Synthesis of diastereomerically and enantiomerically pure 2,3-disubstituted tetrahydrofurans using a sulfoxonium ylide

Article abstract of DOI:10.1021/ja0469075

Nucleophilic substitution reactions of 2,3-epoxy alcohols, easily prepared via Sharpless asymmetric epoxidation chemistry, offer access to a wide variety of enantiomerically pure compounds. In this communication, we describe the use of a Payne rearrangement to control regioselectivity in the ring-opening of a series of 2,3-epoxy alcohols with dimethylsulfoxonium methylide to yield diastereomerically and/or enantiomerically pure disubstituted tetrahydrofuran rings. The factors influencing the success and substitution pattern of the THF ring products are discussed, including steric, electronic, and solvent effects. Copyright

Full text of DOI:10.1021/ja0469075

Published on Web 09/29/2004
Synthesis of Diastereomerically and Enantiomerically Pure 2,3-Disubstituted
Tetrahydrofurans Using a Sulfoxonium Ylide
Jennifer M. Schomaker, Veera Reddy Pulgam, and Babak Borhan*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48823
Received May 25, 2004; E-mail: borhan@cem.msu.edu
Scheme 1
Nucleophilic substitution reactions of 2,3-epoxy alcohols, easily
accessed via Sharpless asymmetric epoxidation, are a useful method
for the preparation of many types of enantiomerically enriched
compounds.1-10 We were interested in transferring the chirality of
an epoxy alcohol to a tetrahydrofuran (THF) via a ring expansion
reaction. It was envisioned that this could be accomplished by
attacking the epoxide with a carbon-based nucleophile containing
within itself a good leaving group.
A common reaction illustrating the use of such a nucleophile is
the Wittig olefination.11,12 Preliminary screening of phosphonium,
Scheme 2
ammonium, arsenium, and sulfur-based ylides prompted the use
of dimethylsulfoxonium methylide, an ylide useful for the prepara-
tion of oxetanes from epoxides.13,14 The heat stability, reactivity,
and easy preparation of this ylide15 allows convenient access to
2,3-disubstituted THF rings in a highly diastereoselective and
enantioselective fashion. The overall strategy is depicted in Scheme
checked by preparing the MPA esters in order to ensure that
1. Asymmetric epoxidation of allylic alcohols such as 1 and 4 yields
racemization was not taking place under the prescribed reaction
epoxides 2 and 5, respectively. The reaction of 2 and 5 with the
ylide generated from trimethylsulfoxonium iodide affords the 2,3-
disubstituted THF rings 3 and 6 in good yields with complete
control of stereochemistry.16 Thus, a cis epoxide yields the
corresponding cis-disubstituted THF ring while the trans epoxide
gives the trans-disubstituted THF ring.
conditions.
Compounds containing an oxygen substituent at C4 of the epoxy
alcohol were good substrates for the Payne rearrangement/ring-
opening/cyclization sequence (Scheme 1 and Table 1, entry 1).8 In
the case of trans epoxy alcohols, products arising from attack at
carbons other than C1 were seen, although in most cases, these
impurities could be easily separated from the desired product.
Presumably, the Payne equilibrium strongly favors the initial 2,3-
epoxy alcohol for trans epoxy alcohols, while the composition of
isomeric epoxy alcohols for cis substrates tends to be more evenly
distributed due to steric interaction between substituents at C1 and
C4 of the cis-2,3-epoxy alcohol.17 Epoxy alcohols containing an
oxygen at C5 or even at C6 were successfully transformed to the
desired THF rings (entries 2-5), although the yields dropped with
increasing carbons in the side chain. Compounds containing simple
alkyl substituents (entries 9-10) gave poor yields due to lack of
good selectivity during the nucleophilic attack by the ylide (C3
attack as a major product). Slow addition of the nucleophile to the
equilibrating mixture of epoxy alcohols has been reported to
partially solve the regioselectivity problem8 but was not particularly
successful in our system.
