Asymmetric epoxy cyclohexenyl sulfones: readily accessible progenitors of stereo defined six-carbon arrays.

Article abstract of DOI:10.1021/ol990523f

[formula: see text] Enantiopure epoxy vinyl sulfones serve as highly effective substrates for a variety of stereo- and regiospecific oxidation and nucleophilic functionalization reactions. These materials can be easily transformed to cyclic and acyclic si

Full text of DOI:10.1021/ol990523f

ORGANIC
LETTERS
1999
Vol. 1, No. 3
355-357
Asymmetric Epoxy Cyclohexenyl
Sulfones: Readily Accessible
Progenitors of Stereodefined Six-Carbon
Arrays1
Martin Hentemann and Philip L. Fuchs*
Department of Chemistry, Purdue UniVersity West Lafayette, Indiana 47907
pfuchs@chem.purdue.edu
Received March 16, 1999
ABSTRACT
Enantiopure epoxy vinyl sulfones serve as highly effective substrates for a variety of stereo- and regiospecific oxidation and nucleophilic
functionalization reactions. These materials can be easily transformed to cyclic and acyclic six-carbon segments. Nucleophilic epoxidation of
3a,b followed by palladium[0] catalysis enables access to differentially protected arene diols 21 and 22.
An unambiguous method for creation of multiple contiguous
stereocenters is a long-standing goal of the synthetic com-
munity. Some of the state-of-the-art methods include the
highly effective iterative aldol strategy and desymmetrization
tactics involving Pd[0] catalysis, chiral bases, or enzymatic
resolution.2 While each of these methods has its own unique
profile of attributes, a truly general solution remains tantaliz-
ingly out of reach.
In a pair of recent publications3 which derived inspiration
from the seminal contributions of Johnson, Lautens, and
Hudlicky,2b,d,e we discussed utilization of enantiopure ep-
oxyvinyltriflates as progenitors of enantiopure cyclic and
acyclic targets. While these findings provided useful infor-
mation, stability difficulties were observed with several of
the compounds. Since vinyl sulfones exhibit superb stability,
we elected to exploit the outstanding enantioselectivities
obtained in the epoxidation of 2-sulfonyl-1,3-cycloalkadienes
using Jacobsen conditions.4
2-Phenylsulfonyl-1,3-cyclohexadiene 1 is available in one
operation from 1,3-cyclohexadiene5 and is regularly prepared
in our laboratories in 100-g lots. Enantiopure epoxide 2,
which has become the “workhorse” of our strategy, has been
prepared in 15-g quantities (72% yield, >96% ee), and this
crystalline white solid (mp 97-99 °C) has excellent handling
properties and stability. Ba¨ckvall has elegantly demonstrated
the synthetic versatility of dienyl sulfones,6 and his observa-
tions coupled with our own have provided an impetus for
further research.
Treatment of epoxide 27 with LiHMDS generates cross-
(4) Hentemann, M. F., Fuchs, P. L. Tetrahedron Lett. 1997, 38, 5615.
(5) Ba¨ckvall, J. E.; Juntunen, S. K.; Andell, O. S. Org. Synth. 1990, 68,
148. The 1,3-cyclohexadiene can be prepared very affordably from
cyclohexene by dibromination and double elimination (Org. Synth. 1973,
Coll. Vol. 5, 285). A more “environmentally friendly” approach to 1 has
also been developed in four steps (∼60% overall) starting from cyclohex-
anone (Evarts, J., unpublished results).
(1) Syntheses via Vinyl Sulfones 81; Chiral Carbon Catalog 4.
(2) (a) Evans, D. A. Aldrichim. Acta 1982, 15, 23. Evans, D. A.; Ng, H.
H.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48, 2127. (b) Hudlicky,
T.; Thorpe, A. J. Chem. Commun. 1996, 1993. (c) Trost, B. M. Pure. Appl.
Chem. 1996, 68, 779. (d) Trost, B. M.; Van Vranken, D. L. Chem. ReV.
1996, 96, 395. (e) Johnson, C. R. Acc. Chem. Res. 1998, 31, 333. Johnson,
C. R.; Golebiowski, A.; Steensma, D. H. J. Am. Chem. Soc. 1992, 114,
9414. (f) Lautens, M.; Ren, Y.; Delanghe, P.; Chiu, P.; Ma, S.; Colucci, J.
Can. J. Chem. 1995, 73, 1251 and references cited therein.
(6) (a) Ba¨ckvall, J.-E.; Chinchilla, R.; Na´jera, C.; Yus, M. Chem. ReV.
1998, 98, 2291 and references cited therein.
(7) By using vigorous mechanical stirring, 2 can be prepared using 1.5
mol % of the Jacobsen catalyst, and 6 mol % of the additive 4-phenylpropyl
pyridine N-oxide and 1.5 equiv of commercial bleach after 15 min at 4 °C.
We have found that the ee % shows some decline with decreasing amounts
of catalyst, with 2-4% being optimal for yield and >96% ee. Results of a
systematic study will be presented in a later publication. ee % determined
by HPLC using Daicel ChiralPak AD column.
(3) (a) Hentemann, M.; Fuchs, P. L.Tetrahedron Lett. 1999, 40, 2699-
2702. (b) Evarts, J. B., Jr.; Fuchs, P. L. Tetrahedron Lett. 1999, 40, 2703-
2706.
10.1021/ol990523f CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/22/1999

