Alternative synthesis of P-chiral phosphonite-borane complexes: Application to the synthesis of phostone-phostone dimers

Article abstract of DOI:10.1021/jo400864s

An improved strategy for the synthesis of P-chiral gluco- and manno-phosphonite-borane complexes is described on the basis of the addition of diethyl phosphonite-borane to a glucal-derived aldehyde, followed by a cyclization coupled with an ethyl/methyl exchange. This direct P(III) strategy facilitates the obtention of various P-chiral phosphonite-boranes, of which further coupling reactions are described leading to the selective synthesis of two phostone dimers.

Full text of DOI:10.1021/jo400864s

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Alternative Synthesis of P‑Chiral Phosphonite-Borane Complexes:
Application to the Synthesis of Phostone−Phostone Dimers
Angelique Ferry,† Gaelle Malik,† Pascal Retailleau,† Xavier Guinchard,† and David Crich*,†,‡
́
̈
†Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette,
France
‡Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
S
* Supporting Information
ABSTRACT: An improved strategy for the synthesis of P-
chiral gluco- and manno-phosphonite-borane complexes is
described on the basis of the addition of diethyl phosphonite-
borane to a glucal-derived aldehyde, followed by a cyclization
coupled with an ethyl/methyl exchange. This direct P(III)
strategy facilitates the obtention of various P-chiral phosphon-
ite-boranes, of which further coupling reactions are described
leading to the selective synthesis of two phostone dimers.
iminosugars in which the anomeric carbon is replaced by a
nitrogen atom.8 Nevertheless, most glycan mimetics designed
to date were intended as glycosidase inhibitors and not as novel
surrogates for oligosaccharides, which is our current goal.
Toward this end we have considered and have presented
preliminary results for two mimetics of the glycosidic bond: (i)
oligohydroxylamines9 and (ii) oligophostones10 (Figure 1).
INTRODUCTION
■
The central role of glycans in many biological processes1 is
widely recognized, and raises the possibility of their use as
therapeutics. Indeed the ability of glycans, and particularly the
β-glucans, to boost biological responses by eliciting natural
defenses such as the production of reactive oxygen species and
phytoallexins, or by the stimulation of macrophages, confers
strong immunostimulating1b−d and antitumoral1a effects on
them. These activities are mediated by a wide range of pattern-
recognition receptors, of which the lectin family is the most
important. Exploitation of these natural polymers requires easy,
reproducible access to well-defined samples on a large scale.
The heterogeneous nature of biological extracts and the
associated problems of purification favor the development of
alternative sources, namely, efficient and stereoselective
chemical synthesis.2 The realization of this potential, however,
is limited in part by the difficulties inherent in glycan synthesis
and most pertinently by the need for the repeated formation of
glycosidic bonds with very high and predictable stereoselectivity
and yield.3 Although enormous progress in glycosylation
technology has been achieved in recent years,3c,4 including
the use of automated polymer-supported methods, glycan
synthesis remains a highly challenging task for all but a few
classes. As such we have been led to consider the synthesis of
glycan mimetics as a possible alternative. Conceptually, this
strategy is analogous to the frequent use of a complex
biologically active natural product as the inspiration for the
design of a less complex but equally potent surrogate.5 The
synthesis of glycan mimetics has been notably developed by
Vasella and co-workers who described the preparation of
oligomeric glycosyl acetylenes,6 but in more recent years the
field has been dominated by “Click” chemistry methods.7
Another class of glycan-mimetics is based on the modification
of the anomeric position and has been dominated by the
Figure 1. Oligohydroxylamines and oligophostones oligomers as
glycan mimetics.
With regard to the synthesis of the oligophostones,11,12 we
have directed our attention to the use of coupling methods
functioning at the P(III) oxidation level in view of their well-
known superiority over P(V)-based methods in the nucleotide
field.13 In particular, we have focused our efforts on the use of
the P-chiral phosphonite-boranes, air-stable analogues of the H-
phosphinates,14 as phostone donors and have described
methods for their stereoselective synthesis and for the
formation of mimetics of three of the four major classes of
glycosidic bond (1,2-trans-equatorial, 1,2-trans-axial, and 1,2-cis-
equatorial; Figure 2).15 Continuing this theme, we present here
Received: April 22, 2013
Published: June 21, 2013
© 2013 American Chemical Society
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an improved synthesis of the phosphonite-boranes and the
synthesis of novel diphostones.
level, albeit with no success and degradation of the substrate.
The more nucleophilic 4-methoxythiophenate anion resulted
unexpectedly in the total deborylation of the phosphonite-
borane, yielding the two gluco- and manno- configurated P-
chiral phosphonites 5gα and 5mα as air-stable compounds
(Scheme 3).19 Classical conditions for the removal of a methyl
Scheme 3. Deborylation of an Ethyl Phosphonite Borane by
Thiolate Anion
Figure 2. Three accessible classes of phostones.
RESULTS AND DISCUSSION
■
Gram scale reaction of the lithium salt of diethoxyphosphine-
borane16 with the glucal-derived aldehydo formate 1 in THF at
−78 °C resulted in a 68% yield of the readily separable diols 2g
and 2m with a dr of 45/55 favoring the glucoisomer (Scheme
1). Under the optimized conditions byproducts arising from the
group at P(V) oxidation level involving the action of TMSBr11c
left the starting material unchanged. The use of sodium iodide
in refluxing acetonitrile11d was successful in partial de-
ethylation, but was accompanied by deborylation and, more
problematically, by the loss of the chiral information at the
phosphorus atom.
Scheme 1. Reaction of Lithio Diethoxyphosphine-Borane
with a Glucal-Derived Aldehyde
The problematic de-ethylation step was circumvented by a
transesterification to the corresponding methyl phosphonite-
boranes (Table 1) and eventual known demethylation.10 The
Table 1. Cyclization with Concomitant Ester Exchange
retention of a formate group and/or premature cyclization were
present in only trace amounts after work up of the initial
reaction mixture.
Base-catalyzed cyclization was performed with the aid of
catalytic sodium ethoxide in ethanol and provided the α- or β-
manno- or glucophosphonites from linear 2g or 2m,
respectively (Scheme 2). Depending on the reaction time and
entry
dep
t (min)
3α/6α
1
2
3
4
5
6
7
8
2g
15
55
100/0
59/41
47/53
39/61
75/25
57/43
35/65
0/100
Scheme 2. Formation of Cyclic Phosphonite Boranes
2g
2g
105
225
15
2g
2m
2m
2m
2m
40
105
20 h
more direct formation of the methyl phosphonite-boranes by
reaction of the aldehydo formate 1 with the lithium salt of
dimethoxyphosphine-borane followed by cyclization was not
attempted because of the unstable and pyrophoric nature of the
necessary phosphine.20 Cyclization of ethyl phosphonite-
boranes 2g and 2m in methanol in the presence of sodium
methoxide afforded the desired cyclic methyl phosphonates 6
(Table 1). Monitoring of this reaction with LC−MS revealed
the relative kinetics of cyclization and equilibration to methyl
phosphonites. For the glucoisomer 2g, the cyclization occurred
very rapidly and was followed by slower transesterification of
3gα to the methyl isomer 6gα. Consequently, under most
conditions the product was obtained as a separable mixture of
ethyl and methyl phosphonites, each in the form of a single α-
diastereoisomer. However, with more concentrated reaction
conditions, it was possible to fully exchange the ethyl group to
the methyl group, enabling isolation of 6gα in 54% yield. For
the mannoisomer, the cyclization took place very rapidly, and
equilibration to the methyl phosphonate 6mα was complete
base concentration, the product 3g was obtained as a mixture of
two diastereoisomers in 90% yield. However, upon standing (3
h), this mixture equilibrates to the more stable α-isomer 3gα,
isolated as a single diastereoisomer in 62% yield.17 In a similar
manner, the manno- precursor 2m furnished the desired
cyclized compound 3mα as a single diastereoisomer in 83%
yield. X-ray crystallographic analysis of 3gα provided the
anomeric stereochemistry (see the Supporting Information),
and acetylation furnished the corresponding esters 4gα, 4gβ
and 4mα in good yields.
De-ethylation of 4gα or 4mα to give the requisite
phosphonite-boranes was attempted under the conditions
known for methyl removal (PhSH, Et3N)18 at the P(III)
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after 20 h,21 providing the methyl phosphonite-borane 6mα in
83% yield. Both compounds 6gα and 6mα were crystalline, and
X-ray analysis confirmed the α-stereochemistry at phosphorus
(see the Supporting Information).
Table 2. Influence of the 2-O-Protecting Group and
Reaction Conditions on Coupling Stereoselectivity
The glucoconfigured methyl phosphonite-borane 6gα was
converted to the corresponding 2-O-acetyl, methoxymethyl,
and allyl derivatives in 75, 99, and 58% yield, respectively,
under standard conditions, and subsequent treatment with
thiophenol and triethylamine18 furnished the three correspond-
ing ammonium phosphonite-boranes 10gα, 11gα, and 12gα in
good yields (Scheme 4). In a similar manner, the mannoisomer
Scheme 4. Formation and Isolation of Ammonium
a
Phosphonite-Boranes
a
entry
R
amine/solvent
α/β ratio
yield (%)
1
2
MOM
MOM
MOM
MOM
MOM
MOM
Ac
NT/THF
0.4/1
0.2/1
−
15
28
0
NT/PhMe
3
NT/CH2Cl2
DMAP/THF
DMAP/PhMe
DMAP/CH2Cl2
DMAP/CH2Cl2
NT/THF
b
4
0.1/1
45
b
5
0/1
66
b
6
1.7/1
0.2/1
0.6/1
0.2/1
2/1
62
b
7
68
c
8
All
ND
c
9
All
DMAP/PhMe
DMAP/CH2Cl2
ND
c
a
10
All
ND
(a) Ac2O, I2 cat. (b) NaHMDS, MOMCl, THF, 0 °C. (c) NaHMDS,
a
b
c
AllBr, THF, 0 °C.
Isolated yields. α/β ratio was measured after m-CPBA oxidation. α/
β ratio was measured by 31P NMR on the crude reaction mixture.
6mα was converted to the ammonium phosphonite-borane
10mα via acetylation and demethylation in 86 and 91% yield,
respectively. Overall, the gluco- and manno-phosphonite-
boranes 10gα and 10mα, whose spectral data agree fully with
that of the samples prepared earlier by the original route,10,22
are obtained by this approach in only four steps (global yield
17−20%) from the aldehyde 1.
glucose series. To confirm this tendency, 10gα was reacted with
13a in the DMAP/CH2Cl2 conditions, leading to the β adduct,
and confirming the influence of the anchimeric assistance. With
a 2-O-allyl ether 12gα, the β isomer 16gβ was obtained as the
major component under both NT/THF and DMAP/PhMe
conditions (Table 2, entries 8 and 9). Gratifingly, however, the
DMAP/CH2Cl2 system favored again the α-diastereoisomer
16gα (Table 2, entry 10).
Turning to the synthesis of diphostones, the glucophostone
19gα10 was selectively debenzylated at the 6-position with
concomitant acetylation by the action of acetic anhydride in the
presence of trifluoroacetic acid,25 and exposure of the crude
reaction mixture to molecular sieves26 in methanol27 furnished
a separable mixture of mono- and di-deprotected compounds
21gα and 22gα in a 61% overall yield for both steps. In the
same manner, the mannophostone 19mβ10 was selectively
debenzylated and acetylated at the 6-position to furnish the
diacetate 20mβ in 90% yield. In this case, epimerization at
phosphorus could not be avoided during the deprotection by
sodium methoxide, and we obtained a separable mixture of
diols 21mα and 21mβ in 93% yield (Scheme 5).28
The key coupling step was accomplished by reaction of the
phosphonite-borane 10gα with alcohol 22gα under the
conditions previously established, in the presence of BOPCl
and DMAP in THF, affording the targeted dimer 23gβ in 77%
yield after m-CPBA oxidation. When diol 21gα was employed
as acceptor under the same conditions, the yield of diphostone
24gβ dropped to a nevertheless respectable 58%. In both cases,
coupling proceeded with complete β-stereoselectivity at
phosphorus and, most notably, with total regioselectively for
the 6-position of 21g−22g. In the same manner, reaction of
10gα with diol 21mβ furnished stereoselectively and
regioselectively the mixed β-(1→6)-gluco-mannophostone
dimer 25gβ in 63% yield (Scheme 6).
