Convenient Synthesis of 3-Glycosylated Isocoumarins

Article abstract of DOI:10.1002/ejoc.201601264

A new route for the synthesis of 3-substituted and 8-hydroxy-3-substituted isocoumarins was developed by modified Julia olefination for initial C–C bond formation between aldehydes and benzylic sulfones. Palladium-catalyzed Meinwald rearrangement was used as a key step for the obtainment of ketone intermediates, which – upon base-promoted intramolecular cyclization – afforded the desired isocoumarins. The developed method paves the way to hitherto unknown 3-glycosylisocoumarins, in general, and 3-glucosylisocoumarins, in particular, wherein the glucosyl moiety is attached to the pyrone ring of the isocoumarin framework.

Full text of DOI:10.1002/ejoc.201601264

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Title: Convenient Synthesis of 3-Glycosylated Isocoumarins
Authors: Indrapal Singh Aidhen; Sudarshan Kasireddy
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COMMUNICATION
Convenient Synthesis of 3-Glycosylated Isocoumarins
Kasireddy Sudarshan,[a] and Indrapal Singh Aidhen*[a]
Abstract: A new route for the synthesis of 3-substituted and 8-
hydroxy-3-substituted isocoumarins has been developed by using
modified Julia olefination for initial C-C bond formation between
aldehydes and benzylic-sulfones. Palladium-catalyzed Meinwald
rearrangement was used as a key step for the obtainment of ketone
intermediates, which on base promoted intramolecular cyclization
afforded the desired isocoumarins. The developed method has
paved the way for hitherto unknown 3-glycosyl isocoumarins in
general and 3-glucosyl isocoumarins in particular wherein the
glucosyl moiety is attached to the pyrone ring of isocoumarin
framework, for the first time.
herein.
Introduction
Dapagliflozin 1 has emerged as a potent and selective Sodium-
Dependent Glucose Cotransporter 2 (SGLT2) inhibitor, which
reduces blood glucose levels in a dose-dependent manner for
the treatment of type 2 diabetes through blocking glucose
reabsorption in the kidneys.[1a-c] Structurally 1 is a C-aryl
glucoside, in which the gluco-configured pyranosyl unit is directly
attached to the aromatic ring. The success of dapagliflozin has
inspired further variation of the ring A of the aglycone part. The
ring A has been replaced with other heteroaryl rings like pyridine,
pyrrole, pyrazine and thiophene.[2a-b] Given the fact that nature
presents several O- or C- linked glycosides of the flavones,[3a-b]
isoflavones,[3c] coumarins[3d] and isocoumarins[3e-g] as valuable
natural products, we became interested in 3-glucosylated
isocoumarins 2 and 3 in particular as new potential structural
motif, worthy of synthesis and biological evaluation. The
hydroxyl group at the 8th position of the isocoumarin framework
has been found to be essential for diverse biological properties
represented by important natural products like Thunberginol A
and B.[4a-b] The C-glucosylated flavones, isoflavones and
coumarins represented by 4, 5 and 6 respectively carry the
glucosyl residue in the aromatic ring (Figure 1). Interestingly, C-
linked coumarins 7[5a-d] and isocoumarins 8 wherein the glycosyl
unit is attached to the pyrone ring are rare in nature and very
limited reports are available for the synthesis of this class of
compounds. To the best of our knowledge, only one isolated
report exists in the literature for C-glycosides of isocoumarin,
wherein the C-3 position contains a glycosyl residue.[6] The
absence of a convenient synthetic route for the access to C-3
glycosyl isocoumarins 8 in general and the need of our targeted
compounds 2 and 3 in particular, motivated us to develop a new
synthetic route. The results of these studies are presented
Figure 1. Structures of important aryl and heteroaryl glycosides
Results and Discussion
The new method reported by us for the synthesis of 3-aryl
isocoumarins[7] wherein -aryl aminonitriles 10 were
conveniently used as acyl anion equivalents for the requisite C-
C bond formation, has a drawback for the synthesis of 8 and 9
because alkylated -alkyl aminonitriles 11a requires strongly
acidic conditions in most cases[8a-f] in contrast to alkylated -aryl
aminonitriles 10a, for the release of carbonyl functionality
(Figure 2). For the sugar based - aminonitriles 12, if availed
and used, the situation with alkylated glycosyl aminonitriles 12a
would be even more detrimental, given the sensitive
functionalities and protections present on the glycosyl part.
Figure 2. Limitations of acyl anion chemistry for the synthesis of 3-glycosyl
isocoumarins 8 and 9.
In this context, a new synthetic scheme was envisaged for the
synthesis of 3-glycosyl-isocoumarins 8, which invoked the use of
modified Julia olefination[9] for the initial C-C bond formation
between the functionalized aldehydes 13 derived from the
carbohydrate domain and sulfone 14a (Figure 3).
