Applying this effect to enhance the reactivity of the oxetane
precursor should make it possible to prepare [2.2.2]-bicyclic
orthoesters under much milder conditions.
Scheme 2. Mechanism of Formation and Rearrangement of
the ABO Orthoester, Shown for Protic Acid Catalysis
To test this hypothesis, alkyl substituents were added to
the oxetane ring of OBO precursor 1. Dimethyl-substituted
oxetanyl alcohol 15 was prepared from 2,2-bis(hydroxy-
methyl)propionic acid via its benzyl ester tBDMS ether 127
(Scheme 4). Introduction of the methyl groups with a
Scheme 4. Synthesis of
3-Hydroxymethyl-2,2,3-trimethyloxetane (15)
disadvantage of using [3.2.1]-bicyclic orthoesters such as 8
is the formation of 3-acyloxytetrahydrofuran side products
(10).3b However, we have shown that THF 10 is formed from
orthoester 8 via the dioxolanium ion (9), rather than directly
from the epoxy ester 6, and that its rate of formation is nearly
1000 times slower than that of the orthoester (8).5 Therefore,
by controlling the concentration of the acid catalyst and the
time, this reaction can be minimized. In some cases, cyclic
ether formation may actually be advantageous, since it
provides a method of deprotection that does not involve
aqueous acid.3 Perhaps the greatest disadvantage of [3.2.1]-
bicyclic orthoesters as a protecting groups compared to
[2.2.2]-bicyclic orthoesters is that they are intrinsically chiral.
This results in diastereomeric product mixtures if the
carboxylic acid is also chiral, which is often the case in
natural products synthesis. Although this problem can be
solved by using an enantiomerically pure epoxide to generate
a homochiral orthoester,3 this approach is impractical.
Grignard reagent, followed by Williamson ether synthesis
and desilylation provided rapid access to the desired product
(15). The oxetane ring was prepared in a modification of a
one-pot procedure8 in which 2 equiv of KOt-Bu were added
to diol 13, followed immediately by 1 equiv of tosyl chloride.
The dimethyl oxetanyl alcohol (15) thus obtained was
esterified with dihydrocinnamic acid and the reactivity of
oxetanyl ester 16 was compared with the corresponding OBO
precursor 18.
The rates of reaction of the two orthoester precursors (16
and 18) were measured simultaneously by 1H NMR kinetics
to ensure identical conditions (Figure 1). Treatment of a
mixed sample of 16 and 18 with 0.2 mM BF3 etherate in
CDCl3 resulted in the rapid reaction of the dimethyl-
substituted oxetane 16 and the much slower reaction of the
OBO precursor 18 (Figure 1, graph a). Under these reaction
conditions, the BF3 reagent appeared to decompose as shown
by steadily decreasing rates over time. However, useful data
were obtained from the initial 10 min of the reaction, which
indicated a 20-fold greater reactivity for 16. A more accurate
comparison was obtained with TFA catalysis by using a
reactivity scale that we previously established (Figure 1,
graph b).5 In this experiment, the formation of the dimethyl-
substituted OBO (DMOBO) orthoester 17 could be shown
to be 85 times faster than that of the OBO orthoester 19,
since the reaction of 20 was 1.8 times faster than that of 16,
and 20 had been found to be 160 times more reactive than
18.5
We recently noted that taxol oxetanyl ester rearranges
under acidic conditions with inversion at the more substituted
center of the oxetane (Scheme 3).4d This phenomenon is
Scheme 3. Rearrangement of the Taxol Oxetane, Shown for
Protic Acid Catalysis
similar to the situation encountered with epoxides, where
alkyl substitution increases the reactivity by stabilizing
carbocationic character in the protonated epoxy intermediate.6
The stability of the OBO and DMOBO orthoesters 17 and
19 toward aqueous acid was measured by comparing their
rates of hydrolysis at pH 4.75 (Figure 1, graph c). Under
(4) (a) Giner, J.-L.; Faraldos, J. A. J. Org. Chem. 2002, 67, 2717-2720.
(b) Faraldos, J. A.; Giner, J.-L. J. Org. Chem. 2002, 67, 4659-4666. (c)
Giner, J.-L.; Ferris, W. V., Jr.; Mullins, J. J. J. Org. Chem. 2002, 67, 4856-
4859. (d) Giner, J.-L.; Faraldos, J. A. HelV. Chim. Acta 2003, 86, 3613-
3622.
(5) Giner, J.-L.; Li, X.; Mullins, J. J. J. Org. Chem. 2003, 68, 10079-
10086.
(7) Heise, A.; Trollsas, M.; Magbitang, T.; Hedrick, J. L.; Frank, C. W.;
Miller, R. D. Macromolecules 2001, 34, 2798-2804.
(8) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4,
4591-4593.
(6) Parker, R. E.; Isaacs, N. S. Chem. ReV. 1959, 59, 737-799.
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Org. Lett., Vol. 7, No. 3, 2005