Preparation of THP-ester-derived pyridinium-type salts and their reactions with various nucleophiles

Article abstract of DOI:10.1002/asia.201200234

Nucleophilic substitution at the anomeric positions of tetrahydropyranyl (THP) and related carbohydrate-derived esters that proceeded through pyridinium-type salt intermediates have been developed. Treatment of the 6-substituted α-acetoxy-tetrahydropyrans

Full text of DOI:10.1002/asia.201200234

DOI: 10.1002/asia.201200234
Preparation of THP-Ester-Derived Pyridinium-Type Salts and their
Reactions with Various Nucleophiles
Hiromichi Fujioka,* Yutaka Minamitsuji, Takahiro Moriya, Kazuhisa Okamoto,
Ozora Kubo, Tomoyo Matsushita, and Kenichi Murai[a]
Abstract: Nucleophilic substitution at
the anomeric positions of tetrahydro-
pyranyl (THP) and related carbohy-
drate-derived esters that proceeded
through pyridinium-type salt intermedi-
ates have been developed. Treatment
of the 6-substituted a-acetoxy-tetrahy-
dropyrans with TMSOTf (TMS=tri-
methylsilyl) and 2-substitutited pyri-
dines, such as 2-p-tolylpyridine and 2-
methoxypyridine, led to the efficient
generation of cis-pyridinium-type salts.
These salts reacted with various nucle-
ophiles, such as alcohols, azides, and or-
ganozinc reagents, to form nucleophil-
ic-substitution products. A characteris-
tic feature of these processes was that
they took place under mild conditions,
which did not affect acid-labile protect-
ing groups. Furthermore, the reactions
that employed azides and C-nucleo-
philes generated 2,6-trans products
with high degrees of stereoselectivity.
Keywords: nucleophilic
substitu-
tion · protecting groups · salt effect ·
synthetic methods
pyran
·
tetrahydro-
Introduction
Many biologically active natural products contain 2,6-disub-
stituted tetrahydropyranyl (THP) systems, such as dissaka-
laides, erythromycin A,[1a] kidamycin,[1b] phorboxazole A,[1c]
and zincophorin (Scheme 1).[1d] Typical methods to construct
these types of substituted frameworks use nucleophilic-sub-
stitution reactions at the anomeric position (2-position) of
THP ethers or esters. For example, various O-, N-, and C-
nucleophiles, including allylsilanes, silyl enol ethers, and
arenes, can be introduced at the anomeric positions of THPs
by using Lewis-acid-promoted reactions through the nucleo-
philic
capture
of
oxocarbenium-ion
intermediates
(Scheme 2).[2] However, processes of this type cannot be ap-
plied to substrates that contain acid-labile groups. The same
limitation applies to glycosylation reactions, in which a pro-
moter, such as a Lewis acid, is required to promote the reac-
tion between a glycosyl donor and acceptor.
In recent years, new glycosylation processes that rely on
pre-activation strategies have garnered considerable atten-
tion (Scheme 3).[3] This general approach, which involves ac-
tivation of the donor prior to the addition of the glycosyl ac-
ceptor, possesses numerous benefits, including the ability to
control chemical and stereochemical selectivities. In this
Scheme 1. Examples of bioactive natural products that contain 2,6-disub-
stituted THP groups.
context, we recently developed a method to activate acetals
for nucleophilic-substitution reactions that involved the
treatment of these substances with TESOTf (TES=triethyl-
silyl) and pyridines, such as 2,4,6-collidine (Scheme 4). The
overall reaction proceeded through the formation of a pyridi-
nium-type salt intermediate, which then underwent nucleo-
philic-substitution reactions with heteroatom-containing nu-
cleophiles, such as H2O,[4] alcohols, azides, and thiols.[5] This
[a] Prof. Dr. H. Fujioka, Y. Minamitsuji, T. Moriya, K. Okamoto,
O. Kubo, T. Matsushita, Dr. K. Murai
Graduate School of Pharmaceutical Sciences
Osaka University, 1–6 Yamada-oka
Suita, Osaka, 565-0871 (Japan)
Fax : (+81)6-6879-8229
E-mail: fujioka@phs.osaka-u.ac.jp
À
strategy has also been applied to C C bond-forming pro-
cesses, wherein Gilman reagents were employed as C-nucle-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200234.
