Synthesis of Enantiopure Dihydropyranones: Aldol-Based Ring Expansion of Dihydrofurans

Article abstract of DOI:10.1021/ol0263595

(Matrix Presented) The stereoselective Birch reduction of 3-methyl-2-furoic acids using a readily available chiral auxilairy is described; by coupling this process to an oxidative cleavage/aldol ring closure sequence we were able to produce highly functio

Full text of DOI:10.1021/ol0263595

ORGANIC
LETTERS
2002
Vol. 4, No. 18
3059-3062
Synthesis of Enantiopure
Dihydropyranones: Aldol-Based Ring
Expansion of Dihydrofurans
,†
Timothy J. Donohoe,* Ali Raoof,‡ Graeme C. Freestone,† Ian D. Linney,§
Andrew Cowley,†,| and Madeleine Helliwell‡,|
Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, U.K., Department of
Chemistry, UniVersity of Manchester, Oxford Road, Manchester M13 9PL, U.K., and
The James Black Foundation, 68 Half Moon Lane, Dulwich, London SE24 9JE, U.K.
timothy.donohoe@chem.ox.ac.uk
Received June 13, 2002
ABSTRACT
The stereoselective Birch reduction of 3-methyl-2-furoic acids using a readily available chiral auxilairy is described; by coupling this process
to an oxidative cleavage/aldol ring closure sequence we were able to produce highly functionalized and enantiopure dihydropyranones in high
yield. This sequence has ample flexibility built into it, either by the use of different electrophiles during reductive alkylation or by subsequent
derivatization of the dihydropyranone after ring expansion.
Recently, we have published the results of our studies into
the partial reduction of aromatic heterocycles.1 While most
attention has been paid to controlling the stereo- and
chemoselectivity of such a process, we have become
interested in further transformations of the dihydro-com-
pounds produced by such methodology. This facet of our
research is best illustrated by our conversion of annulated
dihydrofurans into eight- and nine-membered rings by an
oxidative cleavage strategy, Figure 1.2
oxygen and nitrogen) was intramolecular aldol condensation
of the diketones formed after cleavage by ozonolysis, Scheme
1. In fact, 1,5-dicarbonyl compounds such as 2 were even
sensitive to the silica gel used for chromatography and had
to be handled with care if the integrity of the nine-membered
ring was to be maintained. The regiochemistry of the aldol
product 3 was assigned by X-ray crystal structure of an aldol
adduct 5 that did not readily dehydrate and form an enone.
However, we quickly realized that this process could be
harnessed by reductively alkylating 3-methyl-2-furoic acids,
followed by oxidative cleavage3 and then (dehydrating) aldol
One of the continuing problems that we encountered
during preparation of nine-membered rings (containing both
† University of Oxford.
‡ University of Manchester.
§ James Black Foundation.
| To whom correspondence regarding the crystal structures should be
addressed.
(1) (a) Donohoe, T. J.; Guyo, P. M. J. Org. Chem. 1996, 61, 7664. (b)
Donohoe, T. J.; Guyo, P. M.; Beddoes R. L.; Helliwell, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 667. (c) Donohoe, T. J.; McRiner A. J.; Sheldrake,
P. Org. Lett. 2000, 2, 3861. (d) Donohoe, T. J.; McRiner, A. J.; Helliwell,
M.; Sheldrake, P. J. Chem. Soc., Perkin Trans. 1 2001, 1435.
(2) Donohoe, T. J.; Raoof, A.; Linney, I. D.; Helliwell, M. Org. Lett.
2001, 3, 861.
Figure 1.
10.1021/ol0263595 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/02/2002

