Synthesis of O-spiro-C-aryl glycosides using organocatalysis

Article abstract of DOI:10.1021/jo202353r

An organocatalysis strategy has been developed toward the synthesis of O-spiro-C-aryl glycosides with different configurations in the sugar part. This strategy has been extended to the synthesis of the Papulacandin class of compounds.

Full text of DOI:10.1021/jo202353r

Note
pubs.acs.org/joc
Synthesis of O-Spiro-C-Aryl Glycosides Using Organocatalysis
Prathama S. Mainkar,*,† Kancharla Johny,† Tadikamalla Prabhakar Rao,‡ and Srivari Chandrasekhar*,†
‡
†Division of Natural Products Chemistry and Centre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad, 500 007, India
S
* Supporting Information
ABSTRACT: An organocatalysis strategy has been developed toward the synthesis of O-spiro-
C-aryl glycosides with different configurations in the sugar part. This strategy has been extended to
the synthesis of the Papulacandin class of compounds.
yntheses of C-aryl glycosides have generated a lot of
interest since many natural products that contain this novel
S
structural framework exhibit antibiotic or antiviral activity.1 In
contrast to O-arylglycosides, C-arylglycosides have an aryl ring
directly connected to the sugar core, which confers stability
toward enzymatic and chemical hydrolysis. In addition, it is
believed that they bind to DNA to form stable complexes and
may have interesting biological activities. Papulacandins, which
have a polyhydroxypyran skeleton that is interlaced with a
spiro-tetrahydro-furan frame, exhibited interesting biological
activity and were a choice of target for both medicinal and syn-
thetic organic chemists in addition to biologists.2,3 Papulacan-
dins have been shown to have potent activity against Candida
albicans, Pneumocystis carinii (pneumonia in AIDS patients),4
Geotrichum lactis, Saccharomyces cerevisiae, etc. and are inactive
against filamentous fungi, bacteria, and protozoa.5 All the
members of the papulacandin family target (1,3)-β-D-glucan
synthase, thereby preventing uptake of glucose in the bio-
synthesis of glucan, one of the abundant polysaccharide com-
ponents of cell wall.
This has stimulated the search for new papulacandin
derivatives and other inhibitors of fungal cell wall synthase.
Several new compounds, structurally related to the papula-
candins, have been isolated and synthesized.6 These congeners
vary with respect to the degree of oxidation and saturation of
shorter side chains; however, some analogues display more
drastic modifications to the overall papulacandin structure. On
the basis of the SAR of analogues and derivatives, it has been
concluded that compounds devoid of their fatty side chain(s)
are found to be ineffective as inhibitors. As an extension of the
applications of spiro-C-aryl glycosides, these compounds were
found to have inhibitory activity against sodium-dependent
glucose cotransporter 2 (SGLT2) involved in glucose reabsorp-
tion in the kidney (Figure 1).
There are several reports of partial and total synthesis of
papulacandins and analogues.2−8 The synthetic reports basically
fall under four important categories: (1) coupling of sugar
derivatives (including (un)substituted glycals) with aromatic
moiety;2,7c−f (2) dihydroxylation of vinylfurans;8b,c (3) build-
ing of aromatic ring through metathesis8e or Diels−Alder
Figure 1. Structure of Papulacandins and SGLT2 inhibitors.
reaction,7b,8d aromatization of quinols;7a and (4) stepwise
dihydroxylation of keto-diene derivative.8a The limitation with
using natural sugars (like D-glucose, D-galactose, L-rhamanose)
was that the configuration of the starting material was
predetermined, and hence the scope for synthesizing analogues
Received: November 28, 2011
Published: February 6, 2012
© 2012 American Chemical Society
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Note
was next to nil. To circumvent this, Balachari and O’Doherty
tried to convert both allo and manno configurations to gluco,
but the allo derivative did not yield the required stereo-
chemistry, and the manno derivative gave a mixture of both
manno and gluco isomers.8c In addition, in many cases the
product was a mixture of diastereomers at the anomeric center.
The spiro-C-glycosides were interesting, as these molecules
posed a challenge to synthesize analogues of the sugar
configuration and also to allow flexibility in choosing the
desired configuration. We chose to form the spiro skeleton by
cyclizing the appropriately substituted compound 17, which
gave us the added advantage of getting only one diastereomer
at the anomeric center. Thus, our methodology allowed us to
synthesize allo, gluco, and altro derivatives. In addition, our
strategy has enabled the synthesis of the elusive altro isomer of
the sugar. D-Altrose is an unnatural sugar and differs from
mannose in the configuration at the third carbon. While
D-glucose, D-mannose, and D-galactose are the most abundant
sugars in nature, D-altrose is not found naturally, whereas its
L-isomer has been isolated from bacteria Butyrivibrio fibrisolvens.9
It is interesting to see if the synthesis of an altro configuration
stimulates the existing activity of this class of compounds,
especially in control of diabetes.
The present synthesis of spiro system of papulacandin started
with 3,5-dihydroxybenzoic acid 1, which was converted to a
known acetophenone 2.10 Simultaneous reduction of the ester
and keto groups using LiAH4 at 0 °C gave diol 3 in 90% yield.
Selective protection of the 1° alcohol as TBS ether 4, followed
by IBX oxidation at 0 °C led to acetophenone 5 in 92% yield.
Conversion of 5 to hydroxyacetophenone 6 was facilitated by
use of TMSOTf, 2,6-lutidine, and m-CPBA in 80% yield over
two steps. Both intermediates 5 and 6 were used toward the
synthesis of O-spiro-C-aryl glycosides (Scheme 1).
The sugar part of the molecule was derived from cis-butene-
1,4-diol 7. Conversion of 7 to 8 was carried out by a known
protocol.11 Aldol reaction catalyzed by D-proline led to
D-erythrose derivative 9 in 70% yield with 95% ee and 9:1
diastereomeric excess.12 Coupling of 9 with hydoxyacetophe-
none 6 was carried out in the presence of TiCl4 at −78 °C to
get spiro compounds 10a, 10b, and 10c (75:20:5).13 The
stereochemistry of the major product 10a was confirmed by
NOESY studies, and the H2−H3 relation was found to be syn,
confirming it to have allo configuration. The minor product
10b did not show any 1,3-relations NOEs, so it was fixed as
altro configuration. The strong NOEs of (OCH3)aro−Si(CH3)3
fixed the spiro carbon as thermodynamically favorable anomer
in both of the cases (Figure 2). Deprotection of the silyl group
of the mixture of 10a, 10b, and 10c with TBAF gave 11a in
70% yield with allo configuration of the sugar part. In addition,
Figure 2. Energy minimized structures of 10a and 10b with the
observed strong NOESY relations (blue arrows).
minor quantities of altro 11b and gluco 11c derivatives were
also obtained. Characterization and comparison with the known
spectra (in the case of allo 11a and gluco 11c)8c confirmed the
mixture to be comprising of allo, altro, and gluco configurations in
the sugar components (Scheme 2).