[a]
Kasireddy Sudarshan, Prof. Dr. Indrapal Singh Aidhen
Department of Chemistry
Indian Institute of Technology, Madras, Chennai-600036, India
E-mail: isingh@iitm.ac.in
http://chem.iitm.ac.in/faculty/indrapalsinghaidhen/
Supporting information for this article is given via a link at the end of
the document
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European Journal of Organic Chemistry
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Figure 3. Proposed disconnection for 3-glycosyl isocoumarins 8.
Scheme 2. Synthesis of ketones 19a-e and 22a-e. Reagents and conditions:
(a) NaH, DMF, 0 ºC to r.t. 2-4 h, (63-74%). (b) m-CPBA, CH2Cl2, H2O, pH = 7,
12-14 h, (66-92%). (c) Pd(OAc)2, PBu3, dry t-BuOH, 3-4 h (67-97%).
The sulfones 14a[10] and 14b required for the synthesis of 3-
glycosyl isocoumarins 8 and 8-hydroxy-3-glycosyl isocoumarins
9 respectively were easily synthesized from the corresponding
bromides 15a-b as described in scheme 1. The reaction
sequence involved nucleophilic substitution of the bromides 15a-
b with 2-mercaptobenzothiazole in presence of a base for the
formation of sulfides 16a-b, followed by oxidation of the sulfides
with 30% H2O2 in the presence of sodium tungstate at 0 °C in
MeOH. Both the sulfones (14a and 14b) were obtained as white
crystalline solids.
Similarly, for the synthesis of 8-hydroxy-3-substituted
isocoumarins the same reaction sequence was deployed using
14b as the starting sulfone for arriving at keto lactones 22a-e
(Scheme 2).The Keto esters 19a-e on treatment with DBU in dry
CH2Cl2 afforded the corresponding 3-substituted isocoumarins
23a-e in good yields (Table 1). However, the keto lactones 22a-
e failed to undergo cyclization under same condition. This was
probably due to the unsuitable disposition of the lactone
carbonyl group because of the locked conformation resulting
from the isopropylidene protection. The cyclization, however,
could be easily achieved with the use of NaOMe as a base
resulting in the formation of 8-hydroxy-3-substituted
isocoumarins 24a-e in good yields (Table 1).
Table 1. List of 3-substituted and 8-hydroxy-3-substituted isocoumarins
Scheme 1. Synthesis of sulfones 14a and 14b.
S. No.
R1 in
R1-CHO
13
Before commencing olefination of glycosyl aldehydes 13 with
sulfone 14a, a model study with simple commercially available
aliphatic aldehydes 13a and 13b was undertaken. The alkene
products 17a and 17b were obtained as E/Z mixture which was
evident from the NMR spectroscopy. Similarly other aldehydes
13c-e[11] with additional functionalities such as ether, ester and
N-tert-butoxy carbonyl (Boc) functionalities also underwent clean
reaction with the sulfone 14a affording the corresponding
alkenes 17c-e in good yields. The olefins 17c and 17d were
formed as E/Z mixture whereas olefin 17e was obtained
exclusively as E isomer (Scheme 2). The olefins 17a-e on
treatment with m-CPBA underwent epoxidaton[12] furnishing the
mixture of epoxides 18a-e. These epoxides underwent clean
23a-e (% yield)[a]
23a (83)
24a-e (% yield)[a]
24a (74)
1
2
3
4
13a
13b
13c
13d
23b (91)
23c (76)
23d (84)
24b (68)
24c (92)
24d (82)
5
23e (89)
24e (83)
regioselective Meinwald type rearrangement upon treatment
[13]
with tributylphosphine in presence of Pd(OAc)2
affording the
13e
corresponding keto esters 19a-e as desired in the projected
synthetic scheme.
[a] for the annulation step
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With the successful model studies, efforts were now directed
towards the extending the reaction of sulfones 14a and 14b with
more functionalized aldehydes derived from the carbohydrate
domain.
revealed it to be an inseparable mixture of desired compound
along with 3,4-dihydroisocoumarin compound. The selective
removal of benzyl ether protection, however could be achieved
with the use of BBr3. (Scheme 4).
Scheme 3. Synthesis of 3-glycosyl and 8-hydroxy-3-glycosyl isocoumarins.
