Studies on the biomimetic synthesis of SNF4435 C and D

Article abstract of DOI:10.1021/ol020157r

(equation Presented) The biomimetic synthesis of the bicyclic core of the novel immunosuppresants SNF4435C and SNF4435D is reported. The core framework was efficiently generated from the all-trans tetraene precursor in one step and in good yield.

Full text of DOI:10.1021/ol020157r

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3731-3734
Studies on the Biomimetic Synthesis of
SNF4435 C and D
John E. Moses, Jack E. Baldwin,* Rodolfo Marquez, and Robert M. Adlington
Dyson Perrins Laboratory, Oxford UniVersity, South Parks Road,
Oxford OX1 3QY, U.K.
Andrew R. Cowley
Chemical Crystallography, Oxford UniVersity, South Parks Road,
Oxford OX1 3QR, U.K.
jack.baldwin@chem.ox.ac.uk.
Received August 7, 2002
ABSTRACT
The biomimetic synthesis of the bicyclic core of the novel immunosuppresants SNF4435C and SNF4435D is reported. The core framework was
efficiently generated from the all-trans tetraene precursor in one step and in good yield.
SNF4435C 1 and SNF4435D 2 are novel pentacyclic
immunosuppresants isolated in 2001 by Takahashi from the
culture broth of a strain of Steptomyces spectabilis.1,2
Biologically, both compounds selectively suppress B-cell
growth versus T-cell development. This would indicate a
different mode of action from that of the known immuno-
suppresants cyclosporin A (CsA) and FK-506. This mecha-
nistic difference, however, opens up the possibility of
clic structures exhibiting a hexasubstituted bicyclo[4.2.0] core
comprising a cyclohexadiene unit in the major ring. This
bicyclo[4.2.0]octadiene is connected to a spiro furan unit,
which in turn is connected to a γ-pyrone fragment.
The bicyclic core is also linked to a p-nitro-phenyl ring
like the one present in the p-nitro-acyl-(CdC)n-pyrones
aureothin 3, luteothin 4, neoaureothin 5, luteoreticulin 6, and
spectinabilin 7 (Figure 2).5-7
It is believed that this class of compounds is biosynthesized
from p-amino benzoate 8 and a combination of propionate
(1) Kurosawa, K.; Takahashi, K.; Tsuda, E. J. Antibiotic. 2001, 54, 541.
(2) Takahashi, K.; Tsuda, E.; Kurosawa, K. J. Antibiotic. 2001, 54, 548.
(3) Kurosawa, K.; Takahashi, K.; Fujise, N.; Yamashita, Y.; Washida,
N.; Tsuda, E. J. Antibiotic. 2002, 55, 71.
(4) Kurosawa, K.; Takahashi, K.; Tsuda, E.; Tomida, A.; Tsuro, T. Jpn.
J. Cancer Res. 2001, 92, 1235.
(5) (a) Maeda, K. J. Antibiotic. 1953, 6, 137. (b) Washizo, F.; Umezawa,
H.; Sugiyama, N. J. Antibiotic. 1954, 7, 60. (c) Koyama, Y.; Fukakusa, Y.;
Kyomura, N.; Yamagishi, S.; Arai, T. Tetrahedron Lett. 1969, 355.
(6) (a) Cassinelli, G.; Grein, A.; Orezzi, P.; Penella, P.; Sanfilippo, A.
ArchiV. Microbiol. 1967, 55, 358. (b) Cardani, C.; Ghiringhelli, D.; Silva,
A.; Areamone, F.; Camerino, B.; Cassinelli, G. La Chimica L’Industria
1970, 52, 793.
Figure 1. SNF4435C 1 and SNF4435 D 2.
developing new immunosuppresants based on these novel
compounds (Figure 1).3,4
Structurally, SNF4435C 1 and SNF4435D 2 are pentacy-
(7) Kakinuma, K.; Hanson, C. A.; Rinehart, K. L. Tetrahedron 1976,
32, 217.
10.1021/ol020157r CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/27/2002

