Synthesis, characterization, and coupling reactions of six-membered cyclic P-chiral ammonium phosphonite-boranes; Reactive H-phosphinate equivalents for the stereoselective synthesis of glycomimetics

Article abstract of DOI:10.1021/ja305104b

Stereoselective syntheses of P-chiral ammonium phosphonite-borane complexes in the gluco- and manno-like series have been developed from P(V) phostone derivatives. The coupling reactions of these phostone donors with alcohols have been investigated with particular emphasis on the influence of protecting groups and conditions on stereoselectivity. The phosphonite-borane complexes may be applied directly in the coupling reactions and the products oxidized in situ to give phostone-mimetics of disaccharides. On the basis of these studies, successful protocols were established for the synthesis of β-gluco and α- and β-manno-configured phostones of primary alcohols. Deprotection of the dimeric compounds leads to novel families of α- or β-(1→6)-linked glycomimetics.

Full text of DOI:10.1021/ja305104b

Article
pubs.acs.org/JACS
Synthesis, Characterization, and Coupling Reactions of Six-
Membered Cyclic P-Chiral Ammonium Phosphonite−Boranes;
Reactive H-Phosphinate Equivalents for the Stereoselective Synthesis
of Glycomimetics
Angelique Ferry,† Xavier Guinchard,† Pascal Retailleau,† 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: Stereoselective syntheses of P-chiral ammo-
nium phosphonite-borane complexes in the gluco- and manno-
like series have been developed from P(V) phostone
derivatives. The coupling reactions of these phostone donors
with alcohols have been investigated with particular emphasis
on the influence of protecting groups and conditions on
stereoselectivity. The phosphonite−borane complexes may be
applied directly in the coupling reactions and the products
oxidized in situ to give phostone-mimetics of disaccharides. On
the basis of these studies, successful protocols were established for the synthesis of β-gluco and α- and β-manno-configured
phostones of primary alcohols. Deprotection of the dimeric compounds leads to novel families of α- or β-(1→6)-linked
glycomimetics.
phosphorus-containing glycomimetics based on the replace-
ment of the ring oxygen by a P(V) atom, by virtue of the
location of the phosphorus atom.13 More recently, phosphino-
sugars, or phostines, closely related to phostones, have gained a
renewed synthetic interest14 and have shown anticancer
activities.14b,c In addition to these potent activities, we
considered that the phostone linkage might be a suitable
surrogate of glycosidic bonds for application in oligosaccharide
mimetics and, thus, embarked on the program of exploratory
phostone chemistry and synthesis that we outline in this Article.
Numerous syntheses of simple phostones have been
described in the literature11b−g en route to their development
as glycosidase inhibitors. Despite this, only two actual
disaccharide mimetics based on the gluco-phostone motif
have been reported in the literature, in both of which the inter-
residue phostone ester bond intended to mimic a glycosidic
bond was prepared by esterification at the phosphorus V
oxidation level. This strategy, however, relies on the achiral
phosphonic acid function and furnishes mixtures of α- and β-
glucophosphonates, with a predominance for the β-isomer;11d
furthermore, nothing is known about the inherent diaster-
eoselectivity of such a reaction in the manno-series. Taking
note of the advantages of ease of reaction and yield conferred in
oligonucleotide synthesis and related fields by the use of
coupling reactions conducted at the phosphorus III rather than
INTRODUCTION
■
The efficient synthesis of oligosaccharides for applications in
glycobiology1 and in medicine depends critically on a number
of factors including the yield and stereoselectivity of glycosidic
bond formation.2 Unfortunately, and despite the enormous
advances made on this front in the last two decades, the current
state of the art leaves much to be desired. That this is the case
more than a hundred years after the advent of the Koenings−
Knorr reaction3 is an indication of the magnitude of the
problem and an obvious indication of the need for renewed
effort; it is also an indication that the parallel pursuit of
alternative avenues, such as the development of oligosaccharide
mimetics,4 may be beneficial. This challenge was taken up by
Vasella and co-workers5 in the context of their investigation
into the preparation of oligomeric glycosyl acetylenes, but in
more recent years the preparation of oligosaccharide mimetics
has been dominated by “Click” chemistry6 methods.7 In our
laboratory, we have initiated a glycomimetic program8 and
explored the application of a novel ligation method based on
the desulfurative allylic rearrangement of allylic disulfides9 to
the preparation of oligosaccharide mimetics,10 but ultimately
the goal must be to develop a system that provides the closest
possible analogy to a native glycosidic bond. Phosphonosugars,
or phostones,11 in which the anomeric carbon of a furanose or
pyranose ring is replaced by a phosphonate group have been
advanced as potent therapeutic agents due to their close
relation to glycosidic bonds and their potent ability to act as
glycosidase inhibitors.11d,g,12 Phostones differ from other
Received: May 25, 2012
© XXXX American Chemical Society
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V oxidation level,15 we have focused our attention on the
synthesis of functionalized phostone esters via the intermediacy
of P-chiral hydrogen phosphonites. To our knowledge,
coupling reactions of alcohols with H-phosphinates16 (Figure
1, iv), which possess one degree of oxidation less than H-
Scheme 1. Hydrophosphonylation with Simple
Diastereoinduction
Crystallization from MTBE afforded the pure manno-isomer
3m and enabled crystallographic confirmation of its config-
uration (see the Supporting Information), but did not provide a
means of efficiently accessing the pure gluco-isomer 3g from
the otherwise difficulty separable mixture. Therefore, we
investigated the possibility of enhancing diastereoselectivity
through the use of an external chiral agent. Of the various
systems developed recently for the asymmetric hydrophospho-
nylation of aldehydes,28 we favored that of You29 because of the
relatively low catalyst loadings and its applicability to aliphatic
aldehydes. Accordingly, reaction of aldehyde 2 and dimethyl
phosphite, promoted with titanium tetraisopropoxide, was
conducted in the presence of (R)-3,3′-diiodobinol and
cinchonidine, as described by You for simple achiral aldehydes,
resulting in a 57% yield of an improved 10:90 mixture of 3g and
3m (Table 1, entry 1). Changing the chirality and substitution
Figure 1. Tautomeric forms of H-phosphonates and H-phosphinates
and their borane complexes.