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Results and Discussion
Preparation of THP Pyridinium-type Salts
Initially, we investigated the conditions required to prepare
THP pyridinium-type salts from the reactions of THP ethers
with TESOTf and pyridines. A major issue in these process-
es concerned the selectivity of the reactions that involved
two different ether oxygen centers in THP ethers. Impor-
tantly, the selective coordination of silyltriflate to the exocy-
clic oxygen was required to form THP pyridinium-type salts
that would participate as intermediates in anomeric-substitu-
tion reactions. However, our previous investigation of the
deprotection of THP ethers suggested that the endocyclic
oxygen center in these substances was more reactive. Specif-
ically, we observed the selective coordination of TESOTf to
the less-hindered endocyclic oxygen of THP-protected alco-
hols, followed by displacement with 2,4,6-collidine to form
the ring-opened pyridinium-type salt, which subsequently re-
acted with H2O to give the deprotected alcohol
(Scheme 6).[7]
Scheme 2. Introduction of nucleophiles at the anomeric positions of
THPs.
Scheme 3. Pre-activation method for the introduction of nucleophiles at
the anomeric positions of THPs.
Scheme 4. Nucleophilic-substitution reactions of acetals.
ophiles in reactions with the intermediate pyridinium-type
salts.[6] Moreover, this method employed almost neutral con-
ditions and, as a result, even acid-labile functionalities, such
as a trityl (Tr) group, were tolerated. In a recent investiga-
tion, we applied this strategy, which was regarded as a pre-
activation strategy, for the introduction of nucleophiles, such
as alcohols, azides, and C-nucleophiles, onto the anomeric
centers of 6-alkoxymethyltetrahydropyranyl esters, including
carbohydrate derivatives (Scheme 5).
Scheme 6. Deprotection of THP ethers by using
TESOTf and 2,4,6-collidine.
a combination of
In contrast, we anticipated that, when this procedure was
applied to 6-alkoxymethyl-substituted tetrahydropyran de-
rivatives, TESOTf coordination would occur selectively at
the less-sterically encumbered exocyclic oxygen and, as
a result, that pyridinium-salt formation and subsequent nu-
cleophilic displacement would take place at the THP
anomeric center (Scheme 7).
To explore this proposal, we investigated the reaction of
6-benzyloxymethyl-substituted THP methyl ether 1 with
TESOTf and 2,4,6-collidine (Scheme 8). We observed that
collidinium salts 2a and 2b were not generated in this pro-
cess but instead a small quantity of enol ether 3 was ob-
tained. Based on the thought that the failure of this process
might be a consequence of the poor leaving ability of the
methoxy group, we probed the reaction of 2-acetoxy deriva-
tive 4 with TESOTf and 2,4,6-collidine, followed by the ad-
dition of EtOH. However, again, the reaction led to the for-
mation of enol ether 3 as the major product along with
small amounts of THP ethyl ether 5a. Although the use of
TMSOTf instead of TESOTf led to a slightly improved yield
of compound 5a, the major product was still enol ether 3
(Scheme 9).
Scheme 5. Pre-activation strategy for promoting nucleophilic-substitution
reactions at the anomeric centers of 6-alkoxymethyltetrahydropyranyl
esters.
Abstract in Japanese:
The low yield of substitution product 5a compared to
enol ether 3 in the reaction of THP ester 4 suggested that
the nucleophilic-substitution reaction of the silyltriflate com-
plex was slower than b-elimination, owing to the high basici-
ty and low nucleophilicity of 2,4,6-collidine. To investigate
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THP-Ester-Derived Pyridinium-Type Salts
was used and a long reaction
time was required for its con-
version into compound 5a
(Table 1, entry 7).
The formation of pyridinium-
type salt intermediates in the
substitution-reaction pathway
was demonstrated by using
HRMS (FAB; Scheme 10). MS
(FAB+) analysis of the mixture
from the reaction of compound
4 with TMSOTf (2 equiv) and
2-p-tolylpyridine (3 equiv) in
CH2Cl2 (0.1m) showed a [M]+
peak at m/z 374.2115 with a mo-
lecular formula of C25H28NO2,
which corresponded to 2-p-tol-
ylpyridinium salt 6. Importantly,
a [M]+ peak owing to 2-p-tolyl-
pyridinium salt 7, which would
have been produced from a re-
action initiated by complexa-
tion of the endocyclic oxygen,
was not observed. In addition,
a [M]+ peak that was associated
with the glycosyl triflate 8 was
not found.
