Ring opening of 1,5-dioxaspiro[3.2]hexanes: Selective preparation of α-heterofunctionalized-β′-hydroxy ketones or 2,2-disubstituted oxetanes

Article abstract of DOI:10.1021/ol990039c

(equation presented) 2-Methyleneoxetanes have been converted into 1,5-dioxaspiro[3.2]hexanes with dimethyldioxirane. Reaction of the dioxaspirohexanes with a range of heteroatom nucleophiles, hydride donors, or organoaluminum reagents was successful under

Full text of DOI:10.1021/ol990039c

ORGANIC
LETTERS
1999
Vol. 1, No. 6
825-827
Ring Opening of
1,5-Dioxaspiro[3.2]hexanes: Selective
Preparation of
r-Heterofunctionalized-â′-hydroxy
Ketones or 2,2-Disubstituted Oxetanes
,†
Amy R. Howell* and Albert J. Ndakala
Department of Chemistry, UniVersity of Connecticut, Storrs, Connecticut 06269-3060
howell@nucleus.chem.uconn.edu
Received April 15, 1999
ABSTRACT
2-Methyleneoxetanes have been converted into 1,5-dioxaspiro[3.2]hexanes with dimethyldioxirane. Reaction of the dioxaspirohexanes with a
range of heteroatom nucleophiles, hydride donors, or organoaluminum reagents was successful under neutral or mild conditions, affording,
selectively, polyfunctionalized ketones or 2,2-disubstituted oxetanes.
We have recently developed the first general synthesis of
2-methyleneoxetanes1 and have begun to investigate the
reactivity of this fascinating class. We anticipated that the
electron-rich enol ethers should undergo facile epoxidation
to give 1,5-dioxaspiro[3.2]hexanes, a reaction that had
precedent in the oxidation of allenes to allene oxides and
1,4-dioxaspiro[2.2]pentanes developed by Crandall and co-
workers.2 Indeed, after some experimentation we found that
treatment of 2-methyleneoxetanes with anhydrous dimeth-
yldioxirane (DMDO)3 produced the corresponding dioxa-
spirohexanes in excellent yield.4 Although we appreciated
the unusual structure of this class of compounds (a search
of the literature revealed no general preparation and only
two previous examples of 1,5-dioxaspiro[3.2]hexanes as
unexpected outcomes of unrelated experiments),5 we were
more interested in exploiting their presumed lability.
Our initial goal was to investigate the reactivity of 1,5-
dioxaspiro[3.2]hexanes, particularly to ring-opening reac-
tions. In principle, attack by nucleophiles could occur at C-2
or C-6 (Scheme 1), as either would release the considerable
strain energy in these molecules, and ring openings of both
oxetanes and oxiranes are known.6 We might anticipate,
however, that attack at C-6 would be preferred due to the
greater reactivity of oxiranes. A third possibility (Scheme
1), reaction at C-4 resulting in ring opening of the oxirane
alone, was deemed less likely but could not be discounted.
In general, ring-opening reactions of epoxides require the
use of highly reactive organometallic reagents or the as-
Scheme 1
† Phone (860) 486-3460. Fax (860) 486-2981.
(1) Dollinger, L. M.; Howell, A. R. J. Org. Chem. 1996, 61, 7248-
7249.
(2) Crandall, J. K.; Batal, D. J.; Sebesta, D. P.; Lin, F. J. Org. Chem.
1991, 56, 1153-1166.
(3) Ferrer, M.; Gibert, M.; Sanchez-Baeza, F.; Messeguer, A. Tetrahedron
Lett. 1996, 37, 3585-3586.
(4) Ndakala, A. J.; Howell, A. R. J. Org. Chem. 1998, 63, 6098-6099.
(5) (a) Crandall, J. K.; Salazar, G. E.; Watkins, R. J. J. Am. Chem. Soc.
1987, 109, 4338-4341. (b) Ullman, E. F.; Henderson, W. A. J. Am. Chem.
Soc. 1966, 88, 4942-4960.
10.1021/ol990039c CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/31/1999

