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Palladium-Catalyzed Stereospecific CGlycosylation of Glycals with Vinylogous Acceptors Yuanwei Dai, Baotong Tian, Huan Chen, and Qiang Zhang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00336 • Publication Date (Web): 27 Feb 2019 Downloaded from http://pubs.acs.org on February 27, 2019
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ACS Catalysis
Palladium-Catalyzed Stereospecific C-Glycosylation of Glycals with Vinylogous Acceptors Yuanwei Dai, Baotong Tian, Huan Chen and Qiang Zhang* Department of Chemistry, University at Albany, State University of New York, Albany, 12222 (USA) ABSTRACT: A palladium-catalyzed vinylogous C-glycosylation of α, β-unsaturated lactones (including coumarins) is achieved in high yields with exclusive regio- and stereoselectivity. This efficient protocol is carried out under mild conditions and has an expanded substrate scope (51 examples) as well as high functional-group tolerance. A gram-scale preparation of 2,3-unsaturated C-glycosides illustrated the practicality of this stereoselective vinylogous glycosylation approach. The structural feature of C-glycoside products enables subsequent transformations and provides a wide range of multifunctional and diverse compounds.
KEYWORDS: glycal, palladium catalysis, C-glycosylation, vinylogous allyl alkylation, coumarin
Nature devises ingenious ways to create expanded contents with minimal efforts. Glycosylation is one of such processes that modified aglycones and efficiently populated the diversify substrate libraries.1 The critical roles of oligosaccharide incorporation on the biomolecules have been well recognized and received increased attention in recent years.2 The superior stability of C-glycosides to enzymatic or acidic degradation has demonstrated their effectiveness as the potential therapeutic agents.3 Successful development of sodium/glucose cotransporter-2 (SGLT2) inhibitors against type 2 diabetes (such as dapagliflozin, canagliflozin, and empagliflozin) has highlighted the merits of C-glycosides.4 In addition, successful examples of O-glycoside surrogates with C-glycosidic bonds have created expanded the pharmaceuticals with enhanced physicochemical and pharmacological properties.5 There is a crucial need to attain molecules with versatile C-glycosidic linkages, and the development of a simple strategy that could achieve such goals with high stereoselectivity and practicality is largely desired. The applications of transition metal catalysis for constructing C-glycosyl linkages have significantly increased in recent years.6,7 Pd-catalyzed Heck-type glycosylation using glycals has proved to be a successful strategy to attain 2,3-unsaturated C-glycosides with α-stereoselectivity.8 Unfortunately, the access to high β-selectivity remains largely elusive with Hecktype strategy (Scheme 1a). Liu and co-workers reported an elegant palladium-catalyzed β-selective C-glycosylation via an intramolecular decarboxylative coupling (Scheme 1b),9 but require additional synthetic steps to produce functionalized glycals. Despite the advancement of the C-glycosidic bond construction propelled by previously described approaches, the use of vinylogous nucleophiles in palladium-catalyzed Cglycosylation has not been explored, due to the difficulty of controlling the remote formation of glycosidic bonds with high diastereoselectivity and regioselectivity (e.g., α vs γ-glycosidic product; γ vs γ’-glycosidic product) (Scheme 1c). Inspired by the works in iridium-catalyzed vinylogous allylic alkylation and based on our previous study,10,11 we envisioned that the palladium-catalyzed allylic alkylation of the 3,4-O-carbonate glycal with vinylogous acceptors might accomplish the desired vinylogous C-glycosides with high stereoselectivity via a π-
