Cleavable chiral auxiliaries in 8π (8π, 6π) electrocyclizations

Article abstract of DOI:10.1021/ol061328l

Low to moderate diastereoselectivity was observed in the 8π electrocyclization of a series of chiral auxiliary-bearing tetraenic esters. In the 8-arylmenthyl series, diastereomeric products were separated by chromatography.

Full text of DOI:10.1021/ol061328l

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3553-3556
Cleavable Chiral Auxiliaries in 8
π
(8 , 6 ) Electrocyclizations
π
π
Kathlyn A. Parker* and Zhongyu Wang
Department of Chemistry, Stony Brook UniVersity, Stony Brook, New York 11794-3400
kparker@notes.cc.sunysb.edu
Received May 31, 2006
ABSTRACT
Low to moderate diastereoselectivity was observed in the 8
π electrocyclization of a series of chiral auxiliary-bearing tetraenic esters. In the
8-arylmenthyl series, diastereomeric products were separated by chromatography.
A number of natural products that contain a bicyclo[4.2.0]-
octane or -octadiene have been reported recently.1-4 For
In 2005, the elysiapyrones A and B (2a and 2b) were
isolated from the Pacific Panamanian sea slug Elysia
diomedea,2 and the ocellapyrones (3a and 3b) were isolated
from the Indian Ocean mollusk Placobranchus ocellatu3
(Figure 2).
Figure 1. SNF compounds from Streptomyces spectabilis.
example, in 2001, SNF4435 C and D (1a and 1b, Figure 1),
notable for their immunosuppressant and multidrug resistance
reversal activity, were isolated from the soil organism
Streptomyces spectabilis.1
(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) Cueto, M.; D’Croz, L.; Mate´, J. L.; San-Mart´ın, A.; Darias, J. Org.
Lett. 2005, 7, 415.
(3) (a) Manzo, E.; Ciavatta, M. L.; Gavagnin, M.; Mollo, E.; Wahidulla,
S.; Cimino, G. Tetrahedron Lett. 2005, 46, 465. (b) The structure of
ocellapyrone A was reassigned by total synthesis of the racemic 3a: see
Miller, A. K.; Trauner. D. Angew. Chem., Int. Ed. 2005, 44, 4602. Miller
and Trauner also described the synthesis of racemic 3b.
Figure 2. Bicyclooctadiene derivatives from mollusks.
10.1021/ol061328l CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/08/2006

Scheme 1. Possible 8π, 6π Electrocyclization Products from a
Polypropionate-Derived Tetraene
Figure 3. Shimalactones from the marine fungus Emericella
Variecolor.
Also in 2005, the marine fungus Emericella Variecolor
GF10 yielded the structurally complex shimalactone A (4a)
and its stereoisomer shimalactone B (4b) (Figure 3). The
shimalactones are inducers of neuritogenesis.4
All of these polypropionates are believed to be produced
from linear tetraenes by an 8π, 6π tandem electrocyclization
pathway5 as originally proposed by Black6 for the well-
known polyacetate-derived endiandric acids (e.g., 5a and 5b,
Figure 4).7
aid of a removable chiral appendage. Likewise, the [4.2.0]
ring system of the shimalactones presumably arises by a
nonenzymatic biosynthetic process, and total synthesis of the
pair might be achieved by nonenzymatic cyclization of an
appropriate tetraene.
On the other hand, optical activities for the elysiapyrones
and the ocellapyrones have been reported, and a role for an
enzyme has been invoked.2 Syntheses of the chiral elysiapy-
rones10 or the ocellapyrones3b will require an external
chirality source; these preparations and also those of chiral
analogues of the SNF compounds and the shimalactones
might be based on an approach in which the 8π electrocy-
clization step of the tandem closure was influenced by a
chiral auxiliary.
Numerous chiral auxiliaries derived from chiral natural
products and also from the resolution of synthetic materials
have been shown to affect the diastereomeric excesses
in additions to the olefinic bonds of substituted acrylates.
For the first study of the effectiveness of chiral auxiliaries
in this context, we chose the closure of esters of 4,6,8-
Figure 4. Endiandric acids D and E from leaves of the Australian
tree Endiandra introrsa (Lauraceae).
The 8π, 6π double closure can, in principle, produce four
stereoisomers (Scheme 1). Neither the biosynthesis of the
racemic endiandric acids6 nor that of the diastereomeric SNF
pair5 requires an enzyme for control of relative or absolute
stereochemistry. Both the endiandric acids8 and the SNF
diastereomers9 were prepared by total synthesis without the
(4) (a) Wei, H.; Itoh, T.; Kotoku, N.; Kobayashi, M. Heterocycles 2006,
68, 111. (b) Wei, H.; Itoh, T.; Kinoshita, M.; Kotoku, N.; Aoki, S.;
Kobayashi, M. Tetrahedron 2005, 61, 8054.
(5) (a) Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221. (b) Moses,
J. E.; Baldwin, J. E.; Marquez, R.; Adlington, R. M.; Cowley, A. R. Org.
Lett. 2002, 4, 3731. (c) Parker, K. A.; Lim, Y.-H. Org. Lett. 2004, 6, 161.
(6) Banfield, J. E.; Black, D. St. C.; Johns, S. R.: Willing, R. I. Aust. J.
Chem. 1982, 35, 2247 and references therein.
(7) For a recent review on electrocyclizations in biosynthesis and in
biomimetic schemes, see: Beaudry, C. M.; Malerich, J. P.; Trauner, D.
Chem. ReV. 2005, 105, 4757.
(8) For the biomimetic synthesis of the endiandric acids, see: Nicolaou,
K. C.; Petasis, N. A.; Zipkin, R. E. J. Am. Chem. Soc. 1982, 104, 5560.
(9) (a) Parker, K A.; Lim, Y.-H. J. Am. Chem. Soc. 2004, 126, 15968.
(b) Jacobsen, M. F.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E. Org.
Lett. 2005, 7, 2473. (c) Beaudry, C. M.; Trauner, D. Org. Lett. 2005, 7,
4475.
(10) For the total synthesis of racemic elysiapyrones and racemic
ocellapyrones, see: Barbarow, J. E.; Miller, A. K.; Trauner, D. Org. Lett.
2005, 7, 2901.
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Org. Lett., Vol. 8, No. 16, 2006

