Transition-Metal-Free Synthesis of C-Glycosylated Phenanthridines via K2S2O8-Mediated Oxidative Radical Decarboxylation of Uronic Acids

Article abstract of DOI:10.1021/acs.joc.7b02346

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.

Full text of DOI:10.1021/acs.joc.7b02346

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Article
Transition-Metal-Free Synthesis of C-Glycosylated Phenanthridines
2
2
8
via KSO-Mediated Oxidative Radical Decarboxylation of Uronic Acids
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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TransitionꢀMetalꢀFree Synthesis of CꢀGlycosylated Phenanthridines via
K S O ꢀMediated Oxidative Radical Decarboxylation of Uronic Acids
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Xin Zhou, Peng Wang, Li Zhang, Pengwei Chen, Mingxu Ma, Ni Song, Sumei Ren, and Ming
a,b
Li*
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
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ABSTRACT: We have developed an efficient protocol for the synthesis of Cꢀglycosylated
2 2 8
phenanthridines. Tetrafuranosꢀ4ꢀyl and pentapyranosꢀ5ꢀyl radicals, generated from K S O ꢀmediated
oxidative decarboxylation of furanꢀ and pyranuronic acids, undergo attack to 2ꢀisocyanodiphenyls
and ensuing homolytic aromatic substitution to provide diverse Cꢀglycosylated phenanthridines in
satisfactory yields without resort to transition metals. This reaction tolerates various functional
groups, and enables ready synthesis of complex oligosaccharideꢀbased phenanthridines. The
Cꢀglycosylated phenanthridine derived from
βꢀcyclodextrin 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
1
bioavailability. Over the past decades considerable efforts have been devoted to synthesizing
Cꢀglycosylated 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 Cꢀ4 or Cꢀ5 of tetrafuranosyl or pentapyranosyl units are an important subclass of
Cꢀglycosylated heterocycles. In this field, sugarꢀbased βꢀketoesters and styrene epoxides have
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been converted into Cꢀglycosylated coumarins and isocoumarins using Knoevenagel
2
condensation and palladiumꢀcatalyzed Meinwald rearrangement as the key step, respectively.
Cꢀglycosylated quinoxalines, indoles, pyrazoles, and quinolines as novel chiral heterocycles
have been accomplished by either palladiumꢀ or copperꢀcatalyzed multicomponent sequential
1
1
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reactions using sugarꢀderived terminal alkynes or aldehydes as the starting materials.
Additionally, Cꢀgalactosylated benzothiophene has been prepared relying on
nickel/iridiumꢀbased photocatalystꢀcatalyzed coupling reaction of galactoseꢀderived
4
1
,4ꢀdihydropyridine with 2ꢀbromobenzothiophene. Synthesis of Cꢀribosylated pyridine
derivatives has been achieved by (diacetoxyiodo)benzene (DIB)ꢀmediated Minisci reaction of
5
D
ꢀribofuranuronic acid with pyridineꢀtype heteroarenes. The last two syntheses represent few
examples of preparation of Cꢀglycosylated heteroaromatics involving furanosꢀ4ꢀyl or
pyranosꢀ5ꢀyl radical intermediates, a class of versatile radical species with attractive
6
applications in synthesis of carbohydrate derivatives.
Phenanthridine skeletons are ubiquitous heterocyclic motifs that occur in natural products
and pharmaceutics with a wide spectrum of biological activities such as antibacterial and
7
antitumor. Furthermore, 6ꢀsubsituted phenanthridinium salts, generated by alkylation or
8
protonation of the nitrogen atom, are widely used as DNA and RNA intercalators. Numerous
9
methods have been developed for preparing various phenanthridine derivatives, however, there
is no report on synthesis of sugarꢀbased chiral phenanthridines to date. We describe herein, for
the first time, convenient synthesis of sugarꢀbased phenanthridines as novel molecules of
biological relevance. The synthesis relied on the coupling of 2ꢀisocyanobiphenyls with
2 2 8
furanosꢀ4ꢀyl or pyranosꢀ5ꢀyl radicals formed by K S O ꢀmediated oxidative radical
decarboxylation of readily accessible uronic acids. In addition to environmentalꢀfriendliness
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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 Cꢀglycosylated phenanthridines.
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ꢀ
RESULTS AND DISCUSSION
Synthesis of Uronic Acids. We embarked on our studies by preparing furanꢀ and pyranuronic
acids 2a
–g. They all were uneventfully obtained by treating the corresponding alcohols with
10
(
2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)ꢀoxyl (TEMPO) and DIB in CH
Cl
2 2
/H
2
O
except for 2c,
11
which was prepared by Pinnik oxidation of aldehyde 1c
.
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
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the coupling of Dꢀribofuranuronic acid 2a and 2ꢀisocyanobiphenyl 3a as a model reaction. The
results are outlined in Table 1. Under the identical reaction conditions we developed for
13
synthesis of 6ꢀalkyl phenanthridines, treatment of 2a (3.0 equiv) and 3a (1.0 equiv) with
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Ag
resulted in a set of complex mixture without the desired product being detected (entry 1).
However, replacement of K PO with K HPO ·3H O exerted a pronounced effect on the
reaction, and the coupling products were obtained as an epimeric mixture of ribo and lyxo
configured 4a and 4a' in the yield of 25% and 23%, respectively (entry 2). Switching the solvent
from MeCN/H O 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%
2 3 2 2 8 3 4 2
CO (0.2 equiv) in the presence of K S O (3.0 equiv) and K PO (3.0 equiv) in MeCN/H O
3
4
2
4
2
D
ꢀ
Lꢀ
2
1
4
(entry 3). When the transformation was executed in a mixed solvent of MeCN/H
2
O/DMSO,
15
the yield of 4a was increased to 78% (entry 4). Inspired by Lu’s and Tang’s works, further
optimization revealed that K S O was able to promote the transformation in the absence of
2
2
8
silver salts, thus offering a green approach to glycosylated phenanthridines. Although analytical
afforded a mixture of 4a and 4a' in overall 64% yield at a ratio of 1.9/1 (entry 5), extra
(99.99%) provided 4a as a single product in 67% yield (entry 6). The reaction was
executed in the presence of K (99.99%) and K HPO (99.95%) to afford 4a in 67% yield,
thus completely ruling out the effect of trace transition metal impurities on the transformation
2 2 8
K S O
2 2 8
pure K S O
2
S
2
O
8
2
4
1
6
(
entry 7). Control experiments demonstrated that K
2 2 8
S O was necessary for successful
coupling (entry 8) while K HPO as the additive greatly improved the yield of the present
2
4
transformation (entry 9). Taken together, the recipe used in entry 6 emerged as the choice of the
reaction conditions for synthesis of Cꢀglycosylated phenanthridines from environmental and
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Table 1. The Optimization of Reaction Conditions for Synthesizing 4a.
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c
Grade of reagents
Yield
Entry
Solvent (v/v)
K
2
2
S O
8
K
2
HPO
4
4a
4a'
a,b
1
AR
AR
AR
AR
AR
ER
ER
ꢀꢀ
AR
AR
AR
AR
AR
AR
ER
AR
ꢀꢀ
MeCN/H O (5/1)
complex mixture
2
a
2
MeCN/H O (5/1)
25%
38%
78%
42%
67%
67%
23%
0%
2
a
3
DMSO
a
4
MeCN/DMSO/H O (4/1/1)
0%
2
5
6
7
8
9
MeCN/DMSO/H O (4/1/1)
22%
0%
2
MeCN/DMSO/H O (4/1/1)
2
MeCN/DMSO/H O (4/1/1)
0%
2
MeCN/DMSO/H
2
2
O (4/1/1)
O (4/1/1)
no reaction
ER
MeCN/DMSO/H
26%
0%
c
a
b
Ag CO (0.2 equiv) was used as the catalyst; K PO (3.0 equiv) was used insdead of K HPO ; AR
2
3
3
4
2
4
means analytically pure reagents (99% purity); ER means extra pure reagents (99.99%
purity for K S O ; 99.95% purity for K HPO ).
2 2 8 2 4
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
1
2
feasibility of other 2ꢀisocyanobiphenyls 3b
substituents. Treatment of 2a with 3b stereocontrolly furnished glycophenanthridines 4b
56–71% yields with the retention of the configuration at Cꢀ4 position of the sugar ring (Scheme
–d
equipped with fluoro, methyl, and/or methoxy
–d
–d
in
1
13
2
). The structure of 4a was elucidated by extensive H, C, and 2D NMR experiments. It is
1
worth mentioning that in H NMR spectrum the signals of Hꢀ2, Hꢀ3, and Hꢀ4 on the sugar ring
of 4a appeared downfield than those of the parent acid 2a
and 4.64 ppm). However, the protons assigned to methylene groups of the hexyloxy motif on of
resonated at a field higher 0.78–1.09 ppm than those of 2a 2.98–2.92 (m, 1H, H ), 2.75–2.68
(δ 4.85, 6.40, and 5.95 vs 4.58, 5.19,
4
a
[
δ
a
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a,b
Scheme 2. Synthesis of CꢀGlycosylated Phenanthridines
X2
X2
7'
1
0'
X1
1'
X1
R
O
HOOC
PgO
O
K2S2O8 (3.0 equiv)
+
6'
N
K2HPO4—3H2O (3.0 equiv)
3'
PgO
N
C
n
n
5
'
MeCN/H2O/DMSO
1
2
4 10 R = Ar1ꢀ4
Ar1 X1 = Cl, X = H
2
3a X = Cl, X = H
2a 2g
4/1/1), 70 o
(
C
Ar2 X1 = F, X2 = H
b X = F, X2 = H
1
3
3
3
1
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n = 1 or 2
Ar3 X1 = Me, X2 = H
Ar4 X1 = Me, X2 = OMe
Pg = Protective group
1
2
c X = Me, X = H
d X1 = Me, X = OMe
2
Ha
Ha
Hc
Hc
He
He
Me
O
R
O
R
O
O
R
OBz
R
O
OMe
O
O
MeO
O
O
MeO
O
O
D-ribo/L-arabino
1
1
1
1
4a R = Ar , 67%
5a R = Ar , 49%
6a R = Ar , 58% 7a/7a' = 1:1.2, R = Ar , 78%
2
2
2
2
4b R = Ar , 71%
5b R = Ar , 54%
6b R = Ar , 63% 7b/7b' = 1:1.2, R = Ar , 71%
Xꢀray of 7b'
3
3
3
3
4
c R = Ar , 69%
5c R = Ar , 49%
6c R = Ar , 42% 7c/7c' = 1:1.3, R = Ar , 75%
4
4
4
4
4
d R = Ar , 56%
5d R = Ar , 41%
6d R = Ar , 35% 7d/7d' = 1:0.7, R = Ar , 44%
Xꢀray of 4c
R
O
R
O
STol
O
O
R
O
OMe
OBz
OBz
O
HO
HO
O
OBz
D-gluco/L-ido
a/8a' = 1:1.1, R = Ar , 69%
OBz
c
D-gluco/L-ido
9a/9a' = 1:1.5, R = Ar , 55%
D-galacto/L-altro
1
1
1
8
8
8
8
10a/10a' = 1:2.3, R = Ar , 64%
2
2
2
b/8b' = 1:1.1, R = Ar , 60%
9b/9b' = 1:1.5, R = Ar , 49%
10b/10b' = 1:1.4, R = Ar , 72%
3
3
3
c/8c' = 1.1:1, R = Ar , 62%
9c/9c' = 1:1.5, R = Ar , 54%
10c/10c' = 1:3.3, R = Ar , 74%
Xꢀray of 7d'
4
4
4
d/8d' = 1:1.3, R = Ar , 61%
9d/9d' = 1:1.1, R = Ar , 53%
10d/10d' = 1:1.8, R = Ar , 73%
aIsolated yield. bThe diastereoselectivity ratio was based on the isolated yield. cThe reactions were executed at 90 oC.
