First total synthesis of (+)-podophyllic aldehydes

Article abstract of DOI:10.1246/cl.141061

The first total synthesis of three (+)-podophyllic aldehydes was achieved in a highly enantiocontrolled manner. Key steps include the organocatalyzed highly enantioselective cyclopropanation and Lewis acid-mediated chiral transfer ring expansion with exce

Full text of DOI:10.1246/cl.141061

Received: November 19, 2014 | Accepted: December 3, 2014 | Web Released: December 11, 2014
CL-141061
First Total Synthesis of (+)-Podophyllic Aldehydes
Junki Ito, Daichi Sakuma, and Yoshinori Nishii*
Department of Chemistry, Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano 386-8567
(E-mail: nishii@shinshu-u.ac.jp)
MeO
OMe
SmI2
HMPA
The first total synthesis of three (+)-podophyllic aldehydes
was achieved in a highly enantiocontrolled manner. Key steps
include the organocatalyzed highly enantioselective cyclopropa-
nation and Lewis acid-mediated chiral transfer ring expansion
with excellent level of stereoinduction. This method can alterna-
tively provide (+)- and (¹)-podophyllic aldehydes by switching
the organocatalyst in the asymmetric cyclopropanation.
MeO
OMe
MeO
OMe
OMe
CHO
CO2Me
OH
MeO
Cl
Cl
Cl
R1
3
R1
R1
CO2Me
Excellent
trans-selectivity
2
1
(dr = 3/2−2/1)
MeO
OMe
OMe
OMe
R2
R1
R1
CO2Me
MeO
MeO
Sc(OTf)3
Dihydronaphthalene-type lignans are attracting considerable
attention because of their widespread distribution in nature
and multiple, significant biological activities.1,2 Among them,
(¹)-podophyllic aldehydes A, B, and C exhibit notable
antineoplastic cytotoxicity and apoptosis-inducing activities
(Scheme 1).3 The first reported synthesis of (¹)-podophyllic
aldehydes A, B, and C was started from natural (¹)-podophyl-
lotoxin.3c,3d Although the asymmetric synthesis of both enan-
tiomers is necessary for investigating their structure and activity
relationship, the (+)-podophyllic aldehydes have not been
synthesized. Here, we disclose the first total synthesis of
(+)-podophyllic aldehydes A, B, and C utilizing organocata-
lyzed asymmetric cyclopropanation and Lewis acid-mediated
chiral transfer ring expansion as key reactions.
During the course of our synthetic studies on the trans-
formation of dichlorocyclopropanes.4-6 Recently, we reported
the diastereoselective total synthesis of («)-cyclogalgravin and
its dicarboxy analog utilizing the SmI2-promoted Reformatsky-
type addition of ester 2 to aldehyde and the Sc(OTf)3-mediated
ring expansion of key intermediate 3 (Scheme 2).6b However,
the enantioselectivity of the ring expansion of alcohol 3 to afford
dihydronaphthalene has not been investigated. In addition,
highly enantioselective dichlorocyclopropanation has not yet
been achieved. Therefore, we attempted to synthesize 7a using
the asymmetric cyclopropanation of aldehyde 5 with dimethyl
α-bromomalonate (4) under the presence of organocatalyst 6.7
Fortunately, the cyclopropanation proceeded to afford the
desired optically active diester 7a in 91% yield with 95% ee
(Scheme 3).8 The same cyclopropanation using organocatalyst
D-6 provided the enantiomer 7b in 88% yield with 95% ee.
We used diester 7a for the total synthesis of (+)-podophyllic
aldehydes.
Excellent
trans-selectivity
MeO
OMe
)-Cyclogalgravin (R1, R2 = Me)
MeO
OMe
(
sole product
Dicarboxy analog
(R1 = CO2H or CO2Bn, R2= CO2Me)
Scheme 2. Diastereoselective total synthesis of («)-cyclogalgravin
and its analog form dichlorocyclopropane 1.
MeO
OMe
OMe
Ph
Ph
OTMS
MeO
CO2Me
OMe
OMe
N
cat.