In order to achieve synthesis of a single isomer of the spiro
aryl glycoside, alternate protecting groups were utilized. Thus,
erythrose derivative 12 was obtained by a known protocol in
70% yield from cis-butenediol 7.14 The free hydroxyl of 12 was
protected as TBS ether using TBSOTf at 0 °C15 in 80% yield,
and aldehyde 13 was coupled with substituted acetophenone 5
using TiCl4 at −78 °C to get 14 in 89% yield (90:10 of anti/syn,
on the basis of TLC analysis, as the new center was destroyed
in the next step; the minor isomer was not pure enough to
characterize). The resultant keto polyhydroxy compounds
(both anti and syn isomers) 14 were reacted with
methanesulfonyl chloride and triethylamine, followed by DBU
at 0 °C to get the α,β-unsaturated ketone 15 in 90% yield over
two steps.16 Dihydroxylation8a of the double bond with
osmium tetroxide, NMO at 0 °C yielded diol 16 exclusively
in 80% (98:2 anti/syn), which was converted to 2,2-O-
isopropylidene derivative 17 with 2-methoxypropene and
catalytic pTSA at 0 °C in 90% yield. TBS groups were
removed with tetrabutylammonium fluoride to get 18 in 80%
yield. Compound 18 on reaction with pTSA gave diol, which
cyclized17 in situ to give spiro derivative 198a in 50% yield.
Confirmation of the ring structure was studied by converting
diol into diacetate by standard reaction. Diacetate 20 was
studied in detail to confirm the structure of the sugar part of
Scheme 1. Synthesis of Hydroxyacetophenone Derivative
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Note
Scheme 2. Synthesis of the allo-Papulacandin
the molecule (Figure 3, Scheme 3). Presence of
H3−H6a and H4−H6b and absence of the other NOEs such
where H2−H3 coupling constant is supposed to be less than
3.0 Hz because of diequatorial orientation. NOE between OMe
protons of the aromatic ring and any proton of the sugar ring
could not be observed, and consequently, the stereochemistry
of the glycosidic carbon at the anomeric center could not be
established. The configuration is based on literature precedence
and coupling constants observed for the ring protons.17 The
substitution is α, the thermodynamically favored isomer, and
this is supported by the energy minimized structure.18
Thus, we have synthesized the known allo and gluco isomers
of papulacandin aglycone in addition to the altro isomer, which
is new. The use of organocatalysis to build up sugar moiety and
flexibility of introducing hydroxyls on the double bond allow
one to synthesize any sugar configuration for the spiro-C-
glycoside.
Figure 3. Energy minimized structure of 20 with the observed
important NOESY relations (blue arrows).
as H2−H4 and H3−H5 helped to confirm that the synthesized
molecule had altro configuration of the sugar moiety. This was
also verified by comparing the data of the allo, gluco, and manno
derivatives reported earlier.8c Coupling constant of the H2−H3
EXPERIMENTAL SECTION
■
1
General Methods. H and 13C NMR spectra were recorded in
CDCl3, CD3COCD3 solvents on 300, 500, or 75 MHz (for 13C)
spectrometer at ambient temperature. FTIR spectra were recorded as
KBr thin films or neat. For low (MS) and high (HRMS) resolution,
m/z ratios are reported as values in atomic mass units. All reagents and
is 10.6 Hz, so these two hydrogens are axial in orientation,
4
which gives the molecule C1 conformation rather than C1,
4
Scheme 3. Synthesis of the altro-Papulacandin
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Note
solvents were reagent grade and used without further purification
unless specified otherwise. All reactions were performed under an
atmosphere of nitrogen in flame-dried or oven-dried glassware with
magnetic stirring. Compounds were purified by column chromatog-
raphy over silica gel (SiO2).
(15 mL), dried over Na2SO4, and concentrated under a vacuum.
Crude was purified (8% EtOAc/PE) to give 6 as a white solid (649
mg, 70%): mp 70−72 °C; Rf = 0.5 (15% EtOAc in PE); IR (KBr) νmax
1
3045, 2951, 2934, 1605, 1277, 1161, 1086, 1054, 864, 771 cm−1; H
NMR (300 MHz, CDCl3) δ 7.00 (d, J = 1.9 Hz, 1H), 6.38 (d, J = 1.9
Hz, 1H), 4.89 (s, 2H), 4.61 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 0.96 (s,
9H), 0.11 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 201.2, 163.5, 161.4,
147.7, 103.6, 96.6, 69.8, 63.7, 55.5, 55.3, 25.8, −5.4; MS m/z 363.2 [M
+ Na]+; HRMS calcd for C17H28NaO5Si 363.1598, found 363.1598.
(2R,3R)-3-Hydroxy-2,3-bis-(tert-butyl-diphenylsilanyloxy)-
propionaldehyde (9). D-Proline (0.67 mmol, 77 mg) was added to
aldehyde 8 (2 g, 6.71 mmol) dissolved in a 15 mL mixture of 1,4-
dioxane and DMF (1:1), which was stirred for 48 h at r.t. Resulting
solution was diluted with ethyl acetate (150 mL) and washed
successively with water (100 mL) and brine (100 mL). Separated
organic layer was dried over Na2SO4 and concentrated. Purification of
resulting residue (4% EtOAc in PE) afforded 9 as a clear, colorless oil
in 70% yield ( 1.39 g, 2.33 mmol): [α]20D = −0.5 (c = 1, CHCl3) Rf =
0.5 (10% EtOAc in PE); IR(KBr) νmax 3540, 2933, 1733, 1468, 1428,
1-(2-(Hydroxymethyl)-4,6-dimethoxyphenyl)ethanol (3). A
solution of ester 2 (1 g, 4.15 mmol) in dry ether (10 mL) was
added to LiAlH4 (0.158 g, 4.15 mmol) in ether (5 mL) at 0 °C.