With an improved synthesis of the ammonium phosphonite-
boranes 10−12 in hand, we briefly turned our attention to the
influence of the 2-O-protecting group on coupling stereo-
selectivity and to the preparation of phostone dimers. The new
strategy for the preparation of phosphonite-boranes presented
here afforded the opportunity for the synthesis of 2-O-allyl and
MOM-protected phosphonite-boranes and thus the chance to
explore the influence of these protecting groups on coupling
selectivity.23 The reaction of the novel phosphonite-boranes
11gα and 12gα with alcohols 13 was investigated in the
presence of BOPCl, 3-nitro-1,2,4-triazole (NT) or DMAP as
the amine catalyst in various solvents (Table 2) and the α/β
1
ratios of the coupled products were measured by 31P or H
NMR of the crude reaction mixtures. In some cases, to
circumvent problems of partial deborylation of the products,
the crude coupling reaction mixtures were treated with m-
CPBA before isolation so as to afford the more stable P(V)
oxidation state.24 The MOM-protected compound showed
moderate β-diastereoselectivity and reactivity with NT in THF
and PhMe (Table 2, entries 1 and 2) but did not furnish any
coupling product in CH2Cl2 (Table 2, entry 3). With the
DMAP as the nucleophilic partner in THF and PhMe (Table 2,
entries 4 and 5), the equatorial product 15gβ predominates,
corresponding to a preponderance of inversion in accordance
with our previous findings in the 2-O-acetyl series.10 On the
other hand, the DMAP/CH2Cl2 system furnished the axial
compound as the major diastereoisomer (15gβ/15gα: 1/1.7),
thereby providing the first entry to this configuration in the
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capillary tubes and are uncorrected. High resolution mass spectra
(HRMS) were determined by electrospray ionization (ESI).
Scheme 5. Regioselective Monodebenzylation of Tri-O-
benzylphostones
Diethyl ((1R,2S,3R,4R)-2,3,5-tris(benzyloxy)-1,4-dihydroxy-
pentyl)phosphonite-borane 2m and Diethyl ((1S,2S,3R,4R)-
2,3,5-tris(benzyloxy)-1,4-dihydroxypentyl)phosphonite-bor-
ane 2g. To a solution of diethoxyphosphine-borane (4.08 g, 30
mmol) in THF (40 mL) at −78 °C under an argon atmosphere was
added dropwise n-BuLi (17.5 mL, 25 mmol, 1.43 M solution in
hexane) over 30 min. The resulting solution was stirred for 30 min,
and the addition of the solution of aldehyde 1 (4.48 g, 10 mmol) in
THF (30 mL) was performed dropwise over a 45 min period. The
resulting solution was stirred for 1 h 30 min at −78 °C, quenched by
addition of an aqueous solution of HCl (2 M), and extracted twice by
methyl tert-butylether (MTBE). The combined organic layers were
washed by brine, dried over MgSO4, filtered and concentrated under a
vacuum. The crude mixture was purified by chromatography on silica
gel (eluent: EtOAc/heptane, 1/4), yielding the two diastereoisomers
2m (1.70 g, 3.06 mmol, 31%) and 2g (2.07 g, 3.72 mmol, 37%) as
Scheme 6. Formation of Diphostones
colorless oils. Data for 2m: Rf = 0.15 (EtOAc/heptane, 1:4); [α]24
=
D
+0.22 (c 1.4, CHCl3); IR (neat) νmax 3428, 3031, 2982, 2906, 2869,
2392, 1497, 1454, 1391, 1363, 1069, 1026 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.39−7.25 (m, 15H), 4.70 (d, J = 11.2 Hz, 1H), 4.65 (d, J =
10.8 Hz, 1H), 4.61 (d, J = 10.9 Hz, 1H), 4.55 (d, J = 11.2 Hz, 1H),
4.53 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H), 4.29 (t, J = 6.1
Hz, 1H), 4.20−4.01 (m, 7H), 3.64−3.55 (m, 2H), 1.30 (t, J = 7.1 Hz,
3H), 1.22 (t, J = 7.1 Hz, 3H), 1.16−0.00 (br s, 3H); 13C NMR (75.5
MHz, CDCl3) δ 138.0 (Cq), 137.6 (Cq), 137.5 (Cq), 128.7 (2× CH),
128.6 (2× CH), 128.6 (2× CH), 128.5 (2× CH), 128.4 (CH), 128.2
(3× CH), 128.0 (CH), 79.4 (d, J = 4.4 Hz, CH), 76.4 (d, J = 11.0 Hz,
CH), 73.7 (CH2), 73.2 (CH2), 72.6 (CH2), 71.4 (d, J = 63.1 Hz, CH),
71.2 (CH2), 70.3 (CH), 64.3 (CH2), 64.2 (CH2), 16.7 (d, J = 5.5 Hz,
CH3), 16.6 (d, J = 5.5 Hz, CH3). 31P NMR (122 MHz, CDCl3) δ
140.0−139.0 (m); HRMS (ESI-TOF) calcd for C30H42BO7PNa [M +
Na]+ 579.2659, found 579.2665. Data for 2g: Rf = 0.13 (EtOAc/
CONCLUSION
■
In conclusion, we have established a novel strategy for the
efficient synthesis of P-chiral phosphonite-boranes, which are
key intermediates in the stereoselective synthesis of glycomi-
metics. This strategy is considerably shorter than our previous
route and offers a la carte access to differently protected gluco-
and manno-H-phosphinates. The gluco-configured phosphon-
ite-borane 10gα was suscessfully engaged in the synthesis of β-
(1→6)-pseudodisaccharides 23−25 containing two phostone
rings, potential mimetics of the Glu-β-(1→6)-Glu and Glu-β-
(1→6)-Man disaccharides.
heptane, 1:4); [α]24 = +1.63 (c 1.0, CHCl3); IR (neat) νmax 3507,
D
3031, 2982, 2906, 2868, 2384, 1454, 1391, 1363, 1071, 1022 cm−1; 1H
NMR (300 MHz, CDCl3) δ 7.36−7.25 (m, 13H), 7.23−7.17 (m, 2H),
4.70 (s, 2H), 4.57 (d, J = 11.2 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.48
(d, J = 11.9 Hz, 1H), 4.43 (d, J = 11.2 Hz, 1H), 4.24 (dd, J = 1.1 and
4.0 Hz, 1H), 4.22−4.01 (m, 6H), 3.75 (ddd, J = 2.1 and 5.0 and 7.3
Hz, 1H) 3.70−3.58 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1
Hz, 3H), 1.20−(−0.15) (br s, 3H); 13C NMR (75 MHz, CDCl3) δ
138.2 (Cq), 137.8 (Cq), 137.6 (Cq), 128.6 (6× CH), 128.4 (3× CH),
128.2 (CH), 128.1 (CH), 128.0 (3× CH), 127.9 (CH), 77.0 (d, J =
11.5 Hz, CH), 76.2 (d, J = 6.6 Hz, CH), 74.1 (CH2), 73.6 (2× CH2),
71.7 (CH), 71.1 (CH2), 70.1 (d, J = 62.6 Hz, CH), 64.3 (d, J = 4.9 Hz,
CH2), 64.2 (d, J = 5.5 Hz, CH2), 16.7 (d, J = 5.5 Hz, CH3), 16.6 (d, J =
5.5 Hz, CH3). 31P NMR (122 MHz, CDCl3) δ 140.5−138.5 (m);
HRMS (ESI-TOF) calcd for C30H42BO7PNa [M + Na]+ 579.2659,
found 579.2683.
EXPERIMENTAL SECTION
■
General Information. Reactions were performed using oven-dried
glassware under an atmosphere of argon. All separations were carried
out under flash-chromatographic conditions on silica gel (prepacked
column, 230−400 mesh) at medium pressure (20 psi). Reactions were
monitored by thin-layer chromatography on silica gel plates (60 F254
aluminum sheets), which were rendered visible by ultraviolet and/or
spraying with phosphomolybdic acid (10%) in EtOH or vanillin (15%)
+ sulfuric acid (2.5%) in EtOH followed by heating. THF, CH2Cl2,
DMF, MeOH and MTBE (i.e., methyl tert-butyl ether) were
purchased at the highest commercial quality and used without further
purification. Reagent-grade chemicals were obtained from diverse
commercial suppliers and were used as received. 1H NMR (500 or 300
MHz) and 13C NMR (125 or 75 MHz) spectra were recorded at 298
K. Chemical shifts are given in ppm (δ) and are referenced to the
internal solvent signal or to TMS used as an internal standard.
Multiplicities are declared as follows: s (singlet), brs (broad singlet), d
(doublet), t (triplet), q (quadruplet), dd (doublet of doublet), ddd
(doublet of doublet of doublet), dt (doublet of triplet), m (multiplet),
AB = AB quartet, ABX = ABX system. Coupling constants J are given
in Hz. Carbon multiplicities were determined by DEPT135 experi-
ment. Diagnostic correlations were obtained by two-dimensional
COSY, HSQC and HMBC experiments. Infrared spectra (IR) were
recorded on a FT-IR system and the data are reported in reciprocal
centimeters (cm−1). [α]t (°C)D is expressed in deg cm3 g−1 dm−1, and c
is expressed in g/100 cm3. Melting points were recorded in open
(2S,3S,4S,5S,6R)-2-Boranyl-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-ethoxy-1,2-oxaphosphinan-3-ol 3gα. To a sol-
ution of phosphonate 2g (380 mg, 0.68 mmol) in dry EtOH (3 mL)
was added EtONa (10 wt % solution in EtOH, 3 drops). The resulting
solution was stirred at room temperature for 1 h. Dowex H+ was then
added, and the mixture was further stirred for 10 min, filtered, and
evaporated under a vacuum. The crude mixture was purified by
column chromatography on silica gel (eluent: EtOAc/heptane, 1:4),
yielding the product as an unseparable mixture of two diastereoisomers
3gαβ (313 mg, 0.61 mmol, 90%). Pure 3gα was obtained when the
reaction was performed in similar manner from 2g (60 mg, 0.108
mmol) during 3 h, furnishing 3gα (34 mg, 0.067 mmol, 62%): Rf =
0.32 (EtOAc/heptane, 1:2); mp 85.7−86.5 °C; [α]23 = +68.2 (c 1.0,
D
CHCl3); IR (neat) νmax 3479, 3031, 2983, 2908, 2869, 2397, 1454,
1
1361, 1106, 1057, 1026, 962, 734, 696 cm−1; H NMR (500 MHz,
CDCl3) δ 7.37−7.26 (m, 13H), 7.20−7.13 (m, 2H), 4.92 (d, J = 11.2
Hz, 1H), 4.84 (d, J = 10.6 Hz, 1H), 4.84 (d, J = 11.2 Hz, 1H), 4.62 (d,
J = 12.0 Hz, 1H), 4.60 (d, J = 10.6 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H),
4.26−4.16 (m, 3H), 3.98−3.89 (m, 2H), 3.84 (dd, J = 3.5 and 11.2 Hz,
1H), 3.76 (t, J = 9.6 Hz, 1H), 3.73 (dd, J = 1.9 and 11.3 Hz, 1H), 1.34
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(t, J = 7.1 Hz, 3H), 0.98−0.13 (br s, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.3 (Cq), 137.9 (Cq), 137.8 (Cq), 128.8 (2× CH), 128.7
(2× CH), 128.6 (2× CH), 128.2 (2× CH), 128.2 (2× CH), 128.1 (2×
CH), 128.0 (2× CH), 128.0 (CH), 82.9 (d, J = 1.1 Hz, CH), 77.5
(CH), 76.7 (d, J = 11.0 Hz, CH), 76.4 (CH2), 75.8 (CH2), 73.9
(CH2), 71.7 (d, J = 58.7 Hz, CH), 68.9 (d, J = 7.3 Hz, CH2), 65.4 (d, J
= 2.7 Hz, CH2), 16.8 (d, J = 4.6 Hz, CH3). 31P NMR (122 MHz,
CDCl3) δ 132.0 (br s); HRMS (ESI-TOF) calcd for C28H36BNaO6P
[M + Na]+ 533.2240, found 533.2221.
(m, 2H), 5.46 (dd, J = 9.1 and 10.5 Hz, 1H), 4.87 (d, J = 11.2 Hz, 1H),
4.83 (d, J = 10.6 Hz, 1H), 4.70 (d, J = 11.4 Hz, 1H), 4.65 (d, J = 12.1
Hz, 1H), 4.61 (d, J = 10.6 Hz, 1H), 4.57 (d, J = 12.1 Hz, 1H), 4.32−
4.16 (m, 3H), 4.09 (dt, J = 2.4 and 10.4 Hz, 1H), 3.89 (t, J = 9.7 Hz,
1H), 3.87 (dd, J = 5.2 and 11.5 Hz, 1H), 3.76 (dd, J = 1.9 and 12.2 Hz,
1H), 2.00 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.00−(−0.13) (br s, 3H);
13C NMR (75 MHz, CDCl3) δ 169.1 (d, J = 3.3 Hz, Cq), 138.1 (Cq,),
137.9 (Cq), 137.6 (Cq), 128.7 (2× CH), 128.6 (5× CH), 128.2 (2×
CH), 128.0 (2× CH), 128.0 (2× CH), 127.7 (2× CH), 80.9 (CH),
77.8 (CH), 76.9 (d, J = 11.0 Hz, CH), 76.1 (CH2), 75.9 (CH2), 73.8
(CH2), 70.1 (d, J = 57.1 Hz, CH), 68.7 (d, J = 7.7 Hz, CH2), 65.3 (d, J
= 2.2 Hz, CH2), 20.6 (CH3), 16.7 (d, J = 4.4 Hz, CH3). 31P NMR (122
MHz, CDCl3) δ 131.7−129.8 (m); HRMS (ESI-TOF) calcd for
C30H42BNO7P [M + NH4]+ 570.2792, found 570.2784.
