Practical designed syntheses of all stereoisomeric bis(2,2′)- and tris(2,2′,2″)-tetrahydrofurans

Article abstract of DOI:10.1021/ol0608350

A convenient synthetic entry to the entire group of bis(2,2′)- and tris(2,2′,2″)-tetrahydrofurans has been developed. The method is concise and relies on chromatographic separation, decarbonylation, and annulation to arrive at a specific product of define

Full text of DOI:10.1021/ol0608350

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2635-2637
Practical Designed Syntheses of All
Stereoisomeric Bis(2,2 )- and
Tris(2,2 ,2′′)-tetrahydrofurans
′
′
Leo A. Paquette,* David G. Hilmey, and Judith C. Gallucci
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received April 6, 2006
ABSTRACT
A convenient synthetic entry to the entire group of bis(2,2′)- and tris(2,2′,2′′)-tetrahydrofurans has been developed. The method is concise and
relies on chromatographic separation, decarbonylation, and annulation to arrive at a specific product of defined relative configuration.
Structurally unusual oligo-tetrahydrofurans exemplified by
threo-1 and erythro-2 are of interest for a variety of reasons.
Their ladder-like arrays of oxygen atoms hold the prospect
of binding to cations provided that appropriate conformations
are attainable. The particular three-dimensional features will
depend on a number of factors including control by gauche
effects1 and steric interactions. Interestingly, should the
stereoalignment depicted for 1 be adopted, the termini of
the zigzag chain will continue to be projected in opposite
in-plane directions. Comparable alignment of the oxygen
centers in 2 results instead in twisting of the chain such that
a helical conformation develops (not illustrated). Further-
more, both termini are in this instance properly oriented to
propagate the coiling. While this analysis is somewhat con-
jectural at this time, polyoxymethylene, (OCH2CH2)n, is
known to adopt a gauche rather than a perfectly staggered
spatial arrangement and consequently to assume an overall
helical shape.2
Notwithstanding the considerable promise offered by 1 and
2, minimal progress has been made in accessing this class
of molecules. The major challenge has been the development
of a synthetic route capable of unambiguously distinguishing
the simplest members of the bis(THF) pair 3 and 4.3 In 2004,
Alexakis and co-workers reported an enantioselective ap-
proach to 4.4 However, an unequivocal route to 3 has not
yet been realized, and the tris(THF) subset 5-7 remains
entirely unknown. Herein, we define the means for as-
(2) (a) Ohsaku, M.; Imamura, A. Macromolecules 1978, 11, 970. (b)
Abe, A.; Mark, J. E. J. Am. Chem. Soc. 1976, 98, 6468. (c) Eliel, E. L.
(1) (a) Zefirov, N. S. Tetrahedron 1977, 33, 3193. (b) Zafirov, N. S.;
Samoshin, V. V.; Subbotin, O. A.; Baranenkov, V. I.; Wolfe, S. Tetrahedron
1978, 34, 2953. (c) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry
of Organic Compounds; John Wiley: New York, 1994; pp 605-615.
Acc. Chem. Res. 1970, 3, 1.
(3) Kelly, D. R.; Nally, J. Tetrahedron Lett. 1999, 40, 2209 and references
therein.
(4) Alexakis, A.; Tomassini, A.; Leconte, S. Tetrahedron 2004, 60, 9479.
10.1021/ol0608350 CCC: $33.50
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Published on Web 05/16/2006

