Synthetic studies toward SNF4435 C and SNF4435 D.

Article abstract of DOI:10.1021/ol026069o

[reaction: see text] A synthetic approach toward the immunosuppressants SNF3345 C and SNF4435 D featuring a tandem Stille coupling/electrocyclization cascade is described.

Full text of DOI:10.1021/ol026069o

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2221-2224
Synthetic Studies toward SNF4435 C
and SNF4435 D
Christopher M. Beaudry and Dirk Trauner*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California, Berkeley, California 94720
trauner@cchem.berkeley.edu
Received April 23, 2002
ABSTRACT
A synthetic approach toward the immunosuppressants SNF3345 C and SNF4435 D featuring a tandem Stille coupling/electrocyclization cascade
is described.
SNF4435 C and SNF4435 D are two natural products
recently isolated from a culture broth of Streptomyces
spectabilis.1 Both compounds have been shown to selectively
block induced B-cell proliferation versus induced T-cell
proliferation and show potent immunosuppressive activity
in vitro.2 Hence, they are expected to exhibit a pharmaco-
logical profile different from established immunosuppressant
drugs such as cyclosporin A or FK-506 and represent
important new lead compounds for drug development. In a
separate study, the compounds were shown to reverse
multidrug resistance in tumor cells, rendering them poten-
tially useful in anticancer therapy.3
Their novel skeleton contains a bicyclo[4.2.0]octadiene
nucleus linked to a spiro-fused tetrahydrofuran ring. This
tricyclic core is substituted with an unusual nitrophenyl ring
and a γ-pyrone moiety and contains five stereocenters, two
of which are quaternary.
Biosynthetic considerations further add to the attractiveness
of the SNF4435 compounds as synthetic targets. We propose
that the molecules can be traced back to a common precursor
1 (Scheme 1). Interestingly, compound 1 is a stereoisomer
of spectinabilin, another natural product previously isolated
from S. spectabilis.4
According to our biosynthetic hypothesis, conrotatory 8π-
electrocyclization of 1 affords the cyclooctatrienes 2a and
2b with some induction provided by the stereocenter on the
tetrahydrofuran ring (C6). A subsequent stereoselective
disrotatory 6π-electrocyclization affords SNF4435 C and D.
Presumably, 1 is formed by a polypropionate synthase from
six units of propionyl coenzyme A, one acetyl coenzyme A,
In addition to their interesting biological activity, the
natural products display a fascinating molecular architecture.
(1) (a) Kurosawa, K.; Takahashi, K.; Tsuda, E. J. Antibiot. 2001, 54,
541. (b) Takahashi, K.; Tsuda, E.; Kurosawa, K. J. Antibiot. 2001, 54, 548.
(2) Kurosawa, K.; Takahashi, K.; Fujise, N.; Yamashita, Y.; Washida,
N.; Tsuda, E. J. Antibiot. 2002, 55, 71.
(3) Kurosawa, K.; Takahashi, K.; Tsuda, E.; Tomida, A.; Tsuruo, T. Jpn.
J. Cancer Res. 2001, 92, 1235.
(4) Kakinuma, K.; Hanson, C. A.; Rinehart, K. L., Jr. Tetrahedron 1976,
32, 217. To the best of our knowledge, this interesting antibiotic has not
yet been synthesized.
10.1021/ol026069o CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/30/2002