sistance of Lewis acids to be effective. Two factors, however,
can make oxirane ring opening much less demanding. The
presence of a heteroatom on the epoxide greatly enhances
its susceptibility to cleavage, and this has been used as a
valuable approach to R-functionalized carbonyl compounds.7
In other cases, the release of strain energy associated with
opening some simple or polycyclic epoxides makes them
undergo ring opening or rearrangement reactions under mild
conditions.8 Dioxaspiro[3.2]hexanes contain both of these
reactivity-enhancing elements, and we expected them to be
sensitive to neutral C-O bond cleavage. This expectation
appeared justified when treatment of 1b with water in the
absence of any acid or base gave the ring-opened dihydroxy
ketone 2b in nearly quantitative yield (eq 1). This prompted
us to investigate a number of other nucleophiles in this
reaction, and herein, we report our results.
Table 1
Oxygen-centered nucleophiles such as water and alcohols
are effective without added base (Table 1). A TBDPS ether
(2b) and a carbamate (2c), as expected, survive these mild
conditions. The hydrolysis of 1,5-dioxaspiro[3.2]hexanes
proceeded somewhat more slowly than the corresponding
reactions of 1,4-dioxaspiro[2.2]pentanes as performed by
Crandall and co-workers2 (2 d vs 2 h), and a similar time
differential was noted on reaction with propanol. However,
in the latter case potassium carbonate or sodium hydride was
used by Crandall to accelerate the alcoholysis. Other differ-
ences in the reactivity of these two systems were noted. Thus,
thiophenol alone is effective in ring cleavage of 1,4-
dioxaspiro[2.2]pentanes (21 h, 55%)2 but not 1,5-dioxaspiro-
[3.2]hexanes (2h, 7 d, 30%). However, the thiophenoxide
anion is, not surprisingly, much more effective (2i, 2h, 70%).
Among other nucleophiles, acetate works well (2f) but not
imidazole (2g). So far, we have not been able to efficiently
promote ring opening of dioxaspirohexanes with amines.
Although there are many methods for the preparation of
a Pelter, A.; Vaughan-Williams, G. F.; Rosser, R. M. Tetrahedron 1993,
49, 3007-3034.
(6) (a) Katsuki, T.; Martin, V. S. In Organic Reactions; John Wiley and
Sons: New York, 1996; Vol. 48, pp 1-299. (b) Katsuki, T. Coord. Chem.
ReV. 1995, 140, 189-214. (c) Jacobsen, E. N. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 159-202. (d) Chini,
M.; Crotti, P.; Favero, L.; Macchia, F. Tetrahedron Lett. 1994, 35, 761-
764. (e) Ishihara, K.; Hanaki, N.; Yamamoto, H. J. Am. Chem. Soc. 1993,
115, 10695-10704. (d) Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M.
Tetrahedron Lett. 1994, 35, 7089-7092. (e) Bach, T.; Schroder, J.
Tetrahedron Lett. 1997, 38, 3707-3710.
R-functionalized ketones,9 they frequently encounter regi-
oselectivity problems, require organometallic reagents at low
temperature, or are limited to a single class of R heteroatom.
Consequently, this method appears to be competitively
versatile.
When we switched to nucleophiles that were not used in
Crandalls work, we observed some unexpected and interest-
ing results. Thus, lithium aluminum hydride proceeded as
above, giving the 1,3-diol (2j) as a 15:1 mixture of
(7) (a) Bailey, P. L.; Briggs, A. D.; Jackson, R. W. F.; Pietruszka, J. J.
Chem. Soc., Perkin Trans. 1 1998, 3359-3363. (b) Jackson, R. F. W.;
Palmer, N. J.; Wythes, M. J.; Clegg, W.; Elsegood, M. R. J. J. Org. Chem.
1995, 60, 6431-6440. (c) Satoh, T.; Yamakawa, K. Synlett 1992, 455-
468. (d) Ashwell, M.; Jackson, R. F. W. J. Chem. Soc., Chem. Commun.
1988, 645-647. (e) Adamczyk, M.; Dolence, E. K.; Watt, D. S.; Christy,
M. R.; Reibenspies, J. H.; Anderson, O. P. J. Org. Chem. 1984, 49, 1378-
1382. (f). Barone, A. D.; Snitman, D. L.; Watt, D. S. J. Org. Chem. 1978,
43, 2066-2068.
(9) Parkes K. E. B.; Richardson S. K. Ketones: Dialkyl Ketones. In
ComprehensiVe Organic Functional Group Transformations; Katritzky, A.
R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon Press: Oxford, 1995;
Vol 3, pp 111-204.
(8) Rickborn, B. Acid-catalyzed Rearrangements of Epoxides. In Com-
prehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon
Press: Oxford, 1991; Vol 3, pp 733-775.
826
Org. Lett., Vol. 1, No. 6, 1999

diastereoisomers, resulting presumably from initial reductive
ring opening of the dioxaspirohexane at C-6 and reduction
of the resulting intermediate â-hydroxy ketone. DIBAL,
however, gave a different result. There a dramatic reversal
in regioselectivity was observed arising from ring opening
at the least expected position, C-4, to give the oxetane 3a.
The formation of 3a can be rationalized by coordination of
the Lewis acid to the epoxide oxygen with possible partici-
pation of the oxonium ion 4. Other Lewis acid-linked
In 3a and 3c the relative stereochemistry, a trans relationship
between the incoming nucleophile and the phenyl group, was
determined by NOE experiments. The structure of 3b was
assigned by analogy with these two results.
In summary, we have demonstrated that 1,5-dioxaspiro-
hexanes are cleaved regioselectively to give polyheterofunc-
tionalized compounds, suitable for further elaboration. Our
preliminary results indicate that the regioselectivity of ring
opening is controlled by the nature of the nucleophile and
the conditions used. Studies on the ring opening of 1,5-
dioxaspiro[3.2]hexanes with other nucleophiles and the
application of these observations to the synthesis of cyclic
and acyclic natural products are the focus of ongoing studies.
Acknowledgment. This work was supported by the
University of Connecticut Research Foundation. A.R.H.
thanks the NSF for a CAREER Award. We thank Grace
Ordonio for a repeat preparation of compounds 3a and 3c
and Scott Campbell of Boehringer Ingelheim and Isamir
Martinez and Dr. Tom Leipert (UCONN) for help with NOE
studies.
nucleophiles produced identical results. Thus, TMSN3 or
Me3Al gave the corresponding 2,2-functionalized oxetanes
3b or 3c. Evidence for oxonium ion 4, or a related species,
as a reactive intermediate comes from the diastereomeric ratio
of the products 3a-c. The dioxaspirohexanes 1a-e were
prepared according to our published procedure4 and were
isolated as diastereomeric mixtures (1a 14:1, 1b 1.1:1, 1c
6:1, 1d 6:1, 1e 3:1). It is noteworthy that for the reactions
described in the previous paragraph the spiroketal asymmetric
center was destroyed. Thus, the diastereomeric purity of the
reactants was inconsequential. However, in the reaction of
DIBAL with 1a (a 14:1 mixture of diastereoisomers), 3a, as
an 8:1 mixture, was produced. Further, 3b and 3c, also
prepared from 1a, were isolated as single diastereoisomers.
Supporting Information Available: Experimental pro-
cedures and characterization data, as well as high-resolution
1H NMR spectra for those new compounds for which
elemental analyses are not reported. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL990039C
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