Synthesis of modified methyl furanosides by intramolecular oxa-michael reaction followed by pummerer rearrangement

Article abstract of DOI:10.1021/jo100241e

A new method is described for the synthesis of ribofuranoses modified at the C3 and C5 positions. The key step is an intramolecular oxa-Michael reaction on a vinyl sulfoxide to install the C2 hydroxy group. The methyl furanosides are obtained by Pummerer rearrangement of the sulfoxide into the corresponding aldehyde, acidic deprotection of the benzylidene acetal, and cyclization.

Full text of DOI:10.1021/jo100241e

pubs.acs.org/joc
SCHEME 1. Synthesis of Methyl Furanosides from Vinyl
Sulfoxides
Synthesis of Modified Methyl Furanosides by
Intramolecular Oxa-Michael Reaction followed
by Pummerer Rearrangement
†
Diego Gamba-Sanchez and Joelle Prunet*
,‡
€
†Laboratoire de Syntheꢀse Organique, CNRS UMR 7652,
Ecole Polytechnique, DCSO, F-91128 Palaiseau, France, and
‡WestCHEM, Department of Chemistry, University of
Glasgow, Joseph Black Building, University Avenue,
Glasgow G12 8QQ, U.K.
j.prunet@chem.gla.ac.uk
Received February 10, 2010
The hydroxy group at C2 would be installed diastereoselec-
tively by an intramolecular conjugate addition of a hemiketal
alkoxide, made in situ from a homoallylic alcohol in the
presence of base and excess benzaldehyde, to a vinyl sulf-
oxide.5 The sulfoxide moiety would then be converted to the
corresponding aldehyde by Pummerer rearrangement and
the unnatural methyl furanoside obtained by acidic depro-
tection of the benzylidene acetal and cyclization in methanol.
We first embarked on the synthesis of 3-deoxyribofura-
noses (R1 = R2 = H, Scheme 1). The required substrates for
the oxa-Michael key step could not be prepared efficiently by
cross-metathesis of the corresponding homoallylic alcohols
with phenyl vinyl sulfoxide, as described by Grela and
co-workers.6 Cross-metathesis of the homoallylic alcohols
with phenyl vinyl sulfide was also unsuccessful.7 We thus
resorted to a two-step sequence from homopropargylic
alcohols 1a-c (Scheme 2). Radical addition of thiophenol
to these compounds,8 followed by oxidation of the resulting
sulfides with sodium periodate,9 furnished sulfoxides 2a-c
in good overall yields.10
A new method is described for the synthesis of ribo-
furanoses modified at the C3 and C5 positions. The key
step is an intramolecular oxa-Michael reaction on a vinyl
sulfoxide to install the C2 hydroxy group. The methyl
furanosides are obtained by Pummerer rearrangement
of the sulfoxide into the corresponding aldehyde, acidic
deprotection of the benzylidene acetal, and cyclization.
The key intramolecular conjugate addition required four
additions of 1.1 equiv of benzaldehyde and a substoichio-
metric amount of potassium tert-butoxide (0.1 equiv) for
complete conversion (Scheme 3).11 Benzylidene acetals 3a-c
were formed with excellent diastereoselectivity in favor of the
syn isomer12 (R being linear, branched, or oxygenated). The
Viral infections and cancers constitute major health pro-
blems worldwide. With the emergence of new viruses and the
development of drug resistance, the need for new therapeutic
agents is continuously increasing. Nucleoside analogues play
an extremely important role in the fight against viruses,
especially human immunodeficiency virus (HIV), hepatitis
C virus (HCV), or herpes simplex virus (HSV). So far, more
than 40 antiviral drugs belong to this class of compounds,
including 24 for the therapy of HIV infections,1 so their
synthesis has attracted the attention of numerous chemists.2
In addition, nucleoside analogues have been successfully
used in the treatment of various tumors.3 The most common
access to these compounds involves modifications of natu-
rally occurring nucleosides.4
(5) For a similar reaction with unsaturated esters, see: Evans, D. A.;
Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446. With vinyl sulfones, see:
(a) Grimaud, L.; Rotulo, D.; Ros-Perez, R.; Guitry-Azam, L.; Prunet, J.
Tetrahedron Lett. 2002, 43, 7477. (b) Rotulo-Sims, D.; Prunet, J. Org. Lett.
2007, 9, 4147.