phosphonates (Figure 1, i),15c,d,17 well-known for their
reactions with alcohols15a,18 and in particular in oligonucleotide
synthesis,19 have not been reported previously, outside the
context of the Atherton−Todd reaction.20 Conscious of the
sensitivity of such P(III)-based tervalent substances toward
aerial oxidation, we directed our attention more particularly at
the use of hydrogen phosphonites protected in the form of
their borane adducts (Figure 1, vi). The borane serves not only
to protect the phosphorus center against oxidation,21 but also
provides an original means of blocking the H-phosphinate
function (Figure 1, v) in its tricoordinated P(III) state (v)
rather than the tetra-coordinated P(IV) form15d that is likely to
be largely favored by analogy with the hydrogen phosphite/H-
phosphonate equilibrium,15d,22 but which is not the reactive
form in coupling with alcohols.
The synthesis and reactions of the diesters phosphonite-
boranes (RP(BH3)(OR1)(OR2) have been studied,23 but not
their transformation to the borane adducts (Figure 1, vi). The
acyclic borane complexes of the higher oxidation level
phosphonates (Figure 1, iii) have recently been studied
extensively by Wada and co-workers, who reported their
preparation and uses,24 and in particular on their coupling
reactions with alcohols.24a,c,25 As it was not an issue in these
studies, the stereochemical course of these coupling reactions
was mostly not investigated.26 We describe herein the results of
an extensive study into the synthesis and coupling reactions of
carbohydrate-mimetic cyclic hydrogen or ammonium phos-
phonite−borane complexes, with particular emphasis on the
stereoselectivity of the coupling reactions, of the subsequent
oxidation step, the influence of the neighboring stereogenic
center, and the affixed protecting groups on the yield and
selectivity of the various processes.
Table 1. Asymmetric Hydrophosphonylation
a
b
c
entry
ligand
alk.
T (°C)
dr (3g/3m)
conv. (yield )
1
2
(R)-L1
(R)-L1
(R)-L1
(R)-L1
(R)-L1
(S)-L1
(S)-L1
(R)-L2
(R)-L2
(S)-L2
(S)-L2
( )-L3
CD
CD
CD
CD
C
rt
−20
40
0
10:90
9:91
100% (57%)
86% (59%)
100% (59%)
100% (89%)
67% (36%)
75% (53%)
50% (29%)
100% (77%)
65% (51%)
79% (62%)
73% (64%)
100% (80%)
3
17:83
10:90
47:53
62:48
66:34
70:30
56:44
61:39
72:28
61:39
4
5
0
6
CD
C
0
7
0
8
CD
C
0
9
0
10
11
12
CD
C
0
0
CD
0
RESULTS AND DISCUSSION
a
b
c
■
CD, cinchonidine; C, cinchonine. Determined by HPLC. Isolated
Diastereoselective Phostone Synthesis. We initially
evaluated Drueckhammer’s straightforward synthesis of six-
membered cyclic phostones11c in which a glucal-derived
aldehydo-formate ester is subjected to Abramov reaction11a,b
with trimethylphosphite followed by base-catalyzed cyclization.
Indeed, the first steps of this protocol (Scheme 1) proceeded in
high yield to give the Abramov product as a 57:43 mixture of
isomers in favor of what was subsequently assigned as the
gluco-isomer.27
yields for both diastereoisomers.
of the diol ligand, replacing cinchonidine by cinchonine, or
both did not improve the diastereomeric ratio (Table 1),
although operation at 0 °C did provide a 89% yield of the 10:90
gluco:manno mixture and therefore a practical functioning
gram-scale synthesis of 3m (Table 1, entry 4). In general, it was
found (Table 1) that both chiral promoters were essential for
high diasteroinduction and that while the ratio of diastereomers
B
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could be reversed to favor moderately the gluco isomer (Table
1, entries 6−12) it was not possible to completely overcome
the inherent preference of the arabino-configured aldehyde for
formation of the manno-isomer 3m. Nevertheless, despite the
imperfect nature of the selectivity, the conditions of Table 1,
entry 8 and use of preparative HPLC did afford a working
gram-scale entry into the gluco-isomer 3g.
Treatment of 3g with catalytic sodium methoxide in
methanol promoted cyclization to the cyclic phostones 4gα
and 4gβ in quantitative yield as an inseparable 32:68 mixture of
anomers (Scheme 2).30 In the case of the manno-isomer 3m,
cyclization gave an equimolar mixture of the readily separable
cyclic phostones 4mα and 4mβ in excellent yield (Scheme 2).
favored, whereas the inversion reaction proceeded more rapidly
with introduction of the nucleophile synclinal to the
phosphoryl oxygen (and anti to the methoxy group). The
preferential triflation anti to the phosphoryl oxygen is
presumably the result of the strongly electron-withdrawing
nature of the latter enhancing the acidity of the alcohol,
whereas the lesser steric bulk of the PO bond as compared to
the P−OMe moiety explains the greater ease of substitution of
a triflate group anti to the phosphoryl oxygen.