sembling all five key compounds. The pathway makes
allowance for the independent selection of two options. The
first allows for the chromatographic separation of diastereo-
mers in tandem with crystallographic corroboration of struc-
ture. The companion reaction channel allows for use of the
same scaffolding to reach 5-7 in concise fashion.
achieved by wholesale desilylation and subsequent mono-
protection. The aldehyde produced upon the Swern oxidation
of 10 proved to be an ideal substrate for second-stage
cyclization. It was well appreciated that use had ultimately
to be made of both 11 and 12, and the availability of these
two intermediates in a 1:1 ratio was well suited to this
objective. Moreover, these bis(THF) derivatives proved to
be readily separated by chromatography on silica gel.
Once pure samples of 11 and 12 became available in this
way, each was individually transformed via their free
alcohols into aldehydes 14 and 17, respectively (Scheme 2).
Scheme 2. Independent Access to the Bis(THF) Aldehydes
Realization of the proper atom connectivity began by
coupling of the Normant reagent5 with the known ketone 86
(Scheme 1). Without purification, the resulting diol was
Scheme 1. Generation of Pure Siloxymethyl (2,2)-Bis(THF)
Diastereomers
Thereafter, relative stereochemistries were rigorously estab-
lished on the basis of an X-ray crystallographic determination
of 2,4-dinitrophenylhydrazone 15 (see Figure 1). Elucidation
regioselectively monotosylated at the primary carbinol site.
Spontaneous cyclization ensued7 to generate 9 in 83% overall
yield (Scheme 1). The desymmetrization of 9 was preferably
(5) (a) Cahiez, G.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1978,
3013. (b) Conley, R. T.; Annis, M. C. J. Org. Chem. 1962, 27, 1961. (c)
Ibuka, T.; Mitsui, Y.; Kayashi, K.; Minakata, H.; Inubushi, Y. Tetrahedron
Lett. 1981, 22, 4425. (d) Ibuka, T.; Minakata, H.; Mitsui, Y.; Hayashi, K.;
Taga, T.; Inubushi, Y. Chem. Pharm. Bull. 1982, 30, 2840.
Figure 1. ORTEP diagram of 15.
(6) Calter, M. A.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002, 4, 209.
(7) (a) Negri, J. T.; Rogers, R. D.; Paquette, L. A. J. Am. Chem. Soc.
1991, 113, 5073. (b) Paquette, L. A.; Negri, J. T.; Rogers, R. D. J. Org.
Chem. 1992, 57, 3947. (c) Paquette, L. A.: Stepanian, M.; Mallavadhani,
U. V.; Cutarelli, T. D.; Lowinger, T. B.; Klemeyer, H. J. J. Org. Chem.
1996, 61, 7492.
of these details allowed advances to be made into projected
decarbonylation studies. Early definitive work by Walborsky
and Allen8 involving this reaction constituted important
2636
Org. Lett., Vol. 8, No. 12, 2006

tion prompted clean conversion to 3 and 4, respectively,
without any evidence for the admixture of diastereomers
(Scheme 3).
Scheme 3. Branching of the Reaction Pathways
We were now in a position to introduce the third THF
subunit. In the case of 14, reaction with the Normant reagent
followed by ring closure afforded a pair of readily separable
tris(THF) diastereomers. The stereochemical assignments to
these products awaited the comparable processing of 17.
Once again, low diastereoselectivity was observed, thereby
indicating that chelate control was not operating effectively
in either series. This behavior parallels the response cus-
tomarily seen for the 1,2-addition of Grignard reagents to
highly substituted aldehydes9 and was not unexpected.
Relevantly, the minor product formed in these experiments
proved to be identical and must therefore be 6. On this basis,
the relative configurational assignments to 5 and 7 can be
confidently assigned.
In summary, direct routes to 3-7 have been developed
that allow each target to be generated in stereochemically
pure condition. Issues surrounding the assignment of con-
figuration have been resolved in their entirety. While the
two non-meso structures 4 and 6 have been made available
in racemic condition, opportunities for accessing them
enantioselectively are available at several stages. We continue
to examine the ligating properties and preferred conforma-
tional features of these polytetrahydrofuranyl networks.
Acknowledgment. Financial support of this work was
generously provided by the Astellas USA Foundation and
Sanofi-Aventis.
Supporting Information Available: Experimental pro-
cedures and spectroscopic (1H/13C NMR) characterization for
all new compounds, as well as crystallographic details for
15. This material is available free of charge via the Internet
at http://pubs.acs.org.
precedent. These workers determined that optically active
aldehydes bearing an adjacent stereocenter experience loss
of CO with retention of configuration irrespective of the
particular hybridization at the seat of reaction. Indeed, heating
14 as well as 17 with Wilkinson’s catalyst in xylene solu-
OL0608350
(8) Walborsky, H. M.; Allen, L. E. J. Am. Chem. Soc. 1971, 93, 5465.
(9) For example: Paquette, L. A.; Wiedeman, P. E.; Bulman-Page, P.
C. J. Org. Chem. 1988, 53, 1441.
Org. Lett., Vol. 8, No. 12, 2006
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