Double Lawton SN2′ addition to epoxyvinyl sulfones: Selective construction of the stereotetrads of aplyronine A

Article abstract of DOI:10.1021/ol060530l

Enantiopure epoxyvinyl sulfones function as templates for the diastereoselective construction of the three stereotetrads of aplyronine A. Lawton S_N2′ addition of 3,5-dimethylpyrazole followed by its displacement in an alcohol-directed Lawton S<

Full text of DOI:10.1021/ol060530l

ORGANIC
LETTERS
2006
Vol. 8, No. 14
2905-2908
Double Lawton SN2′Addition to
Epoxyvinyl Sulfones: Selective
Construction of the Stereotetrads of
Aplyronine A†
Ahmad El-Awa and Philip Fuchs*
Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
pfuchs@purdue.edu
Received March 3, 2006
ABSTRACT
Enantiopure epoxyvinyl sulfones function as templates for the diastereoselective construction of the three stereotetrads of aplyronine A.
Lawton SN2 addition of 3,5-dimethylpyrazole followed by its displacement in an alcohol-directed Lawton SN2 reaction establishes the required
′
′
product stereochemistry with high selectivity.
Aplyronine A (1), a polypropionate marine natural product,
was isolated and partially characterized in 1993.1 Its absolute
stereochemistry was fully proven one year later.2 Remarkable
antineoplastic activity against several tumor cell lines,1
scarcity of supply from natural sources, and structural
complexity kindled synthetic efforts of several research
groups.3 Among the structural features of aplyronine A, three
stereotetrads, carbons 7-10, 23-26, and 29-32, and a 24-
membered macrolactone have been central issues of the
previous studies (Figure 1).
In conjunction with our program exploiting sulfone
chemistry for creating stereodefined polypropionate frag-
† Synthesis via vinyl sulfones 92; chiral carbon catalog 14.
(1) Yamada, K.; Ojika, M.; Ishigaki, T.; Yoshida, Y.; Ekimoto, H.;
Arakawa, M. J. Am. Chem. Soc. 1993, 115, 11020-11021.
Figure 1. Aplyronine A and its stereotetrad precursors.
(2) Ojika, M.; Kigoshi, H.; Ishigaki, T.; Tsukada, I.; Tsuboi, T.; Ogawa,
T.; Yamada, K. J. Am. Chem. Soc. 1994, 116, 7441-7442.
ments,4 we needed a new method for preparation of segments
2-4 of aplyronine A (1) (Figure 1).
(3) (a) Kigoshi, H.; Ojika, M.; Ishigaki, T.; Suenaga, K.; Mutou, T.;
Sakakura, A.; Ogawa, T.; Yamada, K. J. Am. Chem. Soc. 1994, 116, 7443-
7444. (b) Paterson, I.; Cowden, C. J.; Woodrow, M. D. Tetrahedron Lett.
1998, 39, 6037-6040. (c) Paterson, I.; Woodrow, M. D.; Cowden, C. J.
Tetrahedron Lett. 1998, 39, 6041-6044. (d) Paterson, I.; Blakey, S. B.;
Cowden, C. J. Tetrahedron Lett. 2002, 43, 6005-6008. (e) Calter, M. A.;
Guo, X. Tetrahedron 2002, 58, 7093-7100. (f) Calter, M. A.; Zhou, J. G.
Tetrahedron Lett. 2004, 45, 4847-4850.
(4) (a) Torres, E.; Y. C.; Kim, I. C.; Fuchs, P. L. Angew. Chem., Int.
Ed. 2003, 42, 3124-3131. (b) Tong, Z.; Ma, S.; Fuchs, P. L. J. Sulfur
Chem. 2004, 1-6. (c) Chen, Y.; Evarts, J. B., Jr.; Torres, E.; Fuchs, P. L.
Org. Lett. 2002, 4, 3571-3574. (d) Hentemann, M.; Fuchs, P. L. Org. Lett.
1999, 1, 355-357.
10.1021/ol060530l CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/15/2006