attempting a synthesis of 1 directly, however, we decided
to probe the proposed electrocyclization cascade with simpli-
fied compounds. Those would incorporate all of the essential
features of the polyene portion and the nitrophenyl substituent
of 1 but lack the γ-pyrone moiety and possibly the tetra-
hydrofuran ring. We now report the results of our studies,
which were guided by the biosynthetic hypothesis presented
above and led to an advanced synthetic precursor of the
SNF4435 compounds.
Scheme 1. Proposed Biosynthesis of the SNF Compounds
Our initial attempts centered on the use of the Still-
Gennari reaction as a method for the installment of (Z)-
configured double bonds (Scheme 2).8
Scheme 2a
and p-aminobenzoic acid as the source of the nitrophenyl
ring.4,5
The electrocyclization cascade bears resemblance to the
one found in the biosynthesis of the endiandric acids initially
proposed by Black6 and synthetically verified by Nicolaou
et al.7 It would be interesting to determine whether the
cyclizations proceed spontaneously at room temperature or
require enzyme catalysis. The two SNF4435 compounds
were isolated in a 2.3:1 ratio, which is roughly the degree
of 1,3-diastereoselection that can be expected in a non-
enzymatic electrocyclization event. Note that according to
our biosynthetic scheme, the minor component SNF4435 D
is not the C6 epimer of SNF4435 C, as originally proposed,
but is instead diastereomeric with respect to all other
stereocenters. The absolute configuration of the natural
products and their relative stereochemistry with respect to
each other remains to be determined.
a Reagents and conditions: (a) 4, KHMDS, 18-C-6, THF, -78
°C (78%). (b) DIBAH, CH2Cl2, - 78 °C (89%). (c) Dess-Martin
periodinane, CH2Cl2, rt. (d) 4, KHMDS, 18-C-6, THF, - 78 °C
(96% from 6). (e) DIBAH, CH2Cl2, -78 °C (> 80% by NMR).
Condensation of the known aldehyde 39 with trifluoroethyl
phosphonate 4 afforded dienoate 5 with excellent diastereo-
selection (Z:E > 20:1).10 Exhaustive reduction of the ester
function gave allylic alcohol 6. Dess-Martin oxidation11 of
6 then set the stage for a second application of reagent 4,
With its four trisubstituted double bonds, three of which
are (Z)-configured, the hypothetical biosynthetic intermediate
1 is in itself a formidable synthetic challenge. Instead of
(8) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(9) Obtained in one step from p-nitrobenzaldehyde and propionalde-
hyde: Hirata, Y.; Nakata, H.; Yamada, K.; Okuhara, K.; Naito, T.
Tetrahedron 1961, 14, 252.
(10) The stereochemistry of the major isomers 5, 7, 16, and 20 was
elucidated by NOESY experiments and in some cases indirectly confirmed
by X-ray structure analysis of compounds 10 and 13 (see Supporting
Information). Similarly, the syn stereochemistry of aldol 12 was validated
by the structure of 13.
(5) (a) Kawai, S.; Kobayashi, K.; Oshima, T.; Egami, F. Arch. Biochem.
Biophys. 1965, 112, 537. (b) Yamazaki, M.; Katoh, F.; Ohishi, J. I.; Koyama,
Y. Tetrahedron Lett. 1972, 26, 2701.
(6) Banfield, J. E.; Black, D. St. C.; Johns, S. R.: Willing, R. I. Aust. J.
Chem. 1982, 35, 2247 and references therein.
(7) (a) Nicolaou, K. C.; Sorensen, E. J. In Classics in Total Synthesis;
VCH: Weinheim, 1996; p 265 and references therein. For a similar
electrocyclization cascade, see: (b) Vogt, P.; Schlageter, M.; Widmer, E.
Tetrahedron Lett. 1991, 32, 4115.
(11) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Boeckman, R. K. Jr.; Pengcheng, S.; Mullins, J. J. Org. Synth. 1999,
77, 141.
2222
Org. Lett., Vol. 4, No. 13, 2002

