Scheme 2. Radical Cyclization of â-Alkoxyvinyl Sulfoxides
Scheme 3. Preparation of â-Alkoxyvinyl Sulfoxidesa
drofuran products in the vinyl ether radical cyclization
reactions should also be considered,3 and we intended to
investigate the possibility of double stereoselection leading
to higher stereoselectivity.
The tosylate 6 was obtained from L-malic acid (5) via a
five-step sequence. Reaction of 6 with ethynyl p-tolyl (R)-
sulfoxide (7)4 in the presence of N-methylmorpholine and
iodide substitution resulted in the formation of the (E)-vinyl
sulfoxide 10a. Reaction of the lithium alkoxide derived from
6 with 7 supplied mainly the (Z)-vinyl sulfoxide 10b after
iodide substitution. Employing the enantiomeric (S)-sulfoxide
8, the alternative vinyl sulfoxides 10c and 10d were also
obtained (Scheme 3).
When the substrate 10a was treated with tributylstannane
in the presence of triethylborane at -20 °C in toluene, a
94:6 mixture of the tetrahydrofuranyl products 11 and 12
was obtained. Under the same reaction conditions, the vinyl
sulfoxide 10b was converted almost exclusively into 11 (11:
12 ) 99:1). The results show clearly that the intrinsic
preference for formation of cis-2,5-disubstituted tetrahydro-
furans predominated in both cases. The vinyl sulfoxide 10a
was a mismatched substrate, and the stereoselectivity suf-
fered. On the contrary, the reaction of 10b was a matched
case and resulted in higher stereoselectivity. The situation
reversed with the diastereomers 10c and 10d for synthesis
of tetrahydrofurans 13 and 14. The reaction of 10c was more
stereoselective (matched case) than the reaction of 10d
(mismatched case); in both cases, 13 was the predominant
product (Scheme 4).
a Key: (1) BH3‚SMe2, (MeO)3B, THF; (2) PhCH(OMe)2, CSA,
DCM; (3) BnBr, NaH, THF; (4) AcOH-H2O (4:1); NaIO4,
MeOH-H2O (4:1); (5) TsCl, TEA, DCM, 0 °C; (6) 2.5 equiv of 7
or 8, 1.0 equiv of NMM, DCM, rt, 18 h; (7) 3.0 equiv of 7 or 8,
1.2 equiv of LHMDS, THF, -78 to -20 °C, 1 h; (8) 3.0 equiv of
NaI, acetone, reflux, 3 h.
was a stereorandom process. Use of (allyl)tri-n-butylstannane
in the presence of boron trifluoride etherate proceeded to
produce 17 stereoselectively in preference to 16. When
stannic chloride was used as the Lewis acid, 17 was still
obtained in better than 10:1 ratio (Scheme 5).5
Use of zinc chloride and zinc iodide reversed the tendency,
and a useful degree of stereoselection in favor of the syn
product 16 was realized. Magnesium bromide etherate was
the best additive in this case resulting in a complete
Scheme 4. Radical Cyclization of â-Alkoxyvinyl Sulfoxidesa
Preparatively, conversion of the vinyl sulfoxide 10c to the
tetrahydrofuran product 13 was the most efficient, from
which the aldehyde 15 was prepared via Pummerer re-
arrangement reaction. Allylation reaction was investigated
under a variety of conditions for chelation (leading to the
threo-syn-tetrahydrofuranyl allyl carbinol 16) or Felkin
stereocontrol (leading to the erythro-anti product 17). Reac-
tion of 15 with allyl Grignard reagent in ether at -78 °C
a Key: (1) 1.2 equiv of n-Bu3SnH, 1.5 equiv of Et3B, toluene,
-20 °C, 30 min. (a) The product ratio was determined by HPLC
analysis: Licrosorb, Hibar RT 250-4, Si 60, hexane/EtOAc ) 50:
50, flow rate ) 2 mL/min, column temperature ) 24.1 °C, detection
at 254 nm.
(3) For references, see: Lee, E. In Radicals in Organic Synthesis, Vol.
2: Applications; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; pp 303-333.
(4) Kosugi, H.; Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J. Org.
Chem. 1987, 52, 1078-1082.
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Org. Lett., Vol. 6, No. 12, 2004