Reaction was stirred for 30 min at same temperature, solution was
cooled to 0 °C, and H2O (0.2 mL), 15% NaOH (0.2 mL), and H2O
(0.6 mL) were added sequentially. Upon warming to room
temperature, white suspension was filtered through Celite (2 g) and
washed with EtOAc (2 × 10 mL). The filtrate was concentrated under
reduced pressure, and crude was purified (30% EtOAc in PE) to result
in diol 3 as a white solid (0.79 g, 90%): mp 85−87 °C; Rf = 0.2 (50%
EtOAc in PE); IR (KBr) νmax 3341, 1605, 1458, 1311, 1149, 1053
1
cm−1; H NMR (300 MHz, CDCl3) δ 6.51(d, J = 2.2 Hz, 1H), 6.43
(d, J = 2.2 Hz, 1H), 5.18 (m, 1H), 4.72 (d, J = 12.8 Hz, 1H), 4.53 (d,
J = 12.8 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 159.2, 158.2, 139.6, 123.4, 105.6, 98.4,
1
1111, 704 cm−1; H NMR (300 MHz, CDCl3): 9.61 (s, 1H), 7.75−
65.5, 63.4, 55.2, 23.7; MS m/z 235.2 [M + Na]+; HRMS calcd for
C11H16NaO4 235.0941, found 235.0917.
7.50 (m, 8H), 7.47−7.32 (m, 12H), 4.24 (dd, 1H, J = 3.9, 1.9 Hz),
4.08−4.02 (m, 1H), 3.80 (dd, J = 9.8, 6.9 Hz), 3.64 (dd, 1H, J = 9.8,
5.9 Hz), 2.16 (d, J = 5.9 Hz), 1.12 (s, 9 H), 1.03 (s, 9H). 13C NMR
(75 MHz, CDCl3) 201.2, 135.8, 135.7, 135.4, 132.6, 132.5, 132.4,
130.1, 129.8, 129.6, 127.8, 127.7, 79.5, 73.9, 63.2, 26.9, 26.6, 19.4,
19.08. Anal. calcd for C36H44O4Si2 (596.90): C, 72.44; H, 7.43. Found:
C, 72.36; H, 7.21.
1-(2-((tert-Butyldimethylsilyloxy)methyl)-4,6-dimethoxy
phenyl)ethanol (4). Diol 3 (6.2 g, 29.2 mmol) was dissolved in dry
CH2Cl2 (40 mL), to which were added imidazole (2.98 g, 43.8 mmol)
and TBS chloride (4.8 g, 32.1 mmol) at 0 °C under nitrogen
atmosphere. Reaction was stirred for 30 min at same temperature.
Water (20 mL) was added to mixture, organic layer was separated, and
aqueous layer was extracted with CH2Cl2 (2 × 30 mL). Combined
organic layers were concentrated under a vacuum. The crude was
purified (5% EtOAc in PE) to afford 4 as a colorless oil (9 g, 95%):
Rf = 0.5 (10% EtOAc in PE); IR (KBr) νmax 3564, 3444, 2955, 1606,
1463, 1149, 1061, 839, 778 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.61
(d, J = 2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 5.05−4.94 (m, 1H), 4.76
(d, J = 12.8 Hz, 1H), 4.68 (d, J = 12.8 Hz, 1H), 3.76 (d, J = 10.5 Hz,
1H), 3.85 (s, 3H), 3.80 (s, 3H), 1.53 (d, J = 6.7 Hz, 1H), 0.95 (s, 9H),
0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.1,
158.4, 139.3, 122.8, 104.1, 98.1, 65.8, 63.4, 55.4, 55.1, 25.8, 23.7, 18.2,
−5.3, −5.4; MS m/z 348.9 [M + Na]+; HRMS calcd for
C17H30NaO4Si 349.1806, found 349.1814.
(1S,5′S)-5′-(tert-Butyldiphenylsilyloxy)-6′-((tert-butyldiphenyl-
silyloxy)methyl)-5,7-dimethoxy-3′,4′,5′,6′-tetrahydro-3H-spiro-
[isobenzofuran-1,2′-pyran]-3′,4′-diol (10a, 10b, 10c). To a
stirred solution of hydroxyacetophenone 6 (340 mg, 1 mmol) in dry
CH2Cl2 (5 mL) was added titanium tetrachloride (1 mL, 1 M solution
in CH2Cl2) at −78 °C slowly under a nitrogen atmosphere. After
5 min, DIPEA (0.26 mL, 1.5 mmol) was added. Resulting red colored
solution was stirred for 15 min at same temperature. Then, a solution
of aldehyde 9 (715 mg, 1.2 mmol) dissolved in dry CH2Cl2 (3 mL)
was added. Stirring was continued overnight at r.t. After completion of
reaction, mixture was cooled to 0 °C, 50% NH4Cl solution (5 mL) was
added, and resulting mixture was stirred for 2 h. Organic layer was
separated, and aqueous layer was extracted with CH2Cl2 (2 × 5 mL).
Combined organic layers were dried over Na2SO4 and concentrated
under a vacuum. Crude was purified (15% EtOAc/hexanes) to yield
pure diols (30%, 289 mg, 75:20:5).
1-(2-((tert-Butyldimethylsilyloxy)methyl)-4,6-dimethoxy
phenyl)ethanone (5). Alcohol 4 (1.5 g, 4.6 mmol) dissolved in 10
mL of THF was added to a stirred solution of IBX (1.93 g, 6.9 mmol)
in dry DMSO (2 mL) at 0 °C. Stirring was continued for an hour at
room temperature. After completion of reaction, EtOAc (30 mL) was
added, and mixture was filtered through a Celite pad (5 g). Filtrate was
washed with water (30 mL) and aqueous NaHCO3 (30 mL) solution.
Organic layer was dried over Na2SO4 and concentrated in vacuo.
