Secondary amine salt catalyzed controlled activation of 2-deoxy sugar lactols towards alpha-selective dehydrative glycosylation

Article abstract of DOI:10.1039/c8ob00423d

A new organocatalytic glycosylation method exploiting the lactol functionality has been disclosed. The catalytic generation of glycosyl oxacarbenium ions from lactols under forcible conditions via weakly Br?nsted-acidic, readily available secondary amine salts affects the diastereoselective glycosylation of 2-deoxypyranoses and furanoses. This operationally simple iminium catalyzed activation of 2-deoxy hemi-acetals is a potential alternative to the existing cumbersome methods that need specialized handling. The mechanisms for this unique transformation and kinetic/thermodynamic effects have been discussed based on both experimental evidence and theoretical studies.

Full text of DOI:10.1039/c8ob00423d

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Secondary Amine Salts Catalyzed Controlled Activation of 2-Deoxy
Sugar Lactols towards Alpha-Selective Dehydrative Glycosylation
Received 00th January 20xx,
Accepted 00th January 20xx
Titli Ghosh,a Ananya Mukherji,a Hemant Kumar Srivastava,a Pavan K. Kancharla*,a
DOI: 10.1039/x0xx00000x
A new organocatalytic glycosylation method exploiting the lactol functionality has been disclosed. Catalytic generation of
glycosyl oxacarbenium ions from lactols under forcible conditions via weakly Bronsted-acidic, readily available secondary
amine salts, affects the diastereoselective glycosylation of 2-deoxypyranoses and furanoses. This operationally simple
iminium catalyzed activation of 2-deoxyhemi-acetals is a potential alternative to the existing cumbersome methods that
needs specialized handling. The mechanism for this unique transformation and kinetic/thermodynamic effects have been
www.rsc.org/
discussed
based
on
both
experimental
evidences
and
theoretical
studies.
Formation of iminium ions1a by the reaction between secondary ethers,15 and hemi-acetals16 have been developed over the past
amines/amine salts and aliphatic/aromatic aldehydes has been two decades.
extensively explored since the seminal work by MacMillan et al.2
Despite the significant advantages, dehydrative glycosylation has
and Barbas et al.3 In case of aliphatic aldehydes,1b the thus
generated iminium ions tautomerize into the corresponding
enamines that are trapped by a multitude of electrophiles (Scheme
1-a) whereas iminium ions formed from α,β-unsaturated aldehydes
are prone to undergo 1,2 or 1,4-nucleophilic addition reactions. Liu
et al. have showcased iminium/enamine catalyzed functionalization
of masked aldehydes i.e. lactols4 and cyclic hemi-aminals5 that
react with nitrostyrenes, α,β-unsaturated ketones and
ketomalonates.4b We envisioned that in the case of lactols, the
iminium ions that tautomerize into enamines, under forcible
conditions could be trapped intramolecularly which upon expulsion
of ammonium species could lead to the generation of
oxacarbenium ions6 (Scheme 1-b), one of the most important
intermediates in organic chemistry. Thus generated oxacarbenium
ions if trapped by nucleophiles like alcohols would lead to the
developement of a novel organocatalytic method for the synthesis
of acetals.
We have chosen 2-deoxysugar lactols as substrates to study the
hypothesis. 2-Deoxysugar acetals i.e. 2-deoxyglycosides are part of
several natural products with anticancer7 and antibiotic
properties7a, 8 and has been shown that these structural motifs are
important for their activity.9 Most of the sugar lactols require the
anomeric derivatization prior to glycosylation and 2-deoxysugars
are no exception.10 However, the derivatized 2-deoxysugar donors
not evolved into a commonly used method owing to the unique
are relatively unstable11 and require careful handling. Several direct
challenges posed by lactol donors e.g the self-condensation
and indirect methods for the synthesis of 2-deoxyglycosides12
reaction of the lactols often compete with the desired glycosylation
13
involving C-2 hetero atom substitutions,11b, 1,2-epoxides,14 enol
product. 2-Deoxy lactols pose a bigger challenge due to it's high
reactivity/nucleophilicity towards self-condensation of the
substrates. The existing methods though highly effective, suffer
16e, 17
from the requirement of more than one reagent,16c,
and
limited applicability.16a, 18 Till date, an effective catalytic method for
the dehydrative glycosylation with a broad scope towards the
synthesis of 2-deoxyglycosides has not been realized. To overcome
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these challenges, a new controlled mode of activation of these us the glycosylation product 2b in 63% yield with 2:1 α:β
substrates is needed. Here, in this communication, we report an selectivity (Table 1, entry 3). The reaction went to completion
unprecedented and operationally simple organocatalytic protocol in 5h with reasonable α-selectivity without requiring any
for the direct dehydrative glycosylation of 2-deoxyglycosides using molecular sieves. Surprisingly, contrary to Siedel’s work, the
secondary amine salts as catalysts that involves the efficient use of reaction lead to decompostion when performed in the
lactol functionality.
