A versatile preparation of 2-methyleneoxetanes

Full text of DOI:10.1021/jo9611733

7248
J . Org. Chem. 1996, 61, 7248-7249
A Ver sa tile P r ep a r a tion of
2-Meth ylen eoxeta n es
Lisa M. Dollinger and Amy R. Howell*
Department of Chemistry, The University of Connecticut,
Storrs, Connecticut 06269-4060
Received J une 21, 1996 (Revised Manuscript Received
September 5, 1996 )
Strained, saturated heterocyclic systems have been
widely employed as molecular templates in the construc-
tion of a host of organic compounds. One largely1-4
unexplored class of strained heterocycles that should
provide remarkable flexibility is the 2-alkylideneoxetanes
1. The unique combination of functionalitiessa reactive
oxetane, an enol cyclic ether, and an exocyclic double
bondsoffers intriguing possibilities for further manipula-
tion. Obviously, ready access to 2-alkylideneoxetanes is
necessary for an exploration of their reactivity and utility.
Two approaches resulting in multiple5 2-alkylideneox-
etanes have been previously described. The first, re-
ported in the late 60’s by Arnold1 and Hammond,2 utilized
the Paterno-Bu¨chi reaction with allenes (see Figure 1,
path a). A very limited range of allenes was used, and
further reaction to give dioxaspiroheptanes 2 and 3 was
common. The other strategy, described by Hudrlik et al.,6
utilized intramolecular O-alkylation of enolates (e.g., 4).
The authors found the requirement for geminal R-disub-
stitution to be too limiting for their purposes and did not
further develop the methodology.7 Thus, we sought a
method that was straightforward, reliable, and versatile.
F igu r e 1. Retrosynthetic analysis for the preparation of
2-alkylideneoxetanes.
Ta ble 1
6
isolated yield (%)
reactant (7)
of 10
a
b
c
d
e
f
g
h
i
R ) CH3; R′ ) (CH2)5
R ) CH3; R′ ) C(CH3)3, Ha
R ) Ph, H; R′ ) H
67
50
51
55
74
43
32
20b
69
R ) Ph, CH3; R′ ) H
R ) Ph, CH2CHdCH2; R′ ) H
R ) Ph, CO(CH2)3CHdCH2; R′ ) H
R ) H; R′ ) PhCH2CH2, H
R ) H; R′ ) Ha
see below
a
These compounds are very volatile and require care when
handling. b 1H NMR of the reaction mixture indicates clean and
complete conversion from reactant to product; consequently, we
believe the isolated yield is a reflection of the extreme volatility
of the product.
An elementary retrosynthetic analysis (Figure 1) of 1
would suggest two straightforward pathways to 2-alkyl-
ideneoxetanes. Path a involves a Paterno-Bu¨chi reac-
tion utilizing an allene as an alkene equivalent. Al-
though, as mentioned above, this pathway is prece-
dented,1,2,8 it has received little attention.9 An alternative
disconnection (path b) would require a â-lactone and an
appropriate alkylidene equivalent. In this paper, we
divulge a novel application of Petasis alkylidenation
chemistry10-12 for the conversion of â-lactones to 2-
methyleneoxetanes (1, R2 ) H) in moderate to good
yields.
The methylenation of lactones can be readily achieved
with the Tebbe reagent (5)13 or by the use of dimethylti-
tanocene (6), as pioneered by Petasis and co-workers.10-12
Interestingly, to our knowledge the methylenation of
â-lactones has not been reported. Obviously, the acid
sensitivity of â-lactones makes the application of these
Lewis acidic reagents questionable. Further, it seems
likely that a similar instability could plague the 2-
methyleneoxetane products.
(1) Arnold, D.; Glick, A. J . Chem. Soc., Chem. Commun. 1966, 813-
814.
(2) Gotthardt, H.; Steinmetz, R.; Hammond, G. S. J . Org. Chem.
1968, 33, 2774-2780.
(3) Gotthardt, H.; Hammond, G. S. Chem. Ber. 1974, 107, 3922-
3927.
(4) Hudrlik, P. F.; Hudrlik, A. M.; Wan, C.-N. J . Org. Chem. 1975,
40, 1116-1120.
To investigate the conversion of â-lactones to 2-meth-
yleneoxetanes, a number of â-lactones were prepared.