allyl-Pd intermediate. Herein, we describe an unprecedented Pd-catalyzed stereoselective synthesis of vinylogous Cglycosides using easily accessible 3,4-O-carbonate glycals in an intermolecular fashion. Our initial choice of pronucleophiles were coumarins considering their abundance motifs in over 1000 natural products and many of which have served as privileged scaffolds in biological and pharmaceutical evaluations.12 We began our studies by exploring bidentate phosphine ligands in the glycosylation of 3-cyano-4-methylcoumarin 1a and 3,4-Ocarbonate galactal 2a 13 in dichloromethane at 25 C. The outcomes are shown in Table 1, no desired product was observed when DPPP or BINAP was used as ligand (entries 1, 2). When the exogenous base was not employed to activate 1a, a combination of Pd(OAc)2 and DPPF successfully furnished the desired C-glycoside 3aa with excellent β-stereocontrol (β/α > 30:1) and regioselectivity (γ/α > 30:1), although in 12% yield (entry 3). We believed that the carbohydrate anion generated in situ from the reaction behaved as the base in the transformation.13 Xantphos was found to be the optimal ligand Scheme 1. Pd-Catalyzed Glycosylation
Stereoselective
Vinylogous
a) Heck-type glycosylation O
PO
O
PO
conditions
Ar
+
Ar-X
PO -R or H R X = B(OH)2, In, ZnCl, SO2Na, NHNH2, I, Br, CO2H, NH2 PO
R
b) Pd-catalyzed intramolecular glycosylation (Liu, X.-W) O
PO
R1 PdLn
R1
PO
-CO2
R2
O O
R2
O
PO PO
O
O
c) this work: Pd-catalyzed vinylogous glycosylation O '
O
+ EWG
O
O O
EWG= CN, COR, CO2R, SO2Ar
ACS Paragon Plus Environment
OR O
Pd catalysis first vinylogous glycosylation
OH OR O
H GWE
-C-glycosides
' O O
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
and afforded 3aa in 44% yield with incomplete conversion of 2a (entry 6). It is worth mentioning that when ligand was not presented, the reaction did not proceed (entry 7). We discovered that the choice of the external base profoundly impacted the reaction yield. Organic and inorganic bases were explored extensively (entries 8-13). DABCO was found to be the optimal base14 and provided 3aa in 88% yield and exclusive βselectivity (entry 13). The β stereochemistry of 3aa was confirmed by 2D NOESY spectrum, in which a strong crosspeak between H-1 (δH 4.56) and H-5 (δH 3.55) was observed.15 Subsequently, we decided to evaluate other reaction parameters such as solvent and catalyst loading. Changing the solvent from dichloromethane to tetrahydrofuran, toluene or chloroform provided the product in a lower yield (entries 15-17). The yield decreased to 59% when reducing the loading of Pd(OAc)2 to 2 mol % (entry 18). Under the optimized conditions (Table 1, entry 13), the scope of the vinylogous glycosylation was investigated. Nucleophile methylcoumarin 1a engaged the rapid C-glycosylation with a range of 3,4-O-carbonate glycals (Table 2). O6 substituted D-
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Table 2. Scope of Glycal Donorsa,b CN O
O +
O
O
Pd(OAc)2 (5 mol %) Xantphos (7.5 mol % )
OR O
O
1a
NC
OR O
HO
DABCO (1.5 equiv) CH2Cl2, rt, 12 h 3
O
O OR O
HO
H
3ai, 85%
H 3ak, 79%
3aj, 73%
O
O
O
OH O O
O
O
H 3an, 83%
H 3am, 83%
H 3al, 85%
HO
O
OTIPS O H
O
O
from L-fucal 2p 3ap, 80%
2p
O
HO
H 3ao, 80%
NTs
O
O
OH O
OH O
O O
O H
H
OH O
OH O
O
NBoc
O
OMe
OH O
OH O OMe O
3aa, R= TIPS, 88% 3ab, R= TBS, 91% 3ac, R= TBDPS, 90% 3ad, R= Ac, 83% 3ae, R= Bz, 82% 3af,R= Me, 83% 3ag,R= Bn, 86% 3ah,R= Boc, 89%
O
=
H
2
from D-allal 2q 3aq, 84%
OTIPS O
O O
CN O
O
O
+
O
1a, 1.5 equiv
OTIPS O
O 2a, 1 equiv
PPh2 PPh2
O PPh2
OTIPS 5 O H 1 O NOE H NC 3aa O
Pd(OAc)2 (5 mol %) ligand (7.5 mol % )
HO
base (1.5 equiv) solvent, rt, 12 h
PPh2
H N
PPh2
PPh2
Xantphos
L1
BINAP
entry
ligand
solvent
1
DPPP
CH2Cl2
2
BINAP
CH2Cl2
3
DPPF
CH2Cl2
base _ _ _ _
L2 yield (%)
b
0
c
/
N.D.
0
N.D.
12
>30:1
4
L1
CH2Cl2
30
>30:1
5
L2
CH2Cl2
_
38
>30:1 >30:1
6
Xantphos
CH2Cl2
_
44
7
_
CH2Cl2
_
0
N.D.