Crude was purified (4% EtOAc in PE) to afford 5 as a light red colored
oil (1.3 g, 90%): Rf = 0.7 (10% EtOAc in PE); IR (KBr) νmax 2931,
allo-Isomer 10a. Data: [α]20 = +14.6 (c = 0.25, CHCl3); Rf = 0.5
D
(30% EtOAc in PE); IR(KBr) νmax 3442, 2933, 1625, 1426, 1105, 703
1
cm −1; H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 6.9 Hz, 2H), 7.69
(d, J = 7.9 Hz, 2H), 7.44−7.20 (m, 12H), 7.10 (t, J = 6.9 Hz, 2H), 7.00
(t, J = 7.9 Hz, 2H), 6.30 (s, 2H), 5.08 (d, J = 12.8 Hz, 1H), 4.98 (d, J =
12.8 Hz, 1H), 4.18−4.03 (m, 3H), 3.96−3.77 (m, 3H), 3.80 (s, 3H),
3.58 (s, 3H), 2.60 (d, J = 6.9 Hz, 1H), 2.43 (d, J = 10.8 Hz, 1H), 1.08
(s, 9H), 0.94 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 162.7, 155.7,
143.2, 135.9, 135.7, 135.6, 133.9, 133.6, 133.5, 133.1, 129.9, 129.8,
129.2, 129.1, 127.7, 127.2, 127.0, 118.3, 110.5, 98.8, 96.5, 73.0, 72.0,
69.0, 67.5, 63.1, 55.6, 55.0, 26.9, 26.6, 19.4, 19.1; MS m/z 828.2
[M + Na]+; HRMS calcd for C47H57O8Si2 805.3586, found 805.3611.
1
1680, 1602, 1252, 1156, 1064, 839, 778 cm−1; H NMR (300 MHz,
CDCl3) δ 6.74 (d, J = 2.2 Hz, 1H), 6.29 (d, J = 2.2 Hz, 1H), 4.66
(s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 2.43 (s, 3H), 0.92 (s, 9H), 0.07
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 203.2, 161.8, 158.9, 143.2,
121.1, 103.2, 96.8, 62.8, 55.5, 55.2, 32.4, 25.8, 18.3, −5.4; MS m/z
347.0 [M + Na]+; HRMS calcd for C17H28NaO4Si 347.1649, found
347.1674.
1-(2-((tert-Butyldimethylsilyloxy)methyl)-4,6-dimethoxy-
phenyl)-2-hydroxyethanone (6). To a stirred solution of ketone 5
(1 g, 2.73 mmol) in dry CH2Cl2 (15 mL) were added 2,6-lutidine
(0.95 mL, 8.19 mmol) and TMSOTf (0.75 mL, 4.09 mmol) at 0 °C,
and mixture was stirred for 1 h. Saturated aqueous NaHCO3 (10 mL)
was added, and two layers were separated. Aqueous layer was extracted
with CH2Cl2 (2 × 10 mL). Combined organic layers were dried over
Na2SO4 and concentrated in vacuo to give crude enol silane as brown
color oil (1.2 g). Crude silane was dissolved in CH2Cl2 (10 mL), and
mCPBA (2.0 g, 8.19 mmol, 70% in H2O) was added at 0 °C. Mixture
was stirred for 1 h at same temperature, and after consumption of
enolate, saturated Na2SO3 (10 mL) was added, and two layers were
separated. Organic layer was washed with saturated NaHCO3 solution
altro-Isomer 10b. Data: [α]20 = −54 (c = 0.5, CHCl3); Rf = 0.4
D
(30% EtOAc in hexanes); IR(KBr) νmax 3440, 2951, 1644, 1032, 702
1
cm−1. H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 7.1 Hz, 2H), 7.79
(d, J = 7.1 Hz, 2H), 7.50−7.22 (m, 16H), 6.39 (s, 1H), 6.26 (s, 1H),
4.91 (m, 1H), 4.85 (d, J = 12.2 Hz, 1H), 4.81 (d, J = 12.2 Hz, 1H),
4.59 (s, 1H), 4.17- 4.10 (m, 1H), 3.90−3.84 (m, 2H), 3.82 (s, 3H),
3.78 (s, 3H), 3.58 (dd, J = 11.2, 5.0 Hz, 1H), 1.16 (s, 9H), 0.81 (s,
9H). 13C NMR (75 MHz, CDCl3) δ 163.0, 143.4, 136.0, 135.4, 132.7,
129.8, 129.7, 129.6, 129.5, 127.8, 127.6, 127.5, 118.0, 114.3, 98.3, 96.6,
79.3, 72.4, 72.0, 69.3, 64.4, 55.6, 55.2, 27.0, 26.6, 19.6; MS m/z 806.1
[M + H]+; HRMS calcd for C47H57O8Si2 805.3586, found 805.3579.
(1S,5′S)-6′-(Hydroxymethyl)-5,7-dimethoxy-3′,4′,5′,6′-tetra-
hydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (11a,
11b, 11c). To a stirred solution of 10a, 10b, and 10c (50 mg, 0.06
mmol) in dry THF (1 mL) was added TBAF (0.3 mL, 1 M in THF) at
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room temperature, and mixture was stirred for 1 h. After consumption
of starting material, reaction was diluted with EtOAc (5 mL) and
filtered through Celite (100 mg). Filtrate was concentrated and puri-
fied (5% MeOH in CH2Cl2) to afford tetrol 11a, 11b, and 11c (14.2
mg, 50%). Data for allo 11a and gluco 11c isomers matched with the
reported values.
Combined organic layers were dried over Na2SO4 and concent-
rated under a vacuum. Crude mesylated product was dissolved in dry
CH2Cl2 (5 mL), DBU (0.4 mL, 2.64 mmol) was added at 0 °C under
nitrogen atmosphere, and mixture was stirred for 30 min. Saturated
NH4Cl solution (5 mL) was added to reaction mixture, and two layers
were separated. Aqueous layer was extracted with CH2Cl2 (2 × 5 mL).
Combined organic layers were dried over Na2SO4 and concentrated in
Altrose Isomer (11b). White solid (yield, 70%): [α]20D = −7.5 (c =
0.2, CHCl3); Rf = 0.5 (SiO2, 10% MeOH in CH2Cl2); IR (KBr) νmax
3384, 2925, 2851, 1610, 1151, 1095, 1005 cm−1; 1H NMR (300 MHz,
CD3OD) δ 6.47 (s, 1H), 6.45 (s, 1H), 5.12 (d, J = 12.6 Hz, 1H), 4.96
(d, J = 12.6 Hz, 1H), 4.68−4.57 (m, 1H), 4.32 (t, J = 7.3 Hz, 1H), 3.85
(s, 3H), 3.80 (s, 3H), 3.88−3.69 (m, 3H); 13C NMR (75 MHz,
CD3OD) δ 164.9, 157.7, 145.5, 115.7, 99.0, 97.9, 82.4, 79.3, 76.3, 74.5,
73.3, 64.0, 57.1, 55.9, 30.7; MS m/z 350.9 [M + Na]+; HRMS calcd for
C15H20NaO8 351.105, found 351.1078.