Acetylation of alcohols 4gα,β and 4mα,β under classical
conditions with acetic anhydride in pyridine afforded the
corresponding acetates 6gα,β and 6mα,β in moderate yield to
good yield, typically accompanied by varying amounts of the
corresponding phosphonic acids 7 resulting from base-
mediated demethylation. Fortunately, the use of acetic
anhydride as solvent in the presence of catalytic iodine proved
equal to the task and provided the desired derivatives in
excellent yield (Scheme 3, conditions a). With the exception of
Scheme 2. Conversion of Hydroxyphosphonates to Cyclic
Phostones
Scheme 3. Acetylation of 4gα,β and 4mα,β
The more facile synthesis of 3m than of 3g coupled with the
ease of separation of 4mα and 4mβ led us to investigate the
inversion of the later pair as an alternative means of entry into
the gluco-series. Attempts at Mitsunobu31 inversion of 4mα or
4mβ under a variety of conditions were unsuccessful, and
therefore we focused on the displacement of sulfonate esters.32
Accordingly, treatment of 4mα and 4mβ with sodium
hexamethyl disilamide followed by N,N-ditriflyl 5-chloro-2-
pyridylamine (Comins’ reagent33) afforded the triflate esters
5mα and 5mβ in 49% and 80% yield, respectively. Treatment
of 5mβ with potassium superoxide34 resulted only in
degradation, but the use of sodium or potassium nitrite as
nucleophile35 afforded the desired inverted alcohol 4gβ in
modest yield (Table 2, entries 1−3). Sodium acetate proved to
Table 2. Inversion at C-2 in the manno-Phostones
(a) Obtained as byproducts on acetylation with Ac2O/pyridine.
a single specific rotation,36 the specific rotations and 31P NMR
chemical shifts of the four acetates 6gα,β and 6mα,β compared
well with those provided earlier by Hanessian, thereby
confirming the assignments of configuration at phosphorus.
Interestingly, we found that increasing the amount of iodine
from 0.5 to 50 mol % in these acetylation reactions resulted in
the selective cleavage of a single benzyl ether at the 6-position
with concomitant acetylation.37 Although variable in terms of
yield, these latter conditions (Scheme 3, conditions b) gave
four diacetylated phostones 8gα,β and 8mα,β, of which two
(8gβ and 8mα) were crystalline and whose X-ray crystallo-
graphic structures (see the Supporting Information) provided
further confirmation of the configuration at phosphorus in the
entire series.
entry triflate
conditions
yield
1
2
3
4
5
5mβ
5mβ
5mβ
5mβ
5mα
KO2 (3 equiv), 18-Cr-6, DMSO, rt
4gβ, 0%
NaNO2 (5 equiv), DMF, 50 °C, 2 h 30 min
KNO2 (5 equiv), DMF, 50 °C, 2 h 30 min
AcONa (3 equiv), DMF, rt, 4 h 30 min
AcONa (3 equiv), DMF, rt, 6 h
4gβ, 28%
4gβ, 22%
6gβ, 31%
6gα, 63%
be marginally more successful and provided the inverted ester
6gβ in a still moderate 31% yield (Table 2, entry 4).
Conversely, treatment of the stereoisomeric triflate 4mα with
sodium acetate proceeded more smoothly and afforded ester
6gα in an acceptable 63% yield (Table 2, entry 5). Intriguingly,
therefore, triflation of the alcohol antiperiplanar to the
phosphoryl oxygen (and synclinal to the methoxy group) was
The introduction of a fourth benzyl ether into phostones
4gα,β and 4mα,β to give the corresponding tetrabenzyl ethers
9gα,β and 9mα by the use of sodium hydride and benzyl
bromide was successful, but was complicated by a competing
demethylation reaction to give the corresponding phosphonic
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acids 10 (Table 3, entries 1 and 238). With alcohol 4mα the use
of heterogeneous conditions with 1 M aqueous sodium
Scheme 4. Synthesis of the Thiophostones 11gα,β, 11mα,β,
12gα,β, and 12mα,β
Table 3. Benzylation of 4gα,β and 4mα,β
a
entry alcohol
conditions
product yield
1
2
3
4mα
NaH, BnBr, DMF, rt, 6 h
9mα
9gα,β
9mα
31%
a
4gα,β NaH, BnBr, THF, TBAI, rt, 6 h
30%
4mα
4mβ
4gα
BnBr, n-Bu4NHSO4, NaOH 1 N/
CH2Cl2, 1 h 30 min
80%
15%
1%
4
5
6
7
BnBr, n-Bu4NHSO4, NaOH 1 N/
CH2Cl2, 3 h 30 min
9mβ
9gα
9gβ
BnBr, n-Bu4NHSO4, NaOH 1 N/
CH2Cl2, 3 h 30 min
4gβ
BnBr, n-Bu4NHSO4, NaOH 1 N/
CH2Cl2, 6 h
2%
(a) From a mixture of 6gα,β.
4mα
Cl3CC(NH)OBn, TfOH cat.
9mα
55%
successfully reduced in this manner and afforded the
corresponding phosphonite−boranes with full retention of
stereochemistry (Scheme 5). The fourth such isomer, the 2-O-
a
Obtained as a 1/2.5 mixture of 9gβ/9gα.
hydroxide and benzyl bromide in dichloromethane39 was
more successful and afforded 9mα in 80% yield (Table 3,
entry 3). Unfortunately, this success did not extend to the other
members of the series when only disappointing results were
obtained (Table 3, entries 4−6). It is noteworthy that the
reactivity order in the diastereomeric pair 4mα,β toward benzyl
bromide and aqueous base, with the more reactive isomer
having the phosphoryl group synclinal to the alcohol, is the
opposite of that noted above for triflation of the same pair
(Table 2). The Bronsted acid-catalyzed benzylation of 4mα
with benzyl trichloroacetimidate and triflic acid11e was also
found to afford 9mα in moderate yield (Table 3, entry 7), but
these conditions were not extended to the other members of
the series.
