The First General Synthesis of 1,5-Dioxaspirohexanes

Full text of DOI:10.1021/jo981309s

6098
J . Org. Chem. 1998, 63, 6098-6099
or basic conditions, this would appear to be a particularly
Th e F ir st Gen er a l Syn th esis of
1,5-Dioxa sp ir o[3.2]h exa n es
demanding transformation for which few of the commonly
used epoxidation reagents are appropriate. Dimethyldiox-
irane (DMDO) has been widely used for the oxidation of
alkenes to epoxides. It can be used under neutral conditions,
produces only inert byproducts, and allows even sensitive
epoxides such as those derived from enol ethers, enol silanes,
and enol esters to be prepared successfully.7 Crandall and
co-workers also described its use for the epoxidation of
allenes to R-hydroxyketones via allene oxides.8 We now wish
to report the successful oxidation of 2-methyleneoxetanes 2
to give 1,5-dioxaspiro[3.2]hexanes 1.
Albert J . Ndakala and Amy R. Howell*
Department of Chemistry, University of Connecticut,
Storrs, Connecticut 06269-3060
Received J uly 7, 1998
From the chemist’s perspective, strained ring systems
present a unique combination of challenge and opportunity.
The challenge undoubtedly arises from the fact that their
inherent instability means any successful syntheses must
employ reagents and conditions compatible with their
preparation and isolation. Conversely, the high reactivity
of mono- and bicyclic small rings under mild conditions,
particularly with respect to rearrangement reactions,1 means
that they can be invaluable for circumventing or minimizing
what would otherwise be long or tedious synthetic strategies.
In addition, the relative rigidity of small rings tends to confer
in them a potential for high chirality transfer such that a
single chiral center can be used to direct subsequent stereo-
selective transformations. Examples of these features can
be found in the chemical literature.1,2 Among heteroatom-
containing small rings, oxiranes and, to a lesser extent,
oxetanes have proved useful as synthetic intermediates
because of their accessibility and multiplicity of reactions.3
1,5-Dioxaspiro[3.2]hexanes 1 combine oxetane and oxirane
ring systems in a single entity. A survey of the literature,
however, indicates that only two examples have been
reported as unexpected outcomes of unrelated experiments,
one from the oxidation of a cumulene4 and the other from
the dimerization of a pyrilium salt.5 Thus, they are a class
of compounds that has not been accessible by any generally
applicable synthetic methodology. The unique structure of
this ring system suggests a number of promising areas of
study, including an investigation of their ring opening and
rearrangement reactions. In this paper, we describe the first
general method for the synthesis, isolation, and character-
ization of 1.
Our initial study of the epoxidation reaction was con-
ducted with 2-methyleneoxetane 2a . DMDO prepared in
acetone9 gave inconsistent results with yields varying
between successive runs. This was attributed to the reactiv-
ity of the products and the difficulty in obtaining rigorously
dry acetone. More successful, however, was the use of the
recently reported anhydrous, “acetone free” DMDO.10 Under
these conditions, epoxidation was essentially quantitative
as can be seen from Table 1. The reactivity of the enol ether
exceeded that of a monosubstituted alkene as evidenced by
the regioselective oxidation of 2c to 1c. However, the
addition of more DMDO caused further oxidation of the
terminal alkene to give the bis-epoxide 1d also in quantita-
tive yield. The formation of the parent 1,5-dioxaspiro[3.2]-
hexane 1f was obvious from the proton NMR spectrum of
the crude reaction mixture, but its enhanced volatility and
decreased stability have, thus far, precluded its isolation.
As expected, TBDPS (1e) and TBDMS (1g) ethers survive
the reaction conditions, and this will facilitate the selective
manipulation of the three hydroxy groups obtained from
hydrolysis of these two compounds (vide infra). The pres-
ence of a BOC group, a carbamate NH, and an allyl residue
in compounds 1h and 1i was also well tolerated.
The diastereoselectivities of the epoxidation reactions
were deduced from the proton NMR spectra. Excellent
diastereoselectivities were observed for a single substituent
at C3 (1a , 1h , and 1i). When a second group was introduced
at the same position, diastereoselectivity was highest when
there was a disparate size between the two groups (cf.
compounds 1b vs 1c and 1d ). These effects were compro-
mised, however, by additional substituents. For example,
both 1e, which has a single substituent at C3 but a geminal
dimethyl group at C4, and 1g, having a trans 3,4-disubsti-
tution pattern, exhibited little diastereoselectivity. It should
be noted at this point that hydrolysis of 1 to give R,â′-
dihydroxy ketones does not result in a chiral center at either
of the two positions arising from the epoxide (ketone and
primary alcohol, respectively), and thus, the issue of
diastereoselectivity is less important than it might appear.
The most direct route to 1 would seemingly involve the
epoxidation of 2-methyleneoxetanes 2, a ring system for
which we have recently described the first general synthe-
sis.6 Given the likely susceptibility of 1 to even mildly acidic
* To whom correspondence should be addressed. Tel.: (860) 486-3460.
Fax: (860) 486-2981. E-mail: howell@nucleus.chem.uconn.edu.
(1) (a) Halton, B. Advances in Strain in Organic Chemistry; J AI Press:
London, 1993; Vol. 3. (b) Bronson, J . J .; Danheiser R. L. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 5, pp 999-1035.
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1997, 38, 7819-7820. (b) Ponten, F.; Magnusson, G. J . Org. Chem. 1997,
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M. E.; MacDonald, T. L. J . Med. Chem. 1997, 40, 3838-3841.
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S0022-3263(98)01309-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/13/1998

Communications
J . Org. Chem., Vol. 63, No. 18, 1998 6099
Ta ble 1
at C3 in compounds 2a , 2h , and 2i, as additional substitu-
ents decrease stereoselectivity.
The internal acetal unit found in the 1,5-dioxaspiro[3.2]-
hexanes 1 should make them particularly susceptible to ring-
opening reactions. For hydrolysis, this appears to be indeed
the case. For example, treatment of 1e with a water/THF
mixture in the absence of any acid gives 3 in 97% yield.
In conclusion, we have reported what we believe to be the
first general synthesis of the 1,5-dioxaspiro[3.2]hexane
framework, demonstrating tolerance of a number of func-
tional groups. We are currently evaluating the reactivity
of these systems and will disclose the results shortly.
Ack n ow led gm en t . This work was supported by the
University of Connecticut Research Foundation. Support
by donors of the Petroleum Research Fund, administered
by the American Chemical Society, is gratefully acknowl-
edged. A.R.H. thanks the NSF for a CAREER Award. We
are grateful for some helpful discussions with Prof. Mes-
seguer, Department of Biological Chemistry, CID (CSIC),
Barcelona, regarding his preparation of “acetone free”
DMDO.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and characterization data for all new compounds, as well
as proton NMR for compounds 1a ,b,d ,i (14 pages).
These data are best explained if epoxidation occurred from
the face of the alkene oriented trans to the single substituent
J O981309S