(2S,3R,4S,5S,6R)-2-Boranyl-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-ethoxy-1,2-oxaphosphinan-3-yl acetate 4mα.
To a solution of alcohol 3mα (23 mg, 0.045 mmol) in Ac2O (1
mL) was added a catalytic amount of I2 (1 mg). The resulting mixture
was stirred at room temperature for 24 h. It was then quenched by
careful addition of saturated aqueous NaHCO3 and stirred for 30 min.
The mixture was then extracted twice by EtOAc. Combined organic
layers were washed by brine, dried over MgSO4, filtered and
concentrated under a vacuum, yielding the acetate 4mα (24 mg,
0.0435 mmol, 97%): Rf = 0.29 (EtOAc/heptane, 1:3); [α]24D = +4.7 (c
1.9, CHCl3); IR (neat) νmax 3064, 3031, 2934, 2405, 1753, 1497, 1454,
1368, 1216, 1095, 1052, 1021, 967 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.39−7.28 (m, 13H), 7.23−7.16 (m, 2H), 5.79 (t, J = 2.9
Hz, 1H), 4.90 (d, J = 10.5 Hz, 1H), 4.77 (d, J = 10.9 Hz, 1H), 4.70 (d,
J = 12.1 Hz, 1H), 4.60 (d, J = 12.1 Hz, 1H), 4.56 (d, J = 10.8 Hz, 1H),
4.55 (d, J = 11.0 Hz, 1H), 4.28−4.15 (m, 3H), 4.12 (dd, J = 3.1 and
9.6 Hz, 1H), 4.00 (t, J = 9.8 Hz, 1H), 3.91 (dd, J = 3.8 and 10.9 Hz,
1H), 3.79 (dd, J = 1.7 and 11.3 Hz, 1H), 2.21 (s, 3H), 1.34 (t, J = 7.1
Hz, 3H), 1.09−(−0.10) (br s, 3H); 13C NMR (75 MHz, CDCl3) δ
169.9 (d, J = 3.7 Hz, Cq), 138.2 (Cq), 137.9 (Cq), 137.4 (Cq), 128.7
(2× CH), 128.6 (2× CH), 128.6 (2× CH), 128.5 (2× CH), 128.3
(CH), 128.2 (CH), 128.0 (2× CH), 127.9 (CH), 78.4 (CH), 77.9 (d,
J = 11.9 Hz, CH), 76.0 (CH2), 73.9 (d, J = 3.7 Hz, CH), 73.8 (CH2),
72.0 (CH2), 69.3 (d, J = 7.3 Hz, CH2), 66.2 (d, J = 63.2 Hz, CH), 65.1
(d, J = 2.7 Hz, CH2), 21.0 (CH3), 16.7 (d, J = 4.6 Hz, CH3). 31P NMR
(122 MHz, CDCl3) δ 133.8−130.0 (m); HRMS (ESI-TOF) calcd for
C30H42BNO7P [M + NH4]+ 570.2792, found 570.2787.
(2S,3R,4S,5S,6R)-2-Boranyl-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-ethoxy-1,2-oxaphosphinan-3-ol 3gα. To a sol-
ution of phosphonate 2m (330 mg, 0.59 mmol) in dry EtOH (2.5 mL)
was added EtONa (10 wt % solution in EtOH, 3 drops). The resulting
solution was stirred at room temperature for 1 h. Dowex H+ was then
added, and the mixture was further stirred for 10 min, filtered, and
evaporated under a vacuum. The crude mixture was purified by
column chromatography on silica gel (eluent: EtOAc/heptane, 1:4),
yielding the product 3gα as a colorless solid (250 mg, 0.49 mmol,
83%): Rf = 0.32 (EtOAc/heptane, 1:2); [α]23D = +38.8 (c 1.0, CHCl3);
IR (neat) νmax 3345, 3064, 3031, 2906, 2869, 2396, 1454, 1364, 1094,
1025, 967 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.26 (m, 13H),
7.20−7.15 (m, 2H), 4.86 (d, J = 10.6 Hz, 1H), 4.71 (s, 2H), 4.64 (d, J
= 12.1 Hz, 1H), 4.56 (d, J = 12.1 Hz, 1H), 4.55 (d, J = 10.6 Hz, 1H),
4.20−4.10 (m, 4H), 4.04 (t, J = 9.5 Hz, 1H), 4.02 (dd, J = 2.8 and 9.3
Hz, 1H), 3.82 (dd, J = 4.3 and 11.2 Hz, 1H), 3.82 (dd, J = 1.6 and 11.2
Hz, 1H), 2.84−2.19 (br s, 1H), 1.29 (t, J = 6.9 Hz, 3H), 0.98−0.13 (br
s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.1 (Cq), 137.9 (Cq), 137.5
(Cq), 128.8 (2× CH), 128.6 (2× CH), 128.6 (2× CH), 128.3 (CH),
128.3 (2× CH), 128.2 (2× CH), 128.1 (CH), 128.0 (2× CH), 127.9
(CH), 80.0 (d, J = 1.8 Hz, CH), 77.7 (d, J = 11.0 Hz, CH), 76.0
(CH2), 73.8 (CH2), 73.5 (d, J = 3.7 Hz, CH), 72.6 (CH2), 69.3 (d, J =
7.3 Hz, CH2), 67.2 (d, J = 62.3 Hz, CH), 64.7 (d, J = 3.7 Hz, CH2),
16.7 (d, J = 4.6 Hz, CH3). 31P NMR (122 MHz, CDCl3) δ 133.4 (br
s); HRMS (ESI-TOF) calcd for C28H40BNO6P [M + NH4]+ 528.2686,
found 528.2664.
(2S,3S,4S,5S,6R)-2-Boranyl-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-ethoxy-1,2-oxaphosphinan-3-yl acetate 4gα
and (2R,3S,4S,5S,6R)-2-Borane-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-ethoxy-1,2-oxaphosphinan-3-yl acetate 4gβ.
To a mixture of both diastereoisomers 3gα and 3gβ (300 mg, 0.588
mmol) in Ac2O (2 mL) was added a catalytic amount of I2 (10 mg).
The resulting mixture was stirred at room temperature for 6 h. It was
then quenched by careful addition of saturated aqueous NaHCO3 and
stirred for 30 min. The mixture was then extracted twice by EtOAc.
Combined organic layers were washed by brine, dried over MgSO4,
filtered and concentrated under a vacuum. The crude mixture was
purified by chromatography on silica gel (eluent: EtOAc/heptane, 1/
3), yielding the two diastereoisomers 4gβ (89 mg, 0.165 mmol, 28%)
and 4gα (122 mg, 0.23 mmol, 39%) as colorless oils. Data for 4gβ: Rf
(2S,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-((benzyloxy)methyl)-
2-ethoxy-1,2-oxaphosphinan-3-yl acetate 5gα. To a solution of
phosphonite-borane 4gα (120 mg, 0.21 mmol) in THF (2 mL) was
added Et3N (603 μL, 4.35 mmol) and thiophenol (609 mg, 4.35
mmol). The resulting solution was stirred at 45 °C for 20 h. It was
then concentrated under a vacuum and purified by column
chromatography on silica gel (eluent: EtOAc/heptane, 1:7), yielding
the phosphonite 5gα as a colorless oil (68 mg, 0.07 mmol, 33%): Rf =
0.30 (EtOAc/heptane, 1:3); [α]24D = +184.0 (c 0.3, CHCl3); IR (neat)
= 0.44 (EtOAc/heptane, 1:2); [α]24 = +51.6 (c 1.0, CHCl3); IR
D
1
νmax 3032, 2929, 1744, 1454, 1369, 1230, 1089, 1043 cm−1; H NMR
(neat) νmax 3064, 3031, 2925, 2870, 2398, 1750, 1454, 1368, 1219,
1054, 1025, 971 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.40−7.25 (m,
13H), 7.20−7.15 (m, 2H), 5.35 (dd, J = 8.5 and 8.9 Hz, 1H), 4.85 (d, J
= 11.7 Hz, 1H), 4.84 (d, J = 11.5 Hz, 1H), 4.74 (d, J = 11.5 Hz, 1H),
4.61 (d, J = 12.0 Hz, 1H), 4.61 (d, J = 10.7 Hz, 1H), 4.53 (d, J = 12.0
Hz, 1H), 4.29−4.11 (m, 3H), 4.05 (dt, J = 2.6 and 9.2 Hz, 1H), 4.00
(t, J = 9.4 Hz, 1H), 3.86 (dt, J = 2.7 and 11.0 Hz, 1H), 3.75 (dd, J = 2.1
and 11.1 Hz, 1H), 2.05 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.00−
(−0.13) (br s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.8 (d, J = 2.7
Hz, Cq), 138.0 (Cq), 137.9 (Cq), 137.8 (Cq), 128.7 (6× CH), 128.2
(CH), 128.1 (2× CH), 128.1 (2× CH), 127.9 (2× CH), 127.8 (2×
CH), 82.2 (d, J = 11.0 Hz, CH), 76.9 (d, J = 5.5 Hz, CH), 76.9 (d, J =
1.6 Hz, CH), 75.7 (CH2), 75.7 (CH2), 73.8 (CH2), 71.8 (d, J = 50.0
Hz, CH), 68.8 (d, J = 7.1 Hz, CH2), 65.0 (d, J = 5.5 Hz, CH2), 20.8
(CH3), 16.5 (d, J = 5.5 Hz, CH3). 31P NMR (122 MHz, CDCl3) δ
140.1−137.3 (m); HRMS (ESI-TOF) calcd for C30H42BNO7P [M +
NH4]+ 570.2792, found 570.2784. Data for 4gα: Rf = 0.26 (EtOAc/
(300 MHz, CDCl3) δ 7.39−7.20 (m, 13H), 7.20−7.10 (m, 2H), 4.99
(dd, J = 10.4 and 25.6 Hz, 1H), 4.83 (d, J = 11.3 Hz, 1H), 4.82 (d, J =
10.5 Hz, 1H), 4.72 (d, J = 11.3 Hz, 1H), 4.64 (d, J = 12.2 Hz, 1H),
4.54 (d, J = 11.8 Hz, 2H), 4.28−4.19 (m, 1H), 4.15 (t, J = 10.3 Hz,
1H), 4.04−3.91 (m, 2H), 3.84 (dd, J = 3.7 and 10.8 Hz, 1H), 3.75 (t, J
= 9.6 Hz, 1H), 3.68 (dd, J = 2.0 and 10.5 Hz, 1H), 2.00 (s, 3H), 1.28
(t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.3 (d, J = 3.7
Hz, Cq), 138.8 (Cq), 138.2 (2× Cq), 128.6 (2× CH), 128.6 (3× CH),
128.5 (2× CH), 128.2 (2× CH), 128.0 (2× CH), 127.8 (CH), 127.7
(CH), 127.7 (2× CH), 81.0 (CH), 78.4 (CH), 75,9 (CH2), 75.7
(CH2), 74.8 (d, J = 114.2 Hz, CH), 73.9 (CH), 73.7 (CH), 65.9 (d, J
= 22 Hz, CH2), 20.9 (CH3), 17.6 (d, J = 5.5 Hz, CH3). 31P NMR (122
MHz, CDCl3) δ 145.5; HRMS (ESI-TOF) calcd for C30H36PO7 [M +
H]+ 539.2199, found 539.2141.