(
m, 1H, Ha'
)
, 0.74
–
0.69 (m, 2H, H
0.10 (m, 1H, Hc') vs 3.86–3.77 (m, 1H, Ha), 3.45–3.36 (m, 1H, Ha'), 1.52–1.45
and Hb'), and 1.31–1.19 (m, 6H, e')]. We attributed these observations to
e b b' d
and He'), 0.67–0.50 (m, 4H, H , H , H , and Hd') and 0.34–0.22
(m,1H, H ), 0.19
–
c
(
m, 2H, H
b
H
c–e and Hc'
–
1
7
the magnetic anisotropy of the aromatic phenanthridine core. Hꢀ2, Hꢀ3, and Hꢀ4 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
1
8
structures. Xꢀray crystallographic analysis of 4c confirmed the stereogenic assignment.
We then explored the reactivity of an array of furanꢀ and pyranuronic acids 2b–g. As outlined in
Scheme 2. 2ꢀDeoxy ribofuranuronic acid 2b underwent the coupling with 3a–d, providing
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stereocontrolly glycophenanthridines 5a–d in 41–54% yields with the configuration of Cꢀ4
conserved. Pleasingly, readily accessible
Dꢀlyxofuranuronic acid 2c was converted into Lꢀribo
phenanthridine derivatives 6a–d in 35–63% yields with the inverted Cꢀ4 configuration of the sugar
1
ring. H NMR spectra of 6a–d with
L
ꢀribo configuration reveal that Hꢀ2, Hꢀ3, and Hꢀ4 on the sugar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ring resonate in the identical regions to those of
Dꢀribo configured 4a–d. These results are ascribed to
17
magnetic anisotropy of the aromatic phenanthridine rings.
Upon subjection of
transformation, glycosylated phenanthridines 7–10 were obtained as diastereomeric mixtures of
ꢀ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 ꢀconfigured glycosylated phenanthrendines moved faster than the
corresponding ꢀ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 ꢀsugarꢀbased phenantheridines. In addition, free
D
ꢀxylofuranuronic acid 2d, glucoꢀ and galactopyranuronic acids 2e–g to the
Dꢀ/L
L
D
L
4ꢀOH is crucial for the transformation of glucuronic acids 2e and 2f, since their congeners with
benzoyl group blocking 4ꢀOH 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
1
9
phenanthridines by the activation of anomeric substituents with thiophilic reagents.
1
8
18
Structurally, Xꢀray crystallographic analysis of 7b' and 7d' supported the stereochemical
3
assignment of glycophenanthridines 7a'ꢀd' (Scheme 2). Additionally, JH,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
αꢀD
ꢀgluco 8a–d,
βꢀLꢀido 8a'–d', and βꢀDꢀgluco 9a–d assumed
4
a typical C
1
conformation while
αꢀ
L
ꢀido and ꢀaltro configured 9a'–d' and 10a'–d' took a
βꢀL
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Table 2. JH,H Coupling Constants of the Sugar Ring of CꢀGlycosylated Phenanthridines 8–10
3
3
3
3
Compound
ꢀgluco 8a–d
ꢀido 8a'–d'
ꢀgluco 9a–d
ꢀido 9a'–d'
J
H1,H2/Hz
J
H2,H3/Hz
J
H3,H4/Hz
9.7
JH4,H5/Hz conformation
4
αꢀD
3.5–3.7
3.3–3.6
9.8–9.9
<1
4.3–5.5
<1
10.0–10.2
8.9–9.4
9.6–9.7
4.4–5.8
<1
9.4
C
1
C
1
C
1
C
4
2
4
4
4
1
β
β
ꢀ
L
8.3–9.0
9.5
4.5–6.1
<1
5.4–5.6
9.2–9.3
2.4–3.4
<1
ꢀD
αꢀ
L
O
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
αꢀD
ꢀgalacto 10a–d
ꢀaltro 10a'–d'
S
C
β
ꢀL
<1
5.5–5.6
8.8–9.1
1
20
O
4 2
C conformation. An unusual S conformation was suggested for Dꢀgalacto configured 10a–d
based on identical NMR data to the reported for the sugar ring of galactosyled benzothiophene, the
4
structure of which has been corroborated by Xꢀray analysis. In addition, it was found that the proton
signals due to the hydroxyl groups resonated relatively downfield in
phenanthridines 8a'–d' and 9a'–d' ( 5.67–6.42 ppm) by comparison with those in the corresponding
ꢀgluco isomers 8a–d and 9a–d ( 3.62–4.33 ppm). We attributed these observations to the
Lꢀido configured
δ
D
δ
formation of relatively strong intramolecular hydrogen bonding of the hydroxyl group with the
nitrogen atom of phenanthridine core in compounds 8a'–d' and 9a'–d' because the two substituents
were synꢀarranged.
Studies on Reaction Mechanism and Correlation of Stereoselectivity to Conformation of
21
Glycosyl radicals. Although oxidative decarboxylation of uronic acids by the action of DIB, lead
22
23
2 2 8
tetraacetate, and photoredox has been well appreciated, such transformations mediated by K S O
along, to the best of our knowledge, are unprecedented. In order to shed light on the reaction
mechanism, we carried out a set of control experiments (Scheme 3). Addition of TEMPO as an
efficient radical scavenger to the reaction mixture of 3a and 2a completely inhibited the formation of
12
4a. Instead, alkoxyamine 11 was isolated in 19% yield along with formamide 12 being obtained in
4% yield in 22 hours. These results suggested that the tetrafuranosꢀ4ꢀyl radical intermediate was
involved in the reaction. Additionally, it has been observed that Minisci reaction works in
7
2
4
photoredoxꢀcatalyzed synthesis of 6ꢀalkyl substituted phenanthridines. However, upon treatment
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9
1
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 3. Preliminary Probe of the Reaction Mechanism
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12a
phenanthridine 13 with 2a under the standard conditions, 4a was not produced. This result clearly
eliminated the possibility that phenanthridines like 13 acted as the active intermediates leading to
glycosylated compounds such as 4a in the present study.
9,12
Based on our observations and the literature results, a mechanism is proposed as depicted in
Scheme 4. Carboxylate derived from deprotonation of 2a with the help of K HPO underwent
peroxydisulfateꢀinduced single electron transfer to give rise to acyloxy radical intermediate I, from
which carbon dioxide extrusion resulted in the formation of ꢀalkoxy radical II . Consistent with the
2
4
α
a
Scheme 4. Proposed Reaction Mechanism and Plausible Conformations of Glycosyl Radicals
for the Formation of 4–10
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conformation of
D
ꢀribofuranosꢀ4ꢀyl radicals formed by radical decarbonylation of αꢀalkoxyacyl
6
e,6f
O
tellurides,
the radical II
a
was assumed to adopt E conformation, where the orbital interaction
between the alkyl radical and the antiperiplanar lone pair of the adjacent furan oxygen increase the
stability and nucleophilicity of the axial radical. Isonitrile 3a approached to II from the β face
a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
instead of concave αꢀface, stereocontrolly giving the imidoyl radical III. Subsequent hemolytic
aromatic substitution in III gave rise to IV. Oxidation of the cyclohexadienyl radical IV by sulfate
radical anion to the corresponding cation V followed by deprotonation eventually delivered 4a with
the conserved configuration at Cꢀ4 position.
According to quasiꢀhomoꢀanomeric effect composed of the interaction of σꢀradical orbital with
25
both nonꢀbonding Oꢀelectron pair of sugar ring oxygen and σ*ꢀorbital of coplar βꢀCꢀO bond,
threeꢀdimensional structures of the intermediate radicals IIb–g are depicted in Scheme 4 as the
assumed conformations. In this way the diastereoselectivity of the formation of 5–10 can be
explained. Similar to II
5a–d because of jointly favorable stereoelectronic and steric effects, which render the approach of
isonitriles from β face. The generation of intermediate II having completely inverted stereocenters
with respect to the radical II accounted for the formation of 6a–d with ꢀribo configuration as the
a b
, II stereoselectively led to the formation of glycosylated phenanthridines
c
a
L
single product. The stereoselectivities of 7 originated from the counteracting influence of the
stereoelectronic factors and the steric effects of the axial oxygenꢀbased substituents of the
intermediates II . Almost equimolar ratios of
D
ꢀ/Lꢀsugars 8 and 9 resulted from the attack of
d
isonitriles to the planar carbon radical center of B1,4 conformers II
e
and II from the top and bottom
f
2
6
g
sides. The axially oriented βꢀCꢀO bond at 4 position in galactopyranosꢀ5ꢀyl radicals allowed II to
4
take a C
1
conformation, where preferential axial attack of isonitriles resulted in the formation of
4
1
Lꢀaltro configured phenanthridines as the major products. The adoption of B1,4 and C for
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9
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
glucopyranosꢀ and galactopyranosꢀ5ꢀyl radicals, respectively, take advantages of
quasiꢀhomoꢀanomeric effect to stabilize the radicals. Such conformations have been suggested by
2
6
electron paramagnetic resonance by Sustmann and coꢀworkers.
