Formal total synthesis of benzylpedamide: The right half of (+)-pederin

Article abstract of DOI:10.1055/S-2008-1077788

The right half of (+)-pederin was synthesized through a convenient and efficient asymmetric synthesis in 14 steps with 8.3% overall yield. The key step was an iodine-induced heterocy-clization to construct the pyran ring. The chiral centers were constructed separately via asymmetric allylation, substrate-controlled diastereoselective reactions, and Sharpless asymmetric dihydroxy-lation.

Full text of DOI:10.1055/S-2008-1077788

1526
LETTER
Formal Total Synthesis of Benzylpedamide: The Right Half of (+)-Pederin
F
ormal Total Synt
e
hesis of Ben
g
zylpedamid
a
e
ng Liu, Jijun Xue, Zhixiang Xie, Liping Wei, Xianshu Zhang, Ying Li*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: liying@lzu.edu.cn
Received 5 February 2008
key building blocks in all subsequent syntheses of pederin
Abstract: The right half of (+)-pederin was synthesized through a
convenient and efficient asymmetric synthesis in 14 steps with
8.3% overall yield. The key step was an iodine-induced heterocy-
clization to construct the pyran ring. The chiral centers were con-
since Matsumoto et al. reported their seminal work in
1988.6a The major synthetic challenge of pedamide is to
construct the pyran ring with three chiral centers stereose-
structed separately via asymmetric allylation, substrate-controlled lectively. We found that iodine-induced heterocyclization
diastereoselective reactions, and Sharpless asymmetric dihydroxy-
lation.
was useful for the asymmetric construction of pyran ring.
Based on this, a new asymmetric synthesis of optically
Key words: synthesis, pedamide, pederin
pure benzylpedamide (2) was developed, in which the
chiral centers were constructed from asymmetric allyla-
tion, substrate-controlled diastereoselective reactions, and
Sharpless asymmetric dihydroxylation.
The pederin family of natural products, consisting of at
least 36 structurally related compounds,1 is an interesting
class of compounds due to their potent cytotoxic activi-
ties. For example, pederin (1), is an effective insect toxin
isolated from Paederus fuscipes.2 It can inhibit mitosis in
Hela cells and block protein and DNA biosynthesis, and
can act as an antitumor and antiviral agent.3 The pederin
family compounds, except psymberin, have almost an
identical tetrahydropyran ring on the left half, but a struc-
turally different tetrahydropyran ring on the right hand
side (Figure 1). The two tetrahydropyran rings are bridged
by an N-acyl aminal linker. The structural similarities be-
tween psymberin and other pederin natural compounds
have been noted.4
The synthesis started from 2,2-dimethylpropane-1,3-diol
(3), which was converted into monoprotected alcohol 4 in
85% yield using a published procedure (Scheme 1).10 The
corresponding aldehyde 5 was subsequently obtained in
99% yield by Swern oxidation of 4. Asymmetric allyla-
tion of 5 using Brown’s chiral allylborane11 gave the ho-
moallylic alcohol in 80% ee. However, it was difficult to
separate the product from isopinocampheol, the byprod-
uct coming from Brown’s borane reagent. Without further
purification, therefore, the mixture was treated with BnCl
and sodium tert-amyloxide (t-AmONa) to give ether 6,
which could be separated by column chromatography in
70% yield in two steps. Deprotection of the MOM group
in 6 under acidic conditions, followed by Swern oxidation
gave aldehyde 8. Lewis acid mediated diastereoselective
allylation of 8 proceeding under SnCl4 chelation12 control
formed a pair of diastereomers in a ratio of 2:1, which
were easily separated by column chromatography to give
9 in 39% yield.13 The configuration of the newly formed
chiral center was controlled by the configuration of sub-
strate 8. In a parallel experiment, reagent-controlled dia-
stereoselective allylation11 of 8 with Brown’s chiral
allylborane was carried out. It gave a much lower conver-
sion (about 4%) and a poorer diastereomeric ratio (about
1.4:1). The substrate may be too bulky for Brown’s allyl-
borane to chelate.
Because of their unique structures and unusual biological
activities, these compounds are important and interesting
synthesis targets. The syntheses towards these compounds
had been reported by many researchers5–9 before. The