conjugated dienyl sulfones 3a,b (functionalized “benzene
hydrates”) almost quantitatively after addition of water or
TBSOTf, respectively (Scheme 1). Compounds 3a,b serve
catalyst cleanly gave 7 in 84% yield, while treatment with
the R,R catalyst gave no reaction in a striking example of
mismatched double stereoselection.10 Not surprisingly,
Jacobsen epoxidation of free alcohol 3a gives only the
aromatization product, diphenyl sulfone, regardless of catalyst
choice or reaction conditions.
Scheme 1. Use of Sulfones in Functionalization Strategya
We have observed that a large variety of nucleophiles11
can be added to vinyl epoxides 2, 5, and 7, in a regiospecific
fashion to give a rich array of stereodefined products.
Extension of this strategy into the crucial domain of
nucleophilic methylation has been extremely successful,
providing selective 1,2- or 1,4-addition products in good
yield. This was of crucial importance because of the
prevalence of polypropionate systems in natural products.12
A previous study had revealed that treatment of dl-epoxy-
vinyl sulfone 2 with trimethylaluminum in the presence of
catalytic methyl copper afforded trans-1,4-adduct 9, while
trimethylaluminum by itself provided the trans-1,2-adduct
11.13 Application of hydrous trimethylaluminum14 to the
enantiopure substrates 2, 5, and 7 has improved the yield
and stereospecificity as shown (Table 2).
a The other enantiomeric series is also available but not shown;
absolute configuration of epoxide 2 is S,S when using the R,R
Jacobsen catalyst.8
as central pivots, enabling increased chemical diversity to
be expressed through a second olefin functionalization step.8
We envisioned that subsequent chemospecific derivatization
of the electron-rich olefin would create an effective stereo-
chemical scaffold for further transformations.
The first approach that was considered was the directed
epoxidation of dienyl alcohol 3a; an undertaking that was
complicated by competitive conjugate epoxidation of the
vinyl sulfone moiety (Table 1). This difficulty was alleviated
Table 2. Nucleophilic Methylation Experiments
Table 1. Epoxidation Results
major product, 1,4:1,2
SM
reagent and solvent
% yield
ratio
2
MeCu(cat.), 1.2 equiv of Me3Al,
THF
10 equiv of Me3Al, H2O, CH2Cl2
MeCu(cat.), 1.2 equiv of Me3Al,
THF
9; 74
8:1
SM
reagents
prod
8
% yield
3a
1.1 equiv of mCPBA, 2.5 equiv of
NaHCO3, CH2Cl2
1.2 equiv of mCPBA,
68 17 (4+6)
2
5
11; 76
13; 91
1:>20
>20:1
3a
4
72 (5:1 4:6)
no buffer, CH2Cl2
5
7
10 equiv of Me3Al, H2O, CH2Cl2
MeCu(cat.), 1.2 equiv of Me3Al,
THF
14; 76
10; 93
1:8
>20:1
3a
3a
oxone, cat. trifluoroacetone
1.5 equiv of CF3CO3H, 5 equiv of
NaHCO3, CH2Cl2, -78 °C
0.025% methyl trioxorhenium,
H2O2
6
4
88 (4:1 6:4)
83 (15:1 4:6)
7
10 equiv of Me3Al, H2O, CH2Cl2
12; 64
10:1
3a
4
74 (3:1 4:6)
Transfer of the newly created array of contiguous stereo-
centers to the acyclic domain requires oxidative cleavage of
the vinyl sulfone moiety. In this instance ozonolysis3 proved
expedient for production of the termini-differentiated six-
carbon segments 16 and 18 (Scheme 2).
3b
3b
3b
oxone, cat. trifluoroacetone
R,R J acobsen Catalyst, NaOCl
S,S J acobsen Catalyst, NaOCl
7
-
7
94
no reaction
84
using buffered trifluoroperacetic acid which provided epoxy
alcohol 5 with improved stereoselectivity relative to mCPBA.
Compound 7 is readily prepared from 3b using either in
situ generated trifluoromethyldioxirane or a second applica-
tion of the Jacobsen conditions.7 Interestingly, use of the S,S
(9) Absolute stereochemistry was determined by opening the epoxide to
form the corresponding bromohydrin and obtaining crystallographic data.
(10) (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1. (b) Jain, N. F.; Takenaka, N.; Panek, J.
S. J. Am. Chem. Soc. 1996, 118, 12475. (c) Doyle, M. P.; Kalinin, A. V.;
Ene, D. G. J. Am. Chem. Soc. 1996, 118, 8837. (d) Evans, D. A.; Dart, M.
J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc. 1995, 117, 9073.
(11) Carbon, nitrogen, and halogen nucleophiles add in good yield in
either a 1,2- or 1,4-sense (manuscript in preparation).
(8) Such directable reactions include cyclopropanation, dihydroxylation,
aminohydroxylation, nucleophilic additions, etc. See: Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(12) Paterson, I. Pure. Appl. Chem. 1992, 64, 1821.
356
Org. Lett., Vol. 1, No. 3, 1999

