quinidine derivatives.7 Here, we report total syntheses of
both 1a and 1b, using the catalytic, asymmetric “inter-
rupted” FeistꢀBenary (IFB) reaction developed by Calter
et al. to install the chirality into the target molecules
(Scheme 1).8 Completion of the synthesis would then
involve aromatization, intramolecular BuchwaldꢀHartwig
reaction to form the benzopyranoid ring, tosylate reduc-
tion, and finally deprotection in the case of glycinol. The
IFB reactions would require dione nucleophiles 2a or 2b
and the β-bromo-R-ketoester electrophiles 3a or 3b, which
were all either known compounds or close analogues.
in the presence of base produced keto ester 7, which was
subjected to Dieckmann condensation to give 2a in 47%
overall yield.
Pyruvate 3a was synthesized according to a well docu-
mented procedure beginning with the lithium trimethy-
lethylenediamine-directed ortho-bromination of p-
anisaldehyde to produce bromoaldehyde 8 (Scheme 3).10
Submission of 8 to a Darzens reaction led to epoxide 9,
which was converted into β-bromo-R-ketoester 3a by
treatment with MgBr2.9
Scheme 3. Synthesis of Pyruvate 3a
Scheme 1. Retrosynthetic Plan for 1a and 1b
With 2a and 3a in hand, the IFB reaction proceeded
smoothly with monoquinidine pyrimidinyl ether 10 as a
catalyst and provided 11 as an inseparable 8.5:1 E/Z
mixture of diastereomers (Scheme 4). Exposure of 11 to
iodobenzene bis(trifluoromethylacetate) (PIFA) produced
the corresponding, unstable dimethoxy acetal,11 which was
subjected to LiHMDS to give unstable phenol 13. Both 12
and 13 were prone to elimination to form the correspond-
ing furans. Tosylation of 13 afforded tosylate 14, still as a
mixture of diastereomers. However, we were able to use
analytical HPLC to determine the enantio- and diastereo-
purity of 14.
The synthesis of dithiane 2a began with the addition of
lithium propiolate with propylene oxide in the presence of
BF3 Et2O to afford alkynyl alcohol 4 (Scheme 2). Oxida-
3
tion of 4 with the Swern reagent or the DessꢀMartin
periodinane provided multiple products. A successful oxi-
dant was silica-gel-supported Jones reagent (SJR), which
gave a mixture of alkyne 5 and allene 6 in quantitative yield
after filtration. Compound 5 was the major initial product
of the reaction but converted into 6 at ꢀ25 °C in under 12
h. Addition of 1,3-propanedithiol to the mixture of 5 and 6
We were initially surprised with the (E)-selectivity of the
IFB reaction of 2a and 3a, as previous examples had
provided (Z)-selectivity, but further analysis of factors
governing the diastereoselectivity of the IFB reaction
provided a rationale (Figure 2). In general, the IFB
reaction of substituted bromoketoesters proceeds via a
dynamic, kinetic resolution, with tetrabutylammonium
iodide (TBAI) serving to convert the bromide into the
corresponding iodide and then constantly racemize this
compound. The previous examples using unsubstituted
aryl substituents yielded the (Z)-R,R-product, with both
the catalyst and the substrate favoring attack, via a
Scheme 2. Synthesis of Dithiane 2a
(8) Calter, M. A.; Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc.
2005, 127, 14566–14567.
(10) (a) Tsuboi, S.; Furutani, H.; Takeda, A.; Kawazoci, K.; Sato, S.
Bull. Chem. Soc. Jpn. 1987, 2475–2480. (b) Coutrot, P.; Legris, C.
Synthesis 1975, 2, 118–120.
(9) (a) Merz, K.-H.; Muller, T.; Vanderheiden, S.; Eisenbrand, G.;
Marko, D.; Brase, S. Synlett 2006, 20, 3461–3463. (b) Lear, Y.; Durst, T.
Can. J. Chem. 1997, 75, 817–824. (c) Comins, D. L.; Brown, J. D. J. Org.
Chem. 1984, 49, 1078–1083.
(11) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287–290.
(12) (a) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem.
Soc. 2000, 122, 10718–10719. (b) Torraca, K. E.; Kuwabe, S.-I.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907–12908.
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