A convenient one-pot approach to Paclitaxel (Taxol) side chain via 1,3-dipolar cycloaddition of carbonyl ylides and N-benzoylbenzyl imines

Article abstract of DOI:10.1016/j.tetlet.2018.01.054

An efficient cascade approach to α-hydroxy-β-amino acid derivatives is reported, which goes through a 1,3-dipolar cycloaddition of carbonyl ylides and N-benzoylbenzyl imines and followed by hydrolysis under acidic conditions. This is the first example of using N-benzoylbenzyl imine as dipolarophile for 1,3-dipolar cycloaddition with carbonyl ylide, which provides a direct and convenient access for the one-pot synthesis of paclitaxel side chain and its derivatives.

Full text of DOI:10.1016/j.tetlet.2018.01.054

Accepted Manuscript
A convenient one-pot approach to Paclitaxel (Taxol) side chain via 1,3-dipolar
cycloaddition of carbonyl ylides and N-benzoylbenzyl imines
Jiajun Sheng, Huan Chang, Yu Qian, Mingliang Ma, Wenhao Hu
PII:
S0040-4039(18)30089-3
https://doi.org/10.1016/j.tetlet.2018.01.054
TETL 49641
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
28 November 2017
15 January 2018
19 January 2018
Please cite this article as: Sheng, J., Chang, H., Qian, Y., Ma, M., Hu, W., A convenient one-pot approach to
Paclitaxel (Taxol) side chain via 1,3-dipolar cycloaddition of carbonyl ylides and N-benzoylbenzyl imines,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.054
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A convenient one-pot approach to Paclitaxel
(Taxol) side chain via 1,3-dipolar
cycloaddition of carbonyl ylides and N-
benzoylbenzyl imines
Leave this area blank for abstract info.
Jiajun Shenga, Huan Changa, Yu Qianb, Mingliang Maa, and Wenhao Hua,b,

1
Tetrahedron Letters
A convenient one-pot approach to Paclitaxel (Taxol) side chain via 1,3-dipolar
cycloaddition of carbonyl ylides and N-benzoylbenzyl imines
Jiajun Shenga, Huan Changa, Yu Qianb, Mingliang Maa, and Wenhao Hua,b,
aShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai, 200062, China
bSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient cascade approach to α-hydroxy-β-amino acid derivatives is reported, which goes
through a 1,3-dipolar cycloaddition of carbonyl ylides and N-benzoylbenzyl imines and
followed by hydrolysis under acidic conditions. This is the first example of using N-
benzoylbenzyl imine as dipolarophile for 1,3-dipolar cycloaddition with carbonyl ylide,
which provides a direct and convenient access for the one-pot synthesis of paclitaxel side
chain and its derivatives.
Available online
Keywords:
2017 Elsevier Ltd. All rights reserved.
Paclitaxel side chain
N-Benzoylbenzyl imines
1,3-Dipolar cycloaddition
Carbonyl ylides
One-pot reaction
Introduction
α-Hydroxy-β-amino acids and their derivatives are the
indispensible moieties of many biological molecules and natural
products.1 The side chain of paclitaxel is one of the most famous
examples, which plays an important role in semi-synthesis of
paclitaxel.2 As a result, considerable efforts have been made to
develop a convenient and efficient route for the direct
construction of this framework. In the recent decades, Sharpless
aminohydroxylation3, Sharpless dihydroxylation4 and selective
ring-opening of epoxides or aziridines with proper nucleophiles5
are the practical methods to synthesize the α-hydroxy-β-amino
acid derivatives. Moreover, the metal-catalyzed multi-component
reactions6 of imines with in situ generated ylide via Mannich type
addition7 and 1,3-dipolar cycloaddition of carbonyl ylide8 have
also been utilized to build the skeleton of α-hydroxy-β-amino
acids.
Among these advances toward the α-hydroxy-β-amino acid
derivatives, approaches to the direct and efficient synthesis of
paclitaxel side chain are rare, and the substrate scope is limited.9
Either in ylide trapping reaction10 (Scheme 1a) or 1,3-dipolar
cycloaddition reaction11 (Scheme 1b), only N-aryl or N-benzyl
imines are demonstrated, which means additional modifications
including protection and deprotection procedures are needed to
finally deliver the paclitaxel side chain from these products.
Inspired by these works and as the continuation of our interest in
Scheme 1. Rh(II) catalyzed multi-component reactions. (a) three-
component reaction of imine, EDA and water. (b) 1,3-dipolar
cycloaddition of EDA, aryl-aldehyde and benzylidenebenzylamine.
(c) one-pot route to paclitaxel side chain.
———
PMP= p-methoxyphenyl. EDA=ethyl diazoacetate. Bz=benzoyl.
 Corresponding author. e-mail: mlma@brain.ecnu.edu.cn (ML Ma)
 Corresponding author. e-mail: huwh9@mail.sysu.edu.cn (WH Hu)