Previous studies from our laboratory have demonstrated
methods for stereocontrolled Lawton SN2′ addition (hybrid
conjugate addition, SN2′ reaction5) of nucleophiles to ep-
oxyvinyl sulfones from either diastereotopic face (R- or
â-1,4).6 We have also effected direct opening of epoxyvinyl
sulfones with inversion of configuration at the epoxide-
bearing carbon (â-1,2). The aplyronine synthesis now
presents an opportunity to complete the synthetic toolkit by
providing a strategy for R-1,2-addition to the epoxide with
net retention of stereochemistry (red structure, Figure 2).
Because Jacobsen epoxidation is also applicable to dienyl
sulfone 6,8 this strategy represents a general framework for
the stereodefined construction of 2-4. Furthermore, because
two of the three stereotetrads of aplyronine A are enantio-
meric, viz., 3 and 4, the synthetic task simplifies to the
preparation of two relative stereochemical relationships.
The appropriate nucleophile for the above strategy should
fulfill certain criteria. Our desire to introduce the second
methyl group via an SN2′ reaction requires that the nucleo-
phile serves as a good leaving group. That means that it
presumably must have a low pKa. Moreover, it must initially
undergo regiospecific Lawton SN2′ addition to the vinyl
epoxide (R- or â-1,4 addition; Figure 2). Finally, its pKa must
be sufficiently low so that it does not affect base-promoted
epoxide rearrangement of 7/8 to the undesired (in this case)
dienylic alcohols 13/14.
Finding a nucleophile that fulfilled the above criteria was
a demanding task. Ethylthiol, pyrrole, lithium diethyl phos-
phite, and acetone cyanohydrin all returned the starting
material. Thiolates, imidazole, and iodide exclusively gave
1,2-addition. Cyanide fostered base-promoted epoxide rear-
rangement. We had previously shown in five- and six-
membered systems that secondary amines gave the desired
1,4-addition products.9 However, because these basic amines
required an additional nitrogen alkylation step to enable bond
scission, we turned to the azole functionality as a compromise
between nucleophilicity and nucleofugacity. Although pyrrole
was totally unreactive, treatment of epoxide 7 with 3,5-
dimethylpyrazole10 resulted in a virtually quantitative yield
of the coveted Lawton SN2′ product 9 as a single diastere-
omer (Scheme 2).
Figure 2. Addition of nucleophiles to cross-conjugated epoxyvinyl
sulfones.
The synthesis begins with enantiopure cross-conjugated
dienyl sulfones 5 and 6, which are both available on the
decagram scale.4a Double stereoselective epoxidation of 5
with Jacobsen’s catalyst7 yields epoxide 7 in 79% yield8
(Scheme 1). 1,4-Addition of a group with hybrid nucleo-
Scheme 1. General Strategy for Stereotetrad Assembly
Scheme 2. Addition of 3,5-Dimethylpyrazole to 7 and 8
philic/nucleofugic character to the epoxyvinyl sulfone moiety
should afford a new substrate 9 bearing a proximal oxygen
moiety appropriate for chelate-mediated SN2′ methylation.
On the other hand, diastereomeric epoxide 8 yielded a 5.8:
(5) For references to the evolution of the Lawton reaction, see: Brocchini,
S. J.; Eberle, M.; Lawton, R. G. J. Am. Chem. Soc. 1988, 110, 5211-5212
and references therein.
(6) Jiang, W.; Lantrip, D. A.; Fuchs, P. L. Org. Lett. 2000, 2, 2181-
2184 and reference 4d.
(9) Pan, Y.; Hardinger, S. A.; Fuchs, P. L. Synth. Commun. 1989, 19,
403-416. Pan, Y.; Hutchinson, D. K.; Nantz, M. H.; Fuchs, P. L.
Tetrahedron 1989, 45, 467-478. Hutchinson, D. K.; Fuchs, P. L. J. Am.
Chem. Soc. 1985, 107, 6137-6138. Hutchinson, D. K.; Fuchs, P. L. J. Am.
Chem. Soc. 1987, 109, 4755-4756. Hutchinson, D. K.; Hardinger, S. A.;
Fuchs, P. L. Tetrahedron Lett. 1986, 27, 1425-1428.
(7) (a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L.
J. Am. Chem. Soc. 1991, 113, 7063-7064. (b) Hentemann, M. F.; Fuchs,
P. L. Tetrahedron Lett. 1997, 38, 5615-5618.
(10) Grekov, A. P.; Veselov, V. Y. Russ. Chem. ReV. 1978, 47, 631-
648.
(8) Torres, E. Ph.D. Thesis, Purdue University, May 2004.
2906
Org. Lett., Vol. 8, No. 14, 2006