vacuo. Crude was purified (5% EtOAc in PE) to yield 15 (1.14 g,
20
90%): [α]
= +11.8 (c = 0.5, CHCl3); Rf = 0.5 (10% EtOAc in
D
hexanes); IR (KBr) νmax 2929, 1661, 1602, 1459, 1255, 1153, 1067,
1
836, 777 cm−1; H NMR (300 MHz, CDCl3) δ 7.28−7.16 (m, 10H),
6.71 (d, J = 2.0 Hz, 1H), 6.63−6.47 (dt, J = 15.8, 5.6, 11.7 Hz, 2H),
6.27 (d, J = 2.0 Hz, 1H), 4.61 (s, 2H), 4.52 (d, J = 11.7 Hz, 1H), 4.41
(s, 2H), 4.34 (d, J = 11.7 Hz, 1H), 4.06 (t, J = 5.0 Hz, 1H), 3.87 (q, J =
4.9 Hz, 1H), 3.76 (s, 3H), 3.62 (s, 3H), 3.47−3.36 (m, 2H), 0.86
(s, 9H), 0.73 (s, 9H), 0.01 (s, 6H), −0.06 (d, J = 1.7 Hz, 3H), −0.09
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 194.9, 161.9, 158.5, 144.2,
143.5, 138.1, 133.7, 128.2, 127.6, 127.5, 119.2, 102.7, 96.8, 79.6, 74.1,
73.3, 71.5, 71.4, 62.2, 55.5, 55.2, 25.9, 25.7, 18.3, 18.0, −4.6, −4.7,
−5.3; MS m/z 743.3 [M + Na]+; HRMS calcd for C41H60NaO7Si2
743.377, found 743.3802.
(2R,3R)-2,4-Bis-(benzyloxy)-3-(tert-butyldimethylsilyloxy)-
butanal (13). Aldehyde 12 (500 mg, 1.6 mmol) was dissolved in dry
CH2Cl2 (10 mL), to which were added 2,6-lutidine (0.3 mL, 2.5
mmol) and TBSOTf (0.42 mL, 1.76 mmol) at 0 °C under nitrogen
atmosphere. Reaction was stirred for 1 h at same temperature. Solution
was diluted with CH2Cl2 (10 mL) and water (10 mL), and both layers
were separated. Organic layer was dried over Na2SO4 and con-
centrated in vacuo. Crude was purified (4% EtOAc in PE) to afford
aldehyde 13 as a colorless liquid (529 mg, 80%): [α]20 D = −2.2 (c = 2,
CHCl3); Rf = 0.6 (10% EtOAc in PE); IR (KBr) νmax 2929, 1728,
(2S,3S,4S,5R)-4,6-Bis-(benzyloxy)-5-(tert-butyldimethylsilyl-
oxy)-1-(2-((tert-butyldimethylsilyloxy)methyl)-4,6-dimethoxy-
phenyl)-2,3-dihydroxyhexan-1-one (16). To a solution of enone
15 (1.2 g, 1.66 mmol) in 12 mL of t-butanol/acetone (1:1) were
added 50% w/v solution of 4-methylmorpholine-N-oxide in water
(1.16 mL, 4.98 mmol) and OsO4 (8.3 mg, 0.03 mmol, 2 mol %) at
0 °C. Reaction was stirred vigorously at 0 °C for 30 h. Mixture was
quenched with solid sodium sulfite (250 mg) at room temperature.
Ethyl acetate (10 mL) was added to reaction, and mixture was filtered
through a pad of Celite (2 g). Organic layers were separated and dried
over Na2SO4. Solvent was removed under reduced pressure. Crude
1
1254, 1110, 836, 779 cm−1; H NMR (300 MHz, CDCl3) δ 9.64 (d,
J = 1.7, 1H), 7.35−7.22 (m, 10H), 4.69 (s, 2H), 4.50 (s, 2H), 4.22
(m, 1H), 3.86 (dd, J = 1.8, 3.2 Hz, 1H), 3.66−3.60 (dd, J = 7.3, 9.4 Hz,
1H), 3.46 (dd, J = 5.4, 9.4 Hz, 1H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.1, 137.7, 137.4,128.2,
128.1, 127.7, 127.5, 127.4, 84.7, 73.2,73.1, 72.9, 70.0, 25.6, 17.9, −4.8,
−5.0. Anal. calcd for C24H34O4Si (414.61): C, 69.52; H, 8.27. Found:
C, 69.41; H, 8.32.
was purified (8% EtOAc in PE) to yield 16 (980 mg, 80%): [α]20
=
D
+15.7 (c = 2, CHCl3); Rf = 0.5 (15% EtOAc in PE); IR (KBr) νmax
(4S,5R)-4,6-Bis-(benzyloxy)-5-(tert-butyldimethylsilyloxy)-1-
(2-((tert-butyldimethylsilyloxy)methyl)-4,6-dimethoxyphenyl)-
3-hydroxyhexan-1-one (14). To a stirred solution of ketone 5 (307
mg, 0.84 mmol) in dry CH2Cl2 (10 mL) was added titanium tetra-
chloride (1 M solution in CH2Cl2, 0.8 mL) at −78 °C slowly under
nitrogen atmosphere. After 5 min, DIPEA (0.21 mL, 1.26 mmol) was
added, and resulting red colored solution was stirred for 15 min at
same temperature. Then, a solution of aldehyde 13 (350 mg, 0.84
mmol) dissolved in dry CH2Cl2 (5 mL) was added. Stirring was
continued for 1 h at same temperature. After completion of reaction,
mixture was warmed to 0 °C, 50% NH4Cl solution (10 mL) was
added, and resulting mixture was stirred for 2 h at room temperature.