2
Tetrahedron
paclitaxel side chain synthesis10, we envisioned that 1,3-dipolar
product was not achieved and only hydrolyzed product of N-
cycloaddition of carbonyl ylide and imine is one of the most
practical strategies to achieve this protocol8,11,12 and if the
protecting group can be replaced with benzoyl, the paclitaxel side
chain could be obtained efficiently in a step-, time-, and energy-
saving manner. To our knowledge, there have been only a few
examples on multi-component reactions involving the imine with
N-benzoyl or other strong electron withdrawing group13, which
remains a great challenge for us to accomplish this route. Herein
we report a new convenient one-pot approach to paclitaxel side
chain via 1,3-dipolar cycloaddition of carbonyl ylides and N-
benzoylbenzyl imines (Scheme 1c).
benzoylbenzyl imine was observed. Benzyl alcohol also failed to
perform the reaction and only addition product13b 4 was obtained
in this condition, which indicated that N-benzoylbenzyl imine
was unstable in the presence of water or alcohol (Scheme 2).
Therefore, we attempted to carry out the 1,3-dipolar
cycloaddition of imine 1a and carbonyl ylide which generated
from 2a and 3a in the absence of protic nucleophiles (entries 1
and 2, Table 1). The corresponding oxazolidine 5 was smoothly
constructed and detected by LC-MS, and two diastereoisomers of
α-hydroxy-β-amino ester 6a were successfully isolated through
column chromatography after treated with trifluoroacetic acid in
40% yield and low diastereoselectivity (syn:anti = 30:70).
To ascertain the generality of this cycloaddition process, we
surveyed a variety of Lewis acid co-catalysts14 which have been
proven to have a great effect on both diastereoselectivity and
yield15 (entries 2 to 5, Table 1), and the AgPF6 gave the better
result. Next, the aldehyde part was investigated. When using aryl
aldehydes with electron donating groups such as p-methoxy and
o-methyl (entries 7 and 10, Table 1), the yield moderately
increased with a loss of diastereoselectivity. On the other hand,
aromatic aldehydes with strong electron withdrawing groups
such as p-trifluoromethyl and p-nitro gave rise to significant
decrease of yield (entries 8 to 9, Table 1). To our surprise, the
aldehyde substrates were not limited to aromatic aldehydes.
When aliphatic aldehydes were used (entries 11 to 15, Table 1),
Scheme 2. Reaction of N-benzoylbenzyl imine and benzyl alcohol.
Result and discussion
We first investigated the Rh2(OAc)4 catalyzed coupling
reaction of N-benzoylbenzyl imine, ethyl diazoacetate (EDA) and
water according to our previous work.10 Unfortunately, the target
Table 1. Optimization of 1,3-dipolar cycloaddition.
Table 2. 1,3-Dipolar cycloaddition of isobutyraldehyde 2f,
EDA 3a and N-benzoylbenzyl imine derivatives 1b-n.
entrya R1
co-catalyst
-
yield (%)b
40
drc (syn:anti)
30:70
58:42
52:48
55:45
55:45
22:78
31:69
43:57
N.A
1
Ph(2a)
2
Ph
Zn(OTf)2
AgPF6
Cu(OTf)2
AgOTf
p-TsOH
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
AgPF6
33
entrya Ar1
Ar2
yield (%)b
56(6b)
42(6c)
56(6d)
51(6e)
47(6f)
drc (syn:anti)
58:42
52:48
54:46
49:51
50:50
55:45
N.A
3
Ph
48
1
m-MeC6H4
Ph
4
Ph
31
2
o-BrC6H4
p -BrC6H4
p -MeOC6H4
p -MeC6H4
p -ClC6H4
p -CF3C6H4
Ph
Ph
5
Ph
33
3
Ph
6
Ph
15
4
Ph
7
p-MeOC6H4(2b)
p-CF3-C6H4(2c)
p-NO2-C6H4(2d)
o-Me-C6H4(2e)
i-Pr(2f)
45
5
Ph
8
26
6
Ph
53(6g)
trace(6h)
42(6i)
9
trace
47
7
Ph
10
11
12
13
14
15
40:60
58:42
N.A
8
m-BrC6H4
p-MeC6H4
o-FC6H4
p-MeOC6H4
p -ClC6H4
p-NO2C6H4
53:47
54:46
45:55
60:40
52:48
N.A
78
9
Ph
48(6j)
Bn(2g)
trace
71
10
11
12
13
Ph
54(6k)
52(6l)
Cyclohexyl(2h)
n-Pr(2i)
56:44
58:42
50:50
Ph
76
Ph
57(6m)
t-Bu(2j)
65
Ph
trace(6n)
a The reaction was carried out with imine 1a (1 equiv.), aldehyde 2a-j (1.5
equivs.), Rh2(OAc)4 (2.0 mol%), co-catalyst (10 mol%) and 4Å MS in CH2Cl2
at room temperature with addition of EDA 3a (1.5 equivs.) over 1h. Then
TFA (3 equivs.) was added and stirred overnight to hydrolyze oxazolidine 5.
b Isolated yield (two diastereoisomers).
a The reaction was carried out with imine 1b-n (1 equiv.), aldehyde 2f (1.5
equivs.), Rh2(OAc)4 (2.0 mol%), AgPF6 (10 mol%) and 4Å MS in CH2Cl2 at
room temperature with addition of EDA 3a (1.5 equivs.) over 1h. Then TFA
(3 equivs.) was added and stirred overnight to hydrolyze oxazolidine 5.
b Isolated yield (two diastereoisomers).
c Determined by 1H NMR spectroscopy of the crude reaction mixture.
c Determined by 1H NMR spectroscopy of the crude reaction mixture.

