Palladium catalysed carbonylation of 2-iodoglycals for the synthesis of C-2 carboxylic acids and aldehydes taking formic acid as a carbonyl source

Article abstract of DOI:10.1039/c9ra03626a

Pd catalyzed carbonylative reaction of 2-iodo-glycals has been developed taking formic acid as a carbonyl source for the synthesis of 2-carboxylic acids of sugars by the hydroxycarbonylation strategy. The methodology was successfully extended to the synthesis of 2-formyl glycals by using a reductive carbonylation approach. Both ester and ether protected glycals undergo the reaction and furnished sugar acids in good yield which is otherwise not possible by literature methods. The C-2 sugar acids were successfully utilized for the construction of 2-amido glycals, 2-dipeptido-glycal by Ugi reaction and C-1 and C-2 branched glycosyl esters.

Full text of DOI:10.1039/c9ra03626a

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Palladium catalysed carbonylation of 2-iodoglycals
for the synthesis of C-2 carboxylic acids and
aldehydes taking formic acid as a carbonyl source†
Cite this: RSC Adv., 2019, 9, 22227
Ajaz Ahmed,ab Nazar Hussain,ab Monika Bhardwaj,b Anuj Kumar Chhalodia,b
ab
Amit Kumarb and Debaraj Mukherjee
*
Pd catalyzed carbonylative reaction of 2-iodo-glycals has been developed taking formic acid as a carbonyl
source for the synthesis of 2-carboxylic acids of sugars by the hydroxycarbonylation strategy. The
methodology was successfully extended to the synthesis of 2-formyl glycals by using a reductive
carbonylation approach. Both ester and ether protected glycals undergo the reaction and furnished
sugar acids in good yield which is otherwise not possible by literature methods. The C-2 sugar acids
were successfully utilized for the construction of 2-amido glycals, 2-dipeptido-glycal by Ugi reaction
and C-1 and C-2 branched glycosyl esters.
Received 14th May 2019
Accepted 4th July 2019
DOI: 10.1039/c9ra03626a
rsc.li/rsc-advances
Sugar acids constitute a diverse family of carbohydrates1 Our experience with glycals6a–f encouraged us to formulate an
which play a crucial role in cell–cell recognition, cellular attractive way to launch carboxylic acid at C-2 position of
adhesion, and virus–host recognition processes, for protec- glycals as shown in Scheme 1 and apply them in the synthesis
tion of cells from pathogen attachment, and in the synthesis of C-2 glycoconjugates.
of biologically active natural products.2 a,b-Unsaturated
This is pertinent to mention that carbonylation reactions
sugar acids such as zanamivir and ianinamivir (Fig. 1) are of C-2 glycals have been successfully carried out by using
subjects of particular interest because of their application as metal carbonyl for the synthesis of C-2 branched glyco-
inhibitors of different glycoproteins such as hemagglutinin conjugates.7a,b In these reaction stoichiometric amount of
(HA) and neuraminidase (NA),3 the major glycoproteins costly Mo(CO)6 is required for such transformation that too
expressed by inuenza viruses. While several reports dealing ends up with some non-carbonylative side products. CO
with the synthesis of carboxylic acids at C-6 and C-1 positions surrogates8,9 such as formic acid, formamide, chloroform
of sugars exist,4a,b there is no established procedure for the and anhydride have been explored in recent times obviating
synthesis of C-2 carboxylic acids. In glycals accessing metal carbonyls and CO gas. Among all formic acid is an
carboxylic group at C-1 position required t-butyl lithium and attractive candidate for insertion of CO in an organic mole-
carbon dioxide treatment at ꢀ78 ꢁC.4c There is only one report cule,10 because it liberates one water molecule aer releasing
available in the literature in which carboxylic group was one CO molecule thereby making the process environmen-
introduced to the C-2 position of glycals by Furstner et al.4c,d tally benign. We felt that palladium catalyzed hydrox-
where the C-2 carboxylic acid was derived from the Pinnick ycarbonylation of stable glycal halides, which are
oxidation of 2-formyl glycal obtained by classical Vilsmeier– conveniently accessed from glycals in good yield, may prove
Haack reaction5 and thereaer utilized in the total synthesis to be the most effective and environmentally benign method
of bioactive natural orevactaene (exhibits HIV-1 inhibitory to prepare such molecules. With our continuous interest in
property). This strategy has certain drawbacks like long synthesis of C-2 branched sugars,11 this time we developed
reaction times with cocktails of oxidants and limited a reagent system for the direct synthesis of C-2 sugar
substrate specicity. For example, it works only with ether
protected sugars like tri-O-benzyl-D-glycal and fails with other
base labile and silyl protecting groups. Further, recovery of 2-
formyl glycals aer base workup is rather low in our hand.
aAcademy of Scientic and Innovative Research, India
bNatural Product Chemistry Division, Indian Institute of Integrative Medicine, India.
E-mail: dmukherjee@iiim.ac.in
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra03626a
Fig. 1 Glycal based acids in drugs.
