Cobalt-catalyzed diastereoselective synthesis of C-furanosides. total synthesis of (-)-isoaltholactone

Article abstract of DOI:10.1021/jo401845q

An array of C-aryl and C-vinyl furanosides were prepared in good yields and diastereoselectivities from C-halogeno furanosides either with aryl Grignard or with vinyl Grignard using the convenient Co(acac)₃/TMEDA catalytic system. This method i

Full text of DOI:10.1021/jo401845q

Article
pubs.acs.org/joc
Cobalt-Catalyzed Diastereoselective Synthesis of C‑Furanosides.
Total Synthesis of (−)-Isoaltholactone
Lionel Nicolas,† Eva Izquierdo,† Patrick Angibaud,‡ Ian Stansfield,‡ Lieven Meerpoel,§
Sebastien Reymond,*,† and Janine Cossy*,†
́
†Laboratoire de Chimie Organique, ESPCI ParisTech, UMR CNRS 7084, 10 rue Vauquelin, 75231 Paris Cedex 05, France
‡Janssen Research & Development, a Division of Janssen-Cilag, BP615, Chaussee
́
du Vexin, 27106 Val de Reuil, France
§Janssen Research & Development, a Division of Janssen Pharmaceutica N.V., Turnhoutsweg 30, 2340 Beerse, Belgium
S
* Supporting Information
ABSTRACT: An array of C-aryl and C-vinyl furanosides were
prepared in good yields and diastereoselectivities from C-
halogeno furanosides either with aryl Grignard or with vinyl
Grignard using the convenient Co(acac)3/TMEDA catalytic
system. This method is illustrated by the total synthesis of the
(−)-isoaltholactone.
α‑selectivities and, in addition, we have demonstrated that a
radical process was operating in the mechanism of the cross-
coupling.17
Herein, we wish to report the synthesis of substituted
C‑furanosides by cobalt-catalyzed cross-coupling of C-bromo
furanosides with Grignard reagents, and the application of this
method to the synthesis of the enantiomer of the antitumor
natural product (+)-isoaltholactone.
INTRODUCTION
■
C-Glycosides and C-furanosides are a rich source of building
blocks to access biologically active cyclic ethers and are potent
targets for the pharmaceutical industry.1,2 In addition, non-
natural C-aryl furanosides, as nucleoside derivatives, provide
research opportunities for the study and probing of
nucleobases.3,4
C-glycosides can be prepared according to different
methods;5,6 however, the formation of the anomeric C−C
bond by a metal-catalyzed cross-coupling between C-halogeno
glycosides and organometallics represents an attractive method.
For instance, Lemaire et al. have reported that the addition of
stoichiometric amounts of Ar2Zn reagents to 1-bromo
glycosides provides C-aryl glycosides with full β-selectivities
in the glucose series and α-selectivities in the mannose series.7
RESULTS AND DISCUSSION
■
Preparation of Substituted C-Aryl and C-Vinyl Furano-
sides. As an extension of the C-aryl and C-vinyl glycosides, an
array of orthogonally protected C-halogeno furanosides 1−718
was prepared and these compounds were subjected to the
cobalt-catalyzed cross-coupling with phenylmagnesium bro-
mide to prepare the corresponding C-phenyl furanosides
(Table 1). When 1-bromo furanosides 119 was treated with
PhMgBr (1.5 equiv) in the presence of Co(acac)3 (5 mol %)
and TMEDA (5 mol %) (Table 1, entry 1), the 1,4-cis furan was
obtained in low yield (22%), due to the high instability of the
starting material. The tert-butyldiphenylsilyl protected or
benzoyl protected C-bromo furanosides 2 and 3 yielded the
1,4-cis furans in 77% and 76% yield, respectively, and the
corresponding trans-diastereoisomers were not isolated (Table
1, entries 2 and 3). However, when the configuration of the
C2/C3 stereocenters was inverted such as in C-bromo
furanosides 4, 5, and 6,20 the 1,4-trans C-phenyl furans were
isolated in 62%, 88%, and 75% yields, respectively (Table 1,
entries 4, 5, and 6). In the absence of any substituent at C2,
́
In addition, to form the C-aryl and C-alkyl bonds, Gagne et al.
described a diastereoselective Negishi coupling catalyzed by
Ni(COD)2/tBu-Terpy yielding glycosides with β-selectivities in
the glucose and galactose series, and α-selectivities in the
mannose series.8 Among the different approaches,9 the metal-
catalyzed cross-coupling between C-halogeno furanosides and
organometallics represents a powerful tool for the preparation
of C-aryl furanosides.10−14 Therefore, the development of a
simple and unified method for the synthesis of C-glycosides and
C-furanosides would represent a major breakthrough in the
field of carbohydrate chemistry. As part of our efforts for the
synthesis of natural products from carbohydrate-based building
blocks15 and nonexpensive metal-catalyzed reactions,16 we
recently described the synthesis of C-aryl and C-vinyl glycosides
using a diastereoselective cobalt-catalyzed cross-coupling
between C-bromo glycosides and Grignard reagents.17 The
C‑aryl and C‑vinyl glycosides were obtained with good
Received: August 20, 2013
© XXXX American Chemical Society
A
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acted with 6 to produce the coupling product in a good yield of
97% and a α/β diastereoselectivity superior to 9:1 (Table 2,
entry 1). When 2-thienylmagnesium bromide was employed, a
53% yield was obtained for the coupling product, even with an
increase of the catalytic charge [Co(acac)3 (10 mol
%)/TMEDA (15 mol %)] (Table 2, entry 2). The cross-
coupling was also operative with 2-methyl-1-propenylmagne-
sium bromide and the corresponding C-vinyl furanoside was
isolated in 66% and with a α/β diastereoselectivity superior to
9:1 (Table 2, entry 3).
Table 1. Scope of the Cobalt-Catalyzed Cross-Coupling C-
Halogeno Furanosides 1-7 with PhMgBr
a
Table 2. Scope of the Cobalt-Catalyzed Cross-Coupling of
a
Grignard Reagents and C-Bromo Furanoside 6
a
Grignard reagent (1.5 equiv) was added at a rate of 2 mL/h; once the
reaction was complete the reaction medium was warmed to rt.
b
c
1
Determined by H NMR spectroscopy. Yield of isolated product.
Co(acac)3 (10 mol %) and TMEDA (15 mol %) were used.
d
Total Synthesis of (−)-Isoaltholactone. To illustrate the
potential of the cobalt-catalyzed cross-coupling of aryl Grignard
reagents with C-halogeno furanosides, the synthesis of
(−)-isoaltholactone was envisaged from the natural D-mannose
and designed to prove that our method can be included in
multistep synthesis.
(+)-Isoaltholactone (+)-8 (Figure 1), a diastereoisomer of
the antitumor agent (+)-altholactone (+)-9,22 was originally
isolated from combined extracts of Goniuothalamus malayanus,
G. montanus, and G. tapis.23 This lactone exhibits significant
biological activities including antitumoral, antifungal, and
antibacterial activities.27,24 The growing interest among the
scientific community for this natural product also led to the
synthesis of different analogues of 8.25 The early approaches
a
PhMgBr (1.5 equiv) was added at a rate of 2 mL/h; once the reaction
b
was complete the reaction medium was warmed to rt. Determined by
c
1H NMR spectroscopy. Yield of isolated product.
