The Catalytically Lignan-Activation-Based Approach for the Synthesis of (epi)-Podophyllotoxin Derivatives

Article abstract of DOI:10.1021/acs.joc.7b00485

Under the effect of a catalytic amount of Au(I) complex, 4-O-(2-cyclopropylethynyl)benzoyl-(epi)-podophyllotoxins, easily prepared via dehydrative condensation between (epi)-podophyllotoxin and ortho-cyclopropylethynylbenzoic acid, could efficiently coupl

Full text of DOI:10.1021/acs.joc.7b00485

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Article
The Catalytically Lignan-Activation-Based Approach
for the Synthesis of (epi)-Podophyllotoxin Derivatives
Jun-Hao Wan, Yang Hu, Hui Liu, Yuan-Hong Tu, Zhong-Yi He, and Jian-Song Sun
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 15 May 2017
Downloaded from http://pubs.acs.org on May 19, 2017
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The Journal of Organic Chemistry
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The Catalytically LignanꢀActivationꢀBased Approach for the
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Synthesis of (epi)ꢀPodophyllotoxin Derivatives
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JunꢀHao Wan,a,b Yang Hu,a Hui Liu,a YuanꢀHong Tu,a ZhongꢀYi He,b,* and JianꢀSong
Suna,*
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aThe National Research Centre for Carbohydrate Synthesis, Jiangxi Normal
University, 99 Ziyang Avenue, Nanchang, 330022 (China).
E-mail: jssun@jxnu.edu.cn
bSchool of Materials Science and Technology, East China Jiaotong University, 808
East Shuanggang Street, Nanchang, 330013 (China).
E-mail: zhyhe@ecjtu.edu.cn
Table of content:
Abstract:
Under
4ꢀOꢀ(2ꢀcyclopropylethynyl)benzoylꢀ(epi)ꢀpodophyllotoxins, easily prepared via
dehydrative condensation between (epi)ꢀpodophyllotoxin and
the
effect
of
catalytic
amount
of
Au(I)
complex,
orthoꢀcyclopropylethynylbenzoic acid, could couple with a variety of nucleophiles,
including alcohol, phenol, aniline, and carbon nucleophiles efficiently to provide
(epi)ꢀpodophyllotoxin derivatives. Thus, the first catalytic and lignanꢀactivationꢀbased
approach for (epi)ꢀpodophyllotoxin derivatization was established. Based on the new
methodology as well as the judicious choice of N3, AZMB, and Cbz protecting groups
set, an efficient approach toward NKꢀ611, an antitumoral agent at phaseꢀII clinical
trial, was established, which features an in situ anomerization of the hemiacetal OHs
in the key condensation step. Counting from the easily available starting material, the
target molecule was obtained with the longest linear sequence of 6 steps and 38%
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overall yield.
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Introduction:
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Great efforts have been devoted to the derivatization of podophyllotoxin (1) and
epiꢀpodophyllotoxin (2), the endeavor has been rewarded by the discovery of
etoposide and teniposide,1 the two widely clinically used antitumoral agents for the
treatment of testicular and smallꢀcell lung cancers, lymphoma, leukemia, and Kaposi’s
sarcoma.2 Broad pharmacological applications result in the full recognition of the
severe undesirable side effects and unsatisfactory pharmaceutical profiles inherent to
etoposide and teniposide. Among others, the development of leucopenia, drug
resistance, and poor water solubility are prominent. To overcome these shortcomings
and search for more ideal surrogates, further studies of (epi)ꢀpodophyllotoxin
((E)ꢀPPT) derivatization are urgently needed. In addition, the demand is further
intensified by the incompletely understood working mechanism of (E)ꢀPPT
derivatives.3 Based on conventional derivatization methods, many pharmaceutically
promising compounds such as NKꢀ611,4 etopophos,5 TOPꢀ53,6 and NPF7 have been
discovered (Figure 1).
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R
O
O
F
HO
O
R1 R2
O
NH
O
A
HO
C
D O
B
O
O
O
O
O
O
O
O
E
O
O
MeO
OMe
OMe
MeO
OMe
MeO
OMe
OH
OH
R1 = H, R2 = OH podophyllotoxin (1)
R1 = OH, R2 = H epi-podophyllotoxin (2)
R = CH3 etoposide
R = 2-thienyl teniposide
NPF
H3C
Me2N
Me
O
O
N
HO
O
O
Me2N
O
O
O
O
O
O
O
O
MeO
OMe
MeO
OMe
OH
TOP-53
OH
NK-611 (3)
Figure 1. The chemical structures of (epi)ꢀpodophyllotoxin and its derivatives.
Conventional (E)ꢀPPT derivatization methods suffer from moderate to low
efficiencies and harsh reaction conditions.8 Recently, the first catalytic glycosylation
derivatization of (E)ꢀPPTs was realized by us based on the Yu glycosylation.9
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Nevertheless,
this
method
can
only
afford
anomerically
linked
(E)ꢀPPTꢀ4ꢀOꢀglycosides.9b The appearances of NPF and TOPꢀ53 call on an efficient
method which can introduce a broad scope of substituents to (E)ꢀPPTs. Derivatization
based on (E)ꢀPPT activation can indeed introduce a variety of substitutes to the
(E)ꢀPPT scaffold, however, no catalytic and efficient approach has been discovered to
date (Figure 2). Under such context, the first catalytically lignanꢀactivationꢀbased
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approach
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(E)ꢀPPT
derivatives
was
established
with
(E)ꢀPPTꢀ4ꢀOꢀalkynylbenzoates as the key intermediates and catalytic amounts of Au(I)
complex as promoter.
Figure 2. Existing (E)ꢀPPT derivatization methods based on lignan activation.
Results and discussion:
Capitalizing on the appealing low oxophilicity and excellent functional group
compatible properties of gold catalyst, orthoꢀalkynyl benzoate has been widely
applied in organic synthesis.9 Inspired by these precedented works, we assume that
(E)ꢀPPT 4ꢀOꢀorthoꢀcyclopropylethynylbenzoates can act as ideal intermediates for
highly efficient derivatization of (E)ꢀPPTs. To reduce this idea to practice, (E)ꢀPPT
4ꢀOꢀorthoꢀcyclopropylethynylbenzoates 4, 5 and 7 were synthesized (Scheme 1).
Thus, under the conventional dehydrative esterification conditions, (E)ꢀPPT 1 and 2
were esterified with orthoꢀcyclopropylethynylbenzoic acid (ABzOH) to deliver 4 and
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5 in high chemical yields (97% and 88%, respectively). 4’ꢀDemethylꢀEPPT 610 was
converted to compound 7 via successive esterification of the phenolic and alcoholic
OHs with CbzCl and ABzOH respectively (66%, 2 steps).
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Scheme 1. Synthesis of orthoꢀcyclopropylethynylbenzoate 4 , 5 and 7.
With intermediates 4, 5, and 7 in hand, now the stage was set for the pivotal
condensation with nucleophiles, and the coupling between 4 and primary alcohol 811
was taken as a model reaction. Pleasantly, when treated with 0.3 equivalents of
Ph3PAuNTf2 in the presence of activated 4A molecular sieves at room temperature,
compound 4 reacted fluently with 6 to furnish 6ꢀOꢀepodophyllotoxinyl glucoside 16
in 92% yield (Scheme 2). Encouraged by the promising result, condensation of 4 with
the more reactive alcoholic nucleophile 911 was then checked under identical
conditions. Expectedly, an even better yield of coupling product 17 was obtained
(95%). Subsequent study revealed that more bulky and inert secondary OHs 1012 and
cholesterol 12 were also viable substrates for the Au(I)ꢀcatalyzed coupling reaction,
furnishing the desired EPPT derivatives 18 and 20 efficiently (93%, 100% yields,
respectively). Surprisingly, when 1,2;5,6ꢀdiisopropylideneꢀαꢀD
ꢀglucofuranoside 1113
was selected as a nucleophile to react with 4 under the identical conditions, despite
also as a secondary hydroxyl group nucleophile, it delivered the conjugating product
19 nonꢀstereoselectively, and a separable mixture of PPT and EPPT isomers
marginally favoring the PPT one was obtained (78% yield, PPT : EPPT = 1.6 : 1). The
abnormal stereoselectivity of compound 11 could presumably be attributed to its inert
reactivity imposed by the two bulky isopropylidenyl protecting groups. Although the
incorporation of sugar residue through the anomeric OH to Cꢀ4 of (E)ꢀPPTs could be
realized via the previously established reverse and direct glycosylation strategies,8a
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nevertheless, direct combination of sugar residues to the Cꢀ4 site of (E)ꢀPPTs via
sugar hydroxyl groups other than the anomeric ones by the conventional strategies, to
the best of our knowledge, has never been investigated. Therefore, our protocol may
find wide application in the diversityꢀoriented synthesis of sugarꢀcontaining (E)ꢀPPT
derivatives. In fact, the anomerically linked EPPT glycosides could also be furnished
efficiently via the new condensation method. Thus, when treated with catalytic
amounts of Au(I) complex, the conjugation between the anomeric OH of 1314 and 4
proceeded without any incident to deliver 21. Because 13 was used directly as mixture
of anomers, the conjugation product 21 was obtained also as a mixture of a pair of
diastereoisomers with the αꢀisomer predominating (85%, α/β = 6 : 1). Attempt to
improve the βꢀselectivity of the anomeric OH nucleophiles via the convenient
protectingꢀgroup effect instead of the laborious acquisition of pure βꢀhemiacetal OH,
4,6ꢀOꢀbenzylidenyl protecting group was invoked, and hemiacetal 1415 equipped with
4,6ꢀOꢀbenzylidenyl group was checked as nucleophile subsequently. Indeed, under the
identical conditions, the reaction between 14 and 4 afforded 22 with an enhanced β/α
ratio of 1 : 1.25 (82%), pointing out a new and convenient direction for the
stereoselective conjugation of hemiacetal nucleophiles. Of particular interest is that
even the highly stericallyꢀdemanding tertiary alcohol 15 could still afford the
conjugating product 23 with excellent yield when reacted with 4 under the catalysis of
Au(I) complex, which further demonstrated the conjugating potential of the new
derivatization protocol.