Not surprisingly, nucleophilic addition at the benzylic position
was favored due to electronic stabilization of the transition state
when an aryl group was substituted at C3 of the epoxy alcohol
(entry 11) and the desired 2,3-substituted THF was obtained only
as a minor product (major product was 30). THF as the solvent
gave exclusively the 3,4-disubstituted product 30 (entry 12) as the
result of C3 attack in 51% yield. It was hoped that more highly
substituted epoxides (entries 14-17) might deter ylide attack at
C3; however, the tendency to favor the 2,3-epoxy alcohol in the
Payne equilibrium led to poor results except when the epoxide was
contained in a ring (entry 8) where the quaternary asymmetric center
could be effectively generated.
Regiochemical control afforded during the epoxide opening by
the nucleophilic ylide is paramount to the success of this reaction.
The Payne rearrangement reaction17,18 has been aptly demonstrated
by both Sharpless8 and Ganem19 to be an effective means of
favoring selective C1 attack of 2,3-epoxy alcohols. Sharpless in
particular has had great success in using sulfur nucleophiles to
access several acyclic diols with good control of regioselectivity.8
We have also found the Payne rearrangement to be useful for
controlling the regioselectivity in dimethylsulfoxonium ylide attack
on the epoxy alcohol. As illustrated in Scheme 2, the transformation
begins with the Payne rearrangement of the enantiomerically pure
2,3-epoxy alcohol 7 leading to the more sterically accessible
terminal epoxide 8. Nucleophilic epoxide opening with the ylide
at C1 leads to the generation of the bis-alkoxide 9, which can
undergo 5-exo-tet ring closure to yield the desired 2,3-disubstituted
THF ring 10 with complete stereochemical fidelity. There was no
evidence of oxetane formation via the 4-exo-tet closure.
A series of epoxy alcohols were synthesized using standard
methodologies. Table 1 lists the conversion of these substrates to
THF rings. In most cases, an excess of ylide greatly increased the
yield, perhaps due to decreased ylide stability at the elevated
reaction temperatures. Concentration was also crucial for the success
of the reaction in that concentrations greater than approximately
0.1 M in epoxy alcohol tend to give allylic alcohols via elimina-
tion20,21 rather than THFs via cyclization. The optical purities of
several of the epoxy alcohols and the corresponding products were
9
13600
J. AM. CHEM. SOC. 2004, 126, 13600-13601
10.1021/ja0469075 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Conversion of 2,3-Epoxy Alcohols to 2,3-Disubstituted THF Ringsa
a Typical reaction conditions (3.0-10.0 equiv trimethylsulfoxonium iodide, NaH, 0.1 M epoxy alcohol in DMSO, 80 °C, 36 h). b In THF with nBuLi as
the base.
Scheme 3
Since it is relatively simple to obtain 2,3-epoxy-alcohols in high
enantiomeric excess via the Sharpless asymmetric epoxidation, this
can be a powerful methodology in gaining entry into the synthesis
of THF rings with stereodefined substituents. Future work is focused
on methods to control regioselectivity of ylide attack, to increase
the extent of substitution by varying groups on the epoxide and
ylide, and to use this approach to synthesize larger rings.
Acknowledgment. Generous support was provided in part by
the Michigan Economic Development Corporation (GR-183). The
authors are thankful for contributions made by Ms. Abra Jeffers.
Utilization of the Payne rearrangement for regiochemical control
Supporting Information Available: Experimental procedures and
spectral data for compounds 3-45 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
was initially invoked since optically enriched 2,3-epoxy alcohols
can be generated with ease; however, in theory, any epoxide
containing a neighboring free hydroxyl available for cyclization
can be used provided the regiochemistry of ylide attack can be
controlled by steric or electronic factors. The substrates in Scheme
3 were prepared to circumvent the problems encountered with alkyl-
substituted epoxy alcohols such as 33 (Table 1, entry 14) in the
Payne rearrangement approach. The reaction could be performed
in either DMSO using ylide generated from trimethylsulfoxonium
iodide and NaH or in THF using ylide generated with nBuLi as
the base. It is known that THF retards Payne rearrangement and
thus is a good medium to promote direct attack of the epoxide with
ylide generated in situ.22 Thus, reaction of 41 (Payne rearranged
equivalent of 33, 2:1 mixture of diastereomers) yielded 34 and 34a
(epimeric at the hydroxyl bearing carbon) in better yields as
compared to the reaction of 33, which would require in situ Payne
rearrangement.