â-Lactones 7a and 7b (Table 1) were synthesized as
described by Schick and co-workers.14 (()-Tropic acid (8)
was converted under Mitsunobu conditions to â-lactone
7c. This lactone was in turn converted to lactone 7d by
deprotonation with LDA, followed by treatment with
(5) Two syntheses of 2-methyleneoxetane (1, R ) R1 ) R2 ) H) have
been described. See ref 4 and: Haslouin, J .; Rouessac, F. C. R. Acad.
Sci., Ser. C 1973, 276, 1691.
(6) Hudrlik, P. F.; Mohtady, M. J . Org. Chem. 1975, 40, 2692-2693.
(7) Hudrlik, P. F. Personal communication.
(8) Crandall, J . K.; Mayer, C. F. J . Org. Chem. 1969, 34, 2814-
2817.
(9) A report describing the preliminary results of our investigation
of some of the factors influencing the regio- and stereochemistry of
the photochemical cycloaddition of allenes and aliphatic aldehydes has
been submitted.
(13) Brown-Wensley, K. A.; Buchwald, S. L.; Cannizzo, L.; Clawson,
L.; Ho, S.; Meinhardt, D.; Stille, J . R.; Straus, D.; Grubbs, R. H. Pure
Appl. Chem. 1983, 55, 1733-1744.
(14) Welder, C.; Kunath, A.; Schick, H. J . Org. Chem. 1995, 60, 758-
760.
(10) Petasis, N.; Bzowej, E. J . Am. Chem. Soc. 1990, 112, 6392-
6394.
(11) Petasis, N.; Akritopoulou, I. Synlett 1992, 665-667.
(12) Petasis, N.; Lu, S.-P. Tetrahedron Lett. 1995, 36, 2393-2396.
S0022-3263(96)01173-5 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 21, 1996 7249
Sch em e 1
methyl iodide.15 Lactone 7e was obtained by the same
procedure, using allyl iodide as the alkylating agent.
Treatment of the enolate of 7c with 5-hexenal, followed
by oxidation with PCC, afforded lactone 7f. Lactone 7g
was prepared16 from 3-hydroxy-5-phenylpentanoic acid
(9), as shown in Scheme 1. Lactone 7i, an intermediate
in a literature synthesis of tetrahydrolipstatin, was
kindly provided by Hoffman LaRoche.
Our concern about the Lewis acidity of the Tebbe
reagent (5) was well founded. Under standard conditions
for Tebbe methylenation with 7c as the substrate, proton
NMR of the crude reaction mixture showed that the
desired product was present, but we were unable to
isolate it in significant quantity. Although we examined
alternative additives (e.g., basic alumina instead of
pyridine) and workup conditions, the outcome was identi-
cal. On the other hand, the weaker Lewis acid, dimeth-
yltitanocene (6), provided moderate to good yields of
2-methyleneoxetanes 10,17 as shown in Table 1.18
Several observations about the methylenation of â-lac-
tones 7 and the isolation of 10 are worth noting. Previous
work by Petasis10 implied that alkylidenation proceeds
via an intermediate that only slowly converts to product.
Thus, disappearance of lactone would not necessarily be
a good indicator of maximum conversion. We found,
however, that for the â-lactones highest yields were
realized by quenching the reaction upon consumption of
the lactone. This does not preclude the formation of a
long-lived intermediate, but might be indicative of prod-
uct instability.19 Toluene proved to be a superior solvent
to THF for the methylenation of â-lactones. It is also
interesting to note that no protection of the alcohol moiety
was required in 7i, which further illustrates the utility
of the Petasis reagent. By far the most critical factor for
optimum yields was the method of purification. Distil-
lation, flash silica, Florisil, and neutral alumina all
destroyed the 2-methyleneoxetanes. Basic alumina yielded
the desired product, but the source and activity of the
basic alumina were also crucial. Silica deactivated with
triethylamine (0.5-1% in the eluting solvent) provided
the most consistent results. The 2-methylene oxetanes
can be stored for long periods and are stable, unless
exposed to traces of acid.
Also noteworthy is the chemoselectivity of dimethylti-
tanocene in reactions with 7e and 7f. In agreement with
observations by Petasis,10 the lactone was methylenated
in preference to reaction with the alkene moiety (7e). In
contrast to prior observations of ketones being more
reactive than esters, in compound 7f the â-lactone was
selectively methylenated. Although this selectivity may
be a result of the hindered nature of the ketone moiety,
it might also be a reflection of a greater reactivity of the
â-lactone. Such selectivity would certainly have implica-
tions in protecting group strategies.