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The effect of the Cꢀ4 configuration of (E)ꢀPPTꢀ4ꢀOꢀorthoꢀcyclopropylethynylbenzote
on the coupling potential was subsequently evaluated (Scheme 2). Thus, the
condensation of EPPTꢀ4ꢀOꢀorthoꢀcyclopropylethynylbenzoate 5 with alcoholic
nucleophiles 8, 9, 10, and 15, the representatives of primary, secondary, and tertiary
alcohols, were conducted, and good to excellent results were obtained (89%, 92%,
83%, and 87%, respectively). The yields are comparable to those obtained with 4,
verifying that the new approach enjoys a broad substrate scope in terms of the lignan
partner. It also should be pointed out that influenced by the αꢀoriented E phenyl ring,
irrespective of the Cꢀ4 configuration of orthoꢀcyclopropylethynylbenzoates, both 4
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and 5 afforded the same coupling products.
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Scheme 2. Coupling of 4 and 5 with alcoholic nucleophiles under the catalysis of
Au(I) complex.
As a general (E)ꢀPPT derivatization protocol, the conjugating partners should not be
restricted to alcoholic nucleophiles, other partners including phenol, amine, as well as
carbon nucleophiles should also be encompassed (Scheme 3). Tyrosine methyl ester
248b featuring a highly acidꢀsensitive benzophenone imine group was chosen as a
representative of the highly functionalized phenolic nucleophile. Benefited from the
mild catalysis conditions, the conjugation between 24 and 4 proceeded so efficiently
that 93% yield of product 30 was obtained, which is much higher than that obtained
with EPPT 4ꢀsulfoxide as intermediate.8b Under identical condensation conditions,
another complex phenolic nucleophile estrone 25 could also couple with 4 smoothly
to furnish 31 stereoselectively (83%). Amination of the Cꢀ4 position of (E)ꢀPPT
derivatives is an extensively investigated (E)ꢀPPT modification reaction.8d The
involvement of the highly reactive and difficultꢀhandling EPPT 4ꢀBr and I
intermediates in precedented methods made the efficiency of amination modifications
far from satisfactory. In sharp contrast, as an ideal conjugating intermediate,
EꢀPPTꢀ4ꢀOꢀorthoꢀalkynyl benzoate 4 delivered the NPF analogue 32 in almost
quantitative yield when reacted with 4ꢀfluoroaniline 26.8b The decreased
nucleophilicity imposed by the highly electronwithdrawing and paraꢀlocated F atom
comprised the stereoselectivity of the condensation, and a mixture of epimers favoring
the EPPT derivative was isolated (EPPT/PPT = 5 : 1). The Cꢀ4 modification with
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carbon nucleophiles has been sparsely studied before, and allylation with
allyltrimethylsilane as carbon nucleophile is the only known carbonꢀsubstituent
modification reaction regarding (E)ꢀPPTs.8b To check the application of the present
method in the synthesis of carbonꢀsubstituent modified (E)ꢀPPT derivatives,
allyltrimethylsilane 27 was investigated to conjugate with 4. Again, the desired
allylated EPPT 33 was isolated in a good 84% yield. Replacing 27 with the more
reactive and widely accessible silyl enol ethers 28 and 29 to react with 4 led to the
formation of conjugating products 34 and 36 stereoselectively (the N values of 27 and
28 are 1.8, 6.2, respectively), paving the way for the easy accessibility of
carbonꢀsubstituent modified (E)ꢀPPTs (82% and 100%, respectively).16 Nevertheless,
the stereoselectivity of the carbonꢀnucleophiles is highly substrateꢀsensitive, as
exemplified by the condensation between 28 with 7 which offered 35 as an
inseparable mixture of EPPT and PPT derivatives (5 : 1, favoring the EPPT isomer)
with high combined yield (82%). In view of the fact that EPPTꢀ35 is a key
intermediate for the synthesis of Topꢀ53,6 this protocol provides an alternative and
direct synthetic approach to get this biologically significant compound
(conventionally detour route was adopted).8c The high chemical yields as well as the
good to excellent stereoselectivity qualifies the coupling protocol to be an ideal
approach for the synthesis of carbonꢀsubstitute modified EPPT derivatives.
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Scheme 3. Coupling of 4, 7 with other nucleopihles.
The assignment of the Cꢀ4 configuration of (E)ꢀPPT residues can be easily made by
the J values of Hꢀ4, which are around 8.0 Hz for PPT derivatives (3,4ꢀprotons are anti
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arranged) and 4.0 Hz for EPPT analogues (3,4ꢀprotons are synꢀdisposed). The
chirality of the sugar anomeric positions can be determined according to the coupling
constants of the anomeric protons (for β isomers: J > 7.5 Hz; for α isomers: J < 4.5
Hz). Taking advantages of HꢀH COSY (for the assignment of Hꢀ4) and NOE spectra,
the Cꢀ4 chirality of all carbonꢀnucleophileꢀmodified (E)ꢀPPT derivatives can be
ascertained.19
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To check the synthetic application of the protocol, the synthesis of NKꢀ611 (3) was
conducted subsequently. Compared with etoposide, NKꢀ611 carries a dimethyl amino
group at the glucose moiety. The introduction of an amino group can dramatically
improve the water solubility of NKꢀ611, and consequently the corresponding
pharmaceutical profiles and efficiency. The superior antitumor activity qualifies
NKꢀ611 to be a promising surrogate to etoposide and teniposide and promote it enter
phaseꢀII clinical trial now. The presence of amino group indeed brings about evident
improvement in bioactivity, meanwhile, it also makes the synthesis of NKꢀ611 more
challenging. With classical reverse glycosylation as the key step, known synthetic
approaches toward NKꢀ611 suffer from tedious or low conjugation stereocontrol as
well as unsatisfactory overall efficiency.17 To facilitate the following clinical trials, a
more efficient approach for NKꢀ611 synthesis is highly desired. Leveraging on the
Au(I)ꢀcatalyzed lignan activation protocol, a new and efficient route to NKꢀ611 was
set up.
The synthesis commenced with azidoglucoside 37,18 prepared from glucosamine in 5
steps with 34% overall yield. Ethylidenation of 37 under the effect of DME and TsOH
was followed by dehydrative esterification with AZMBOH to transform 37 to 39 via
intermediate 38 (76%, 2 steps). Removal of the anomeric TBS with HF/pyridine at
low temperature afforded 40, which is ready for the subsequent coupling with lignan
moiety (95%). Under the catalysis of Ph3PAuNTf2, the coupling between 40 and 7
proceeded inefficiently, and only 50% yield of 41 was isolated. Nevertheless, the
stereoselectivity was high and only the β condensation product was obtained.
Replacing Ph3PAuNTf2 with the more reactive Ph3PAuOTf led to a dramatic
enhancement in chemical yield (74%), meanwhile the excellent βꢀselectivity was
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maintained. It also should be pointed out that the originally devised Au(I)ꢀcatalyzed
glycosylation9b could not be applied in this key condensation reaction because
glucosyl donors carrying N3 substitute at their 2 position are prone to afford the
undesired αꢀglycosylation isomers.12b With ample amounts of 41 in hand,
Pd(OH)2ꢀcatalyzed hydrogenation was then adopted to reduce the azido group and
remove the AZMB, Cbz protecting groups simultaneously, delivering 42 in 85% yield.
Finally, reductive amination with 37% formaldehyde solution and NaBH3CN was
applied to incorporate the two methyl groups to NH2 of 42 to complete the synthesis
of NKꢀ611 (3). Fortunately, the spectra of the synthetic sample were proved to be
identical to those reported in literature,17,19 verifying the correctness of the synthetic 3
(Scheme 4). Thanks to the judicious choice of AZMB and Cbz as protecting groups
which can be removed in the same pot as the reduction of N3, with 37 as starting
material the synthetic sequence can be telescoped to 6 steps. Also, benefited from the
high yield and stereoselectivity of the pivotal conjugating step, the overall yield could
reach as high as 38%. The high condensation stereoselectivity as well as the good
overall efficiency further demonstrated the potential of the new protocol in complex
(E)ꢀPPT derivatives synthesis.
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Scheme 4. Synthesis of NKꢀ611 (3).
It is worth mentioning that to secure the desired βꢀselectivity of the condensation
between 40 and 7, neither special cautions nor additional manipulations are required.
Moreover, the 40 involved Au(I)ꢀcatalyzed condensations could tolerate well the
structure variation of the lignan moiety, as exemplified by the conjugation with PPT
orthoꢀcyclopropylethynylbenzoate 4 to afford 43 (89%, Scheme 5).
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Scheme 5. Condensation of 43 with 4.
All applied nucleophiles can be roughly divided into three categories: the hydroxyl
nucleophiles (except for 11), carbonꢀtype nucleophiles, as well as special nucleophiles.
For hydroxyl type of nucleophiles, the stereoselectivity of the condensation with
4ꢀOꢀ(2ꢀcyclopropylethynyl)benzoylꢀ(epi)ꢀpodophyllotoxins is presumably steered by
the SN1 reaction mechanism. Thus, coordination of the gold(I) catalyst to the triple
bond of orthoꢀcyclopropylethynylbenzoate unite elicits the collapse of 4 to generate
pꢀoxygenꢀstabilized benzylic cation species B and isochromenꢀ4ꢀyl gold(I) complex A.
Stereoselectively, constrained by the transꢀfused Dꢀlactone ring, the species B adopt
preferably the 2H1 conformation with the bulky Eꢀring axially occupying the αꢀface of
2
the Cꢀring. The H1 conformer of B favor the attack of nucleophiles from the βꢀface
both stereoelectronically and sterically (route a versus route b), therefore delivering
the EPPT derivatives predominantly regardless of the chirality of the starting
4ꢀOꢀ(2ꢀcyclopropylethynyl)benzoylꢀ(epi)ꢀpodophyllotoxin
(Figure
3).
