Oxidative rearrangement of 2-alkoxy-3,4-dihydro-2H-pyrans: Stereocontrolled synthesis of 4,5-cis-disubstituted tetrahydrofuranones

Article abstract of DOI:10.1016/j.tetlet.2005.12.120

Oxidation of 2-alkoxy-3,4-dihydro-2H-pyrans with dimethyldioxirane followed by Jones oxidation leads to rearrangement and stereocontrolled formation of 4,5-cis-disubstituted tetrahydrofuranones; the method is applied to the synthesis of the whisky lactone 13 and cognac lactone 14.

Full text of DOI:10.1016/j.tetlet.2005.12.120

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1617–1619
Oxidative rearrangement of 2-alkoxy-3,4-dihydro-2H-pyrans:
stereocontrolled synthesis of 4,5-cis-disubstituted
tetrahydrofuranones
Alan Armstrong* and Hunsuk Chung
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
Received 29 November 2005; accepted 21 December 2005
Available online 19 January 2006
Abstract—Oxidation of 2-alkoxy-3,4-dihydro-2H-pyrans with dimethyldioxirane followed by Jones oxidation leads to rearrange-
ment and stereocontrolled formation of 4,5-cis-disubstituted tetrahydrofuranones; the method is applied to the synthesis of the
whisky lactone 13 and cognac lactone 14.
ꢀ 2006 Elsevier Ltd. All rights reserved.
We recently reported the aminative rearrangement of 2-
alkoxy-3,4-dihydro-2H-pyrans 1, allowing a concise and
stereocontrolled synthesis of substituted pyrrolidines (2,
X = NTs) (Scheme 1), which harnesses the initial 4+2-
cycloaddition reaction between an enone and an enol
ether to construct the carbon framework.1 Products 2
are useful bis-electrophiles for synthesis of azabicycles.2
The oxygen version of this rearrangement could poten-
tially provide an equally rapid approach to tetra-
hydrofurans (2, X = O), which are present in a wide
range of natural products. Indeed, there are several spe-
cific examples of the use of this ring contraction process
for the synthesis of spiroacetals,3 and oxidative rear-
rangement of two very simple substrates using mCPBA
was reported by Hall in 1970.4 We wished to explore the
generality of the method and, in line with our work in
the pyrrolidine series, we were particularly interested
in whether substituents on the pyran substrate 1 could
control the relative configuration of the THF products.
Here we report our preliminary work towards this goal,
leading to a stereocontrolled synthesis of 4,5-cis-disub-
stituted tetrahydrofuranones, a class which relatively
"X+"
R1
+
OR2
X
R1
O
OR2
R1
O
1
OR2
O
2
X
X
R1
OR2
R1
O
O
OR2
Scheme 1.
Keywords: Oxidation; Epoxidation; Dimethyldioxirane; Lactone; Tetrahydrofuran.
*
Corresponding author. Tel.: +44 (0)20 7594 5876; fax: +44 (0)20 7594 5804; e-mail: A.Armstrong@imperial.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.120

1618
A. Armstrong, H. Chung / Tetrahedron Letters 47 (2006) 1617–1619
R2
R1 R2
Yb(fod)3,
55 oC, 5 d
R1
1 eq DMDO
5
4
+
OR3
OEt
acetone
/ CH2Cl2
O
R
O
R
O
OEt
O
OR3
9 R = nPr, 70%
7 R = nPr
8 R = nBu
O
3
4 R3 = Et or nBu
5 R3 = H
10 R = nBu, 65%
i) 1 eq DMDO,
acetone/CH2Cl2
R2
R1
4
Jones
oxidation
+
R
R
O
O
O
O
O
ii) Jones
oxidation
5
O
O
O
O
6
11a R = nPr, 58%
12a R = nBu, 48%
11b R = nPr, 12%
12b R = nBu, 6%
Scheme 2.
1. NaBH4, MeOH
few synthetic methods for THF synthesis address,5 and
application of the method to the synthesis of c-lac-
tone-containing natural products.