8
Xantphos
CH2Cl2
i-Pr2NEt
77
>30:1
9
Xantphos
CH2Cl2
Et3N
68
>30:1
10
Xantphos
CH2Cl2
DBU
9
>30:1
11
Xantphos
CH2Cl2
i-Pr2NH
31
>30:1
12
Xantphos
CH2Cl2
Cs2CO3
75
>30:1
13
Xantphos
CH2Cl2
DABCO
91 (88d)
>30:1
14
Xantphos
DCE
DABCO
85
>30:1
15
Xantphos
THF
DABCO
35
>30:1
16
Xantphos
toluene
DABCO
24
>30:1
17
Xantphos
CHCl3
DABCO
72
>30:1
18e
Xantphos
CH2Cl2
DABCO
59
>30:1
[a] Reaction conditions: 0.15 mmol of 1a, 0.1 mmol of 2a, 0.15 mmol of base, 5 mol % Pd(OAc)2, 7.5 mol % ligand in solvent (2 mL). [b] Dibromomethane as the internal standard was used to determine yields by 1H NMR analysis. [c] Single isomer, β/α ratio and regioselectivity (γ/α > 30:1) were determined by 1H NMR analysis. [d] Isolated yield. [e] Pd(OAc)2 (2 mol %) and xantphos (3 mol %) were used. N.D.= not determined. DBU: 1,8diazabicyclo[5.4.0]undec-7-ene. DCE: 1,2-dichloroethane. DABCO: 1,4-diazabicyclo[2.2.2]octane.
OMe
7
OH O O
H
3ar, 80%
3as, 65%
pharmaceutical-derived substrates:
MeO
H
from deoxycholic acid 3at, 84%
Cl O
H
H
O
O O S N(n-Pr)2 O
O
H
from linoleic acid
O
O HO
H H
from stearic acid
H
PPh2
PPh2
CH3 16
OH O O
O
O
O
O
O
OH
O
2q
O
natural product-derived substrates:
Table 1. Optimization of the Vinylogous Glycosylation of 1a and 2aa
O
O
N OH O O
OH O O
OMe
from Probenecid
H from Indometacin
3au, 75%
3av, 68%
O
O H from Isoxepac 3aw, 83%
[a] Reaction conditions: Coumarin 1a (0.15 mmol), glycal 2 (0.1 mmol), Pd(OAc)2 (5 mol %), xantphos (7.5 mol %), DABCO (0.15 mmol), CH2Cl2 (2 mL). Single isomer (β/α > 30:1, γ/α > 30:1), determined by 1H NMR analysis. [b] Isolated yield.
galactals equipped with distinct functional groups were evaluated, electronic or steric hindrance effects did not impact the yields, and the products are generally produced in great yields with excellent β-stereocontrol (3aa-3al). Product 3aj containing an acid labile MOM group was generated in good yield. Furthermore, high yields were observed when glycals were functionalized with piperonylic ester, NHBoc, NTs, alkene groups (3am-3ao, 3as). β-C-glycoside 3ap was the single glycosyl adduct while 3,4-O-carbonate L-fucal 2p16 was employed. It is clear that sterically hindered group at C6 will not have an influence on the stereoselectivity of our transformation. The coupling of 3,4-O-carbonate D-allal 2q with cyanocoumarin provided the corresponding C-glycosides in good yields and high α-selectivity (3aq). To further investigate the versatility of this vinylogous glycosylation method, we next applied the optimized conditions to a series of commercially