For
carbonꢀtype nucleophiles such as 27ꢀ29,16 the stereoselectivity of their condensation
with 4ꢀOꢀ(2ꢀcyclopropylethynyl)benzoylꢀ(epi)ꢀpodophyllotoxins is probably jointly
controlled by both SN1 and SN2 reaction mechanisms. In these cases, the chirality of
4ꢀOꢀ(2ꢀcyclopropylethynyl)benzoylꢀ(epi)ꢀpodophyllotoxins has a profound effect on
the chiral outcome of the condensations: with 4ꢀOꢀ(2ꢀcyclopropylethynyl)benzoyl
ꢀpodophyllotoxin as starting material, both SN1 and SN2 substitution processes give
the same EPPT products, and accordingly satisfactory stereoselectivity is obtained
(for
33,
34,
and
36);
on
the
contrary,
for
4ꢀOꢀ(2ꢀcyclopropylethynyl)benzoylꢀepiꢀpodophyllotoxin 7, substitutions via SN1 and
SN2 mechanisms lead to EPPT and PPT derivatives, respectively, thus the
stereocontrol of conjugation is compromised (35). Regarding special nucleophiles 11
and 26, a competitive trapping of B by A is tentatively proposed (Figure 3), which
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will
bring
about
the
in
situ
formation
of
5
6
4ꢀOꢀ(2ꢀcyclopropylethynyl)benzoylꢀepiꢀpodophyllotoxin due to either the extremely
7
8
steric hindrance or the weak basicity. Similar to the cases for the carbonꢀtype
9
nucleophiles,
the
appearance
of
10
11
12
13
14
15
16
17
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4ꢀOꢀ(2ꢀcyclopropylethynyl)benzoylꢀepiꢀpodophyllotoxin will lead to the decrease in
conjugation stereoselectivity (19 and 32).
Hemiacetals 13, 14, and 40 are more challenging substrates, as the
stereoselectivities regarding the lignan (PPT/EPPT) and the sugar residues (α/β)
should be simultaneously controlled to guarantee the coupling efficiency. Although
the condensation via intermediate B could control the PPT/EPPT selectivity,
hemiacetals 13 and 14 used as mixtures of a pair of epimers afforded the coupling
products 21 and 22 non seteroselectively (α/β mixtures of glucosides were obtained).
In sharp contrast, 40 delivered the condensation product 41 and 43 stereoselectively
(βꢀglucosides were obtained) due to the considerable nucleophilitiy difference
between 40α and 40β. The high reactivity of 40β resulted from the loneꢀpair electrons
repulsion exerted by the pyranꢀring oxygen atom20 renders the attack of 40β to B
proceed smoothly to give the desirable product 43 (route c). On the contrary,
influenced by the combined deactivating effects of N3 (F
N
= 0.48)21 and ethylidenyl
3
groups, the similar attack of 40α to B is prohibited (route d). As a result, only the
βꢀcondensation product is formed. In fact, during the condensation, an anomerization
of 40α to 40β takes place to ensure the high stereoselectivity regarding the sugar
subunit, and the pursuit of pure 40β as nucleophile, which is generally a quite difficult
and laborious process, to guarantee the reasonable conjugating stereoselectivity is not
necessary.
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Figure 3. Plausible mechanism for the (E)ꢀPPT orthoꢀcyclopropylethynylbenzoate
involved stereoselective condensation.
Conclusions
To summarize, under the promotion of catalytic amounts of gold(I) complex, (E)ꢀPPT
4ꢀOꢀorthoꢀcyclopropylethynylbenzaotes could react efficiently with a variety of
nucleophiles including alcohols, phenols, aniline, and carbon nucleophiles to furnish
(E)ꢀPPT derivatives with good to excellent yields and stereoselectivity. The new
protocol represents the first catalytically lignanꢀactivationꢀbased (E)ꢀPPT
modification method, and it will dramatically facilitate the accessibility of (E)ꢀPPT
analogues, especially the carbonꢀsubstituent modified (E)ꢀPPT derivatives.
Leveraging on this (E)ꢀPPT modification protocol, the synthetic investigation toward
NKꢀ611 was also conducted, through which the most concise and efficient route
featuring a kinetic anomerization of the hemiacetal OHs in the key condensation step
was established.
Experimental section
Podophyllotoxin 4ꢀOꢀorthoꢀcyclopropylethynylbenzoate (4)
To a solution of podophyllotoxin 1 (3.5 g, 8.5 mmol) and orthoꢀalnynylbenzoic acid
(2.4 g, 12.8 mmol) in dry CH2Cl2 (10 mL) was successively added DMAP (1.6 g, 12.8
o
mmol) and DCC (3.5 g, 17.0 mmol) at 0 C. Then the resultant reaction mixture was
warmed to room temperature, and the stirring was continued for another 2 h, at which
time TLC showed that all starting material disappeared. CH2Cl2 was added to dilute
the reaction mixture and the resulting solution was washed with water and saturated
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brine successively. Evaporation and concentration under reduced pressure to give a
residue which was further purified by silica gel chromatography (PE/EA = 3 : 1) to
25
1
7
afford 4 (4.8 g, 97%) as a white solid: [α]D = ꢀ169.1 (c 1.0, CHCl3); H NMR (400
MHz, CDCl3) δ 7.88 (dd, J = 1.2, 8.0 Hz, 1 H), 7.51ꢀ7.43 (m, 2 H), 7.35 (dt, J = 1.6,
7.6 Hz, 1 H), 6.95 (s, 1 H), 6.57 (s, 1 H), 6.46 (s, 2 H), 6.20 (d, J = 8.0 Hz, 1 H), 5.98
(dd, J = 1.6, 3.6 Hz, 2 H), 4.65 (d, J = 4.0 Hz, 1 H), 4.54 (dd, J = 6.0, 8.8 Hz, 1 H),
4.36 (t, J = 8.8 Hz, 1 H), 3.79 (s, 3 H), 3.77 (s, 6 H), 3.12ꢀ3.06 (m, 1 H), 3.03 (dd, J =
4.0, 14.4 Hz, 1 H), 1.29ꢀ1.24 (m, 1 H), 0.85ꢀ0.79 (m, 2 H), 0.78ꢀ0.72 (m, 2 H); 13C
NMR (100 MHz, CDCl3) δ 173.3, 166.6, 152.2, 147.7, 147.2, 136.6, 134.4, 134.0,
132.0, 131.5, 130.8, 129.4, 128.0, 126.8, 124.1, 109.3, 107.5, 107.1, 101.2, 99.2, 73.9,
73.7, 71.1, 60.3, 55.7, 45.2, 43.4, 38.3, 8.34; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C34H31O9 583.1963; found 583.1968.
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
(epi)ꢀPodophyllotoxin 4ꢀOꢀorthoꢀcyclopropylethynylbenzoate (5)
Similar procedure as that used for the synthesis of 4 was applied to get 5 from 2 (495
25
1
mg, 88%) as a white solid: [α]D = ꢀ50.8 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.89 (dd, J = 1.2, 8.0 Hz, 1 H), 7.49 (dd, J = 1.6, 8.0 Hz, 1 H), 7.45 (td, J =
1.6, 7.2 Hz, 1 H), 7.33 (td, J = 1.6, 8.0 Hz, 1 H), 7.00 (s, 1 H), 6.58 (s, 1 H), 6.46 (d, J
= 3.6 Hz, 1 H), 6.32 (s, 2 H), 6.00 (d, J = 1.2 Hz, 1 H), 5.96 (d, J = 1.6 Hz, 1 H), 4.72
(d, J = 5.2 Hz, 1 H), 4.45 (dd, J = 8.0, 8.8 Hz, 1 H), 4.17 (dd, J = 8.8, 10.8 Hz, 1 H),
3.82 (s, 3 H), 3.76 (s, 6 H), 3.53 (dd, J = 4.8, 14.0 Hz, 1 H), 3.14ꢀ3.07 (m, 1 H),
1.40ꢀ1.36 (m, 1 H), 0.92ꢀ0.89 (m, 2 H), 0.81ꢀ0.73 (m, 2 H); 13C NMR (100 MHz,
CDCl3) δ 174.0, 165.9, 152.3, 148.5, 147.1, 137.0, 134.3 (2 C), 132.6, 131.7, 130.4,
130.2, 127.5, 126.9, 124.1, 109.7, 109.5, 107.8, 101.2, 99.3, 76.8, 74.3, 68.6, 67.4,
60.4, 55.9, 43.6, 41.5, 36.6, 8.54, 8.50; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C34H31O9 583.1963; found 583.1968.
4’ꢀDemethylꢀ4’ꢀOꢀ(benzyloxycarbonyl)
4ꢀOꢀorthoꢀcyclopropylethynyl benzoate (7)
epiꢀpodophyllotoxin
To a solution of 6 (500 mg, 1.25 mmol) in dry CH2Cl2 (6 mL) was added dry Et3N
o
(0.3 mL, 2.2 mmol) and CbzCl (0.27 mL, 1.9 mmol) at 0 C. Then the reaction
mixture was warmed to room temperature, and the stirring was continued for another
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4 h. Diluted with ethyl acetate, and then the resultant mixture was washed with water
band brine successively. Evaporation under reduced pressure to furnish the crude
product which was further purified by silica gel chromatography (PE/EA = 2 : 1) to
give the 4’ꢀOꢀCbzꢀepiꢀpodophyllotoxin intermediate.
