Development of Routes for the Stereoselective Preparation of β-Aryl- C-glycosides via C-1 Aryl Enones

Article abstract of DOI:10.1021/acs.orglett.0c02843

A wide range of enones derived from d-glucal, d-galactal, l-rhamnal, d-rhamnal, and l-arabinal underwent Heck-coupling with various arylboronic acids bearing electron-donating and -withdrawing groups in the presence of palladium acetate and 1,10-phenanthroline. These reactions provided synthetically useful C-1 aryl enones in good yields. Many sensitive functional groups as well as protecting groups present in arylboronic acids and enones, respectively, remained intact under optimized conditions. The stereoselective hydrogenation of C-1 aryl enones with Pd-C/H2 provides the β-isomer of 2-deoxy-aryl-C-glycosides in excellent yield. The C-1 aryl enones were also used as precursors for the synthesis of 2-hydroxy-β-aryl-C-glycosides. Regioselective C-2 halogenations and vinylations of C-1 aryl enones were achieved in excellent yields.

Full text of DOI:10.1021/acs.orglett.0c02843

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Letter
Development of Routes for the Stereoselective Preparation of
β‑Aryl‑C‑glycosides via C‑1 Aryl Enones
Adesh Kumar Singh, Vimlesh Kumar Kanaujiya, Varsha Tiwari, Shahulhameed Sabiah,
and Jeyakumar Kandasamy*
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ABSTRACT: A wide range of enones derived from D-glucal, D-galactal, L-rhamnal, D-rhamnal, and L-arabinal underwent Heck-
coupling with various arylboronic acids bearing electron-donating and -withdrawing groups in the presence of palladium acetate and
1,10-phenanthroline. These reactions provided synthetically useful C-1 aryl enones in good yields. Many sensitive functional groups
as well as protecting groups present in arylboronic acids and enones, respectively, remained intact under optimized conditions. The
stereoselective hydrogenation of C-1 aryl enones with Pd-C/H2 provides the β-isomer of 2-deoxy-aryl-C-glycosides in excellent yield.
The C-1 aryl enones were also used as precursors for the synthesis of 2-hydroxy-β-aryl-C-glycosides. Regioselective C-2
halogenations and vinylations of C-1 aryl enones were achieved in excellent yields.
ryl-C-glycosides are unique structural motifs found
aryl halides, arylboronic acids, etc.) leads to the formation of
either 2-deoxy-2,3-unsaturated aryl-C-glycosides (through β-
hydride elimination)4 or 2,3-deoxy-2,3-unsaturated aryl-C-
glycosides5 (through β-heteroatom elimination), largely
based on the protecting groups. However, it is important to
note that the majority of these reactions provide α-selective
aryl-C-glycosides, whereas β-anomers are more predominant in
nature.
A
embedded in plenty of biologically relevant natural
products (Figure 1).1 It is worth mentioning that recently
In one of the approaches, Yang et al. demonstrated the
transformation of 2,3-deoxy-2,3-unsaturated α-aryl-C-glyco-
sides (obtained through Heck coupling from glycal and aryl
bromides) into 2-deoxy-β-aryl-C-glycosides via sequence
oxidation−reduction reactions.4b Some recent approaches,
including the Heck coupling of glycals with aryldiazonium
salts followed by acid-catalyzed anomerization of the resulting
α-C-glycosides6 or the use of limitedly available 3,5-anti-glycals
as the substrates7 in Heck coupling, provide 2,3-deoxy-3-keto
β-C-glycosides. However, these approaches suffer from a
Figure 1. Biologically relevant natural and synthetic aryl-C-glycosides.
many synthetic aryl-C-glycosides have been approved for the
treatment of type-2 diabetes (i.e., SGLT1/SGLT2 inhibitors).2
The majority of the naturally occurring aryl-C-glycosides are of
two types, namely, 2-hydroxy-β-aryl-C-glycosides and 2-deoxy-
β-aryl-C-glycosides.
