Transition-Metal-Free Synthesis of C-Glycosylated Phenanthridines

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Transition-Metal-Free Synthesis of C-Glycosylated Phenanthridines via KSO-Mediated Oxidative Radical Decarboxylation of Uronic Acids 2

2

8

Xin Zhou, Peng Wang, Li Zhang, Pengwei Chen, Mingxu Ma, Ni Song, Sumei Ren, and Ming Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02346 • Publication Date (Web): 20 Dec 2017 Downloaded from http://pubs.acs.org on December 21, 2017

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The Journal of Organic Chemistry

Transition-Metal-Free Synthesis of C-Glycosylated Phenanthridines via K2S2O8-Mediated Oxidative Radical Decarboxylation of Uronic Acids Xin Zhou,a Peng Wang,a Li Zhang,a Pengwei Chen,a Mingxu Ma,a Ni Song,a Sumei Ren,a and Ming Li*a,b a

Key Laboratory of Marine Medicine, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, P. R. China

b

Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, P. R. China

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Table of Contents Graphic

ABSTRACT: We have developed an efficient protocol for the synthesis of C-glycosylated phenanthridines. Tetrafuranos-4-yl and pentapyranos-5-yl radicals, generated from K2S2O8-mediated oxidative decarboxylation of furan- and pyranuronic acids, undergo attack to 2-isocyanodiphenyls and ensuing homolytic aromatic substitution to provide diverse C-glycosylated phenanthridines in satisfactory yields without resort to transition metals. This reaction tolerates various functional groups, and enables ready synthesis of complex oligosaccharide-based phenanthridines. The C-glycosylated phenanthridine derived from β-cyclodextrin has been prepared, which might be potential in medicinal and biological chemistry due to its flexible conformation.

INTRODUCTION

The installation of sugar residues is considered to be an effective structural modification of various natural products and bioactive compounds, which can enhance hydrophilicity of the molecules

concerned,

thus

improving

their

ensuing

pharmacological

activities

and

bioavailability.1 Over the past decades considerable efforts have been devoted to synthesizing C-glycosylated heteroarenes because of their potential applications in medicinal chemistry and chemical biology. Compounds in which the heteroaryl group of biological relevance is directly linked to C-4 or C-5 of tetrafuranosyl or pentapyranosyl units are an important subclass of C-glycosylated heterocycles. In this field, sugar-based β-ketoesters and styrene epoxides have ACS Paragon Plus Environment

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been converted into C-glycosylated coumarins and isocoumarins using Knoevenagel condensation and palladium-catalyzed Meinwald rearrangement as the key step, respectively.2 C-glycosylated quinoxalines, indoles, pyrazoles, and quinolines as novel chiral heterocycles have been accomplished by either palladium- or copper-catalyzed multicomponent sequential reactions using sugar-derived terminal alkynes or aldehydes as the starting materials.3 Additionally,

C-galactosylated

nickel/iridium-based

benzothiophene

photocatalyst-catalyzed

has

coupling

been reaction

prepared of

relying

on

galactose-derived

1,4-dihydropyridine with 2-bromobenzothiophene.4 Synthesis of C-ribosylated pyridine derivatives has been achieved by (diacetoxyiodo)benzene (DIB)-mediated Minisci reaction of 5

D-ribofuranuronic acid with pyridine-type heteroarenes. The last two syntheses represent few

examples of preparation of C-glycosylated heteroaromatics involving furanos-4-yl or pyranos-5-yl radical intermediates, a class of versatile radical species with attractive applications in synthesis of carbohydrate derivatives.6 Phenanthridine skeletons are ubiquitous heterocyclic motifs that occur in natural products and pharmaceutics with a wide spectrum of biological activities such as antibacterial and antitumor.7 Furthermore, 6-subsituted phenanthridinium salts, generated by alkylation or protonation of the nitrogen atom, are widely used as DNA and RNA intercalators.8 Numerous methods have been developed for preparing various phenanthridine derivatives,9 however, there is no report on synthesis of sugar-based chiral phenanthridines to date. We describe herein, for the first time, convenient synthesis of sugar-based phenanthridines as novel molecules of biological relevance. The synthesis relied on the coupling of 2-isocyanobiphenyls with furanos-4-yl or pyranos-5-yl radicals formed by K2S2O8-mediated oxidative radical decarboxylation of readily accessible uronic acids. In addition to environmental-friendliness