Scheme 5. Reduction of Thiophostones to Phosphonite−
Borane Complexes
Preparation of Phosphonite−Borane Complexes. With
two sets of four diastereomeric phostones 6gα,β, 6mα,β,
9gα,β, and 9mα,β in hand, attention was focused on their
reduction to the corresponding P(III) derivatives. None of the
classical reduction protocols for the reduction of phosphoryl
systems were satisfactory for our purposes. We focused instead
on the initial conversion of the phosphoryl group to the
corresponding thiophosphoryl system by means of equilibra-
tion with Lawesson’s reagent, a transformation that is known to
take place with retention of configuration at phosphorus.11f
Thus, the fully protected phostones 6gα,β, 6mα,β, 9gα,β, and
9mα,β were heated to 70 °C in toluene with an excess of
Lawesson’s reagent resulting in the formation of what we dub
the thiophostones (11gα,β, 11mα,β, 12gα,β, and 12mα,β) in
moderate to good yield (Scheme 4) with no loss of
stereochemical integrity.40 Gratifyingly, the isomers 11gα and
11gβ were readily separable by chromatography at this stage,
making it possible to carry the much more difficultly separable
glucosyl acetates to this stage as an anomeric mixture.
(a) 11% of a 2-deacetylated product. (b) 23% of a product with loss of
phosphorus function was obtained (see the Supporting Information).
acetyl-β-manno system 11mβ, did not afford the desired
product but gave instead 11% of a desacetyl product. In
contrast, in the tetra-O-benzyl series, only one of the four
diastereomers, the 2-O-benzyl-α-manno system 12mα, was
amenable to reduction in this manner with the other three
isomers either failing (12gαβ) to react or undergoing
decomposition (12mβ) under the reaction conditions (Scheme
5). Previous workers had described the reaction of Raney Ni
with sialyl derived-thiophostones to be completely ineffective.42
Evidently, the success of the thiophostone reduction is strongly
dependent on both the O2 protecting group and the
stereochemistry at phosphorus. Benzyl ethers, with the one
Reduction of the thiophostones 11gα,β, 11mα,β, 12gα,β,
and 12mα,β was investigated using Raney-Ni41 with immediate
trapping of the reduced products in the form of phosphonite−
borane adducts due to the high degree of sensitivity of the
uncomplexed phosphonites to aerial oxidation. In the 2-O-
acetyl series, three of the four available diastereomers were
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exception, are generally detrimental, consistent with the failures
reported earlier by other groups whereas acetate esters are
acceptable except for the one case in which a fragmentation was
observed.
Table 4. Coupling of the Per-O-benzyl Donor 16mα
Finally, in preparation for the coupling reactions, the
phosphonite ester−borane complexes were cleaved to the
corresponding phosphonite−borane complexes, which were
conveniently isolated in the form of their triethylammonium
salts. A number of conditions were investigated for this
transformation including the use of sodium iodide11c and of
bromotrimethylsilane11d to no avail. DABCO, whose successful
use had been reported previously in a similar reaction24e and
which is known to cleave phosphine−borane complexes
effectively,43 had no effect in the transformations at hand.
The use of an excess of thiophenol and of triethylamine in THF
at room temperature,24a,c,44 however, proved to be effective and
enabled the isolation of the ammonium phosphinates, in the
form of their borane complexes in high yield following silica gel
chromatography (Scheme 6). One isomer, the 2-O-acetyl-β-
a
entry
X+
conditions
product, % yield
1
2
3
4
5
6
7
H
H
H
17, PyNTP, MeCN
18mα, 26%
0%
17, PyBOP, DMF
17, BOPCl, NT, THF
17, PyBOP, DMF
18mα, 63%
0%
HNEt3
HNEt3
HNEt3
HNEt3
b
17, BOPCl, NT, THF
MeOH, BOPCl, NT, THF
17, BOPCl, DMAP, THF
18mα, 82%
14mα, 74%
c
18mαβ, <35%
Scheme 6. Demethylation to Ammonium Phosphonite−
Borane Complexes
a
b
c
Isolated yields. 0.8 equiv of alcohol 17 was used. Obtained as a
mixture of deborylated/borylated products. Following oxidation with
m-CPBA, a 2:1 mixture of 21mα and 21mβ was obtained.
BOPCl/NT system gave 82% of 18mα as a single
diastereoisomer (Table 4, entry 5). A further coupling of
16mα was conducted with methanol as acceptor using the
BOPCl/NT system, resulting in the formation of the α-methyl
product 14mα (Table 4, entry 6) and thereby confirming the
retentive nature of these substitutions. A final coupling of
16mα with 17 employing DMAP rather than NT was
complicated by partial deborylation in the course of the
reaction, resulting in a low yield (Table 4, entry 7) and
difficulties in the assignment of anomeric stereochemistry.
Nevertheless, after oxidation with m-CPBA, it was determined
that a 2:1 ratio of anomers had been formed that favored the β-
anomer. Given the evident importance of the nitrotriazole in
these coupling reactions, the stereochemical outcome with
overall retention of configuration is best rationalized in terms of
an initial invertive displacement of the activated phosphonite by
the heterocycle or its conjugate base followed its invertive
displacement by the alcohol.
