Efficient chirality transfer in the Sml2-mediated cyclization of aldehydo β-alkoxyvinyl sulfoxides: Asymmetric synthesis of 3-hydroxyoxanes

Article abstract of DOI:10.1021/ol071176+

Stereoselective syntheses of 3-hydroxyoxanes were achieved via efficient chirality transfer in the Sml₂-mediated cyclization reactions of aldehydo β-alkoxyvinyl sulfoxides.

Full text of DOI:10.1021/ol071176+

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3225-3228
Efficient Chirality Transfer in the
SmI2-Mediated Cyclization of Aldehydo
â
-Alkoxyvinyl Sulfoxides: Asymmetric
Synthesis of 3-Hydroxyoxanes
Jae Hoon Jung, Yong Wook Kim, Min Ah Kim, Soo Young Choi,
Young Keun Chung, Tae-Rae Kim, Seokmin Shin, and Eun Lee*
Department of Chemistry, College of Natural Sciences, Seoul National UniVersity,
Seoul 151-747, Korea
eunlee@snu.ac.kr
Received May 19, 2007
ABSTRACT
Stereoselective syntheses of 3-hydroxyoxanes were achieved via efficient chirality transfer in the SmI2-mediated cyclization reactions of aldehydo
-alkoxyvinyl sulfoxides.
â
Chiral sulfoxides are important intermediates in modern
asymmetric synthesis.1 Diastereoselective intermolecular
â-addition of alkyl radicals to chiral vinyl sulfoxides was
reported by Toru and co-workers.2 Malacria and co-workers
reported successful examples of asymmetric carbocycle
synthesis via diastereoselective intramolecular radical addi-
tion reactions of chiral vinyl sulfoxides.3 Stereochemical
aspects of asymmetric oxacycle synthesis via radical cy-
clization of chiral â-alkoxyvinyl sulfoxides prepared from
primary alcohols have been discussed by Malacria and co-
workers.4 In the radical cyclization of chiral â-alkoxyvinyl
sulfoxides prepared from secondary alcohols, the intrinsic
preference for formation of cis-2,5-disubstituted oxolanes
predominated, the sulfoxide chirality playing a secondary
role. Double stereoselection in this type of radical cyclization
provided a viable route for the stereoselective synthesis of
oxolanyl allyl carbinols when coupled with subsequent
Pummerer rearrangement and allylstannane reaction.5 This
protocol was used for the stereoselective synthesis of
rolliniastatin 1 and jimenezin.6
Cyclization of aldehydo â-alkoxyvinyl sulfoxides under
reductive conditions offers opportunities of controlling two
stereocenters in 3-hydroxyoxane products via sulfoxide
chirality transfer. We report in this communication results
of the SmI2-mediated cyclization reactions of aldehydo
â-alkoxyvinyl sulfoxides, which led to stereoselective and
stereospecific preparation of 3-hydroxyoxanes (Scheme 1).
The reaction of the prototype aldehydo â-alkoxyvinyl
sulfoxide 1 with SmI2 in the presence of methanol proceeded
smoothly to yield a single 3-hydroxyoxane product 3 in 93%
yield (Scheme 2). Reaction of the (Z)-(S)-isomer 2 also
produced a single cyclization product 4.7 Dess-Martin
(1) (a) Ferna´ndez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651-3706. (b)
Pellissier, H. Tetrahedron 2006, 62, 5559-5601.
(2) Mase, N.; Watanabe, Y.; Ueno, Y.; Toru, T. J. Org. Chem. 1997,
62, 7794-7800.
(3) (a) Delouvrie˘, B.; Fensterbank, L.; Lacoˆte, E.; Malacria, M. J. Am.
Chem. Soc. 1999, 121, 11395-11401. (b) Brebion, F.; Vitale, M.;
Fensterbank, L.; Malacria, M. Tetrahedron: Asymmetry 2003, 14, 2889-
2896.
(5) Keum, G.; Kang, S. B.; Kim, Y.; Lee, E. Org. Lett. 2004, 6, 1895-
1897.
(6) (a) Keum, G.; Hwang, C. H.; Kang, S. B.; Kim, Y.; Lee, E. J. Am.
Chem. Soc. 2005, 127, 10396-10399. (b) Hwang, C. H.; Keum, G.; Sohn,
K. I.; Lee, D. H.; Lee, E. Tetrahedron Lett. 2005, 46, 6621-6623.
(4) Zahouily, M.; Journet, M.; Malacria, M. Synlett 1994, 366-368.
10.1021/ol071176+ CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/21/2007