In some cases, such as 42, the choice of solvent is not important
(55% with THF, 56% with DMSO) but, more often than not, can
be crucial to the success of the reaction. For example, 44 was treated
with dimethylsulfoxonium methylide in both DMSO and tetrahy-
drofuran as solvents. In DMSO, the desired 40 (diastereomeric
mixture) was obtained in 18% yield and the elimination product in
27% yield, results similar to entry 17 in Table 1. However, when
the reaction was performed in THF as the solvent, 40 was obtained
in 53% yield (mixture of diastereoismers) with no evidence of
elimination products. Racemization was a problem with epoxide
45, since the enantiomeric compounds resulting from Payne
rearrangement both undergo indiscriminate attack by the ylide.
In conclusion, we have developed a new method for the synthesis
of 2,3-substituted THF rings. The stereochemistry that is set by
the asymmetric epoxidation is translated fully to the final product.
References
(1) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; Wiley-VCH: New York, 1993; pp 101-158.
(2) Sasaki, M.; Tanino, K.; Hirai, A.; Miyashita, M. Org. Lett. 2003, 5, 1789-
1791.
(3) Poch, M.; Alcon, M.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron
Lett. 1993, 34, 7781-7784.
(4) Choudary, B. M.; Rani, S. S.; Kantam, M. L. Synth. Commun. 1990, 20,
2313-2317.
(5) Kirshenbaum, K. S.; Sharpless, K. B. Chem. Lett. 1987, 11-14.
(6) Ko, S. Y.; Sharpless, K. B. J. Org. Chem. 1986, 51, 5413-5415.
(7) Behrens, C. H.; Sharpless, K. B. J. Org. Chem. 1985, 50, 5696-5704.
(8) Behrens, C. H.; Ko, S. Y.; Sharpless, K. B.; Walker, F. J. J. Org. Chem.
1985, 50, 5687-5696.
(9) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557-1560.
(10) Roush, W. R.; Brown, R. J.; Dimare, M. J. Org. Chem. 1983, 48, 5083-
5093.
(11) Walker, B. J. Organophosphorus Chem. 1996, 27, 264-307.
(12) Vedejs, E.; Peterson, M. J. In Topics in Stereochemistry; John Wiley &
Sons: New York, 1994; Vol. 21, pp 1-157.
(13) Okuma, K.; Tanaka, Y.; Kaji, S.; Ohta, H. J. Org. Chem. 1983, 48, 5133-
5134.
(14) Fitton, A. O.; Hill, J.; Jane, D. E.; Millar, R. Synthesis 1987, 1140-1142.
(15) Trost, B. M.; Melvin, L. S., Jr. Sulfur Ylides. Emerging Synthetic
Intermediates; Academic Press: New York, 1975; Vol. 31.
(16) Possible counterion influence in the conversion of 2 to 3 was investigated
with using Li, Na, and K salts. The isolated yields of 3 LiHMDS,
NaHMDS, and KHMDS as bases were 59%, 92%, and 82%, respectively.
Per the suggestion of the reviewer, microwave-assisted conversion of 2
to 3 with NaHMDS as the base in DMSO greatly reduced the reaction
time (30 pulses, 15 s/pulse) while maintaining a high yield of product
(see Supporting Information for details).
(17) Payne, G. B. J. Org. Chem. 1962, 27, 3819-3822.
(18) Hanson, R. M. Org. React. 2002, 60, 1-156.
(19) Wrobel, J. E.; Ganem, B. J. Org. Chem. 1983, 48, 3761-3764.
(20) Rickborn, B.; Thummel, R. P. J. Org. Chem. 1969, 34, 3583-3586.
(21) Alcaraz, L.; Cridland, A.; Kinchin, E. Org. Lett. 2001, 3, 4051-4053.
(22) Page, P. C. B.; Rayner, C. M.; Sutherland, I. O. J. Chem. Soc., Perkin
Trans. 1 1990, 1375-1382.
JA0469075
9
J. AM. CHEM. SOC. VOL. 126, NO. 42, 2004 13601