Synthesis of Skeletally Diverse Small Molecules
A R T I C L E S
Scheme 10
4-hydrido-2-R-acetoxyalkyl furan 34, each bearing a single
deactivating substituent, were resistant to oxidation at 0 °C
(Scheme 7B and C, respectively), even though both substrates
were oxidized quantitatively in 1 h at room temperature. By
combining these two deactivating substituents into the same
substrate (43), a distinct skeletal outcome was achieved upon
exposure to the same reagents at room temperature, that is,
preservation of the initial furan skeleton via complete resistance
to oxidation.
Scheme 11 a
The ability of electron-withdrawing substituents to deactivate
nearby olefins toward electrophilic reagents is well-known.33
In early studies of furan oxidation, Clauson-Kaas and co-workers
noted that furan derivatives having highly electron-withdrawing
substitutents (e.g., furoic acid and R-acetylfuran) were resistant
to oxidation with molecular bromine.34 It seems reasonable that
the deactivating effect of the bromine substituent at the
4-position is predominantly due to its electron-withdrawing
nature (Pauling electronegativity35 for -Br is 2.8 as opposed
to 2.1 for -H), although steric effects may also contribute.
The deactivating effect of the 2-R-acetoxyalkyl group is likely
the result of two factors: (1) the electron-withdrawing nature
of the acetoxy group, and (2) the removal of the hydrogen-
bond donating hydroxyl group on the R-carbon, which likely
facilitates furan oxidation via intramolecular directing of the
NBS reagent. This proposed two-fold effect is consistent with
the classic studies by Henbest and co-workers on the epoxidation
of cyclohexene and its derivatives using the oxidant perbenzoic
acid.36
As shown in Scheme 8, treatment of 4-aryl-2-R-hydroxyalkyl
furan 44 with NBS resulted in oxidative ring expansion to yield
the expected aryl-substituted cyclic hemiketal 48. However,
when exposed to acidic conditions (e.g., PPTS), complete
conversion into a new product was observed, identified as the
R-keto furan 49.37
The basis for this reactivity is not known. A similar type of
reaction, involving the Br2/H2SO4-mediated transformation of
an R-hydroxy-â-butoxycarbonyl furan into an R-keto-â-butoxy-
carbonyl derivative, was reported in early studies by Achma-
towicz,6 who proposed the intermediacy of an enediol tautomer.
The oxidative ring expansion and acid-promoted rearrange-
ment observed for 4-m-methylphenyl-2-R-hydroxyalkyl furan
44 proved to be general for a series of related 4-aryl-2-R-
hydroxyalkyl furans that were synthesized and tested. It was
observed that this outcome is more preferred with substrates
having electron-donating aryl substituents (e.g., p-methoxyphe-
nyl) versus electron-withdrawing aryl substituents (e.g., 2,4-
dichlorophenyl).
a X ) (S)-4-benzyl-2-oxazolidinone, Ar ) m-methylphenyl. Reagents
and conditions: (a) 9-BBN, THF, room temperature, 5 h; 4,5-dibromo-
furaldehyde (38), PdCl2dppf, NaOH, THF:H2O 5:1, 65 °C, 18 h, 0.188
mequiv/g; (b) 9-BBN, THF, room temperature, 5 h; 4-m-MePh-5-bromo-
furaldehyde (53), PdCl2dppf, NaOH, THF:H2O 5:1, 65 °C, 22 h, 0.545
mequiv/g; (c) (S)-(+)-4-benzyl-3-propionyl-2-oxazolidinone, n-Bu2BOTf,
Et3N, CH2Cl2, 72 h, -78 to 0 °C; 30% aqueous H2O2, pH 7 buffer, MeOH,
4 °C, 12 h, 42, >95%, purity >90%, 44, 95%, purity >90%; (d) Ac2O,
i-Pr2NEt, DMAP, CH2Cl2, room temperature, 28 h, 43, 90%, purity >90%,
45, 84%, purity >90%; (e) NBS, NaHCO3, NaOAc, THF:H2O 4:1, room
temperature, 1 h; PPTS, CH2Cl2, 40-45 °C, 20 h, 46, 82%, purity 90%,
43, 88%, purity >90%, 49, 74%, purity 72%, 50, 72%, purity 66%.
As shown in Scheme 6, model substrate 42 having a bromine
atom at the 4-position of furan and a hydroxyl group on the
R-carbon of the 2-substituent underwent quantitative, NBS-
mediated oxidative ring expansion to yield the anticipated cyclic
hemiketal 46 as a >9:1 mixture of epimers.32 However, upon
exposure to the same acidic conditions (PPTS in CH2Cl2 at 40
°C) that effected dehydration with the hemiketal derived from
the oxidation of model substrate 33 (having a hydrogen atom
at the 4-position of furan, see 33 f 36, Scheme 3), the bromine-
substituted cyclic hemiketal 46 remained unchanged. It seems
plausible that formation of an oxocarbenium ion intermediate,
presumably required for dehydration to occur, is disfavored both
electronically and sterically by the electronegative and large (1,2-
type strain) bromine substituent.
In contrast, the 4-bromo-2-R-acetoxyalkyl furan 43 proved
completely resistant to NBS-mediated oxidation and was
likewise unchanged upon subsequent treatment with PPTS,
resulting in preservation of the original R-alkoxyalkyl furan
skeleton. As shown in Scheme 7, the deactivating effect of both
the 4-bromo and the 2-R-acetoxyalkyl substituents toward furan
oxidation was observed independently when the reaction was
performed at 0 °C (∼1 h reaction time). As a point of reference,
the 4-hydrido-2-R-hydroxyalkyl furan 33 was readily oxidized
both at room temperature and at 0 °C by NBS (Scheme 7A).
Hovever, both the 4-bromo-2-R-hydroxyalkyl furan 42 and the
As shown in Scheme 9, when treated with the same oxidative
and acidic reagents, 4-aryl-2-R-acetoxyalkyl furan 45 was
(33) (a) Swern, D. J. Am. Chem. Soc. 1947, 69, 1692-1698. (b) Swern, D.
Chem. ReV. 1949, 45, 1-68.
(34) Clauson-Kaas, N.; Limborg, F.; Fakstorp, J. Acta Chem. Scand. 1948, 2,
109-115.
(35) (a) Pauling, L. The Nature of the Chemical Bond, 3rd ed.; Cornell University
Press: Ithaca, NY, 1960. (b) Carey, F. A.; Sundberg, R. J. AdVanced
Organic Chemistry, Part A: Structure and Mechanisms, 3rd ed.; Plenum
Press: New York, 1990; p 15.
(31) The HWE olefination, reduction, functionalization, and dihydroxylation
sequence was also explored with these and related substrates; however,
the length of the synthesis pathway precluded the generation of the desired
macrobead-bound diols with acceptable macrobead integrity and compound
purity.
(32) The stereochemistry at the anomeric carbon of cyclic ketal 46 was tentatively
assigned as R on the basis of two-dimensional NOESY and one-dimensional
nOe experiments.
(36) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958-1965.
(37) (a) Epimerization of the potentially labile methyl-bearing stereogenic center
in 49 was not observed. This observation is consistent with the lack of
epimerization observed with the structurally similar Evans’ extended
polypropionate (â-ketoimide) reagents. (b) Evans, D. A.; Clark, J. S.;
Metternich, R.; Novack, V. J.; Sheppard, G. S. J. Am. Chem. Soc. 1990,
112, 866-868. (c) Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L.
Tetrahedron 1992, 48, 2127-2142.
9
J. AM. CHEM. SOC. VOL. 126, NO. 43, 2004 14099