presence of thiourea20 even at elevated temperature. After
further optimization studies we found that the reaction gives
excellent results (Table 1, entry 4) with toluene as solvent at
Table 1 Optimization Studies
Scheme 2. Initial studies
General acetal synthesis using δꢀValerolactol. Reaction conditions: 0.98 mmol
of 1a, 0.13 mmol of benzyl alcohol/4b/4i and 20 mol% of 3d, 100oC, 5h. [a] No
dimerization of 1a was observed [b] Anomeric ratios were determined from
crude 13C NMR analysis. [c] Anomeric ratios were determined from crude 1H
NMR analysis.
Though reminiscent to a recent development of an oxa-Pictet
Spengler reaction via oxacarbenium ion catalyzed by
pyrrolidine salts,19 the current strategy involving the sugar
lactols has several challenges. 1) Generation of the iminium
ion III is dependent on the percentage of sugar lactol existing
in its open chain form (Figure 1, III). 2) The generated iminium
ion III must possess the necessary electrophilicity to react with
the unactivated primary and secondary sugar alcohols (Figure
Entry
Sub
Cat.
Product
Yield%
α:β[j]
1, IV or
V) and 3) the leaving group ability of pyrrolidinium
1
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
3a
3d
3d
3d
3b
3c
3d
3e
3f
2b
2b
2b
2b
5b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2c
0
0
ꢀ
ꢀ
species to generate the oxacarbenium ion (Figure 1, VI or VII).
We embarked upon to test the hypothesis by chosing δ-
Valerolactol 1a and benzyl alcohol as model substrates using
simple pyrrolidine hydrochloride 3d as the organocatalyst
2[a]
3[b]
4
63
87
46
81
47
85
86
0
2:1
5:1
4:1
4:1
4:1
4:1
5:1
ꢀ
5[c]
6
7[d]
8
(Scheme 2). After
a few failed attempts at various
temperatures, we were delighted to see that the acetal
formation is clean at 100oC and gave the desired product 2a-1
in 96% yield. Similar reactions were performed with activated
and deactivated sugar acceptors 4b and 4i that also proceeded
with yields of 71% and 74% respectively (Scheme 2, 2a-2, 2a-
9
10[e]
11
12
13
14[f]
15[g]
16[h]
17[i]
18
19
20
3g
3h
3i
77
0
3:1
ꢀ
3). We then swiftly shifted our focus to the more complex 2-
3j
76
38
85
85
83
81
85
80
1.5:1
4:1
2:1
2.5:1
1.5:1
10:1
6:1
4:1
deoxysugar lactols as the coupling partners. We have chosen
isopropanol to perform the optimization studies with the sugar
lactols. Initial attempts with 10 mol% pyrrolidinium
hydrochloride 3d and glycosyl donor 1b in the presence of
isopropanol as the acceptor and toluene as solvent did not
lead to any glycosylation product even after 24h at room
temperature (Table 1, entry 2). However, after several
attempts at various temperatures (Table 1, entries 3-4), the
reaction when performed with 1.5 eq. of isopropanol with
respect to the lactol donor 1b in the presence of 20 mol% of
the organocatalyst 3d at 80oC in toluene as solvent, provided
3d
3d
3d
3d
3d
3d
3d
1d
1e
2d
2e
Reaction conditions: 0.12 mmol of 1b-e, 0.18 mmol of isopropanol and 20
mol% of 3a-j, toluene, 100oC, 5h, (24h for 2c and 2e) [a] RT, 24h [b] temp 80oC
[c] 1 eqv. of acceptor 4b was used [d]10 mol% of 3d was used [e] anomeric
benzoate was observed in HRMS by using 20 mol% of catalyst 3g at 100oC [f]
10 mol% of TBAF was used as an additive [g] 10 mol% of TBAI was used as an
additive [h] 80oC, DCE was used as a solvent [i] 80oC (1:1 ACN: DCM) was used
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100oC with improved α selectivity. Interestingly, the formation difference to the reactivity and yielded the glycosylated
of the dimerized product 5d was not observed under these
catalytic conditions. Several other secondary amine salts were
tested but none of them provided further improvements.