(2S,3R,4S,5S,6R)-4,5-Bis(benzyloxy)-6-((benzyloxy)methyl)-
2-ethoxy-1,2-oxaphosphinan-3-yl acetate 5mα. To a solution of
phosphonite-borane 4mα (143 mg, 0.26 mmol) in THF (2.5 mL) was
added Et3N (720 μL, 5.18 mmol) and thiophenol (725 mg, 5.18
mmol). The resulting solution was stirred at 45 °C for 20 h. It was
heptane, 1:3); [α]24 = +94.2 (c 1.2, CHCl3); IR (neat) νmax 3064,
D
3031, 2936, 2870, 2400, 1760, 1454, 1368, 1215, 1054, 1025, 977
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.40−7.22 (m, 13H), 7.20−7.10
6862
dx.doi.org/10.1021/jo400864s | J. Org. Chem. 2013, 78, 6858−6867

The Journal of Organic Chemistry
Featured Article
1
then concentrated under a vacuum and purified by column
chromatography on silica gel (eluent: EtOAc/heptane, 1:7), yielding
the phosphonite 5mα as a colorless oil (93 mg, 0.173 mmol, 66%): Rf
1050, 1026, 974, 735, 698 cm−1; H NMR (500 MHz, CDCl3) δ
7.35−7.25 (m, 13H), 7.19−7.13 (m, 2H), 4.84 (d, J = 10.7 Hz, 1H),
4.69 (s, 2H), 4.62 (d, J = 11.9 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.53
(d, J = 10.7 Hz, 1H), 4.21−4.17 (m, 1H), 4.14−4.09 (m, 1H), 4.05 (t,
J = 9.2 Hz, 1H), 3.99 (dd, J = 9.2 and 2.7 Hz, 1H), 3.80 (dd, J = 11.3
and 4.0 Hz, 1H), 3.74 (d, J = 11.0 Hz, 3H), 3.77−3.69 (m, 1H), 2.54
(d, J = 17.7 Hz, 1H), 0.96−0.18 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.0 (Cq), 137.9 (Cq), 137.5 (Cq), 128.8 (2× CH), 128.6
(2× CH), 128.6 (2× CH), 128.3 (CH), 128.2 (2× CH), 128.2 (2×
CH), 128.1 (CH), 128.1 (2× CH), 127.9 (CH), 80.0 (d, J = 2.2 Hz,
CH), 77.8 (d, J = 11.5 Hz, CH), 75.9 (CH2), 73.8 (CH2), 73.3 (d, J =
3.8 Hz, CH), 72.5 (CH2), 69.2 (d, J = 7.1 Hz, CH2), 66.9 (d, J = 63.1
Hz, CH), 54.5 (d, J = 3.3 Hz, CH3); 31P NMR (122 MHz, CDCl3) δ
137.7−134.7 (m); HRMS (ESI-TOF) calcd for C27H38BNO6P [M +
NH4]+ 514.2530, found 514.2551. Anal. Calcd for C27H34BO6P: C,
65.34; H, 6.90. Found: C, 65.35; H, 6.86. In some cases, the β isomer
was isolated and characterized. Data for 6mβ: Rf = 0.17 (EtOAc/
heptane 1:3); [α]26D = +7.2 (c 0.5, CHCl3); IR (neat) νmax 3435, 3032,
= 0.33 (EtOAc/heptane, 1:3); [α]24 = +24.3 (c 0.8, CHCl3); IR
D
(neat) νmax 3031, 2929, 2893, 1743, 1454, 1368, 1228, 1093, 1040
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.41−7.23 (m, 13H), 7.19−7.10
(m, 2H), 5.42 (dd, J = 3.3 and 15.2 Hz, 1H), 4.86 (d, J = 10.5 Hz, 1H),
4.71 (d, J = 11.0 Hz, 1H), 4.68 (d, J = 12.2 Hz, 1H), 4.56 (d, J = 12.2
Hz, 1H), 4.51 (d, J = 11.0 Hz, 1H), 4.49 (d, J = 10.5 Hz, 1H), 4.25−
4.16 (m, 1H), 4.12 (dd, J = 3.4 and 9.6 Hz, 1H), 4.01−4.82 (m, 4H),
3.71 (dd, J = 1.9 and 10.9 Hz, 1H), 2.19 (s, 3H), 1.26 (t, J = 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 170.7 (d, J = 2.2 Hz, Cq), 138.5
(Cq), 138.4 (Cq), 138.2 (Cq), 128.5 (6× CH), 128.3 (2× CH), 128.2
(2× CH), 128.0 (2× CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 79.0
(CH), 75.8 (CH2), 75.0 (d, J = 7.7 Hz, CH), 74.7 (d, J = 4.9 Hz, CH),
73.7 (CH2), 71.9 (CH), 71.8 (CH2), 70.1 (d, J = 3.3 Hz, CH2), 65.6
(d, J = 20.9 Hz, CH2), 21.3 (CH3), 17.4 (d, J = 6.0 Hz, CH3). 31P
NMR (122 MHz, CDCl3) δ 146.5; HRMS (ESI-TOF) calcd for
C30H36PO7 [M + H]+ 539.2199, found 539.2189.
2924, 2379, 1454, 1072, 1029, 970, 737, 699 cm−1; H NMR (500
1
(2S,3S,4S,5S,6R)-2-Boranyl-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-methoxy-1,2-oxaphosphinan-3-ol 6gα. To a
solution of phosphonate 2g (542 mg, 0.9759 mmol) in dry MeOH
(7 mL) was added MeONa (25 wt % solution in MeOH, 30 drops).
The resulting solution was stirred at room temperature overnight.
Dowex H+ was then added, and the mixture was further stirred for 10
min, filtered, and evaporated under a vacuum. The crude mixture was
purified on silica gel (eluent: EtOAc/heptane 1:2), yielding the
product 6gα as a colorless oil (260 mg, 0.52 mmol, 54%): mp 85.2−
MHz, CDCl3) 7.36−7.24 (m, 13H), 7.23−7.18 (m, 2H), 4.72 (d, J =
11.2 Hz, 1H), 4.67 (d, J = 11.5 Hz, 1H), 4.62 (d, J = 11.3 Hz, 1H),
4.59−4.54 (m, 2H), 4.49 (d, J = 12.0 Hz, 1H), 4.33 (dd, J = 8.0 and
3.2 Hz, 1H), 4.31−4.25 (m, 1H), 4.12−4.07 (m, 1H), 4.04 (t, J = 7.4
Hz, 1H), 3.88 (d, J = 11.0 Hz, 3H), 3.85 (ddd, J = 10.9, 4.6, and 1.1
Hz, 1H), 3.77 (dd, J = 10.7 and 3.9 Hz, 1H), 2.61 (br s, 1H), 0.92−
0.09 (m, 3H); 13C NMR (125 MHz, CDCl3) 138.0 (Cq), 137.8 (Cq),
137.4 (Cq), 128.9 (2× CH), 128.7 (2× CH), 128.7 (2× CH), 128.5
(CH), 128.2 (3× CH), 128.1 (2× CH), 128,0 (CH), 128.0 (2× CH),
79.9 (d, J = 4.6 Hz, CH), 76.9 (d, J = 6.4 Hz, CH), 74.5 (CH2), 73.6
(CH2), 73.2 (d, J = 4.6 Hz, CH), 73.2 (CH2), 69.3 (d, J = 5.5 Hz,
CH2), 67.0 (d, J = 44.9 Hz, CH), 55.5 (d, J = 4.6 Hz, CH3); 31P NMR
(122 MHz, CDCl3) 138.0−136.1 ppm; HRMS (ESI-TOF) calcd for
C27H34BO6P [M + NH4]+ 514.2530, found 514.2528.
(2S,3S,4S,5S,6R)-2-Boranyl-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-methoxy-1,2-oxaphosphinan-3-yl acetate 7gα.
To a solution of phosphonate 6gα (148.5 mg, 0.30 mmol) in acetic
anhydride (2.4 mL) was added I2 (1.5 mg, 0.006 mmol, 2 mol %) and
dry pyridine (3 drops, cat). The resulting solution was stirred at room
temperature for 4 h. The reaction was quenched by a saturated
aqueous solution of Na2S2O3. A saturated solution of NaHCO3 and
EtOAc were added to the reaction mixture and stirred for 30 min. The
two layers were separated, and the aqueous layer was extracted twice
with EtOAc. Combined organic layers were dried over MgSO4, filtered
and evaporated. The crude mixture was purified on silica gel (eluent:
EtOAc/heptane 1:3), yielding the product 7gα as a colorless oil (151
mg, 0.28 mmol, 94%), which data correspond to those previously
reported.10
(2S,3R,4S,5S,6R)-2-Boranyl-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-methoxy-1,2-oxaphosphinan-3-yl acetate 7mα.
To a solution of phosphonate 6mα (467 mg, 0.94 mmol) in acetic
anhydride (7.3 mL) was added I2 (5.3 mg, 0.019 mmol, 2 mol %) and
dry pyridine (5 drops, cat). The resulting solution was stirred at room
temperature for 4.5 h. The reaction was quenched by a saturated
aqueous solution of Na2S2O3. A saturated solution of NaHCO3 and
EtOAc were added to the reaction mixture and stirred for 30 min. The
two layers were separated, and the aqueous layer was extracted twice
with EtOAc. Combined organic layers were dried over MgSO4, filtered
and evaporated. The crude mixture was purified on silica gel (eluent:
EtOAc/heptane 15:85), yielding the product 7mα as a colorless oil
(436 mg, 0.81 mmol, 86%), which data correspond to those previously
reported.10
(2S,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-((benzyloxy)methyl)-
2-boranyl-2-methoxy-3-(methoxymethoxy)-1,2-oxaphosphi-
nane 8gα. To a solution of 6gα (30 mg, 0.06 mmol) at −78 °C in
THF (0.6 mL) were added a solution of NaHMDS in THF (1M) (72
μL, 0.072 mmol, 1.2 equiv) and MOMCl (9.1 μL, 0,12 mmol, 2
equiv). The resulting mixture was stirred at −10 °C overnight. A
saturated solution of NH4Cl was added to the reaction, and the two
layers were separated. Aqueous layer was extracted three times with
EtOAc. Combined organic layers were washed by brine, dried over
87.0 °C; [α]23 = +74.6 (c 1.5, CHCl3); IR (neat) νmax 3490, 3064,
D
3031, 2921, 2869, 2398, 1454, 1361, 1106, 1056, 1026, 973, 736, 697
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.38−7.25 (m, 13H), 7.20−7.11
(m, 2H), 4.91 (d, J = 11.1 Hz, 1H), 4.84 (d, J = 10.5 Hz, 1H), 4.82 (d,
J = 11.1 Hz, 1H), 4.62 (d, J = 11.9 Hz, 1H), 4.60 (d, J = 10.5 Hz, 1H),
4.54 (d, J = 12.1 Hz, 1H), 4.22−4.13 (m, 1H), 3.99−3.89 (m, 2H),
3.87−3.79 (m, 1H), 3.83 (d, J = 10.9 Hz, 3H), 3.79−3.69 (m, 2H),
2.49−2.05 (br s, 1H), 1.22−(−0.08) (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.2 (Cq), 137.9 (Cq), 137.8 (Cq), 128.8 (2× CH), 128.7
(2× CH), 128.7 (2× CH), 128.2 (CH), 128.2 (CH), 128.1 (3× CH),
128.0 (2× CH), 128.0 (2× CH), 82.9 (d, J = 1.6 Hz, CH), 77.4 (CH),
76.7 (CH), 76.4 (CH2), 75.8 (CH2), 73.8 (CH2), 71.7 (d, J = 58.7 Hz,
CH), 68.8 (d, J = 7.1 Hz, CH2), 55.3 (d, J = 3.3 Hz, CH3); 31P NMR
(122 MHz, CDCl3) δ 136.6−133.3 (m); HRMS (ESI-TOF) calcd for
C27H38BNO6P [M + NH4]+ 514.2530, found 514.2532. In some cases,
the β isomer was isolated and characterized. Data for 6gβ: Rf = 0,17
(EtOAc/heptane, 1:3); [α]26D = +42.0 (c 0.7, CHCl3); IR (neat) νmax
1
3502, 3030, 2868, 2376, 1454, 1062, 1029, 969, 738, 698 cm−1; H
NMR (500 MHz, CDCl3) δ 7.34−7.29 (m, 13H), 7.18−7.16 (m, 2H),
4.86 (d, J = 11.2 Hz, 1H), 4.83 (d, J = 10.7 Hz, 1H), 4.81 (d, J = 11.2
Hz, 1H), 4.61−4.58 (m, 2H), 4.51 (d, J = 11.8 Hz, 1H), 4.23−4.19
(m, 1H), 3.93−3.87 (m, 3H), 3.86−3.83 (m, 1H), 3.82 (d, J = 11.3
Hz, 3H), 3.74 (dd, J = 11.0 and 2.4 Hz, 1H), 2.29 (br s, 1H), 0.86−
0.22 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 138.0 (Cq), 137.9 (Cq),
137.8 (Cq), 128.9 (2× CH), 128.7 (2× CH), 128.7 (2× CH), 128.3
(CH), 128.2 (3× CH), 128.1 (CH), 128.1 (2× CH), 128.0 (2× CH),
83.9 (d, J = 11.9 Hz, CH), 76.9 (CH), 76.7 (CH), 75.8 (CH2), 75.4
(CH2), 73.7 (CH2), 71.1 (d, J = 52.2 Hz, CH), 68.9 (d, J = 7.3 Hz,
CH2), 55.0 (d, J = 4.6 Hz, CH3); 31P NMR (122 MHz, CDCl3) δ
145.8−144.4 (m); HRMS (ESI-TOF) calcd for C27H38BNO6P [M +
NH4]+ 514.2530, found 514.2500.