Scheme 1. Reactions of â-Alkoxyvinyl Sulfoxides
Scheme 3. Transition State Structures for Reactions
of 1 and 2
sulfones 17 and 18, both of which were converted into a
single keto sulfone 20. A single sulfone 19 was obtained
from m-CPBA oxidation of 15 and 16. A second keto sulfone
21 was obtained via Dess-Martin oxidation of 19, which
confirms the trans-2,6-disubstitution pattern in the products
15 and 16.
oxidation of 3 led to a ketone product 5, which was identified
unambiguously as the (S,R) product.8 The alternative (S,S)
ketone 6 was obtained from 4. On the other hand, m-CPBA
oxidation of 3 and 4 produced two sulfone diastereomers 7
and 8, confirming the structural assignments.
Scheme 4. Synthesis of 3-Hydroxyoxanes from â-Alkoxyvinyl
Sulfoxides 9-12
Scheme 2. SmI2-Mediated Cyclization of â-Alkoxyvinyl
Sulfoxides 1 and 2
The SmI2-mediated 6-exo cyclization reactions of aldehydo
â-alkoxyvinyl sulfoxides were indeed stereoselective and
stereospecific. The observed stereoselectivity may be ex-
plained by proposing the “eclipsed lone pair”3a transition
states A and B, in which the sulfoxide oxygen-coordinated
samarium ketyl group necessarily approaches the double
bond opposite from the bulky aryl group (Scheme 3).9,10
Reactions of four â-alkoxyvinyl sulfoxides, 9-12, were
then investigated. A single product 13 was obtained from
SmI2-mediated cyclization of 9 in 90% yield. Likewise,
diastereomeric 3-hydroxyoxane derivatives 14-16 were
obtained from the reaction of 10-12 (Scheme 4). m-CPBA
oxidation of 13 and 14 produced a diastereomeric pair of
The transition state structures C and D for the reaction of
9 and 10 may be proposed following the rationale already
used for structures A and B (Scheme 5). In the transformation
of 11 into the product 15, the transition state structure E
appears to play an important role. It is more difficult to
propose a transition state structure for the 12-16 conversion;
in fact, the expected product would be 22 via the transition
state structure G. A possible transition state structure F for
conversion of 12 into 16 does not adopt the familiar chairlike
conformation through sulfoxide oxygen-samarium coordi-
nation.
(7) In this case, the product 4 was obtained in low yield; a large quantity
of the retro hetero-Michael product was obtained.
(8) CCDC-645184 contains the supplementary crystallographic data for
this paper. This data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(9) For results of an ab initio study on the conformations of methyl vinyl
sulfoxide, see: Tietze, L. F.; Schuffenhauer, A.; Schreiner, P. R. J. Am.
Chem. Soc. 1998, 120, 7952-7958.
(10) Results of ab initio calculations on (E)-(S)- and (Z)-(S)-phenyl
â-methoxyvinyl sulfoxides are presented in the Supporting Information. In
both cases, global minimum structures were obtained with the sulfur lone
pair electrons syn coplanar with respect to the double bonds.
Extension of this method for synthesis of hydroxyoxolanes
was not straightforward. In practice, the unstable aldehyde
substrates obtained from the primary alcohol precursors via
3226
Org. Lett., Vol. 9, No. 17, 2007