10
11
12
13
14
15
16
17
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21
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Subsequently, to a solution of 4’ꢀOꢀCbzꢀepiꢀpodophyllotoxin intermediate (667 mg,
1.25 mmol) and orthoꢀcyclopropylethynylbenzoic acid (516 mg, 1.87 mmol) in dry
CH2Cl2 (4 mL) was added DMAP (229 mg, 1.87 mmol) and DCC (516 mg, 2.5 mmol)
o
successively at 0 C. After the addition was completed, the reaction mixture was
warmed to room temperature, and the stirring was continued for another 3 h. Dilution
with ethyl acetate and resultant mixture was then washed with water, brine
successively. Dried with Na2SO4, then the volatile solvent was removed under
reduced pressure to give the crude product which was then chromatographed (PE/EA
= 4 : 1) to produce 7 (577.6 mg, 66% for 2 steps) as a white solid: [α]D25 = ꢀ66.9 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 2.4, 7.6 Hz, 1 H), 7.49ꢀ7.30 (m,
8 H), 7.01 (s, 1 H), 6.57 (s, 1 H), 6.46 (d, J = 3.6 Hz, 1 H), 6.34 (d, 2 H), 6.01 (d, J =
1.2 Hz, 1 H), 5.97 (d, J = 1.6 Hz, 1 H), 5.27 (s, 2 H), 4.74 (d, J = 5.2 Hz, 1 H), 4.45
(dd, J = 7.6, 8.8 Hz, 1 H), 4.18 (dd, J = 8.8, 10.8 Hz, 1 H), 3.70 (s, 6 H), 3.55 (dd, J =
5.2, 10.4 Hz, 1 H), 3.10ꢀ3.01 (m, 1 H), 1.41ꢀ1.34 (m, 1 H), 0.92ꢀ0.90 (m, 2 H),
0.80ꢀ0.76 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 173.9, 165.9, 152.7, 151.3, 148.6,
147.2, 137.3, 134.7, 134.3, 132.2, 131.7, 130.4, 130.2, 128.1 (3 C), 127.8, 127.6,
126.9, 124.1, 109.8, 109.6, 107.3, 101.3, 99.3, 74.3, 70.0, 68.6, 67.4, 55.9, 43.7, 41.5,
36.6, 8.6, 8.5, ꢀ0.0; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C41H35O11 703.2174;
found 703.2183.
Methyl 2,3,4ꢀtriꢀOꢀbenzoylꢀ6ꢀOꢀepodophyllotoxylꢀαꢀ
To solution of (30 mg, 0.05
2,3,4ꢀtriꢀOꢀbenzoylꢀαꢀ ꢀglucopyranoside 8 (30 mg, 0.06 mmol) in dry CH2Cl2 (2 mL)
D
ꢀglucopyranoside (16)
mmol) and methyl
a
4
D
was added 4Å MS under nitrogen atmosphere. The resulting mixture was stirred at
room temperature for 30 minutes and then Ph3PAuNTf2 (11 mg, 0.015 mmol) was
added. The stirring was continued at room temperature for 4 h (until 4 was consumed
as monitored by TLC). The mixture was filtered, the filtrate was concentrated under
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reduced pressure to yield a residue, which was further purified by silica gel column
chromatography (Petroleum ether/ethyl acetate 3:1) to provide 16 (41 mg, 92%) as a
white solid: [α]D25 = +7.0 (c 1.05, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J
= 1.2, 8.0 Hz, 2 H), 7.87 (dd, J = 1.2, 8.0 Hz, 2 H), 7.78 (dd, J = 1.2, 8.0 Hz, 2 H),
7.47ꢀ7.39 (m, 2 H), 7.34ꢀ7.26 (m, 5 H), 7.21ꢀ7.17 (m, 2 H), 6.68 (s, 1 H), 6.42 (s, 1 H),
6.15 (s, 2 H), 6.09 (t, J = 10.0 Hz, 1 H), 5.87 (d, J = 1.6 Hz, 1 H), 5.81 (d, J = 1.6 Hz,
1 H), 5.51 (t, J = 9.6 Hz, 1 H), 5.20 (dd, J = 3.6, 10.0 Hz, 1 H), 5.14 (d, J = 3.6 Hz, 1
H), 4.50 (dd, J = 8.8, 10.8 Hz, 1 H), 4.47 (d, J = 1.6 Hz, 1 H), 4.36 (d, J = 3.2 Hz, 1
H), 4.34 (t, J = 8.0 Hz, 1 H), 4.12ꢀ4.08 (m, 1 H), 3.82 (dd, J = 2.4, 10.4 Hz, 1 H), 3.70
(s, 3 H), 3.64 (s, 6 H), 3.62 (dd, J = 4.8, 10.4 Hz, 1 H), 3.38 (dd, J = 5.2, 14.0 Hz, 1
H), 3.35 (s, 3 H), 2.85ꢀ2.76 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 173.9, 164.7 (2
C), 164.3, 151.4, 147.4, 145.5, 136.1, 134.4, 132.5, 132.3, 132.0, 131.5, 128.8, 128.7,
128.6, 128.1, 127.9, 127.8, 127.4 (2 C), 127.3, 127.2, 110.0, 108.4, 107.2, 100.4, 96.0,
74.4, 70.9, 69.3, 68.6, 68.0, 66.5, 59.6, 55.2, 54.6, 43.0, 39.9, 37.3; HRMS (ESIꢀTOF)
m/z: [MꢀH]+ calcd for C50H47O16 903.2870; found 903.2863.
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
The condensation of 5 and 8 under identical conditions also afforded 16 (39 mg,
89%).
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀepodophyllotoxylꢀαꢀ
Similar procedure as that used for the synthesis of 16 was subjected to 4 and 9 to
Dꢀglucopyranoside (17)
25
1
deliver 17 (41 mg, 95%) as a light yellow solid: [α]D = ꢀ19.8 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.40ꢀ7.23 (m, 15 H), 6.81 (s, 1 H), 6.52 (s, 1 H), 6.22 (s, 2
H), 6.00 (d, J = 1.6 Hz, 1 H), 5.95 (d, J = 1.6 Hz, 1 H), 5.01 (d, J = 10.8 Hz, 1 H),
4.90 (d, J = 11.2 Hz, 1 H), 4.83 (d, J = 12.0 Hz, 1 H), 4.82 (d, J = 10.4 Hz, 1 H), 4.68
(d, J = 12.4 Hz, 1 H), 4.57 (d, J = 4.4 Hz, 1 H), 4.56 (d, J = 1.2 Hz, 1 H), 4.55 (d, J =
11.2 Hz, 1 H), 4.35 (d, J = 3.2 Hz, 1 H), 4.32ꢀ4.24 (m, 2 H), 4.01 (t, J = 9.2 Hz, 1 H),
3.79 (s, 3 H), 3.75 (m, 1 H), 3.73 (s, 6 H), 3.71 (m, 1 H), 3.61ꢀ3.51 (m, 1 H),
3.43ꢀ3.31 (m, 2 H), 3.34 (s, 3 H), 2.85ꢀ2.76 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ
175.0, 152.5, 148.4, 146.7, 138.6, 138.2, 138.1, 137.2, 135.4, 132.5, 129.0, 128.5 (2
C), 128.4, 128.2, 128.1 (2 C), 128.0 (3 C), 127.9, 127.7, 127.6, 110.7, 109.8, 108.3,
101.5, 98.0, 82.0, 80.2, 77.8, 75.8, 75.4, 74.9, 73.5, 70.6, 69.5, 67.5, 60.8, 56.3, 55.3,
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43.9, 41.0, 38.5; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C50H52O13Na 883.3300;
3
4
5
6
found 883.3319.
7
8
The condensation between 5 and 9 under identical conditions afforded 17 (40 mg,
9
92%).
10
11
12
13
14
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16
17
18
19
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Methyl 2,3ꢀdiꢀOꢀbenzoylꢀ4ꢀOꢀepodophyllotoxylꢀ6ꢀOꢀbenzylꢀαꢀ
Dꢀglucopyranoside
(18)
Similar procedure as that applied for the synthesis of 16 was adopted for the
25
conjugation between 4 and 10 to afford 18 (41.2 mg, 93%) as a white solid: [α]D
=
ꢀ25.3 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 2 H), 7.60 (dd, J = 1.2,
8.0 Hz, 2 H), 7.48ꢀ7.40 (m, 4 H), 7.37ꢀ7.24 (m, 7 H), 6.81 (s, 1 H), 6.03 (s, 2 H), 5.86
(d, J = 1.2, 1 H), 5.82 (d, J = 1.6 Hz, 1 H), 5.69 (dd, J = 9.2, 10.0 Hz, 1 H), 5.60 (s, 1
H), 5.25 (dd, J = 3.6, 10.0 Hz, 1 H), 5.15 (d, J = 4.0 Hz, 1 H), 5.02 (d, J = 12.0 Hz, 1
H), 4.55 (d, J = 12.0 Hz, 1 H), 4.34 (t, J = 9.6 Hz, 1 H), 4.18ꢀ4.10 (m, 3 H), 3.90ꢀ3.87
(m, 1 H), 3.80ꢀ3.73 (m, 2 H), 3.77 (s, 3 H), 3.72 (s, 6 H), 3.68 (dd, J = 2.4, 11.2 Hz, 1
H), 3.44 (dd, J = 5.6, 14.0 Hz, 1 H), 3.41 (s, 3 H), 2.41ꢀ2.32 (m, 1 H); 13C NMR (100
MHz, CDCl3) δ 175.1, 165.9, 165.2, 152.3, 147.9, 146.1, 137.1, 136.8, 135.9, 133.3,
132.8, 132.3, 129.8, 129.2 (2 C), 129.1, 129.0, 128.6, 128.5, 128.4, 127.9, 111.0,
109.5, 108.4, 101.2, 97.2, 74.2, 71.8, 71.4, 71.3, 71.1, 70.3, 67.2, 66.8, 60.7, 56.3,
55.5, 43.7, 39.6, 38.1; HRMS (ESIꢀTOF) m/z: [M+NH4]+ calcd for C50H52O15N
906.3332; found 906.3337.
Compound 5 could also reacted with 10 efficiently to afford 18 (36.8 mg, 83%) under
identical reaction conditions.
1,2;5,6ꢀDiisopropylideneꢀ3ꢀOꢀpotophyllotoxylꢀαꢀ
D
ꢀglucofuranoside (PPTꢀ19) and
ꢀglucofuranoside (EPPTꢀ19)
1,2;5,6ꢀDiisopropylideneꢀ3ꢀOꢀepotophyllotoxylꢀαꢀ
D
The condensation of 4 and 11 under identical conditions as those applied for the
synthesis of 16 to afforded PPTꢀ19 (31.3 mg, 48%) and EPPTꢀ19 (19.7 mg, 30%).