Scheme 2. Proposed Conversion of Spectinabilin 7 into 1 and
2
Figure 2. p-Nitro-acyl-(CdC)n-pyrones aureothin 3, luteoreticulin
4, luteothin 5, neoaureothin 6, and spectinabilin 7.
and acetate units, as demonstrated in the biosynthesis of
aureothin 3.8
the biosynthesis of the bicyclic[4.2.0] core of the endiandric
acids proposed by Black10 has been experimentally demon-
strated by the work of Nicolaou.11 Likewise, Widmer12 has
employed this type of approach in his studies on vitamin A.
As far as our approach to spectinabilin 7 is concerned,
we decided to use a stabilized ylide Wittig approach as to
ensure the correct geometry at each of the first three double
bonds starting from nitrobenzaldehyde 14.13 The final
trisubstituted olefin would be installed through a normal
Wittig approach starting from the bis-functionalized ylide
13. The ylide itself could be generated from lactol 16, which
would provide us with an easily accessible handle for the
introduction of the pyrone unit (Scheme 3).
In the case of spectinabilin 7, it is expected that a para-
amino benzoate unit 8 will combine with an equimolar
amount of acetate and six propionate units 9, the same ratio
found in the SNF compounds 1 and 2. Hence, a clear link
between these metabolites and tetraene 10 can be proposed
(Scheme 1).
Scheme 1. Proposed Biosynthesis of 1 and 2
Scheme 3. Retrosynthetic Analysis of Spectinabilin
The combination of this biosynthetic information, together
with the inherent instability of spectinabilin 7 over a period
of time, prompted us to consider the possibility that spec-
tinabilin is a direct precursor of SNF4435C 1 and SNF4435D
2 via either an in vitro or in vivo double-bond isomerization.7
In our proposed biosynthesis, we envisaged SNF4435C 1
and SNF4435D 2 as having originated from the (E,Z,Z,Z)-
tetraene 10, an isomer of spectinabilin 7 that is able to
undergo a thermal 8π conrotatory electrocyclization to
generate the cyclooctatetraene 11. This cyclooctatetraene 11
can then undergo a further thermal 6π electron disrotatory
cyclization to generate the desired bicyclic [4.2.0] core
(Scheme 2).
Our synthesis began with p-nitro-benzaldehyde 14, which
was treated under Wittig conditions to generate the desired
conjugated ester 17, which was efficiently reduced to the
allylic alcohol 18 in good yield. Swern oxidation of alcohol
(10) Banfield, J. E.; Black, D. St. C.; Johns, S. R.; Willing, S. R. Aust.
J. Chem. 1982, 35, 2247.
(11) (a) Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J.
Am. Chem. Soc. 1982, 104, 5555. (b) Nicolaou, K. C.; Petasis, N. A.;
Uenishi, J.; Zipkin, R. E. J. Am. Chem. Soc. 1982, 104, 5557. (c) Nicolaou,
K. C.; Zipkin, R. E.; Petasis, N. A. J. Am. Chem. Soc. 1982, 104, 5558. (d)
Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E. J. Am. Chem. Soc. 1982,
104, 5560.
A comparable approach has been recently reported by
Trauner.9 A similar double-electrocyclization hypothesis for
(8) (a) Yamakazi, M.; Maebayashi, Y.; Katoh, H.; Ohishi, J. I.; Koyama,
Y. Chem. Phar. Bull. 1975, 23, 569. (b) Yamazaki, M.; Katoh, F.; Ohishi,
J. I.; Koyama, Y. Tetrahedron Lett. 1972, 2701.
(12) Vogt, P.; Schlageter, M.; Widmer, E. Tetrahedron Lett. 1991, 32,
4115.
(9) Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221.
(13) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
3732
Org. Lett., Vol. 4, No. 21, 2002