Deprotection Studies. With the glycosylated phenanthridines in hand, deprotection was
attempted (Scheme 5). Transacetalization to remove isopropylidene of glycophenanthridine 4a with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
70% trifluoroacetic acid in hexanol led to 14a and 14a' in 39% and 28% yields, respectively. This
observation indicated that the CꢀC bond connecting the aryl substituent and the sugar residue was
labile to acid, and easily leading to epimerization during the reaction. Removal of benzoyl groups
proceeded uneventfully under Zemplén conditions. Glycosylated phenanthridines 8a–c and 8a'–c'
were converted into 15a–c and 15a'–c' in 45–76% yield by treatment with sodium methoxide in
1
4
methanol. H NMR spectroscopic data indicated that
conformation as that of 8a–c while ꢀido configurated 15a'–c' adopted the flipped C
Scheme 5. Deprotection of the Glycophenanthridines
Lꢀgluco configurated 15a–c had the same C
1
1
4
L
4 1
from the C
conformation of the precursors 8a'–c'.
Synthesis of OligosaccharideꢀBased Phenanthridines. To demonstrate further the power of the
present reaction, we applied the protocol to synthesis of oligosaccharideꢀbased phenanthridines
(Scheme 6). Disaccharideꢀderived acid 20 was prepared following a threeꢀstep reaction sequence
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composed of TMSOTfꢀcatalyzed glycosylation of glucosyl derivative 16 and
Lꢀrhaminosyl
27
trichloroacetimidate 17 (to 18), regioselective removal of acetyl group (to 19), and ensuing
oxidation of primary alcohol to carboxylic acid. It was found that the coupling of 20 with isonitrile
3c gave 21 as the sole product by cleanly transforming the Dꢀgluco unit into the Lꢀido fragment.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
However, the reaction at 70 °C proceeded sluggishly, and glycophenanthridine 21 was obtained in 23%
o
yield in 10 h. Increasing the reaction temperature to 90 C drove the reaction to completion in 4 h,
1
and affording 21 in 68% yield. Deprotection of 21 with sodium methoxide to 22 in 77% yield. H
1
NMR spectra revealed that
Scheme 6a).
ꢀcyclodextrin (
efforts have been invested in synthesizing structurally modified
L
ꢀidopyranosyl residue in 21 and 22 assumed a C
4
conformation
(
β
β
ꢀCD) is a cyclic heptamer comprised of
α
ꢀ(1→4)ꢀ
Dꢀglucopyranosyl units. Great
β
ꢀCDs since these compounds have a
broad range of applications in catalysis, recognition of organic molecules and biomacromolecules,
and targeted drug/DNA delivery owing to their changed cavity size and/or the improved complexing
2
8
ability. The vast majority of current approaches to modified
β
ꢀCDs focus on the functionalization of
29
30
one or more hydroxyl groups of
β
ꢀCD, few methodologies are based on radical chemistry. To our
3
1
delight, uronic acid 24, generated by oxidation of βꢀCD derivative 23, uneventfully underwent the
transformation with 3c to furnish unprecedented phenanthridineꢀdecorated cyclodextrin 25 in 85%
1
yield (Scheme 6b). The structure of 25 was confirmed by the wellꢀresolved H NMR spectrum in
o
I
deuterated dimethyl sulfoxide at 70 C, which revealed that Hꢀ5 appeared at 5.87 ppm as a doublet
3
I
I
(
d, JHꢀ4 , Hꢀ5 = 8.7 Hz), resembling that of 8c. Finally, cyclodextrin 25 was converted into 26 in 70%
yield by globally removing acetyl groups with methoxylic sodium methoxide (Scheme 6b). It should
1
o
6
be pointed out that H NMR spectrum of 26 in DMSOꢀd at 25 C showed two sets of signals
assigned to aromatic protons while these signals merged into one set upon raising the probe
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2
2
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2
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3
3
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3
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 6. Synthesis of OligosaccharideꢀBased Phenanthridines
a)
AcOH C
Me
BzO
2
O
OBn
OBz
O
O
CCl3
TMSOTf
CH2Cl2
O
AcO
HO
O
OBn
OBz
+
O
NH
OBz
BzO
o
0 C, 90%
OBz
OBz
OBz BzO
BzO
16
17
18
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ar3
R
Me
RO
RO
Me
BzO
3
c, K S O ,
AcCl, MeOH,
CH2Cl2, rt, 83%
2
2
8
O
O
O
O
K2HPO4—3H2O
O
OBn
O
OBn
MeCN/H2O/DMSO
o
90 C, 4 h, 68%
BzO
OR RO
OR
OBz BzO
OBz
1
9 R = CH OH
2
1 R = Bz
TEMPO, DIB
CH Cl /H O
rt, 95%
2
MeONa
MeOH
2
2
2
20 R = COOH
2
2 R = H
b)
OAc
OR
Ar3
R
5I
5I
3
c, K S O
O
O
2 2 8
O
O
K2HPO4—3H2O
O
1I
O
1I
O
O
3I
3I
O
O
MeCN/H O/DMSO
2
OAc 6AcO
OR
RO
6
AcO
o
RO
OAc
90 C, 4 h, 85%
OR
TEMPO, DIB
CH Cl / H O
4 C, 48 h, 73%
23 R = CH OH
2
25 R = Ac
26 R = H
MeONa
MeOH
2
2
2
o
1
24 R = COOH
o
temperature to 70 C. These observations indicated that 26 underwent a fast conformational
exchange at room temperature on the NMR time scale. This is appealing for developing
molecular architectures.
βꢀCDꢀbased
ꢀ
CONCLUSIONS
In summary, we have developed an efficient approach to glycosylated phenanthridines by treating
2ꢀisocyanobiphenyls with tetrafuranosꢀ4ꢀyl and pentapyranosꢀ5ꢀyl radicals generated from
K
2
S
2
O
8
ꢀmediated oxidative radical decarboxylation of uronic acids. This reaction enjoys an ample
substrate scope and a good functional group tolerance, and permits the functionalization of ꢀCD,
thus providing a novel access to sophisticated ꢀCD architectures of interest. The present method not
β
β
only is a valuable addition to the existing modern synthetic arsenal to phenanthridine derivatives of
interest, but also provides an operatically simple protocol for the generation of versatile
tetrafuranosꢀ4ꢀyl and pentapyranosꢀ5ꢀyl radicals, thereby facilitating their potential applications in
organic synthesis.
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ꢀ
EXPERIMENTAL SECTION
General information
All reactions were carried out under an atmosphere of argon in glassware with magnetic stirring
unless otherwise indicated. All commercially obtained reagents were used as received, except where
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 2 8 2 4
specified otherwise. Extra pure K S O and K HPO were purchased from SigmaꢀAldrich. Flash
column chromatography was performed on Silica Gel H (300ꢀ400 mesh, Qingdao, China). Analytical
thin layer chromatography was performed on Silicycle Silia Plate glassꢀbacked plates coated with
silica gel (60 Å pore size, Fꢀ254 indicator) and visualized by exposure to ultraviolet light and/or
staining with 8% sulfuric acid in methanol. The melting points (mp) were determined when left
untouched on an Xꢀ4ꢀMP apparatus from Beijing Tech. Instrument Co. (Beijing, China).
Highꢀresolution mass spectra were obtained using a Thermo LTQ Orbitrap XL high resolution mass
1
13
spectrometer. Optical rotations were determined with a JASCO Pꢀ1010 digital polarimeter. H, C,
NOE, DEPTꢀQ, COSY, HSQC and HMBC spectra were recorded on an Agilent DD2 500 MHz NMR
spectrometer with Me Si as the internal standard. Chemical shifts are recorded in δ values, and J
4
values were given in Hz.
32
Hexyl 2,3ꢀOꢀIsopropylideneꢀβꢀ
et al was slightly modified to prepare alcohol 1a. Specifically, to a 100 mL round bottom flask were
added ꢀribose (3.0 g, 20 mmol, 1.0 equiv), nꢀhexanol (37.7 mL, 300 mmol, 15 equiv), acetone (17.7
mL, 240 mmol, 12 equiv), and concentrated H SO (0.53 mL, 10 mmol, 0.5 equiv) at 0 °C. The
resulting mixture was heated to 60 °C for 9 h, then the mixture was cooled to room temperature and
quenched with Et N (2.8 mL, 20 mmol, 1 equiv). The solution was concentrated, diluted with EtOAc,
and poured slowly into a saturated aqueous NaHCO . The organic phase was separated and the
Dꢀribofuranoside (1a). The procedure reported by Hergenrother
D
2
4
3
3
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5
5
5
5
5
5
5
6
aqueous layer was extracted four times with EtOAc. The combined organic layers were dried over
Na
2
SO
4
, filtered, and concentrated. The residue was purified by silica gel column chromatography
= 0.75
) δ 5.06 (s,
1H), 4.84 (d, J = 5.9 Hz, 1H), 4.60 (d, J = 5.9 Hz, 1H), 4.42 (s, 1H), 3.77–3.72 (m, 1H), 3.72–3.67
(petroleum ether/EtOAc 7:1) to afford 1a (4.55 g, 16.6 mmol, 83%) as a colorless oil. R
f
2
D
2
1
(petroleum ether/EtOAc 1:1); [
3 3
α] = –61.9 (c 0.75, CHCl ); H NMR (500 MHz, CDCl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(m, 1H), 3.64–3.58 (m, 1H), 3.50–3.44 (m, 1H), 3.40 (dd, J = 10.9, 2.3 Hz, 1H), 1.61–1.54 (m, 2H),
1
3
1
1
3
.48 (s, 3H), 1.34–1.25 (m, 9H), 0.88 (t, J = 6.8 Hz, 3H); C NMR (126 MHz, CDCl ) δ 112.1,
09.0, 88.4, 86.1, 81.7, 68.9, 64.2, 31.6, 29.5, 26.5, 25.8, 24.8, 22.6, 14.1; HRMS (ESI) m/z Calcd
+
for C H O [M+H] 275.18530, found 275.18483.