(6) Michrowska, A.; Bieniek, M.; Kim, M.; Klajn, R.; Grela, K. Tetra-
hedron 2003, 59, 4525. The best yield for the cross-metathesis leading to 2a
was 18% in the presence of 2 mol % of Grubbs 2 catalyst and 0.3 equiv of
titanium tetraisopropoxide. Complete conversion for this reaction was only
observed with a full equivalent of the ruthenium catalyst.
(7) For a successful ROM/CM cascade with phenyl vinyl sulfide, see:
Katayama, H.; Urushima, H.; Nishioka, T.; Wada, C.; Nagao, M.; Ozawa,
F. Angew. Chem., Int. Ed. 2000, 39, 4513.
(8) Griesbaum, K. Angew. Chem., Int. Ed. Engl. 1970, 9, 273.
(9) Leonard, N. J.; Johnson, C. R. J. Org. Chem. 1962, 27, 282.
(10) Throughout this study, sulfoxides were obtained as a 1:1 mixture of
E/Z isomers and a 1:1 mixture of diastereomers at the sulfur center.
(11) Oxa-Michael reaction of sulfoxide 2a with benzaldehyde and
KHMDS furnished 3a in 55% yield.
We report here a new method for the construction of
ribofuranoses with modifications at the 3- and 5-positions
(Scheme 1) that could be converted to original nucleoside
analogues not readily available by classical synthetic routes.
(1) De Clercq, E. Nat. Rev. Drug. Discov. 2007, 6, 1001.
(2) Ichikawa, E.; Kato, K. Curr. Med. Chem. 2001, 8, 385.
(3) Matsuda, A.; Sasaki, T. Cancer Sci. 2004, 95, 105.
(4) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
(12) The syn stereochemistry was proven by NOE experiments performed
on benzylidene acetal 3c.
DOI: 10.1021/jo100241e
r
Published on Web 04/12/2010
J. Org. Chem. 2010, 75, 3129–3132 3129
2010 American Chemical Society

Gamba-Sanchez and Prunet
SCHEME 5. Synthesis of 1,2-Anti Alcohols 7a-c
JOCNote
SCHEME 2. Synthesis of Vinyl Sulfoxides 2a-c
SCHEME 3. Oxa-Michael Reaction of Vinyl Sulfoxides 2a-c
SCHEME 6. Synthesis of 1,2-Syn Alcohols 10a,c
SCHEME 4. Synthesis of Methyl 3-Deoxyfuranosides 4a-c
(Scheme 5). Silyl ethers 5a,b were obtained by protection of
the corresponding known Hoppe homoaldol adducts.18
Fritsch-Buttenberg-Wiechel19 rearrangement of the result-
ing vinyl carbamates to the alkynes followed by hydrolysis of
the triethylsilyl ethers by pyridinium p-toluenesulfonate in
MeOH/water gave homopropargylic alcohols 6a,b in excel-
lent overall yields. Finally, sulfoxides 7a,b were obtained as
before by radical addition of thiophenol to 6a,b and sodium
periodate oxidation of the resulting sulfides.10 Fritsch-
Buttenberg-Wiechel rearrangement of compound 6c (R =
BnOCH2) only led to decomposition products, so sulf-
oxide 7c was prepared by NaIO4 oxidation of known alcohol
8c.20,10
We also synthesized 1,2-syn alcohols 10a,c (Scheme 6).
Vinyl sulfoxide 10a was made by Peterson olefination21 of
known aldehyde 9a,22 followed by NaIO4 oxidation of the
resulting vinyl sulfide.10 Compound 10c was more conveni-
ently prepared via alkyne 12c (Scheme 6). Known epoxide
11c23 was opened by lithium-acetylide complex in a mixture
of DMSO and HMPA to furnish homopropargylic alcohol
12c in excellent yield and with total regioselectivity.24 Sub-
sequent transformation of 12c into 10c was effected as
previously shown in Schemes 2 and 5.10
stereogenicity of the sulfoxide has no notable influence on
the selectivity of the oxa-Michael reaction, but the Z sulf-
oxides react slower than the E isomers.13
For the conversion of protected diols 3a-c into the
ribofuranose derivatives 4a-c (Scheme 4), Pummerer rear-
rangement14 must be performed prior to the hydrolysis of the
benzylidene acetal. This rearrangement was not effective on
the sulfoxide compounds bearing the free diol. Acidic cycli-
zation in methanol of the unpurified aldehyde intermediates
then led to methyl 3-deoxyfuranosides 4a-c in good yields
and good to excellent selectivity in favor of the 1,2-trans
isomer.15 Compound 4c (R = BnOCH2), a protected form of
3-deoxyribofuranose, is a precursor of cordycepin (30-deoxy-
adenosine), which has been reported to present antitu-
moral16 and antiviral activities.17
Once this new method had been validated for the con-
struction of 3-deoxyribofuranose analogues, we turned our
attention to the synthesis of 3-substituted sugar derivatives
(R1 or R2 = Me, Scheme 1). The required vinyl sulf-
oxide precursors of these furanoses bear a substituent at
the allylic position, and we first prepared 1,2-anti alcohols 7
(13) Recovered vinyl sulfoxides from incomplete conjugate addition
reactions were enriched in Z diasteromers.