trimethyl-(2E,4Z,6Z,8E)-9-(4-nitrophenyl)nonatetraenic acid
(see Scheme 2). This system has the important feature of
measured directly from the NMR spectrum of this mixture.
We first examined the utility of the exceptionally convenient
Corey-Sarakinos sulfone 8a11 in this sequence. Thus, acid
7, from basic hydrolysis of the known 6, underwent DCC
coupling with alcohol 8a, providing iododiene 9a in 95%
yield. However, standard stannylation conditions, intended
to afford the auxiliary-bearing diene 10a, were unsuccessful,
leading to the product of elimination from the â-acyloxy
sulfone (see the Supporting Information).
Scheme 2. Preparation of Diastereomeric SNF Analogues
That Bear Cleavable Chiral Auxiliaries
Because we had sulfide 8b, an intermediate in the synthesis
of sulfone 8a in hand, we next prepared iodo ester 9b.
Stannylation provided ester 10b which underwent the
coupling/electrocyclization procedure with vinyl iodide 11
to give a mixture of ring-closed products 13b and 14b. The
NMR spectrum of the mixture showed two diastereomers in
a ratio of 1:1.5.
Convinced that the sulfone 12a, if it could be prepared,
would provide a larger bias toward a preferred transition state
for the 8π closure,12 we reexamined the stannylation of iodo
ester 9a. A combination of lower reaction temperature and
shorter time allowed isolation of the desired vinyl stannane
10a which was then submitted to the coupling/electrocy-
clization procedure with vinyl iodide 11. An NMR analysis
of the resulting mixture revealed two diastereomeric bicy-
clooctadienes 13a and 14a in a ratio of 4:1.
The effects of the 8-arylmenthyl chiral auxiliaries were
examined next. Both the phenyl- and the naphthyl-substituted
menthols (8c and 8d) were prepared according to the
literature procedures.13,14 Esterification of acid 7 with alcohol
8c followed by stannylation and Stille coupling gave a
mixture of bicyclic esters 13c and 14c. The ratio of
diastereomers was 1:2. Likewise, esterification of acid 7 with
alcohol 8d, stannylation of 9d, and Stille coupling gave a
mixture of esters 13d and 14d. Here the ratio of isomers
was also 1:2.
Hoping to influence the ratio of diastereomers in the
product mixture by the “additive effect” described by
Tsutsumi, Kakiuchi, and co-workers,15 we repeated our
coupling/cyclization protocol in both arylmenthyl ester
sequences (9c f 13c + 14c) and (9d f 13d + 14d) in the
presence of 10 molar equiv of naphthalene. In the phenyl-
menthyl sequence, no change in ratio was observed. For the
naphthylmenthyl series, the ratio shifted from 1:2 to 1:2.5.
Diastereomeric excesses for all experiments are summarized
in Table 1 in the Supporting Information.
being stereoselective for the “endo” product in the second
step of the double closure.5 Therefore, product analysis is
simplified to the ratio of two endo diastereomers. An
additional advantage for us was that precursors for the key
building blocks of the tetraene substrate were available in
our laboratory.
Our plan was to couple the iodo acid 7 with a chiral
alcohol auxiliary alcohol 8, convert the iodo ester 9 to the
vinyl stannane 10, and then carry out a Stille coupling with
the known iododiene 11.5a The resulting tetraene 12 can then
undergo the 8π/6π tandem closure to give a mixture of
diastereomers 13 and 14. The diastereomeric excess can be
(11) Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741. Because the
product analysis was one of diastereomers, we worked with racemic 8a
and 8b.
(12) Sarakinos and Corey (ref 11) had reported that the Lewis acid-
catalyzed Diels Alder reactions of acrylates of the â-hydroxy sulfones were
more stereoselective than those of the corresponding sulfides, noting that
sulfide complexation might be involved. One might expect this result also
on the basis of the buttressing effect of the sulfone oxygens.
(13) (a) Ort, O. Org. Synth. 1987, 65, 203. (b) Corey, E. J. Ensley, H.
E. J. Am. Chem. Soc. 1995, 97, 6908.
(14) D’Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986, 108, 8112.
(15) Tsutsumi, Kakiuchi, and co-workers showed that aromatic cosolutes
altered the ratio of diastereomers resulting from [2 + 2] additions to
arylmenthyl esters of cyclohexenonecarboxylic acids; see: Tsutsumi, K.;
Nakano, H.; Furutani, A.; Endou, K.; Merpuge, A.; Shintani, T.; Morimoto,
T.; Kakiuchi, K J. Org. Chem. 2004, 69, 785.
Org. Lett., Vol. 8, No. 16, 2006
3555