In this context, numerous methods have been developed for
the preparation of 2-hydroxy-β-aryl-C-glycosides.1a−g More-
over, recently, a radical-mediated stereoselective one-step
preparation of 2-hydroxy-β-aryl-C-glycosides has been demon-
strated.1h−j In contrast, only limited methods are available for
the synthesis of 2-deoxy-β-aryl-C-glycosides.1a−g,3 Glycals are
important precursors that are widely employed in the
preparation of 2-deoxy-aryl-C-glycosides. Palladium-catalyzed
Heck-type coupling of glycals with various aryl donors (e.g.,
Received: August 25, 2020
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limited substrate scope as they require fully armed protecting
groups (e.g., benzyl or silyl) containing glycal substrates for the
Heck coupling reaction.4b,6,7 To this end, recently, Nishimura
et al. reported the iridium-catalyzed ligand-controlled stereo-
selective synthesis of both α- and β-aryl-C-glycosides from
glycals and arenes bearing a directing group.3e
acids to glycal enones and (ii) the stereoselective reduction of
C-1 aryl enones. Nevertheless, C-1 aryl enones can also serve as
precursors for the preparation of 2-hydroxy-β-aryl-C-glycosides
(vide infra).
The first step is crucial because there are possibilities for a
1,4-conjugate addition reaction as well as C-2 arylation. Hence,
at the outset, we focused on the optimization of Heck coupling
using galactal-enone 1a and phenylboronic acid 2a as model
substrates. (See SI-Table 1 in the Supporting Information.)
The reaction was screened with different solvents (THF, DMF,
CH3CN, DMA, NMP, DCE, 1,4-dioxane, and AcOH), ligands
(2,2′-bpy, 1,10-Phen, DABCO, Et3N, pyridine, DMAP,
TMEDA, PPh3, and Dppe), bases (Na2CO3, Cs2CO3, and
NaOAc), and temperatures (80−150 °C) in the presence of
palladium catalysts such as Pd(OAc)2, Pd(dba)2, Pd2(dba)3,
Pd(PPh3)4, and PdCl2.
To our delight, the desired product 1aa was obtained in 86%
yield at 100 °C in DMF in the presence of 10 mol % palladium
acetate and 1,10 phenanthroline (20 mol %) (Scheme 3).
Under these optimized conditions, the 1,4-addition product
2aa was observed in a negligible amount (<5%), whereas C2-
arylation product 1aa′ was not observed.
On the contrary, cross-coupling of C-1-functionalized glycals
(e.g., C-1 metal glycals or iodoglycals)8 with appropriate aryl
donors leads to the formation of 2-deoxy-1,2-unsaturated aryl-
C-glycosides, which can be efficiently transformed to both 2-
hydroxy-β-aryl-C-glycosides and 2-deoxy-β-aryl-C-glycoside-
s.1a−c However, the preparation of C-1-functionalized glycals
is usually associated with many difficulties, including the use of
a strong base such as t-BuLi, harsh reaction conditions, the
incompatibly of traditional protecting groups, and so on.8,9 To
this end, Niu et al. recently demonstrated the preparation of C-
1 aryl glycals from C-1 glycal sulfones via a nickel-catalyzed
Suzuki−Miyaura coupling reaction with aryl boronic acids.10
Enones that are derived from glycals via the selective
oxidation of the C-3 hydroxyl group (i.e., glycal-enone) using
hypervalent iodine compounds11 have been previously ex-
plored in the synthesis of C-glycosides.12 For instance, the
palladium-catalyzed addition of benzene to glycal-enones
provides a mixture of the oxidative coupling product (i.e., C-
1 aryl enones) and the 1,4-conjugate addition product (i.e., α-
C-aryl 3-keto glycosides) in different ratios.12a However, this
reaction is limited to benzene (Scheme 1, eq 1). On the
Scheme 3. Optimization of the Reaction Conditions for the
Oxidative Heck Coupling Reaction
Scheme 1. Enone-Mediated Synthesis of C-Glycosides
With the optimized conditions in hand, we investigated the
scope of arylboronic acids in the coupling reaction with
galactal enone 1a (Scheme 4). Initially, the reactions were
attempted with arylboronic acids bearing electron-donating
groups (EDGs) and electron-withdrawing groups (EWGs) at
the para position. EDG-functionalized arylboronic acids
efficiently participated in the coupling reaction and gave the
desired products 1ab−1ae in 80−83% yields within 4−12 h.