14 27
5
Hexyl 2,3ꢀOꢀIsopropylideneꢀβꢀDꢀribofuranuronic acid (2a). A 100 mL roundꢀbottom flask was
charged with dichloromethane (30 mL) and deionized water (10 mL). Alcohol 1a (1.5 g, 5.47 mmol,
1.0 equiv), TEMPO (128 mg, 0.82 mmol, 0.15 equiv), and DIB (3.52 g, 10.94 mmol, 2.0 equiv) were
added. After the reaction was stirred for 10 h at rt, a saturated aqueous Na
followed by extraction with EtOAc (30 mL × 4). The combined organic layers were washed with
brine (30 mL × 2), dried over Na SO . The solid was filtered off and the filtrate was concentrated.
The crude mixture was purified by silica gel column chromatography (petroleum ether/EtOAc 10:1
3:1) to afford 2a (1.07 g, 3.7 mmol, 68%) as a colorless oil. R = 0.35 (petroleum ether/EtOAc
) δ 5.19 (d, J = 5.8 Hz, 1H), 5.15 (s,
H), 4.64 (s, 1H), 4.57 (d, J = 5.8 Hz, 1H), 3.86–3.77 (m, 1H), 3.45–3.36 (m, 1H), 1.52–1.45 (m, 2H)
2 2 3
S O (30 mL) was added
2
4
→
f
2
D
0
1
2
1
1
3 3
:1); [α] = –48.8 (c 1.5, CHCl ); H NMR (500 MHz, CDCl
1
3
3
.48 (s, 3H), 1.32 (s, 3H), 1.31–1.19 (m, 6H), 0.87 (t, J = 6.6 Hz, 3H); C NMR (126 MHz, CDCl )
δ 175.1, 113.0, 108.5, 84.4, 83.7, 82.3, 68.8, 31.7, 29.3, 26.4, 25.7, 25.0, 22.7, 14.2; HRMS (ESI) m/z
+
Calcd for C14
H
25
O
6
[M+H] 289.1646, found 289.1653.
Methyl 2ꢀdeoxyꢀ3ꢀOꢀmethylꢀαꢀ
D
ꢀribofuranuronic acid (2b). According to the procedure for the
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conversion of 1a into 2a, 1b (1.24 g, 7.65 mmol, 1.0 equiv) was treated with TEMPO (179 mg,
1
.15 mmol, 0.15 equiv) and DIB (4.93 g, 15.3 mmol, 2.0 equiv) in CH Cl /H O (44 mL, v/v 3:1) at rt
2
2
2
for 18 h. After workꢀup, the residue was purified by silica gel column chromatography [petroleum
ether/EtOAc (1:1) → EtOAc → CH Cl /MeOH (9:1)] to afford 2b (737 mg, 4.19 mmol, 55%) as a
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
D
0
1
colorless oil. R
f
= 0.16 (EtOAc 100%); [α]
3 3
= +82.7 (c 0.63, CHCl ); H NMR (500 MHz, CDCl ) δ
5
1
.25 (d, J = 5.3 Hz, 1H), 4.67 (d, J = 2.8 Hz, 1H), 4.09–4.04 (m, 1H), 3.43 (s, 6H), 2.23–2.16 (m,
13
3
H), 2.15–2.09 (m, 1H); C NMR (126 MHz, CDCl ) δ 175.2, 106.6, 83.7, 81.8, 58.1, 56.0, 38.5;
+
HRMS (ESI) m/z Calcd for C
Benzoyl 2,3ꢀOꢀisopropylideneꢀαꢀ
1.22 g, 4.18 mmol, 1.0 equiv) in tꢀBuOH (27 mL) were added NaH
.5 equiv) in water (5.4 mL), 2ꢀmethylꢀ2ꢀbutene (2.34 mL, 20.9 mmol, 5.0 equiv), and NaClO
7
H
13
O
5
[M+H] 177.0757, found 177.0755.
3
4
D
ꢀlyxofuranuronic acid (2c). To a solution of aldehyde 1c
PO ·H O (978 mg, 6.27 mmol,
(1.34
(
2
4
2
1
2
g, 12.54 mmol, 3.0 equiv) in turn at 15 °C. The reaction mixture was stirred for 6 h at the same
temperature followed by acidification with 1.0 M aqueous HCl. The mixture was extracted with
EtOAc (20 mL × 6). The combined organic layers were dried over anhydrous Na SO . The solid was
2
4
filtered off and the filtrate was concentrated. The crude product was purified by silica gel column
chromatography [petroleum ether/EtOAc (1:1) → CH Cl /MeOH (8:1)] to afford 2c (1.23 g, 4.0
mmol, 96%) as a white solid. R = 0.58 (CH Cl /MeOH 8:1); [α]
) δ 7.99 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 6.55
s, 1H), 5.24–5.20 (m, 1H), 4.92 (d, J = 5.8 Hz, 1H), 4.88 (d, J = 4.2 Hz, 1H), 1.52 (s, 3H), 1.36 (s,
2
2
2
D
0
1
f
2
2
3
= +10.1 (c 1.0, CHCl ); H NMR
(500 MHz, CDCl
3
(
13
3
H); C NMR (126 MHz, CDCl
3
) δ 170.2, 164.7, 133.9, 129.9, 129.1, 128.7, 114.4, 101.3, 84.4,
+
81.4, 80.2, 77.4, 77.2, 76.9, 26.1, 25.1; HRMS (ESI) m/z Calcd for C15
16
H O
7
Na [M+Na] 331.0788,
found 331.0782.
1,2ꢀOꢀisopropylideneꢀ3ꢀOꢀmethylꢀαꢀDꢀxylofuranuronic acid (2d). According to the procedure for
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5
the conversion of 1a into 2a, alcohol 1d (1.01 g, 4.95 mmol, 1.0 equiv) was treated with TEMPO
116 mg, 0.74 mmol, 0.15 equiv) and DIB (3.18 g, 9.9 mmol, 2.0 equiv) in CH Cl /H O (36 mL, v/v
:1) at 15 °C for 24 h. After workꢀup, the residue was purified by silica gel column chromatography
petroleum ether/EtOAc (3:1) → EtOAc → CH Cl /MeOH (6:1)] to afford 2d (1.01 g, 4.64 mmol,
(
2
2
2
3
[
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
f 3
94%) as a colorless oil. R = 0.14 (EtOAc 100%); [α]26D= –22.7 (c 1.0, CHCl ); H NMR (500 MHz,
6
DMSOꢀd ) δ 5.83 (d, J = 3.7 Hz, 1H), 4.55 (d, J = 3.8 Hz, 1H), 4.28 (d, J = 3.2 Hz, 1H), 3.80 (d, J =
13
3
.2 Hz, 1H), 3.26 (s, 3H), 1.37 (s, 3H), 1.24 (s, 3H).; C NMR (126 MHz, DMSOꢀd
6
) δ 176.1, 110.7,
ꢀ
1
04.4, 84.6, 81.2, 81.1, 57.3, 26.7, 26.3; HRMS (ESI) m/z Calcd for C
9
H
13
O
6
[M–H] 217.0718,
found 217.0720.
Methyl 2,3ꢀdiꢀOꢀbenzoylꢀαꢀDꢀglucopyranuronic acid (2e). According to the procedure for the
3
6
conversion of 1a into 2a, 1e (1.40 g, 3.48 mmol, 1.0 equiv) was treated with TEMPO (82 mg, 0.52
mmol, 0.15 equiv) and DIB (2.24 g, 6.96 mmol, 2.0 equiv) in CH Cl /H O (28 mL, v/v 3:1) at 5 °C
2
2
2
for 18 h. After workꢀup, the residue was purified by silica gel column chromatography [petroleum
ether/EtOAc (3:2) → dichloromethane/EtOAc (1:1) → dichloromethane/MeOH (4:1)] to afford 2e
20
D
1
(1.28 g, 3.08 mmol, 88%). R
f
= 0.42, (CH
2
Cl
2
/MeOH 4:1); [α]
= +122.1 (c 1.0, CHCl
3
); H NMR
(500 MHz, CDCl
3
) δ 7.98 (d, J = 7.5 Hz, 2H), 7.95 (d, J = 7.4 Hz, 2H), 7.53–7.45 (m, 2H), 7.37–
7
1
1
.31 (m, 4H), 5.86 (t, J = 9.2 Hz, 1H), 5.64–5.46 (brs, 2H), 5.26–5.18 (m, 2H), 4.39 (d, J = 9.9 Hz,
1
3
3
H), 4.14 (t, J = 9.5 Hz, 1H), 3.45 (s, 3H); C NMR (126 MHz, CDCl ) δ 172.7, 166.8, 166.1, 133.6,
33.5, 130.03, 129.99, 129.4, 129.0, 128.6, 128.5, 97.5, 72.5, 71.3, 70.7, 69.9, 56.2; HRMS (ESI)
+
m/z Calcd for C21
H
20
O
9
Na [M+Na] 439.1000, found 439.0987.
pꢀTolyl 2,3ꢀdiꢀOꢀbenzoylꢀ1ꢀthioꢀβꢀDꢀglucopyranuronic acid (2f). According to the procedure for
37
the conversion of 1a into 2a, 1f (1.2 g, 2.42 mmol, 1.0 equiv) was treated with TEMPO (57 mg,
2 2 2
0.36 mmol, 0.15 equiv) and DIB (1.56 g, 4.85 mmol, 2.0 equiv) in CH Cl /H O (36 mL, v/v 3:1) at 5
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8
9
°
C for 18 h. After workꢀup, the residue was purified by silica gel column chromatography [petroleum
ether/EtOAc (3:1) → EtOAc → CH
3
white solid. R = 0.5 (CH Cl /EtOAc 4:1); [α] = +71.6 (c 1.05, CHCl ); H NMR (500 MHz,
2 2
Cl /MeOH (4:1)] to afford 2f (0.96 g, 1.89 mmol, 78%) as a
2
D
0
1
f
2
2
pyridineꢀd ) δ 8.18 (d, J = 7.5 Hz, 2H), 8.05 (d, J = 7.0 Hz, 2H), 7.68 (d, J = 7.3 Hz, 2H), 7.42 (t, J =
5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.3 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.5 Hz, 2H), 7.26–7.20 (m, 2H), 7.03 (d, J = 7.1 Hz,
13
2
H), 6.36–6.29 (m, 1H), 5.93–5.86 (m, 1H), 5.64–5.53 (m, 1H), 4.82–4.58 (m, 2H), 2.13 (s, 3H); C
NMR (126 MHz, pyridineꢀd
24 8
30.5, 130.0, 129.4, 129.1, 87.2, 78.4, 72.3, 71.7, 21.4; HRMS (ESI) m/z Calcd for C27H O
5
) δ 168.1, 166.8, 166.2, 138.7, 134.1, 133.8, 133.7, 130.9, 130.7, 130.6,
1
SNa
+
[
M+Na] 531.1084, found 531.1091.