because it obviated the use of transition metals such as silver salts frequently used in decarboxylation, this reaction showed a broad substrate scope and a good compatibility with functional groups, thus providing a green and efficient avenue of synthesis of structurally diverse C-glycosylated phenanthridines. RESULTS AND DISCUSSION Synthesis of Uronic Acids. We embarked on our studies by preparing furan- and pyranuronic acids 2a–g. They all were uneventfully obtained by treating the corresponding alcohols with (2,2,6,6-tetramethylpiperidin-1-yl)-oxyl (TEMPO) and DIB in CH2Cl2/H2O10 except for 2c, which was prepared by Pinnik oxidation of aldehyde 1c.11 The Optimization of Reaction Conditions. With the uronic acids in hand, we set out to Scheme 1. Preparation of Uronic Acids


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optimize the reaction conditions for synthesizing glycosylated phenanthridines by performing the coupling of D-ribofuranuronic acid 2a and 2-isocyanobiphenyl 3a12 as a model reaction. The results are outlined in Table 1. Under the identical reaction conditions we developed for synthesis of 6-alkyl phenanthridines,13 treatment of 2a (3.0 equiv) and 3a (1.0 equiv) with Ag2CO3 (0.2 equiv) in the presence of K2S2O8 (3.0 equiv) and K3PO4 (3.0 equiv) in MeCN/H2O resulted in a set of complex mixture without the desired product being detected (entry 1). However, replacement of K3PO4 with K2HPO4·3H2O exerted a pronounced effect on the reaction, and the coupling products were obtained as an epimeric mixture of D-ribo and L-lyxo configured 4a and 4a' in the yield of 25% and 23%, respectively (entry 2). Switching the solvent from MeCN/H2O to dimethyl sulfoxide (DMSO) greatly improved the stereochemical outcome of the reaction, thus 4a was produced as the sole product, albeit in a moderate yield of 38% (entry 3).14 When the transformation was executed in a mixed solvent of MeCN/H2O/DMSO, the yield of 4a was increased to 78% (entry 4). Inspired by Lu’s and Tang’s works,15 further optimization revealed that K2S2O8 was able to promote the transformation in the absence of silver salts, thus offering a green approach to glycosylated phenanthridines. Although analytical K2S2O8 afforded a mixture of 4a and 4a' in overall 64% yield at a ratio of 1.9/1 (entry 5), extra pure K2S2O8 (99.99%) provided 4a as a single product in 67% yield (entry 6). The reaction was executed in the presence of K2S2O8 (99.99%) and K2HPO4 (99.95%) to afford 4a in 67% yield, thus completely ruling out the effect of trace transition metal impurities on the transformation (entry 7).16 Control experiments demonstrated that K2S2O8 was necessary for successful coupling (entry 8) while K2HPO4 as the additive greatly improved the yield of the present transformation (entry 9). Taken together, the recipe used in entry 6 emerged as the choice of the reaction conditions for synthesis of C-glycosylated phenanthridines from environmental and



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Table 1. The Optimization of Reaction Conditions for Synthesizing 4a.

Entry

Grade of reagentsc

Yield

Solvent (v/v)

4a

4a'

K2S2O8

K2HPO4

AR

AR

MeCN/H2O (5/1)

2a

AR

AR

MeCN/H2O (5/1)

25%

23%

a

AR

AR

DMSO

38%

0%

4a

AR

AR

MeCN/DMSO/H2O (4/1/1)

78%

0%

5

AR

AR


42%

22%

6

ER

AR


67%

0%

7

ER

ER


67%

0%

8

--

AR


9

ER

--


1

a,b

3

a

complex mixture

no reaction 26%

0% c

b

Ag2CO3 (0.2 equiv) was used as the catalyst; K3PO4 (3.0 equiv) was used insdead of K2HPO4; AR means analytically pure reagents (99% purity); ER means extra pure reagents (99.99% purity for K2S2O8; 99.95% purity for K2HPO4).