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reactions. In order to synthesize selectively the desired product
3a, we then decided to screen different ligands starting with the
bidentate ligand L2, keeping other parameters as in entry 1. To
our delight complete conversion of starting material was
observed with 3a as exclusive product in 72% yield (Table 1,
entry 2). Encouraged with this result, we next reduced the
reaction period to 6 h (Table 1, entry 3) to note that the yield
went up to 80%. Further reduction of the time period to 1.5 h
still enabled complete conversion along with improved yield
(81%) of 3a without any detrimental effect on selectivity (Table
1, entry 4), but reduction in reaction time to 1 h led to decrease
in yield (Table 1 entry 5). Other ligands such as L3, L4, L5 and L6
produced mixture of both 3a and 3a0 along with poor overall
yields (Table 1 entry 6–9). Next we investigated the role of
different Pd catalysts such as Pd(PPh)3, Pd(TFA)2 and PdCl2
(Table 1 entry 10–12) and found that Pd(OAc)2 is the best cata-
lyst for this transformation.
Utilising the optimised reaction condition (Table 1, entry 4),
we then checked the substrate scope (Table 2) using different 2-
iodo-glycals. Di-O-benzyl-2-iodo-L-rhamnal 1b was tested to get
a better yield of the product 3b, (85%). The galactal substrate
also furnished the desired 2-carboxyl galactal 3c in good yield
(76%). In order to broaden the substrate scope the reactivity of
glycals protected with different protecting groups was next
investigated. Gratifyingly, 2, 3-acetonide protected 2-iodo-D-
Scheme 1 Art of launching carboxyl group in sugars.
carboxylic acids from 2-iodo glycals using formic acid as
carbonyl source. Further, we transformed the synthesized
acid for the synthesis of different C-2 branched
glycoconjugates.
Preliminary experiments were conducted by using 2-iodo-
glycal 1a, HCOOH as carbonyl source, N,N0-dicyclohex-
ylcarbodiimide, (DCC) as an activator and xantphos as a ligand.
When 1a was reacted with 5 mol% Pd(OAc)2, 10 mol% of
xantphos, 1 equiv. of DCC, 2 equiv. of formic acid and 2 equiv. of
triethyl amine as base in DMF at 90 ꢁC for 16 h the desired
product 3a was obtained along with 3a0 in 60 : 40 ratio with
overall 63% yield (Table 1, entry 1). Perusal of the literature
revealed that ligands play a crucial role in such carbonylation
Table 1 Optimization of the reaction conditionsa
Entry
Pd source
Ligand
Time (h)
Conversion (%)
(3a : 3a0)
Yieldb (overall)%
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh)3
Pd(TFA)2
PdCl2
L1
L2
L2
L2
L2
L3
L4
L5
L6
L2
L2
L2
16
16
6
1.5
1
16
16
16
16
2
90
99
99
99
90
40
30
10
10
75
35
23
60 : 40
>99 : 1
>99 : 1
>99 : 1
>99 : 1
45 : 55
30 : 70
—
63
72
80
81
73
23
15
Traces
Traces
21
27
11
9
—
10
11
12
>99 : 1
>99 : 1
>99 : 1
2
2
a
Reaction conditions: 1a (0.18 mmol), 2a (0.36 mmol), Pd(OAc)2 (0.009 mmol), L2 (0.018 mmol), N,N0-dicyclohexylcarbodiimide (DCC) (0.18 mmol),
triethylamine (0.36 mmol) at 90 ꢁC for 2 h. b Yield of isolated product. Pd 5 mol% and ligand 10 mol% were used. Ratio of 3a and 3a0 and conversion
were determined through 1H NMR.
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Table 2 Substrate scopea
Entry Substrate
Product
Time (h) Yieldb (%)
1
1.5
1.5
1.5
81
85
76
Scheme 2 Synthesis of silyl protected C-2 carboxylic acid.
2
3
4
5
6
1.5
2
75
76
73
Scheme 3 Synthesis of 2-formyl glycals.
2.5
7
2.5
75
a
Reaction conditions: 1 (1 equiv.), 2a (2 equiv.), Pd(OAc)2 (5 mol%), L2
(10 mol%), DCC (1 equiv.), triethylamine (2 equiv.) at 90 ꢁC for 1.5 to
2.5 h in 3 mL of DMF. b Yield of isolated product.
galactal 1d survived under the reaction condition and yielded
the product 3d in good yield (75%). Tri-O-ethyl-2-iodoglucal 1e
also reacted well and formed the respective acid derivative 3e in
(76%) yield. Next we utilized different glycals having silicon
based protection or ester protection. Tri-O-acetyl-2-iodoglucal 1f
and di-O-acetyl-2-iodoxylal 1g were also well tolerated under the
reaction condition and gave the desired products 3f–3g in
reasonable yields (73–75%). 2-Bromo-glucal was next tested
under the optimized reaction condition and the desired
Scheme 4 Synthesis of amides using 3a. Reaction conditions: (a) 3a
(1.5 equiv.), aniline (1 equiv.), anisaldehyde (1 equiv.), cyclohexyl
isocyanate (1 equiv.) in ethanol at rt for 48 h; (b) 3a (1.0 equiv.), SOCl2
(1.5 equiv.), NH4OH (37%, 2 mL) in THF for 2 h; (c) 3a (1.0 equiv.), PCl5
(1.2 equiv.), pyridine (6 equiv.), 8-aminoquinoline (1.2 equiv.) in DCM
for 5 h.