Towards this objective, we chose aldehydes 13f-k[14] as
representative examples and prepared them according to the
literature known protocols. The choice of these aldehydes was
purely dictated by the ready availability of starting materials and
the convenience of synthetic methods used to prepare them. All
these aldehydes 13f-k successfully reacted with the sulfones
14a and 14b under the optimized conditions to afford the
corresponding olefins 17f-k and 20f-j respectively with E isomer
as the major product (Scheme 3). These olefins were converted
to the corresponding 3-glycosylated isocoumarins 8a-f and 8-
hydroxy-3-glycosylated isocoumarins 9a-e respectively by a
sequence of reactions described in scheme 3. In case of
isocoumarin 8b, it was observed that the epoxy ester 18g
directly annulated to 8b without the intermediacy of keto ester
19g.
Further, to demonstrate the generality of the developed route,
another sulfone 14c, [16] containing oxygenation pattern present
in natural orsellinic acid, was synthesized and used for reaction
with -C-glucopyranosyl aldehyde 13l. The expected
isocoumarin 25 was obtained there by demonstrating the
usefulness of the developed method (Scheme 5).
With the obtainment of 3-glycosyl (8a-f) and 8-hydroxy-3-
glycosyl isocoumarins (9a-e), the developed route was now
utilized for the synthesis of targeted 3-glucosylated isocoumarins
2 and 3. The -C-glucopyranosyl aldehyde 13l[15] was subjected
to olefination with sulfones 14a and 14b to obtain the
corresponding olefins 17l (as E/Z mixture) and 20k (as E
isomer) respectively in good yields. (Scheme 4). These olefins
on epoxidation followed by palladium catalyzed rearrangement
gave ketones 19l and 22k respectively. Base promoted
intramolecular cyclization of 19l and 22k resulted in
corresponding isocoumarins 8g and 9f respectively. Finally for
the synthesis of the targeted isocoumarins 2 and 3 in particular,
the removal of benzyl ether protection in 8g and 9f was
attempted under hydrogenation condition. Although catalytic
hydrogenation under balloon pressure in the presence of Pd/C in
dry THF did remove the benzyl ether protections, it also reduced
Scheme 4. Synthesis of 3-glucosyl (2) and 8-hydroxy-3-glucosyl isocoumarins
(3). Reagents and conditions: (a) NaH, DMF, 0 ºC to r.t. 2-4 h, (60% for 17l
1
the C3-C4 double bond of the isocoumarin ring. The H-NMR
spectrum of the homogenous product obtained during
hydrogenation reaction (TLC, Rf = 0.1, 10% MeOH: EtOAc)
and 20k). (b) m-CPBA, CH2Cl2, H2O, pH
21k). (c) Pd(OAc)2, PBu3, dry t-BuOH, 3-4 h (81% for 19l , 98% for 22k). (d)
= 7, 12-14 h, (81% for 18l, 84% for
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European Journal of Organic Chemistry
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silica gel column chromatography to obtain the corresponding epoxides
18a-m or 21a-k respectively as diasteromeric mixture.
DBU, dry CH2Cl2, 12-14 h (75%). (e) NaOMe, dry MeOH, 2-4 h, (80%) (f) BBr3,
dry CH2Cl2, -78 °C, 12 h.
General Procedure for epoxides to ketones rearrangement
(Procedure C): To a solution of epoxides 18a-m or 21-a-k (1 equiv.) and
palladium acetate (0.3 equiv.) in degassed anhydrous tBuOH was added
tributylphosphine (1.3 equiv.) under nitrogen atmosphere at room
temperature. The reaction mixture was stirred at reflux for 4 h (monitored
by TLC). The solvent was removed under reduced pressure and purified
by column chromatography to yield keto esters 19a-m or keto lactones
22a-k respectively.
Scheme 5. Synthesis of isocoumarin 25.
The synthesis of 2 and 3 constitutes the first report in the
literature for C-anomerically linked glucosyl unit to the pyrone
ring of the isocoumarin at C-3 position.
General Procedure for synthesis of 3-substituted isocoumarins
(Procedure D): To a solution of aryl ketones 19a-m (1 equiv.) in dry
CH2Cl2 (4 mL), DBU (2 equiv.) was added under inert atmosphere. The
reaction mixture was stirred for 12 h. Then 20 mL DCM was added to the
reaction mixture. The mixture was washed with 5% hydrochloric acid (20
mL). After that, the organic layer was washed with 20 mL water and
finally dried over Na2SO4. The organic layer was concentrated under
reduced pressure and the obtained residue was purified by column
chromatography over silica gel to yield the corresponding 3-substituted
isocoumarins 23a-e, 8a-g and 25.
Conclusions
Synthesis of 3-glycosyl and 8-hydroxy-3-glycosyl-substituted
isocoumarins has been achieved for the first time. The synthetic
scheme banks on the convenience of C-C bond formation
through Julia olefination reaction and subsequent Meinwald
rearrangement for acquiring the requisite carbon framework. The
developed methodology has large substrate scope and wide
functional group compatibility during the implementation of the
synthetic scheme.