economic viewpoints. The Scope and Limitations of the Reaction. With the above results in hand, the scope and limitations of the present methodology were systematically examined. We first evaluated the feasibility of other 2-isocyanobiphenyls 3b–d12 equipped with fluoro, methyl, and/or methoxy substituents. Treatment of 2a with 3b–d stereocontrolly furnished glycophenanthridines 4b–d in 56–71% yields with the retention of the configuration at C-4 position of the sugar ring (Scheme 2). The structure of 4a was elucidated by extensive 1H,

13

C, and 2D NMR experiments. It is

worth mentioning that in 1H NMR spectrum the signals of H-2, H-3, and H-4 on the sugar ring of 4a appeared downfield than those of the parent acid 2a (δ 4.85, 6.40, and 5.95 vs 4.58, 5.19, and 4.64 ppm). However, the protons assigned to methylene groups of the hexyloxy motif on of 4a resonated at a field higher 0.78–1.09 ppm than those of 2a [δ 2.98–2.92 (m, 1H, Ha), 2.75–2.68


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Scheme 2. Synthesis of C-Glycosylated Phenanthridinesa,b X2 1

X

+

N 1

2

O

O

Ha Ha

O 4a 4b 4c 4d

Hc Hc

n

2a 2g

He

Me

OMe

O

R

O

MeO 5a 5b 5c 5d

X-ray of 4c

O

HO

R = Ar1, 49% R = Ar2, 54% R = Ar3, 49% R = Ar4, 41% OMe OBz

6a 6b 6c 6d

1

1-4

R

OBz

MeO

O

R = Ar1, 58% R = Ar2, 63% R = Ar3, 42% R = Ar4, 35% R

O

STol OBz

HO

N 5'

1

X = Cl, X2 = H X1 = F, X2 = H X1 = Me, X2 = H X1 = Me, X2 = OMe

Ar Ar2 Ar3 Ar4

O

O O

D-ribo/L-arabino 7a/7a' = 1:1.2, R = Ar1, 78% 7b/7b' = 1:1.2, R = Ar2, 71% 7c/7c' = 1:1.3, R = Ar3, 75% 7d/7d' = 1:0.7, R = Ar4, 44%

OBz

OBz

D-gluco/L-ido

D-gluco/L-idoc

8a/8a' = 1:1.1, R = Ar1, 69% 8b/8b' = 1:1.1, R = Ar2, 60% 8c/8c' = 1.1:1, R = Ar3, 62% 8d/8d' = 1:1.3, R = Ar4, 61%

3'

n = 1 or 2

He

R

X-ray of 7d'

O

R

7' 6'

n

4 10 R = Ar

Pg = Protective group

O

R = Ar1, 67% R = Ar2, 71% R = Ar3, 69% R = Ar4, 56%

PgO

MeCN/H 2O/DMSO (4/1/1), 70 oC

X1

O

R

K2S2O8 (3.0 equiv) K2HPO43H2O (3.0 equiv)

PgO

C

3a X = Cl, X = H 3b X1 = F, X2 = H 3c X1 = Me, X2 = H 3d X1 = Me, X2 = OMe R

O

HOOC

9a/9a' = 1:1.5, R = Ar1, 55% 9b/9b' = 1:1.5, R = Ar2, 49% 9c/9c' = 1:1.5, R = Ar3, 54% 9d/9d' = 1:1.1, R = Ar4, 53%

X2

10'

1'

R O

X-ray of 7b'

O

O O

O

D-galacto/L-altro

10a/10a' = 1:2.3, R = Ar1, 64% 10b/10b' = 1:1.4, R = Ar2, 72% 10c/10c' = 1:3.3, R = Ar3, 74% 10d/10d' = 1:1.8, R = Ar4, 73%

Isolated yield. bThe diastereoselectivity ratio was based on the isolated yield. cThe reactions were executed at 90 oC.