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To test the utility of sugar acids in the synthesis of C-2 gly-
coconjugates, sugar acid 3a was successfully utilized for the
synthesis of C-2 linked dipeptides via Ugi reaction (Scheme 4,
5a). The simple amide 5b was also synthesised from 3a using
thionyl chloride and ammonium hydroxide; the product is
otherwise difficult to synthesize via the existing methods.
Where substituted amides are synthesized. The acid chloride of
3a could be successfully coupled with 8-aminoquinoline,
leading to the amide 5c in good yield. In order to test the
reactivity of the acid 3a, we used it as a glycosyl acceptor in
glycosylation reaction by treating with a suitable glycosyl donor
like 6, when the pseudodisaccharide 7 was isolated in good yield
(63%) with a mixture of anomers. On the other hand, treatment
with aryne precursor 8 resulted in the formation of compound 9
in excellent yield (84%) via coupling of aryne with the sugar
acid. When sugar acid 3a was treated with thiophenol thioester
11 was isolated in excellent yield (Scheme 5).
Scheme 5 Utilization of 3a for establishing ester linkages.
A plausible reaction mechanism has been proposed for
hydroxycarbonylation of 2-iodoglycals (Scheme 6). Initially
Pd(0) is generated in situ in the presence of ligand Ln. The
catalytic cycle then starts with oxidative addition of Pd(0) to 2-
iodoglycal A which produces the pallado complex B.
Coordination and insertion of carbon monoxide generated
in situ by the combination of DCC and formic acid leads to the
formation of acyl Pd(II) complex C. Formic acid attack on
complex C via transmetallation affords the intermediate D with
release of HI. Pd(0) could be regenerated for the next catalytic
cycle aer reductive elimination from complex D with forma-
tion of anhydride E. Decomposition of the anhydride with
release of one molecule of CO generates the desired sugar acid
F.
In conclusion we have developed an efficient and mild Pd
catalysed synthetic strategy for hydroxycarbonylation of 2-
iodoglycals using the cheap reagent formic acid as CO source
and 1 equiv. of DCC as an activator. The methodology was
successfully extended to various glycals with different protect-
ing groups like acetonide, ether, ester and silicon based ones. 2-
Formyl glycals were also synthesised by using reductive
carbonylation approach. The synthesised sugar acid could be
used in the synthesis of glycoconjugates, pseudodisaccharides,
for aryl ester and thioester.
compound 3a was obtained in good yield although it takes 3 h
to complete the reaction.
TBS protected sugars acids are used in the total synthesis of
various bioactive natural products by activating the anomeric
carbon which is otherwise not possible with other protecting
groups. In the literature in order to get such types of acids
multiple steps are required along with poor overall yield. By
utilizing carbonylation strategy under Pd catalysis we were able
to synthesis the TBS protected acids in just 2 h when substrate
1h was reacted with HCOOH under Pd catalysis to generate
product 3h in good yield.
Aer successful execution of our strategy for hydrox-
ycarbonylation of 2-iodoglycals, we became interested to
apply the same carbonylative approach for the synthesis of 2-
formyl glycals. In the literature formylation at C-2 of glycals
has been carried out either by Vilsmeier–Haack or XtalFluor-
E catalyzed reactions (Scheme 3).5,12 We utilized the reduc-
tive carbonylation approach employing triethylsilyl hydride
(1.2 equiv.) as a hydride source keeping other reagents same
as for acid synthesis. To our delight, the required 2-formyl
glycals were obtained in good to excellent yields (Scheme 3,
3aa–3ae).
Scheme 6 Plausible mechanism of hydroxycarbonylation reaction.
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Conflicts of interest
6 (a) A. K. Kusunuru, K. Chatanya, M. B. Tatina, V. B. Prasad
and D. Mukherjee, Org. Lett., 2015, 17, 3742; (b)
M. B. Tatina, A. K. Kusunuru and D. Mukherjee, Org. Lett.,
2015, 17, 4624; (c) M. R. Lambu, S. K. Yousuf,
D. Mukherjee and S. C. Taneja, Org. Biomol. Chem., 2012,
10, 9090; (d) M. B. Tatina, S. K. Yousuf and D. Mukherjee,
Org. Biomol. Chem., 2012, 10, 5357; (e) S. K. Yousuf,
S. C. Taneja and D. Mukherjee, Org. Lett., 2011, 13, 576; (f)
N. Hussain, M. B. Tatina, F. Rasool and D. Mukherjee, Org.
Biomol. Chem., 2016, 14, 9989.
There are no conicts to declare.
Acknowledgements
A. A. and N. H. thank CSIR and UGC New Delhi for SRF/JRF.
IIIM Publication No. IIIM/2298/2019.
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