For the less polar PPTꢀ19: [α]D25 = ꢀ80.3 (c 1.26, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 6.87 (s, 1 H), 6.54 (s, 1 H), 6.25 (s, 2 H), 6.00 (d, J = 1.6 Hz, 1 H), 5.99 (d, J = 3.6
Hz, 1 H), 5.98 (d, J = 3.6 Hz, 1 H), 4.60 (d, J = 4.8 Hz, 1 H), 4.59 (d, J = 3.6 Hz, 1 H),
4.54 (d, J = 3.2 Hz, 1 H), 4.44 (dd, J = 8.4, 10.8 Hz, 1 H), 4.36 (t, J = 8.0 Hz, 1 H),
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4.27ꢀ4.22 (m, 2 H), 3.85 (dd, J = 2.0, 10.0 Hz, 1 H), 3.80 (s, 3 H), 3.74 (s, 6 H),
3.72ꢀ3.61 (m, 2 H), 3.45 (dd, J = 5.2, 14.0 Hz, 1 H), 2.91ꢀ2.82 (m, 1 H); 1.49 (s, 3 H),
1.39 (s, 3 H), 1.36 (s, 3 H), 1.33 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 175.1, 152.5,
148.5, 146.7, 137.2, 135.5, 132.4, 129.0, 112.3, 110.8, 109.7, 108.3, 106.4, 101.5,
101.1, 84.0, 79.5, 75.0 (2 C), 71.9, 70.7, 67.5, 60.7, 56.3, 43.9, 40.9, 38.4, 27.2, 26.5,
24.0; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C34H41O13 657.2542; found 657.2537.
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
25
For the polar EPPTꢀ19: [α]D = ꢀ58.2 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ
6.98 (s, 1 H), 6.55 (s, 1 H), 6.22 (s, 2 H), 6.00 (d, J = 3.6 Hz, 1 H), 5.98 (d, J = 1.2 Hz,
1 H), 5.90 (d, J = 4.0 Hz, 1 H), 4.73 (d, J = 2.8 Hz, 1 H), 4.61 (d, J = 5.6 Hz, 1 H),
4.57 (d, J = 3.6 Hz, 1 H), 4.39 (t, J = 8.0 Hz, 1 H), 4.31 (dd, J = 8.4, 10.8 Hz, 1 H),
4.21 (d, J = 2.8 Hz, 1 H), 4.13ꢀ4.06 (m, 2 H), 4.03 (dd, J = 5.6, 8.4 Hz, 1 H), 3.95 (dd,
J = 4.4, 5.2 Hz, 1 H), 3.80 (s, 3 H), 3.74 (s, 6 H), 3.52 (dd, J = 5.6, 14.0 Hz, 1 H),
3.00ꢀ2.91 (m, 1 H), 1.52 (s, 3 H), 1.35 (s, 3 H), 1.32 (s, 3 H), 1.26 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 174.7, 152.6, 148.6, 146.7, 137.3, 135.4, 133.0, 128.0, 112.2,
111.0, 110.0, 109.0, 108.3, 105.3, 101.5, 82.8, 81.3, 80.0, 73.3, 72.3, 67.4, 67.2, 60.7,
56.3, 44.0, 40.6, 38.4, 26.8, 26.6, 26.3, 25.1, 24.7; HRMS (ESIꢀTOF) m/z: [M+H]+
calcd for C34H41O13 657.2542; found 657.2532.
3ꢀOꢀePodophyllotoxylꢀcholesterol (20)
Similar procedure as that used for the synthesis of 16 was adopted to conduct the
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condensation between 4 and 12 to furnish 20 (54.6 mg, 100%) as a white solid: [α]D
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= ꢀ56.8 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 6.84 (s, 1 H), 6.51 (s, 1 H),
6.27 (s, 2 H), 6.00 (d, J = 1.2 Hz, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 5.39 (d, J = 5.2 Hz,
1 H), 4.65 (d, J = 3.2 Hz, 1 H), 4.60 (d, J = 5.2 Hz, 1 H), 4.40 (t, J = 8.0 Hz, 1 H),
4.26 (dd, J = 8.4, 11.2 Hz, 1 H), 3.80 (s, 3 H), 3.73 (s, 6 H), 3.39 (dd, J = 5.2, 14.0 Hz,
1 H), 3.28ꢀ3.22 (m, 1 H), 2.88ꢀ2.80 (m, 1 H), 2.38ꢀ2.26 (m, 2 H), 2.07ꢀ1.79 (m, 5 H),
1.68ꢀ1.42 (m, 8 H), 1.37ꢀ1.22 (m, 5 H), 1.01 (s, 3 H), 0.93 (d, J = 6.4 Hz, 3 H), 0.88
(d, J = 1.6 Hz, 3 H), 0.86 (d, J = 2.0 Hz, 3 H), 0.68 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 175.0, 152.6, 148.2, 147.1, 140.3, 137.2, 135.3, 132.2, 130.5, 122.2, 110.4,
109.3, 108.3, 101.4, 79.2, 71.3, 67.8, 60.7, 56.8, 56.3, 56.2, 50.2, 43.9, 42.4, 41.2,
39.8, 39.5, 39.4, 38.5, 37.2, 36.9, 36.2, 35.8, 31.9 (2 C), 29.7, 29.4, 28.2, 28.0, 24.3,
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23.8, 22.8, 22.6, 21.1, 19.4, 18.7, 11.9; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C49H67O8 783.4830; found 783.4824.
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epiꢀPodophyllotoxin 2ꢀOꢀbenzoylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀα/βꢀDꢀglucopyranoside (21)
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Similar procedure as that used for the synthesis of 16 was applied for the coupling
between 4 and 13 to produce 21 as a mixture of α/β isomers (81 mg, 85%) as a white
solid. An aliquot of pure αꢀisomer was obtained by silica gel chromatography for
detailed characterization: [α]D25 = +54.2 (c 0.63, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.00 (dd, J = 1.2, 8.0 Hz, 2 H), 7.62ꢀ7.57 (m, 1 H), 7.48 (t, J = 7.6 Hz, 2 H),
7.42ꢀ7.31 (m, 5 H), 7.27ꢀ7.25 (m, 3 H), 7.20ꢀ7.07 (m, 7 H), 6.49 (s, 1 H), 6.21 (s, 2 H),
5.96 (d, J = 1.6 Hz, 1 H), 5.92 (d, J = 1.2 Hz, 1 H), 5.34 (d, J = 4.0 Hz, 1 H), 5.28 (dd,
J = 3.6, 10.0 Hz, 1 H), 4.80ꢀ4.70 (m, 5 H), 4.63 (d, J = 5.2 Hz, 1 H), 4.59 (d, J = 12.0
Hz, 1 H), 4.46 (d, J = 10.4 Hz, 1 H), 4.23 (dd, J = 4.4, 10.8 Hz, 1 H), 4.08 (t, J = 9.6
Hz, 1 H), 4.01 (t, J = J = 8.0 Hz, 1 H), 3.84 (t, J = 9.2 Hz, 1 H), 3.79 (s, 3 H), 3.71 (s,
6 H), 3.68ꢀ3.60 (m, 3 H), 3.45 (dd, J = 5.6, 14.0 Hz, 1 H), 2.86ꢀ2.77 (m, 1 H); 13C
NMR (100 MHz, CDCl3) δ 174.6, 165.7, 152.6, 148.5, 147.0, 137.9 (2 C), 137.6,
137.3, 135.1, 133.8, 132.5, 129.6, 129.0, 128.9, 128.8, 128.5, 128.4, 128.3, 128.2,
128.0, 127.9, 127.8 (2 C), 127.7, 110.6, 110.3, 108.3, 101.5, 98.6, 79.7, 77.9, 76.0,
75.6, 75.5, 73.8, 73.7, 71.4, 68.0, 66.6, 60.7, 56.3, 43.9, 40.9, 38.3; HRMS (ESIꢀTOF)
m/z: [M+Cl]ꢀ calcd for C56H54O14Cl 985.3197; found 985.3226.
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epiꢀPodophyllotoxin
2ꢀOꢀbenzoylꢀ3ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀα/βꢀDꢀglucopyranoside (22)
Identical conditions to those used for the synthesis of 16 were applied to the
condensation of 4 and 14 to produce 22 as a mixture of α/β isomers (70.3 mg, 82%) as
a white solid: [α]D25 = +32.9 (c 0.87, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.99 (dd,
J = 1.2, 8.4 Hz, 2 H), 7.79 (dd, J = 1.2, 8.4 Hz, 1.6 H), 7.64ꢀ7.36 (m, 14.4 H),
7.23ꢀ7.09 (m, 9 H), 6.94 (s, 1 H), 6.66 (s, 0.8 H), 6.52 (s, 1 H), 6.27 (s, 0.8 H), 6.21 (s,
2 H), 6.13 (s, 1.6 H), 5.984 (d, J = 1.6 Hz, 1 H), 5.976 (d, J = 1.2 Hz, 1 H), 5.87 (d, J
= 1.6 Hz, 0.8 H), 5.69 (d, J = 1.6 Hz, 0.8 H), 5.64 (s, 0.8 H), 5.60 (s, 1 H), 5.40 (d, J =
3.6 Hz, 1 H), 5.26 (dd, J = 7.2, 9.2 Hz, 1 H), 5.25 (dd, J = 4.0, 9.2 Hz, 0.8 H),
4.89ꢀ4.80 (m, 3 H), 4.75ꢀ4.69 (m, 2.8 H), 4.66 (d, J = 5.2 Hz, 1 H), 4.47ꢀ4.39 (m, 1.6
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H), 4.32 (d, J = 5.2 Hz, 0.8 H), 4.26 (t, J = 8.0 Hz, 0.8 H), 4.20ꢀ4.06 (m, 3 H), 3.97 (t,
J = 8.0 Hz, 1 H), 3.91ꢀ3.79 (m, 4 H), 3.78 (s, 3 H), 3.76 (s, 2.4 H), 3.71 (s, 6 H), 3.69
(s, 4.8 H), 3.58ꢀ3.50 (m, 1 H), 3.42 (dd, J = 5.2, 14.0 Hz, 1 H), 3.16 (dd, J = 5.6, 14.0
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Hz, 0.8 H), 2.86ꢀ2.76 (m, 1.8 H); C NMR (100 MHz, CDCl3) δ 174.5 (2 C), 165.8,
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164.9, 152.6, 152.5, 148.6, 148.4, 146.9, 146.6, 137.9, 137.8, 137.3, 137.2, 137.1,
137.0, 135.2, 135.1, 133.9, 132.9, 132.6, 129.7, 129.6, 129.5, 129.2, 129.1, 128.8 (2
C), 128.3 (3 C), 128.2 (2 C), 128.0, 127.9, 127.8, 127.7, 127.6, 126.0, 125.9, 110.8,
110.5, 109.9, 108.7, 108.3, 108.2, 101.6, 101.4, 101.3 (2 C), 100.0, 99.1, 82.2, 81.7,
75.4, 74.8, 73.9, 73.8, 73.4, 68.6, 68.5, 67.6, 66.5, 66.4, 63.1, 60.7 (2 C), 56.3, 43.9,
43.7, 40.8, 40.7, 38.2, 37.6; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C49H47O14
859.2960; found 859.2948.