Figure 1. Structures of (+)-isoaltholactone, (+)-8, and (+)-altholac-
tone, (+)-9.
almost no selectivity was observed for the cross-coupling
product. Indeed, the cross-coupling between Hoeffer’s chloro-
ribofuranose 721 and phenylmagnesium bromide afforded the
desired compound in 60% yield with poor diastereoselectivity
(α/β = 1.3:1) (Table 1, entry 7). Therefore, contrary to the
C‑bromo glycosides, the diastereoselectivity of the cobalt-
catalyzed cross-coupling of C-halogeno furanosides is con-
trolled by the substituent present at C2.
include an epoxidation followed by a cyclization in order to
install the C2- and C3-stereogenic centers,29,26 and an
asymmetric Pd-catalyzed cross-coupling to introduce the
phenyl group.29,27 Direct syntheses from natural-based building
blocks were also realized.28 To our knowledge, the preparation
of 8 by a metal-catalyzed cross-coupling from a C-halogeno
furanoside has never been realized.
A range of Grignard reagents was examined using 6 as the
C‑bromo furanoside. 4-Fluorophenylmagnesium bromide re-
B
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In our retrosynthetic analysis (Scheme 1), the Z double bond
of (−)-isoaltholactone 8 would be introduced by a Still-Gennari
reaction applied to an aldehyde coming from the selective
cleavage of the acetonide at C4 of C-furanoside 10, followed by
an oxidative cleavage of the obtained diol. C-Furanoside 10
would be prepared through the cobalt-catalyzed cross-coupling
between C-bromo furanoside 6 and phenylmagnesium bromide
(Table 1, entry 6), and 6 would be easily synthesized in two
steps from D-mannose 11 as described in the literature.24
CONCLUSION
■
In summary, we have developed a diastereoselective cobalt-
calatyzed cross-coupling of C-halogeno furanosides with aryl
and vinyl Grignard reagents using a cheap and convenient
Co(acac)3/TMEDA catalytic system, providing C-furanosides
in moderate to good yields. Contrary to the C-bromo-
glycosides,17 the orthogonally protected C-halogeno furano-
sides displayed a different behavior as the obtained selectivities
were dependent on the C2 substituent. This cross-coupling was
finally utilized to access (−)-isoaltholactone in seven steps and
in 20% overall yield for D-mannose.
Scheme 1. Retrosynthesis Analysis of (−)-Isoaltholactone
(−)-8
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H NMR spectra were
recorded at 400 MHz and data are reported as follows: chemical
shift in ppm from tetramethylsilane as an internal standard with the
residual solvent peak as an internal indicator (CDCl3 δ: 7.26, C6D6 δ:
7.16), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet or overlap of nonequivalent resonances, br = broad),
integration. 13C NMR spectra were recorded at 100 MHz and the data
are reported as follows: chemical shift in ppm from tetramethylsilane
as an internal standard with the residual solvent peak as an internal
indicator (CDCl3 δ: 77.16, C6D6 δ: 128.06). THF was dried over Na/
benzophenone prior to distillation or using a solvent purification
system. TMEDA was dried over CaH2 prior to distillation. TLC was
performed on silica gel plates visualized either with a UV lamp (254
nm) or using solution of p-anisaldehyde-sulfuric acid-acetic acid in
EtOH followed by heating. Purification was performed on silica gel
(230−400 mesh). High-resolution mass spectra (HRMS) were
performed using electrospray ionization (ESI) with Orbitrap mass
analysis. Mass spectra with electronic impact (MS-EI) were recorded
on a GC/MS (70 eV). C-Aryl and C-vinyl glycosides were prepared
and described in reference 17a. The C-halogeno furanosides 1,24 6,25
and 726 were prepared according to reference reported procedures.
General Procedure for the Cobalt-Catalyzed Cross-Cou-
pling. A solution of the alkenyl or aryl Grignard reagent in THF (1.5
equiv) was added dropwise (at a rate of 2 mL.h−1 using a syringe
pump) to a solution of alkyl halide (1 equiv, 0.1 M), Co(acac)3 (5 mol
%), and TMEDA (5 mol %) in THF at 0 °C. The reaction medium
was warmed to room temperature and after 1 h (at this temperature);
the reaction was quenched by adding an aqueous solution of 1 M HCl.
After extractive workup, the crude product was purified by silica gel
chromatography.
The substituted furanoside 10 (Table 1, entry 6) was treated
with 5 mol % of BiCl3 in MeCN to deliver chemoselectively
diol 12 in 55% yield (Scheme 2). Oxidative cleavage of this 1,2-
diol with NaIO4 (THF/pH 7 buffer) afforded the correspond-
ing aldehyde 13, which was directly treated with the Still-
Gennari phosphonoacetate I, providing α,β-unsaturated ester
14 in 51% yield (two steps). Finally, a one-pot acetonide
deprotection/transesterification sequence using a catalytic
amount of p-toluenesulfonic acid provided (−)-8 in quantita-
tive yield. (−)-Isoaltholactone 8 was prepared in 7 steps from
20
D-mannose in 20% global yield. The optical rotation ([α]D
−23.0 (c = 0.15, EtOH);28b natural product: [α]D20 + 20.0 (c=
0.20, EtOH)26f) and the spectroscopic data of (−)-8 were in
agreement with those reported in the literature.26f,28b
a
Scheme 2. Synthesis of (−)-Isoaltholactone
a
KHMDS = potassium bis(trimethylsilyl)amide, TsOH = p-toluenesulfonic acid, 18-C-6 = 1,4,7,10,13,16-hexaocyclooctadecane.
C
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(2R,3R,4S,5S)-2-(Acetoxymethyl)-5-phenyl-tetrahydrofuran-
133.4, 129.9, 129.8, 128.5, 127.8, 125.9, 114.6, 87.2, 85.2, 84.5, 81.7,
64.1, 27.8, 26.9, 25.7, 19.4; MS (EI) m/z: 373 (14), 295 (23), 242
(10), 241 (43), 223 (11), 217 (12), 199 (29), 189 (10), 163 (54), 162
(12), 161 (90), 143 (20), 139 (27), 135 (25), 133 (10), 129 (11), 115
(12), 105 (30), 103 (69), 91 (100), 77 (26), HRMS (ESI): Calcd for
C30H36O4SiNa [M+Na]+: 511.2275. Found: 511.2274.