(2S,3R,4S,5S,6R)-2-Boranyl-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-methoxy-1,2-oxaphosphinan-3-ol 6mα. To a
solution of phosphonate 2m (1.11 g, 1.98 mmol) in dry MeOH (14
mL) was added MeONa (10 wt % solution in EtOH, 30 drops). The
resulting solution was stirred at room temperature overnight. Dowex
H+ was then added, and the mixture was further stirred for 10 min,
filtered, and evaporated under a vacuum. The crude mixture was
purified by column chromatography on silica gel (eluent: EtOAc/
heptane, 1:2), yielding the product 6mα as a colorless solid (816 mg,
1.64 mmol, 83%): mp 71.1−72.7 °C; [α]23 = +52.0 (c 0.5, CHCl3);
D
IR (neat) νmax 3474, 3064, 3031, 2869, 2396, 1454, 1364, 1096, 1070,
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Featured Article
MgSO4, filtered and concentrated yielding 8gα as a colorless oil (32
mg, 0.06 mmol, 99%): Rf = 0.54 (EtOAc/heptane 3:7); [α]24D = +45.3
(c 0.5, CHCl3); IR (neat) νmax 3064, 3031, 2925, 2867, 2398, 1454,
1110, 1050, 1021, 993, 970, 749, 736, 697 cm−1; 1H NMR (500 MHz,
CDCl3) 7.37−7.23 (m, 13H), 7.14−7.07 (m, 2H), 4.89 (d, J = 11.3
Hz, 1H), 4.87−4.83 (m, 3H), 4.82 (d, J = 10.4 Hz, 1H), 4.61 (d, J =
11.9 Hz,1H), 4.58 (d, J = 10.7 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H),
4.19−4.13 (m, 1H), 4.08−4.01 (m, 2H), 3.85 (d, J = 11.0 Hz, 3H),
3.85−3.75 (m, 2H), 3.73 (dd, J = 11.3 and 1.2 Hz, 1H), 3.42 (s, 3H),
1.00−0.26 (m, 3H); 13C NMR (75 MHz, CDCl3) 138.2 (Cq), 137.9
(Cq), 137.7 (Cq), 128.7 (4× CH), 128.6 (2× CH), 128.1 (CH), 128.1
(2× CH), 128.0 (2× CH), 128.0 (CH), 127.9 (CH), 127.6 (2× CH),
98.3 (d, J = 3.3 Hz, CH2), 82.6 (CH), 77.7 (CH), 76.6 (d, J = 10.4 Hz,
CH), 76.5 (CH2), 75.9 (CH2), 74.9 (d, J = 56.5 Hz, CH), 73.8 (CH2),
MHz, CDCl3) 139.1 (Cq), 138.6 (Cq), 138.3 (Cq), 128.6 (2× CH),
128.5 (4× CH), 128.2 (2× CH), 128.1 (2× CH), 127.9 (CH), 127.7
(CH), 127.6 (2× CH), 127.5 (CH), 98.1 (d, J = 3.3 Hz, CH2), 83.9
(CH), 79.7 (CH), 78.6 (d, J = 49.4 Hz, CH), 75.9 (CH2), 75.6 (CH2),
73.7 (CH2), 72.6 (d, J = 8.8 Hz, CH), 70.6 (d, J = 7.1 Hz, CH2), 56.6
(CH3), 45.5 (CH2), 9.0 (CH3); 31P NMR (122 MHz, CDCl3) 102.8−
100.1 (m) ppm; HRMS (ESI-TOF) calcd for C28H35BO7P [M-
HNEt3]− 525.2219, found 525.2206.
Triethylammonium (2S,3S,4S,5S,6R)-3-(allyloxy)-4,5-bis-
(benzyloxy)-6-((benzyloxy)methyl)-2-boranyl-1,2-oxaphos-
phinan-2-olate 12gα. To a solution of 9gα (40.8 mg, 0.076 mmol)
in THF (0.8 mL) were added thiophenol (0.156 mL, 1.52 mmol, 20
equiv) and triethylamine (0.212 mL, 1.52 mmol, 20 equiv). The
resulting mixture was stirred at rt for 60 h. CHCl3 and
triethylammonium buffer (1 N) were added to the reaction, and the
two layers were separated. Aqueous layer was extracted three times
with CHCl3. Combined organic layers were dried over MgSO4, filtered
and concentrated. The crude mixture was purified on silica gel (eluent:
CH2Cl2 then CH2Cl2/MeOH/NEt3 100:1:1) yielding 12gα as a
colorless oil (36.5 mg, 0.059 mmol, 78%): Rf = 0.50 (CH2Cl2/MeOH
9:1); [α]24D = +21.7 (c 1.6, CHCl3); IR (neat) νmax 3031, 2982, 2918,
2867, 2385, 1454, 1115, 1070, 1046, 990, 957, 749, 739, 699 cm−1; 1H
NMR (300 MHz, CDCl3) 12.89−12.54 (br s, 1H), 7.40−7.20 (m,
13H), 7.20−7.10 (m, 2H), 5.96 (ddt, J = 17.1, 10.4, and 5.8 Hz, 1H),
5.28 (dd, J = 17.1 and 1.7 Hz, 1H), 5.16−5.08 (m, 1H), 4.91 (d, J =
10.9 Hz, 1H), 4.83 (d, J = 10.7 Hz, 1H), 4.78 (d, J = 10.7 Hz,1H),
4.61−4.40 (m, 4H), 4.36−4.24 (m, 2H), 4.020 (td, J = 10.0 and 2.4
Hz, 1H), 3.79−3.70 (m, 2H), 3.60 (t, J = 9.8 Hz, 1H), 3.60−3.52 (m,
1H), 3.00 (q, J = 7.2 Hz, 6H), 1.25 (t, J = 7.3 Hz, 9H), 0.99−(−0.09)
(m, 3H); 13C NMR (75 MHz, CDCl3) 139.2 (Cq), 138.6 (Cq), 138.5
(Cq), 135.6 (CH), 128.5 (2× CH), 128.5 (2× CH), 128.5 (2× CH),
128.2 (2× CH), 128.1 (2× CH), 128.1 (2× CH), 127.7 (CH), 127.7
(CH), 127.6 (CH), 117.2 (CH2), 83.8 (CH), 81.8 (d, J = 49.9 Hz,
CH), 79.2 (CH),76.3 (CH2), 75.6 (CH2), 74.4 (d, J = 2.2 Hz, CH),
73.6 (CH2), 73.1 (d, J = 9.3 Hz, CH2), 70.4 (d, J = 7.1 Hz, CH2), 45.5
(CH2), 8.7 (CH3); 31P NMR (122 MHz, CDCl3) 104.5−100.4 (m)
ppm; HRMS (ESI-TOF) calcd for C29H40BNO6P [M-HNEt3+NH4]+
540.2692, found 540.2690.
68.7 (d, J = 7.7 Hz, CH2), 57.1 (CH3), 55.1 (d, J = 2.7 Hz, CH3); 31
P
NMR (122 MHz, CDCl3) 135.4−132.4 (m) ppm; HRMS (ESI-TOF)
calcd for C29H42BNO7P [M + NH4]+ 558.2792, found 558.2791.
(2S,3S,4S,5S,6R)-3-(Allyloxy)-4,5-bis(benzyloxy)-6-((benzyl-
oxy)methyl)-2-boranyl-2-methoxy-1,2-oxaphosphinane 9gα.
To a solution of 6gα (100 mg, 0.2 mmol) in THF (2 mL) were
added at −78 °C a solution of NaHMDS in THF (1M) (0.24 mL, 0.24
mmol, 1.2 equiv) and allylbromide (0.035 mL, 0,4 mmol, 2 equiv).
The resulting mixture was stirred at −10 °C overnight. The reaction
mixture was warmed to 10 °C, and additional solution of NaHMDS in
THF (1M) (0.08 mL, 0.08 mmol, 0.4 equiv) and allylbromide (9 μL,
0,1 mmol, 0.5 equiv) were added, and the reaction was stirred for 6 h.
A saturated solution of NH4Cl was added to the reaction, and the two
layers were separated. Aqueous layer was extracted three times with
EtOAc. Combined organic layers were washed with brine, dried over
MgSO4, filtered and concentrated. The crude mixture was purified on
silica gel (eluent: EtOAc/heptane 5:95) yielding 9gα as a colorless oil
(62 mg, 0.12 mmol, 58%): Rf = 0.44 (EtOAc/heptane 2:8); [α]24
=
D
+52.4 (c 0.5, CHCl3); IR (neat) νmax 3064, 3031, 2925, 2869, 2397,
1
1454, 1064, 1025, 990, 974, 736, 697 cm−1; H NMR (500 MHz,
CDCl3) 7.37−7.24 (m, 13H), 7.17−7.10 (m, 2H), 5.99−5.88 (ddt, J =
17.1, 10.4, and 6.1 Hz, 1H), 5.32 (dd, J = 17.1 and 1.2 Hz, 1H), 5.23
(dd, J = 10.4 Hz, 1H), 4.91 (d, J = 10.7 Hz, 1H), 4.84 (d, J = 10.7 Hz,
1H), 4.81 (d, J = 10.7 Hz,1H), 4.60 (d, J = 11.9 Hz, 1H), 4.57 (d, J =
10.4 Hz, 1H), 4.53 (d, J = 12.2 Hz, 1H), 4.39 (dd, J = 11.9 and 5.8 Hz,
1H), 4.26 (dd, J = 12.2 and 6.1 Hz, 1H), 4.18−4.12 (m, 1H), 4.00 (td,
J = 9.8 and 1.5 Hz, 1H), 3.83 (d, J = 11.0 Hz, 3H), 3.84−3.80 (m, 1H),
3.78−3.70 (m, 3H), 1.02−0.27 (m, 3H); 13C NMR (75 MHz, CDCl3)
138.4 (Cq), 137.9 (Cq), 137.9 (Cq), 134.0 (CH), 128.6 (6× CH),
128.1 (CH), 128.0 (6× CH), 128.0 (CH), 128.0 (CH), 119.0 (CH2),
82.6 (CH), 78.8 (d, J = 56.0 Hz, CH), 77.4 (CH),76.7 (CH2), 76.4 (d,
J = 10.4 Hz, CH), 75.9 (CH2), 74.9 (d, J = 2.2 Hz, CH2), 73.8 (CH2),
68.8 (d, J = 7.7 Hz, CH2), 55.2 (d, J = 3.3 Hz, CH3); 31P NMR (122
MHz, CDCl3) 134.6−130.9 (m) ppm; HRMS (ESI-TOF) calcd for
C30H38BNaO6P [M + Na]+ 559.2397, found 559.2399.
Triethylammonium (2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-6-
((benzyloxy)methyl)-2-boranyl-3-(methoxymethoxy)-1,2-oxa-
phosphinan-2-olate 11gα. To a solution of 8gα (146 mg, 0.27
mmol) in THF (3 mL) were added thiophenol (0.56 mL, 5.4 mmol,
20 equiv) and triethylamine (0.76 mL, 5.4 mmol, 20 equiv). The
resulting mixture was stirred at rt for 4 days. CHCl3 and
triethylammonium buffer (1 N) were added to the reaction, and the
two layers were separated. Aqueous layer was extracted three times
with CHCl3. Combined organic layers were washed three times with
triethylammonium buffer (1 N), dried over MgSO4, filtered and
concentrated. The crude mixture was purified on silica gel (eluent:
CH2Cl2 then CH2Cl2/MeOH/NEt3 100:1:1) yielding 11gα as a
colorless oil (147 mg, 0.234 mmol, 87%): Rf = 0.54 (CH2Cl2/MeOH
9:1); [α]24D = +18.3 (c 0.5, CHCl3); IR (neat) νmax 2922, 2383, 1453,
1397, 1359, 1059, 1026, 999, 957, 918, 750, 737, 697 cm−1; 1H NMR
(500 MHz, CDCl3) 7.37−7.22 (m, 13H), 7.19−7.12 (m, 2H), 4.98−
4.85 (m, 4H), 4.83 (d, J = 10.7 Hz, 1H), 4.56 (d, J = 10.4 Hz, 1H),
4.54 (d, J = 12.2 Hz,1H), 4.51 (d, J = 11.6 Hz, 1H), 4.33−4.26 (m,
1H), 4.03 (td, J = 9.8 and 2.4 Hz, 1H), 3.84−3.76 (m, 2H), 3.74 (dd, J
= 10.4 and 5.8 Hz, 1H), 3.58 (t, J = 9.8 Hz, 1H), 3.43 (s, 3H), 3.00−
2.88 (m, 6H), 1.22 (t, J = 7.3 Hz), 0.91−0.11 (m, 3H); 13C NMR (75
(2R,3R,4S,5R,6S)-2-((((2R,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-
((benzyloxy)methyl)-3-(methoxymethoxy)-2-oxido-1,2-oxa-
phosphinan-2-yl)oxy)methyl)-6-methoxytetrahydro-2H-
pyran-3,4,5-triyltribenzoate 18. To a solution of 11gα (10 mg,
0.016 mmol) in dry toluene (1.9 mL) were added sequentially diol 13a
(9.7 mg, 0.019 mmol, 1.2 equiv), DIPEA (28 μL, 0.16 mmol, 10
equiv), DMAP (5.9 mg, 0.048 mmol, 3 equiv) and 4 Å molecular
sieves (20 mg). The resulting mixture was stirred at rt for 1 h and Bop-
Cl (12.2 mg, 0.048 mmol, 3 equiv) was added. The resulting mixture
was stirred at rt overnight, diluted with CHCl3 and a saturated solution
of NaHCO3. Aqueous layer was extracted three times with CHCl3.
