-2483A (5) and
waol A (6). The iodide and hydroxy groups of 14 are in a
diequatorial arrangement. Formation of the epoxide requires
either that the pyran ring of 14 adopts a boat conformation
with these groups anti-periplanar or that the flexible cis-fused
isomer 18 adopts the chair conformation with the iodide and
hydroxy groups anti-periplanar.
3
We were initially puzzled as to why 12a undergoes facile
iodoetherification to give 16, while 9a fails to give the more
stable isomer 14 with an equatorial hydroxy group. Closer
examination of the literature revealed that Chamberlin and
7
Yoshida had made related observations and that Chamberlin
8
and Hehre had explained the origins of these effects.
(-)-Dihydro-4-hydroxy-5-methyl-2-furanone (10b) was
10
Cyclizations in which the nucleophile is in the R group
proceed slowly through the disfavored π complex 13 with
the hydrogen eclipsed with the double bond and rapidly
through the favored π complex 15 with the hydroxy group
eclipsed with the double bond. The π complex formed from
prepared by Hatakeyama’s procedure in >90% ee. Dihy-
11
4
droxylation of methyl 3Z-pentenoate with OsO and NMO
and treatment of the resulting diol with acid gave (()-10b.
Treatment with Novozyme lipase, vinyl acetate, and 1,4,8,-
11-tetrathiacyclotetradecane in diisopropyl ether gave (-)-
10b and the enantiomeric acetate.
9a has the hydrogen eclipsed with the double bond and
therefore cyclizes slowly to give 14. The π complex formed
from 12a has the hydroxy group eclipsed with the double
bond and therefore cyclizes rapidly to give 16.
We were pleased to find that the selectivity for 9 in the
aldol reaction improves with an alkyl substituent on the
furanone. Treatment of the dianion of 10b with 11 affords
38% of the desired adduct 9b and only 14% of 12b after
A more reactive iodinating agent is needed to convert 9a
to 14 in high yield. Bis(sym-collidine)IPF
6
is a very reactive
AgNO chromatography (Scheme 2). Iodoetherification of
3
but moisture-sensitive iodinating reagent that can easily be
9b provides 88% of iodo alcohol 8b, which gives 79% of
9
prepared in situ from bis(sym-collidine)AgPF
We were delighted to find that reaction of bis(sym-collidine)-
AgPF (1.6 equiv) and iodine (1.2 equiv) in CH Cl , addition
6
and iodine.
TAN-2483A (5) on treatment with Et N in CH Cl at 25 °C
3
2
2
1
13
for 3 d (Scheme 5). The H and C NMR spectra of 5 are
6
2
2
of 9a, and stirring for 1.5 h affords 80% of 14, which can
be purified by flash chromatography on water-deactivated
silica gel (Scheme 4). Partial isomerization to the more stable
Scheme 5
Scheme 4
identical to those of the natural product. The optical rotation,
[
R]
D
-236, has the same sign but is somewhat smaller than
-292, confirming the assignment of the
that reported, [R]
D
absolute stereochemistry.
Propenyl lactone 9c was made by modification of Griengl’s
12
procedure (Scheme 6). Reaction of 2E-butenal with NaCN
1
3
14
and HCl and silylation gives 34% (unoptimized) of 22.
15
Reaction of 22 with Zn, TMSCl, and BrCH
6% of keto ester 23, which is reduced with NaBH
2
CO
2
Me affords
in
8
4
(
10) Nishiyama, T.; Nishioka, T.; Esumi, T.; Iwabuchi, Y.; Hatakeyama,
cis-fused isomer 18 occurs otherwise. Treatment of either
S. Heterocycles 2001, 54, 69.
1
4 or 18 with Et
3
N in CH
2
Cl
2
for 3 d at 25 °C affords
(11) Krebs, E.-P. HelV. Chim. Acta 1981, 64, 1023.
(
12) Johnson, D. V.; Fischer, R.; Griengl, H. Tetrahedron 2000, 56, 9289.