20
3,4-diyl diacetate. (from 1, Table 1, entry 1) [α]D −1.2 (c 0.6,
CHCl3); IR (neat): 2917, 1741, 1372, 1215, 1090, 1042, 901, 762, 699,
1
605 cm−1; H NMR (400 MHz, CDCl3) δ 7.40−7.28 (m, 5H), 5.27
(tapp, J = 5.1 Hz, 1H), 5.09 (tapp, J = 5.9 Hz, 1H), 5.00 (d, J = 6.9 Hz,
1H), 4.45 (dd, J = 11.6, 2.8 Hz, 1H), 4.32 (m, 1H), 4.28 (dd, J = 11.6,
4.3 Hz, 1H), 2.10 (s, 6H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.7, 169.8, 138.1, 128.6, 128.5, 126.0, 82.2, 79.8, 76.7, 71.6, 63.7,
20.9, 20.7; MS (EI) m/z: 216 (13), 174 (42), 173 (11), 161 (10), 158
(11), 157 (100), 133 (14), 131 (12), 128 (8), 115 (14), 107 (30), 105
(20), 103 (11), 91 (21), 86 (12), 85 (54), 79 (11), 77 (14), 69 (19);
HRMS (ESI): Calcd for C17H20O7Na [M+Na]+: 359.1101. Found:
359.1102.
((3aR,4R,6aR)-6-Bromo-2,2-dimethyl-tetrahydrofuro[3,4-d]-
[1,3]dioxol-4-yl)methyl benzoate (3). To a solution of
(3aR,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyl-tetrahydrofuro[3,4-d]-
[1,3]dioxol-4-ol29 (1.11 g, 5.84 mmol) in dry pyridine (5.8 mL), was
added 1.1 equiv of benzoyl chloride (903 mg, 0.75 mL, 6.42 mmol).
The reaction was stirred at room temperature overnight. The reaction
was quenched with water and extracted with CH2Cl2. The organic
layer was washed with brine and dried over MgSO4. The solvent was
removed under reduced pressure, and the product was purified by
silica-gel chromatography (PE/EtOAc, 80/20) to yield ((3aR,4R,6aR)-
6-Hydroxy-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl
benzoate as a 66:33 mixture of α- and β-isomers (791 mg, 2.7 mmol,
46%): IR (neat): 3434, 2987, 2941, 1719, 1451, 1374, 1269, 1067,
1026, 867, 709 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 8.3,
1.2 Hz, 1.32H), 7.98 (dd, J = 8.3, 1.2 Hz, 0.66H), 7.60−7.53 (m, 1H),
7.47−7.40 (m, 2H), 5.51 (s, 0.33H), 5.49 (brs, 0.66H), 4.80 (brd, J =
6.0 Hz, 0.66H), 4.76 (dd, J = 6.3, 1.5 Hz, 0.33H), 4.69 (d, J = 6.0 Hz,
0.66H), 4.67 (m, 0.33H), 4.56−4.5 (m, 1.32H), 4.46−42 (m, 0.66H),
4.39−4.32 (m, 1H), 4.04 (brs, 0.33H), 3.71 (brs, 0.66H), 1.58 (s, 1H),
1.48 (s, 2H), 1.38 (s, 1H), 1.33 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 166.6, 166.2, 133.5, 133.3, 129.9, 129.7, 129.7, 129.5, 128.7, 128.5,
114.2, 112.8, 103.2, 97.6, 86.0, 87.9, 82.1, 82.1, 79.3, 78.7, 65.8, 65.7,
26.6, 26.2, 25.1, 24.9; MS (EI) m/z: 279 ([M-Me]+, 7), 114 (15), 113
(7), 106 (8), 105 (100), 86 (6), 85 (7), 77 (28), 69 (11), 68 (18), 59
(24), 51 (7); HRMS (ESI): Calcd for C15H18O6Na [M+Na]+:
317.0996. Found: 317.0997. To a solution of ((3aR,4R,6aR)-6-
Hydroxy-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl
benzoate (791 mg, 2.7 mmol) in dry CH2Cl2 (27 mL) at 0 °C was
added 3 equiv of bromotrimethylsilane (1.06 mL, 8.1 mmol). The
reaction was stirred at room temperature during 2 h. The solvent was
removed under reduced pressure, and the product was purified over a
short pad of silica gel (PE/EtOAc, 90/10) to yield 3 as a 85:15 mixture
of α- and β-isomers (142 mg, 0.41 mmol, 15%) which was directly
(((3aR,4R,6R,6aR)-6-Bromo-2,2-dimethyl-tetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)methoxy)(tert-butyl)diphenylsilane (2). To a
solution of (3aR,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-ol29 (1.14 g, 5.99 mmol) and
imidazole (1.04 g, 16.7 mmol, 2.8 equiv) in dry DMF (3 mL), was
added tert-butyl(chloro)diphenylsilane (1.8 g, 1.7 mL, 6.6 mmol, 1.1
equiv). After 2 h at room temperature, the reaction was quenched with
water and extracted with CH2Cl2. The organic layer was washed with
brine and dried over MgSO4. The solvent was removed under reduced
pressure, and the product was purified by silica-gel chromatography
(PE/Et2 O, 90/10) to yield (3aR,6R,6aR)-6-((tert-
Butyldiphenylsilyloxy)methyl)-2,2-dimethyl-tetrahydrofuro[3,4-d]-
[1,3]dioxol-4-ol as a 69:31 mixture of α- and β-isomers (1.15 g, 2.34
mmol, 39%): IR (neat): 3423, 3071, 2933, 2858, 1427, 1210, 1104,
1069, 999, 870, 822, 740, 701, 613 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.69−7.63 (m, 4H), 7.48−7.40 (m, 6H), 5.63 (dd, J = 11.3,
4.0 Hz, 0.31H), 5.36 (d, J = 10.6 Hz, 0.69H), 4.78 (dd, J = 6.2, 0.8 Hz,
0.31H), 4.72 (brd, J = 5.9 Hz, 0.69H), 4.67 (dd, J = 6.2, 4.0 Hz,
0.31H), 4.61 (d, J = 5.9 Hz, 0.69H), 4.55 (d, J = 10.6 Hz, 0.69H), 4.29
(m, 0.69H), 4.15 (m, 0.31H), 3.96 (dd, J = 11.3 Hz, 0.31H), 3.83 (dd,
J = 11.5, 2.7 Hz, 0.69H), 3.81 (dd, J = 11.2, 2.7 Hz, 0.31H), 3.83 (dd, J
= 11.5, 2.7 Hz, 0.69H), 3.62 (dd, J = 11.2, 2.7 Hz, 0.31H), 1.56 (s,
0.93H), 1.48 (s, 2.07H), 1.40 (s, 0.93H), 1.32 (s, 2.07H), 1.09 (s,
4.14H), 1.06 (s, 1.86H); 13C NMR (100 MHz, CDCl3) δ 135.9, 135.7,
134.9, 132.8, 132.5, 131.7, 131.6, 130.6, 130.4, 130.2, 130.1, 128.3,
128.2, 128.0, 127.8, 113.1, 112.3, 103.5, 98.2, 87.2, 82.1, 81.8, 81.4,
79.6, 66.2, 65.6, 27.0, 26.6, 26.3, 25.1, 24.8, 19.2; MS (EI) m/z: 413
([M-Me]+, 2), 187 (29), 257 (14), 241 (48), 235 (17), 223 (16), 207
(18), 205 (20), 200 (19), 199 (100), 197 (18), 193 (14), 189 (20),
183 (17), 181 (51), 177 (19), 167 (15), 165 (12), 163 (77), 161 (50),
157 (15), 139 (70), 135 (50), 129 (68), 121 (18), 115 (29), 105 (39),
101 (27), 91 (85), 85 (20), 79 (26), 77 (34), 73 (22), 69 (19), 59
(52), 57 (17), 55 (53); HRMS (ESI): Calcd for C24H32O5SiNa [M
+Na]+: 451.1911. Found: 451.1916.