The oxa-Michael reaction was then studied with sub-
strates 7a-c (Scheme 7). Benzylidene acetals 13a-c were
produced with excellent diastereoselectivity in favor of the
1,3-syn diastereomers. In the case of vinyl sulfoxide 7b, when
(14) Feldman, K. S. Tetrahedron 2006, 62, 5003.
(15) The trans stereochemistry was assigned by comparison of the 1H
NMR spectrum of 4c (known compound) with the literature data: Jones, M.
F.; Noble, S. A.; Robertson, C. A.; Storer, R.; Highcock, R. M.; Lamont, R.
B. J. Chem. Soc., Perkin Trans. 1 1992, 1427.
(16) Nakamura, K.; Yoshikawa, N.; Yamaguchi, K; Kagota, S.;
Shinozuka, K.; Kinutomo, M. Anticancer Res. 2006, 26, 43.
(17) Luo, G. X.; Hamatake, R. K.; Racela, J.; Rigat, K. L.; Lemm, J.;
Colonno, R. J. J. Virol. 2000, 851.
(18) (a) Kalkofen, R.; Brandau, S.; Wibbeling, B.; Hoppe, D. Angew.
Chem., Int. Ed. 2004, 43, 6667. (b) Risatti, C. A.; Taylor, R. E. Angew. Chem.,
Int. Ed. 2004, 43, 6671.
(20) This alcohol was synthesized by regio- and diastereoselective addi-
tion of the anion of crotyl phenyl sulfide to benzyloxyacetaldehyde; see:
Gamba-Sanchez, D.; Oriez, R.; Prunet, J. Tetrahedron Lett. 2009, 50, 883.
(21) Chen, F.; Mudryk, B.; Cohen, T. Tetrahedron 1999, 55, 3291.
(22) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201.
(23) Fuganti, C.; Grasseli, P.; Sevi, S.; Zirotti, C. Tetrahedron Lett. 1982,
23, 4269.
ꢁ ꢁ
(19) Ferezou, J.-P.; Julia, M.; Li, Y.; Liu, L. W.; Pancrazi, A. Bull. Soc.
Chim. Fr. 1995, 132, 428.
(24) Parker, K. A.; Chang, W. Org. Lett. 2005, 7, 1785.
3130 J. Org. Chem. Vol. 75, No. 9, 2010

Gamba-Sanchez and Prunet
JOCNote
SCHEME 7. Oxa-Michael Reaction of Vinyl Sulfoxides 7a-c
and 10a,c
TABLE 1. Synthesis of Methyl Furanosides 15a-c and 16a,c
R1
R2
substrate
product
yield (%)
1,2-trans/1,2-cis
H
H
H
CH3
CH3
CH3
CH3
CH3
H
13a
13b
13c
14a
14c
15a
15b
15c
16a
16c
75
80
69
60
57
94:6
95:5
84:16
1:1
H
1:1
for the construction of highly oxygenated natural products
such as the polyene antibiotics.
Experimental Section
the reaction was performed at 0 °C, only decomposition was
observed. However, we were pleased to see that at -78 °C,
13b was obtained in good yield with the same selectivity.
The same reaction conditions were applied to 10a and 10c
(Scheme 7). In this case, the 1,3-syn selectivity for 14a and 14c
is slightly eroded because the methyl group in the 1,3-syn
isomer occupies an axial position and is equatorial in the
1,3-anti isomer, which lowers the energy difference between
these two isomers.