conformation; addition to the unshielded face of the π system
then leads to the predominance of one diastereomeric
product. In the absence of coordinating effects however, the
cycloaddition transition states corresponding to the s-cis,syn
and s-trans,syn conformations of acrylates are nearly isoen-
ergetic.19 The product distributions in our electrocyclic
cascade show that the s-cis,syn and s-trans,syn helical
transition states (Figure 5) are also of similar energies.
Thus, in the nitrophenyl-substituted E,Z,Z,E-tetraene series
which was the subject of this initial study, none of the
standard chiral auxiliaries influenced the 8π closure to
provide a product with the high diastereomeric excess
required for direct application in asymmetric synthesis.
Indeed, the modest excesses obtained highlight the need for
examining alternative auxiliaries and/or modifying one of
those already tested to favor either the s-cis,syn or the
s-trans,syn conformation. On the other hand, the diastereo-
meric products in the arylmenthyl series were easily separated
on chromatography, providing compounds that offer access
to chiral analogues of both SNF4435 C and D. Each of these
esters is a prospective chiral intermediate for elaboration to
designed drug candidates in the SNF series.
Figure 5. General structures for the reactive helical conformations
for 8π electrocyclization of tetraene esters 12. For 12a, X ) S, Y
) O, aromatic system is â-naphthyl; for 12b, X ) S, Y ) electron
pair, aromatic system is â-naphthyl; for 12c, X ) C, Y ) CH3,
aromatic system is phenyl; for 12d, X ) C, Y ) CH3, aromatic
system is â-naphthyl.
Acknowledgment. This contribution was supported in
part by the National Institutes of Health (CA-87503 and GM-
74776) and by the National Science Foundation (CHE-
0131146, NMR instrumentation).
Although cycloaddition reactions of related arylmenthyl
and Corey-Sarakinos acrylates are often reported to give
high diastereomeric excesses,16 the protocols for these
optimized reactions are based on Lewis acid catalysis. Studies
by Houk17 and also d’Angelo18 suggest that Lewis acid
coordination and possibly hydrogen-bonding solvents favor
the s-trans conformation of unsaturated esters over the s-cis
Supporting Information Available: Detailed descrip-
tions of the experimental procedures and complete analytical
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) For a recent review on π-shielding that includes a number of
examples of the use of the aryl menthyl auxiliaries, see: Jones, G. B.
Tetrahedron 2001, 57, 7999.
(17) Loncharich, R. J.; Schwartz, T. R.; Houk, K. N. J. Am. Chem. Soc.
1987, 109, 14.
OL061328L
(18) Dumas, F.; Mezrhab, B.; d’Angelo, J.; Riche, C.; Chiaroni, A. J.
Org. Chem. 1996, 61, 2293.
(19) Curran, D. P.; Kim, B. H.; Piyasena, H. P.; Loncharich, R. J.; Houk,
K. N. J. Org. Chem. 1987, 52, 2137 and references therein.
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