1
engaged in the cross-coupling reaction: H NMR (400 MHz, CDCl3)
δ 8.08 (d, J = 8.5, 2H), 7.58 (t, J = 8.5, 1H), 7.45 (t, J = 8.5, 2H), 6.48
(s, 0.85H), 5.54 (s, 0.15H), 5.28 (d, J = 5.8 Hz, 0.85H), 4.98 (dd, J =
5.8, 1.4 Hz, 0.85H), 4.81 (dd, J = 5.8, 1.4 Hz, 0.15H), 4.72−4.67 (m,
1.7H), 4.61 (m, 0.15H), 4.60 (dd, J = 14.3, 9.5 Hz, 0.85H) 4.49 (m,
0.15H), 4.38 (dd, J = 6.8, 3.0 Hz, 0.15H), 1.50 (s, 0.45H), 1.48 (s,
2.55H), 1.35 (s, 2.55H), 1.33 (s, 0.45H); 13C NMR (100 MHz,
CDCl3): δ (α-isomer): 166.2, 133.4, 130.0, 129.6, 128.6, 114.0, 91.9,
90.5, 88.3, 81.5, 62.7, 26.8, 25.5.
To a solution of (3aR,6R,6aR)-6-((tert-butyldiphenylsilyloxy)-
methyl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (465 mg,
1.1 mmol) in dry CH2Cl2 (11 mL) at 0 °C was added
bromotrimethylsilane (0.43 mL, 3.3 mmol, 3 equiv). After 2 h at
room temperature, the solvent was removed under reduced pressure,
and the product was filtered through a short pad of silica gel (PE/
EtOAc, 90/10) to yield 2 (281 mg, 0.57 mmol, 52%) which was
((3aR,4R,6S,6aS)-2,2-Dimethyl-6-phenyl-tetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)methyl benzoate. (from 3, Table 1, entry 3)
20
[α]D −42.8 (c 0.95, CHCl3); IR (neat): 3033, 2987, 2937, 1720,
1
1451, 1373, 1267, 1211, 1070, 1025, 859, 709, 699 cm−1; H NMR
(400 MHz, CDCl3) δ 7.94 (dd, J = 8.3, 1.4 Hz, 2H), 7.50 (tt, J = 8.3,
1,4 Hz, 1H), 7.38−7.32 (m, 4H), 7.28−7.23 (m, 2H), 7.22−7.18 (m,
1H), 4.94 (d, J = 5.0 Hz, 1H), 4.69 (dd, J = 6.8, 4.2 Hz, 1H), 4.57 (dd,
J = 11.8, 3.8 Hz, 1H), 4.56 (dd, J = 6.8, 5.0 Hz, 1H), 4.48 (dd, J = 11.8,
4.5 Hz, 1H), 4.39 (brq, J = 4.0 Hz, 1H), 1.58 (s, 3H), 1.30 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.4, 139.7, 133.3, 129.8, 128.7, 128.6,
128.0, 125.7, 115.1, 87.3, 86.1, 82.2, 82.0, 64.7, 27.7, 25.7; MS (EI) m/
z: 339 ([M-Me]+, 1), 174 (34), 157 (8), 131 (9), 106 (9), 105 (100),
91 (9), 77 (32), 69 (29), 68 (44); HRMS (ESI): Calcd for
C21H22O5Na [M+Na]+: 377.1359. Found: 377.1362.
(((3aS,4R,6aS)-6-Bromo-2,2-dimethyl-tetrahydrofuro[3,4-d]-
[1,3]dioxol-4-yl)methoxy)(tert-butyl)diphenylsilane (4). To a
solution of (3aS,6R,6aS)-6-(Hydroxymethyl)-2,2-dimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-ol30 (468 mg, 2.46 mmol) and
imidazole (427 mg, 6.9 mmol, 2.8 equiv) in dry DMF (1.2 mL), was
added tert-butyl(chloro)diphenylsilane (744 mg, 0.7 mL, 2.7 mmol, 1.1
equiv). After 2 h at room temperature, the reaction was quenched with
water and extracted with CH2Cl2. The organic layer was washed with
1
directly engaged in the cross-coupling reaction: H NMR (400 MHz,
CDCl3) δ 7.74−7.70 (m, 4H), 7.47−7.40 (m, 6H), 6.45 (s, 1H), 5.16
(d, J = 5.8 Hz, 1H), 4.88 (dd, J = 5.8, 1.6 Hz, 1H), 4.49 (ddd, J = 8.5,
6.1, 1.6 Hz, 1H), 4.04 (dd, J = 10.7, 8.5 Hz, 1H), 3.92 (dd, J = 10.7, 6.1
Hz, 1H), 1.50 (s, 3H), 1.36 (s, 3H), 1.13 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 135.7, 133.1, 133.0, 129.9, 128.4, 127.8, 113.5, 92.6,
90.9, 90.3, 81.3, 62.0, 26.9, 26.7, 25.5, 19.3.
tert-Butyl(((3aR,4R,6S,6aS)-2,2-dimethyl-6-phenyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)diphenylsilane.