Scheme 2
Table 3. Nucleophilic Epoxidation Scheme
rxna
R
reagents
prod
% yield
Azidation of 2 using Yb catalysis followed by methanolic
ozonolysis in the presence of bicarbonate gives ester-
aldehyde 16 after reductive quench. The intermediate acyl
sulfone15 can also be trapped by stoichiometric amine to give
the corresponding amide. Ozonolysis of 17 followed by
dimethyl sulfide quench and addition of benzylamine gives
amide-ester 18 after simple workup.
a
b
c
d
e
H
TBS
H
TBS
TBS
TBHP, cat Triton B, CH2Cl2
TBHP, cat Triton B, CH2Cl2
TBSCl, imidazole, CH2Cl2
5% Pd(PPh3)4, THF
10
23
22
24
25
92
95
97
86
84
5% Pd(PPh3)4, THF
a The other enantiomeric series is also available but not shown.
Another very attractive feature of the epoxyvinyl sulfones
is their ability to selectively undergo nucleophilic reaction
at the electron-deficient olefin. This concept has been
superbly demonstrated by Ba¨ckvall on racemic sulfones,6b
so we sought an extension of his findings by exploiting the
allylic oxygen substituent to control the stereochemistry of
nucleophilic addition. As seen in Table 3, the free hydroxyl
group in 3a effectively directs the epoxidation, exclusively
giving the syn epoxy-alcohol 8 in excellent yield. Similarly,
epoxidation of silyl ether 3b solely afforded the anti product
20. With each of these protected epoxy alcohols it was
envisioned that we could utilize our LHMDS ring-opening
reaction (Scheme 1) to generate enantiopure arene diols.
Unfortunately, our initial attempts met with failure, so we
had to employ an alternate approach.
This route was particularly attractive because it conformed
to an approach which employs catalytic reagents.3 Treatment
of both 19 and 20 with catalytic palladium[0] in THF cleanly
provided dienylic diols 21 and 22 under very mild conditions
(Table 3). Compounds 21 and 22 bear a strong resemblance
to the arene diols developed by Hudlicky16 and provide a
point of commonality between the two strategies. While the
Hudlicky aryl halide enzyme oxidation strategy has the
advantage of brevity, our approach is able to substantially
extend the scope of these materials by making readily
available both stereoisomers in either enantiomeric config-
uration with differentiable hydroxyl functionality, thereby
enabling a wealth of stereochemical permutations.
Acknowledgment. We acknowledge Arlene Rothwell and
Karl Wood for mass spectral data and the NIH for partial
support of this project (GM 32693). Dr. Douglas Lantrip is
thanked for assistance in manuscript preparation.
The route adopted again advanced the findings of Ba¨ckvall
with Pd[0]-catalyzed conversion of vinyl epoxides to dienes.6a
(13) Saddler, J. C.; Fuchs, P. L. J. Am. Chem. Soc. 1981, 103, 2112.
(14) Miyashita, M.; Hoshino, M.; Yoshikoshi, A. J. Org. Chem. 1991,
56, 6483.
OL990523F
(15) (a) Schank, K.; Werner, F. Liebigs Ann. Chem. 1979, 1977. (b)
Adam, W.; Hadjiarapoglou, L. Tetrahedron Lett. 1992, 33, 469. (c) Claes,
M. G.; Lo¨fstro¨m, A. M.; Ericsson, L. B.; Juntunen, S. K.; Ba¨ckvall, J. E.
J. Org. Chem. 1995, 60, 3586.
(16) (a)Hudlicky, T.; Luna, H.; Barbieri, G., Kwart, L. D. J. Am. Chem.
Soc. 1988, 110, 4735. (b) Hudlicky, T.; Price, J. D., Rulin, F.; Tsunoda, T.
J. Am. Chem. Soc. 1990, 112, 9439. (c) Hudlicky, T.; Rouden, J.; Luna, H.
J. Org. Chem. 1993, 58, 985.
Org. Lett., Vol. 1, No. 3, 1999
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