On the contrary, EWG-functionalized arylboronic acids took
a slightly longer time (6−24 h) and provided the enones 1af−
1ak in 60−80% yields. Furthermore, we have investigated the
reaction of meta-substituted as well as sterically hindered
ortho-substituted arylboronic acids under optimized con-
ditions. All of these substrates smoothly participated in the
coupling reaction and gave the enones 1al−1ap in good to
excellent yields. To expand the scope, we investigated the
coupling reaction of glucal-enone (1b) with different EDG-
and EWG-substituted arylboronic acids. All of these reactions
smoothly proceeded under optimized conditions to afford the
desired products 1ba−1bk in 58−75% yields. Furthermore, in
the search for the substrate scope, different benzyl-protected
glycal-enones prepared from L-rhamnal, D-rhamnal, and L-
arabinal were subjected to the oxidative coupling reactions. To
our delight, these reactions gave the enones 1ca, 1cb, 1da, and
1ea−1ec in 60−70% yields within 2−10 h.
contrary, rhodium-catalyzed 1,4-conjugate addition of arylbor-
onic acids to acetylated enones results in the formation of α-
selective C-aryl 3-keto glycosides (Scheme 1, eq 2).12b
However, no further efforts have been made toward the
establishment of protocols for the preparation of β-aryl-C-
glycosides from glycal-enones.
We have recently reported a palladium-catalyzed aryldiazo-
nium-salt-mediated stereocontrolled synthesis of 2-deoxy-α-
and β-aryl-C-glycosides from glycals and anti-glycals (i.e., C-3
configuration-inverted glycals), respectively.7b,13 In a continu-
ation of these works as well as in the light of the report of Ville
et al.,12a we envisioned a two-step protocol for achieving 2-
deoxy-β-aryl-C-glycosides from glycal-enones, as shown in
Scheme 2. The steps include (i) the synthesis of C-1 aryl
enones via the regioselective oxidative coupling of arylboronic
Scheme 2. Stereoselective Formation of β-Aryl-C-glycosides
via C-1 Aryl Enones
Having explored the scope of different arylboronic acids and
glycal-enones, we investigated the compatibility of different
traditional protecting groups in the coupling reaction. In this
context, acetyl-, pivaloyl-, benzoyl-, MOM-, and TBDPS-
protected enones were prepared and subjected to the oxidative
coupling reaction with different arylboronic acids bearing
B
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Scheme 4. Reaction of Glycal Enones with Arylboronic
Acids
Table 1. Optimization of the Reaction Conditions for the
a b
,
Reduction from Aryl Enone (1aa) with Different Reducing
a
Agents
b
yield %
S no.
conditions
3aa
4aa
5aa
1
2
3
4
10% Pd/C, H2 (1 atm), MeOH, RT
10% Pd/C, H2 (1 atm), EtOAc, RT
NaBH4, MeOH, RT
45
84
<5
<5
40
<5
nd
nd
nd
nd
75
70
LiAlH4, THF, RT
a
Conditions: aryl enone 1aa (0.15 mmol) and NaBH4 or LiAlH4 (1.2
equiv) or 10% Pd/C (20 mg)/H2 balloon were stirred in the
b
appropriate solvent (3 mL). Isolated yield.
After the successful identification of the optimized
conditions (Table 1, entry 2), the stereoselective hydro-
genation of various C-1 aryl enones was investigated using Pd-
C/H2 in EtOAc (Scheme 5). To our delight, benzyl-, acetyl-,
Scheme 5. Stereoselective Hydrogenation of Aryl Enones
a b
,
with Pd-C/H2 in Ethyl Acetate or Methanol
a
Conditions: enone (0.25 mmol) and arylboronic acid 2 (0.5 mmol,
2.0 equiv), Pd(OAc)2 (5.6 mg, 10 mol %), and 1,10-Phen (9 mg, 20
b
mol %) were stirred in DMF (3 mL) under an O2 balloon. Isolated
yield.
EDGs and EWGs. Pivaloyl- and benzoyl-protected enones
participated in the coupling reaction in a short span of time
and gave enones 1ga−1hc in 70−90% yields. On the contrary,
acetyl-protected enones gave the desired products 1fa−1fc in
relatively low yields. However, to our delight, acid-sensitive
MOM- and TBDPS-protected glycal-enones efficiently partici-
pated in the reaction and gave the corresponding enones 1ia-
1jb in 65−85% yields. Additionally, we attempted the model
reaction (Scheme 3) on a 1.0 mmol scale and obtained aryl
enone 1aa in 74% yield. (See the Supporting Information.)