,2:3,4ꢀdiꢀOꢀisopropylideneꢀαꢀ ꢀgalactopyranuronic acid (2g). According to the procedure for
1
D
38
the conversion of 1a into 2a, 1g (400 mg, 1.54 mmol, 1.0 equiv) was treated with TEMPO (36 mg,
0.23 mmol, 0.15 equiv) and DIB (992 mg, 3.08 mmol, 2.0 equiv) in CH Cl /H O (15 mL, v/v 3:1) at
9 °C for 18 h. After workꢀup, the residue was purified by silica gel column chromatography
[petroleum ether/EtOAc (1:1) → CH Cl /MeOH (9:1)] to afford 2g (342 mg, 1.25 mmol, 81%) as the
2
2
2
1
2
2
26
D
1
colorless oil. R
CDCl
.42–4.36 (m, 1H), 1.53 (s, 3H), 1.46 (s, 3H), 1.35 (s, 6H).; C NMR (126 MHz, CDCl
10.3, 109.5, 96.5, 71.8, 70.7, 70.6, 68.3, 26.1, 26.0, 24.9 (s), 24.5; HRMS (ESI) m/z Calcd for
f
= 0.45 [CH
Cl
2 2
/MeOH (9:1)]; [α]
=
–79.4 (c 1.0, CHCl
3
); H NMR (500 MHz,
3
) δ 5.64 (d, J = 4.3 Hz, 1H), 4.69 (d, J = 7.6 Hz, 1H), 4.63 (d, J = 7.6 Hz, 1H), 4.46 (s, 1H),
13
4
3
) δ 171.1,
1
ꢀ
C H O [M–H] 273.0980, found 273.0978.
12
17
7
Hexyl (4R)ꢀ4ꢀCꢀ(2'ꢀchlorophenanthridinꢀ6'ꢀyl)ꢀ2,3ꢀOꢀisopropylideneꢀβꢀDꢀerythroside (4a). To
a 25 mL vial charged with magnetic stirring bar were added isonitrile 3a (50 mg, 0.234 mmol, 1.0
equiv), uronic acid 2a (202 mg, 0.702 mmol, 3.0 equiv), K
2
4 2
HPO ·3H O (160 mg, 0.702 mmol, 3.0
equiv), K
2
S
2
O
8
(190 mg, 0.702 mmol, 3.0 equiv), and MeCN/H
2
O/DMSO (6 mL, v/v/v 4:1:1). The
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6
resultant mixture was evacuated and backfilled with argon for 3 times. The reaction was stirred
vigorously at 70 °C for 4 h. At this stage, CH Cl (10 mL) and water (200 mL) were added. The
2
2
organic layer was separated and the aqueous layer was extracted with CH
2 2
Cl (20 mL × 3). The
combined organic layers were washed with brine (20 mL × 2), dried over Na SO . After filtration
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and evaporation of the solvent, the residue was purified by silica gel column chromatography
(toluene/EtOAc 50:1) to afford 4a (71 mg, 0.157 mmol, 67%) as a white foam. R
f
= 0.44 (petroleum
2
D
0
1
ether/EtOAc 25:1); [α]
= –1.1 (c 1.95, CH
2
Cl
2
); H NMR (500 MHz, CDCl
3
) δ 8.59 (d, J = 8.2 Hz,
1
1
5
3
H), 8.53 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.85 (t, J = 7.6 Hz,
H), 7.74 (t, J = 7.6 Hz, 1H), 7.64 (dd, J = 8.7, 2.2 Hz, 1H), 6.40 (d, J = 5.9 Hz, 1H), 5.95 (s, 1H),
.11 (s, 1H), 4.85 (d, J = 5.9 Hz, 1H), 2.98–2.92 (m, 1H), 2.75–2.68 (m, 1H), 1.63 (s, 3H), 1.49 (s,
13
H), 0.74–0.69 (m, 2H), 0.67–0.50 (m, 7H), 0.34–0.22 (m, 1H), 0.19–0.10 (m, 1H); C NMR (126
) δ 158.3, 141.3, 133.1, 132.2, 130.7, 129.1, 127.9, 127.5, 125.3, 125.1, 122.3, 121.6,
12.0, 109.0, 86.0, 85.7, 81.5, 67.5, 31.4, 28.9, 26.8, 25.3, 22.3, 14.0; HRMS (ESI) m/z Calcd for
MHz, CDCl
3
1
+
C26H31ClNO [M+H] 456.1936, found 456.1946.
4
Hexyl (4S)ꢀ4ꢀCꢀ(2'ꢀchlorophenanthridinꢀ6'ꢀyl)ꢀ2,3ꢀOꢀisopropylideneꢀβꢀDꢀerythroside (4a').
According to the procedure for 4a except that analytical K
served as the catalyst, isonitrile 3a (28 mg, 0.13 mmol, 1.0 equiv) reacted with uronic acid 2a (112
mg, 0.39 mmol, 3.0 equiv) in MeCN/H O/DMSO (6 mL, v/v/v, 4:1:1) for 4 h at 70 °C. After workꢀup
as usual, the residue was purified by silica gel column chromatography (petroleum ether/EtOAc 9:1)
to afford 4a (25 mg, 0.055 mmol, 42%) and 4a' (14 mg, 0.032 mmol, 22%). R = 0.17 (petroleum
) δ 8.56 (d, J = 7.8 Hz,
H), 8.50 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.65 (d,
2 2 8
S O (105 mg, 0.39 mmol, 3.0 equiv)
2
f
2
D
0
1
3 3
ether/EtOAc 25:1); [α] = +23.3 (c 0.83, CHCl ); H NMR (500 MHz, CDCl
2
J = 8.7 Hz, 1H), 5.87 (d, J = 4.1 Hz, 1H), 5.48 (s, 1H), 5.32 (t, J = 4.9 Hz, 1H), 4.81 (d, J = 5.8 Hz,
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H), 3.84–3.76 (m, 1H), 3.57–3.50 (m, 1H), 1.64–1.56 (m, 2H), 1.38–1.27 (m, 6H), 1.32 (s, 3H),
1
3
3
.20 (s, 3H), 0.88 (t, J = 6.6 Hz, 3H); C NMR (126 MHz, CDCl ) δ 155.1, 141.9, 132.9, 132.3,
131.9, 130.8, 129.2, 127.8, 127.1, 125.3, 125.2, 122.5, 121.7, 113.3, 105.8, 85.0, 82.9, 82.3, 68.0,
+
31.8, 29.6, 25.9, 25.7, 24.8, 22.7, 14.2; HRMS (ESI) m/z Calcd for C H ClNO [M+H] 456.1936,
26
31
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
found 456.1943.
Hexyl (4R)ꢀ4ꢀCꢀ(2'ꢀfluorophenanthridinꢀ6'ꢀyl)ꢀ2,3ꢀOꢀisopropylideneꢀ
β
ꢀDꢀerythroside (4b).
According to the procedure for 4a, isonitrile 3b (50 mg, 0.25 mmol, 1.0 equiv) reacted with uronic
acid 2a (219 mg, 0.76 mmol, 3.0 equiv) in MeCN/H O/DMSO (6 mL, v/v/v, 4:1:1) for 4 h at 70 °C.
After workꢀup as usual, purification by silica gel column chromatography (toluene/EtOAc 25:1)
2
2
0
afforded 4b (78 mg, 0.178 mmol, 71%). R
f
= 0.41 (petroleum ether/EtOAc 25:1); [α] = –5.4 (c 1.2,
D
1
CH
2
Cl
2
); H NMR (500 MHz, CDCl
3
) δ 8.59 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.16–8.08
(m, 2H), 7.84 (t, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.43 (td, J = 8.8, 2.4 Hz, 1H), 6.41 (d, J =
.9 Hz, 1H), 5.96 (s, 1H), 5.11 (s, 1H), 4.86 (d, J = 5.9 Hz, 1H), 3.00–2.90 (m, 1H), 2.75–2.68 (m,
5
1H), 1.63 (s, 3H), 1.49 (s, 3H), 0.78–0.68 (m, 2H), 0.67–0.49 (m, 7H), 0.33–0.23 (m, 1H), 0.21–0.11
13
(m, 1H); C NMR (126 MHz, CDCl
3
) δ 161.6 (d, JCꢀF = 247.5 Hz), 157.2, 139.7, 132.9 (d, JCꢀF = 9.2
Hz), 132.7 (d, JCꢀF = 4.1 Hz), 130.4, 127.8, 127.5, 125.5 (d, JCꢀF = 9.1 Hz), 122.4, 117.4 (d, JCꢀF
=
24.3 Hz), 112.0, 108.9, 106.9 (d, JCꢀF = 23.3 Hz), 86.0, 85.7, 81.5, 67.5, 31.3, 28.9, 26.8, 25.3, 25.2,
19
22.2, 14.0; F NMR (470 MHz, CDCl
3
) δ ꢀ113.00 – ꢀ112.90 (m); HRMS (ESI) m/z Calcd for
+
C H FNO [M+H] 440.2232, found 440.2240.
26
31
4
Hexyl (4R)ꢀ4ꢀCꢀ(2'ꢀmethylphenanthridinꢀ6'ꢀyl)ꢀ2,3ꢀOꢀisopropylideneꢀβꢀDꢀerythroside (4c).
According to the procedure for 4a, isonitrile 3c (50 mg, 0.26 mmol, 1.0 equiv) reacted with uronic
acid 2a (224 mg, 0.78 mmol, 3.0 equiv) in MeCN/H O/DMSO (6 mL, v/v/v, 4:1:1) for 4 h at 70 °C.