13) Anderson, J. R.; Edwards, R. L.; Whalley, A. J. S. J. Chem. Soc.,
epoxides 19 or 20, which react further to give 87% of 21,
(
Perkin Trans. 1 1982, 215.
(
8) Chamberlin, A. R.; Mulholland, R. L., Jr.; Kahn, S. D.; Hehre, W. J.
J. Am. Chem. Soc. 1987, 109, 672.
9) (a) Homsi, F.; Robin, S.; Rousseau, G. Org. Synth. 1999, 77, 206.
b) Brunel, Y.; Rousseau, G. J. Org. Chem. 1996, 61, 5793. (c) Evans, R.
(14) (a) Brussee, J.; Loos, W. T.; Kruse, C. G.; Van Der Gen, A.
Tetrahedron 1990, 46, 979. (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.
(
(
D.; Magee, J. W.; Schauble, J. H. Synthesis 1988, 862.
(15) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
Org. Lett., Vol. 5, No. 4, 2003
453

1
7
pentenoate. Addition of 2,4-hexadienal (11) to the dianion
of 28 provides 29% of 29 and 30% of 30. Iodoetherification
of 29 affords 92% of 31 (Scheme 8). Treatment of 31 with
Scheme 6
Scheme 8
MeOH at -15 °C to give 97% of 24 as a 5:1 mixture of
isomers. Deprotection with TBAF in CH CN and acid-
3
catalyzed lactonization provides 63% of (()-10c and 13%
of (()-25.16
Treatment of the dianion of 10c with 2,4-hexadienal (11)
affords 44% of the desired adduct 9c and 21% of 12c after
AgNO
c provides 95% of iodo alcohol 8c, which gives 98% of 6
on treatment with Et N in CH Cl at reflux overnight. The
H and C NMR spectra of 6 are identical to those of FD-
11 (waol A), indicating that the revised structure we
3
chromatography (Scheme 2). Iodoetherification of
9
3
2
2
1
13
Et
and 61% of recovered 31. As expected, the spectral data of
2 are different from those of TAN-2483B (4), which is
isomeric to TAN-2483A (5) at C7a while 32 is isomeric at
7
C . The formation of 32 from 31 is much slower than with
the other iodohydrins, suggesting that the â-methyl group
of 31 makes conformations with the iodide and hydroxy
groups anti-periplanar more strained. Treatment of 31 with
3 2 2
N in CH Cl at reflux for 3 d provides only 32% of 32
2
proposed is correct.
3
Hydrolysis of 6 with KOH in MeOH/H
2
O, followed by
, affords
8% of 26 with H and C NMR spectral data identical to
2 2
acidification and immediate reaction with CH N
1
13
3
those for FD-212 (waol B) and 47% of MeOH adduct 27
resulting from conjugate addition of methoxide and proto-
nation to give the cis-fused ring system (Scheme 7).
5
equiv of the stronger base DBN in CH
2 2
Cl for 1 h at 0 °C
gives 89% of 32.
In conclusion, we have reassigned the structures of waols
A and B as 6 and 26 and completed the first syntheses of
these molecules and (-)-TAN-2483A (5) in three steps from
lactones 9 by aldol reaction, iodoetherification, and elimina-
tion.
Scheme 7
Acknowledgment. We thank the National Institutes 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 and Dr. Kazutoshi Mizoue, Taisho Phar-
maceutical Co. for copies of the spectra of waols A and B.
We prepared lactone 28 as a potential precursor to TAN-
483B by addition of OsO and NMO to methyl 3E-
4
Supporting Information Available: Experimental pro-
cedures and spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
2
(16) Attempted enzymatic resolution of 10c, as successfully carried out
for 10b, gives the opposite enantiomer, (+)-10c, in 18% ee. Reduction of
OL0273405
1
4
2
3 with NaBH4 and D-tartaric acid and further elaboration yields 30% of
(+)-10c (38% ee) and 45% of 25.
(17) Harcken, C.; Br u¨ ckner, R.; Rank, E. Chem. Eur. J. 1998, 4, 2342.
454
Org. Lett., Vol. 5, No. 4, 2003