20
(from 2, Table 1, entry 2) [α]D −5.6 (c 1.0, CHCl3); IR (neat):
3069, 2930, 2857, 1427, 1211, 1110, 1073, 860, 822, 737, 697, 610
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.67−7.62 (m, 4H), 7.38−7.17
(m, 11H), 4.84 (d, J = 5.3 Hz, 1H), 4.75 (dd, J = 6.7, 3.9 Hz, 1H), 4.47
(dd, J = 6.7, 5.4 Hz, 1H), 4.14 (q, J = 3.9 Hz, 1H), 3.88 (dd, J = 11.2,
3.9 Hz, 1H), 3.81 (dd, J = 11.2, 3.9 Hz, 1H), 1.56 (s, 3H), 1.29 (s,
3H), 1.00 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 140.1, 135.8,
D
dx.doi.org/10.1021/jo401845q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
brine and dried over MgSO4. The solvent was removed under reduced
pressure, and the product was purified by silica gel chromatography
(CH2Cl2/MeOH 95/5) to yield (3aS,6R,6aS)-6-((tert-
Butyldiphenylsilyloxy)methyl)-2,2-dimethyl-tetrahydrofuro[3,4-d]-
[1,3]dioxol-4-ol as a 78:22 mixture of α- and β-isomers (498 mg, 1.16
mmol, 47%): IR (neat): 3422, 3071, 2933, 2857, 1427, 1373, 1209,
1086, 998, 823, 803, 740, 701, 613 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.73−7.69 (m, 4H), 7.44−7.35 (m, 6H), 5.38 (s, 0.78H),
4.98 (brd, J = 8.0 Hz, 0.22H), 4.75 (dd, J = 5.9, 3.6 Hz, 0.78H), 4.73
(dd, J = 6.3, 3.5 Hz, 0.22H), 4.58 (d, J = 5.9 Hz, 0.78H), 4.49 (dd, J =
6.3, 3.5 Hz, 0.22H), 4.33 (m, 0.78H), 3.99 (dd, J = 10.5, 5.5 Hz,
0.78H), 3.98 (dd, J = 10.1, 7.3 Hz, 0.22H), 3.91 (dd, J = 10.1, 5.4 Hz,
0.22H), 3.90 (dd, J = 10.5, 6.8 Hz, 0.78H), 3.69 (ddd, J = 7.3, 5.4, 3.5
Hz, 0.22H), 1.45 (s, 0.66H), 1.36 (s, 3H), 1.32 (s, 2.07H), 1.28 (s,
2.34H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.8, 133.7,
129.8, 129.7, 127.8, 127.7, 113.1, 112.6, 101.4, 96.9, 85.6, 81.1, 79.9,
79.5, 78.3, 76.3, 62.1, 61.4, 26.9, 26.2, 25.9, 25.2, 25.1, 19.4; MS (EI)
m/z: 413 ([M-Me]+, 4), 371 (10), 283 (16), 257 (29), 253 (12), 241
(41), 235 (34), 223 (19), 207 (23), 205 (26), 200 (18), 199 (92), 197
(20), 193 (30), 189 (25), 183 (18), 181 (41), 177 (32), 167 (14), 163
(100), 161 (24), 157 (17), 139 (80), 135 (53), 133 (15), 129 (63),
123 (14), 121 (19), 119 (26), 117 (20), 115 (43), 105 (47), 103 (11),
101 (46), 91 (86), 85 (13), 79 (32), 78 (12), 77 (40), 73 (14), 69
(14), 59 (54), 57 (21), 55 (51); HRMS (ESI): Calcd for
C24H32O5SiNa [M+Na]+: 451.1911. Found: 451.1912. To a solution
of (3aS,6R,6aS)-6-((tert-Butyldiphenylsilyloxy)methyl)-2,2-dimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol −4-ol (236 mg, 0.55 mmol) in dry
CH2Cl2 (5.5 mL) at 0 °C was added bromo-trimethylsilane (0.15 mL,
1.1 mmol, 2 equiv). After 2 h at room temperature, the solvent was
removed under reduced pressure, and the product was eluated through
a pad of silica gel (PE/Et2O, 90/10) to yield 4 which was directly
(400 MHz, CDCl3) δ 8.10−8.04 (m, 2H), 7.62−7.54 (m, 1H), 7.48−
7.41 (m, 2H), 5.48 (s, 0.78H), 5.05 (brd, J = 11.8 Hz, 0.22H), 4.87
(dd, J = 5.9, 3.6 Hz, 0.78H), 4.79 (dd, J = 6.0, 3.5 Hz, 0.22H), 4.71
(dd, J = 11.2, 3.1 Hz, 0.78H), 4.69 (m, 0.22H), 4.66 (d, J = 6.0 Hz,
0.78H), 4.57−4.45 (m, 2H), 3.92 (ddd, J = 7.4, 4.2, 3.3 Hz, 0.22H),
1.55 (s, 0.66H), 1.48 (s, 2.34H), 1.38 (s, 0.66H), 1.33 (s, 2.34H); 13C
NMR (100 MHz, CDCl3) δ 170.5, 166.6, 133.8, 133.2, 130.3, 130.0,
129.9, 128.6, 128.5, 113.7, 113.1, 101.6, 97.2, 85.6, 80.0, 79.8, 78.7,
78.4, 73.9, 63.4, 63.0, 26.2, 26.0, 25.1, 24.9; MS (EI) m/z: 279 ([M-
Me]+, 6), 114 (7), 113 (7), 106 (8), 105 (100), 85 (6), 77 (25), 68
(18), 59 (24), 51 (6); HRMS (ESI): Calcd for C15H18O6Na [M+Na]+:
317.0996. Found: 317.0996. To a solution of ((3aS,4R,6aS)-6-
hydroxy-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl
benzoate (233 mg, 0.79 mmol) in dry CH2Cl2 (8 mL) at 0 °C was
added bromotrimethylsilane (0.21 mL, 1.6 mmol, 2 equiv). The
reaction was stirred at room temperature for 2 h. The solvent was
removed under reduced pressure, and the product was eluated through
a short pad of silica gel (PE/Et2O, 90/10) to yield 5 (122 mg, 0.34
mmol, 43%) which was directly engaged in the cross-coupling
reaction: IR (neat): 2989, 1720, 1267. 1210, 1097, 1072, 857, 710,
1
688, 637 cm−1; H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.3 Hz,
2H), 7.58 (t, J = 8.3 Hz, 1H), 7.45 (t, J = 8.3 Hz, 2H), 6.47 (s, 1H),
5.19 (d, J = 5.8 Hz, 1H), 4.95 (dd, J = 5.8, 3.7 Hz, 1H), 4.77 (dd, J =
11.5, 3.5 Hz), 4.59 (m, 1H), 4.53 (dd, J = 11.5, 7.4 Hz, 1H), 1.47 (s,
3H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 133.4,
130.0, 129.8, 128.6, 113.7, 92.8, 90.1, 81.5, 78.6, 61.8, 26.1, 25.1; MS
(EI) m/z: 443 ([M(81Br)-Me]+, 4), 441 ([M(79Br)-Me]+, 5), 277 (5),
160 (6), 158 (7), 106 (8), 105 (100), 97 (5), 77 (28), 69 (7), 68 (8),
59 (7), 51 (8).
((3aS,4R,6R,6aR)-2,2-Dimethyl-6-phenyl-tetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)methyl benzoate. (from 5, Table 1, entry 5)
[α]D20 −18.6 (c 1.1, CHCl3); IR (neat): 3062, 2988, 2938, 2872, 1720,
1
engaged in the cross-coupling step: (174 mg, 0.26 mmol, 64%): H
1
1270, 1209, 1105, 1070, 1027, 862, 711 cm−1; H NMR (400 MHz,
NMR (400 MHz, CDCl3) δ 7.73 (t, J = 8.1 Hz, 4H), 7.45−7.37 (m,
6H), 6.44 (s, 1H), 5.16 (d, J = 5.8 Hz, 1H), 4.84 (dd, J = 5.8, 3.6 Hz,
1H), 4.42 (ddd, J = 6.6, 5.9, 3.6 Hz, 1H), 4.06 (dd, J = 10.7, 5.9 Hz,
1H), 3.92 (dd, J = 10.7, 6.6 Hz, 1H), 1.33 (s, 3H), 1.30 (s, 3H), 1.08
(s, 9H); 13C NMR (100 MHz, CDCl3): δ: 135.8, 133.4, 133.3, 129.8,
127.8, 113.2, 93.8, 90.1, 94.0, 78.4, 60.7, 26.9, 26.1, 25.3, 19.4; MS (EI)
m/z: 337 (3), 295 (11), 209 (7), 208 (12), 206 (61), 115 (5), 74 (8),
73 (100).