After exploring the first step, we investigated the second
step, that is, the stereoselective reduction of C-1 aryl enones. It
has been previously shown that the reduction of C-1 aryl
enones with Pd/C−H2 provides 2-deoxy-β-aryl-C-glycosides
with high stereoselectivity.3c,4b,12a In light of these reports, the
benzyl-protected galactal-enone (1aa) was chosen as the
model substrate and subjected to the reduction with Pd-C/
H2 (Table 1).
The reaction in MeOH and EtOAc gave the desired 2-
deoxy-β-aryl-C-glycoside 3aa in 45 and 84% yields, respec-
tively. We observed the fully deprotected aryl β-glycoside 4aa
in 40% yield in methanol. It is also interesting to note that the
reduction of 1aa with sodium borohydride and lithium
aluminum hydride results in the formation of 5aa as the
major product (>70%) via chemo- and stereoselective
reduction of the ketone group.
a
Conditions: aryl enone (0.15 mmol) and 10% Pd/C (20 mg) were
stirred in ethyl acetate (3 mL) or methanol (3 mL) under a H2
b
balloon. Isolated yield.
pivaloyl-, benzoyl-, and MOM-protected C-1 aryl enones were
successfully transformed into partially protected 2-deoxy-β-
aryl-C-glycosides 3aa−3an in 74−95% yields. In particular,
benzyl groups remained intact under the standard reaction
conditions. Furthermore, we have attempted the preparation of
fully deprotected 2-deoxy-β-aryl-C-glycosides from benzyl-
protected C-1 aryl enones (Scheme 5). To our delight, this
transformation was efficiently achieved by using Pd-C/H2 in
methanol. Under these conditions, different benzyl-protected
C-1 aryl enones were directly transformed into corresponding
unprotected C-aryl glycosides 4aa−4ah in 70−88% yields.
The assignment of an anomeric configuration (i.e., β) to the
resulted products (i.e., 3aa−3an and 4aa−4ah) was estab-
lished based on the spectral data (1D, 2D, and NOE NMR
experiments) and previous reports.3c,4b,12a For instance, in H
1
NMR, the anomeric proton of the products appear as a doublet
of a doublet with a large coupling constant for JH‑1 and JH‑2a
(>10 Hz, e.g., 11.4 Hz for 3aa) due to the axial−axial coupling,
which confirms the formation of a β anomer. A simultaneous
C
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reduction of CO and CC bonds in C-1 aryl enones from
the α-face results in the formation of 1,3-syn aryl-C-
glycosides.3c,4b,12a
Scheme 8. Plausible Mechanism of the Reaction
The C-1 aryl enones could serve as an important precursor
for the preparation of 2-hydroxy-β-aryl-C-glycosides (Scheme
6).
Scheme 6. Synthesis of 2-Hydroxy-β-aryl-C-glycosides
AcOH. The complex F undergoes oxidation in the presence of
oxygen to form C-1 aryl enone (H) and (L)Pd(O2) (G). The
complex G converts into Pd(OAc)2(L) in the presence of
HOAc, and the catalytic cycle is resumed.16b The arylated
enone (H) transforms into 2-deoxy-β-C-aryl glycosides by an
α-face hydrogenation reaction with Pd/C-H2.3c,4b,12a
The formation of 1,4-conjugate addition side product (J)
could be considered as evidence for the proposed mechanism.
For instance, in the presence of H+, the palladium enolate D
undergoes hydrolysis to provide the 1,4-addition product 2aa
in high yield. (See SI-Table 1, entry 12 in the Supporting
Information.)
For instance, the chemo- and stereoselective reduction of C-
1 aryl enones 1aa, 1ae, and 1ba with NaBH4−CeCl3 gave the
allyl alcohols 5aa, 5ab, and 5ac, respectively. Furthermore,
these compounds were subjected to benzyl protection followed
by hydroboration to obtain 2-hydroxy-β-aryl-C-glycosides 7aa,
7ab, and 7ac in good yields.