Application of the BOPCl/NT conditions to the coupling of
the 2-O-acetyl gluco-configured donors 15gα or 15gβ and
acceptor 17 resulted in the formation of the two diastereomeric
products 19gβ and 19gα in 57:43 and 68:32 ratios, respectively,
favoring in both cases the β product (Table 5, entries 1 and 2).
Increasing the amount of NT employed significantly increased
the yield of the coupling but had no effect on the
stereoselectivity, whereas reducing the amount of NT
employed led to an improved stereoselectivity but at the
expense of the yield (Table 5, entries 3−5). Replacing NT by 4-
dimethylaminopyridine (DMAP) gave the optimum results, a
fully β-selective reaction and an isolated yield of 74% (Table 5,
entry 6). Application of these later conditions to the anomeric
donor 15gβ also resulted in the unique formation of the β-
product in good yield (Table 5, entry 7). With donor 15gβ, in
the absence of either NT or DMAP, excellent selectivity was
observed, but only a low yield of the product was obtained and
the additional complication of competing deborylation was
noted (Table 5, entry 8). On the other hand, with the isomeric
donor 15gα, no coupling was observed in the absence of the
gluco salt 15gβ, provided crystals suitable for X-ray diffraction
and hence confirmation of the stereochemical outcome of these
processes (see the Supporting Information).
Coupling Reactions of Phosphonite−Borane Com-
plexes. We first studied coupling with the per-O-benzyl
protected mannosyl donor 16mα so as to avoid all potential
problems arising from the participation of protecting groups.
Adopting conditions recommended by the Wada group in their
work on phosphotriester synthesis with phosphonite−borane
complexes,24c the protio form of 16mα (as opposed to the
triethylammonium salt) was coupled to the primary acceptor
17 by means of 3-nitro-1,2,4-triazolyl-1-yl-tris(pyrrolidin-1-
yl)phosphonium hexafluorophosphate45 (PyNTP) in the
presence of diisopropylethylamine in acetonitrile at room
temperature, giving rise to the formation of the disaccharide
mimetic 18mα with complete retention of configuration at
phosphorus, albeit in only modest yield (Table 4, entry 1). The
use of benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hex-
afluorophosphate (PyBOP) under similar conditions (Table 4,
entry 2) failed to give any of the desired compound, while the
use of the closely related benzotriazol-1-yloxy-tris-
(dimethylamino)phosphonium chloride (BOPCl) reagent in
the presence of 3-nitro-1,2,4-triazole (NT),24a a critical
component of the PyNTP system, gave the desired product
18mα in 63% yield as a single diastereoisomer (Table 4, entry
3). The simple PyBOP system was again ineffective with the
triethylammonium salt of 16mα (Table 4, entry 4), whereas the
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Table 5. Coupling of the 2-O-Acetyl Gluco Donors 15gα,β
Table 6. Coupling of the 2-O-Acetyl Manno Donor 15mα
a
entry
amine/solvent
19mβ/19mα
20mβ/20mα
yield
b
1
2
3
4
5
6
7
8
NT/THF
9/91
62%
96%
NT/PhMe
0/100
b
NT/CH2Cl2
DMAP/THF
DMAP/PhMe
DMAP/CH2Cl2
DMAP/MeCN
10/90
80/20
60/40
98%
b
b
49%
73%
a
entry
donor
ROH
17
amine (equiv)
% yield, product ratio
23/77
0/100
38%
91%
0%
1
2
15gα
15gβ
15gβ
15gβ
15gβ
15gβ
15gα
15gβ
15gα
15gβ
15gα
NT (3)
54, 19gβ:19gα = 57:43
46, 19gβ:19gα = 68:32
83, 19gβ:19gα = 56:44
44, 19gβ:19gα = 84:16
21, 19gβ:19gα = 84:16
74, 19gβ:19gα = 100:0
67, 19gβ:19gα = 100:0
17
NT (3)
−/THF
3
17
NT (20)
NT (1)
a
b
Isolated yields. Yield and ratio measured after oxidation.
4
17
5
17
NT (0.5)
DMAP (3)
DMAP (3)
processes. This choice is further guided by the obvious
influence of the nucleophilic catalysts 3-nitro-1,2,4-triazole47
and DMAP in the coupling process. An interesting feature of
the nucleophilic catalysis observed concerns the charge state of
the intermediate adducts. Thus, while the nitrotriazole with its
pKa of 5.1947 must lead to a neutral adduct under the reaction
conditions,24a the use of DMAP necessarily infers the close
association of two at least formal positive charges, and it is
interesting to speculate that such a system is stabilized by
proximity to the hydride system (Figure 2). In these structures,
6
17
7
17
b
8
17
25, 19gβ:19gα = 100:0
9
17
0, −
c
c
10
11
MeOH
MeOH
DMAP (3)
DMAP (3)
82, 13gβ:13gα = 66:34
69, 13gβ:13gα = 85:15
a
b
Isolated yields. Obtained as a 1:1 mixture with the deborylated
c
product. 7.7 equiv of MeOH was used.
amine catalyst (Table 5, entry 9). Finally, both anomeric
donors were coupled to methanol under the optimal
conditions, resulting in good yields of the methyl esters 13gα
and 13gβ in anomeric mixtures that favored the β-isomer in
each case (Table 5, entries 10 and 11), possibly indicating a
different mechanism for coupling to the more highly reactive
alcohol.