Scheme 7. Selective nucleophilic substitution of 6-alkoxymethyltetrahydropyranyl ethers at their anomeric po-
sitions.
Scheme 8. Reaction of THP ether 1 with TESOTf and 2,4,6-collidine.
Analysis of the 1H NMR
spectra of starting THP ester 4
(cis/trans=1:1.5) and the mix-
ture that was formed by the re-
action of this THP ester with
TMSOTf and 2-p-tolylpyridine
in CD2Cl2 (Figure 1, also see
the Supporting Information)
demonstrated that complete
conversion of the substrate
Scheme 9. Reaction of THP ester 4 with silyltriflate and 2,4,6-collidine, followed by the addition of EtOH.
this issue further, we performed the reactions of compound
4 with TMSOTf and other pyridines (Table 1). These results
showed that the use of 2,6-lutidine was not effective
(Table 1, entry 2) but that, when the less-bulky 2-pi-
coline was used, the pyridinium-type salt was effi-
took place to form the pyridinium-type salt intermediate.
Furthermore, the presence of a doublet-of-doublets (J=10.0
ciently formed and reacted with EtOH to produce
compound 5a in 73% yield, although a long reac-
tion time was required (Table 1, entry 3). However,
the reaction with 2,2’-bipyridyl, which is known to
be an efficient base for the transformations of me-
thoxymethyl (MOM) ethers into alcohols[8] and
methylene acetals into 1,2- or 1,3-diols,[9] gave com-
pound 5a in almost the same high yield but in
a much shorter reaction time (Table 1, entry 4). The
use of other 2-substituted pyridines, including 2-
phenylpyridine and 2-p-tolylpyridine, also led to
minimization of the contribution of b-elimination
and efficiently generated compound 5a as the main
product (Table 1, entries 5 and 6). Finally, a highly
Table 1. The use of various pyridines in the TMSOTf-promoted reactions of THP
ester 4 with EtOH.
Entry
Pyridines
t
Yield [%] of 5a (trans/cis)[a]
Yield [%] of 3
1
2
3
4
5
6
7
2,4,6-collidine
2,6-lutidine
2-picoline
2,2’-bipyridyl
2-phenylpyridine
2-p-tolylpyridine
pyridine
2 h
5 min
27 h
15 min
30 min
30 min
4 d[b]
18 (64:36)
trace
51
65
9
73 (63:37)
71 (71:29)
83 (68:32)
86 (67:33)
30 (65:35)
16
trace
trace
trace
[a] Stereoisomeric ratios were determined by using 1H NMR spectroscopy; [b] un-
stable pyridinium salt was formed when pyridine reacted pyridinium salt remained.
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Scheme 10. Possible intermediates in the reaction of compound 4 with
TMSOTf and 2-p-tolylpyridine.
Scheme 11. A plausible mechanism for formation of pyridinium-type salts
in the TMSOTf-promoted reactions of THP ester 4.
Scheme 12. Plausible mechanisms for formation of enol ether 3 in the
TMSOTf-promoted reactions of THP ester 4.
either E2 elimination (route C) or pyridine-induced deproto-
nation of the oxocarbenium-ion intermediate (route D;
Scheme 12). Independent of which pathway was involved in
the enol-ether formation, the steric bulk of the pyridine de-
rivative would be a governing factor in determining the
yield of the substitution product. In the case of 2,6-disubsti-
tuted pyridines, such as 2,4,6-collidine and 2,6-lutidine, enol
ether 3 was produced by one of the elimination pathways,
whereas the reactions that used less-hindered 2-monosubsti-
tuted pyridines, such as 2-p-tolylpyridine, afforded the de-
sired substitution products (Scheme 13).