2
After workꢀup as usual, purification by silica gel column chromatography (petroleum ether/EtOAc
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1
1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
f
5:1) afforded 4c (75 mg, 0.18 mmol, 69%) as a yellow solid. mp 55–57 °C; R = 0.3 (petroleum
2
D
0
1
2 2 3
ether/EtOAc 25:1); [α] = –4.2 (c 1.5, CH Cl ); H NMR (500 MHz, CDCl ) δ 8.61 (d, J = 8.3 Hz,
1H), 8.57 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.68 (t,
J = 7.6 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 6.44 (d, J = 5.9 Hz, 1H), 5.98 (s, 1H), 5.11 (s, 1H), 4.87 (d,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 5.9 Hz, 1H), 2.98–2.91 (m, 1H), 2.77–2.70 (m, 1H), 2.62 (s, 3H), 1.63 (s, 3H), 1.49 (s, 3H),
13
0.75–0.66 (m, 2H), 0.66–0.48 (m, 7H), 0.34–0.22 (m, 1H), 0.21–0.10 (m, 1H); C NMR (126 MHz,
CDCl
3
) δ 156.8, 141.3, 137.0, 133.0, 130.4, 130.3, 130.1, 127.3, 127.0, 125.0, 124.0, 122.2, 121.6,
111.9, 108.9, 86.0, 85.8, 81.6, 67.4, 31.4, 28.9, 26.8, 25.3, 22.2, 22.1, 14.1; HRMS (ESI) m/z Calcd
+
for C H NO [M+H] 436.2482, found 436.2488.
27 34
4
Hexyl (4R)ꢀ4ꢀCꢀ(2'ꢀmethylꢀ8'ꢀmethyoxyphenanthridinꢀ6'ꢀyl)ꢀ2,3ꢀOꢀisopropylideneꢀ
erythroside (4d). According to the procedure for 4a, isonitrile 3d (50 mg, 0.224 mmol, 1.0 equiv)
reacted with uronic acid 2a (193 mg, 0.672 mmol, 3.0 equiv) in MeCN/H O/DMSO (6 mL, v/v/v,
:1:1) for 4 h at 70 °C. After workꢀup as usual, purification by silica gel column chromatography
(toluene/EtOAc 60:1) afforded 4d (58 mg, 0.125 mmol, 56%). R = 0.24 (petroleum ether/EtOAc
βꢀDꢀ
2
4
f
20
D
1
2
1
0:1); [α]
= –11.1 (c 3.8, CH
2
Cl
2
); H NMR (500 MHz, CDCl
3
) δ 8.47 (d, J = 9.0 Hz, 1H), 8.19 (s,
H), 7.98 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 9.0, 1.8
Hz, 1H), 6.42 (d, J = 5.8 Hz, 1H), 5.89 (s, 1H), 5.12 (d, J = 1.0 Hz, 1H), 4.87 (d, J = 5.8 Hz, 1H),
3
0
.99 (s, 3H), 3.01–2.96 (m, 1H), 2.85–2.79 (m, 1H), 2.59 (s, 3H), 1.65 (s, 3H), 1.49 (s, 3H), 0.75–
13
.68 (m, 2H), 0.68–0.51 (m, 7H), 0.34–0.24 (m, 1H), 0.21–0.11 (m, 1H); C NMR (126 MHz,
CDCl
3
) δ 158.4, 155.9, 140.5, 137.0, 130.4, 129.3, 127.4, 126.4, 124.1, 123.8, 121.07, 121.05, 111.8,
108.8, 107.0, 86.0, 85.9, 81.7, 67.5, 55.8, 31.5, 29.0, 26.8, 25.3, 25.1, 22.2, 22.1, 14.1; HRMS (ESI)
+
m/z Calcd for C28
H
36NO
5
[M+H] 466.2588, found 466.2592.
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Page 23 of 58
The Journal of Organic Chemistry
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Methyl (4R)ꢀ4ꢀCꢀ(2'ꢀchlorophenanthridinꢀ6'ꢀyl)ꢀ3ꢀOꢀmethylꢀ2ꢀdeoxyꢀαꢀDꢀerythroside (5a).
According to the procedure for 4a, isonitrile 3a (50 mg, 0.234 mmol, 1.0 equiv) reacted with uronic
acid 2b (124 mg, 0.702 mmol, 3.0 equiv) in MeCN/H O/DMSO (6 mL, v/v/v, 4:1:1) for 4 h at 70 °C.
After workꢀup as usual, purification by silica gel column chromatography (toluene/EtOAc 9:1)
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
D
0
afforded 5a (39 mg, 0.115 mmol, 49%). R
f
= 0.28 (petroleum ether/EtOAc 4:1); [α] = +94.2 (c 1.3,
1
CH
2
Cl
2
); H NMR (500 MHz, CDCl
3
) δ 8.57 (d, J = 8.2 Hz, 1H), 8.53–8.47 (m, 2H), 8.12 (d, J = 8.7
Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.66 (dd, J = 8.7, 2.2 Hz, 1H), 5.94 (d, J =
3
1
1
.8 Hz, 1H), 5.37 (d, J = 5.5 Hz, 1H), 4.81–4.76 (m, 1H), 3.57 (s, 3H), 3.42 (s, 3H), 2.57–2.50 (m,
13
H), 2.26 (d, J = 14.1 Hz, 1H); C NMR (126 MHz, CDCl ) δ 157.6, 141.8, 133.2, 132.4, 132.1,
3
31.0, 129.2, 128.3, 126.5, 125.4, 125.2, 122.6, 121.7, 106.4, 83.3, 83.0, 57.9, 55.9, 38.4; HRMS
+
(
ESI) m/z Calcd for C19
H19ClNO
3
[M+H] 344.1048, found 344.1057.
Methyl (4R)ꢀ4ꢀCꢀ(2'ꢀfluorophenanthridinꢀ6'ꢀyl)ꢀ3ꢀOꢀmethylꢀ2ꢀdeoxyꢀ
According to the procedure for 4a, isonitrile 3b (50 mg, 0.254 mmol, 1.0 equiv) reacted with uronic
acid 2b (134 mg, 0.762 mmol, 3.0 equiv) in MeCN/H O/DMSO (6 mL, v/v/v, 4:1:1) for 4 h at 70 °C.
After workꢀup as usual, purification by silica gel column chromatography (toluene/EtOAc 9:1)
αꢀDꢀerythroside (5b).
2
2
D
0
afforded 5b (45 mg, 0.137 mmol, 54%). R
f
= 0.44 (petroleum ether/EtOAc 4:1); [α]
= +129.8 (c
1
0
.93, CH
2
Cl
2
); H NMR (500 MHz, CDCl
3
) δ 8.54–8.47 (m, 2H), 8.21–8.12 (m, 2H), 7.86 (t, J = 7.6
Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.45 (td, J = 8.6, 2.7 Hz, 1H), 5.94 (d, J = 3.8 Hz, 1H), 5.37 (d, J =
5
1
.5 Hz, 1H), 4.83–4.78 (m, 1H), 3.57 (s, 3H), 3.42 (s, 3H), 2.58–2.50 (m, 1H), 2.25 (d, J = 14.1 Hz,
13
3
H); C NMR (126 MHz, CDCl ) δ 161.6 (d, JCꢀF = 248.2 Hz), 156.5, 140.2, 132.9 (d, JCꢀF = 8.8 Hz),
132.8, 130.7, 128.3, 126.4, 125.6 (d, JCꢀF = 248.2 Hz), 125.0, 122.7, 117.5 (d, JCꢀF = 25.2 Hz), 107.0
19
(
d, JCꢀF = 23.9 Hz), 106.4, 83.2, 83.0, 57.9, 55.9, 38.4; F NMR (470 MHz, CDCl
3
) δ ꢀ112.54 –
+
ꢀ112.46 (m); HRMS (ESI) m/z Calcd for C19
H
19FNO
3
[M+H] 328.1343, found 328.1350.
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Methyl (4R)ꢀ4ꢀCꢀ(2'ꢀmethylphenanthridinꢀ6'ꢀyl)ꢀ3ꢀOꢀmethylꢀ2ꢀdeoxyꢀαꢀDꢀerythroside (5c).
According to the procedure for 4a, isonitrile 3c (38 mg, 0.197 mmol, 1.0 equiv) reacted with uronic
acid 2b (100 mg, 0.57 mmol, 3.0 equiv) in MeCN/H O/DMSO (4.2 mL, v/v/v, 4:1:1) for 4 h at 70 °C.
After workꢀup as usual, purification by silica gel column chromatography (petroleum ether/EtOAc
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
D
0
4:1) afforded 5c (31 mg, 0.096 mmol, 49%). R
f
= 0.27 (petroleum ether/EtOAc 4:1); [α] = +128.3 (c
1
0
.8, CH
2
Cl
2
); H NMR (500 MHz, CDCl
3
) δ 8.64 (d, J = 8.3 Hz, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.34
(
s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.84 (t, J = 8.2 Hz, 1H), 7.72 (t, J = 8.2 Hz, 1H), 7.55 (d, J = 8.4 Hz,
1
2
1
5
H), 5.95 (d, J = 3.8 Hz, 1H), 5.38 (d, J = 4.8 Hz, 1H), 4.84–4.80 (m, 1H), 3.57 (s, 3H), 3.42 (s, 3H),
1
3
.63 (s, 3H), 2.60–2.52 (m, 1H), 2.27–2.23 (m, 1H); C NMR (126 MHz, CDCl ) δ 156.2, 141.7,
3
37.2, 133.2, 130.43, 130.4, 130.3, 127.4, 126.3, 125.1, 124.1, 122.5, 121.7, 106.4, 83.4, 83.0, 57.9,
+
5.9, 38.5, 22.2; HRMS (ESI) m/z Calcd for C20
H22NO
3
[M+H] 324.1594, found 324.1599.
Methyl (4R)ꢀ4ꢀCꢀ(2'ꢀmethylꢀ8'ꢀmethoxyphenanthridinꢀ6'ꢀyl)ꢀ3ꢀOꢀmethylꢀ2ꢀdeoxyꢀαꢀDꢀ
erythroside (5d). According to the procedure for 4a, isonitrile 3d (50 mg, 0.224 mmol, 1.0 equiv)
reacted with uronic acid 2b (118 mg, 0.672 mmol, 3.0 equiv) in MeCN/H O/DMSO (6 mL, v/v/v,
2
4
:1:1) for 4 h at 70 °C. After workꢀup as usual, purification by silica gel column chromatography
petroleum ether/EtOAc 3:1) afforded 5d (32 mg, 0.091 mmol, 41%). R = 0.29 (petroleum
) δ 8.53 (d, J = 9.1 Hz,
(
f
2
D
0
1
2 2 3
ether/EtOAc 3:1); [α] = +114.6 (c 1.7, CH Cl ); H NMR (500 MHz, CDCl
1
3
2
H), 8.24 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.53–7.41 (m, 2H), 5.91 (d, J =
.7 Hz, 1H), 5.39 (d, J = 5.4 Hz, 1H), 4.80–4.72 (m, 1H), 3.99 (s, 3H), 3.58 (s, 3H), 3.44 (s, 3H),
13
3
.60 (s, 3H), 2.54–2.48 (m, 1H), 2.25 (d, J = 14.1 Hz, 1H); C NMR (126 MHz, CDCl ) δ 158.7,
155.2, 140.9, 137.2, 130.4, 129.4, 127.5, 126.3, 124.2, 124.1, 121.5, 121.1, 106.3, 105.9, 83.6, 83.2,
+
5
7.9, 55.8, 55.6, 38.3, 22.1; HRMS (ESI) m/z Calcd for C21
H24NO
4
[M+H] 354.1700, found
354.1706.