a

(m, 1H, Ha'), 0.74–0.69 (m, 2H, He and He'), 0.67–0.50 (m, 4H, Hb, Hb', Hd, and Hd') and 0.34–0.22 (m,1H, Hc), 0.19–0.10 (m, 1H, Hc') vs 3.86–3.77 (m, 1H, Ha), 3.45–3.36 (m, 1H, Ha'), 1.52–1.45 (m, 2H, Hb and Hb'), and 1.31–1.19 (m, 6H, Hc–e and Hc'–e')]. We attributed these observations to the magnetic anisotropy17 of the aromatic phenanthridine core. H-2, H-3, and H-4 on 4a are outside of phenanthridine ring and locate the deshielding zone. Thus their resonance shifts to low field. Conversely, the methylene protons of the hexyloxy moiety are in the region above the phenanthridine ring and are shielded. Therefore, resonances of these protons appear at high field. 1

H NMR spectra of 4b–d resembled that of 4a, indicating that they have identical stereochemical

structures. X-ray crystallographic analysis of 4c confirmed the stereogenic assignment.18 We then explored the reactivity of an array of furan- and pyranuronic acids 2b–g. As outlined in Scheme 2. 2-Deoxy ribofuranuronic acid 2b underwent the coupling with 3a–d, providing



stereocontrolly glycophenanthridines 5a–d in 41–54% yields with the configuration of C-4 conserved. Pleasingly, readily accessible D-lyxofuranuronic acid 2c was converted into L-ribo phenanthridine derivatives 6a–d in 35–63% yields with the inverted C-4 configuration of the sugar ring. 1H NMR spectra of 6a–d with L-ribo configuration reveal that H-2, H-3, and H-4 on the sugar ring resonate in the identical regions to those of D-ribo configured 4a–d. These results are ascribed to magnetic anisotropy of the aromatic phenanthridine rings.17 Upon subjection of D-xylofuranuronic acid 2d, gluco- and galactopyranuronic acids 2e–g to the transformation, glycosylated phenanthridines 7–10 were obtained as diastereomeric mixtures of D-/L-configured sugars in 44–78% yields at the ratio ranging from 1: 0.7 to 1: 3.3 (Scheme 2). We

found that the synthesized L-configured glycosylated phenanthrendines moved faster than the corresponding D-configured counterparts on silica gel plate of thin layer chromatography. Accordingly, all of the epimers could be separated easily by flash silica gel chromatographic column, thus opening up a way for synthesizing the rare L-sugar-based phenantheridines. In addition, free 4-OH is crucial for the transformation of glucuronic acids 2e and 2f, since their congeners with benzoyl group blocking 4-OH failed to react productively under the identical conditions. Access to glycophenanthridines 9 from thioglycoside 2f not only implies that the anomeric thiophenyl group is compatible with the present reaction, but also offers the handle for further elaboration of these chiral phenanthridines by the activation of anomeric substituents with thiophilic reagents.19 Structurally, X-ray crystallographic analysis of 7b'18 and 7d'18 supported the stereochemical assignment of glycophenanthridines 7a'-d' (Scheme 2). Additionally, 3JH,H coupling constants of the sugar ring were used to determine the conformation of pentapyranoid phenanthridines 8–10. As shown in Table 2, the data reveal that α-D-gluco 8a–d, β-L-ido 8a'–d', and β-D-gluco 9a–d assumed a typical 4C1 conformation while α-L-ido and β-L-altro configured 9a'–d' and 10a'–d' took a


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Table 2. 3JH,H Coupling Constants of the Sugar Ring of C-Glycosylated Phenanthridines 8–10 Compound α-D-gluco 8a–d β-L-ido 8a'–d' β-D-gluco 9a–d α-L-ido 9a'–d' α-D-galacto 10a–d β-L-altro 10a'–d' 1

3

JH1,H2/Hz 3.5–3.7 3.3–3.6 9.8–9.9

Transition-Metal-Free Synthesis of C-Glycosylated Phenanthridines

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