11a R = nPr
12a R = nBu
2. (Im)2CS, DCE, 80 oC
3. nBu3SnH, AIBN,
R
O
O
13 R = nBu, 36%
(over 3 steps)
toluene
A range of substrates 3 (Scheme 2) was prepared by
Lewis acid-catalysed enol ether/enone cycloaddition.1,6
We were pleased to find that treatment of 3a with a solu-
tion of dimethyldioxirane (DMDO) in acetone7 did
effect the desired oxidative rearrangement. However,
even when the DMDO solution was dried over K2CO3
prior to use, we obtained a mixture of lactol 5a as well
as the expected lactol ether product 4a. In order to con-
verge these to a single product, as well as to remove the
lactol stereocentre to allow stereochemical analysis, we
treated the product mixture with Jones reagent to pro-
vide lactone 6a cleanly in good yield (Scheme 2; Table
1, entry 1). This process was then applied to substrate
3b bearing a CH3-substituent at C4. The corresponding
lactone 6b was obtained as a 3:1 mixture of diastereo-
mers, and NOE studies indicated that the cis-isomer
was the major.8 This outcome is consistent with initial
epoxidation of 3b on the less hindered face, trans to
the R1-substituent. Pleasingly, as would be expected,
higher levels of stereocontrol were observed with more
sterically demanding and branched R1 substituents
(entries 3–6), with only the 4,5-cis-isomer being observed
in some cases (entries 5 and 6). The process tolerates the
presence of an oxygen functionality (entry 3), an isolated
alkene (entry 6) and a quaternary centre in the substrate
(entry 7). However, to date, substrates with a hydrogen
in place of the methyl group at C6, which would lead
initially to aldehyde-containing products, do not under-
go the desired rearrangement with DMDO.
14 R = nPent, 49%
(over 3 steps)
Scheme 3.
With the method established as a stereocontrolled route
to 4,5-cis-disubstituted tetrahydrofuranones, we demon-
strated its application to natural product targets, lac-
tones 13 and 14 (Scheme 3) partly responsible for
aroma and flavour in whisky and cabernet sauvignon
wine.10 The requisite substrates 9 and 10 were again pre-
pared using a hetero Diels–Alder reaction. Oxidative
rearrangement with DMDO followed by Jones oxida-
tion proceeded to give a mixture of diastereomers (5:1
1
for 11a; 8:1 for 12a by H NMR analysis), from which
the desired cis-isomers could be separated (58% for
11a; 48% for 12a). The superfluous ketone moiety was
removed by reduction (NaBH4) followed by Barton-
McCombie deoxygenation, providing the cis-lactones
13 and 14, the spectroscopic data of which matched
those reported for the natural products.11
In conclusion, we have developed a concise stereo-
controlled route to 4,5-cis-disubstituted tetrahydrofura-
nones via oxidative rearrangement of readily available
2-alkoxy-3,4-dihydro-2H-pyrans. Efforts to extend this
to enantioselective synthesis via use of catalytic asym-
Table 1. Conversion of pyrans 3 to lactones 6a
Entry
3
R1
R2
R3
Yieldb
d.r.c
1
2
3
4
5
6
7
a
b
c
d
e
f
H
Me
CH2OBn
iPr
H
H
H
H
H
H
Me
nBu
nBu
Et
69
53
48
63
65
64
50
—
3:1d
95:5
9:1
nBu
Et
Ph
>95:5e
>95:5e
—
(CH2)4CH@CHEt
Me
Et
nBu
g
a Typical procedure: see Ref. 9.
b Isolated yield of 6 over two steps from 3.
c Estimated by integration of the 1H NMR spectrum of the crude reaction mixture.
d Isomers separable by column chromatography: cis-lactone 32%, trans-lactone 10%.
e Only the cis product observed by 1H NMR.

A. Armstrong, H. Chung / Tetrahedron Letters 47 (2006) 1617–1619
1619
To a solution of 2-alkoxydihydropyran 3d (191 mg,
0.9 mmol) in CH2Cl2 (10 mL) under nitrogen was added
DMDO/acetone solution (20 mL of 0.045 M, 0.9 mmol).
The mixture was stirred for 30 min at 0 ꢁC followed by 3 h
at room temperature, then washed with saturated aqueous
NaHCO3 solution and evaporated to give a mixture of
lactol 5d and lactol ether 4d. This mixture was dissolved in
acetone (10 mL) at 0 ꢁC and Jones reagent (0.9 mL of
3.0 M, 2.7 mmol) was added dropwise. After stirring for
3 h, the excess of oxidant was quenched by the dropwise
addition of 2-propanol until the brown colour of the
mixture turned green. The reaction mixture was diluted
with diethyl ether and the precipitated chromium salts
were dissolved by the addition of saturated aqueous
NH4Cl solution. The organic layer was separated and the
aqueous layer was extracted with diethyl ether. The
combined organics were dried (MgSO4) and evaporated.