Combined organic layers were washed with brine, dried on MgSO4
and concentrated under a vacuum. It was dissolved in CH2Cl2 (10
mL) and m-CPBA was added (wet solid containing 77 wt % in m-
CPBA, 27.6 mg, 0.16 mmol). The resulting solution was stirred for 30
min at room temperature. An aqueous saturated solution of Na2S2O3
and CH2Cl2 were added to the mixture, and the layers were separated.
Aqueous layer was extracted twice by CH2Cl2. Combined organic
layers were dried over MgSO4, filtered and evaporated. Purification on
silica gel (eluent: heptane/EtOAc 7:3, then 6:4 and finally 1:1) yielded
a mixture of 18gβ and 18gα as a colorless oil (10.8 mg, 0.0106 mmol,
66%): IR (neat) νmax 3014, 2966, 2928, 2870, 1729, 1452, 1260, 1106,
1
1093, 1068, 1052, 1027, 999, 748, 709, 667 cm−1; H NMR (500
MHz, CDCl3) 8.00−7.95 (m, 4H), 7.95−7.91 (m, 4H), 7.87−7.82 (m,
4H), 7.54−7.45 (m, 4H), 7.44−7.22 (m, 40H), 7.16−7.10 (m, 4H),
6.20−6.12 (m, 2H), 5.57 (t, J = 9.8 Hz, 1H), 5.52 (t, J = 9.8 Hz, 1H),
5.29−5.20 (m, 4H), 4.90−4.79 (m, 6H), 4.77 (s, 2H), 4.62−4.54 (m,
4H), 4.51−4.43 (m, 4H), 4.36−4.24 (m, 5H), 4.14 (dd, J = 10.8 and
8.8 Hz, 1H), 4.11−3.98 (m, 5H), 3.88−3.78 (m, 3H), 3.75 (dt, J =
11.3 and 3.2 Hz, 1H), 3.72−3.40 (m, 3H), 3.47 (s, 3H), 3.44 (s, 3H),
3.39 (s, 3H), 3.33 (s, 3H); 13C NMR (125 MHz, CDCl3) 166.0 (Cq),
166.0 (Cq), 166.0 (2× Cq), 165.5 (Cq), 165.4 (Cq), 138.4 (Cq), 138.2
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Featured Article
(Cq), 138.0 (Cq), 138.0 (2× Cq), 137.9 (Cq), 133.7 (CH), 133.6
(CH), 133.6 (CH), 133.6 (CH), 133.3 (CH), 133.3 (CH), 130.1 (4×
CH), 130.1 (2× CH), 130.1 (2× CH), 129.9 (2× CH), 129.9 (2×
CH), 129.4 (CH), 129.4 (CH), 129.3 (CH), 129.2 (CH), 129.1
(CH), 128.9 (CH), 128.7 (2× CH), 128.6 (6× CH), 128.6 (6× CH),
128.6 (4× CH), 128.5 (3× CH), 128.0 (2× CH), 128.0 (3× CH),
128.0 (2× CH), 127.9 (3× CH), 127.9 (5× CH), 97.8 (d, J = 1.8 Hz,
CH2), 97.6 (d, J = 1.8 Hz, CH2), 97.2 (CH), 97.1 (CH), 84.0 (d, J =
4.6 Hz, CH), 84.0 (CH), 77.9 (CH), 77.0 (d, J = 5.5 Hz, CH), 76.6
(CH2), 76.5 (CH2), 75.7 (CH), 75.6 (CH2), 75.6 (CH2), 75.5 (CH),
73.8 (CH2), 73.7 (CH2), 73.4 (d, J = 143.9 Hz, CH), 72.4 (d, J = 143.9
Hz, CH), 72.2 (CH), 72.2 (CH), 70.5 (2× CH), 69.4 (CH), 69.4
(CH), 68.9 (d, J = 6.4 Hz, CH), 68.8 (d, J = 6.4 Hz, CH), 68.6 (d, J =
10.1 Hz, CH2), 68.5 (d, J = 10.1 Hz, CH2), 65.9 (d, J = 7.3 Hz, CH2),
65.3 (d, J = 4.4 Hz, CH2), 56.4 (CH3), 56.3 (CH3), 56.0 (CH3), 55.9
(CH3). 31P NMR (202 MHz, CDCl3) 21.5 and 17.2 ppm; HRMS
(ESI-TOF) calcd for C56H58O16P [M + H]+ 1017.3462, found
1017.3503.
((2S,3R,4S,5S,6R)-3-Acetoxy-4,5-bis(benzyloxy)-2-methoxy-
2-oxido-1,2-oxaphosphinan-6-yl)methyl acetate 20mβ. To a
solution of 19mβ (90 mg, 0.181 mmol) in Ac2O (1 mL) was added
TFA (0.2 mL), and the resulting solution was stirred at room
temperature for 6 h and then concentrated under a vacuum.
Purification on silica gel (eluent: EtOAc/heptane, 1:1) afforded the
known diester 20mβ (80 mg, 0.163 mmol, 90%) as a colorless oil for
which data correspond to those previously reported.10
methyl)-2-methoxy-1,2-oxaphosphinane 2-oxide 21mα. To a
solution of diester 20mβ (80 mg, 0.163 mmol) in MeOH (1 mL) was
added NaOMe (7 wt % solution in MeOH, 2 drops), and the resulting
mixture was stirred at room temperature for 4 h. It was then quenched
by addition of Amberlite H+ resin, filtered and evaporated. Purification
on silica gel (eluent: EtOAc) afforded the diol 21mβ (30 mg, 0.073
mmol, 45%) and diol 21mα (32 mg, 0.078 mmol, 48%) as colorless
oils. Data for 21mβ: [α]23D = +3.30 (c 1, CHCl3); IR (neat) νmax 3328,
2926, 1455, 1218, 1091, 1028, 989 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.40−7.29 (m, 10H), 4.91 (d, J = 10.9 Hz, 1H), 4.72 (s,
2H), 4.69 (d, J = 10.9 Hz, 1H), 4.45 (dd, J = 2.7 and 9.8 Hz, 1H),
4.27−4.18 (m, 1H), 4.15 (dd, J = 2.8 and 9.1 Hz, 1H), 4.09 (d, J = 9.4
Hz, 1H), 3.93 (d, J = 10.7 Hz, 3H), 3.91−3.86 (m, 2H), 2.80−2.53 (br
s, 2H); 13C NMR (75 MHz, CDCl3) δ 137.9 (Cq), 137.3 (Cq), 128.8
(2× CH), 128.7 (2× CH), 128.4 (CH), 128.2 (2× CH), 128.1 (CH),
128.1 (2× CH), 81.6 (d, J = 6.6 Hz, CH), 77.1 (d, J = 3.3 Hz, CH),
75.7 (CH2), 73.4 (d, J = 1.6 Hz), 72.7 (CH2), 64.8 (d, J = 146.0 Hz,
CH), 61.9 (d, J = 9.3 Hz, CH2), 54.8 (d, J = 6.6 Hz, CH3). 31P NMR
(202 MHz, CDCl3) δ 21.6 ppm; HRMS (ESI-TOF) calcd for
C20H26O7P 409.1416 [M + H]−, found 409.1425. Data for 21mα:
[α]23D = +20.5 (c 1.3, CHCl3); IR (neat) νmax 3348, 2925, 1455, 1260,
1090, 1027, 997 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.40−7.20 (m,
10H), 4.89 (d, J = 10.6 Hz, 1H), 4.73 (d, J = 11.8 Hz, 1H), 4.64 (d, J =
11.7 Hz, 1H), 4.63 (d, J = 10.6 Hz, 1H), 4.33 (dd, J = 3.0 and 8.5 Hz,
1H), 4.12 (t, J = 9.5 Hz, 1H), 3.91−7.78 (m, 4H), 3.71 (d, J = 10.5 Hz,
3H), 3.27 (br s, 1H), 2.32 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ
138.0 (Cq), 137.7 (Cq), 128.7 (2× CH), 128.6 (2× CH), 128.3 (2×
CH), 128.2 (3× CH), 128.1 (CH), 81.1 (d, J = 6.0 Hz, CH), 78.6 (d, J
= 6.0 Hz, CH), 75.8 (CH2), 73.0 (d, J = 2.7 Hz), 72.2 (CH2), 63.6 (d,
J = 144.4 Hz, CH), 62.0 (d, J = 8.8 Hz, CH2), 52.6 (d, J = 7.7 Hz,
CH3). 31P NMR (202 MHz, CDCl3) δ 21.3 ppm; HRMS (ESI-TOF)
calcd for C20H26O7P 409.1416 [M + H]−, found 409.1423.
(2R,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-(hydroxymethyl)-2-
methoxy-2-oxido-1,2-oxaphosphinan-3-yl acetate 22gα and
(2R,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-3-hydroxy-6-(hydroxy-
methyl)-2-methoxy-1,2-oxaphosphinane 2-oxide 21gα. To a
solution of phosphonate 19gα (227 mg, 0.42 mmol) in Ac2O (2.0
mL) was added TFA (0.4 mL), and the resulting solution was stirred
at room temperature for 7 h and then concentrated under a vacuum.
Purification on silica gel (eluent: EtOAc/heptane, 1:2) afforded the
diester 20gα (215 mg, 0.42 mmol, quant.), which was directly engaged
in the next step. It was dissolved in MeOH (7 mL) and 4 Å molecular
sieves (freshly activated, 300 mg) was added. The resulting mixture
was stirred at room temperature for 24 h and then filtered on Celite
and concentrated under a vacuum. Purification on silica gel (eluent:
EtOAc/heptane, 1:1 then EtOAc) afforded monoester 22gα (60 mg,
0.147 mmol, 35%) and diol 21gα (50 mg, 0.11 mmol, 26%) as
(2S,3S,4S,5S,6R)-2-(((2R,3S,4S,5S,6R)-3-Acetoxy-4,5-bis-
(benzyloxy)-2-methoxy-2-oxido-1,2-oxaphosphinan-6-yl)-
methoxy)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-oxido-
1,2-oxaphosphinan-3-yl acetate 23gβ. To a solution of 10gα
(66.0 mg, 0.106 mmol) in dry THF (4 mL) were added sequentially 4
Å molecular sieves (110 mg), phostone 22gα (57.5 mg, 0.128 mmol,
1.2 equiv), DIPEA (185 μL, 1.065 mmol, 10 equiv), DMAP (39 mg,
0.319 mmol, 3 equiv) and Bop-Cl (81.5 mg, 0.319 mmol, 3 equiv), and
the resulting mixture was stirred at rt overnight, filtered on a pad of
silica gel and then concentrated under a vacuum. It was dissolved in
CH2Cl2 (10 mL), and m-CPBA was added (wet solid containing 77 wt
% in m-CPBA, 224 mg, 1.0 mmol). The resulting solution was stirred
for 10 min at room temperature. An aqueous saturated solution of
Na2S2O3 and CH2Cl2 were added to the mixture, and the layers were
separated. Aqueous layer was extracted twice by CH2Cl2. Combined
organic layers were dried over MgSO4, filtered and evaporated.