4ꢀOꢀAdamantanylꢀepiꢀpodophyllotoxin (23)
Following the similar procedure as that used for the synthesis of 16, condensation
between 4 and 15 afforded 23 (44.4 mg, 81%) as a white solid: [α]D25 = ꢀ53.2 (c 1.26,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.96 (s, 1 H), 6.48 (s, 1 H), 6.25 (s, 2 H), 5.98
(d, J = 1.6 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 4.93 (d, J = 3.6 Hz, 1 H), 4.59 (d, J =
5.6 Hz, 1 H), 4.38 (dd, J = 8.0, 10.8 Hz, 1 H), 4.28 (t, J = 8.0 Hz, 1 H), 3.80 (s, 3 H),
3.74 (s, 6 H), 3.41 (dd, J = 5.2, 13.6 Hz, 1 H), 2.84ꢀ2.75 (m, 1 H), 2.22 (bs, 3 H), 1.86
(s, 6 H), 1.71 (q, J = 12.0 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 175.3, 152.5,
147.7, 146.9, 137.2, 135.6, 132.6, 131.9, 110.4, 109.6, 108.4, 101.3, 74.7, 69.0, 64.8,
60.7, 56.3, 43.9, 43.4, 41.1, 38.5, 36.2, 30.8; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C32H37O8 549.2483; found 549.2480.
Compound 5 could also react with 15 under identical conditions to afford 23 in a 87%
yield.
Methyl NꢀdiphenylmethyleneꢀL
ꢀ(4ꢀOꢀepotophyllotoxyphenyl)ꢀalaninate (30)
Under identical conditions as those applied in the synthesis of 16, conjugation
between 4 and 24 proceeded fluently to generate 30 (70.2 mg, 93%) as a white solid:
[α]D25 = ꢀ124.0 (c 1.26, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.8 Hz, 2
H), 7.42ꢀ7.29 (m, 6 H), 7.02 (d, J = 8.4 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 6.70 (d, J
= 7.2 Hz, 2 H), 6.64 (s, 1 H), 6.57 (s, 1 H), 6.30 (s, 2 H), 5.96 (d, J = 1.2 Hz, 1 H),
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5.92 (d, J = 1.2 Hz, 1 H), 5.40 (d, J = 3.6 Hz, 1 H), 4.69 (d, J = 5.2 Hz, 1 H), 4.35 (t, J
= 8.0 Hz, 1 H), 4.28 (dd, J = 4.4, 9.2 Hz, 1 H), 4.13 (dd, J = 8.4, 10.8 Hz, 1 H), 3.81
(s, 3 H), 3.74 (s, 9 H), 3.46 (dd, J = 5.2, 14.0 Hz, 1 H), 3.27 (dd, J = 4.4, 13.6 Hz, 1
H), 3.20 (m, 1 H), 3.08ꢀ3.00 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 174.5, 172.2,
170.9, 157.0, 152.7, 148.8, 147.2, 139.3, 137.3, 136.0, 134.8, 132.4, 132.2, 131.7,
131.3, 130.4, 130.0, 128.8 (2 C), 128.6, 128.3, 128.2, 128.1, 127.6, 115.7, 110.2,
109.3, 108.2, 101.6, 73.4, 67.5, 67.3, 60.8, 56.3, 52.3, 43.8, 41.6, 38.9, 38.1; HRMS
(ESIꢀTOF) m/z: [M+Na]+ calcd for C45H41NO10Na 778.2623; found 778.26218.
3ꢀOꢀePodophyllotoxyl estrone (31)
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The similar procedure as that adopted for the synthesis of 16 was used to produce 31
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via the coupling of 4 and 25 (55.3 mg, 83%) as a white solid: [α]D = ꢀ42.2 (c 1.1,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 7.6 Hz, 1 H), 6.76ꢀ6.68 (m, 3 H),
6.58 (s, 1 H), 6.32 (s, 2 H), 5.98 (d, J = 1.6 Hz, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 5.47 (d,
J = 3.6 Hz, 1 H), 4.70 (d, J = 4.8 Hz, 1 H), 4.35 (t, J = 8.0 Hz, 1 H), 4.16 (dd, J = 8.4,
10.8 Hz, 1 H), 3.81 (s, 3 H), 3.76 (s, 6 H), 3.48 (dd, J = 4.8, 14.0 Hz, 1 H), 3.10ꢀ3.03
(m, 1 H), 2.92ꢀ2.88 (m, 2 H), 2.55 (dd, J = 8.8, 18.8 Hz, 1 H), 2.43ꢀ2.38 (m, 1 H),
2.28 (m, 1 H), 2.18ꢀ1.96 (m, 4 H), 1.69ꢀ1.41 (m, 6 H), 0.93 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 174.6, 156.4, 152.7, 148.7, 147.2, 138.4, 137.3, 134.9, 133.5, 132.3,
129.0, 126.8, 115.9, 112.9, 110.2, 109.4, 108.3, 101.6, 72.7, 67.7, 60.8, 56.3, 50.4,
48.0, 44.0, 43.8, 41.6, 38.2 (2 C), 35.9, 31.6, 29.7, 26.5, 25.9, 21.6, 13.9; HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C40H43O9 667.2902; found 667.2932.
NꢀePodophyllotoxylꢀ4ꢀfluoroaniline and Nꢀpodophyllotoxylꢀ4ꢀfluoroaniline (32)
Upon subjected to the identical conditions to those used for the synthesis of
compound 16, 26 reacted with 4 to afford 32 as a mixture of EPPT and PPT
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derivatives (50.7 mg, 100%, EPPT/PPT = 5 : 1) as a light yellow solid: [α]D
=
ꢀ104.4 (c 0.66, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 0.25 H), 6.96ꢀ6.89 (m,
2.5 H), 6.76 (s, 1 H), 6.71 (dd, J = 4.0, 8.8 Hz, 0.5 H), 6.53 (s, 0.25 H), 6.52 (2 1 H),
6.50 (dd, J = 4.0, 8.8 Hz, 2 H), 6.38 (s, 0.5 H), 6.32 (s, 2 H), 5.96ꢀ5.93 (m, 2.5 H),
4.64ꢀ4.58 (m, 2.5 H), 4.40 (t, J = 8.0 Hz, 1 H), 4.26 (dd, J = 7.2, 8.8 Hz, 0.25 H), 4.01
(dd, J = 8.4, 10.4 Hz, 1.25 H), 3.80 (s, 3.75 H), 3.77 (s, 1.5 H), 3.75 (s, 6 H), 3.18 (dd,
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J = 4.8, 14.0 Hz, 1 H), 3.04ꢀ2.95 (m, 1 H), 2.91 (dd, J = 4.8, 14.0 Hz, 0.25 H),
2.75ꢀ2.65 (m, 0.25 H), 1.26 (s, 1.25 H); 13C NMR (100 MHz, CDCl3) δ 174.7, 174.3,
157.3, 155.0, 152.6 (2 C), 148.3, 147.7, 147.6, 143.8, 137.5, 137.3, 135.7, 135.1,
131.7, 131.5, 130.6, 129.0, 128.2, 125.3, 116.3, 116.2, 116.1, 116.0, 113.1, 113.0,
110.1, 116.2, 116.1, 116.0, 113.1, 113.0, 110.1, 109.9, 109.1, 108.7, 108.4, 106.9,
101.6, 101.4, 71.2, 68.8, 60.7, 56.4, 56.3, 53.3, 46.4, 44.0, 43.6, 41.8, 38.7; HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C28H26FNO7 508.1766; found 508.1762.
4ꢀDeoxyꢀ4ꢀallylꢀepiꢀpodophyllotoxin (33)
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Similar procedure as that used for the synthesis of 16 was adopted to get 33 (37 mg,
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84%) as a white solid: [α]D = ꢀ66.7 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
6.73 (s, 1 H), 6.47 (s, 1 H), 6.29 (s, 2 H), 5.95 (d, J = 1.2 Hz, 1 H), 5.94 (d, J = 1.2 Hz,
1 H), 5.84ꢀ5.78 (m, 1 H), 5.16ꢀ5.10 (m, 2 H), 4.57 (d, J = 5.2 Hz, 1 H), 4.28ꢀ4.25 (m,
2 H), 3.80 (s, 3 H), 3.74 (s, 6 H), 3.31ꢀ3.26 (m, 1 H), 3.10 (dd, J = 5.2, 14.0 Hz, 1 H),
3.02ꢀ2.94 (m, 1 H), 2.62ꢀ2.54 (m, 1 H), 2.46ꢀ2.39 (m, 1 H); 13C NMR (100 MHz,
CDCl3) δ 175.0, 152.4, 147.1, 146.9, 137.1, 136.7, 136.1, 133.1, 130.9, 116.9, 110.1,
108.7, 108.4, 101.2, 69.0, 60.7, 56.2, 44.1, 42.3, 38.5, 37.7, 36.2; HRMS (ESIꢀTOF)
m/z: [M+H]+ calcd for C25H27O7 439.1751; found439.1747.