Column chromatography (1:1 EtOAc/petrol) afforded
lactone 6d (96 mg, 63% over two steps from 3d) as a
colourless oil and as an inseparable 9:1 mixture of
diastereoisomers by 1H NMR, mmax/cmÀ1 2965, 2933,
2879, 1787, 1720, 1644; dH (250 MHz, CDCl3) 4.88
(1Hmajor, d, J 7.1 Hz, OCH), 4.56 (1Hminor, d, J 4.9 Hz,
OCH) 2.64–2.34 (3H, m, COCH2, CH), 2.29 (3Hmajor, s,
CH3), 2.26 (3Hminor, s, CH3), 1.90 (1Hminor, m, CHCH3),
1.68 (1Hmajor, m, CHCH3), 0.99 (3Hmajor, d, J 6.6 Hz,
CHCH3), 0.96 (3Hminor, d, J 2.1 Hz, CHCH3), 0.94
(3Hminor, d, J 2.1 Hz, CHCH3), 0.87 (3Hmajor, d, J
6.7 Hz, CHCH3); dC (125 MHz, CDCl3) resonances for
major isomer: 205.7 (CH3CO), 175.4 (OCO), 84.3 (CH),
metric Diels–Alder or epoxidation processes are under-
way in our labs.
Acknowledgements
We thank Bristol-Myers Squibb, Merck Sharp and
Dohme and Pfizer for unrestricted support of our
research programme.
References and notes
1. Armstrong, A.; Cumming, G. R.; Pike, K. Chem. Com-
mun. 2004, 812–813.
2. Armstrong, A.; Shanahan, S. E. Org. Lett. 2005, 7, 1335–
1338.
3. (a) Ireland, R. E.; Ha¨bich, D. Chem. Ber. 1981, 114, 1418–
1427; (b) Ireland, R. E.; Ha¨bich, D. Tetrahedron Lett.
1981, 21, 1389–1392; (c) McRae, K. J.; Rizzacasa, M. A. J.
Org. Chem. 1997, 62, 1196–1197.
4. Chernoff, H. C.; Hall, S. S. Chem. Ind. 1970, 896–897.
5. Reviews of THF synthesis: (a) Boivin, T. L. B. Tetra-
hedron 1987, 43, 3309–3362; (b) Figadere, B.; Harmange,
J. Tetrahedron: Asymmetry 1993, 4, 1711–1754; (c) Urich,
K. Synthesis 1995, 115–132; Examples dealing with 2,3-
disubstituted THFs: (a) Burke, S. D.; Jung, K. W.
Tetrahedron Lett. 1994, 35, 5837–5840; (b) Hartung, J.;
Schmidt, P. Synlett 2000, 367–370; (c) Judka, M.;
Ma˛kosza, M. Chem. Eur. J. 2002, 8, 4234–4240; (d)
Sutterer, A.; Moller, K. D. J. Am. Chem. Soc. 2000, 122,
5636–5637; (e) Guidon, Y.; Labelle, M. J. Am. Chem. Soc.
1989, 111, 2204–2210.
6. (a) Danishefsky, S.; Bednarsky, M. J. Am. Chem. Soc.
1983, 105, 3716–3717; (b) Danishefsky, S.; Bednarsky, M.
Tetrahedron Lett. 1984, 7, 721–724.
7. Solutions of DMDO in acetone (ca. 0.05 M; titrated
against iodine before use) prepared according to the
procedures in: (a) Burke, S. D.; Danheiser, R. L. Oxidizing
and Reducing Agents. In Handbook of Reagents for
Organic Synthesis; Wiley: New York, 1999; Vol. 2, pp
149–152; (b) Adam, W.; Bialas, J.; Hadjiarapoglou, L.
Chem. Ber. 1991, 124, 2377–2378.
46.4 (CH2), 31.3 (CH), 29.1 (CH), 27.6 (CH3), 21.4, 20.0
+
(CH3); m/z (CI) 188 (MNH4+, 100%); Found: MNH4
,
188.1289. C9H14O3 requires: MNH4+, 188.1287.
10. (a) Conner, J. M.; Paterson, A.; Piggott, J. R. J. Sci. Food
Agric. 1993, 62, 169–174; (b) Lee, K. Y. M.; Paterson, A.;
Piggott, J. R. J. Inst. Brew. 2000, 106, 203–208; (c) Ebata,
T.; Matsumoto, K.; Yoshikoshi, H. Heterocycles 1993, 36,
1017–1026; (d) Kepner, R. E.; Webb, A. D.; Muller, C. J.