Purification on silica gel (eluent: EtOAc/heptane 1:1) yielded 23gβ as
colorless oils that solidified upon standing. Data for 22gα: [α]23
=
D
+42.7 (c 0.6, CHCl3); IR (neat) νmax 3408, 3064, 3032, 2929, 1757,
1
1455, 1370, 1291, 1214, 1046, 1019, 993, 871, 741, 699 cm−1; H
NMR (500 MHz, CDCl3) δ 7.40−7.23 (m, 10H), 5.55 (d, J = 10.4 Hz,
1H), 4.87 (d, J = 10.7 Hz, 2H), 4.71 (t, J = 12.2 Hz, 2H), 4.08−3.79
(m, 5H), 3.89 (d, J = 10.7 Hz, 3H), 2.93−2.39 (br s, 1H), 2.01 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 169.0 (Cq), 137.9 (Cq), 137.5
(Cq), 128.7 (2× CH), 128.7 (2× CH), 128.3 (2× CH), 128.2 (2×
CH), 128.0 (CH), 127.8 (CH), 82.6 (d, J = 8.2 Hz, CH), 78.3 (d, J =
5.5 Hz, CH), 77.5 (CH), 76.1 (CH2), 75.8 (CH2), 68.1 (d, J = 146.6
Hz, CH), 61.5 (d, J = 9.9 Hz, CH2), 53.7 (d, J = 6.6 Hz, CH3), 20.6
(CH3). 31P NMR (202 MHz, CDCl3) δ 15.9 ppm; HRMS (ESI-TOF)
calcd for C22H31NO8P 468.1787 [M + NH4]+, found 468.1776. Data
a colorless oil (75 mg, 0.0782 mmol, 74%): [α]23 = +26.0 (c 0.51,
D
CHCl3); IR (neat) νmax 3032, 2926, 1753, 1454, 1265, 1214, 1046,
1026, 979 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.40−7.23 (m, 23H),
7.19−7.08 (m, 2H), 5.53 (t, J = 10.5 Hz, 1H), 5.33 (t, J = 10.0 Hz,
1H), 4.88 (d, J = 11.4 Hz, 1H), 4.87 (d, J = 10.5 Hz, 1H), 4.86 (d, J =
12.7 Hz, 1H), 4.85 (d, J = 10.7 Hz, 1H), 4.74 (d, J = 12.6 Hz, 1H),
4.70 (d, J = 11.7 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 10.6
Hz, 1H), 4.63 (d, J = 10.7 Hz, 1H), 4.53−4.45 (m, 1H), 4.52 (d, J =
12.0 Hz, 1H), 4.36−4.24 (m, 2H), 4.17−4.07 (m, 2H), 4.02−3.88 (m,
2H), 3.87−3.85 (m, 1H), 3.87 (d, J = 10.5 Hz, 3H), 3.78−3.69 (m,
2H), 2.00 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 169.8 (d, J = 3.3 Hz,
Cq), 168.9 (d, J = 4.4 Hz, Cq), 138.0 (Cq), 137.9 (Cq), 137.7 (Cq),
137.7 (Cq), 137.2 (Cq), 128.8 (2× CH), 128.7 (2× CH), 128.6 (5×
CH), 128.5 (2× CH), 128.4 (CH), 128.3 (2× CH), 128.1 (3× CH),
128.0 (2× CH), 127.9 (2× CH), 127.5 (2× CH), 127.7 (2× CH),
82.7 (d, J = 7.7 Hz, CH), 82.5 (d, J = 11.0 Hz, CH), 77.8 (CH), 77.4
(CH), 76.3 (CH2), 76.2 (CH2), 76.0 (d, J = 2.7 Hz, CH), 75.8 (CH2),
75.6 (dd, J = 4.9 and 7.1 Hz, CH), 73.7 (CH2), 68.2 (d, J = 145.5 Hz,
CH), 68.2 (d, J = 9.3 Hz, CH2), 68.0 (d, J = 146.6 Hz, CH), 65.4 (dd,
J = 6.6 and 10.4 Hz, CH2), 53.7 (d, J = 6.6 Hz, CH3), 20.7 (CH3), 20.6
(CH3). 31P NMR (202 MHz, CDCl3) δ 18.1, 14.4 ppm; HRMS (ESI-
for 21gα: [α]23 = +34.8 (c 0.6, CHCl3); IR (neat) νmax 3334, 3064,
D
3032, 2923, 2872, 1455, 1271, 1217, 1134, 1103, 1049, 1025, 991, 863,
1
735, 698 cm−1; H NMR (500 MHz, CDCl3) δ 7.43−7.22 (m, 10H),
4.98 (d, J = 10.7 Hz, 1H), 4.89 (d, J = 10.4 Hz, 1H), 4.87 (d, J = 10.7
Hz, 1H), 4.68 (d, J = 10.7 Hz, 1H), 4.23−4.15 (m, 1H), 4.00−3.73
(m, 5H), 3.91 (d, J = 10.4 Hz, 3H), 3.38−2.50 (br s, 1H); 13C NMR
(75 MHz, CDCl3) δ 138.4 (Cq), 137.8 (Cq), 128.7 (2× CH), 128.6
(2× CH), 128.3 (2× CH), 128.2 (3× CH), 128.0 (CH), 84.3 (d, J =
9.9 Hz, CH), 78.0 (d, J = 4.9 Hz, CH), 76.9 (CH), 76.6 (CH2), 75.7
(CH2), 69.7 (d, J = 143.3 Hz, CH), 61.5 (d, J = 9.3 Hz, CH2), 54.2 (d,
J = 7.1 Hz, CH3). 31P NMR (202 MHz, CDCl3) δ 20.9 ppm; HRMS
(ESI-TOF) calcd for C20H25NaO7P [M + Na]+ 431.1236, found
431.1215.
(2S,3R,4S,5S,6R)-4,5-Bis(benzyloxy)-3-hydroxy-6-(hydroxy-
methyl)-2-methoxy-1,2-oxaphosphinane 2-oxide 21mβ and
(2R,3R,4S,5S,6R)-4,5-Bis(benzyloxy)-3-hydroxy-6-(hydroxy-
6865
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The Journal of Organic Chemistry
Featured Article
TOF) calcd for C50H60NO15P2 [M + NH4]+ 976.3438, found
976.3439.
127.7 (2× CH), 82.6 (d, J = 11.0 Hz, CH), 81.6 (d, J = 7.1 Hz, CH),
77.9 (CH), 76.3 (CH2), 76.0 (d, J = 2.7 Hz, CH), 75.7 (CH2), 75.7
(CH2), 74.7 (dd, J = 6.6 and 2.7 Hz, CH), 73.7 (CH2), 73.1 (d, J = 1.6
Hz, CH), 72.5 (CH2), 68.7 (d, J = 145.5 Hz, CH), 68.3 (d, J = 10.4
Hz, CH2), 66.1 (d, J = 7.1 Hz, CH2), 65.1 (d, J = 144.4 Hz, CH), 55.3
(d, J = 7.1 Hz, CH3), 20.7 (CH3). 31P NMR (122 MHz, CDCl3) 19.3
and 17.6 ppm; HRMS (ESI-TOF) calcd for C48H55O14P2 [M + H]+
917.3067, found 917.3063.
(2S,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-((benzyloxy)methyl)-
2-(((2R,3S,4S,5S,6R)-4,5-bis(benzyloxy)-3-hydroxy-2-methoxy-
2-oxido-1,2-oxaphosphinan-6-yl)methoxy)-2-oxido-1,2-oxa-
phosphinan-3-yl acetate 24gβ. To a solution of 10gα (10.0 mg,
0.016 mmol) in dry THF (0.8 mL) were added sequentially 4 Å
molecular sieves (20 mg), diol 21gα (8 mg, 0.0192 mmol, 1.2 equiv),
DIPEA (28 μL, 0.16 mmol, 10 equiv), DMAP (6.0 mg, 0.048 mmol, 3
equiv) and Bop-Cl (12.0 mg, 0.048 mmol, 3 equiv), and the resulting
mixture was stirred at rt overnight, filtered on a pad of silica gel and
then concentrated under a vacuum. It was dissolved in CH2Cl2 (1 mL)
and m-CPBA was added (wet solid containing 77 wt % in m-CPBA, 36
mg, 0.16 mmol). The resulting solution was stirred for 30 min at room
temperature. An aqueous saturated solution of Na2S2O3 and CH2Cl2
were added to the mixture, and the layers were separated. Aqueous
layer was extracted twice by CH2Cl2. Combined organic layers were
dried over MgSO4, filtered and evaporated. Purification on silica gel
(eluent: EtOAc) yielded 24gβ as a colorless oil (9.2 mg, 0.010 mmol,
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra for all new compounds and CIF files for all
crystallographic structures. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: DCrich@chem.wayne.edu.
■
58%): [α]23 = +36.3 (c 0.92, CHCl3); IR (neat) νmax 3294, 2925,
D
1
1753, 1455, 1367, 1220, 1054, 1028, 992 cm−1; H NMR (500 MHz,
Notes
The authors declare no competing financial interest.
CDCl3) δ 7.37−7.20 (m, 22H), 7.17−7.10 (m, 2H), 5.36 (t, J = 10.1
Hz, 1H), 4.90 (d, J = 11.0 Hz, 1H), 4.87 (d, J = 10.2 Hz, 1H), 4.86 (d,
J = 11.2 Hz, 1H), 4.84 (d, J = 12.1 Hz, 1H), 4.82 (d, J = 11.2 Hz, 1H),
4.71 (d, J = 11.5 Hz, 1H), 4.62 (d, J = 10.1 Hz, 1H), 4.60 (d, J = 12.0
Hz, 1H), 4.60 (d, J = 10.4 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.47−
4.42 (m, 1H), 4.36−4.28 (m, 2H), 4.13 (dt, J = 2.4 and 10.1, 1H),
4.10−4.01 (m, 2H), 3.95 (t, J = 9.6 Hz, 1H), 3.91−3.80 (m, 2H), 3.88
(d, J = 10.4 Hz, 3H), 3.74 (dd, J = 1.9 and 11.2 Hz, 1H), 3.62 (t, J =
9.8 Hz, 1H), 3.40 (br s, 1H), 1.98 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 169.9 (d, J = 3.7 Hz), 138.2 (Cq), 138.1 (Cq), 137.9 (Cq),
137.8 (Cq), 137.5 (Cq), 128.8 (3× CH), 128.8 (2× CH), 128.7 (4×
CH), 128.6 (2× CH), 128.3 (CH), 128.2 (2× CH), 128.2 (CH),
128.1 (2× CH), 128.0 (2× CH), 128.0 (2× CH), 128.0 (2× CH),
127.8 (2× CH), 84.3 (d, J = 8.2 Hz, CH), 82.6 (d, J = 11.9 Hz, CH),
77.9 (CH), 77.0 (CH), 76.4 (CH2), 76.3 (CH2), 76.1 (d, J = 1.8 Hz,
CH), 75.8 (CH2), 75.7 (CH2), 75.5 (dd, J = 4.6 and 6.4 Hz, CH), 73.7
(CH2), 69.7 (d, J = 144.8 Hz, CH), 68.3 (d, J = 10.1 Hz, CH2), 68.0
(d, J = 146.6 Hz, CH), 65.9 (d, J = 6.4 and 7.3 Hz, CH2), 54.0 (d, J =
7.3 Hz, CH3), 20.7 (CH3). 31P NMR (202 MHz, CDCl3) δ 18.9, 18.3
ppm; HRMS (ESI-TOF) calcd for C48H58NO14P2 [M + NH4]+
934.3333, found 394.3364.
ACKNOWLEDGMENTS
A. F. and G. M. thank the ICSN for financial support.
■
REFERENCES
(1) (a) Ross, G. D.; Vetvicka, V.; Yan, J.; Xia, Y.; Vetvickova,
Immunopharmacology 1999, 42, 61−74. (b) Descroix, K.; Vetvicka, V.;
̀
Laurent, I.; Jamois, F.; Yvin, J.-C.; Ferrieres, V. Bioorg. Med. Chem.
2010, 18, 348−357. (c) Vetvicka, V.; Yvin, J.-C. Int. Immunopharmacol.
2004, 4, 721−730. (d) Chlubnova, I.; Sylla, B.; Nugier-Chauvin, C.;
Daniellou, R.; Legentil, L.; Kralova, B.; Ferrieres, V. Nat. Prod. Rep.
2011, 28, 937−952. (e) Yan, J.; Vetvicka, V.; Xia, Y.; Coxon, A.;
Carroll, M. C.; Mayadas, T. N.; Ross, G. D. J. Immunol. 1999, 163,
3045−3052.
(2) (a) Stallforth, P.; Lepenies, B.; Adibekian, A.; Seeberger, P. H. J.
Med. Chem. 2009, 52, 5561−5577. (b) Seeberger, P. H. Nat. Chem.
Biol. 2009, 5, 368−372.
■
́
J.
(3) (a) Demchenko, A. V. Handbook of Chemical Glycosylation:
Advances in Stereoselectivity and Therapeutic Relevance; Wiley-VCH:
Weinheim, 2008. (b) Galan, M. C.; Benito-Alifonso, D.; Watt, G. M.