4ꢀDeoxyꢀ4ꢀ(2ꢀformylethyl)ꢀepiꢀpodophyllotoxin (34)
Similar procedure as that used for the synthesis of 16 was adopted to get 34 (37 mg,
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82%) as a white solid: [α]D = ꢀ55.5 (c 0.64, CHCl3); 1H NMR (400 MHz, CDCl3) δ
9.88 (s, 1 H), 6.63 (s 1 H), 6.47 (s, 1 H), 6.29 (s, 2 H), 5.96 (d, J = 1.2 Hz, 1 H), 5.94
(d, J = 1.6 Hz, 1 H), 4.57 (d, J = 5.2 Hz, 1 H), 4.33 (dd, J = 7.6, 9.6 Hz, 1 H),
3.87ꢀ3.84 (m, 1 H), 3.80 (s, 3 H), 3.75 (s, 6 H), 3.62 (dd, J = 9.2, 11.2 Hz, 1 H),
3.06ꢀ2.99 (m, 2 H), 2.85ꢀ2.77 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 199.8, 174.5,
152.5, 147.5, 147.2, 137.2, 135.6, 132.3, 131.0, 110.2, 108.4, 101.4, 69.7, 60.8, 56.2,
48.3, 44.0, 41.8, 35.0, 32.7; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C24H25O8
441.1544; found 441.15467.
4’ꢀDemethylꢀ4’ꢀOꢀ(benzyloxycarbonyl)ꢀ4ꢀdeoxyꢀ4ꢀ(2ꢀformylethyl)ꢀ(epi)ꢀpodophyl
lotoxin (35)
Similar procedure as that used for the synthesis of 16 was adopted to get 35 (23 mg,
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82%) as an inseparable mixture of EPPTꢀ35 and PPTꢀ35 (5 : 1) as a white solid: [α]D
= ꢀ80.2 (c 0.77, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1.2 H), 7.43ꢀ7.33 (m,
6 H), 6.74 (s, 0.2 H), 6.62 (s, 1 H), 6.54 (s, 0.2 H), 6.46 (s, 1 H), 6.45 (s, 0.2 H), 6.31
(s, 2 H), 5.97 (d, J = 1.2 Hz, 0.2 H), 5.96ꢀ5.94 (m, 2 H), 5.26 (s, 0.4 H), 5.256 (s, 2 H),
4.62 (d, J = 3.6 Hz, 0.2 H), 4.59 (d, J = 4.8 Hz, 1 H), 4.36 (m, 0.2 H), 4.32 (dd, J =
7.2, 9.2 Hz, 1 H), 4.04 (dd, J = 9.2, 10.8 Hz, 0.2 H), 3.85ꢀ3.81 (m, 1.2 H), 3.72 (s, 1.2
H), 3.69 (s, 6 H), 3.61 (dd, J = 9.2, 10.8 Hz, 1 H), 3.05ꢀ2.96 (m, 2.4 H), 2.86ꢀ2.75 (m,
2.4 H); 13C NMR (100 MHz, CDCl3) δ 199.8, 174.4, 153.1, 151.6, 151.5, 147.6, 147.2,
138.6, 135.1, 132.4, 130.7, 128.5, 128.4, 128.2, 110.3, 108.1, 107.9, 101.4, 70.3, 69.7,
56.2, 48.2, 44.0, 41.8, 35.0, 32.7; HRMS (ESIꢀTOF) m/z: [M+NH4]+ calcd for
C31H32O10N 578.2021; found 578.2042.
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4ꢀDeoxyꢀ4ꢀbenzoymethyl epiꢀpodophyllotoxin (36)
Condensation between 4 and 29 was conducted under the identical conditions as those
used for the synthesis of compound 16, delivering 36 (51 mg, 100%) as a white solid:
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[α]D = ꢀ27.9 (c 1.26, CHCl3); H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 1.2, 8.4
Hz, 2 H), 7.63ꢀ7.59 (m, 1 H), 7.51 (t, J = 7.6 Hz, 2 H), 6.70 (d, 1 H), 6.50 (d, 1 H),
6.32 (s, 2 H), 5.96 (d, J = 1.6 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 4.60 (d, J = 4.8 Hz,
1 H), 4.35 (dd, J = 7.6, 9.2 Hz, 1 H), 4.07 (qd, J = 2.0, 6.0 Hz, 1 H), 3.81 (s, 3 H),
3.76 (s, 6 H), 3.60ꢀ3.49 (m, 2 H), 3.24 (dd, J = 2.0, 19.2 Hz, 1 H), 3.14ꢀ3.04 (m, 1 H),
2.94 (dd, J = 4.8, 14.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 198.0, 174.8, 152.5,
147.5, 147.1, 137.1, 135.9, 135.8, 133.9, 133.0, 131.1, 128.9, 128.0, 110.2, 108.4,
108.3, 101.4, 70.2, 60.8, 56.2, 44.1, 42.9, 41.9, 35.2, 34.2; HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C30H29O8 517.1857; found 517.1851.
tertꢀButyldimethylsily 2ꢀdeoxyꢀ2ꢀazidoꢀ4,6ꢀdiꢀOꢀethylideneꢀβꢀDꢀglucopyranoside
(38)
To a solution of 37 (500 mg, 1.57 mmol) and dimethyl acetal (0.5 mL, 4.71 mmol) in
dry acetonitrile (10 mL) was added TsOH (27 mg, 0.16 mmol). The reaction mixture
was stirred at room temperature for 4 h at which time TLC showed that all starting
material was completely consumed. Ethyl acetate was added to dilute the reaction
mixture, the resulting solution was washed successively with saturated NaHCO3,
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water, and brine, then dried over Na2SO4. Filtration and concentration to yield the
crude product which was further purified by silica gel chromatography (PE/EA = 4 : 1)
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to afford 38 (471 mg, 87%) as a syrup: [α]D = ꢀ7.0 (c 1.26, CHCl3); H NMR (400
MHz, CDCl3) δ 4.60 (q, J = 4.8 Hz, 1 H), 4.45 (d, J = 7.6 Hz, 1 H), 3.98 (dd, J = 5.2,
10.4 Hz, 1 H), 3.43 (d, J = 10.4 Hz, 1 H), 3.38 (d, J = 9.2 Hz, 1 H), 3.22 (t, J = 9.2 Hz,
1 H), 3.15ꢀ3.09 (m, 3 H), 1.23 (d, J = 5.2 Hz, 3 H), 0.77 (s, 9 H), 0.00 (s, 3 H), ꢀ.002
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ 99.8, 97.5, 80.2, 71.5, 69.1, 68.0, 66.3, 25.5,
20.2, 17.9, ꢀ4.4, ꢀ5.2; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C14H28N3O5Si
346.1793; found 346.1796.
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tertꢀButyldimethylsily
2ꢀdeoxyꢀ2ꢀazidoꢀ4,6ꢀdiꢀOꢀethylideneꢀ3ꢀOꢀ(2ꢀazidomethyl)benzoylꢀβꢀDꢀglucopyran
oside (39)
To a solution of 38 (56 mg, 0.16 mmol) and (2ꢀazidomethyl)benzoic acid (57 mg, 0.32
mmol) in dry CH2Cl2 (3 mL) was added DMAP (39 mg, 0.32 mmol) and DCC (66 mg,
o
0.32 mmol) successively at 0 C. Then the reaction mixture was warmed to room
temperature and was stirred at the same temperature for 4 h. Dilution with ethyl
acetate was followed by washing with water and brine successively. Dried over
Na2SO4 and concentrated under reduced pressure to give the crude product which was
further purified by silica gel chromatography (PE/EA = 6 : 1) to deliver 39 (71 mg,
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88%) as a syrup: [α]D = ꢀ21.3 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.84
(dd, J = 1.6, 8.0 Hz, 1 H), 7.43 (td, J = 1.2, 7.6 Hz, 1 H), 7.36 (dd, J = 1.6, 8.0 Hz, 1
H), 7.28 (td, J = 1.6, 7.6 Hz, 1 H), 5.10 (t, J = 10.0 Hz, 1 H), 4.67ꢀ4.56 (m, 2 H), 4.52
(q, J = 5.2 Hz, 1 H), 4.00 (dd, J = 4.8, 10.4 Hz, 1 H), 3.45ꢀ3.32 (m, 3 H), 3.26ꢀ3.19 (m,
13
1 H), 1.13 (d, J = 5.2 Hz, 3 H), 0.76 (s, 9 H), 0.00 (s, 3 H), ꢀ0.01 (s, 3 H); C NMR
(100 MHz, CDCl3) δ 165.6, 137.3, 132.9, 130.8, 129.8, 128.7, 128.2, 99.8, 97.7, 78.4,
71.8, 68.0, 67.2, 66.6, 53.5, 52.9, 25.5, 20.3, 17.9, ꢀ4.4, ꢀ5.2; HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C22H33N6O6Si 505.2225; found 505.2227.
2ꢀDeoxyꢀ2ꢀazidoꢀ4,6ꢀdiꢀOꢀethylideneꢀ3ꢀOꢀ(2ꢀazidomethyl)benzoyl
ꢀDꢀglucopyranose (40)
To a solution of 39 (128.4 mg, 0.26 mmol) in dry pyridine (2 mL) was added
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HF/pyridine (0.32 mL, 3.57 mmol) dropwise at 0 C. The resultant mixture was
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stirred at the same temperature for 3 h, at which time TLC showed that all starting
material disappeared. Dilution with ethyl acetate was followed by washing with water,
1N HCl, aqueous saturated NaHCO3, and brine successively. The organic phase was
dried over Na2SO4, and then filtered. Evaporation to remove volatile solvent gave the
crude product which was further purified by silica gel chromatography (PE/EA = 3 : 1)
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to give 40 (94.5 mg, 95%) as a mixture of two epimers as a syrup: [α]D = +16.9 (c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 4.4 Hz, 1 H), 8.00 (d, J = 4.0
Hz, 1 H), 7.62ꢀ7.42 (m, 6 H), 5.81 (t, J = 10.0 Hz, 1 H), 5.44 (d, J = 3.2 Hz, 1 H),
5.34 (t, J = 10.0 Hz, 1 H), 4.89 (d. J = 8.0 Hz, 1 H), 4.85ꢀ4.70 (m, 6 H), 4.23 (dd, J =
4.4, 10.4 Hz, 1 H), 4.17ꢀ4.10 (m, 2 H), 3.63ꢀ3.45 (m, 6 H), 3.44 (dd, J = 3.6, 10.4 Hz,
1 H), 1.34 (d, J = 4.8 Hz, 3 H), 1.32 (d, J = 4.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ 165.9 (2 C), 165.7 (2 C), 137.3, 137.2, 133.0, 132.9, 130.9, 129.9, 129.8, 128.8,
128.6, 128.2 (2 C), 100.0, 99.9, 96.8, 93.2 (2 C), 79.1, 78.3, 72.0 (2 C), 69.9 (2 C),
68.3, 67.9, 66.6 (2 C), 65.9, 62.8 (2 C), 62.3, 52.9, 52.8, 20.2 (2 C); HRMS
(ESIꢀTOF) m/z: [M+Na]+ calcd for C16H18N6O6Na 413.1180; found 413.1182.