111 mixture of isomeric products under the same set of
conditions.12 Numerous reaction conditions were examined,
and the best variant involved ethanol as the solvent (Scheme
2) and resulted in a 13:1 ratio in favor of the desired product
10. Recrystallization gave 10 in ca. 30:1 ratio and 76%
yield,13 obviating tedious chromatography.14
sium alkoxide 10A and 10B is postulated (Figure 3).
Attention was then directed toward Lawton SN2′ methyl-
ation (Scheme 3). Expecting hydroxyl group direction of the
Scheme 3. Lawton SN2′ Methylation
Figure 3. Temperature-dependent reversal of selectivity in the
addition of MeMgBr to 10.
Conformation 10A has the magnesium coordinated to both
the alkoxide and the nitrogen of the pyrazole ring, which
results in blockage of the â-face of the seven-membered ring,
and consequently, addition of the methyl group is only
possible from the R-face, resulting in an anti relationship
between the alkoxide and the new methyl group. This
conformation is preferred in the crystal structure of 10, which
shows a hydrogen bond between the hydroxyl group and the
pyrazole nitrogen.18 Evidence for the hydrogen bond in
solution is provided by the 1H NMR spectrum, which exhibits
the hydroxyl hydrogen resonance at 6.9 δ, indicative of
hydrogen bonding to the nitrogen atom of the pyrazole ring.
Furthermore, that hydrogen exhibits a coupling constant of
11.1 Hz19 with the hydrogen vicinal to it. That value indicates
a rigid trans-diaxial relationship between both hydrogens,
which puts the hydroxyl hydrogen in an ideal position for
hydrogen bonding with the nitrogen atom. In conformation
10B, the magnesium ion is not coordinated to the pyrazole
nitrogen and directs the attack of the methyl group from the
â-face either after Schlenck equilibrium and replacement of
the bromide by a methyl ligand or from another methyl-
magnesium bromide molecule in the same aggregate. Be-
cause addition of the methyl group to conformation 10B is
an intramolecular event, whereas addition to conformation
10A is an intermolecular event, the desired epimer prevails
at ambient temperature via rapid equilibration of 10A and
10B. However, at -45 °C, the equilibrium presumably
greatly favors conformation 10A resulting in skewing the
product ratio in favor of the undesired epimer.
methylation reaction, we screened a number of alternative
methylating agents. Methyllithium (2.2 equiv) resulted in
complicated product mixtures. Trimethylaluminum plus
methyllithium yielded a single diastereomer yet failed to
deliver more than 50% conversion. Finally, the use of 3 equiv
of methyl Grignard reagent in ether proved optimal, yielding
the stereotetrad in more than 95% conversion and 20:1 ratio
in favor of the desired 11 syn.
The reaction of 10 with MeMgBr under conditions
identical to those of 9 resulted in a 10:1 ratio of epimers in
favor of the desired product 12 syn. Attempts to increase
the selectivity by running the reaction at 0 °C instead of at
ambient temperature resulted in a disappointing 1:1 mixture
of 12 syn/anti epimers. Excitingly, when the reaction was
run at -45 °C,15 it gave a 4:1 ratio favoring 12 anti.16 Finally,
when the reaction was run completely at ambient tempera-
ture, a 20:117 selectivity was obtained in favor of the desired
12 syn. This temperature-dependent selectivity was not
paralleled in the case of 9, which was totally inert to
methylmagnesium bromide at temperatures below -30 °C
for more than 40 h.
To explain the temperature-dependent reversal of selectiv-
ity, equilibrium between two conformations of the magne-
(11) Unless otherwise specified, diastereomeric ratios are based on crude
1H NMR integration.
(12) Attempts to isolate and characterize the minor product by chroma-
tography resulted in its conversion to three inseparable compounds.
(13) The yield after flash column chromatography is 90%.
(14) The relative and absolute stereochemistries were determined by
X-ray analysis of a single crystal. See Supporting Information.
(15) The reaction is very slow at -45 °C requiring 3 days for completion.
(16) The relative stereochemistry of the alternate epimer was confirmed
by X-ray analysis of a single crystal.
(18) See crystal structure in Supporting Information.
(19) The fact that directly attached electronegative atoms tend to reduce
J values further corroborates the degree of the conformational rigidity.
See: Friebolin, H. Basic One- and Two-Dimensional NMR Spectroscopy,
3 ed.; Wiley-VCH: Weinheim, 1998; Chapter 3, p 93.
(17) After flash column chromatography, the ratio becomes 50:1.
Org. Lett., Vol. 8, No. 14, 2006
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It is remarkable that, although vinyl sulfones are amenable
to SN2 attack by Grignard reagents, 11 syn and 12 syn do
not further react under the above reaction conditions, and
no trimethyl products were isolated even using 2.6 equiv of
methylmagnesium bromide, which indicates a significant
difference in reactivity between the starting material and
product.
Scheme 5. Oxidative Cleavage of Vinyl Sulfone Stereotetrads
Di-TBS protected 13 and 14 were found to be crystalline,
which permitted X-ray confirmation18 of the relative and
absolute stereochemistries of 11 syn and 12 syn (Scheme
4). Having stereotetrad 12 syn in hand guarantees the
Scheme 4. Preparation of Crystalline Derivatives of 16 and 17
A. The method relies on catalytic asymmetric and substrate-
directed reactions for stereocontrol, thereby avoiding the use
of chiral auxiliaries. Two sequential highly chemo- and
stereoselective Lawton SN2′ reactions serve to establish the
desired product stereochemistry. Progress toward the syn-
thesis of aplyronine A, and further extension of this
methodology for the construction of other polypropionate
fragments, will be published in due course.
Acknowledgment. A.E. dedicates this work to Ahmad
Shams, an inspiring high school chemistry teacher. We thank
Arlene Rothwell and Karl Wood for providing MS data.
preparation of the enantiomeric stereotetrad 3.
Oxidative cleavage of the stereotetrads 11 syn and 1520
yielded termini differentiated stereotetrads 16 and 17 (Scheme
5) which are being advanced with other fragments for
assembly of aplyronine A.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds,
including X-ray data for 10, 11 anti di-TBS, 13, and 14
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
In conclusion, we have developed a unified strategy for
the synthesis of the polypropionate fragments of aplyronine
(20) Obtained by selective deprotection of 14. See Supporting Informa-
tion.
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