tion in contrast to the results in the 6-exo cyclizations.
Presumably, sulfoxide oxygen-samarium coordination is less
important in the 5-exo cyclization reactions, which should
be much faster than the 6-exo cyclization. The intrinsic
preference for formation of cis-2,5-disubstituted oxolanes
prevails in these cases, and transition states H-K may be
proposed for the conversion of 23-26 (Scheme 7).
Scheme 5. Transition State Structures for Reactions of 9-12
Scheme 7. Transition State Structures for Reactions of 23-26
Dess-Martin oxidation were directly reacted with samarium
iodide for 5-exo cyclization reactions. Adopting this protocol,
a single hydroxyoxolane product 27 was obtained from
aldehyde 23 in 68% (two steps) yield. The reaction of
alternative aldehydes 24-26 afforded the products 28-30
stereoselectively. A single sulfone product 31 was obtained
from the m-CPBA oxidation of sulfoxides 27 and 28. A
second sulfone 32 was obtained from sulfoxides 29 and 30.
Sulfones 31 and 32 were converted into a single keto sulfone
33 (Scheme 6).
The results may be summarized as follows.
(1) In the 6-exo cyclization of aldehydo (Z)-â-alkoxyvinyl
sulfoxides (10 and 11), sulfoxide chirality transfer through
the sulfoxide oxygen-samarium coordination determines the
stereochemistry of the newly generated stereogenic centers
at C-2 and C-3 regardless of the carbinol chirality. The
intrinsic preference for cis-2,6-disubstituted oxane may be
overruled, and trans-2,6-disubstituted oxane 15 is formed
from 11.
It is to be emphasized that only cis-2,5-disubstituted
3-hydroxyoxolane products were obtained via 5-exo cycliza-
(2) Concerning the 6-exo cyclization of aldehydo (E)-â-
alkoxyvinyl sulfoxides, stereoselectivity may easily be
predicted in the matched case (9), but it is difficult to suggest
the correct transition state structure in the mismatched case
(12). The importance of the sulfoxide oxygen-samarium
coordination is not evident in the mismatched case.
(3) In the 5-exo cyclization of aldehydo (E)- and (Z)-â-
alkoxyvinyl sulfoxides (23-26), the sulfoxide oxygen-
samarium coordination is not important, and cis-2,5-
disubstituted oxolanes are formed regardless of the sulfoxide
chirality. The C-3 configuration of the 3-hydroxyoxolane
products may be predicted by considering sterically less-
hindered transition state structures.
Scheme 6. Synthesis of 3-Hydroxyoxolanes from
â-Alkoxyvinyl Sulfoxides 23-26
The oxacyclic products obtained in the present studies may
serve as precursors in further transformations. For example,
sodium amalgam reduction of the sulfone functional group
in 31 and reductive debenzylation by Raney nickel afforded
the known diol 34,11 which constitutes a formal synthesis of
(+)-epimuscarine (35)12 (Scheme 8).
(11) (a) Mubarak, A. M.; Brown, D. M. J. Chem. Soc., Perkin Trans. 1
1982, 809-813. (b) Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc. 2002,
124, 3608-3613.
(12) For more recent syntheses of 35, see: (a) Hartung, J.; Kneuer, R.
Tetrahedron: Asymmetry 2003, 14, 3019-3031. (b) Popsavin, V.; Beric´,
O.; Popsavin, M.; Radic´, L.; Csana´di, J.; CÄ irin-Novta, V. Tetrahedron 2000,
56, 5929-5940.
Org. Lett., Vol. 9, No. 17, 2007
3227

Acknowledgment. This work was supported by a grant
from MarineBio21, Ministry of Maritime Affairs and Fisher-
ies, Korea, and by a grant from the Korea Research
Foundation (MOEHRD) (KRF-2005-070-C00073). Brain
Korea 21 graduate fellowship grants to J. H. Jung, Y. W.
Kim, and M. A. Kim and a Seoul Science Fellowship grant
to J. H. Jung are gratefully acknowledged.
Scheme 8. Formal Synthesis of Epimuscarine
Supporting Information Available: Experimental pro-
1
cedures (36 pages) and H NMR and 13C NMR spectra of
The method described in this communication opens up
new ways for the preparation of functionalized oxacycles,
which will facilitate syntheses of complex natural products
and bioactive molecules.
the intermediates and products (48 pages). This material is
available free of charge via the Internet at http://pubs.acs.org.
OL071176+
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