General Procedure for synthesis of 8-hydroxy-3-substituted
isocoumarins (Procedure E): To a solution of the aryl ketones 22a-k (1
equiv.) in dry MeOH (3 mL), NaOMe (1.1 equiv.) was added under inert
atmosphere. The reaction mixture was stirred for 6 h under inert
atmosphere at room temperature. Then the solvent was evaporated
under reduced pressure and the residue was purified by silica gel column
chromatography to obtain the corresponding 8-hydroxy-3-substituted
isocoumarins 24a-e, 9-f.
Experimental Section
General procedure Debenzylation reaction (Procedure F): To a
solution of isocoumarins 8g or 9f (1 equiv.) in dry CH2Cl2 (6 mL) was
added BBr3 (1.0 M in CH2Cl2, 8 equiv.) at −78 °C under nitrogen
atmosphere and was stirred at same temperature for 12 h.The progress
of the reaction was monitored by TLC, after complete consumption of
starting material the reaction mixture was quenched with MeOH (2 mL) at
−78 °C. The mixture was evaporated in vacuo. The residue was diluted
with EtOAc and the organic solution was washed with brine solution (10
mL). The organic layer was dried over anhydrous sodium sulphate and
then filtered. The filtrate was concentrated under vacuum and subjected
to purification by silica gel column chromatography to yield the
corresponding isocoumarins 2 and 3.
General Procedure for Julia olefination of sulfones with aldehydes
(Procedure A): To a suspension of NaH (2 equiv.) in dry DMF (2 ml per
100 mg of the aldehyde), a solution of sulfones 14a or 14b (1 equiv.) was
added at 0 °C. The solution turned to reddish orange color which
indicates the formation of carbanion. After 10 minutes, a solution of
aldehydes 13a-l (1 equiv.) in dry DMF (1 ml per 100 mg of the aldehyde)
was added to the reaction mixture. The disappearance of reddish orange
color was observed. The reaction mixture was allowed to attain room
temperature and maintained for further 2.5 h. After the complete
consumption of starting material, the reaction mixture was quenched with
saturated ammonium chloride solution (10 mL) followed by water addition
(10 mL) and extracted with ethyl acetate (3×15 mL). The combined
organic layer was washed with 20% aqueous cold solution of NaOH
(3×15 mL) to remove by-product 2-hydroxybenzothiazole followed by
water (10 mL) and brine (10 mL). The collected organic layer was dried
over anhydrous Na2SO4, filtered, concentrated and subjected to
purification by silica gel column chromatography to yield the
corresponding alkenes 17a-m or 20a-k respectively as diasteromeric
mixture.
Acknowledgements
The authors thank the Department of Science and Technology
(DST), New Delhi, for funding towards the 400 MHz NMR
spectrometer to the Department of Chemistry, Indian Institute of
Technology Madras (IIT-Madras), under Intensification of
Research in High Priority Areas (IRPHA) scheme and ESI-MS
facility under Fund for Improvement of Science & Technology
Infrastructure (FIST) program. K.S. acknowledges the University
Grants Commission (UGC) New Delhi, for a Senior Research
Fellowship.
General Procedure for epoxidation (Procedure B): To a solution of
alkenes 17a-m or 20a-k (1 equiv.) in CH2Cl2/ phosphate buffer (pH 7,
the buffer was prepared by adding 1.56g of NaH2PO4.2H2O in 10 mL (1
M) and 1.42g of anhydrous Na2HPO4 in 10 mL (1 M), (1:1, 8 mL) was
added portion wise m-CPBA (3 equiv.) at 0 °C. After stirring at rt for 12 h,
the organic phase was separated and the aqueous phase was washed
with dichloromethane (2 × 50 mL). The combined organic phases were
washed with saturated sodium thiosulfate and saturated sodium
bicarbonate solutions. The collected organic layer was dried over
anhydrous Na2SO4, filtered, concentrated and subjected to purification by
Keywords: Glucosyl isocoumarins • Julia olefination •
Epoxidation • Cyclization • Rearrangement
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Entry for the Table of Contents
Layout 2:
COMMUNICATION
3-Glycosyl Isocoumarins*
Kasireddy Sudarshan, Indrapal Singh
Aidhen*
1 – 6
Convenient Synthesis of 3-
Glycosylated Isocoumarins
3-substituted and 8-hydroxy-3-substituted isocoumarins are synthesized using
modified Julia olefination for the initial carbon-carbon bond formation reaction.
Palladium catalyzed Meinwald rearrangement of epoxides to ketones is used as
key step in this study. A variety of aldehydes derived from carbohydrates reacted
successfully for the synthesis of both 3-glycosyl in general and 3-glucosyl
substituted isocoumarins in particular.
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