The BOPCl coupling conditions were also applied to the
mannosyl donor 15mα, which bears a 2-O-acetyl protecting
group. Both the NT and the DMAP promoter systems were
assayed as were a variety of different solvents leading to the
results presented in Table 6. Under certain conditions (Table 6,
entries 1, 3, 4, and 5), to circumvent problems from partial
deborylation of the products, the reaction mixtures were treated
with m-CPBA before isolation so as to afford the more stable
P(V) oxidation state, as both the oxidation deborylation
process and the simple peracid oxidation of P(III) systems are
known to proceed with retention of configuration. With
nitrotriazole as nucleophilic partner in three different solvents,
the axial product predominates, corresponding to a prepon-
derance of retention of configuration (Table 6, entries 1−3). In
contrast, with DMAP as promoter, the selectivity is solvent
dependent with good to excellent α-selectivity being exhibited
in dichloromethane and acetonitrile (Table 6, entries 6 and 7)
and moderate to good β-selectivity in THF and toluene (Table
6, entries 4 and 5). In the absence of either NT or DMAP, no
coupling product was formed (Table 5, entry 8).
Figure 2. Hypothetical intermediate structures in the coupling
reactions of 16mα catalyzed by nitrotriazole and by DMAP. Counter
ions have been omitted for clarity.
the amine may occupy the equatorial site, such as is typical in
glycosyl imidazolinium48 and pyridinium salts,49 or the axial
position. The equatorial preference of cationic substituents at
the anomeric center is classically referred to as the reverse
anomeric effect,49a for which the most reasonable current
explanation simply revolves around the steric bulk of the
solvated cation (and its associated anion), which causes it to
occupy the least hindered site. The α-glycosyl pyridinium salts,
Stereoselectivity of the Coupling Reaction. Concerning
the mechanism of nucleophilic substitution at phosphorus,46
the formal charge resident on phosphorus in the phosphonite−
borane complexes studied inclines us to exclude the possibility
of dissociative mechanisms and to focus instead on associative
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while sterically more demanding, are currently considered to
benefit from the anomeric effect50 due to the powerfully
electron-withdrawing effect of the positively charged hetero-
cycle.51 For the pyridinium phosphinate−boranes proposed
here, steric arguments favoring the equatorial system are less
compelling due to the longer bonds of both the ring oxygen,
C2, and the heterocyclic nitrogen to the phosphorus center
than to the anomeric carbon in simple sugars.
absence of the nucleophilic catalyst; evidence for such kinetic
effects with a variety of classical donors is known even if their
extent has recently been questioned.56 However, the alternative
possibility of the intervention of an α-glucosyl triazole or
pyridinium salt, according to the additive employed, cannot be
ruled out. In this respect, we note that glycosyl pyridinium salts
are routinely prepared by the reaction of peracetylated glycosyl
donors with pyridine; that is, the pyridinium salt is more stable
than the cyclic dioxalenium ion. The reduced selectivity in the
presence of greater amounts of the triazole catalyst is probably
best explained by an increase in the equilibrium population of
the covalently bound β-triazolyl species (Figure 3).
With the α-manno-configured donor 15mα, a priori the most
favorable system among those studied for the involvement of
neighboring group participation, the situation appears more
complex, and the selectivity was found to be dependent on
solvent, at least with DMAP as the nucleophilic partner (Table
6). The α-anomeric product 19mα or 20mα that predominates
under most conditions can be interpreted in terms of
neighboring group participation with a cyclic dioxolenium ion
intermediate as depicted in Figure 4, but the possibility of a β-
In the case of the per-O-benzyl donor 16mα, which, with the
nitrotriazole-based systems studied, affords exquisitely α-
selective reactions (Table 4), it is evident that following initial
activation the nucleophilic catalyst enters to give equatorial
adducts of the type depicted in Figure 1 that are ultimately
displaced by the incoming nucleophile to give the α-linked
product. However, when NT was replaced by DMAP (Table 4,
entry 7), a moderately β-selective reaction was observed albeit
in only low yield. This latter result might be viewed as
indicative of greater stability of the α-pyridinium salt versus its
β-anomer or, conversely, of the operation of a Curtin−
Hammett-type scenario in which the α- and β-pyridinium salts
are in rapid dynamic equilibrium, with the less stable α-anomer
being the more reactive of the two. In support of this argument,
which draws on the Lemieux mechanism for the bromide anion
catalyzed synthesis of α-glucosides,52 we note that recent
studies on the use of glucosyl pyridinium salts as glycosylating
agents indicate that the α-isomer is the more reactive of the two
anomers.53 In a similar vein, we also note the recent proposal of
α-glycosyl pyridinium salts as the reactive species in the DMAP
catalyzed β-selective addition of alcohols to 2-nitroglycals.54
With regard to the 2-O-acetyl donors studied (15gα,β, 15mα,
and 16mα), the situation is more complex, and it is evident that
the acetate group influences the mechanism. Such a
phenomenon closely parallels that seen in standard glycosyl
donors and might be attributed to one or more of a
combination of factors including neighboring group partic-
ipation,55 anchimeric assistance, and the simple electron-
withdrawing (disarming) effect of the ester group. In the
glucose series where both anomeric donors 15gβ and 15gα are
available for study, there is a clear preference for the formation
of the β-anomeric product (Table 5) whatever the config-
uration of the donor employed except at higher concentrations
of the nitrotriazole catalyst suggestive of neighboring group
participation via a five-membered cyclic intermediate (Figure 3)
following the initial activation. The difference in reactivity
between the α- and β-donors 15gα and 15gβ in the absence of
nucleophilic catalysis is suggestive of anchimeric assistance to
the departure of the leaving group by the trans-ester in the
Figure 4. Hypothetical intermediates leading to the formation of β-
and α-products from the donor 15mα. Partial charges at boron and
phosphorus have been omitted for clarity.