the hydroxyl group to give 7 in excellent overall yield,
Scheme 2. Reductive alkylation of 7 in liquid ammonia
Scheme 1a
Scheme 2a
a Reagents and conditions: (a) O2/O3, CH2Cl2, -78 °C, then
DMS; (b) SiO2.
ring closure to give enantiopure dihydropyranones, Figure
2.4 In this scenario, there is only one likely regiochemical
outcome from the aldol reaction of postulated keto-aldol 6.
a Reagents and conditions: (a) SOCl2 then (S)-prolinol, CH2Cl2,
NaOH; (b) NaH, BnBr, TBAI, THF; (c) Li (4 equiv), NH3 (l), THF,
-78 °C, then isoprene, then MeI or i-BuI (10 equiv); (d) 2 M HCl
(aq), ∆, 2.5 h; (e) 2,6-dimethylphenol, EDCl (2 equiv), DMAP
(cat.), CH2Cl2, rt; (f) O2/O3, CH2Cl2, -78 °C, then DMS; (g) CSA,
toluene or xylene, ∆.
proceeded well and we chose two electrophiles to illustrate
that both reactive (MeI) and relatively unreactive (iBuI)
alkylating agents work in this reaction. In both cases, the
1
diastereoselectivity was very high (measured by H NMR
spectroscopy on the crude reaction mixtures and compared
against a 1:1 mixture of diastereoisomers).7 Moreover, the
acid 10, released from 8, was shown to have g94% ee by
chiral shift NMR experiments in the presence of R-methyl-
benzylamine (measured against a racemic standard). Given
that the dr of 9 is secure, the enatiomeric excess of 11 can
be assumed to be 92% by analogy. The absolute stereo-
chemistry of both 10 and 11 was proven by correlation of
their sign of optical rotation to known compounds.5
Figure 2.
Another big advantage of this protocol is that 3-substituted
furans are excellent substrates for the stereoselective Birch
reduction using two different auxiliaries (Xc);5 this, of course,
should enable us to prepare the corresponding dihydro-
pyranones in enantiomerically pure form after ring expansion.
We investigated stereoselective reduction and ring cleavage
using O-benzylprolinol as an auxiliary5 because it is signifi-
cantly easier to obtain than the bis-methoxymethylpyrrolidine
alternative.6
Despite several attempts, we had no success in cleaving
the alkene with an auxiliary still attached to the molecule
(9) and multicomponent mixtures were obtained in each case.
Therefore, the prolinol moiety was cleaved under mild acidic
conditions and coupled to 2,6-dimethylphenol to provide an
inert but easily removable group on the C-2 carbonyl
(Scheme 2). Oxidative cleavage of 12 and 13 with ozone
gave the keto-aldehydes after DMS workup. Although these
Therefore, we took commercially available 3-methyl-2-
furoic acid, coupled it to (+)-S-prolinol, and then benzylated
(3) See Landais, Y.; Zekri, E. Tetrahedron Lett. 2001, 42, 6547.
(4) See: (a) Danishefsky, S.; Cavanaugh, R. J. Am. Chem. Soc. 1968,
90, 520. (b) Danishefsky, S.; Cain P.; Nagel, A. J. Am. Chem. Soc. 1975,
97, 380. (c) Danishefsky, S.; Cain, P. J. Org. Chem. 1975, 40, 3606. (d)
Kutney, J. P.; Grice, P.; Piotrowska, K.; Rettig, S. J.; Szykula, J.; Trotter,
J.; Chu, L. V. HelV. Chim. Acta 1983, 66, 1820.
1
aldehydes were not isolated, they could be observed by H
NMR spectroscopy and were treated directly with CSA,
which promoted a (dehydrating) aldol reaction to form the
six-membered ring system directly and in one pot.8 Basic
(5) Donohoe,T. J.; Calabrese, A. A.; Stevenson, C. A.; Ladduwahetty,
T. J. Chem. Soc., Perkin Trans. 1 2000, 3724.
(6) (a) Donohoe, T. J.; Helliwell, M.; Stevenson C. A.; Ladduwahetty,
T. Tetrahedron Lett. 1998, 39, 3071. (b) Donohoe, T. J.; Calabrese, A. A.;
Guillermin, J.-B.; Walter, D. S. Tetrahedron Lett. 2001, 42, 5841.
(7) More accurate measurements on the crude mixture means that we
have revised the diastereoselectivity of the reaction 7 f 8 upwards from
13:1 to 20:1; see ref 5.
3060
Org. Lett., Vol. 4, No. 18, 2002