Benzylidene acetals 13 and 14 were converted to the
corresponding methyl furanosides 15 and 16 by Pummerer
rearrangement to the corresponding aldehydes followed
by acidic treatment in the presence of methanol (Table 1),
under the conditions described in Scheme 4. The 1,2-trans
product is the major diastereomer for compounds 15 (R1 = H,
R2 = Me), with the methoxy substituent trans to both the
OH at C2 and the Me group at C3. In the case of acetals 16
(R1 = Me, R2 = H), the OH and the Me groups are on
opposite faces, so these products are formed as 1:1 mixtures
of 1,2-trans and 1,2-cis isomers.
Furanoses similar to 15c and 16c (R = BnOCH2) have
been synthesized from xylose,25 but all the other ketals
reported here are not readily available by known modifica-
tions of natural sugars. Variation of the R, R1, and R2 groups
would easily lead to a large number of unnatural ribofur-
anoses (Table 1).
In conclusion, we have developed a short and efficient
methodology for the synthesis of ribofuranoses modified at
the C3 and C5 positions. A diastereoselective oxa-Michael
reaction is employed to install the hydroxy group at C2, and
the ribofuranose analogues are then obtained by Pummerer
rearrangement followed by cyclization to the methyl furano-
sides. Although this method has been developed on racemic
subsrates, it could easily be transposed to the synthesis of
enantiopure furanosides, as vinyl carbamates 5a,b,18 alde-
hyde 9a,22 and epoxide 11c23 have been described as single
enantiomers.
Conjugate addition. (2R*,4R*,6R*)-4-Phenethyl-2-phenyl-
6-(phenylsulfinylmethyl)-1,3-dioxane 3a. To a solution of vinyl
sulfoxide 2a (213 mg, 0.71 mmol) in THF (7.1 mL) at 0 °C was
added t-BuOK (8 mg, 0.071 mmol) followed by benzaldehyde
(79 μL, 0.78 mmol), and the resulting mixture was stirred for
15 min at 0 °C. A second portion of t-BuOK and benzaldehyde
was added, after 15 min a third portion was added, and after
15 min a fourth addition was made. The resulting mixture was
then stirred at 0 °C for 2 h and quenched with a saturated
aqueous NH4Cl solution. The aqueous phase was extracted
three times with Et2O, and the combined organic extracts were
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The crude residue was purified by silica
gel column chromatography with AcOEt/petroleum ether
(30:70-40:60) to give 199 mg (70%) of the desired ketal 3a as
a pale yellow oil (syn/anti > 98:2, 1:1 mixture of diastereomers
at the sulfur center): 1H NMR (CDCl3, 400 MHz) δ 7.18-7.66
(m, 15H), 5.67 (s, 0.5H), 5.41 (s, 0.5H), 4.48-4.55 (m, 0.5H),
4.08-4.15 (m, 0.5H), 3.83-3.92 (m, 0.5H), 3.74-3.81 (s, 0.5H),
3.31 (dd, J = 13.3, 6.6 Hz, 0.5H), 2.70-2.97 (m, 3.5H),
1.97-2.06 (m, 1H), 1.48-1.87 (m, 3H); 13C NMR (CDCl3,
100 MHz) δ 144.4 (C), 143.3 (C), 141.56 (C), 141.54 (C), 138.1
(C), 138.0 (C), 131.1 (CH), 131.0 (CH), 129.3 (CH), 128.77
(CH), 128.75 (CH), 128.5 (CH), 128.43 (CH), 128.42 (CH),
128.35 (CH), 128.2 (CH), 128.1 (CH), 126.0 (CH), 125.9 (CH),
124.2 (CH), 123.7 (CH), 100.4 (CH), 75.5 (CH), 75.4 (CH),
70.8 (CH2), 70.4 (CH2), 64.4 (CH2), 62.0 (CH2), 37.3 (CH2),
37.1 (CH2), 36.4 (CH2), 36.2 (CH2), 31.1 (CH2), 31.0 (CH2); IR
(CH2Cl2, cm-1) 3394, 3058, 3036, 2925, 2860, 1958, 1887, 1813,
1725, 1702, 1494, 1446, 1341, 1276, 1044, 1021, 909; HRMS (EI)
Mþ calcd for C25H26O3S 406.1603, found 406.1608.