pyridinium salt cannot be excluded particularly in view of the
apparent requirement of DMAP for the formation of the
coupling product. The preferential formation of the β-product
19mβ or 20mβ (Table 6, entries 4 and 5) and its formation to a
significant extent in other cases (Table 6, entries 6 and 8) must
be interpreted by the intervention of an α-adduct with DMAP
(Figure 3) that is stabilized with respect to the corresponding
more polar β-adduct or the polar dioxalenium ion in the less
polar solvents in which the phenomenon occurs. In this
context, it is important to note that the anomeric effect is larger
in mannose than in glucose because of the antiperiplanar nature
of the C2−O2 bond with respect to the axial glycosidic bond
and, moreover, that the anomeric effect is greater in
peracetylated mannose than in mannose itself.57 Thus, the α-
pyridinium salt can be expected to be more likely to play a role
in the manno- rather than in the gluco-series, and this role is
likely to be more important in the case of the acetylated
mannosyl donor 15mα than in that of the benzylated mannosyl
donor 16mα.
One final unknown is the extent to which, if any, dihydrogen
bonding intervenes to direct the incoming nucleophile. Thus, a
so-called dihydrogen bond between the hydridic hydrogen of
Figure 3. Hypothetical intermediates leading to the formation of β-
and α-products from the donors 15gα and 15gβ. Partial charges at
boron and phosphorus have been omitted for clarity.
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phosphine boranes and the acidic hydrogen of phenols has
been advanced based on crystallographic evidence.58 Accord-
ingly, the possibility exists of such a dihydrogen bond between
the incoming alcohol and the borane of one or more of the
likely intermediates and that it directs the alcohol to the same
face of the system as the borane moiety in a solvent-dependent
manner. The possibility that donor−acceptor hydrogen
bonding directs glycosylation reactions59 has been raised in
recent years and is a subject of ongoing discussion in the
literature.60
Deborylation and Oxidative Deborylation. The ability
to both deborylate the phosphonite−borane adducts following
coupling and to oxidize the subsequent phosphonites to the
P(V) oxidation in a predictable, stereospecific manner is a
critical element in the overall protocol. Accordingly, we
investigated a number of conditions for deborylation. Among
the conditions assessed, tetrafluoroboric acid in dichlorome-
thane,23a the dimethoxytrityl cation generated from dimethox-
ytrityl methyl ether with dichloroacetic acid,61 and displace-
ment with either trimethylphosphite or hexamethylphospho-
triamide all were unsuccessful and left the starting material
unchanged.62 DABCO, which is reported to be the reagent of
choice for deborylation of phosphine−boranes,43 removed the
borane moiety from the disaccharide 18mα giving the
corresponding phosphonite quantitatively, as determined by
31P NMR spectroscopy; oxidative workup was then performed
in situ to afford the corresponding phosphonate 21mα. With
I2,63 concentrated nitric acid,64 and diethyl bromomalonate,65
all reagents known to oxidize simple phosphines with inversion
of configuration,66 a single α-diastereomer that unexpectedly
retained the configuration of the initial phosphonite−borane
was obtained in 43%, 37%, and 21% yields, respectively
(Scheme 7). Hydroxylamine, a further reagent known to
Assignment of Stereochemistry. The β-glucophostones
4gβ and 6gβ were obtained, respectively, by sodium nitrite and
sodium acetic acetate displacement of the triflate group from
5mβ, which itself was derived from 4mβ by triflation (Table 2).
Therefore, as the structure of 4gβ was confirmed by X-ray
crystallographic analysis (see the Supporting Information), the
configurations of 4mβ, 5mβ, and 6gβ are established by direct
correlation and those of their anomers by default. The
structures of compounds 8gβ and 8mα were also established
crystallographically, which confirms by default those of their
anomers 8gα and 8mβ. Subsequently, beyond the use of
standard one and two-dimensional 1H and 13C methods for the
assignment and verification of stereochemistry at C2 (gluco/
manno) of the various phostone derivatives, we have relied on
2
the use of JH2−P coupling constants for the determination of
configuration at phosphorus, with spectral analysis being
1
facilitated by the large (>100 Hz) JP,C2 coupling constant
and the consequent easy identification of H2. In the gluco-
series, we found the 2JH2−P coupling constant to be consistently
smaller for the α-series (1.7−4.6 Hz) in which the phosphoryl
(PO) bond is gauche to the C2−H2 bond than for the β-
series (6.4−10.4 Hz) in which the PO and C2−H2 bonds
are antiperiplanar. The NMR-derived configurations are in full
accord with those derived above crystallographically and by
chemical correlation. These crystallographically supported
2
correlations of JH2−P coupling constants with anomeric
stereochemistry for the gluco-phostones agree neither with
Drueckhammer who, in his pioneering work on the
phostones,11c adduced the opposite rule, nor with Claesson
and co-workers42 who subsequently upheld Drueckhammer
albeit without experimental support. At present, we are unable
to rationalize this difference in interpretation. Correlation of the
2JH2−P coupling constants with anomeric stereochemistry is not
applicable in the manno-series due to the gauche relationship of
H2 to the PO bond in both anomers.
Scheme 7. Conversion of the Phosphonite−Borane 18mα to
the Phosphonate 21mα
In many cases, supporting data may also be gleaned from the
31P chemical shift of the phostones with the axial P−OMe
group resonating some 2−4 ppm more upfield than the
corresponding equatorial P−OMe moiety.11e We found this
rule to apply in the 4, 6, and 9 series; a larger chemical shift
difference of 8−14 ppm was observed in the thiophostones 11
and 12. This effect is less pronounced in the manno series than
in the gluco series, and is reduced to zero for 11mα and 11mβ.