Figure 1. 1H NMR spectra of: a) THP ester 4, b) the mixture produced by
its reaction with TMSOTf and 2-p-tolylpyridine.
and 2.0 Hz) at d=5.68 ppm demonstrated that the anomeric
proton was axial. The signal at d=6.34 ppm did not corre-
spond to an equatorial 2-proton in the pyridinium-type salt
intermediate but rather the a-proton of enol ether 3, which
was formed during the acquisition of the NMR spectra at
room temperature, owing to the instability of the pyridini-
um-type salt to generate enol ether 3 above 08C. These re-
sults showed that the 2-p-tolylpyridine group in the salt
adopted an equatorial orientation and that the salt pos-
sessed 2,6-cis stereochemistry. It has been previously report-
ed that equatorial THP 2-pyridinium-type salts are fa-
vored.[10]
Based on these observations, we proposed a mechanism
(Scheme 11) for the formation of the salt intermediate in
the TMSOTf-promoted reaction of THP ester 4. Because
a cis/trans ratio of 1:1.5 of compound 4 was not reflected in
pyridinium-type salt 6 (cis only), salt-formation did not
appear to occur via route A, which involved the SN2-type
concerted nucleophilic addition of 2-p-tolylpyridine and the
elimination of acetate. Instead, a pathway (route B) in
which the reaction proceeded through the formation of, and
pyridine addition to, an oxocarbenium-ion intermediate was
more likely. Enol ether 3 was generated in this process by
Use of Alcohol Nucleophiles
Having established optimized conditions (TMSOTf-2-p-tol-
ylpyridine) for the substitution reaction of THP ester 4, the
scope of this substitution process was investigated with a va-
riety of alcohols (Table 2). Alcohols other than EtOH
(Table 2, entry 1), including benzyl and secondary alcohols
(Table 2, entries 2 and 3), participated in this reaction to
form their corresponding THP ethers in high yields. When
the less-nucleophilic phenol was used, the desired product
(5d) was generated in moderate yield (Table 2, entry 4).
Moreover, when propargyl alcohol was the nucleophile, the
reaction proceeded with high efficiency (Table 2, entry 5). In
all cases, 2,6-trans products were formed in higher yields
than their corresponding 2,6-cis isomers.[11]
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THP-Ester-Derived Pyridinium-Type Salts
Table 4. Reaction of sugar derivatives.
Entry
Donor
Acceptor t [h] Product Yield [%] (a/b)[a]
1
2
EtOH
13
3
3
14a
14b
73 (45:55)
57 (62:38)
3
4
EtOH
13
2
3
15a
15b
88 (63:37)
65 (85:15)
[a] Stereoisomeric ratios were determined by using 1H NMR spectrosco-
py.
The reactions of 2-deoxysugar derivatives were also exam-
ined (Table 4).[13] 2-Deoxyglucose derivative 11 and 2-deoxy-
galactose derivative 12 reacted smoothly with EtOH to form
their respective glycosidic ethers (Table 4, entries 1 and 3).
Glucose derivative 13, which possessed a free primary alco-
hol group, also served as a nucleophile in this process
(Table 4, entries 2 and 4). These findings showed that this
method could be applied to the synthesis of disaccharides.
Scheme 13. Effects of the steric bulk of the pyridine derivative on
TMSOTf-promoted reactions of THP ester 4.
Table 2. Reaction of 4 with various alcohols.
Entry
R
t
5
Yield [%]
trans/cis[a]
Use of Azide as a Nucleophile
1
2
3
4
5
Et
Bn
iPr
30 min
1 h
30 min
1 h
5a
5b
5c
5d
5e
86
88
80
43
83
67:33
79:21
71:29
77:23
85:15
The use of this method for the formation of glycosyl azide
was also probed. Under the optimized conditions, which
have previously been shown to be applicable to the forma-
tion of N,O-acetal,[5] THP ester 4 reacted with NaN3 in the
presence of [18]crown-6 to form their corresponding azide
(16) in excellent yield (Table 5, entry 1). Moreover, by using
Ph
propargyl
30 min
[a] Stereoisomeric ratios were determined by using 1H NMR spectrosco-
py.
Table 3. Reactions of compound 9 with EtOH.
Table 5. Reaction conditions.