Am. J. Enol. Viticult. 1972, 23, 103–105; (e) Otsuka, K.;
Zenibayashi, Y.; Itoh, M.; Totsuka, A. Agric. Biol. Chem.
1974, 38, 485–490; (f) Pollnitz, A. P.; Jones, G. P.; Sefton,
M. A. J. Chromatogr. A 1999, 857, 239–246.
11. Data for 13: 1H NMR (250 MHz, CDCl3) 4.44 (1H, dd, J
5.8, 4.5 Hz, OCH), 2.66 (1H, dd,
J 17.0, 8.0 Hz,
8. Expected key NOE interactions between the substituents
at C4 and C5 were observed in the major isomers.
9. Typical procedure for oxidative rearrangement: synthesis
of lactone 6d. To n-butyl vinyl ether (6.0 mL, 47 mmol)
were added methyl vinyl ketone (3.1 mL, 24 mmol) and
Yb(fod)3 (1.0 g, 0.94 mmol). After heating in a pressure
tube at 55 ꢁC for 3 days, the solution was purified
by column chromatography (5:95 ether/petrol) to give
dihydropyran 3d (3.8 g, 75%) as a 6:1 inseparable mixture
of diastereoisomers and as a pale yellow oil, mmax/cmÀ1
2958, 2873, 1721, 1678; dH (250 MHz, CDCl3) peaks for
major isomer: 4.84 (1H, dd, J 9.4, 2.1 Hz, OCHO), 4.36
(1H, d, J 0.7 Hz, CCH), 3.90 (1H, dt, J 9.5, 6.6 Hz,
OCH2), 3.47 (1H, dt, J 9.5, 6.7 Hz, OCH2), 2.08 (1H, dqq,
J 12.3, 4.1, 2.1 Hz, CCH), 1.86 (1H, ddt, J 12.6, 6.2,
1.7 Hz, CH), 1.71 (1H, s, CH3), 1.64–1.25 (6H, m,
3 · CH2), 0.94–0.82 (9H, m, 3 · CH3); m/z (CI) 213
(MH+, 100%); Found: MH+, 213.1860. C13H24O2
requires: MH+, 213.1854. The minor isomer, which
became more significant on standing due to epimerisation,
showed distinct 1H NMR resonances at 5.01 (1H, t, J
2.7 Hz, OCHO) and 4.49 (1H, d, J 0.7 Hz, CCH).
OC(O)CH2), 2.60–2.50 (1H, m, CHCH3), 2.16 (1H, dd, J
17.0, 4.0 Hz, OC(O)CH2), 1.80–1.27 (6H, m, 3 · CH2),
0.98 (3H, d, J 7.0 Hz, CH3CH), 0.91 (3H, t, J 7.1 Hz,
CH2CH3); dC (125 MHz, CDCl3) 176.9 (OCO), 83.7
(CHCO), 37.6 (CH), 33.0 (CH2), 29.6 (CH2), 28.0 (CH2),
22.5 (CH2), 13.9 (CH3), 13.8 (CH3). These data are in
accord with the literature: (a) Reissig, H.; Angert, H.;
Kunz, T.; Janowitz, A.; Handke, G.; Bruce-Adjei, E. J.
Org. Chem. 1993, 58, 6280–6285; (b) Moret, E.; Schlosser,
M. Tetrahedron Lett. 1984, 25, 4491–4494.
Data for 14: 1H NMR (250 MHz, CDCl3) 4.40 (1H, dd, J
5.8, 4.5 Hz, OCH), 2.66 (1H, dd,
J 16.9, 7.8 Hz,
OCOCH2), 2.60–2.50 (1H, m, CHCH3), 2.16 (1H, dd, J
16.9, 3.9 Hz, OCOCH2), 1.69–1.26 (8H, m, 3CH2), 0.98
(3H, d, J 7.0 Hz, CH3CH), 0.87 (3H, t, J 7.0 Hz,
CH2CH3), dC (125 MHz, CDCl3) 176.8 (OCO), 83.6
(CHCO), 37.6, 31.6, 29.8, 25.6, 22.5 (5 · CH2), 33.0
(CH), 25.1, 13.9 (CH3, CH3). These data are in accord
with the literature: (a) Jefford, C. W.; Sledeski, A. W.;
Boukouvalas, J. Helv. Chim. Acta 1989, 72, 1362–1370; (b)
Rojo, J.; Garcia, M.; Carretero, J. C. Tetrahedron 1993,
49, 9787–9800.