In addition to using the cyclic vinyl sulfones as direct
precursors of termini-differentiated acyclic heptyl fragments
analogous to the hexyl compounds, these materials can also
serve as precursors of side chain-functionalized monocyclic
intermediates. For example, IKD-8344 9 (Figure 2) is a C2
Table 1. Oxidation of Cycloheptadienyl Sulfones
yield
no. sm
reagents and conditions
prod(s)
(%) (ee)
1
4b 6% (R,R) J acobsen cat.,
NaOCl, amine oxide, 0 °C, 6 h
4b (S,S) J acobsen cat., as above
5b 1a, LiHMDS; 1b, TBDMSCl
5b 1a, LiHMDS; 1b, NH4Cl
6a TFA cat./Oxone, MeCN, 0 °C,
30 min
5b
81 (95%)
2
3
4
5
en t-5b 79 (95%)
6b
8b
s/a -7a 1/4; 88%2c
s/a -7b 47/46
96
99
6
6b TFA cat./Oxone, MeCN, 0 °C,
30 min
7
8
6b mCPBA, CH2Cl2, 25 °C, 2 h
6b 8% (R,R) J acobsen cat., NaOCl, s/a -7b 7/85 (>97%)
s/a -7b 56/34
amine oxide, 0 °C, 10 h
6b (S,S) J acobsen cat., as above
Figure 2.
9
s/a -7b 85/7 (>98%)
(entries 1 and 2, Table 1).4 Treatment of epoxyvinyl sulfone
5b with LiHMDS generates sulfonyl-substituted silyl ether
6b or dienylic alcohols 8b depending upon whether the
reaction is quenched with TBDMS-Cl or water (entries 3and
4, Table 1). The cyclohexenyl and cycloheptenyl compounds
fundamentally differ with respect to stereochemical control
in subsequent epoxidation reactions. While cyclohexadienyl
silyl ether 6a affords anti epoxy silyl ether anti-7a with
excellent substrate-mediated selectivity, similar selectivity
is not obtained with either the seven-membered silyl ether
6b or alcohol 8b.
symmetric 28-membered ring diolide which appears to have
potential as an anticancer agent.5 The secoacid segments of
9 can be envisioned to arise from one molecule of the
enantiomer of enantiopure anti-7b and two molecules of syn-
7b.
Access to the two key intermediates for preparation of
IKD-8344 required development of new methodology for
the stereoselective introduction of the pendant methyl groups.
SN2′ methylation of syn-7b and anti-7b proved especially
informative. For example, ent-syn-7b can be efficiently
transformed to either key intermediate all-syn 11 or its anti-
syn diastereomer 14 (relevant X-ray in Supporting Informa-
tion), respectively (Figure 3). Similar reactions on ent-anti-
7b serve to generate alcohol 16, but under the stronger Lewis
acid conditions 15 is not produced. Access to 15 was secured
via Mitsunobu inversion6 of 11. The product formed in the
trimethylaluminum (or HF) reaction with ent-anti-7b is
bridged tetrahydrofuran 18.
In the case of silyl ether 6b, both achiral reagents generate
mixtures of the syn and anti epoxides s/a-7b (entries 6 and
7, Table 1). This stereochemical problem was solved by
reagent-based double stereoselection via hypochlorite ep-
oxidation of silyl ether 6b in the presence of the enantiopure
Jacobsen catalysts to provide epoxides syn-7b and anti-7b
with ∼12:1 selectivity (entries 8 and 9, Table 1). Chroma-
tography or crystallization of these mixtures provided pure
diastereomers in >75% yield and >97%ee. By comparison,
epoxidation of the free alcohol 8b was far more complicated.
Oxidation of the allylic alcohol moiety of 8b to enone
occurred at competitive rates to epoxidation of the olefin,
rendering the process inefficient (see Supporting Informa-
tion).
The regiochemistry of intramolecular oxygen alkylation
of epoxide ent-anti-7b to 18 initially appears surprising,
since one might have expected the compound to suffer attack
at the allylically activated bond to afford iso-18. Molecular
mechanics reveals that backside access to both carbons of
the epoxide moiety is feasable. Energy calculations do not
substantially favor one 6/5 ring system over the other.
Bidentate coordination of the acid catalyst with both the
epoxide and the sulfonyl oxygen may provide a rationale for
the observed regioselectivity. As the reaction proceeds to
form 18, two-point bonding of the acid is maintained
throughout, while opening to iso-18 requires disruption of
The simplicity and high yields of the five-operation
syntheses of syn-7b and anti-7b provide an excellent pair
of intermediates for further modification.
(3) (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2801. (b) Hughes, D. L.; Smith, G. B.; Liu, J.;
Dezeny, G. C.; Senanayake, C. H.; Larsen, R. D.; Verhoeven, T. R.; Reider,
P. J. J. Org. Chem. 1997, 62, 2222. (c) Palucki, M.; McCormick, G. J.;
Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5457
(5) Minami, Y.; Yoshida, K.-i.; Azuma, R.; Nishii, M.; Inagaki, J.-i.;
Nohara, F. Tetrahedron Lett. 1992, 33, 7373.
(4) Hentemann, M. F.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 5615.
(6) Mitsunobu, O. Synthesis 1981, 81, 1-28.
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Org. Lett., Vol. 2, No. 15, 2000