Entry
R
9 (trans/cis)
10
Yield [%]
trans/cis[a]
Entry
Conditions
t [min]
Yield [%]
trans/cis[a]
1
2
TBS
Tr
9a (37:63)
9b (34:66)
10a
10b
80
76
73:27
74:26
1
2
3
4
NaN3, [18]crown-6
TMSN3
TMSN3, TBAF
TMSN3, TBAT
60
–
30
5
88
N.R.
60
65:35
–
>95:5
>95:5
[a] Stereoisomer ratios were determined by using 1H NMR spectroscopy.
88
[a] Stereoisomeric ratios were determined by using 1H NMR spectrosco-
py. N.R.=no reaction.
Further studies of this process found that acid-labile
groups, such as TBS and trityl ethers, were stable under the
reaction conditions (Table 3, entries 1 and 2). Because the
previously reported methods for promoting these types of
substitution reactions employed acidic conditions that did
not tolerate the presence of acid-labile groups,[12] this result
demonstrated the power of this procedure.
a combination of TMSN3 and tetrabutylammonium difluoro-
triphenylsilicate (TBAT) to promote this process, the forma-
tion of the desired product (16) occurred in excellent yield
with high trans selectivity (Table 5, entry 4).
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Hiromichi Fujioka et al.
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also did not react to yield substitution products (Table 6, en-
tries 2 and 3). On the other hand, the reaction of diphenyl-
zinc (Ph2Zn) with the pyridinium-type salt of THP ester 4
produced the desired product (19a) in 40% yield (Table 6,
entry 4). Importantly, the 2,6-trans/cis diastereomeric ratio
of the product was >95:5. Thus, the nature and level of the
stereoselectivity were similar to those by using Lewis-acid-
promoted methods.[18a] Exploration of the addition of diphe-
nylzinc to several pyridinium-type salts showed that the re-
action of the one salt that was derived from 2-methoxypyri-
dine and compound 4 was optimal (Table 6, entry 5).
Scheme 14. Reaction of THP ester 9b with TMSN3 and TBAT.
Next, this azidation process was applied to THP ester 9b,
which contained a trityl group (Scheme 14). The desired
product (17) was formed without the loss of the acid-labile
trityl group in moderate yield with high diastereoselectivity.
The reaction of a pyridinium-type salt that was derived from
2-deoxyglucose derivative 11 with TMSN3 and TBAT also
proceeded efficiently to form the desired azide product but
with only moderate diastereoselectivity (Scheme 15). These
With the optimized conditions in hand, the scope of the
substitution reaction was explored by using several types of
organozinc (R2Zn) reagents (Table 7). The reactions of aro-
matic zinc reagents produced the desired products in excel-
Table 7. Reactions of salts that were derived from compound 4 and 2-
methoxypyridine with various organozinc reagents.
Entry
R
t [h]
19
Yield [%][b] (trans/cis)[c]
Scheme 15. Reaction of glycosyl ester 11 with TMSN3 and TBAT.
1
2
3
4
R’=H
R’=Me
R’=F
2
7
8
4
19a
19b
19c
19d
95 (>95:5)
89 (>95:5)
87 (>95:5)
70 (>95:5)
findings showed that this mild and high-yielding method can
be used to prepare glycosyl azides, which are potentially
useful substrates in click chemistry[14] and Staudinger liga-
tion[15] approaches for the generation of glycoarrays[16] and
glycoconjugates.[17]
R’=CO2Me
5
5
19e
89 (>95:5)
6
5
8
19 f
19g
83 (>95:5)
86 (>95:5)
Use of C-Nucleophiles
7[a]
Finally, we considered the use of C-nucleophiles in substitu-
tion reactions with pyridinium-type salts that were derived
from THP and other related esters.[18–21] The 2-p-tolylpyridi-
nium salt of compound 4 did not react with the Gilman re-
agent (Ph2CuLi), which was previously observed to partici-
pate in similar alkylation reactions of acetals (Table 6,
entry 1).[6] Phenyl lithium and phenyl magnesium bromide
8
9
Me
Et
vinyl
4
7
3
3
5
19h
19i
19j
19k
19l
76 (91:9)
70 (>95:5)
81 (>95:5)
80 (89:11)
77 (>95:5)
10[a]
11[a]
12[a]
[a] The C-nucleophilic-substitution process was performed at 08C;
[b] yield of isolated product; [c] stereoisomeric ratios were determined
by using H NMR spectroscopy.