Organic layer was separated, and aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). Combined organic layers were dried over
Na2SO4 and concentrated under a vacuum. Crude was purified (20%
EtOAc in PE) to yield 14 as a viscous liquid (552 mg, 70%, 20% of syn
diastereomer): [α] 20D = −10 (c = 0.5, CHCl3); Rf = 0.3 (30% EtOAc
in hexanes); IR (KBr) νmax 3505, 2952, 2930, 1601, 1459, 1254, 1152,
1
3462, 2930, 1677, 1601, 1459, 1108, 1067, 837, 777 cm−1; H NMR
(300 MHz, CDCl3) δ 7.34−7.10 (m, 10H), 6.90 (d, J = 2.2 Hz, 1H),
6.16 (d, J = 2.2 Hz, 1H), 5.31 (d, J = 5.2 Hz, 1H), 4.88 (d, J = 15.8 Hz,
1H), 4.77 (d, J = 10.5 Hz, 1H), 4.59 (d, J = 3.0 Hz, 1H), 4.55 (s, 1H),
4.41 (d, J = 12.0 Hz, 1H,), 4.36 (d, J = 12.0 Hz, 1H), 4.18 (dt, J = 1.5,
6.0 Hz, 1H), 3.88 (d, J = 4.5 Hz, 1H), 3.82−3.75 (m, 1H), 3.78
(s, 3H), 3.63−3.54 (m, 2H), 3.43 (s, 3H), 3.40 (dd, J = 6.0, 9.0 Hz,
1H), 2.39 (d, J = 8.3 Hz, 1H), 0.93 (s, 9H), 0.78 (s, 9H), 0.05−0.04
(s, 6H), 0.01 (s, 3H), 0.00 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 204.5, 163.1, 159.7, 146.4, 138.8, 138.0, 128.3, 128.2, 127.9, 127.5,
127.4, 103.7, 96.7, 80.9, 73.9, 73.2, 73.1, 72.1, 71.8, 62.5, 55.3, 25.9,
25.7, 18.3, 18.0, −4.5, −5.0, −5.2, −5.3; MS m/z [M + Na]+ 777.8;
HRMS calcd for C41H63O9Si2 755.4005, found 755.4026.
((4R,5S)-5-((1S, 2R)-1, 3-Bis-(benzyloxy)-2-(tert-
butyldimethylsilyloxy)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
(2-((tert-butyldimethylsilyloxy)methyl)-4,6-dimethoxyphenyl)-
methanone (17). A solution of diol 16 (800 mg, 1.05 mmol),
2-methoxypropene (0.30 mL, 3.17 mmol), and pTSA (10.5 mg,
5 mol %) in dry CH2Cl2 (5 mL) was vigorously stirred at 0 °C for
10 min. The mixture was neutralized with aqueous NaHCO3, and
layers were separated. Aqueous phase was extracted with CH2Cl2
(2 × 5 mL). Combined organic layers were washed with brine
(10 mL), dried over Na2SO4, and concentrated under a vacuum.
Crude was purified (6% EtOAc in PE) to yield 17 (749 mg, 90%):
[α]20D = +4.6 (c = 1, CHCl3); Rf = 0.6 (10% EtOAc in PE); IR (KBr)
νmax 2931, 2856, 1680, 1601, 1459, 1253, 1153, 1069, 836, 776 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.28−7.15 (m, 10H), 7.01−7.06 (dd,
1
1068, 837, 778 cm−1; H NMR (300 MHz, CDCl3) δ 7.30−7.11 (m,
10H), 6.75 (d, J = 2.2 Hz, 1H), 6.23 (d, J = 2.2 Hz, 1H), 4.78−4.43
(m, 6H), 4.21−4.11 (m, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 3.65−3.59
(m, 1H), 3.50−3.40 (m, 2H), 3.32−3.22 (m, 1H), 2.84 (d, J = 9.8 Hz,
1H), 2.79 (d, J = 9.8 Hz, 1H) 0.90 (s, 9H), 0.83 (s, 9H), 0.04 (s, 6H),
0.02 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 206.1, 162.0, 158.7,
143.6, 138.6, 138.1, 128.1, 120.8, 127.6. 127.5, 127.3, 120.3, 103.1,
96.7, 83.7, 73.9, 73.2, 72.5, 72.0, 68.7, 62.7, 55.4, 55.2, 47.8, 25.9, 25.8,
18.3, 18.0, −4.4, −4.8, −5.3; MS m/z 761.4 [M + Na]+; HRMS calcd
for C41H63O8Si2 739.4056, found 739.4094.
J = 6.0, 3.0 Hz, 2H), 6.81 (d, J = 2.2 Hz, 1H), 6.23 (d, J = 2.2 Hz, 1H),
4.97 (d, J = 5.2 Hz, 1H), 4.71−4.28 (m, 2H), 4.54−4.47 (dd, J = 5.2,
9.8 Hz, 2H), 4.44 (s, 2H), 4.15 (m, 1H), 3.76 (s, 3H), 3.68 (dd, J =
9.8, 4.5 Hz, 1H), 3.67−3.54 (m, 1H), 3.59 (s, 3H), 3.49 (dd, J = 6.0,
9.8 Hz, 1H), 1.22 (s, 3H), 1.20 (s, 3H), 0.87 (s, 9H), 0.83 (s, 9H),
0.02 (s, 3H), 0.01 (s, 3H), −0.01 (s, 3H), −0.06 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 203.1, 161.5, 159.5, 144.7, 138.4, 128.2, 128.0,
127.5, 127.3, 127.2, 118.3, 110.6, 102.9, 96.9, 83.5, 82.3, 77.8, 73.5,
73.2, 72.2, 71.7, 62.4, 55.7, 55.2, 27.5, 26.2, 25.9, 18.3, 18.1, −4.4, −4.7,
(4S,5R,E)-4,6-Bis-(benzyloxy)-5-(tert-butyldimethylsilyloxy)-
1-(2-((tert-butyldimethylsilyloxy)methyl)-4,6-dimethoxyphenyl)-
hex-2-en-1-one (15). To an ice-cooled solution of alcohol 14 (1.3 g,
1.76 mmol) in dry CH2Cl2 (5 mL) were added triethylamine (0.5 mL,
3.5 mmol) and mesyl chloride (0.11 mL, 1.43 mmol) under a nitrogen
atmosphere. Ice bath was removed, and flask was fitted with reflux
condenser. Reaction was heated to reflux for 1 h, mixture was cooled
to room temperature, and water (5 mL) was added to it. Both layers
were separated, and aqueous layer was extracted with CH2Cl2 (2 × 10 mL).
2523
dx.doi.org/10.1021/jo202353r | J. Org. Chem. 2012, 77, 2519−2525

The Journal of Organic Chemistry
Note
−5.3; MS m/z 816.6 [M + Na]+, 794.6 [M + H]+; HRMS calcd for
C44H67O9Si2 795.4318, found 795.4351.
ASSOCIATED CONTENT
■
S
* Supporting Information
((4R,5S)-5-((1R,2R)-1,3-Bis-(benzyloxy)-2-hydroxypropyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)(2-(hydroxymethyl)-4,6-
dimethoxyphenyl)methanone (18). To a stirred solution of 17
(1 g, 1.25 mmol) in dry THF (10 mL) was added TBAF (3.7 mL, 1 M
in THF) at 0 °C, and mixture was stirred for 1 h. After consumption of
starting material, saturated NH4Cl (10 mL) and EtOAc (10 mL) were
added to reaction. Organic layer was separated, and aqueous layer was
extracted with EtOAc (2 × 5 mL). Combined organic layers were
concentrated in vacuo to yield diol as colorless oil (566 mg, 80%). The
crude diol was taken up to next reaction without further purification.