CDCl3) δ 8.07 (dd, J = 8.4, 1.3 Hz, 2H), 7.58 (tdd, J = 8.3, 6.7, 1.3 Hz,
1H), 7.27 (t, J = 8.3 Hz, 2H), 7.19 (d, J = 4.5 Hz, 4H), 7.12−7.08 (m,
1H), 5.10 (brs, 1H), 4.82 (dd, J = 6.0, 1.2 Hz, 1H), 4.64 (dd, J = 6.0,
4.0 Hz, 1H), 4.58 (dd, J = 11.7, 4.4 Hz, 1H), 4.43 (dd, J = 11.7, 7.3 Hz,
1H), 4.14 (ddd, J = 7.3, 4.4, 4.0 Hz, 1H), 1.43 (s, 3H), 1.21 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 166.5, 138.4, 133.1, 130.1, 129.8,
128.8, 128.4, 127.6, 125.6, 113.3, 87.5, 84.9, 81.3, 78.7, 63.5, 26.4, 25.1;
MS (EI) m/z: 339 ([M-Me]+, 1), 174 (6), 157 (9), 131 (8), 106 (9),
105 (100), 77 (31), 69 (26), 68 (47), 58 (5), 51 (6); HRMS (ESI):
Calcd for C21H22O5Na [M+Na]+: 377.1359. Found: 377.1361.
(3aS,4R,6R,6aR)-4-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyl-6-phenyl-tetrahydrofuro[3,4-d][1,3]dioxole (10).31
tert-Butyl(((3aS,4R,6R,6aR)-2,2-dimethyl-6-phenyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)diphenylsilane.
20
(from 4, Table 1, entry 4) [α]D +6.5 (c 1.05, CHCl3); IR (neat):
3070, 2931, 2857, 1427, 1371, 1209, 1141, 1090, 1001, 823, 805, 739,
1
700, 613 cm−1; H NMR (400 MHz, CDCl3): δ: 7.66−7.63 (m, 4H),
20
(from 6, Table 1, entry 6, Scheme 1) [α]D −1.6 (c 0.8, CHCl3);
7.33−7.25 (m, 10H), 7.20−7.16 (m, 1H), 5.07 (brs, J = 5.3 Hz, 1H),
4.82 (dd, J = 6.0, 1.0 Hz, 1H), 4.47 (brd, J = 6.0 Hz, 1H), 3.99−3.93
(m, 3H), 1.39 (s, 3H), 1.25 (s, 3H), 1.00 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 138.9, 135.7, 133.7, 133.6, 129.6, 128.6, 127.7, 127.6,
127.3, 125.5, 112.7, 87.6, 84.7, 81.6, 81.2, 62.1, 26.9, 26.4, 25.3, 19.3;
MS (EI) m/z: 473 ([M-Me]+, 1), 317 (15), 295 (12), 241 (26), 199
(22), 193 (14), 191 (13), 163 (37), 161 (73), 143 (16), 139 (20), 135
(18), 133 (28), 117 (11), 115 (14), 105 (28), 103 (68), 91 (100), 77
(22), HRMS (ESI): Calcd for C30H36O4SiNa [M+Na]+: 511.2275.
Found: 511.2272.
mp = 122−124 °C; IR (neat): 2986, 2934, 2878, 1603, 1495, 1449,
1371, 1257, 1208, 1160, 1118, 1064, 977, 891, 846, 734, 699 cm−1; 1H
NMR (400 MHz, C6D6) δ 7.23 (d, J = 8.3 Hz, 2H), 7.10 (t, J = 8.3 Hz,
2H), 7.03 (d, J = 8.3 Hz, 1H), 5.26 (brs, 1H), 4.65 (dd, J = 12.6, 6.6
Hz, 1H), 4.61 (dd, J = 6.6, 1.3 Hz, 1H), 4.32 (m, 2H), 4.20 (dd, J =
8.6, 6.6 Hz, 1H), 3.96 (dd, J = 6.6, 3.6 Hz, 1H), 1.47 (s, 6H), 1.34 (s,
3H), 1.16 (s, 3H); 13C NMR (100 MHz, C6D6) δ 139.6, 128.9, 127.5,
125.8, 112.7, 109.1, 88.2, 85.6, 82.2, 81.6, 74.1, 67.4, 27.1, 26.5, 25.7,
24.9; MS (EI) m/z: 305 ([M-Me]+, 25), 187 (10), 145 (10), 141 (13),
131 (17), 115 (15), 107 (7), 105 (22), 103 (19), 101 (100), 99 (12),
98 (11), 91 (35), 85 (7), 83 (8), 81 (10), 78 (7), 77 (21), 73 (21), 72
(17), 70 (10), 69 (7), 68 (20), 59 (24), 55 (11).
((3aS,4R,6R,6aS)-6-Bromo-2,2-dimethyl-tetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)methyl benzoate (5). To a solution of
(3aS,6R,6aS)-6-(Hydroxymethyl)-2,2-dimethyl-tetrahydrofuro[3,4-d]-
[1,3]dioxol-4-ol30 (310 mg, 1.6 mmol) in dry pyridine (3.2 mL), was
added benzoyl chloride (252 mg, 0.21 mL, 1.8 mmol, 1.1 equiv). The
reaction was stirred at room temperature for 4 h. Benzoyl chloride 0.26
equiv (0.05 mL) was added to the medium. After one night at room
temperature, the reaction was quenched with water and extracted with
CH2Cl2. The organic layer was washed with brine and dried over
MgSO4. The solvent was removed under reduced pressure, and the
product was purified by silica gel chromatography (PE/EtOAc, 80/20)
to yield ((3aS,4R,6aS)-6-hydroxy-2,2-dimethyl-tetrahydrofuro[3,4-d]-
[1,3]dioxol-4-yl)methyl benzoate as a 78:22 mixture of α and β
isomers (233 mg, 0.79 mmol, 49%): IR (neat): 3434, 2988, 2941,
α-1′,2′-Dideoxy-3′,5′-di-O-toluoyl-1′-(3-phenyl)-
ribofuranose.32 (from 7, Table 1, entry 7) [α]D +5.3 (c 1.5,
20
CHCl3); IR (neat): 3032, 2951, 1712, 1611, 1266, 1177, 1102, 1019,
1
839, 751, 698 cm−1; H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3
Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.39 (t, J =
7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.20 (d,
J = 8.0 Hz, 2H), 5.64 (ddd, J = 6.8, 3.7, 3.0 Hz, 1H), 5.35 (dd, J = 7.1,
6.1 Hz, 1H), 4.80 (dd, J = 4.8, 3.0 Hz, 1H), 4.64 (dd, J = 11.8, 4.8 Hz,
1H), 4.62 (dd, J = 11.7, 4.8 Hz, 1H), 2.84 (ddd, J = 13.7, 7.1, 6.8 Hz,
1H), 2.44 (s, 3H), 2.42 (s, 3H), 2.36 (ddd, J = 13.7, 6.1, 3.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 166.5, 166.2, 144.0, 143.9, 142.5,
129.9, 129.8, 129.3, 129.1, 128.5, 127.5, 127.2, 126.9, 125.7, 82.2, 80.3,
1
1718, 1269, 1209, 1097, 1069, 1026, 999, 861, 708 cm−1; H NMR
E
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The Journal of Organic Chemistry
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76.5, 64.7, 40.5, 21.8; MS (EI) m/z: 274 (11), 198 (7), 197 (48), 196
(6), 183 (9), 169 (12), 168 (16), 165 (9), 154 (6), 119 (39), 106 (8),
105 (100), 91 (24), 77 (54), 65 (9), 51 (10).