3
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the desired product was obtained in apparently increasing
yield with slightly promoted diastereoselectivity.
Isobutyraldehyde 2f gave the best performance, which improved
the yield to 78% with 58:42 (syn:anti) diastereoselectivity. To the
best of our knowledge, aliphatic aldehydes involved 1,3-dipolar
cycloaddition of carbonyl ylides were very rare11.
With the optimized reaction conditions established, a variety
of imines were tested subsequently. As was shown in Table 2, in
most cases, substituent imines afforded the target products in
comparable yields and diastereoselectivities. However, when the
imines with strong electron-withdrawing groups either on Ar1 or
Ar2 were used, only complex mixtures were obtained and trace
desired product was detected (entries 7 and 13, Table 2).
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It was notable that 3c showed much better dr ratio (syn:anti =
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8 was successfully obtained in 69% yield with 66:34 (syn:anti)
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(Scheme 3b).
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A facile and convenient approach to the α-hydroxy-β-amino
acids and their derivatives has been reported, which goes through
1,3-dipolar cycloaddition and followed by hydrolysis under
acidic conditions. Carbonyl ylides generated from aliphatic
aldehyde and N-benzoylbenzyl imines are the matching
components in this strategy. This method provides a direct access
for the one-pot synthesis of paclitaxel side chain and derivatives
of them. Further investigations of diastereoselectivity and
enantioselectivity control are underway in our lab.
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This work was supported by the National Natural Science
Foundation of China (21572067 and 21332003) and the
Program for Guangdong Introducing Innovative and
Enterpreneurial Teams (2016ZT06Y337).
References and notes
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Highlights:



One-pot synthesis of paclitaxel side chain and its derivatives.
Using imines with N-benzoyl as dipolarophile in cycloaddition with carbonyl ylide.
Using carbonyl ylides generated from aliphatic aldehydes in this strategy.