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Page 25 of 58
The Journal of Organic Chemistry
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Benzoyl (4S)ꢀ4ꢀCꢀ(2'ꢀchlorophenanthridinꢀ6'ꢀyl)ꢀ2,3ꢀOꢀisopropylideneꢀβꢀLꢀerythroside (6a).
According to the procedure for 4a, isonitrile 3a (28 mg, 0.13 mmol, 1.0 equiv) reacted with uronic
acid 2c (120 mg, 0.39 mmol, 3.0 equiv) in MeCN/H O/DMSO (3 mL, v/v/v, 4:1:1) for 8 h at 70 °C.
After workꢀup as usual, purification by silica gel column chromatography (toluene/EtOAc 80:1)
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
D
0
afforded 6a (36 mg, 0.075 mmol, 58%). R
f
= 0.45 (petroleum ether/EtOAc 5:1); [α] = +40.5 (c 0.7,
1
CH
2
Cl
2
); H NMR (500 MHz, CDCl
3
) δ 8.47 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.35 (d, J
=
8.2 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.72–7.65 (m, 2H), 7.21 (t, J = 7.4
Hz, 1H), 6.94 (d, J = 7.7 Hz, 2H), 6.76 (t, J = 7.7 Hz, 2H), 6.51 (s, 1H), 6.41 (d, J = 5.8 Hz, 1H),
1
3
6
1
1
.17 (s, 1H), 5.14 (d, J = 5.8 Hz, 1H), 1.68 (s, 3H), 1.53 (s, 3H); C NMR (126 MHz, CDCl ) δ
3
64.4, 157.9, 141.3, 133.3, 132.9, 132.1, 132.0, 130.9, 129.2, 129.1, 128.9, 128.3, 127.6, 127.3,
25.5, 124.7, 122.2, 121.8, 112.8, 103.0, 86.8, 86.0, 81.8, 26.8, 25.4; HRMS (ESI) m/z Calcd for
+
C
27
H
23ClNO
5
[M+H] 476.1259, found 476.1264.
Benzoyl (4S)ꢀ4ꢀCꢀ(2'ꢀfluorophenanthridinꢀ6'ꢀyl)ꢀ2,3ꢀOꢀisopropylideneꢀ
According to the procedure for 4a, isonitrile 3b (26 mg, 0.13 mmol, 1.0 equiv) reacted with uronic
acid 2c (120 mg, 0.39 mmol, 3.0 equiv) in MeCN/H O/DMSO (3 mL, v/v/v, 4:1:1) for 4 h at 70 °C.
After workꢀup as usual, purification by silica gel column chromatography (petroleum ether/EtOAc
βꢀLꢀerythroside (6b).
2
2
D
0
1
5:1) afforded 6b (38 mg, 0.083 mmol, 63%). R
f
= 0.35 (petroleum ether/EtOAc 15:1); [α] = +42.2
1
(
2
c 0.65, CH Cl
2
); H NMR (500 MHz, CDCl
3
) δ 8.47 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H),
8
.16–8.10 (m, 1H), 8.03 (d, J = 10.1 Hz, 1H), 7.78–7.65 (m, 2H), 7.47 (t, J = 8.3 Hz, 1H), 7.19 (t, J =
.3 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 6.75 (t, J = 7.5 Hz, 2H), 6.51 (s, 1H), 6.42 (d, J = 5.6 Hz, 1H),
7
1
3
6.17 (s, 1H), 5.15 (d, J = 5.6 Hz, 1H), 1.69 (s, 3H), 1.53 (s, 3H); C NMR (126 MHz, CDCl
3
) δ
1
64.5, 161.7 (d, JCꢀF = 248.3 Hz), 156.8, 139.7, 132.8, 132.7 (d, JCꢀF = 9.1 Hz), 132.6 (d, JCꢀF = 4.4
Hz), 130.7, 129.1, 128.9, 128.3, 127.6, 127.3, 125.9 (d, JCꢀF = 9.3 Hz), 124.6, 122.3, 117.5 (d, JCꢀF
=
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9
2
4.3 Hz), 112.8, 107.1 (d, JCꢀF = 23.3 Hz), 103.0, 86.8, 86.0, 81.8, 26.8, 25.4; F NMR (470 MHz,
+
CDCl
460.1555.
Benzoyl (4S)ꢀ4ꢀCꢀ(2'ꢀmethylphenanthridinꢀ6'ꢀyl)ꢀ2,3ꢀOꢀisopropylideneꢀ
According to the procedure for 4a, isonitrile 3c (25 mg, 0.13 mmol, 1.0 equiv) reacted with uronic
acid 2c (120 mg, 0.39 mmol, 3.0 equiv) in MeCN/H O/DMSO (3 mL, v/v/v, 4:1:1) for 4 h at 70 °C.
After workꢀup as usual, the residue was purified by silica gel column chromatography
3
) δ ꢀ112.34 – ꢀ112.27 (m); HRMS (ESI) m/z Calcd for C27
H23FNO
5
[M+H] 460.1555, found
β
ꢀLꢀerythroside (6c).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
(toluene/EtOAc 80:1) to afford 6c (25 mg, 0.055 mmol, 42%). R
f
= 0.44 (petroleum ether/EtOAc
2
D
0
1
8
8
7
:1); [α]
= +46.5 (c 0.5, CH Cl ); H NMR (500 MHz, CDCl ) δ 8.49–8.41 (m, 2H), 8.25 (s, 1H),
2
2
3
.04 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H),
.17 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 6.71 (t, J = 7.6 Hz, 2H), 6.52 (s, 1H), 6.45 (d, J =
13
5.7 Hz, 1H), 6.20 (s, 1H), 5.16 (d, J = 5.7 Hz, 1H), 2.65 (s, 3H), 1.69 (s, 3H), 1.53 (s, 3H); C NMR
(
126 MHz, CDCl ) δ 164.4, 156.3, 141.1, 137.1, 132.7, 132.5, 130.22, 130.19, 130.15, 129.0, 128.9,
3
127.4, 127.3, 126.9, 124.5, 124.1, 122.0, 121.5, 112.5, 103.0, 86.7, 86.0, 81.7, 26.7, 25.2, 22.0;
+
HRMS (ESI) m/z Calcd for C28
H26NO
5
[M+H] 456.1805, found 456.1806.
Benzoyl (4S)ꢀ4ꢀCꢀ(2'ꢀmethylꢀ8'ꢀmethyoxyphenanthridinꢀ6'ꢀyl)ꢀ2,3ꢀOꢀisopropylideneꢀ
erythroside (6d). According to the procedure for 4a, isonitrile 3d (29 mg, 0.13 mmol, 1.0 equiv)
reacted with uronic acid 2c (120 mg, 0.39 mmol, 3.0 equiv) in MeCN/H O/DMSO (3 mL, v/v/v,
:1:1) for 4 h at 70 °C. After workꢀup as usual, the residue was purified by silica gel column
chromatography (petroleum ether/EtOAc 15:1) to afford 6d (22 mg, 0.045 mmol, 35%). R = 0.27
) δ 8.33 (d,
βꢀLꢀ
2
4
f
2
D
0
1
2 2 3
(petroleum ether/EtOAc 15:1); [α] = +33.8 (c 0.65, CH Cl ); H NMR (500 MHz, CDCl
J = 9.0 Hz, 1H), 8.16 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.78–7.73 (m, 1H), 7.50 (d, J = 8.3 Hz, 1H),
7.34–7.28 (m, 1H), 7.17 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 7.9 Hz, 2H), 6.71 (t, J = 7.6 Hz, 2H), 6.54 (s,
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H), 6.44 (d, J = 5.7 Hz, 1H), 6.12 (s, 1H), 5.15 (d, J = 5.7 Hz, 1H), 3.97 (s, 3H), 2.64 (s, 3H), 1.69
13
3
(s, 3H), 1.53 (s, 3H); C NMR (126 MHz, CDCl ) δ 164.6, 158.6, 155.5, 140.5, 137.3, 132.7, 130.2,
129.4, 129.2, 129.0, 127.6, 126.1, 124.4, 123.7, 121.5, 121.2, 112.6, 106.7, 103.1, 86.9, 86.1, 82.0,
+
55.8, 26.8, 25.2, 22.2; HRMS (ESI) m/z Calcd for C H NO [M+H] 486.1911, found 486.1904.