(13), 77 (44), 71 (11), 59 (97), 57 (39), 55 (20); HRMS (ESI): Calcd
for C15H20O5Na [M+Na]+: 303.1202. Found: 303.1202.
(Z)-Methyl-3-((3aS,4R,6R,6aR)-2,2-dimethyl-6-phenyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acrylate (14). To a solu-
tion of 12 (388 mg, 1.39 mmol) in THF (7.5 mL) and pH7 phosphate
buffer solution (7.5 mL) was added NaIO4 (0.89 g, 4.17 mmol, 3
equiv). The reaction was stirred at room temperature for 1 h, filtered
over a short pad of Celite and extracted with EtOAc. The organic layer
was dried over MgSO4, and the solvent was removed under reduced
pressure to provide aldehyde 13 which was not purified and used
directly in the next step. To a solution of 18-crown-6 ether (1.62 g,
6.12 mmol, 4.4 equiv) and methyl 2-(bis(2,2,2-trifluoro-ethoxy)-
phosphoryl)acetate I (0.58 mL, 2.78 mmol, 2 equiv) in dry THF (22
mL) at −78 °C was added 2.2 equiv of potassium bis(trimethylsilyl)-
amide (6 mL, 0.5 M in toluene). The reaction mixture was stirred for 5
min, and aldehyde 13 in dry THF (2 mL) was added via cannula. After
1.5 h at −78 °C, the reaction was quenched with NH4Cl saturated
solution, warmed up to room temperature, and extracted with Et2O.
The organic layer was washed with brine and dried over Na2SO4. The
solvent was removed under reduced pressure, and the product was
purified by silica gel chromatography (PE/Et2O, 95/5) to yield the
(3aS,4R,6R,6aR)-4-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-(4-
fluorophenyl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxole.
20
(from 6, Table 2, entry 1) [α]D +18.0 (c 0.9, CHCl3); IR (neat):
2986, 2937,1606, 1508, 1371, 1256, 1209, 1158, 1118, 1064, 1013,
978, 896, 841 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 8.9,
5.3 Hz, 2H), 7.03 (tapp, J = 8.9 Hz, 2H), 5.13 (brs, 1H), 4.91 (brd, J =
6.0 Hz, 1H), 4.75 (dd, J = 6.0, 3.8 Hz, 1H), 4.48 (dd, 7.3, 5.4 Hz, 1H),
4.16 (d, J = 5.4 Hz, 2H), 3.83 (dd, J = 7.3, 3.8 Hz, 1H), 1.55 (s, 3H),
1.42 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 162.2 (d, J1C−F = 244 Hz), 134.2 (d, J4C−F = 3 Hz), 127.2 (d, J3
=
C−F
8 Hz), 115.6 (d, J2
= 21 Hz), 113.0, 109.3, 87.5, 84.6, 81.4, 81.2,
C−F
73.6, 67.0, 27.0, 26.3, 25.2, 24.8; MS (EI) m/z: 324 (5), 323 ([M-
Me]+, 29), 205 (10), 163 (7), 149 (8), 141 (10), 133 (5), 125 (5), 123
(12), 121 (8), 109 (22), 102 (6), 101 (100), 99 (10), 98 (10), 85 (5),
83 (7), 81 (14), 73 (13), 72 (15), 70 (8), 69 (5), 68 (15), 59 (18);
HRMS (ESI): Calcd for C18H23FNaO5 [M+Na]+: 361.1422. Found:
361.1422.
(3aS,4R,6S,6aS)-4-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyl-6-(thiophen-2-yl)-tetrahydrofuro[3,4-d][1,3]-
dioxole.33 (from 6, Table 2, entry 2). [α]D20 +32.4 (c 1.2, CHCl3); IR
(neat): 2928, 1410, 1311, 1207, 1083, 1018, 970, 703 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.27 (brd, J = 5.0 Hz, 1H), 6.99 (dd, J = 5.0, 3.5
Hz, 1H), 6.95 (dt, J = 3.5, 1.2 Hz, 1H), 5.32 (brs, 1H), 5.02 (brd, J =
5.9 Hz, 1H), 4.82 (dd, J = 5.9, 3.6 Hz, 1H), 4.45 (ddd, J = 7.5, 6.2, 4.5
Hz, 1H), 4.14 (dd, J = 8.7, 6.2 Hz, 1H), 4.09 (dd, J = 8.7, 4.5 Hz, 1H),
3.88 (dd, J = 7.5, 3.6 Hz, 1H), 1.55 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H),
1.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.3, 127.3, 125.5,
124.7, 113.1, 109.4, 86.8, 82.2, 81.4, 81.2, 73.3, 67.2, 27.0, 26.2, 25.3,
24.9; MS (EI) m/z: 234 (9), 217 (6), 175 (6), 141 (11), 137 (21), 136
(100), 145 (45), 121 (34), 101 (62), 99 (8), 98 (12), 91 (7), 81 (11),
77 (10), 73 (12), 72 (13), 68 (16), 59 (14), 55 (8); HRMS (ESI):
Calcd for C16H22O5SNa [M+Na]+: 349.1080. Found: 349.1079.
(3aS,4R,6R,6aR)-4-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyl-6-(2-methylprop-1-enyl)-tetrahydrofuro[3,4-d][1,3]-
dioxole. (from 6, Table 2, entry 3) [α]D20 +23.1 (c 1.29, CHCl3); mp
= 66−67 °C; IR (neat): 2985, 2935, 1671, 1454, 1371, 1256, 1208,
α,β-unsaturated ester 14 (214 mg, 0.71 mmol, 51% after 2 steps).33
b
[α]D20 −6.0 (c 0.1, CHCl3); IR (neat): 2926, 2854, 1719, 1438, 1372,
1
1223, 1198, 1161, 1090, 1066, 1047, 857, 820, 746, 708 cm−1; H
NMR (400 MHz, C6D6) δ 7.29 (d, J = 8.1 Hz, 2H), 7.10 (t, J = 8.1 Hz,
2H), 7.02 (t, J = 8.1 Hz, 1H), 6.60 (dd, J = 11.6, 6.6 Hz, 1H), 5.86 (dd,
J = 11.6, 1.7 Hz, 1H), 5.77 (ddd, J = 6.6, 4.1, 1.7 Hz, 1H), 5.41 (brs,
1H), 4.98 (dd, J = 5.9, 4.1 Hz, 1H), 4.70 (brd, J = 5.9 Hz, 1H), 3.22 (s,
3H), 1.54 (s, 3H), 1.16 (s, 3H); 13C NMR (100 MHz, C6D6) δ 166.1,
147.0, 139.5, 128.8, 127.5, 125.9, 120.4, 112.7, 88.1, 85.7, 83.5, 78.7,
50.9, 26.7, 25.0; MS (EI) m/z: 305 ([M+H]+,1), 289 ([M-Me]+, 3),
197 (17), 187 (12), 161 (37), 140 (38), 132 (47), 131 (100), 125
(13), 121 (15), 115 (11), 111 (45), 108 (36), 107 (12), 105 (35), 104
(20), 103 (24), 98 (40), 91 (25), 83 (11), 81 (38), 78 (11), 77 (26),
59 (25), 55 (12), 53 (11); HRMS (ESI): Calcd for C17H20O5Na [M
+Na]+: 327.1203. Found: 327.1203.