available pharmaceuticals and natural productderived glycals. All the substrates furnished the desired Cglycosides in great yields and exclusive stereoselectivity (3ar3aw). Subsequently, we explored the reaction scope using different vinylogous nucleophiles (Table 3). Coumarins substituted by either electron withdrawing groups such as F, Cl, Br, NO2 and CN or electron donating groups (e.g., methyl, OMe and OBn) were compatible with our optimized reaction conditions,
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ACS Catalysis Scheme 2. Gram-scale Derivatizations
Table 3. Scope of Vinylogous Acceptorsa, b O
O
OTIPS O +
O
O
R 2a
OH OR O
DABCO (1.5 equiv) CH2Cl2, rt, 12 h
O
OH OTIPS O
H NC
O
Me
O
O
5na, 91%
OH OTIPS O
5ra, 61%
d
O OH OTIPS O
O HO
OH OTIPS O H NC
OH OTIPS O
‘ O
6aa, 57%
O
O
H
6ea, 67%d
O O
H
O
O
O
H NC
O
H O
6fa, 63%d
O
O
O Ph
6ga, 54%d
O
3aa
1) OsO4, NMO, t-BuOH/ H2O (10:1), rt, 12 h, 82%
10% Pd/C, H2
2) Ac2O, DMAP, CH2Cl2 rt, 6 h, 95%
EtOAc, rt, 24 h 86%
m-CPBA, CH2Cl2, rt
OH OTIPS O O H 8
OH OTIPS O 3aa
O
H
BocHN
NC OTIPS O
O 11
H PhO2S
OTIPS O
O O
3ap
O
H O OH OTIPS O O
CH2Cl2, rt, 12 h, 75% ( > 30:1)
HO 2a
H
O
=
Pd(OAc)2 (10 mol %) Xantphos (15 mol % )
O +
10
O
H N
H
OTIPS O
O
Boc-Lys(Boc)-Gly-OH EDC, DMAP, DIPEA DCM, rt, 24 h, 84%
O
O
9
DMP, NaHCO3
24 h, 78%
H
BocHN
O
OH OTIPS O
DCM, rt, 2 h, 95%
O
H
12
O
OH OTIPS O
H
O
d
6da, 52%c
6ca, 64%
OAcOTIPS
O P OEt OEt
H EtO2C
O
2a
O
H NC
(b) product derivatizations
H
OH OTIPS O
OH OTIPS O
OH OTIPS O
OH OTIPS O
5ta, 87%
OH OTIPS O
DABCO (1.5 equiv) CH2Cl2, rt, 12 h 92% yield (1.29 g) > 30:1
O
H NC
O OH OTIPS O
O O 6ba, 49%d
O
O
NC 5dp, 85%
x-ray of 5dp
O O
5sa, 53%
Cl
Pd(OAc)2 (5 mol %) Xantphos (7.5 mol % )
OTIPS O
O
O
H AcO OAc 7 O
O
O
O
O
H NC
O
H NC
O 5qa, 75%d
O +
1a O
O
O
H NC
O
5oa, R= Et, 64%c 5pa,R= Bn, 70%c
OH OTIPS O
OH OTIPS O
CN
H RO2C
O
H NC
5ia, R= Me, 90% 5ja, R= F, 84% 5ka, R= OAc, 80% 5la, R= OBn, 91% 5ma, R= OMe, 88%
Product
(a) gram-scale synthesis O
OH OTIPS O
OH OTIPS O
O
O
5ba, R= Me, 90% 5ca, R= Et, 88% 5da, R= Cl, 94% 5ea, R= F, 88% 5fa, R= Br, 74% 5ga, R= NO2, 52% 5ha, R= CN, 63%
Cl
R
OH OTIPS O
and
R
H GWE O 5 or 6
1 or 4 R
H NC
Pd(OAc)2 (5 mol %) Xantphos (7.5 mol % )
EWG
Synthesis
O O
6ha, 70%d
[a] Reaction conditions: 1 or 4 (0.15 mmol), glycal 2a (0.1 mmol), Pd(OAc)2 (5 mol %), xantphos (7.5 mol %), DABCO (0.15 mmol), CH2Cl2 (2 mL). Single isomer (β/α > 30:1, γ/α > 30:1), determined by 1H NMR analysis. [b] Isolated yield. [c] t-BuOK (0.15 mmol) as the base instead. [d] Reaction performed at 40 °C.