Only two peaks could be observed at 5.67 and 5.41 ppm
(1:1 ratio) for the acetal protons, corresponding to the two
diastereomers at the sulfur center. No trace of the anti isomers
could be detected.
(2R*,4R*,5R*,6R*)-5-Methyl-4-phenethyl-2-phenyl-6-(phenyl-
sulfinylmethyl)-1,3-dioxane 13a. The above procedure was used
with vinyl sulfoxide 7a (230 mg, 0.732 mmol). The crude residue
was purified by silica gel column chromatography with AcOEt/
petroleum ether (30:70-40:60) to give 193 mg (63%) of the
desired ketal 13a as a pale yellow oil (syn/anti > 98:2, 1:1
mixture of diastereomers at the sulfur center): 1H NMR
(CDCl3, 400 MHz) δ 7.66-7.68 (m, 2H), 7.60-7.62 (m, 1H),
7.49-7.52 (m, 3H), 7.35-7.43 (m, 4H), 7.26-7.31 (m, 2H),
7.18-7.23 (m, 3H), 5.73 (s, 0.5H), 5.36 (s, 0.5H), 4.15 (td, J =
10.3, 1.6 Hz, 0.5H), 3.54 (td, J = 7.5, 2.6 Hz, 1H), 3.32-3.37 (m,
1H), 3.14 (dd, J = 13.4, 2.9 Hz, 0.5H), 3.08 (dd, J = 13.1, 1.9 Hz,
In addition to new furanose analogues of therapeutic
interest, the intermediate sulfoxides (as well as the corres-
ponding transposed aldehydes) flanked by a protected
1,3-diol motif are useful synthons that could be employed
ꢁ
(25) Couturier, S.; Aljarah, M.; Gosselin, G.; Mathe, C.; Perigaud, C.
ꢁ
Tetrahedron 2007, 63, 11260.
J. Org. Chem. Vol. 75, No. 9, 2010 3131

Gamba-Sanchez and Prunet
JOCNote
0.5H), 2.88-3.00 (m, 1H), 2.84 (dd, J = 13.2, 10.8 Hz, 0.5H),
2.68-2.79 (m, 1H), 1.97-2.10 (m, 1H), 1.74-1.91 (m, 1.5H),
1.59-1.63 (m, 0.5H), 0.83 (d, J = 6.6 Hz, 1.5H), 0.76 (d, J = 6.7
Hz, 1.5H); 13C NMR (CDCl3, 100 MHz) δ 144.6 (C), 143.4 (C),
141.9 (C), 141.8 (C), 138.2 (C), 138.0 (C), 131.1 (CH), 130.9
(CH), 129.3 (CH), 129.2 (CH), 128.7 (CH), 128.5 (CH), 128.46
(CH), 128.40 (CH), 128.37 (CH), 128.2 (CH), 128.1 (CH), 125.9
(CH), 125.86 (CH), 125.84 (CH), 124.4 (CH), 123.7 (CH), 99.9
(CH), 99.8 (CH), 80.9 (CH), 80.8 (CH), 76.3 (CH), 75.7 (CH),
62.9 (CH2), 60.4 (CH2), 38.5 (CH), 38.0 (CH), 34.6 (CH2), 34.2
(CH2), 31.2 (CH2), 31.0 (CH2), 12.0 (CH3), 11.8 (CH3); IR
(CH2Cl2, cm-1) 3424, 3034, 2963, 2927, 2251, 1957, 1889,
1814, 1731, 1602, 1491, 1449, 1403, 1343, 1265, 1253, 1215,
1130, 1080, 1063, 1047, 929; HRMS (EI) Mþ calcd for C26H28-
O3S 420.1759, found 420.1761.
crude residue was purified by silica gel column chromatography
with AcOEt/petroleum ether (30:70-50:50) to give 503 mg
(80%) of the desired tetrahydrofuran 4a as a pale yellow oil
and a trans/cis (89:11) mixture. Only the NMR data for the trans
isomer is described: 1H NMR (CDCl3, 400 MHz) δ 7.17-7.30
(m, 5H), 4.79 (s, 1H), 4.30-4.37 (m, 1H), 4.24 (bs, 1H), 3.36
(s, 3H), 2.64-2.83 (m, 2H), 1.79-2.01 (m, 5H); 13C NMR
(CDCl3, 100 MHz) δ 141.8 (C), 128.38 (CH), 128.36 (CH),
125.8 (CH), 108.8 (CH), 78.7 (CH), 76.2 (CH), 54.2 (CH3), 39.5
(CH2), 38.0 (CH2), 32.5 (CH2); IR (CH2Cl2, cm-1) 3602, 3047,
3033, 2991, 2939, 1952, 1879, 1810, 1753, 1690, 1602, 1494, 1446,
1378, 1346, 1312, 1191, 1157, 1099, 1040, 971; HRMS (EI) Mþ
calcd for C13H18O3 222.1256, found 222.1251.