3
We also noted a consistently higher value for the JP,OMe
coupling constant for the equatorial P−OMe groups than for
the axial P−OMe systems, with the sole exception of the two
manno derivatives 4mα and 4mβ. IR spectroscopy gave a final
confirmation of the anomeric configuration of all compounds.
As described by Thiem,11a we observed the axial PO bonds
to have a γmax of 1260 cm−1, whereas the equatorial PO bond
has γmax 1290 cm−1.
In the solid state, all of the compounds analyzed crystallo-
graphically exhibit a well-defined chair conformation, even
those with an axial P−-OMe group, although it had been
suggested previously that such compounds may also adopt a
twist boat conformation.11e,70 The crystallographically observed
oxidize phosphines with inversion of configuration,67 was
ineffective. The unexpected retention of configuration in these
oxidations finds parallel in the work of Mikolajczyk who
observed that oxidation of acyclic phosphonites with dimethyl
selenoxide proceeds with inversion of configuration, but that of
cyclic phosphonites with retention.68 Direct oxidative debor-
ylation of 18mα with m-CPBA24e,69 was found to be more
convenient than the two step protocol and gave 21mα in 72%
yield with full retention of configuration consistent the
literature on the oxidation of P(III) derivatives with peracids
(Scheme 7).
2
chair conformations persist in solution as their JH2,P coupling
constants were typically <5 Hz, whereas they are known to be
in the range of 30−35 Hz for six-membered cyclic
phosphonates that adopt boat or twist-boat conformations.11a,42
Exploration of Acceptor Scope and Limitations and
Final Deprotection. The couplings of donors 15gα,β, 15mα,
and 16mα were explored with a range of primary alcohols (17,
H
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Table 7. Coupling Reactions of Ammonium Boranophosphonites and Subsequent Oxidation and Deprotection
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Table 7. continued
a
b
1
Isolated yields. Anomeric ratio of 1:4 α:β determined by H NMR on the crude reaction mixture; the yield is for the pure isolated β-isomer.
22−28), prepared by standard means, leading to the results
reported in Table 7. The coupled products either were isolated
and characterized and subsequently oxidized to the phospho-
nates with m-CPBA (Table 7, entries 1−8, 13−16) or were
engaged directly in the oxidative deborylation without
intermediate purification (Table 7, entries 9−12). A final
example (Table 7, entry 17) was not subjected to deborylation
or oxidation because of the olefinic character of the aglycone.
Each of these coupling reactions proceeded with moderate to
good yield and with excellent stereoselectivity consistent with
the patterns established in the exploratory phase of the
investigation (vide supra). The only exception to this rule
was couplings conducted with donor 15mα under conditions
optimized for formation of the β-anomer (Table 7, entries 9
and 10) when approximately 4:1 mixtures of diastereomers
were observed in which the desired β-anomer nevertheless
predominated. Attempts to extend the various coupling
reactions to the use of secondary alcohols as acceptors such
as menthol or methyl 2,3-O-isopropylidene-L-rhamnopyrano-
side were, however, generally unsuccessful giving only low
yields of disaccharides, presumably for steric reasons arising
from the presence of the borane moiety at the reaction center.
All oxidation reactions proceeded with clean retention of
configuration at phosphorus.
end, working with the simple methyl phosphonates, we
determined that exposure to BCl3 in dichloromethane followed
by workup with MeOH in the standard manner71 is a
convenient and suitable method for the removal of benzyl
ethers without concomitant cleavage of the phosphonate group
(Table 8, entries 1 and 2). This protocol was also applicable to
the methyl thiophosphonate 12mβ (Table 8, entry 3) giving
the fully deprotected thiophostone 47mβ. Hydrogenolysis over
palladium on charcoal was also found to be suitable for the
removal of benzyl ethers (Table 8, entry 4).71 With respect to
the removal of carboxylate esters, careful treatment with
sodium methoxide in methanol was found to be suitable
provided that the reaction was carefully monitored and
quenched before the onset of the slower transesterification of
the phosphonate group. Thus, phostone 21mα was exposed to
sodium methoxide to remove the three benzoate esters
followed, after extractive workup, by BCl3 resulting overall in
the phostone 48mα in 70% overall yield (Table 8, entry 5).
Unfortunately, the methyl glucoside moiety of 48mα was
scrambled during the course of the methanolic workup of BCl3
(Table 8, entry 5). Treatment with BCl3 followed by MeOH
was effective for the removal of the acetonide group in 36mα
concomitant with cleavage of the benzyl ethers (Table 8, entry
6). Transesterification with sodium methoxide in methanol
followed hydrogenolysis in a mixture of acetic acid and aqueous
THF was found to be suitable for the complete deprotection of
42mα giving phostone 50mα in 58% yield for the two steps
(Table 8, entry 7). Finally, transesterification and hydro-
Finally, we turned to the deprotection of selected examples
with the goal of identifying conditions suitable for the removal
of both acid and base labile protecting groups without
detriment to the cyclic phosphonate functionality. To this
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deprotection conditions were established. Further work will
be reported in due course.
Table 8. Deprotection of Phostones
ASSOCIATED CONTENT
* Supporting Information
Full characterization data and copies of spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
dcrich@chem.wayne.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
A.F. thanks the ICSN for financial support.
■
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■
Asymmetric hydrophosphonylation methodology enables opti-
mization of the Drueckhammer synthesis of six-membered
phostones for the formation of the manno-isomer, of which
inversion affords ready access to the gluco-series. Subsequent
conversion to the thiophostones with Lawesson’s reagents
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diastereomeric phostones, the β-gluco, and α- and β-manno-
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