29
28
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
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3
3
3
4
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4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(4R)ꢀ4ꢀCꢀ(2'ꢀchlorophenanthridinꢀ6'ꢀyl)ꢀ1,2ꢀOꢀisopropylideneꢀ3ꢀOꢀmethylꢀ
and (4S)ꢀ4ꢀCꢀ(2'ꢀchlorophenanthridinꢀ6'ꢀyl)ꢀ1,2ꢀOꢀisopropylideneꢀ3ꢀOꢀmethylꢀ
7a'). According to the procedure for 4a, isonitrile 3a (28 mg, 0.13 mmol, 1.0 equiv) reacted with
uronic acid 2d (85 mg, 0.39 mmol, 3.0 equiv) in MeCN/H O/DMSO (3 mL, v/v/v, 4:1:1) for 10 h at
0 °C. After workꢀup as usual, the residue was purified by silica gel column chromatography
petroleum ether/EtOAc 6:1) to afford 7a (17 mg, 0.044 mmol, 34%) and 7a' (22mg, 0.057 mmol,
β
ꢀLꢀthreoside (7a)
βꢀL
ꢀthreoside
(
2
7
(
2
D
0
1
4
4%). For 7a: R
) δ 8.57 (d, J = 8.3 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.21 (d, J
8.8 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.67–7.64 (m, 1H), 6.36 (d, J = 3.8
f
= 0.14, petroleum ether/EtOAc 6:1; [α]
2 2
= –40.3 (c 0.75, CH Cl ); H NMR (500
MHz, CDCl
3
=
Hz, 1H), 6.06 (d, J = 3.3 Hz, 1H), 4.79 (d, J = 3.9 Hz, 1H), 4.35 (d, J = 3.3 Hz, 1H), 2.98 (s, 3H),
13
1
1
.65 (s, 3H), 1.43 (s, 3H); C NMR (126 MHz, CDCl
3
) δ 154.9, 141.9, 133.1, 132.1, 130.8, 129.2,
27.9, 126.1, 125.1, 125.0, 122.5, 121.7, 112.0, 105.1, 87.1, 82.4, 82.3, 58.3, 27.1, 26.5; HRMS (ESI)
+
m/z Calcd for C21
H
21ClNO
4
[M+H] 386.1154, found 386.1163. For 7a': R
f
= 0.45 (petroleum
2
D
0
1
ether/EtOAc 6:1); [α]
= –22.4 (c 0.1, CH
2
Cl
2
); H NMR (500 MHz, CDCl
3
) δ 8.58–8.49 (m, 3H),
8.12 (d, J = 8.7 Hz, 1H), 7.89–7.83 (m, 1H), 7.78–7.72 (m, 1H), 7.68–7.64 (m, 1H), 6.11 (d, J = 4.2
Hz, 1H), 5.72 (d, J = 4.1 Hz, 1H), 5.22 (d, J = 4.1 Hz, 1H), 4.84–4.82 (m, 1H), 3.55 (s, 3H), 1.34 (s,
1
3
3H), 1.23 (s, 3H); C NMR (126 MHz, CDCl
3
) δ 156.3, 141.5, 133.3, 132.4, 132.2, 130.9, 129.2,
128.2, 127.2, 125.5, 125.4, 122.4, 121.8, 113.7, 106.0, 86.1, 85.5, 84.7, 58.1, 27.1, 26.9; HRMS (ESI)
+
m/z Calcd for C21
H
21ClNO
4
[M+H] 386.1154, found 386.1165.
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(
4R)ꢀ4ꢀCꢀ(2'ꢀfluorophenanthridinꢀ6'ꢀyl)ꢀ1,2ꢀOꢀisopropylideneꢀ3ꢀOꢀmethylꢀ
β
ꢀ
L
ꢀthreoside (7b)
and
(4S)ꢀ4ꢀCꢀ(2'ꢀfluorophenanthridinꢀ6'ꢀyl)ꢀ1,2ꢀOꢀisopropylideneꢀ3ꢀOꢀmethylꢀβꢀLꢀthreoside
(7b'). According to the procedure for 4a, isonitrile 3b (26 mg, 0.13 mmol, 1.0 equiv) reacted with
uronic acid 2d (85 mg, 0.39 mmol, 3.0 equiv) in MeCN/H O/DMSO (3 mL, v/v/v, 4:1:1) for 10 h at
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
70 °C. After workꢀup as usual, the residue was purified by silica gel column chromatography
(
petroleum ether/EtOAc 5:1) to afford 7b (15 mg, 0.041 mmol, 31%) and 7b' (19 mg, 0.051 mmol,
2
D
0
4
0%) as a white solid. For 7b: R
f
= 0.25 (petroleum ether/EtOAc 5:1); [α]
) δ 8.52 (d, J = 8.3 Hz, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.29–8.25 (m, 1H),
.16–8.13 (m, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.48–7.43 (td, J = 8.7, 2.7 Hz,
H), 6.36 (d, J = 3.8 Hz, 1H), 6.05 (d, J = 3.3 Hz, 1H), 4.79 (d, J = 3.9 Hz, 1H), 4.35 (d, J = 3.3 Hz,
2 2
= –35.4 (c 1.1, CH Cl );
1
H NMR (500 MHz,CDCl
3
8
1
1
13
3
H), 2.98 (s, 3H), 1.65 (s, 3H), 1.43 (s, 3H); C NMR (126 MHz, CDCl ) δ 162.5 (d, JCꢀF = 252.0
Hz), 153.8, 140.3, 132.9 (d, JCꢀF = 9.3 Hz), 132.6 (d, JCꢀF = 4.3 Hz), 130.6, 127.9, 126.1, 125.4 (d,
CꢀF = 8.9 Hz), 125.0, 122.7, 117.6 (d, JCꢀF = 24.2 Hz), 112.0, 106.9 (d, JCꢀF = 23.3 Hz), 105.1, 87.1,
J
19
82.4, 82.3, 58.3, 27.1, 26.5; F NMR (470 MHz, CDCl ) δ ꢀ112.83 – ꢀ112.75 (m); HRMS (ESI) m/z
3
+
Calcd for C21
H21FNO
4
[M+H] 370.1449, found 370.1458. For 7b': mp 99–102 °C; R
f
= 0.58
2
D
0
1
(
petroleum ether/EtOAc 5:1); [α]
= –6.5 (c 0.25, CH
2
Cl
2
); H NMR (500 MHz,CDCl
3
) δ 8.52 (d, J =
8
7
.2 Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.20–8.16 (m, 1H), 8.15–8.12 (, 1H), 7.82 (t, J = 7.5 Hz, 1H),
.73 (t, J = 7.6 Hz, 1H), 7.47–7.43 (m, 1H), 6.12 (d, J = 4.0 Hz, 1H), 5.72 (d, J = 4.1 Hz, 1H), 5.24
13
(
d, J = 3.8 Hz, 1H), 4.85 (d, J = 3.8 Hz, 1H), 3.56 (s, 3H), 1.35 (s, 3H), 1.26 (s, 3H); C NMR (126
MHz, CDCl ) δ 161.2 (d, JCꢀF = 247.7 Hz), 155.1, 139.8, 132.9 (d, JCꢀF = 9.3 Hz), 132.8 (d, JCꢀF = 4.1
3
Hz), 130.6, 128.1, 127.1, 125.8 (d, JCꢀF = 9.3 Hz), 125.2, 122.5, 117.5 (d, JCꢀF = 24.3 Hz), 113.7,
19
1
07.0 (d, JCꢀF = 23.3 Hz), 105.9, 86.0, 85.6, 84.6, 58.0, 27.1, 27.0; F NMR (470 MHz, CDCl
3
) δ
+
ꢀ112.57 – ꢀ112.48 (m); HRMS (ESI) m/z Calcd for C21
H
21FNO
4
[M+H] 370.1449, found 370.1450.
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(
4R)ꢀ4ꢀCꢀ(2'ꢀmethylphenanthridinꢀ6'ꢀyl)ꢀ1,2ꢀOꢀisopropylideneꢀ3ꢀOꢀmethylꢀ
β
ꢀ
L
ꢀthreoside (7c)
and
(4S)ꢀ4ꢀCꢀ(2'ꢀmethylphenanthridinꢀ6'ꢀyl)ꢀ1,2ꢀOꢀisopropylideneꢀ3ꢀOꢀmethylꢀβꢀLꢀthreoside
(7c'). According to the procedure for 4a, isonitrile 3c (25 mg, 0.13 mmol, 1.0 equiv) reacted with
uronic acid 2d (85 mg, 0.39 mmol, 3.0 equiv) in MeCN/H O/DMSO (3 mL, v/v/v, 4:1:1) for 10 h at
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
70 °C. After workꢀup as usual, the residue was purified by silica gel column chromatography
(
petroleum ether/EtOAc 9:1) to afford 7c (15 mg, 0.041 mmol, 32%) and 7c' (20 mg, 0.055 mmol,
2
D
0
1
4
3%). For 7c: R
) δ 8.64 (d, J = 8.3 Hz, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.34 (s, 1H), 8.18 (d, J = 8.3 Hz,
H), 7.82 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.56–7.53 (m, 1H), 6.37 (d, J = 3.8 Hz, 1H),
.06 (d, J = 3.2 Hz, 1H), 4.79 (d, J = 3.8 Hz, 1H), 4.35 (d, J = 3.2 Hz, 1H), 2.95 (s, 3H), 2.62 (s, 3H),
f
= 0.09 (petroleum ether/EtOAc 9:1); [α]
2 2
= –42.0 (c 0.9, CH Cl ); H NMR (500
MHz, CDCl
3
1
6
1
13
3
.65 (s, 3H), 1.43 (s, 3H); C NMR (126 MHz, CDCl ) δ 153.4, 141.8, 137.0, 132.9, 130.43, 130.4,
130.3, 127.1, 126.0, 125.0, 123.8, 122.5, 121.6, 111.0, 105.1, 87.1, 82.6, 82.4, 58.3, 27.1, 26.5, 22.1;
+
HRMS (ESI) m/z Calcd for C22
H24NO
4
[M+H] 366.1700, found 366.1705. For 7c': R
f
= 0.31
2
D
0
1
(petroleum ether/EtOAc 9:1); [α]
= –26.7 (c 0.85, CH Cl ); H NMR (500 MHz, CDCl ) δ 8.62 (d, J
2
2
3
=
8.3 Hz, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.84–7.77 (m, 1H),
7
.69 (t, J = 7.4 Hz, 1H), 7.56–7.53 (m, 1H), 6.12 (d, J = 4.2 Hz, 1H), 5.72 (d, J = 4.3 Hz, 1H), 5.27
13
(
d, J = 4.1 Hz, 1H), 4.86–4.84 (m, 1H), 3.56 (s, 3H), 2.63 (s, 3H), 1.36 (s, 3H), 1.28 (s, 3H); C
NMR (126 MHz, CDCl ) δ 154.8, 141.4, 137.2, 133.1, 130.5, 130.3, 130.2, 127.3, 126.9, 125.3,
24.2, 122.3, 121.7, 113.7, 105.9, 86.1, 85.7, 84.7, 58.1, 27.2, 27.0, 22.1; HRMS (ESI) m/z Calcd for
3
1
+
C
22
H
24NO
4
[M+H] 366.1700, found 366.1707.
(4R)ꢀ4ꢀCꢀ(2'ꢀmethylꢀ8'ꢀmethoxyphenanthridinꢀ6'ꢀyl)ꢀ1,2ꢀOꢀisopropylideneꢀ3ꢀOꢀmethylꢀβꢀLꢀthr
eoside (7d) and (4S)ꢀ4ꢀCꢀ(2'ꢀmethylꢀ8'ꢀmethoxyphenanthridinꢀ6'ꢀyl)ꢀ1,2ꢀOꢀisopropylideneꢀ3ꢀOꢀ
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