The trans/cis ratio was determined by the relative integrations
of the peaks for the acetal protons at 4.79 (s, trans isomer) and
4.94 ppm (d, J = 4.4 Hz, cis isomer).
Only two peaks could be observed at 5.73 and 5.36 ppm
(1:1 ratio) for the acetal protons, corresponding to the two
diastereomers at the sulfur center. No trace of the anti isomers
could be detected.
(2R*,3R*,4R*,5R*)-2-Methoxy-4-methyl-5-phenethyltetra-
hydrofuran-3-ol 15a. The above procedure was applied to ketal
13a (225 mg, 0.535 mmol). The crude residue was purified by
silica gel column chromatography with AcOEt/EP (30:70-
50:50) to afford tetrahydrofuran 15a (95 mg, 75%) as a pale
yellow oil and a trans/cis (94:6) mixture. Only the NMR data for
(2R*,4R*,5S*,6R*)-5-Methyl-4-phenethyl-2-phenyl-6-(phenyl-
sulfinylmethyl)-1,3-dioxane 14a. The above procedure was used
with vinyl sulfoxide 10a (120 mg, 0.38 mmol). The crude residue
was purified by silica gel column chromatography with AcOEt/
petroleum ether (30:70-40:60) to give 130 mg (81%) of the
desired ketal 14a as a pale yellow oil. The product is a 88:12
mixture of isomers (syn/anti) and a 1:1 mixture of diastereomers
at the sulfur center for the syn isomer. Only the two syn
1
the trans isomer are described: H NMR (CDCl3, 400 MHz)
δ 7.16-7.30 (m, 5H), 4.78 (s, 1H), 3.98 (d, J = 4.3 Hz, 1H),
3.85(td, J = 8.8, 3.6 Hz, 1H), 3.37 (s, 3H), 2.84-2.91 (m, 1H),
2.66-2.74 (m, 1H), 2.07-2.14 (m, 1H), 1.87-1.97 (m, 1H),
1.71-1.81 (s, 1H), 1.04 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 142.1 (C), 128.3 (CH), 125.7 (CH), 108.8 (CH), 84.1
(CH), 78.2 (CH), 54.3 (CH3), 40.9 (CH), 37.7 (CH2), 32.5 (CH2),
9.8 (CH3); IR (CH2Cl2, cm-1) 3611, 3086, 3071, 3044, 3029,
2992, 2934, 2831, 1949, 1876, 1811, 1603, 1583, 1496, 1455, 1381,
1315, 1283, 1255, 1193, 1154, 1104, 1032; HRMS (EI) Mþ calcd
for C14H20O3 236.1413, found 236.1410.