Part of crude product was purified for characterization (35% EtOAc in
PE) to yield 18: [α]20D = +2.6 (c = 1, CHCl3); Rf = 0.5 (40% EtOAc in
PE); IR (KBr) νmax 3380, 2930, 2867, 1609, 1455, 1346, 1221, 1153,
1
Copies of H NMR and 13C NMR spectra for all compounds
described. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: prathama@iict.res.in; srivaric@iict.res.in.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
1095, 741, 699 cm−1; H NMR (300 MHz, CD3COCD3) δ 7.43−
■
K.J. thanks the Council of Scientific Industrial Research (CSIR),
New Delhi, for a research fellowship, and P.S.M. thanks DST
for WOS-A (GAP-0317). The authors thank Dr. B. V. Rao for
fruitful discussions. S.C. is thankful to DST, New Delhi, for a
research grant (SR/S1/OC-65/2009).
7.720 (m, 10H), 6.43 (d, J = 1.5 Hz, 1H), 6.41 (d, J = 1.5 Hz, 1H),
5.08−4.75 (m, 6H), 4.63−4.53 (m, 2H), 4.17 (m, 1H), 3.91 (dd, J =
3.7, 6.0 Hz, 1H), 3.76−3.79 (dd, J = 3.7, 8.3 Hz, 1H), 3.83 (s, 3H),
3.80 (s, 3H), 3.75−3.67 (m, 1H), 1.31 (s, 3H), 1.25 (s, 3H); 13C NMR
(75 MHz, CD3COCD3) δ 207.2, 164.4, 157.7, 145.0, 140.8, 140.2,
129.9, 129.4, 129.0, 111.0, 109.9, 99.5, 98.4, 82.0, 81.7, 78.7, 75.7, 74.6,
72.4, 56.8, 29.0, 27.8; MS m/z 549.1 [M − H2O]+. Anal. calcd for
C32H38O9 (566.25): C, 67.83; H, 6.76. Found: C, 67.82; H, 6.67.
1S,3′R,5′S)-5′-(Benzyloxy)-6′-(benzyloxymethyl)-5,7-dime-
thoxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-
pyran]-3′,4′-diol (19). Diol 18 (100 mg, 0.17 mmol) was dissolved
in MeOH (2 mL) and cooled to 0 °C. Dry pTSA (3.4 mg, 10 mol %)
was added to it, ice bath was removed, and mixture was stirred for 1 h
at room temperature. Reaction was quenched with solid NaHCO3
solution and filtered through Celite (100 mg). MeOH was removed
under a vacuum, residue was partitioned between EtOAc (3 mL) and
water (3 mL), and two layers were separated. Aqueous layer was
extracted with EtOAc (2 × 5 mL). Combined organic layers dried over
Na2SO4 and concentrated in vacuo. Crude was purified (40% EtOAc
REFERENCES
■
(1) General reviews of C-aryl glycosides: (a) Levy, D. E.; Tang, C. In
The Chemistry of C-Glycosides; Elsevier Science: Tarrytown, NY, 1995.
(b) Nicotra, F. Top. Curr. Chem. 1997, 187, 55−83. (c) Liu, L.;
McKee, M.; Postema, M. H. D. Curr. Org. Chem. 2001, 5, 1133−1167.
(2) For total synthesis of Papulacandin D: (a) Denmark, S. E.;
Kobayashi, T.; Regens, C. S. Tetrahedron 2010, 66, 4745−4759.
(b) Denmark, S. E.; Regens, C. S.; Kobayashi, T. J. Am. Chem. Soc.
2007, 129, 2774−2776. (c) Barrett, A. G. M.; Pea, M.; Willardsen, J. A.
J. Org. Chem. 1996, 61, 1082−1100.
(3) (a) Kaneto, R.; Chiba, H.; Agematu, H.; Shibamoto, N.;
Yoshioka, T.; Nishida, H.; Okamoto, R. J. Antibiot. 1993, 46, 247−250.
(b) Chiba, H.; Kaneto, R.; Agematu, H.; Shibamoto, N.; Yoshioka, T.;
Nishida, H.; Okamoto, R. J. Antibiot. 1993, 46, 356−358. (c) Aoki, M.;
Andoh, T.; Ueki, T.; Masuyoshi, S.; Sugawara, K.; Oki, T. J. Antibiot.
1993, 46, 952−960. (d) Okada, H.; Nagashima, M.; Suzuki, H.;
Nakajima, S.; Kojiri, K.; Suda, H. J. Antibiot. 1996, 49, 103−106.
(e) Traxler, P.; Fritz, H.; Fuhrer, H.; Richter, W. J. J. Antibiot. 1980,
33, 967−978.
in PE) to yield 19 (43 mg, 50%): [α]20 = −48 (c = 1, CHCl3); Rf =
D
0.2 (60% EtOAc in PE); IR (KBr) νmax 3443, 2926, 2864, 1610, 1345,
1
1154, 1093, 1022, 743 cm−1; H NMR (300 MHz, CDCl3) δ 7.44−
7.27 (m, 10H), 6.37 (d, J = 1.5 Hz, 1H), 6.32 (d, J = 1.5 Hz, 1H),
5.10−4.93 (dd, J = 12.8, 34.7 Hz, 2H,), 4.85−4.73 (dd, J = 10.5, 22.6
Hz, 2H), 4.53 (s, 2H), 4.51−4.43 (m, 1H), 4.41−4.32 (m, 1H), 4.13−
3.97 (m, 2H) 3.89−3.81 (m, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.72−
3.64 (dd, J = 4.5, 9.8 Hz, 1H), 2.52 (d, J = 9.0 Hz, 1H), 1.88 (d, J =
7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 162.9, 155.7, 143.3, 138.2,
138.0, 128.4, 128.3, 128.2, 128.1, 127.8, 127.6, 127.5, 127.4, 117.8,
111.7, 98.2, 96.7, 73.5, 73.1, 72.5, 71.2, 70.9, 70.1, 68.4, 55.5, 55.4,
55.3; MS m/z [M + H]+ 509.2; HRMS calcd for C29H33O8 509.2170,
found 509.2176.