aldol conditions (Et3N, ∆) were also capable of producing
15, although the overall yield was lower. Given their origin,
it is reasonable to assume that the enantiomeric excesses of
the six-membered ring compounds 14 and 15 are as equally
high as 10 and 11, the five-membered progenitors.
The sense of stereoselectivity displayed during the reduc-
tive alkylation step is noteworthy and consistent with the
formation of an E-enolate A (after addition of two electrons
and a proton to 7, Figure 3).
formation of an extended enolate with LDA, followed by
kinetic protonation at C-411 gave the enol ethers 16 and 17,
Scheme 3. Our ability to migrate the alkene in this manner
Scheme 3a
a Reagents and conditions: (a) LDA, THF, -78 °C; (b) NH4Cl
(aq); (c) TBSOTf; (d) PCC, t-BuOOH.
has clear ramifications for further functionalization at C-6.
In fact, the extended enolate could be trapped with a
silylating agent to provide diene 18 in good yield. Moreover,
the enone could also be oxidized to the corresponding lactone
19 with PDC/t-BuOOH,12 again increasing the flexibility of
the sequence to encompass sugar substitution patterns.
Finally, we also investigated reduction of the C-3 keto
group and found that excellent levels of diastereoselectivity
could be achieved for 1,2-reduction of both 14 and 15,
especially when using a bulky hydride source and low
temperatures, Scheme 4. The lower yield recorded with
Figure 3.
To achieve high stereoselectivity, chelation control is
necessary, and the (sacrificial) benzyl group is a source of
such a chelating oxygen, generated in situ, B.5,9 We presume
that coordination of the two O-Li species is instrumental
in preventing rotation about the C-N bond and so providing
a basis for discrimination between the two enolate faces.10
Under the low-temperature regimen, the lithium alkoxide that
remains is unreactive toward the alkylating agent and is
simply protonated upon workup.
Scheme 4
Next, we investigated some of the reactivity of the
dihydropyranones produced via this sequence. For example,
(8) Representative Experimental Procedure. Dihydrofuran 12 (3.31
g, 13.5 mmol) was dissolved in dichloromethane (80 mL) and cooled to
-78 °C under an atmosphere of oxygen. Ozone was bubbled through the
reaction mixture for 45 min, until the solution turned blue, after which time
it was saturated with oxygen for 5 min, followed by argon for a further 5
min. Dimethyl sulfide (30 mL, 410 mmol) was added to the reaction mixture,
which was allowed to stir and warm to room temperature over 16 h. The
resultant solution was concentrated under reduced pressure to yield a yellow
oil, dissolved in xylene (50 mL) before the addition of D-(+)-camphor
sulfonic acid (624 mg, 2.69 mmol). This was stirred and heated to 110 °C
for 16 h before being allowed to cool to room temperature. The reaction
mixture was concentrated under reduced pressure, and purification by
column chromatography (silica, eluting with petrol/ethyl acetate 90:10)
afforded the title compound 14 as a yellow oil (2.52 g, 72%): 1H NMR
(200 MHz, CDCl3) δ 1.83 (3H, s), 2.09 (6H, s), 4.50 (1H, ddd, J ) 20,
3.7, and 2.1 Hz), 4.97 (1H, ddd, J ) 20, 2.7, and 2.1 Hz), 6.26 (1H, ddd,
J ) 11, 2.7, and 2.1 Hz), 7.00-7.05 (3H, m), 7.09 (1H, ddd, J ) 11, 3.7,
and 2.1 Hz).
(9) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis; Wiley: New York, 1991.
(10) Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras. A. G.;
Welch, M. J. Am. Chem. Soc. 1988, 110, 7828.
(11) Extended enolates, like pentadienyl anions, react with electrophiles
at the middle carbon; see: Fleming, I. Frontier Orbitals and Organic
Chemical Reactions; Wiley: Chichester, 1976.
(12) Schultz, A. G.; Taveras, A. G.; Harrington, R. E. Tetrahedron Lett.
1988, 29, 3907.
DIBAl-H as a nucleophile reflects competing attack at the
ester carbonyl in the presence of excess reagent. The sense
of diastereoselectivity was confirmed by X-ray crystal-
lography on a p-nitrobenzoate derivative 22 and is consistent
with axial attack of hydride on a conformation of the ketone
that places the bulky alkyl groups equatorial and the ester
group axial.
Org. Lett., Vol. 4, No. 18, 2002
3061

To conclude, we have shown that the reductive alkylation/
aldol ring expansion sequence is capable of producing
(enantiopure) dihydropyranone building blocks in excellent
yields using a readily available chiral auxiliary. This
methodology has been used without any problems on a
multigram scale. These compounds have a range of func-
tionality suitable for further derivatization and preliminary
experiments have shown that functionalized sugar templates
can be easily prepared. We expect this methodology to have
potential in the synthesis of biologically active compounds,
and further work is in progress.
Acknowledgment. We thank the EPSRC and the James
Black Foundation for funding this project and Pfizer for
unrestricted financial support.
Supporting Information Available: Detailed spectro-
scopic data for new compounds and representative experi-
mental procedures, plus X-ray data for compounds 5 and
22. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0263595
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Org. Lett., Vol. 4, No. 18, 2002