Org. Biomol. Chem. 2011, 9, 3598−3610. (c) Guinchard, X.; Picard, S.;
Crich, D. In Modern Tools for the Synthesis of Complex Bioactive
Molecules; Arseniyadis, S., Cossy, J., Eds.; John Wiley & Sons: New
York, 2012; pp 395−432. (d) Zhu, X.; Schmidt, R. R. Angew. Chem.,
Int. Ed. 2009, 48, 1900−1934. (e) Hsu, C.-H.; Hung, S.-C.; Wu, C.-Y.;
Wong, C.-H. Angew. Chem., Int. Ed. 2011, 50, 11872−11923. (f) Wu,
C. Y.; Wong, C. H. Top. Curr. Chem. 2011, 301, 223−252. (g) Crich,
(2S,3S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-((benzyloxy)methyl)-
2-(((2R,3R,4S,5S,6R)-4,5-bis(benzyloxy)-3-hydroxy-2-methoxy-
2-oxido-1,2-oxaphosphinan-6-yl)methoxy)-2-oxido-1,2-oxa-
phosphinan-3-yl acetate 25gβ. To a solution of 10gα (33.2 mg,
0.051 mmol) in dry THF (1.9 mL) were added sequentially 4 Å
molecular sieves (60 mg), diol 21mβ (25 mg, 0.06 mmol, 1.2 equiv),
DIPEA (89 μL, 0.51 mmol, 10 equiv), DMAP (24.6 mg, 0.15 mmol, 3
equiv) and Bop-Cl (38.6 mg, 0.15 mmol, 3 equiv), and the resulting
mixture was stirred at rt overnight, filtered on a pad of silica gel and
then concentrated under a vacuum. It was dissolved in CH2Cl2 (1
mL), and m-CPBA was added (wet solid containing 77 wt % in m-
CPBA, 88 mg, 0.51 mmol). The resulting solution was stirred for 20
min at room temperature. An aqueous saturated solution of Na2S2O3
and CH2Cl2 were added to the mixture, and the layers were separated.
Aqueous layer was extracted twice by CH2Cl2. Combined organic
layers were dried over MgSO4, filtered and evaporated. Purification on
silica gel (eluent: EtOAc) yielded 25gβ as a colorless oil (29.3 mg,
́
D. Acc. Chem. Res. 2010, 43, 1144−1153. (h) Bohe, L.; Crich, D.
Trends Glycosci. Glycotechnol. 2010, 22, 1−15. (i) Sylla, B.; Descroix,
K.; Pain, C.; Gervaise, C.; Jamois, F.; Yvin, J.-C.; Legentil, L.; Nugier-
̀
Chauvin, C.; Daniellou, R.; Ferrieres, V. Carbohydr. Res. 2010, 345,
1366−1370. (j) Spijker, N. M.; van Boeckel, C. A. A. Angew. Chem.,
Int. Ed. 1991, 30, 180−183.
(4) (a) Joe, M.; Bai, Y.; Nacario, R. C.; Lowary, T. L. J. Am. Chem.
Soc. 2007, 129, 9885−9901. (b) Adams, E. L.; Rice, P. J.; Graves, B.;
Ensley, H. E.; Yu, H.; Brown, G. D.; Gordon, S.; Monteiro, M. A.;
Papp-Szabo, E.; Lowman, D. W.; Power, T. D.; Wempe, M. F.;
Williams, D. L. J. Pharmacol. Exp. Ther. 2008, 325, 115−123. (c) Mo,
K.-F.; Li, H.; Mague, J. T.; Ensley, H. E. Carbohydr. Res. 2009, 344,
439−447. (d) Chu, K.-C.; Ren, C.-T.; Lu, C.-P.; Hsu, C.-H.; Sun, T.-
H.; Han, J.-L.; Pal, B.; Chao, T.-A.; Lin, Y.-F.; Wu, S.-H.; Wong, C.-H.;
Wu, C.-Y. Angew. Chem., Int. Ed. 2011, 50, 9391−9395. (e) Fraser-
Reid, B.; Lu, J.; Jayaprakash, K. N.; Lopez, J. C. Tetrahedron:
Asymmetry 2006, 17, 2449−2463. (f) Tanaka, H.; Kawai, T.; Adachi,
Y.; Hanashima, S.; Yamaguchi, Y.; Ohno, N.; Takahashi, T. Bioorg.
Med. Chem. 2012, 20, 3898−3914. (g) Tanaka, H.; Kawai, T.; Adachi,
Y.; Ohno, N.; Takahashi, T. Chem. Commun. 2010, 46, 8249−8251.
0.0032 mmol, 63%): [α]21 = +47.5 (c 0.1, CHCl3); IR (neat) νmax
D
3318, 3033, 2931, 2866, 1755, 14554, 1368, 1220, 1088, 1054, 1028,
1
992, 736, 698 cm−1; H NMR (300 MHz, CDCl3) 7.31−7.11 (m,
23H), 7.11−7.01 (m, 2H), 5.27 (t, J = 10.0 Hz, 1H), 4.85−4.69 (m,
3H), 4.68−4.44 (m, 6H), 4.44−4.29 (m, 4H), 4.29−4.16 (m, 2H),
4.12−4.00 (m, 2H), 3.95 (t, J = 9.4 Hz, 1H), 3.90−3.72 (m, 2H), 3.82
(d, J = 10.5 Hz, 3H), 3.61 (d, J = 10.9 Hz, 1H), 2.83 (d, J = 21.1 Hz,
1H), 1.90 (s, 3H); 13C NMR (75 MHz, CDCl3) 170.0 (d, J = 3.3 Hz,
Cq), 138.1 (Cq), 137.8 (Cq), 137.7 (Cq), 137.7 (Cq), 137.3 (Cq), 128.9
(2× CH), 128.7 (4× CH), 128.4 (CH), 128.2 (3× CH), 128.2 (3×
CH), 128.2 (3× CH), 128.1 (CH), 128.0 (3× CH), 128.0 (3× CH),
6866
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Featured Article
(5) Roy, R. Glycomimetics: Modern Synthetic Methodologies; American
Chemical Society: Washington, D.C., 2005.
(6) Bruno, B.; Vasella, A. In Acetylene Chemistry; Diederich, F., Stang,
P. J., Tykwinski, R. R., Ed.; Wiley-VCH: Weinheim, 2005; pp 173−
231.
(21) Earlier quench of the reaction allowed the isolation of the β
isomer 6mβ also. Comparison of NMR data for 6mβ and 6mα
supports the α/β assignements. See the Experimental Section for
characterization data.
(22) Previous route afforded compounds 10 in 6 steps from aldehyde
1 with global yields ranging from 6 to 8%.
(7) (a) Hanson, S. R.; Greenberg, W. A.; Wong, C.-H. QSAR Comb.
(23) In previous studies, we observed that the BOPCl promoted
reaction of 10gβ with alcohol 13a led to 14gβ with full β-selectivity
when conducted in the presence of DMAP in THF, whereas an α/β
mixture was obtained using NT as nucleophilic catalyst. See ref 10.
(24) Both the oxidative deborylation process and simple peracid
oxidation of P(III) systems are known to proceed with retention of
configuration. See ref 10
(25) (a) Miquel, N.; Doisneau, G.; Beau, J.-M. Angew. Chem., Int. Ed.
2000, 39, 4111−4114. (b) Prosperi, D.; Ronchi, S.; Lay, L.; Rencurosi,
A.; Russo, G. Eur. J. Org. Chem. 2004, 2004, 395−405.
(26) 4 Å activated molecular sieves were used.
(27) Ravindranathan Kartha, K. P.; Mukhopadhyay, B.; Field, R. A.
Carbohydr. Res. 2004, 339, 729−732.
(28) It is noteworthy that when Ravindranathan Kartha’s conditions
(see ref 27) were used in the mannose series, the product was obtained
as a complex mixture of 2-, 6-, and 2,6-deacetylated products, some of
the products being epimerized at the phosphorus.
́
Sci. 2007, 26, 1243−1252. (b) Gyorgydeak, Z.; Thiem, J. Adv.
̈
Carbohydr. Chem. Biochem. 2006, 60, 103−182. (c) Dedola, S.;
Nepogodiev, S. A.; Field, R. A. Org. Biomol. Chem. 2007, 5, 1006−
1017. (d) Dondoni, A. Chem.Asian J. 2007, 2, 700−708. (e) Nicotra,
F.; Cipolla, L.; Peri, F.; La Ferla, B.; Redaelli, C. Adv. Carbohydr. Chem.
Biochem. 2007, 61, 353−398.
(8) Compain, P.; Martin, O. R. Iminosugars: From Synthesis to
Therapeutic Applications; Wiley: Chichester, 2007.
(9) (a) Malik, G.; Guinchard, X.; Crich, D. Org. Lett. 2012, 14, 596−
599. (b) Malik, G.; Ferry, A.; Guinchard, X.; Cresteil, T.; Crich, D.
Chem.Eur. J. 2012, 19, 2168−2179. (c) Malik, G.; Ferry, A.;
Guinchard, X.; Crich, D. Synthesis 2013, 45, 65−74.
(10) Ferry, A.; Guinchard, X.; Retailleau, P.; Crich, D. J. Am. Chem.
Soc. 2012, 134, 12289−12301.
(11) (a) Darrow, J. W.; Drueckhammer, D. G. Bioorg. Med. Chem.
1996, 4, 1341−1348. (b) Thiem, J.; Gunther, M. Phosphorus, Sulfur
̈
́
Silicon Relat. Elem. 1984, 20, 67−79. (c) Hanessian, S.; Galeotti, N.;
Rosen, P.; Oliva, G.; Babu, S. Bioorg. Med. Chem. Lett. 1994, 4, 2763−
2768. (d) Darrow, J. W.; Drueckhammer, D. G. J. Org. Chem. 1994, 59,
2976−2985. (e) Harvey, T. C.; Weiler, L.; Withers, S. G. J. Org. Chem.
1997, 62, 6722−6725. (f) Hanessian, S.; Rogel, O. J. Org. Chem. 2000,
65, 2667−2674.
(12) Phostones, or closely related phostines, have recently attracted
attention for their biological activities; see: (a) Cristau, H.-J.;
Monbrun, J.; Schleiss, J.; Virieux, D.; Pirat, J.-L. Tetrahedron Lett.
2005, 46, 3741−3744. (b) Pirat, J.-L.; Virieux, D.; Clarion, L.; Volle, J.-
N.; Bakalara, N.; Mersel, M.; Montbrun, J.; Cristau, H.-J. WO
2009004096A1 I, 2009. (c) Clarion, L.; Jacquard, C.; Sainte-Catherine,
O.; Loiseau, S.; Filippini, D.; Hirlemann, M.-H.; Volle, J.-N.; Virieux,
D.; Lecouvey, M.; Pirat, J.-L.; Bakalara, N. J. Med. Chem. 2012, 55,
2196−2211.
(13) (a) Stawinski, J. In Handbook of Organophosphorus Chemistry;
Engel, R., Ed.; Marcel Dekker: Hoboken, New Jersey, 1992; pp 377−
434. (b) Stawinski, J.; Kraszewski, A. Acc. Chem. Res. 2002, 35, 952−
960. (c) Kraszewski, A.; Stawinski, J. Trends Org. Chem. 2003, 10, 1−
19. (d) Kraszewski, A.; Stawinski, J. Pure Appl. Chem. 2007, 79, 2217−
2227.
(14) (a) Yudelevich, V. I.; Sokolov, L. B.; Ionin, B. I. Russ. Chem. Rev.
1980, 49, 46−58. (b) Montchamp, J.-L. J. Organomet. Chem. 2005,
690, 2388−2406. (c) Bravo-Altamirano, K.; Coudray, L.; Deal, E. L.;
Montchamp, J.-L. Org. Biomol. Chem. 2010, 8, 5541−5551.
(15) Continuing the use of carbohydrate-based nomenclature, we
apply a modification of the Rosanoff convention to describe the
stereochemistry at phosphorus in the cyclic phostones. Thus, for the D-
configured sugars studied that essentially adopt the 4C1 chair
conformation, the equatorial ester mimicking the glycosidic bond is
termed the β-anomer, while its axial counterpart is named as the α-
anomer. See ref 10.
(16) Belabassi, Y.; Antczak, M. I.; Tellez, J.; Montchamp, J.-L.
Tetrahedron 2008, 64, 9181−9190.
(17) It was however observed that the two possible diastereoisomers
were obtained in 90% yield when the reaction was performed within 1
h. We conclude that the cyclization takes place rapidly affording the
two possible diastereoisomers that subsequently equilibrate to the
more stable α isomer.
(18) (a) Wada, T.; Shimizu, M.; Oka, N.; Saigo, K. Tetrahedron Lett.
2002, 43, 4137−4140. (b) Sato, K.; Oka, N.; Fujita, S.; Matsumura, F.;
Wada, T. J. Org. Chem. 2010, 75, 2147−2156. (c) Daub, G. W.; Van
Tamelen, E. E. J. Am. Chem. Soc. 1977, 99, 3526−3528.
(19) We previously noted that their methyl analogues were extremely
prone to oxidation.
(20) Centofanti, L. F. Inorg. Chem. 1973, 12, 1131−1133.
6867
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