H
MeO2C
6
MeO2C
MeO2C
+
Br
2,6-lutidine
CH2Cl2
CHO
7a
4
OHC
5
5
91%, 95% ee
OMe
MeO
MeO
Ph
Ph
N
H
D-6
cat.
OTMS
CO2Me
CO2Me
+
4
2,6-lutidine
CH2Cl2
7b
OHC
88%, 95% ee
Scheme 3. Organocatalyzed asymmetric cyclopropanations.
aldehyde group in diester 7a using NaBH4, the lactonization of
the resulting alcohol with a catalytic amount of p-toluenesul-
fonic acid (PTS) in CHCl3 gave γ-lactone 8 in 86% yield (2
steps) with 95% ee.8 Optical purity of lactone 8 was observed by
HPLC analysis using a chiral column. The ee of the aforemen-
tioned asymmetric cyclopropanation was estimated based on the
HPLC analysis of lactone 8. Treatment of γ-lactone 8 with 3,4-
methylenedioxyphenylmagnesium bromide in THF resulted in
a highly regioselective Grignard reaction on a slightly strained
lactone ring to give β-ketoester 9 in 94% yield. After benzoyl
protection of the hydroxy group in β-ketoester 9, the reduction
of the resulting benzoyl-protected β-ketoester 10 (95% yield
from 9) with NaBH4 afforded hydroxyester 11 in 70% yield
(dr = 6/1, 95% ee). Although the stereochemistry of the newly
formed benzylic alcohol was in a 6:1 ratio, both diastereomers
were converted into the same enantiomer of dihydronaphthalene
Scheme 4 outlines the asymmetric synthesis of dihydro-
naphthalene 12 from diester 7a. After the reduction of the
OHC
HO
OHC
O
O
O
O
(-)-podophyllic aldehydes
RO2C
A: R = Me
C
OMe
B: R =
MeO
OMe
MeO
OMe
OMe
OMe
12. Treatment of the diastereoisomeric mixture of hydroxyester
OMe
OMe
6a,9
11 with BF3¢OEt2
in 1,2-dichloroethane (EDC) at 83 °C
Scheme 1. (¹)-Podophyllic aldehydes.
resulted in a chiral transfer ring expansion to provide dihydro-
Chem. Lett. 2015, 44, 297–299 | doi:10.1246/cl.141061
© 2015 The Chemical Society of Japan | 297

MeO
OMe
OMe
CO2Me
OBz
O
O
O
O
O
O
MeO
OMe
OMe
OH
OH
MeO
OMe
OMe
O
OR
g
h
MeO2C
O
MeO2C
MeO2C
MeO2C
O
d
a, b
c
97%
OH
CHO
MeO
MeO
MeO
96% OMe
OMe
OMe
MeO
OMe
8
7a
9
O
OMe
12
OMe
13
86% (2 steps) (95% ee)
MeO OMe
OMe
94%
(+)-podophyllic aldehyde C (R = H)
(95% ee)
i
O
O
14 (R = Bz)
98%
OMe
O
O
BzO
OMe
e
MeO2C
OMe
OMe
OMe
O
O
O
O
O
O
MeO2C
O
MeO2C
f
OH
CHO
HO
OBz
OBz
j, k
l
m
14
11
12
10
MeO
MeO
16
OMe
OMe
O
O
93% (95% ee)
O
O
95%
O
O
70%
OMe
OMe
92%
93% (2 steps)
15
Scheme 4. Reagents and conditions: (a) NaBH4, THF, MeOH; (b)
cat. PTS, CHCl3; (c) 3,4-methylenedioxyphenylmagnesium bromide,
THF; (d) BzCl, Et3N, CH2Cl2; (e) NaBH4, THF, MeOH; (f) BF3¢OEt2,
EDC.