affording triene ester 7. Again, very high diastereoselectivity
(Z:E > 20:1) was observed.10 However, despite many
attempts, we were unable to convert 7 into the aldehyde 9
as a precursor for the final olefination. This was mostly due
to the instability of the intermediary allylic alcohol 8 toward
aqueous workup. Furthermore, 7 readily underwent disro-
tatory electrocyclization at room temperature to afford
cyclohexadiene carboxylate 10. Unfortunately, this reaction
proved to be essentially irreversible, rendering 10 useless
as an intermediate in our synthesis.
In an attempt to avoid the unwanted 6π-electrocyclization
and to circumvent sensitive triene intermediates, we decided
to install the third double bond at a later stage of the synthesis
via stereospecific syn elimination of a secondary hydroxy
group (Scheme 3). This strategy was again inspired by
secondary alcohol as the TBS ether gave 14. Reduction of
14 afforded a sensitive aldehyde that was subjected to a
Horner-Wadsworth-Emmons olefination with the known
phosphono γ-butyrolactone 15.15 This afforded (Z)-config-
ured alkylidene lactone 16 as the major diastereomer.10 The
deprotection of 16 proved surprisingly difficult, presumably
as a result of steric hindrance of the silyl ether. Nevertheless,
it could be achieved by treating 16 with HF-pyridine in
methanol to afford secondary alcohol 17.16
Unfortunately, all attempts to effect dehydration of 17 via
syn elimination leading to tetraene 18 and ultimately 19 were
unsuccessful. Exposure of 17 to Burgess’ reagent,17 DCC/
CuCl,18 or other dehydrating conditions, as well as attempts
to prepare the corresponding xanthates, only led to complex,
intractable product mixtures.
At this point we decided to resort to transition metal
catalyzed cross-couplings along the central σ bond of the
desired tetraene system (Scheme 4).19 This highly convergent
strategy was initially set aside because of anticipated
difficulties in procuring the corresponding (Z)-substituted
vinyl halide and vinylmetalloid building blocks.
Scheme 3a
Eventually, however, it was found that aldehyde 3
underwent a clean Stork-Zhao olefination20 to afford trisub-
stituted vinyl iodide 20 as the sole isolable diastereomer.10
Furthermore, the known (Z)-substituted vinyl iodide 22 could
be obtained in one step from propargyl alcohol (21) through
a stereoselective carbocupration/iodination sequence.21 Oxi-
dation of the allylic alcohol function with concomitant
olefination of the unstable intermediary aldehyde following
Barrett’s protocol22 afforded iodo dienoate 23.23 Conversion
of this material into the sensitive vinyl stannane 24 set the
stage for the key cross coupling of the two fragments.24
In the event, reaction of 20 and 24 in the presence of
catalytic amounts of Pd(MeCN)2Cl225 afforded bicyclo[4.2.0]-
octadiene 27 in 40% overall yield (not optimized). This
tandem transformation presumably proceeds through the
intermediacy of tetraene ester 25, which undergoes a rapid
(13) Heathcock, C. H. In Modern Synthetic Methods; Scheffold, R., Ed.;
VCH: Weinheim, 1992; pp 1-102 and references therein.
(14) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114,
9434.
(15) (a) Lee, K.; Jackson, J. A.; Wiemer, D. F. J. Org. Chem. 1993, 58,
5967. (b) Snider, B. B.; Lu, Q. Synth. Commun. 1997, 27, 1583.
(16) Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y. J.
Am. Chem. Soc. 1988, 110, 4685.
a Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2,
rt. (b) 11, Bu2BOTf, Et3N, THF, -78 f 0 °C (90% from 6). (c)
MeHNOMe‚HCl, AlMe3, PhMe, rt (78%). (d) TBSCl, Im, DMF,
DMAP, rt (99%). (e) DIBAH, CH2Cl2, -78 °C. (f) 15, KHMDS,
18-C-6, THF, -78 f 0 °C (63% from 14). (g) HF-Py, Py, MeOH,
rt (76%).
(17) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973,
38, 26.
(18) (a) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem.
Soc. 1995, 117, 5776. (b) Alexandre, D.; Rouessac, F. Bull. Soc. Chim. Fr.
1971, 1837.
(19) For a review, see: Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(20) (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. (b) Chen,
J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827.
(21) (a) Duboudin, J. G.; Jousseaume, B.; Bonakdar, A. J. Organomet.
Chem. 1979, 168, 227. (b) Han, Q.; Wiemer, D. F. J. Am. Chem. Soc. 1992,
114, 7692.
(22) Barrett, A. G. M.; Hamprecht, D.; Ohkubo, M. J. Org. Chem. 1997,
62, 9376.
(23) Unfortunately, all attempts to effect an analogous condensation with
phosphonolactone 15 were unsuccessful because of the instability of (Z)-
3-iodomethacrolein under the reaction conditions.
biogenetic considerations. The biosynthesis of the hypotheti-
cal precursor 1 presumably involves several reduction and
dehydration steps mediated by a polypropionate synthase
complex.
Dess-Martin oxidation of allylic alcohol 6, followed by
reaction of the crude product with the boron enolate of
oxazolidinone 1112 afforded aldol 12 with the expected high
syn diastereoselectivity.10,13 Conversion of 12 into the Wein-
reb amide 13,14 followed by protection of the hindered
(24) (a) Vanderwal, C. D.; Vosburg, D. A.; Sorensen, E. J. Org. Lett.
2001, 3, 4307. (b) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108,
3033.
(12) Gage, J. R.; Evans, D. A. Organic Syntheses; Wiley: New York,
1993; Collect. Vol. VIII, p 339.
Org. Lett., Vol. 4, No. 13, 2002
2223