(−)-Isoaltholactone.31 33b. To a solution of 14 (31 mg, 0.1
f,
mmol) in a 95:5 mixture of toluene/water (1.5 mL) was added a
catalytic amount of paratoluenesulfonic acid. The reaction was stirred
at 100 °C for 2.5 h. The reaction was diluted with water and extracted
with CH2Cl2. The phases were separated and the organic layer was
dried over MgSO4 and the solvent was removed under reduced
pressure, to afford (−)-8 without purification in quantitative yield:
1
1161, 1116, 1064, 974, 942, 890, 849 cm−1; H NMR (400 MHz,
C6D6) δ 5.07 (m, 1H), 4.89 (brd, J = 8.0, Hz, 1H), 4.63 (brq, J = 5.9
Hz, 1H), 4.50 (dd, J = 5.9, 3.6 Hz, 1H), 4.28 (dd 5.9, 0.8 Hz, 1H), 4.23
(dd, J = 8.4, 5.8 Hz, 1H), 4.02 (dd, J = 8.4, 6.4 Hz, 1H), 3.86 (dd, J =
6.9, 3.5 Hz, 1H), 1.49 (s, 3H), 1.48 (s, 3H), 1.48 (s, 6H), 1.33 (s, 3H),
1.17 (s, 3H); 13C NMR (100 MHz, C6D6) δ 136.7, 122.5, 112.5, 109.1,
87.3, 82.2, 81.4, 74.1, 67.5, 27.2, 26.5, 25.7, 25.0, 18.3; MS (EI) m/z:
283 ([M-Me]+, 25), 181 (6), 165 (11), 141 (32), 138 (11), 111 (11),
101 (100), 99 (27), 98 (32), 87 (19), 95 (30), 93 (10), 85 (45), 83
(52), 81 (42), 79 (10), 73 (16), 72 (26), 70 (21), 69 (35), 68 (38), 67
(11), 59 (36), 55 (25), 53 (13); HRMS (ESI): Calcd for C16H26NaO5
[M+Na]+: 321.1672. Found: 321.1668.
20
[α]D −23.0 (c 0.15, EtOH); IR (neat): 3240, 2928, 1721, 1577,
1
1397, 1313, 1144, 1104, 1038, 1024, 760, 701 cm−1; H NMR (400
MHz, CDCl3) δ 7.39−7.30 (m, 5H), 6.87 (dd, J = 10.0, 4.5 Hz, 1H),
6.20 (dd, J = 10.0, 0.7 Hz, 1H), 5.05 (t app, J = 5.5 Hz, 1H), 4.88 (m,
1H), 4.78 (d, J = 7.3 Hz, 1H), 4.27 (dd, J = 7.3, 5.5 Hz, 1H), 3.16 (brs,
1H); 13C NMR (100 MHz, CDCl3) δ 161.4, 142.0, 138.6, 128.8,
128.4, 125.9, 123.1, 83.4, 78.7, 78.5, 67.9; MS (EI) m/z: 232 (M+•, 9),
136 (7), 107 (23), 98 (8), 97 (100), 95 (28), 91 (12), 79 (18), 77
(16), 69 (11); HRMS (ESI): Calcd for C13H12O4Na [M+Na]+:
255.0628. Found: 255.0631.
(R)-1-((3aS,4R,6R,6a)-2,2-Dimethyl-6-phenyl-tetrahydrofuro-
[3,4-d][1,3]dioxol-4-yl)ethane-1,2-diol (12). To a solution of 10
(804 mg, 2.5 mmol) in acetonitrile (25 mL) were added BiCl3 (40 mg,
0.13 mmol, 5 mol %) and water (0.1 mL). The reaction was stirred at
room temperature for 1 h, and then the solvent was removed under
reduced pressure. Purification by silica gel chromatography (PE/
EtOAc, 60/40 to 50/50) yielded the desired diol 12 (388 g, 1.39
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 1-4, cross-coupling
products from Table 1 and Table 2, as well as compounds 12,
14, and (−)-8 are provided. This material is available free of
charge via the Internet at http://pubs.acs.org/.
mmol, 55%).33 [α]D +20.6 (c 1.1, CHCl3); IR (neat): 3421, 3061,
2935, 2872, 1373, 1260, 1208, 1083, 1048, 1026, 979, 887, 857, 803,
737, 702 cm−1; 1H NMR (400 MHz, C6D6) δ 7.33 (d, J = 8.1 Hz, 2H),
7.23 (t, J = 8.1 Hz, 2H), 7.13 (t, J = 8.1 Hz, 1H), 5.35 (brs, 1H), 4.72
(brd, J = 5.8 Hz, 1H), 4.57 (dd, J = 5.8, 3.7 Hz, 1H), 4.38 (m, 1H),
4.14 (dd, J = 11.5, 3.3 Hz, 1H), 4.07 (dd, J = 8.6, 3.7 Hz, 1H), 4.03
(dd, J = 11.5, 5.8 Hz, 1H), 3.72 (brs, 1H), 3.23 (brs, 1H), 1.60 (s, 3H),
1.31 (s, 3H); 13C NMR (100 MHz, C6D6) δ 139.4, 128.8, 127.5, 125.8,
112.9, 88.0, 85.4, 81.9, 81.0, 70.7, 64.9, 26.5, 25.1; MS (EI) m/z: 265
([M-Me]+, 11), 162 (12), 161 (10), 145 (29), 133 (34), 132 (15), 131
(44), 120 (18), 117 (11), 115 (18), 113 (14), 107 (100), 105 (67),
103 (30), 98 (21), 91 (80), 86 (77), 85 (16), 82 (20), 79 (34), 78
b
20
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: sebastien.reymond@espci.fr. Fax: (+33)140794660.
Tel: (+ 33)140794429.
*E-mail: janine.cossy@espci.fr. Fax: (+33)140794660. Tel: (+
33)140794429.
F
dx.doi.org/10.1021/jo401845q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(h) Franco
Lett. 1990, 31, 6347.
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is, P.; Perilleux, D.; Kempener, Y.; Sonveaux, E. Tetrahedron
Notes
The authors declare no competing financial interest.
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D. M.; Simpson, P.; McSwine, D. J.; Reamer, R. A.; Verhoeven, T. R.;
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ACKNOWLEDGMENTS
■
Janssen Research & Development, a Division of Janssen-Cilag,
is gratefully acknowledged for financial support.
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dx.doi.org/10.1021/jo401845q | J. Org. Chem. XXXX, XXX, XXX−XXX