1
diastereomers are described: H NMR (CDCl3, 400 MHz) δ
7.10-7.68 (m, 15H), 5.68, 5.37 (2s, 1H), 4.57 (dt, J = 10.6, 2.0
Hz, 0.5H), 4.22-4.26 (m, 0.5H), 3.92-3.96 (m, 0.5H), 3.83-
3.87 (m, 0.5H), 3.28 (dd, J = 13.4, 7.6 Hz, 0.5H), 2.92-2.97 (m,
1H), 2.63-2.83 (m, 2.5H), 1.99-2.09 (m, 1H), 1.66-1.77 (m,
1.5H), 1.50-1.55 (m, 0.5H), 1.05, 0.97, 0.76 (3d, J = 6.7, 7.0, 6.6
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ144.7 (C), 143.2 (C),
141.6 (C), 141.5 (C), 138.3 (C), 138.1 (C), 131.1 (CH), 131.0
(CH), 129.3 (CH), 129.2 (CH), 128.8 (CH), 128.7 (CH), 128.5
(CH), 128.4 (CH), 128.2 (CH), 128.0 (CH), 126.1 (CH), 126.0
(CH), 125.9 (CH), 124.1 (CH), 123.7 (CH), 101.5 (CH), 101.2
(CH), 79.7 (CH), 79.6 (CH), 74.3 (CH), 73.9 (CH), 62.7 (CH2),
58.9 (CH2), 35.3 (CH), 34.7 (CH), 34.2 (CH2), 34.1 (CH2), 31.6
(2R*,3R*,4S*,5R*)-2-Methoxy-4-methyl-5-phenethyltetra-
hydrofuran-3-ol 16a. The above procedure was applied to ketal
14a (300 mg, 0.71 mmol). The crude residue was purified by
silica gel column chromatography with AcOEt/EP (30:70-
70:30) to afford tetrahydrofuran 16a (101 mg, 60%) as a pale
yellow oil and a trans/cis (50:50) mixture: 1H NMR (CDCl3, 400
MHz) δ 7.16-7.30 (m, 5H), 4.88 (d, J = 4.4 Hz, 0.5H), 4.78 (d,
J = 1.7 Hz, 0.5H), 4.15-4.26 (m, 1H), 3.90-3.92 (m, 0.5H),
3.78-3.84 (m, 0.5H), 3.48 (s, 1.5H), 3.42 (s, 1.5H), 2.78-2.91
(m, 1H), 2.58-2.68 (m, 1H), 2.09-2.21 (m, 1H), 1.65-1.90 (m,
2H), 1.03 (d, J = 7.3 Hz, 1H), 0.97 (d, J = 7.2 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 142.1 (C), 141.9 (C), 128.44 (CH),
128.42 (CH), 128.3 (CH), 125.8 (CH), 125.7 (CH), 110.4 (CH),
101.7 (CH), 83.2 (CH), 81.3 (CH), 78.5 (CH), 55.4 (CH3), 55.3
(CH3), 43.2 (CH), 41.7 (CH), 33.6 (CH2), 33.2 (CH2), 32.8
(CH2), 31.5 (CH2), 6.4 (CH3), 6.3 (CH3); IR (CH2Cl2, cm-1
)
2979, 2953, 2861, 1959, 1889, 1814, 1603, 1584, 1496, 1478, 1454,
1444, 1407, 1389, 1347, 1312, 1215, 1177, 1135, 1123, 1087, 1042,
1028; HRMS (EI) Mþ calcd for C26H28O3S 420.1759, found
420.1761.
The syn/anti ratio was determined by the relative integrations
of the peaks for the acetal protons at 5.68 and 5.37 ppm (syn
isomers) and at 6.01 (anti isomer).
Pummerer Reaction and Acidic Cyclization. (2R*,3R*,5R*)-
2-Methoxy-5-phenethyltetrahydrofuran-3-ol 4a. TFAA (1.71 g,
11.3 mmol) was added to a solution of ketal 3a (1.15 g, 2.83
mmol) in CH2Cl2 (30 mL) at 0 °C. The mixture was stirred for
about 30 min at this temperature. Then a 2 N aqueous NaOH
solution (30 mL) and 15 mL of THF was added, and the mixture
was warmed and stirred for 90 min at 20 °C. The organic phase
was extracted three times with CH2Cl2, dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was
dissolved in MeOH (115 mL), camphorsulfonic acid (CSA)
(130 mg, 0.56 mmol) was added, and the mixture was stirred
overnight. The reaction mixture was quenched with Et3N
(pH ∼8) and diluted with saturated aqueous NaHCO3. The
aqueous phase was extracted three times with AcOEt, and the
combined organic extracts were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The
(CH2), 32.6 (CH2), 12.0 (CH3), 11.9 (CH3); IR (CH2Cl2, cm-1
)
3604, 3526, 3085, 3068, 3055, 3048, 1995, 2937, 2661, 2254, 1950,
1877, 1810, 1733, 1603, 2583, 1496, 1479, 1454, 1411, 1380, 1304,
1283, 1221, 1191, 1154, 1105, 1081, 1049; HRMS (EI) Mþ calcd
for C14H20O3 236.1413, found 236.1420.
Acknowledgment. Financial support was provided by the
CNRS and the Ecole Polytechnique. D.G.-S. acknowledges
COLFUTURO for a fellowship. We thank Rafael Ros-Perez
and Aude Maguer for preliminary experiments.
Supporting Information Available: Experimental proce-
dures and full characterization for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3132 J. Org. Chem. Vol. 75, No. 9, 2010