generating γ-glycosidic products with good to excellent yields and β-stereoselectivity (5ba-5ma). Disubstituted cyanocoumarins 1n also underwent facile glycosylation with 2a. Coumarin 4o and 4p, reported as less efficient or even unreactive in literature,17 reacted smoothly with glycal donor 2a in the presence of potassium tert-butoxide to afford the product in good yields and a similar level of β-stereoselectivity (5oa5pa). Furthermore, product 5qa and 5ra containing a naphthyl moiety were formed in moderate yields and uniformly excellent β-stereoselectivity. Coumarin derived from khellin, an herbal medicine, was also a compatible sustrate for the reaction conditions. To our delight, product 5ta containing a phosphate ester moiety was isolated in 87% yield and excellent stereoselectivity. In addition, 3,4-O-carbonate L-fucal 2p was evaluated, the coupling of 2p with cyanocoumarin 1d gave a single β-C-glycoside 5dp, which was determined by the single crystallographic X-ray analysis. The success of the reaction scope was not just limited to the coumarin systems, the expanded substrate scaffolds were evaluated which would grant extensive C-glycoside entities. The catalyst system was applied to the acceptors without the fused benzene ring. It is encouraging to discover that α, βunsaturated δ-lactone (4a-4b) were suitable substrates to undergo the vinylogous glycosylation in decent yields and excellent stereoselectivity (6aa-6ba). Notably, no γ’-adduct was detected in the reaction of 4a. α, β-Unsaturated γ-lactones
bearing either alkyl, aryl or heteroaromatic groups (2-furayl) were well accepted (6ca-6ga). Furthermore, related benzenesulfonyl substituted lactone (4h) could be employed as a nucleophile and afforded 6ha as a single isomer in good yield. A gram-scale preparation of 3aa illustrated the practicality of our stereoselective vinylogous glycosylation approach, which afforded the glycosyl adduct in 92% yield and excellent β-stereocontrol (Scheme 1, a). To demonstrate the synthetic relevance of our studies, the conversion of the products to potentially bioactive derivatives were explored. Accordingly, the subjection of 3aa to dihydroxylation and acetylation provided glycoside 7 as a single diastereomer, which suggests that α-face of 3aa was the site of dihydroxylation (Scheme 2, b). m-CPBA-mediated epoxidation of 3aa afforded glycoside 8 in 78% yield as a single diastereomer.15 The β-rhodinose 9 was also easily achieved by hydrogenation. Furthermore, oxidation of 3aa with Dess-Martin periodinane provided an e n o n e s u g a r Scheme 3. Proposed Mechanism Pd(OAc)2, ligand
O
3 Pd(0)Ln
OH OR O PdLn
H X D
C
O
OR O A PdLn
O
RO ba se
O O B PdL n X
1
ACS Paragon Plus Environment
O O
O
OR O 2
O
X O
O O
O
O
CO2
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
10 in 95% yield. EDC-mediated esterification of 3aa was carried out with Boc-protected dipeptide to afford 11 in high yield. Finally, a Pd-catalyzed O-glycosylation of compound 3ap with 3,4-O-carbonate galactal 2a generated the desired disaccharide 12 in 75% yield exclusively. A proposed mechanism based on the experimental results and literature precedence,19 is depicted in Scheme 3. Palladium(II) acetate is initially reduced by phosphine ligand to furnish Pd(0),20 association of Pd(0) with the olefin of glycal 2 from less-hindered α-face yields complex A. The π-allyl-Pd(II) intermediate B is obtained after an oxidative additiondecarboxylation sequence. Next, nucleophilic addition of dienolate C to Pd(II) intermediate B generates complex D. Finally, desired glycoside 3 is released and the regenerated Pd(0) is employed for the next catalytic cycle. In summary, we have developed a general and practical palladium-catalyzed stereospecific vinylogous C-glycosylation of α, β-unsaturated lactones with glycals for the first time. This newly developed method provides easy access to a wide range of vinylogous C-glycosides in high yields with excellent regioselectivity and stereocontrol. In addition, our protocol shows a broad substrate scope and excellent functional group compatibility. Furthermore, the C-glycosides can be rapidly derivatized by chemo- and diastereoselective methods to a wide range of multifunctional and diverse compounds in single-step transformations. Taken together, our effective approach provides a practical tool for the stereoselective synthesis of novel biologically important C-glycoside entities. The biological evaluations of our products and derivatives are underway.
ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and compound characterization (PDF) X-ray data file (CIF)
AUTHOR INFORMATION Corresponding Author * E-mail:
[email protected] Funding Sources We thank National Science Foundation (CHE 1710174), and the University at Albany-SUNY for funding supports to Q. Zhang. Thanks are extended to National Science Foundation (CHE 1337594) for acquiring of the Bruker diffractometer to University at Albany-SUNY.
Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT Dr. Zheng Wei (University at Albany−SUNY) is acknowledged for assistance with X-ray analysis.
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