main contributors are Matsumoto,6 Nakata,7 Kocienski,8
and Rawal9 and their co-workers. Most of these reported
works are focused on the synthesis of the different right
molecular segments. Among these various fragments,
pedamide6c and its analogues8e,9b have been adopted as
OMe
OMe
O
Treating compound 9 with 1.5 equivalents of I2 and 1.5
equivalents of NaHCO3 under heterogeneous conditions
at 0 °C gave the desired pyran 10 in 87% yield and its
epimer in 11% yield.14 The diastereomers were separated
by column chromatography. The diastereoselectivity was
controlled by substrate and the addition to the C=C bond
was anti.15 The relative configuration of the newly formed
chiral center was confirmed by NMR analysis
(Scheme 2). This is the first case using iodine to induce
the heterocyclization in the synthesis of pederin com-
pounds, although heterocyclization has been reported in
the synthesis of this kind of compounds.5d,f,6d,9c
O
OH
O
H2N
OMe
MeO
O
H
N
OMe
OH
O
OMe
OBn
2
1
Figure 1
SYNLETT 2008, No. 10, pp 1526–1528
Advanced online publication: 16.05.2008
x
x
.x
x
.2
0
0
8
DOI: 10.1055/s-2008-1077788; Art ID: W02708ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Formal Total Synthesis of Benzylpedamide
1527
OH OH
OBn
O
OH OMOM
OBn OH
O
OMOM
OBn OMOM
a
f
c, d
e
b
8
3
4
7
5
6
h
TMS
O
O
OBn OH
I
I
OH
H
Cl
Bn
Sn
g
Cl
Cl
Cl
i
OH
O
O
OBn
10
OBn
9
11
O
O
O
BzO
OMe
HO
OMe
OMe
I
OMe
OMe
j
l
m, n
OMe
k
2
OBn
OBn
OBn
12
14
13
Scheme 1 Reagents and conditions: (a) MOMCl, NaH, THF, r.t., 3 h, 85%; (b) DMSO, oxalyl chloride, CH2Cl2, –78 °C, 1 h, 99%; (c) (+)-
B-allyldiisopinocampheylborane, Et2O, –95 °C, 80% ee; (d) BnCl, t-AmONa, DMSO, r.t., 70% (two steps); (e) HCl (3 M, aq), MeOH, reflux,
3 h, 97%; (f) DMSO, oxalyl chloride, CH2Cl2, –78 °C, 1 h, 99%; (g) SnCl4, allyl trimethylsilane, CH2Cl2, –78 °C, 4 h, 58%, dr = 2:1; (h) I2,
NaHCO3, Et2O, H2O, 0 °C, 8 h, 98%, dr = 8:1; (i) AD-mix-a, MeSO2NH2, NaHCO3, t-BuOH, H2O, 0 °C, 12 h, 96%, dr = 1.6:1; (j) MeI, NaH,
DMF, r.t., 1 h, 98%; (k) BzONa, NMP, 100 °C, 6 h, 93%; (l) K2CO3, MeOH, r.t., 4 h, 98%; (m) CrO3, H2SO4, acetone, 0 °C, 2 h; (n) PyBOP,
HOBt, DIPEA, NH4Cl, DMF, r.t., 1.5 h, 83% (two steps).
under basic conditions gave 14 in 98% yield. Jones’ oxi-
OBn OH
HO
I
dation of alcohol 14 followed by benzotriazol-1-yl-
oxytripyrrolidinophosphonium hexafluorophosphate (Py-
BOP)–N-hydroxybenzotriazole (HOBt)-mediated amida-
tion7f,18 with NH4Cl gave the desired benzylpedamide (2),
the right half of pederin, in 83% yield over two steps.
OBn
9
H
O
O
I
In conclusion, an efficient and convenient method for the
asymmetric synthesis of benzylpedamide (2), the right
half of bioactive (+)-pederin (1), was developed in 14
steps with more than 8% overall yield. The key step is the
diastereoselective iodine-induced hetereocyclization.
This is a new method for the synthesis of pedamide and
will find wide application for the synthesis of similar
compounds.
H
I
H
O
H
H
NMR
OBn
Ph
10
Scheme 2 Mechanism of cyclization and configuration assurance of
product
The last chiral center was constructed from Sharpless
asymmetric dihydroxylation.7f,16 The terminal olefin 10
was treated with commercially available AD-mix-a to
form a pair of diastereomers in 96% yield with a diaste-
reomeric ratio of 1.6:1. The major epimer was the desired
one and was purified by column chromatography. The
configuration of the newly formed chiral center was con-
trolled by the dihydroxylation reagent. The dihydroxyla-
tion increased the enantiomeric purity of the product
because it transformed most of the enantiomer of 10 into
a chromatographically separable diastereomer of 11. Sub-
sequent dimethylation converted diol 11 into ether 12 in
98% yield without affecting the iodide part at all. The last
difficult part of this synthesis was to convert iodide 12
into alcohol 14. We tried several oxidative and nucleo-
philic substitution conditions,17 but all of them failed. Fi-
nally, iodide 12 was treated with BzONa in NMP
according to the literature14b and gave ester 13 smoothly
in 93% yield. Removal of the benzoyl group in ester 13
Acknowledgment
We thank the National Natural Science Foundation of China for fi-
nancial support (Project 20672050).
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1528
D. Liu et al.
LETTER
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