Stereoselection in radical cyclization of β-alkoxyvinyl sulfoxides: Synthesis of tetrahydrofuranyl allyl carbinols

Article abstract of DOI:10.1021/ol049676f

Equation presented. Tetrahydrofuranyl allyl carbinols may be prepared stereoselectively via radical cyclization of β-alkoxyvinyl sulfoxides, Pummerer rearrangement, and reaction with allylstannane.

Full text of DOI:10.1021/ol049676f

ORGANIC
LETTERS
2004
Vol. 6, No. 12
1895-1897
Stereoselection in Radical Cyclization of
â-Alkoxyvinyl Sulfoxides: Synthesis of
Tetrahydrofuranyl Allyl Carbinols
,†
Gyochang Keum,† Soon Bang Kang,‡ Youseung Kim,‡ and Eun Lee*
School of Chemistry and Molecular Engineering, Seoul National UniVersity,
Seoul 151-747, Korea, and Biochemicals Research Center, Korea Institute of Science
and Technology, Seoul 130-650, Korea
eunlee@snu.ac.kr
Received February 24, 2004
ABSTRACT
Tetrahydrofuranyl allyl carbinols may be prepared stereoselectively via radical cyclization of â-alkoxyvinyl sulfoxides, Pummerer rearrangement,
and reaction with allylstannane.
Tetrahydrofuranyl carbinols are familiar motifs in numerous
natural product structures with high biological activities.1 We
were interested in developing general methods for generation
of the tetrahydrofuranyl carbinol derivatives A and B. One
possibility would be allylation of the tetrahydrofuranyl
aldehydes C, which may be obtained from Pummerer
rearrangement of the corresponding sulfoxides D. Radical
cyclization of â-alkoxyvinyl sulfoxides E prepared from
secondary alcohols F would then be the first reaction of the
sequence (Scheme 1).
4a in 70:30 ratio. The (Z)-derivative 2a was converted into
a 12:88 mixture of 3a and 4a (Scheme 2). The stereoselec-
tivity was explained invoking s-trans vinyl sulfoxide transi-
tion-state conformations for radical cyclization. Better ste-
reoselectivities were obtained for dimethyl derivatives 1b
and 2b.
In the 5-exo radical cyclization reactions of â-alkoxyvinyl
sulfoxides prepared from secondary alcohols, the intrinsic
preference for the formation of cis-2,5-disubstituted tetrahy-
Stereochemical aspects of radical cyclization of â-alkoxy-
vinyl sulfoxides have already been discussed. Malacria and
co-workers reported that radical cyclization reactions of
optically pure â-alkoxyvinyl sulfoxides led to significant
diastereoselection.2 In their work, radical cyclization of the
substrate 1a resulted in the formation of the products 3a and
Scheme 1. Tetrahydrofuranyl Allyl Carbinols
† Seoul National University.
‡ Korea Institute of Science and Technology.
(1) Annonaceous acetogenins are representative examples. See, for
example: Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.;
McLaughlin, J. L. Nat. Prod. Rep. 1996, 275-306.
(2) Zahouily, M.; Journet, M.; Malacria, M. Synlett 1994, 366-368.
10.1021/ol049676f CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/13/2004

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.
1896
Org. Lett., Vol. 6, No. 12, 2004

presence of magnesium bromide etherate also proceeded
stereoselectively producing 16 as the sole product in high
yield.
Scheme 5. Pummerer Rearrangement and Allylationa
In summary, double stereoselection in radical cyclization
reaction of â-alkoxyvinyl sulfoxides presents a viable route
for stereoselective synthesis of tetrahydrofuranyl allyl carbinols
when coupled with subsequent Pummerer rearrangement and
allylstannane reaction. Application of the strategy in the
synthesis of oxacyclic natural products will be reported in
due course.
Acknowledgment. We thank the Ministry of Science and
Technology, Republic of Korea, and KISTEP for a National
Research Laboratory grant (1999).
Supporting Information Available: Selected experi-
1
mental procedures and H and 13C NMR spectra of 11, 13,
and 15-17. This material is available free of charge via the
Internet at http://pubs.acs.org.
a Key: (1) TFAA, pyridine, MeCN, 30 min; KOAc, H2O, 2 h.
(a) Addition of allylstannane or allylsilane into a solution containing
15 and Lewis acid. (b) Addition of Lewis acid into a solution
containing 15 and allylstannane. (c) Diastereomeric ratio was
determined by capillary GC analysis.
OL049676F
(5) The results are contrary to expectation. There is an example of a
related system in which SnCl4 was used as a Lewis acid in chelation-
controlled Sakurai reaction: Koert, U.; Stein, M.; Wagner, H. Liebigs Ann.
1995, 1415-1426. In our case, it may be important to realize that there are
three oxygen atoms per molecule for coordination.
(6) Use of magnesium bromide for chelation-controlled allyl transfer
reaction for a R-benzyloxyaldehyde was reported: Keck, G. E.; Boden, E.
P. Tetrahedron Lett. 1984, 25, 265-268.
stereocontrol,6 and 16 was obtained in high yield as the
exclusive product. Reaction of (allyl)trimethylsilane in the
Org. Lett., Vol. 6, No. 12, 2004
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