The C-2-functionalized glycals are useful precursors in the
preparation of various natural products and biologically active
compounds.14 In this context, to demonstrate the further use
of aryl enones, we investigated the C-2 functionalization
reactions (Scheme 7). The regioselective halogenation of aryl
In conclusion, we have successfully developed an efficient
method for the stereoselective synthesis of 2-deoxy-aryl-C-
glycosides from enones derived from glycals. Different enones
derived from D-glucal, D-galactal, L-rhamnal, D-rhamnal, and L-
arabinal underwent a regioselective coupling reaction with
electron-donating- and electron-withdrawing-functionalized
arylboronic acids and provided C-1 aryl enones in good to
excellent yields. Various functional groups in arylboronic acids
including, halo, nitro, cyano, aldehyde, carboxylic acids, and so
on were found to be stable under the standard reaction
conditions. Moreover, many protecting groups in enones were
also found to be compatible during the coupling reaction. A
controlled stereoselective reduction of C-1 arylated enones
provides partially protected as well as fully deprotected 2-
deoxy-β-aryl-C-glycosides in excellent yields. The C-1 aryl
enones are useful precursors for the preparation of 2-hydroxy-
β-aryl-C-glycosides.
a b
,
Scheme 7. C-2 Functionalization of Aryl Enones
a
Condition A: Aryl enone (0.15 mmol) was stirred in DCM with
NBS (1.0 equiv) or NCS (2.0 equiv) or NIS (2.0 equiv) at RT.
Condition B: Aryl enone (0.1 mmol), styrene (1.5 equiv), AgOAc
(2.5 equiv), and Pd(OAc)2(10 mol %) were stirred in DMF/DMSO
b
(9:1, 3 mL) at 100 °C. Isolated yield.
enones 1aa, 1ae, and 1ba with N-halo succinimides in DCM
results in the formation of C-2 bromo, chloro, and iodo enones
8aa−8ae in excellent yields at room temperature. Similarly, the
regioselective vinylation of aryl enone 1ae with styrenes was
achieved in good yield in the presence of Pd(OAc)2 (Scheme
7, 9aa and 9ab).15
A plausible mechanism for the palladium-catalyzed oxidative
coupling reaction is shown in Scheme 8. Palladium acetate
coordinates with 1,10-phenanthroline to form an electron-rich
palladium(II) complex A.16a This complex undergoes trans-
metalation with arylboronic acid to form the complex B, which
was added to the enone from the α-face to provide
intermediate C. This intermediate undergoes a palladotropic
shift to form enolate D and rearranges to E, which is suitable
for syn-β-H elimination. Finally, the reductive elimination
leads to the formation of (L)Pd(0)−product complex (F) and
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02843.
Experimental procedures and characterization data (1H
and 13C NMR, HRMS) for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Jeyakumar Kandasamy − Department of Chemistry, Indian
Institute of Technology (BHU), Varanasi, Uttar Pradesh
221005, India; orcid.org/0000-0003-3285-971X;
Email: jeyakumar.chy@iitbhu.ac.in
D
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Authors
pubs.acs.org/OrgLett
Letter
Azevedo, H. F. Z.; Guimaraes, C. R. W.; Miranda, L. S. M.; de Souza,
R. O. M. A. Synthetic strategies toward SGLT2 inhibitors. Org. Process
Res. Dev. 2018, 22, 467−488.
Adesh Kumar Singh − Department of Chemistry, Indian
Institute of Technology (BHU), Varanasi, Uttar Pradesh
221005, India
Vimlesh Kumar Kanaujiya − Department of Chemistry, Indian
Institute of Technology (BHU), Varanasi, Uttar Pradesh
221005, India
Varsha Tiwari − Department of Chemistry, Indian Institute of
Technology (BHU), Varanasi, Uttar Pradesh 221005, India
Shahulhameed Sabiah − Department of Chemistry, Pondicherry
University, Pondicherry 605014, India
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02843
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.K. acknowledges DST-India (DST/INT/MPG/P-09/2016)
and Max-Planck Society-Germany for financial support
through the Indo-Max Planck partner group project. A.K.S.
acknowledges the CSIR for the senior research fellowship (file
no: 09/1217(0005/2015-EMR-I)). S.S acknowledges Pondi-
cherry University for the mass analysis. V.K.K. acknowledges
IIT (BHU) for a research fellowship. J.K. acknowledges
Central Instrumentation Facility Center (CIFC)-IIT BHU for
the NMR facilities. Dedicated to Professor Timor Baasov, the
recipient of the Israel Chemical Society NCK-prize 2020.
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