(4) (a) Per
1981, 129, 249−252. (b) Varona, R.; Per
́
ez, P.; Varona, R.; Garcia-Acha, I.; Duran
́
, A. FEBS Lett.
, A. FEMS
́
ez, P.; Duran
́
Microbiol. Lett. 1983, 20, 243−247. (c) Baguley, B. C.; Rommele, G.;
Gruner, J.; Wehrli, W. Eur. J. Biochem. 1979, 97, 345−351. (d) Debono,
M.; Gordee, R. S. Annu. Rev. Microbiol. 1994, 48, 471−497.
(e) Schmatz, D. M.; Romancheck, M. A.; Pittarelli, L. A.; Schwartz,
R. E.; Fromtling, R. A.; Nollstadt, K. H.; Vanmiddlesworth, F. L.;
Wilson, K. E.; Turner, M. J. Proc. Natl. Acad. Sci. U. S. A. 1990, 87,
5950−5954. (f) Kanai, Y; Lee, W. S.; You, G.; Brown, D.; Hediger,
M. A. J. Clin. Invest. 1994, 93, 397−404.
(1S,3′R,5′R)-5′-(Benzyloxy)-6′-(benzyloxymethyl)-5,7-dime-
thoxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-
pyran]-3′,4′-diyl Diacetate (20). To a stirred solution of diol 19
(96.5 mg, 0.19 mmol) in dry CH2Cl2 (2.0 mL) was added pyridine (63
μL, 0.78 mmol), followed by acetic anhydride (55 μL, 0.59 mmol) and
DMAP (2.3 mg, 10 mol %) at 0 °C. Resulting mixture was allowed to
stir at room temperature for 4 h. Saturated NaHCO3 solution (1 mL)
was added, and organic layer was separated. Aqueous layer was
extracted with CH2Cl2 (2 × 2 mL). Combined organic layers were
concentrated in vacuo. Crude was purified (20% EtOAc/hexanes) to
(5) Traxler, P.; Gruner, J.; Auden, J. A. J. Antibiot. 1977, 30, 289−296.
(6) (a) Xu, B.; Lv, B.; Feng, Y.; Xu, G.; Du, J.; Welihinda, A.; Sheng,
Z.; Seed, B.; Chen, Y. Bioorg. Med. Chem. Lett. 2009, 19, 5632−5635.
(b) Lv, B.; Xu, B.; Feng, Y.; Peng, K.; Xu, G.; Du, J.; Zhang, L.; Zheng,
W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda, A.; Seed, B.;
Chen, Y. Bioorg. Med. Chem. Lett. 2009, 19, 6877−6881.
(7) For synthesis of spirocyclic core of papulacandin D: (a) Parker,
K. A.; Georges, A. T. Org. Lett. 2000, 2, 497−499. (b) Danishefsky, S.;
Phillips, G.; Ciufolini, M. Carbohydr. Res. 1987, 171, 317−327.
(c) Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163−7169.
(d) Dubois, E.; Beau, J.-M. Tetrahedron Lett. 1990, 31, 5165−5168.
(e) Dubois, E.; Beau, J.-M. J. Chem. Soc., Chem. Commun. 1990, 1191−
1192. (f) Rosenblum, S.; Bihovsky, R. J. Am. Chem. Soc. 1990, 112,
2746−2748.
yield 20 (107 mg, 95%) as a colorless oil: [α]20 = −31.4 (c = 0.5,
D
CHCl3); Rf = 0.2 (30% EtOAc in PE); IR (KBr) νmax 2924, 1744,
1609, 1225, 1022, 771 cm−1.1H NMR (300 MHz, CDCl3) δ 7.45−7.23
(m, 10H), 6.37−6.23 (m, 3H), 5.51 (dd, J = 10.6, 3.3 Hz, 2H), 5.07
(d, J = 12.6 Hz, 1H), 4.93 (d, J = 12.6 Hz, 1H), 4.73 (d, J = 12.4 Hz,
1H), 4.63 (d, J = 12.2 Hz, 1H), 4.54 (s, 2H), 4.44−4.31 (m, 1H), 4.19
(m, 1H), 3.93 (t, J = 9.8 Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.74 (dd,
J = 10.3, 4.5 Hz, 1H), 2.0 (s, 3H), 1.76 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.2, 169.2, 156.2, 143.2, 138.3, 138.1, 128.3, 128.2, 127.7,
116.6, 110.5, 98.0, 75.2, 74.7, 73.3, 73.2, 72.9, 71.7, 70.9, 68.7, 68.6,
55.6, 55.5, 20.9, 20.4; MS m/z 592.9 [M + H]+; HRMS calcd for
C33H37O10 593.2381, found 593.2378.
(8) (a) Ahmed, M. M.; O’Doherty, G. A. Tetrahedron Lett. 2005, 46,
4151−4155. (b) Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2,
863−866. (c) Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2,
4033−4036. (d) Subrahmanyam, A. V; Palanichamy, K; Kaliappan, K. P
2524
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The Journal of Organic Chemistry
Note
Chem.Eur. J. 2010, 16, 8545−8556. (e) Yamamoto, Y; Yamashita, K;
Hotta, T; Hashimoto, T; Kikuchi, M; Nishiyama, H Chem.Asian. J.
2007, 2, 1388−1399.
(9) Stack, R. J. US patent 4966845, 1990.
(10) (a) Varseev, G. N.; Maier, M. E. Angew. Chem., Int. Ed. 2006, 45,
4767−4771. (b) Maresh, J.; Zhang, J.; Tzeng, Y. L; Goodman, N. A;
Lynn, D. G. Bioorg. Med. Chem. Lett. 2007, 17, 3281−3286.
(11) Choi, W. B.; Wilson, L. J.; Yeola, S.; Liotta, D. C.; Schinazi, R. F.
J. Am. Chem. Soc. 1991, 113, 9377−9379.
(12) Northhrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2004, 43, 2152−2154.
(13) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752−
1755.
(14) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 3696−3697.
(15) Davies, S. G.; Nicholson, R. L.; Smith, A. D. Org. Biomol. Chem.
2005, 3, 348−359.
(16) Hammond, G. B.; Cox, M. B.; Wiemer, D. F.; Oare, D. A.;
Hendeson, M. A.; Sanner, M. A.; Heathcock, C. H. J. Org. Chem. 1990,
55, 132−157.
(17) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105,
4406−4440.
(18) Molecular dynamics for the energy minimized conformation of
10a, 10b, and 20 were carried out using Insight II program on a
Silicon Graphics work station.
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