1
Table 6. Nucleophilic-substitution reactions of various pyridinium-type
salts and C-nucleophiles.
lent yields with high levels of trans selectivity (Table 7, en-
tries 2–4). Electron-deficient nucleophiles participated in
this reaction (Table 7, entries 3 and 4) and 2-methoxyphen-
yl-, 2-naphthyl-, and heteroaromatic zinc reagents were also
good substrates for the substitution reaction (Table 7, en-
tries 5–7). Dimethylzinc and diethylzinc, as well as divinyl-
zinc, di(phenylalkynyl)zinc, and di(trimethylsilylalkynyl)-
zinc, reacted with the salt that was derived from 2-methoxy-
pyridine and compound 4 to form their corresponding prod-
ucts in good yields and stereoselectivities (Table 7, en-
tries 8–12).
À
Entry Pyridine
Ph M
t [h] Yield [%][a] trans/cis[b]
1
2
3
4
5
2-p-tolylpyridine
Ph2CuLi
PhLi
PhMgBr
Ph2Zn
Ph2Zn
–
–
–
7
2
trace
dec.
dec.
40
–
–
–
2-p-tolylpyridine
2-p-tolylpyridine
2-p-tolylpyridine
2-methoxypyridine
>95:5
>95:5
95
[a] Yield of isolated product; [b] stereoisomeric ratios were determined
by using H NMR spectroscopy. dec.=decomposed.
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THP-Ester-Derived Pyridinium-Type Salts
Scheme 17. Plausible reaction mechanisms for the substitution reactions
with heteronucleophiles.
Scheme 16. Reactions of THP and related esters in the presence of Et2Zn
or Ph2Zn; the C-nucleophilic-substitution reactions were carried out at
408C in 1,2-dichloroethane (DCE).
Conclusions
We have developed a nucleophilic-substitution reaction at
the anomeric position of THP esters. The process, which em-
ploys a pre-activation strategy, relies on the initial formation
of a pyridinium-type salt intermediate that acted as an oxo-
carbenium-ion equivalent. Alcohols, azides, and C-nucleo-
philes were introduced onto the anomeric centers of both
THP and the carbohydrate substrates. Furthermore, this
method afforded 2,6-trans products with high levels of ste-
reoselectivity in reactions that generated azide and C-nucle-
ophile adducts. Moreover, the process proceeded under mild
conditions and, as a result, it was applicable to the reactions
of THP and related esters that contained acid-labile func-
tional groups. We believe that this method will be a useful
tool for the synthesis of carbohydrates and biologically
active THP-containing natural products.
The attractive features of this C-nucleophile-substitution
process were exemplified by the processes (Scheme 16) in
which THP ester 9b, which contained a trityl group, was
used as the reactant. The reactions of a salt that was derived
from compound 9b with diphenyl- and diethyl zinc occurred
under mild conditions to produce their respective products,
which retained the acid-sensitive trityl group. In addition,
the salt that arose from 2-deoxyglucose-derived glycosidic
ester 11 also participated in reactions with organozinc re-
agents to generate C-glycosides (Scheme 16).
Mechanism of the Nucleophilic-Substitution Process
The reactions of 2-p-tolylpyridinium salts with heteronucleo-
philes suggested that the mechanisms shown in Scheme 17
were plausible. The observation that the reactions of 2,6-cis-
substituted pyridinium-type salts with alcohols proceeded
with low levels of diastereoselectivity suggested that the
process likely proceeded in an SN1 fashion via an oxocarbe-
nium-ion intermediate. On the other hand, when the more-
nucleophilic TMSN3 participated in the reaction, an SN2
pathway was more likely followed, based on the observation
that 2,6-cis-substituted pyridinium-type salts yielded pre-
dominantly 2,6-trans products.