O
O
CHO
O
O
O
O
O
O
O
CO2R
OMe
O
CO2R
CO2H
o
n
MeO
MeO
18 (R = Me)
OMe
MeO
OMe
MeO
OMe
OMe
OMe
OMe
OMe
17
(+)-podophyllic aldehyde A (R = Me)
BzO
85% (3 steps) (95% ee)
B (R = 3,4,5-trimethoxybenzyl)
R
Chiral transfer
ring expansion
MeO2C
HO
MeO2C
OMe
OMe
19 (R = 3,4,5-trimethoxybenzyl)
R
S
OBz
72% (3 steps) (95% ee)
S
OMe
Scheme 6. Reagents and conditions: (g) DIBAH, CH2Cl2; (h)
MnO2, CH2Cl2; (i) BzCl, Et3N, CH2Cl2; (j) cat. PTS, ethylene glycol,
benzene; (k) KOH, MeOH; (l) Et3N, (COCl)2, DMSO, CH2Cl2;
(m) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O; (n) RX,
K2CO3, DMF; (o) 4 M aqueous HCl solution, THF.
11
95% ee
12 95% ee
O
O
O
O
Intramolecular
Friedel-Crafts
BF3·OEt2
MeO OMe
OMe OMe
– OH–
Proposed mechanism
MeO
OMe
OMe
OMe
ring opening
OMe
R
of dihydronaphthalene 12 with excellent stereoinduction in the
following Friedel-Crafts-type cyclization.
R
O
O
O
O
OBz OMe
R
H
S
OBz
S
OBz
OMe
OMe
F3B
Further functional transformations leading to target com-
pounds were performed as follows (Scheme 6). The reduction of
12 with DIBAH (excess) in CH2Cl2 gave diol 13 in 96% yield.
Treatment of diol 13 with activated MnO2 resulted in the
regioselective oxidation of the allylic alcohol to afford (+)-
podophyllic aldehyde C in 97% yield with 95% ee. Benzoyl
protection of (+)-podophyllic aldehyde C with BzCl and Et3N
in CH2Cl2 provided aldehyde 14 in 98% yield. After acetal
protection of aldehyde 14 with ethylene glycol, the hydrolysis of
the resulting acetal with KOH yielded alcohol 15 in 93% yield
(2 steps). Swern oxidation of alcohol 15 afforded aldehyde 16
in 92% yield.11 The Pinnick (Kraus) oxidation of aldehyde 16
provided carboxylic acid 17.12 Thus, carboxylic acid 17 was
obtained through the stepwise oxidation of alcohol under mild
conditions. Other direct oxidations such as the Jones oxidation
of alcohol provided naphthalenes. The methylation of acid 17
using MeI with K2CO3 in DMF to yield ester 18, followed by
treatment of ester 18 with a 4 M aqueous HCl solution in THF
resulted in the removal of the acetal to furnish (+)-podophyllic
aldehyde A in 85% (three steps overall yield from 16) with
95% ee.
D
E
F
O
O
O
O
O
O
Scheme 5. Proposed mechanism for the Lewis acid-mediated chiral
transfer ring expansion.
naphthalene 12 in 93% yield with 95% ee. The ee of dihydro-
naphthalene 12 was determined by HPLC analysis using a chiral
column. Thus, almost complete stereoinduction from cyclo-
propane (95% ee) to dihydronaphthalene (95% ee) was
performed. The same reaction using Sc(OTf)3,6 which was used
in the diastereoselective synthesis of («)-cyclogalgravin
(Scheme 2), gave dihydronaphthalene 12 (59% yield, 95% ee)
with inseparable complex mixtures.
The proposed mechanism of chirality transfer mediated by
BF3¢OEt2 is as follows (Scheme 5). First, BF3¢OEt2 coordinates
to the oxygen of the OH in alcohol 11 to give an intermediate D.