4’ꢀDemethylꢀ4’ꢀOꢀ(benzyloxycarbonyl)
epiꢀpodophyllotoxin
4ꢀOꢀ2’’ꢀdeoxyꢀ2’’ꢀazidoꢀ3’’ꢀOꢀ(azidomethyl)benzoylꢀ4’’,6’’ꢀdiꢀOꢀethylideneꢀβꢀDꢀgl
ucopyranoside (41)
Except for the catalyst, identical conditions to the synthesis of 16 was applied for the
25
reaction between 7 and 40 to furnish 41 (33.6 mg, 74%) as a white solid: [α]D
=
ꢀ17.2 (c 0.53, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 1.6, 8.0 Hz, 1 H),
7.62 (td, J = 1.6, 7.6 Hz, 1 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.46ꢀ7.32 (m, 6 H), 6.83 (s, 1
H), 6.57 (s, 1 H), 6.27 (s, 2 H), 6.03 (d, J = 1.2 Hz, 1 H), 6.01 (d, J = 1.2 Hz, 1 H),
5.29 (t, J = 10.0 Hz, 1 H), 5.26 (s, 2 H), 5.00 (d, J = 3.2 Hz, 1 H), 4.84ꢀ4.70 (m, 4 H),
4.68 (d, J = 5.2 Hz, 1 H), 4.44 (dd, J = 8.8, 10.8 Hz, 1 H), 4.32ꢀ4.23 (m, 2 H), 3.67 (s,
6 H), 3.65ꢀ3.55 (m, 3 H), 3.49ꢀ3.43 (m, 1 H), 3.40 (dd, J = 5.6, 14.0 Hz, 1 H),
13
2.96ꢀ2.88 (m, 1 H), 1.33 (d, J = 5.2 Hz, 3 H); C NMR (100 MHz, CDCl3) δ 174.4,
165.6, 153.1, 151.6, 149.1, 147.3, 138.1, 137.3, 135.1, 133.0, 132.6, 130.8, 129.9,
128.5 (2 C), 128.4, 128.2 (2 C), 127.2, 111.2, 108.8, 107.7, 101.8, 100.5, 100.0, 78.2,
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73.7, 71.6, 70.4, 67.9, 67.4, 66.7, 64.7, 56.2, 52.9, 44.0, 41.0, 37.5, 20.2; HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C45H43N6O15 907.2781; found 907.2791.
4’ꢀDemethylꢀepiꢀpodophyllotoxin
9
4ꢀOꢀ2’’ꢀdeoxyꢀ2’’ꢀaminoꢀ4’’,6’’ꢀdiꢀOꢀethylideneꢀβꢀDꢀglucopyranoside (42)
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To a solution of 41 (20 mg, 0.022 mmol) in MeOH (2 mL) was added Pd(OH)2/C (20
o
mg). After the reaction vessel was immersed in a ꢀ78 C cool bath, the vessel was
evacuated and then refilled with H2 (balloon). The process was repeated for three
times, and then the reaction mixture was warmed to room temperature. The stirring
was continued for 12 h under H2 atmosphere (1 atm). Filtration was followed by
concentration under reduced pressure to afford the crude product which was further
purified by silica gel chromatography (CH2Cl2/MeOH = 20 : 1) to yield 42 (10.9 mg,
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85%) as a white solic: [α]D = ꢀ78.4 (c 0.5, CHCl3); H NMR (400 MHz, C5D5N) δ
7.33 (s, 1 H), 6.81 (s, 1 H), 6.79 (s, 2 H), 5.96 (s, 2 H), 5.71 (s, 1 H), 5.05 (d, J = 4.0
Hz, 1 H), 5.046 (d, J = 7.6 Hz, 1 H), 4.90ꢀ4.86 (m, 2 H), 4.72 (dd, J = 8.8, 10.8 Hz, 1
H), 4.38ꢀ4.33 (m, 2 H), 4.07 (t, J = 9.2 Hz, 1 H), 3.77 (s, 6 H), 3.75ꢀ3.60 (m, 4 H),
3.30ꢀ3.24 (m, 2 H), 1.43 (d, J = 4.8 Hz, 3 H); 13C NMR (100 MHz, C5D5N) δ 175.1,
148.6, 148.4, 147.2, 137.0, 133.3, 130.3, 130.1, 110.4, 109.6 (2 C), 105.0, 101.8, 99.6,
81.9, 74.1, 73.4, 68.4, 68.3, 67.2, 59.0, 56.3, 44.1, 41.7, 38.1, 20.5; HRMS (ESIꢀTOF)
m/z: [M+H]+ calcd for C29H34NO12 588.2076; found 588.2068.
NKꢀ611 (3)
To a solution of 42 (56 mg, 0.095 mmol) in MeOH (1.5 mL) was added sodium
cyanoborohydride (20 mg, 3.34 mmol) and aqueous formaldehyde (37%, 84 µL). The
mixture was stirred at room temperature for 4 h, then concentrated in vacuo. Column
chromatography (CH2Cl2/MeOH = 20 : 1) of the obtained residue on silica gel
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afforded 3 (52 mg, 84%) as a white solid: [α]D = ꢀ32.3 (c 1.26, CHCl3); H NMR
(400 MHz, CDCl3) δ 6.75 (s, 1 H), 6.58 (s, 1 H), 6.22 (s, 2 H), 6.03ꢀ6.02 (m, 2 H),
5.42 (bs, 1 H), 5.01 (d, J = 2.8 Hz, 1 H), 4.89 (d, J = 8.4 Hz, 1 H), 4.80 (q, J = 5.2 Hz,
1 H), 4.66 (d, J = 5.6 Hz, 1 H), 4.40 (dd, J = 8.8, 10.4 Hz, 1 H), 4.28 (t, J = 8.0 Hz, 1
H), 4.21 (dd, J = 4.8, 10.4 Hz, 1 H), 3.76 (s, 6 H), 3.67ꢀ3.59 (m, 2 H), 3.42ꢀ3.30 (m, 3
H), 2.96ꢀ2.87 (m, 1 H), 2.49ꢀ2.44 (m, 1 H), 2.32 (bs, 6 H), 1.42 (d, J = 4.8 Hz, 3 H);
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13C NMR (100 MHz, CDCl3) δ 174.7, 148.8, 147.0, 146.4, 134.2, 133.0, 130.6, 127.5,
111.3, 109.0, 107.8, 101.7, 99.7, 97.8, 80.8, 68.1 (2 C), 67.7, 66.7, 56.5, 43.7, 41.3,
37.4, 20.3; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C31H37NO12Na 638.2208;
found 638.2193.
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epiꢀpodophyllotoxin
4ꢀOꢀ2’’ꢀdeoxyꢀ2’’ꢀazidoꢀ3’’ꢀOꢀ(azidomethyl)benzoylꢀ4’’,6’’ꢀdiꢀOꢀethylideneꢀβꢀDꢀgl
ucopyranoside (43)
Identical conditions to the synthesis of 16 was applied for the reaction between 4 and
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40 to furnish 43 (39.3 mg, 89%) as a white solid: [α]D = ꢀ67.1 (c 0.5, CHCl3); H
NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 1.2, 7.6 Hz, 1 H), 7.62 (td, J = 1.6, 7.6 Hz, 1
H), 7.54 (dd, J = 1.2, 7.6 Hz, 1 H), 7.46 (td, J = 1.6, 7.6 Hz, 1 H), 6.82 (s, 1 H), 6.58
(s, 1 H), 6.24 (s, 2 H), 6.03 (d, J = 1.2 Hz, 1 H), 6.01 (d, J = 1.6 Hz, 1 H), 5.29 (t, J =
9.6 Hz, 1 H), 5.02 (d, J = 2.8 Hz, 1 H), 4.85 (d, J = 7.6 Hz, 1 H), 4.83 (AB, 2 H),
4.74ꢀ4.70 (m, 1 H), 4.66 (d, J = 5.6 Hz, 1 H), 4.44 (dd, J = 8.8, 10.8 Hz, 1 H),
4.32ꢀ4.23 (m, 2 H), 3.80 (s, 3 H), 3.73 (s, 6 H), 3.66ꢀ3.56 (m, 3 H), 3.49ꢀ3.43 (m, 1 H),
3.39 (dd, J = 5.6, 14.4 Hz, 1 H), 3.00ꢀ2.92 (m, 1 H), 1.33 (d, J = 4.8 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 174.5, 165.6, 152.6, 149.1, 147.2, 137.3 (2 C), 135.1,
133.0 (2 C), 130.9, 129.9, 128.5, 128.2, 127.0, 111.1, 108.8, 108.2, 101.7, 100.4,
100.0, 78.2, 73.7, 71.5, 67.9, 67.4, 66.6, 64.7, 60.8, 56.2, 52.9, 43.9, 40.9, 37.6, 20.2;
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C38H39N6O13 787.2570; found 787.2565.
Associated content
The Supporting Information is available free of charge on the ACS Publications
website at DOI:.
Copies of NMR spectra of all new compounds including 2D NMR for 33 and 34
(PDF)
Acknowledgements
This work was financially supported by the Natural Science Foundation of Jiangxi
Province (20161ACB20005) and NSF of China (21372252 and 21572081). The
Starting Foundation for Doctors of Jiangxi Normal University is also highly
appreciated.
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