18, afforded the desired aldehyde intermediate, which was
promptly olefinated under Wittig conditions to the conjugated
ester 19 in excellent yield for both steps (Scheme 4).
We envisaged that such a highly strained tetraene ester
(as demonstrated by the >130° angle between C4, C5, and
C6 and the 45° dihedral angle of the C8-C9 double bond)
would be prone to isomerization under the right conditions.
Once the desired isomerization had taken place, we would
then expect the tetraene 22 to have the necessary (E,Z,Z,E)-
geometry for the double electrocyclization to take place.
With the required tetraene 22 in hand, the desired
isomerizations were attempted under metal(II)-catalyzed
conditions. Our choice of conditions stemmed from the well-
known ability of palladium(II) salts to interact and isomerize
conjugated double-bond systems through either a carbocation
or a π-allylic complex.15
Scheme 4
Thus, treatment of the tetraene ester 22, with dichlorobis-
(acetonitrile)palladium(II) at room temperature, effected the
desired cyclization, generating the desired bicyclo[4.2.0]
octadiene core 25 of the SNF compounds in reasonable yield
and as a single diastereomer. The observed product stereo-
chemistry is consistent with a double isomerization taking
place to generate the (E,Z,Z,E)-tetraene 23, which undergoes
the expected tandem double electrocyclization to sequentially
generate cyclooctatetraene 24 and bicyclo[4.2.0] octadiene
25 (Scheme 6).
Enoate 19 was then subjected to a further reduction/
oxidation cycle to efficiently generate dienaldehyde 20,
which was then subjected under the same Wittig conditions
as before to afford the expected trienoate as a single isomer
21. Finally, treatment of trienoate 21 to reduction and
oxidation afforded the crucial trienaldehyde 12 in good
overall yield.
At this point, however, it was decided to generate a
simpler, readily accessible model of spectinabilin 7 on which
the validity of our biomimetic isomerization hypothesis could
be readily assessed. Thus, treatment of trienaldehyde 12 with
ethyl triphenyl phosphonoacetate generated the desired
tetraene ester 22 in good yield and as a single double-bond
isomer (Scheme 5).
Scheme 6
Scheme 5
Trauner and co-workers have very recently reported the
synthesis of the methyl analogue of ester 25 via the assumed
in situ preparation of the methyl analogue of the E,Z,Z,E-
tetraene 23 via Stille methodology.9 It was therefore decided
to synthesize the tetraene methyl ester analogue 26 for further
structural corroboration. Thus, treatment of trienaldehyde 12
with methyl triphenylphosphonoacetate proceeded cleanly
and in good yield to afford the desired methyl ester 26.
Methyl ester 26 was then subjected to the same Pd(II)-
catalyzed isomerization conditions as before, to afford
bicyclic compound 27 in good yield and as a single
diastereomer. The one- and two-dimensional 1H NMR data
The (E,E,E,E)-double-bond stereochemistry was cor-
roborated by X-ray analysis, which interestingly revealed a
significant lack of planarity in the tetraene ester 22 due to
the strong steric interactions between the alkene methyl
substituents (Figure 3).14
(14) Atomic coordinates for 22 are available upon request from the
Cambridge Crystallographic Data Centre, University Chemical Laboratory,
Lensfield Road, Cambridge CB2 1EW (Deposition number CCDC 190072).
The crystallographic numbering system differs from that used in the text;
therefore, any request should be accompanied by the full literature citation
of this paper.
(15) (a) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67,
4627. (b) Sen, A.; Lai, T.-W. Inorg. Chem. 1981, 20, 4036. (c) Sen, A.;
Lai-T.-W. Inorg. Chem. 1984, 23, 3257.
Figure 3. X-ray structure of tetraene 22.
Org. Lett., Vol. 4, No. 21, 2002
3733

electrocyclization to generate 25 and 27 immediately occurs.
The double-electrocyclization steps may possibly benefit
from the Pd(II) catalysis.
Scheme 7
In conclusion, we have demonstrated a connection between
spectinabilin 7 and the SNF family of compounds by
efficiently generating the SNF core structures 25 and 27 from
the all-trans tetraene esters 22 and 26 in a single step and in
good yield. It is intriguing to consider that (E,E,E,E)-
spectinabilin 7 in the presence of an available metal cation
could be a possible biological precursor of the SNF family
of compounds. An alternative possibility is that both spec-
tinabilin 7 and the SNF compounds 1 and 2 share a common
biological pathway that differs at a stage when the double-
bond geometries of the tetraene are established.
obtained for the methyl ester 27 were identical to the
literature data.9
Finally, preliminary results in the treatment of either
tetraene esters 22 or 26 under a variety of both thermal and
photochemical conditions failed to generate any of the desired
target products 25 or 27. These results, taken together with
those from the related bicyclo[4.2.0] octadiene systems
reported by Nicolaou11 and Widmer12 in which the electro-
cyclizations spontaneously take place at or below room
temperature, indicate that once the (E,E,E,E)-tetraenes 22
or 26 have been isomerized to the corresponding (E,Z,Z,E)-
isomers by Pd(II) catalysis at room temperature, the double
Acknowledgment. We thank the EPSRC for funding to
J.E.M. We thank Dr. B. ODell for NMR assistance.
Supporting Information Available: Experimental pro-
cedures for compounds 22 and 25-27 and NMR data for
compounds 25 and 27. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL020157R
3734
Org. Lett., Vol. 4, No. 21, 2002