Moreover, chiral L-proline 3a when used (Table 1, entry 1),
lead to the decomposition of the starting lactol donor 1b
.
Diethylamine hydrochloride 3c (Table 1, entry 6) gave almost
similar yields and selectivities albeit a little more hygroscopic
than the pyrrolidine hydrochloride. The Macmillian’s
imidazoline salt 3e (Table 1, entry 8) also resulted in
diminished rate of the reaction and in yields. Use of a chiral
amine salt has shown no bearing on the stereoselectivity of
the reaction. Indoline hydrochloride 3b (Table 1, entry 5)
afforded the glycosylation product in 46% yield but resulted in
considerable formation of the undesired trehalose analogue
5d (~20%) presumably because of the increased Bronsted
acidic nature of the catalyst. In order to examine the effect of
the counterion in the present organocatalytic glycosylation, we
investigated the coupling reaction with several pyrrolidine
salts bearing different counterions (Table 1, entries 9-13). Salts
with tetrafluoroborate and the trifluoroacetate anions (3h and
3j respectively, Table 1, entries 11, 13) hardly made any
Scheme 4. Organocatalytic dehydrative glycosylation: Scope of sugar
acceptors. Reaction conditions: 0.12 mmol of glycosyl donor 1b,1d, 0.13 mmol
of 4b-c, 4h, (0.24 mmol of 4g) and 20 mol% of 3d, 100oC, 5h, (7h for 5g and
16h for 5d). [a] Anomeric ratios were determined from crude NMR analysis.
[b] No acceptor was used. [c] 20 mol% of 3f was used for 5c, 5d and 5g and 0-
10% dimerized product 5d was found.
product 2b in almost identical yields and selectivities
suggesting that pyrrolidine salts generated with strong acids
are ideal for these reactions. However, the reaction with
pyrrolidine tosylate 3f (Table 1, entry 9) is slightly sluggish and
also effects the anomeric selectivity, whereas the pyrrolidine
salts of benzoate 3g (Table 1, entry 10) and 3,4-
Scheme 3. Organocatalytic dehydrative glycosylation: Scope of Nonꢀ
carbohydrate acceptors. Reaction conditions: 0.12 mmol of 1b. 1f, 0.13 mmol of
4a,4e,4iꢀ4q and 20 mol% of 3d, 100oC, 5h. [a] Anomeric ratios (α:β) were
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dinitrobenzoate 3i (Table 1, entry 12) only resulted in the reaction conditions to provide the glycoside in 71% yield with
decomposition of the starting materials. Having successfully high α-selectivity (13:1, α:β, Scheme 3). Both the primary
tested several secondary amine salts, we decided to probe the alcohols derived from glucose and galactose were successfully
effect of armed and disarmed 2-deoxy lactol donors in this coupled with 2-deoxy lactol 1b in 69% and 64% yields
coupling reaction. The disarmed triacetylglucopyranose respectively (5b and 5f respectively). Noteworthy is the fact
derivative 1c gave the corresponding isopropyl glycoside 2c that these charge-neutral amine catalysts did not hamper the
with excellent yields (Table 1, entry 18) albeit with surprisingly stability of the acid sensitive acetonide protecting group.
improved
anomeric
selectivity.
The
armed Similarly, the secondary alcohol diacetonide glucose gave the
tribenzylgalactopyranose 1d derivative provided the desired coupled product 5g in 73% yield albeit with 3f as the catalyst.
product in 85% yield and 6:1 α:β selectivity (Table 1, entry 19). However, when no acceptor is used, the armed 2-deoxy lactol
All the anomeric configurations/ratios were confirmed after 1b in the presence of catalyst 3f lead to the corresponding
extensive NMR analysis.21
α→α-trehalose analogue 5d as major diastereomer.22 More
strikingly, the coupling reaction between the galacto-
configured 2-deoxy lactol 1d and the galactose derived
diacetonide acceptor in the presence of pyrrolidine tosylate 3f
as the catalyst lead to a single diastereomer (only α) in 76%
yield. Next, we decided to inspect the orthogonality of these
organocatalytic conditions towards the conventional
thioglycoside donors. To this end, we treated the donor 1b
under the standard reaction conditions with 6-
hydroxythioglycoside 4h. The coupling reaction proceeded
with 74% yield (Scheme 4) and 5:1 α:β selectivity showing the
potentiality of the current organocatalytic glycosylation as an
orthogonal method. The utility of the current method has also
been showcased in the synthesis of 2-deoxyfuranosides23 6a
along with 6b which were obtained in 87% and 58% yields
respectively (Scheme 5). However, the coupling reaction is
observed to be unselective.