Experimental Section
General Procedure for the Introduction of an Alcohol
2-p-Tolylpyridine (3 equiv) and TMSOTf (2 equiv) were added to a solu-
tion of starting THP ester (1 equiv) in CH2Cl2 (0.1m) at 08C under a N2
atmosphere. The mixture was stirred at 08C until the disappearance of
the starting material was confirmed by TLC analysis. Next, the alcohol
(3 equiv) was added and the resulting mixture was stirred vigorously. Fol-
lowing disappearance of the polar 2-p-tolylpyridinium salt intermediate
The mechanism for the reac-
tions of C-nucleophiles is
shown in Scheme 18. MS
1
(FAB+) and H NMR spectros-
copy demonstrated that these
reactions took place through in-
itially formed 2,6-cis-pyridini-
um-type
salt
intermediates
(e.g., 22).[21] The formation of
substitution products 19 from
these intermediates could occur
through concerted (route A) or
non-concerted pathways (route
B).[18a]
Scheme 18. Plausible reaction mechanisms for C-nucleophilic-substitution reactions.
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by TLC analysis, the mixture was quenched with aqueous NaHCO3 and
extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered,
and concentrated in vacuo to afford a residue that was subjected to
column chromatography on silica gel to give the product.
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General Procedure for the Introduction of an Azide
2-p-Tolylpyridine (3 equiv) and TMSOTf (2 equiv) were added to a solu-
tion of starting THP ester (1 equiv) in CH2Cl2 (0.1m) at 08C under a N2
atmosphere. The mixture was stirred at 08C until the disappearance of
starting material had been confirmed by TLC analysis. Next, TMSN3
(3 equiv) and TBAT (3 equiv) were added and the resulting mixture was
stirred vigorously. Following disappearance of the polar 2-p-tolylpyridini-
um salt intermediate by TLC analysis, the mixture was quenched with
aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was
dried over Na2SO4, filtered, and concentrated in vacuo to afford a residue
that was subjected to column chromatography on silica gel to give the
product.
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General Procedure for the Introduction of a C-Nucleophile
2-Methoxypyridine (3 equiv) and TMSOTf (2 equiv) were added to a so-
lution of starting THP ester (1 equiv) in CH2Cl2 (0.1m) at 08C under
a N2 atmosphere. The mixture was stirred at 08C until the disappearance
of the starting material was confirmed by TLC analysis. Next, a solution
of R2Zn in THF (3 equiv) was added and the resulting mixture was
stirred vigorously. Following disappearance of the polar 2-methoxypyridi-
nium salt intermediate by TLC analysis, the mixture was quenched with
aqueous 3.5% HCl and stirred for more than 10 min at 08C and extract-
ed with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo to afford a residue that was subjected to column
chromatography on silica gel to give the product.
Acknowledgements
This work was financially supported by the Hoansha Foundation, the
Uehara Memorial Foundation, and by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
[11] The configuration of the major product was determined by the J
1
value of the anomeric proton in the H NMR spectrum, NOE DIFF
experiments, or literature data.
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THP-Ester-Derived Pyridinium-Type Salts
MuÇoz, J. Morales-Sanfrutos, F. Hern ꢂ-Mateo, F. G. Calvo-Flores,
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[22] MS (FAB+) of the mixture that was obtained from the reaction of
TMSOTf (2 equiv) and 2-methoxypyridine (3 equiv) in CH2Cl2
(0.1m) showed a [M]+ peak of 2-methoxypyridinium salt 22 at m/z
314.1772, with a formula of C19H24NO3. Furthermore, the 1H NMR
spectrum of the reaction mixture in CD2Cl2 showed that the 2-me-
thoxypyridine was oriented equatorially in a highly stereoselective
manner and that 2-methoxypyridinium salt 22 was 2,6-cis. 1H NMR
spectra of the reaction mixture are shown in Supporting Informa-
tion.
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Received: March 14, 2012
Published online: && &&, 0000
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Synthetic Methods
Hiromichi Fujioka,*
Yutaka Minamitsuji, Takahiro Moriya,
Kazuhisa Okamoto, Ozora Kubo,
Tomoyo Matsushita,
Kenichi Murai
&&&& — &&&&
Preparation of THP-Ester-Derived
Pyridinium-Type Salts and their Reac-
tions with Various Nucleophiles
Salty but sweet: Nucleophilic substitu-
tion at the anomeric position of tetra-
hydropyranyl esters via pyridinium-
type salt intermediates proceeded
without affecting acid-labile protecting
groups owing to the use of mild reac-
tion conditions (see scheme).
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