Although we are especially interested in exploring the
reactivity of 2-alkylideneoxetanes, the obvious structural
homology between â-lactones and 2-methyleneoxetanes
has encouraged us to investigate the latter as structural
isosteres of the former. This is of particular interest
because, recently, several â-lactones have been identified
as inhibitors of some therapeutically important serine
and cysteine proteases by virtue of an enzyme-catalyzed
ring-opening reaction.20-22 Consequently, we have con-
verted compound 10i to 2-methyleneoxetane 11a ,23 an
analog of the pancreatic lipase inhibitor, tetrahydrolip-
statin (11b),24-26 and will be investigating the biological
activity of it and other alkylideneoxetanes.
In conclusion, we have disclosed the first reliable and
straightforward preparation of 2-methyleneoxetanes in
good isolated yields. Investigation of the diverse utility
of this intriguing class of compounds is currently under-
way and will be reported in due course.
Ack n ow led gm en t. Support by donors of the Petro-
leum Research Fund, administered by the American
Chemical Society, and the University of Connecticut
Research Foundation is gratefully acknowledged. We
would also like to thank Bob Grubbs, Nicos Petasis, and
Dominic McGrath for helpful discussions. In addition,
we would like to thank Lisa Newell for preparing
3-hydroxy-5-phenylpentanoic acid (9) and Gan Wang for
preparing lactone 7e. We are especially grateful to Sven
Taylor (Hoffman La Roche) for generously providing
tetrahydrolipstatin precursor 7i.
(15) Mulzer, J .; Kerkmann, T. J . Am. Chem. Soc. 1980, 102, 3620-
3622.
(16) Cappozzi, G.; Roelens, S.; Talami, S. J . Org. Chem. 1993, 58,
7932-7936.
(17) Representative experimental for the preparation of 2-methyl-
eneoxetanes: Dimethyltitanocene (0.5 M in toluene, 19.5 mL, 9.7
mmol) and 3-phenyloxetan-2-one (7c) (0.96 g, 6.5 mmol) were stirred
at 75 °C under N2 in the dark. The reaction was monitored by TLC,
and after the disappearance of the starting material (2-15 h) the
solution was cooled and concentrated to half of its original volume.
An equal volume of petroleum ether was then added, at which point a
yellow precipitate formed. The mixture was passed through Celite with
petroleum ether until the filtrate was colorless. After concentration,
if large amounts of solid were present, the mixture was diluted with
petroleum ether and filtered through Celite again. The residue was
then purified by flash chromatography on silica gel (petroleum ether/
ethyl acetate/triethylamine 98.5:0.5:1).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for all compounds (17 pages).
J O9611733
(20) Tomoda, H.; Kumagai, H.; Tanaka, H.; Omura, S. Biochim.
Biophys. Acta 1987, 922, 351-356.
(21) Greenspan, M. D.; Bull, H. G.; Yudkovitz, J . B.; Hanf, D. P.;
Alberts, A. W. Biochem. J . 1993, 289, 889-895.
(22) Mayer, R. J .; Louis-Flamberg, P.; Elliott, J . D.; Fisher, M.;
Leber, J . Biochem. Biophys. Res. Commun. 1990, 169, 610-616.
(23) Compound 11a was prepared from 10i by the method used in
the synthesis of 11b cited in ref 26. Experimental and spectral details
can be found in the supporting information.
(18) All new compounds are fully characterized, and the requisite
data can be found in the supporting information.
(19) Concerned about the stability of both â-lactones and 2-meth-
yleneoxetanes at elevated temperatures, in separate experiments we
heated 7c and 10c at 70 °C in toluene for 24 h. The lactone appeared
to be unchanged; on the other hand, the oxetane showed significant
decomposition.
(24) Zhi, J .; Melia, A. T.; Guerciolini, R.; Chung, J .; Kinberg, J .;
Hauptman, J . B.; Patel, I. H. Clin. Pharm. Ther. 1994, 56, 82-85.
(25) Stalder, H.; Schneider, P. R.; Oesterhelt, G. Helv. Chim. Acta
1990, 73, 1022-1034.
(26) Borgstrom, B. Biochim. Biophys. Acta 1988, 962, 308-316.