Scheme 5. Glycosylation of 2-deoxyribofuranoses.
Reaction conditions: 0.16 mmol of 1g, 0.18 mmol of isopropanol/4b and 20 mol%
of 3d, 100oC, 5h. [a] Anomeric ratios (α:β) were determined from crude NMR
analysis.
As depicted in the proposed mechanism (Figure 1), the
In order to understand the scope of the newly developed reaction could proceed either via the formation of a cyclic
aminal IV or a mixed aminoacetal V. Attempts to isolate or
iminium catalyzed glycosylation, the coupling reaction was
characterize the cyclic aminal IV or the iminium III only
resulted in failure (See supporting information for VT NMR
performed with a variety of alcohols as acceptors. Again,
commercially cheap, robust and easily accessible pyrrolidine
hydrochloride 3d, was chosen as the optimized catalyst to
study the substrate scope. All the non-carbohydrate primary
alcohols gave the desired glycosylation products with excellent
yields and good to high levels of α-selectivites (Scheme 3). The
sterically demanding cholesterol also gave corresponding
glycoside 5e in 62% yield and 3.5:1 α:β selectivity. The coupling
with the tertiary 1-adamantanol also reacted well under the
studies). A control experiment was performed with simple
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pyrrolidine
The reaction lead to an intractable mixture of products, gained by
emphasizing the importance of ammonium species in B and forward reaction is preferred for Path A. Thus, the
catalyzing the reaction. The reaction when tested with 20 existence of is energetically not possible. We repeated these
3
(Scheme 6-2) instead of the corresponding salt. by IV is around 3 kcal/mol higher compared to the stabilization
V
. In addition, reverse reaction is preferred for Path
V
mol% of pyrrolidine benzoate 3g (vide supra) as the catalyst, calculations at various DFT methods and basis sets and found
led to the decomposition of the starting material. However, that the level of the calculations does not affect the trend of
the mass spectral analysis of the crude reaction mixture the results, Table S2. DFT calculations clearly showed that Path
revealed the formation of glycosyl benzoate (Table 1, entry 10) A is preferred for the reaction.
which suggests the possible intermediacy of oxacarbenium ion
in these reactions. Other possible mechanisms involving the
Conclusions
direct generation of oxacarbenium ions catalyzed by the weak
Bronsted-acidity of pyrrolidinium species or by the possible
In conclusion, we have developed for the first time, an
release of HCl from secondary amine salts cannot be ruled out.
organocatalytic, α-selective direct dehydrative glycosylation
To test this hypothesis, we elected to perform the
method for the synthesis of various 2-deoxyglycosides
glycosylation reaction in the presence of triethylamine
including 2-deoxypyranoses and furanoses. The role of
hydrochloride salt (Schem-6-3) and 1 M HCl (Scheme-6-4) that
secondary amine salts as a source of iminium ions and thereby
obviates the possibility of iminium species. However, the
generating oxacarbenium ions that react with alcohols in a
reaction in former case resulted in an intractable mixture
stereoselective mode, has been effectively utilized in the
(Scheme 6-3) whereas no reaction happened in the later. All
current protocol. The orthogonality of this protocol to
these experiments strengthen the distinctive role of the
thioglycosides besides the functional group tolerance has been
secondary amine salts catalyzing the reaction. Besides, the
well depicted. The method successfully gave glycosylated
anomerization experiment (Scheme 6-1) confirmed the kinetic
products with primary, secondary and tertiary alcohols with
origins of the observed α-selectivities and thus, further
equal efficiency. DFT calculations at various levels indicated
strengthening the unique mode of activation by the secondary
that Path A is preferred. Further studies on extending the
amine salts.
methodology towards β-selective 2-deoxy glycosylations are
under progress in our laboratory and will be communicated in
due course.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
PKK and HKS are thankful to SERB (DST, New Delhi) for the
financial assistance through ECRA (ECR/2016/000262) and
Ramanujan Fellowship (SB/S2/RJN-004/2015).
Notes and references
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB00423D
Organocatalytic alpha-seletive dehydrative glycosylation method for the synthesis of 2-deoxyglycosides