group and the adjacent methyl group in the step leading to
cyclobutane formation (26 f 27). The relative stereochem-
istry of 27 was confirmed by NOESY experiments (Figure
1 and Supporting Information).26
Scheme 4a
Figure 1. Selected NOE signals of compound 27.
In summary, we have outlined a synthetic strategy toward
SNF4435 C and SNF4435 D that is guided by their proposed
biosynthesis (Scheme 1). A novel Stille coupling/electro-
cyclization tandem reaction has been developed. Our most
advanced compound (27) contains a substantial part of the
natural products, featuring three out of five stereocenters and
their core bicyclo[4.2.0]octadiene skeleton. Its carbomethoxy
substituent provides a functional handle for the installation
of the spiro-fused tetrahydrofuran ring. Studies toward the
asymmetric synthesis of 27 and related intermediates as well
as the total synthesis of the SNF4435 compounds are
underway in our laboratories and will be reported in due
course.
a Reagents and conditions: (a) Ph3PCH2CH3+I-, n-BuLi, rt f
I2, -78 °C f NaHMDS, 3, THF, -20 °C (56%). (b) MeMgBr,
cat. CuI, Et2O, -40 °C f I2, rt (64%). (c) Dess-Martin periodi-
nane, Ph3PdCHCOOMe, PhCOOH, CH2Cl2, DMSO, rt (70%). (d)
Me3SnSnMe3, Pd(PPh3)4, PhH, 70 °C (>95% by NMR). (e)
Pd(MeCN)2Cl2, DMF, rt (40% from 20).
Acknowledgment. We thank Dr. Frederick J. Hollander,
Dr. Allen G. Oliver, and Aubry K. Miller for the crystal
structure determination of compounds 10 and 13. Financial
support by Merck & Co. is gratefully acknowledged.
electrocyclization cascade similar to the one proposed in
Scheme 1 (25 f 26 f 27). It is interesting to speculate
whether the transition metal catalyzes the electrocyclizations,
potentially providing an opportunity for asymmetric synthe-
sis.
The high stereoselectivity of the overall reaction can be
explained by the concerted nature of the electrocyclizations
and the avoidance of torsional strain between the nitrophenyl
Supporting Information Available: Spectroscopic and
analytical data for compounds 20, 23, 24, and 27 and X-ray
structures of compounds 10 and 13. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL026069O
(25) (a) Paquette, L. A.; Barriault, L.; Pissarnitski, D.; Johnston, J. N. J.
Am. Chem. Soc. 2000, 122, 619. (b) Nicolaou, K. C.; Li, Y.; Weyershausen,
B.; Wei, H.-X. Chem. Commun. 2000, 307. For an extensive review of the
Stille reaction, see: (c) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org.
React. 1994, 50, 1.
(26) The spectral data of 27 resemble the corresponding signals of the
SNF compounds. For instance, the vinylic proton at C14 is markedly shifted
upfield (δ 5.00 in SNF4435 C, 4.93 in SNF4435 D, and 4.41 in 27).
2224
Org. Lett., Vol. 4, No. 13, 2002