The hydrogen bond between OH and the carbonyl group should
play a chelation-like role in the intermediate D. Successive
BF3-promoted elimination of the OH group affords the cationic
intermediate E. A highly regioselective ring-opening occurs to
give cationic intermediate F, and then the Friedel-Crafts-type
cyclization sequentially proceeds to afford dihydronaphthalene
12.10 Although the chirality of the 3,4,5-trimethoxybenzyl
position of the cationic intermediate E disappears and changes
to sp2-carbocation in the intermediate F, after the cyclopropane-
ring opening, the chirality is reconstructed as S in the 1 position
Similarly, after the benzylation of acid 17 using 3,4,5-
trimethoxybenzyl bromide, deprotection of the acetal in the
resulting ester 19, using diluted aqueous HCl solution in THF,
produced (+)-podophyllic aldehyde B in 72% yield (3 steps
overall yield from 16) with 95% ee. The 1H- and 13C NMR
spectral data for the synthesized (+)-podophyllic aldehydes A,
B, and C were in agreement with those reported for (¹)-podo-
phyllic aldehydes3 derived from podophyllotoxin. Optical
298 | Chem. Lett. 2015, 44, 297–299 | doi:10.1246/cl.141061
© 2015 The Chemical Society of Japan

2275.
purities (95% to 96% ee) of the synthesized (+)-podophyllic
aldehydes A, B, and C were observed by HPLC analysis using a
chiral column.8
5
6
a) T. Nagano, J. Motoyoshiya, A. Kakehi, Y. Nishii, Org. Lett. 2008,
10, 5453. b) E. Yoshida, T. Nagano, J. Motoyoshiya, Y. Nishii,
Chem. Lett. 2009, 38, 1078 (open access article).
a) E. Yoshida, K. Nishida, K. Toriyabe, R. Taguchi, J. Motoyoshiya,
Y. Nishii, Chem. Lett. 2010, 39, 194. b) D. Sakuma, J. Ito, R. Sakai,
R. Taguchi, Y. Nishii, Chem. Lett. 2014, 43, 610 (open access
article).
a) H. Xie, L. Zu, H. Li, J. Wang, W. Wang, J. Am. Chem. Soc. 2007,
129, 10886. References for the original catalyst (Hayashi-Jørgensen
catalyst), see: b) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A.
Jørgensen, Angew. Chem., Int. Ed. 2005, 44, 794. c) Y. Hayashi, H.
Gotoh, T. Hayashi, M. Shoji, Angew. Chem., Int. Ed. 2005, 44, 4212.
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Kjærsgaard, K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 18296.
See Supporting Information.
a) Related benzannulation of aryl(dichlorocyclopropyl)methanols to
afford achiral naphthalenes, see: Y. Tanabe, S. Seko, Y. Nishii, T.
Yoshida, N. Utsumi, G. Suzukamo, J. Chem. Soc., Perkin Trans. 1
1996, 2157, and ref 4b. b) Chirality exchange banzanulation to
provide axially chiral 1-arylnaphthalenes, see ref 4a.
In conclusion, the first total synthesis of (+)-podophyllic
aldehydes A, B, and C with high ee was achieved using the
organocatalyzed asymmetric cyclopropanation and Lewis acid-
mediated chiral transfer ring expansion of the cyclopropane to
give the optically active dihydronaphthalenes with excellent
level of stereoinduction. Finally, (+)-podophyllic aldehydes A,
B, and C were obtained in 30% (16 steps), 26% (16 steps),
and 43% overall yield (8 steps), respectively. This method can
provide (¹)-podophyllic aldehydes using diester 7b instead of
7a.13
7
8
9
This research was partially supported by Grant-in-Aids for
Scientific Research on Basic Area (C) No. 23550048 from JSPS.
We thank Prof. Tanabe (Kwansei Gakuin University) for his
encouragement.
Supporting Information is available electronically on J-STAGE.
10 Interestingly, instead of the Friedel-Crafts-type attack of methyl-
enedioxybenzene, the nucleophilic attack of the OH group to cationic
benzyl position occurred to cyclize a furofuran ring in the efficient
total synthesis of (+)-sesamin and (+)-sesamol: R. Ishikawa, N.
Yoshida, Y. Akao, Y. Kawabe, M. Inai, T. Asakawa, Y. Hamashima,
T. Kan, Chem. Lett. 2014, 43, 1572 (Editor’s choice and open access
article).
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13 We also synthesized (¹)-podophyllic aldehydes A, B, and C starting
from 7b. See Supporting Information.
Chem. Lett. 2015, 44, 297–299 | doi:10.1246/cl.141061
© 2015 The Chemical Society of Japan | 299