Total synthesis of cyclogalgravin and its dicarboxyl analog using sc(otf)3-mediated highly diastereoselective ring expansion of 1-(arylhydroxymethyl)cyclopropanecarboxylates

Article abstract of DOI:10.1246/cl.131179

The total synthesis of cyclogalgravin and its dicarboxyl analog was achieved by using the SmI2-promoted Reformatsky type reaction and Sc(OTf)3-mediated diastereoselective ring expansion as key steps.

Full text of DOI:10.1246/cl.131179

CL-131179
Received: December 17, 2013 | Accepted: January 7, 2014 | Web Released: January 11, 2014
Total Synthesis of («)-Cyclogalgravin and Its Dicarboxyl Analog
Using Sc(OTf)3-mediated Highly Diastereoselective Ring Expansion
of 1-(Arylhydroxymethyl)cyclopropanecarboxylates
Daichi Sakuma, Junki Ito, Ryo Sakai, Ryota Taguchi, 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)
The total synthesis of («)-cyclogalgravin and its dicarboxyl
analog was achieved by using the SmI2-promoted Reformatsky
type reaction and Sc(OTf)3-mediated diastereoselective ring
expansion as key steps.
6 (R º H) has not been investigated. Here, we report the
diastereoselective ring expansion and its application for the total
synthesis of («)-cyclogalgravin and its dicarboxyl analog.
Scheme 3 outlines the diastereoselective synthesis of
dihydronaphthalenes 11a and 11b. We synthesized 8a-11a and
8b-11b from 7a and 7b, respectively. Initially, alkene 7a was
converted to dichlorocyclopropane 8a by a conventional
method6 using CHCl3, 50%-NaOH, and a catalytic amount of
benzyltriethylammonium chloride. After the benzyl protection
of alcohol 7b, dichlorocyclopropanation of the resulting benzyl
ether with the same reagents afforded cyclopropane 8b.
Methoxycarbonylation of dichlorocyclopropane 8a with n-BuLi
and ClCO2Me gave methyl 1-chlorocyclopropanecarboxylate 9a
(3/2 mixture of diastereoisomers) with moderate diastereose-
lectivity. Carboxylation of dichlorocyclopropane 8b with t-BuLi
and CO2, followed by treatment of the resulting carboxylic acid
with K2CO3 and MeI afforded α-chloro ester 9b (2/1 mixture
of diastereoisomers).3,4,7 The SmI2-promoted Reformatsky type
reaction3a of α-chloroester 9 to 3,4-dimethoxyphenyl aldehyde
yielded alcohol 10 with excellent trans-stereoselectivity (trans-
add/cis-add > 99/1) and poor Re-/Si-face selectivity (-OH: 1/1
1-Aryl-1,2-dihydronaphthalene analogs are attracting con-
siderable attention owing to their distribution in nature (i.e.,
cyclogalgravin, trilobatins A and B),1 and significant biological
activities of their analogs2 (i.e., podophyllic aldehyde 1 and its
derivative 2), such as antineoplastic cytotoxicity and apoptosis-
inducing activities2d (Scheme 1).
We have recently reported the highly stereoselective SmI2-
promoted Reformatsky type reaction of 1-chlorocyclopropane-
carboxylate 4 derived from dichlorocyclopropane 3, and the
Sc(OTf)3-mediated highly regioselective ring expansion of
cyclopropylmethanol 5 to give 1-aryl-1,2-dihydronaphthalene
6 (R = H) (Scheme 2).3-5 However, the diastereoselectivity of
the ring expansion to afford 1-aryl-2-R-1,2-dihydronaphthalene
R3
R2
OR1 (-)-Cyclogalgravin: R1 = Me, R2 = Me, R3 = Me
R1 = H, R2 = CO2H
Trilobatin A and B:
OR1
MeO
OMe
MeO
OMe
OH
HO
OMe
O
a
b
MeO
R3
=
O
O
Cl
Cl
OR1
O
*
OH
OR1
Me
*
OH
O
Me Cl
8a 84%
CO2Me
Me
,
OH
HO
OH
CO2H
7a
9a 71%
Trilobatin B
Trilobatin A
OHC
O
O
MeO
2) a
OMe
MeO
OMe
Podophyllic aldehyde (PA) 1: R = Me
OMe
RO2C
1) c,
OH
1) d
2) e
MeO
OMe
PA 2: R =
Cl
Cl
Cl
OMe
OMe
MeO
OMe
CO2Me
BnO
OMe
BnO
7b
8b 91% (2 steps)
9b 64% (2 steps)
MeO
OMe
R
Scheme 1. 1-Aryl-1,2-dihydronaphthalene analogs.
MeO
MeO
R
CO2Me
CO2Me
OH
SmI2
Ph
CO2Me
Cl
Ph
Cl
Cl
HMPA, THF
f
g
9a,
9b
R
4
R
3
CHO
Ph
CO2Me
OH
R
CO2Me
MeO
OMe
MeO
OMe
11a (R = Me) 81%
R
Sc(OTf)3
Ring-expansion
10a (R = Me) 80%
10b (R = CH2OBn) 87%
Ph
11b (R = CH2OBn) 73%
5
6
Scheme 3. Reagents and conditions: (a) CHCl3, 50%-NaOH,
cat. benzyltriethylammonium chloride; (b) n-BuLi, ClCO2Me, THF;
(c) BnBr, NaH, DMF; (d) t-BuLi, CO2, THF; (e) K2CO3, MeI, DMF;
(f) SmI2, HMPA, veratraldehyde, THF; (g) Sc(OTf)3, CH2Cl2.
Scheme 2. Synthesis of 1-aryl-1,2-dihydronaphthalene from di-
chlorocyclopropane.
610 | Chem. Lett. 2014, 43, 610–611 | doi:10.1246/cl.131179
© 2014 The Chemical Society of Japan

10
11
OMe
OMe
Me
Me
OMe
OMe
HO
Me
1) i
2) j
h
Intramolecular
Friedel-Crafts
Sc(OTf)3
11a
fast
MeO
OMe
MeO
MeO
OMe
MeO
MeO
MeO
OMe
12 94%
OMe
MeO
MeO
ring
R
O
MeO
(
)-Cyclogalgravin 71%
O
O
Sc(OTf)3
OH
a
- OH-
elimination
H
H
R
R
MeO2C
OMe
OMe
OMe
OMe
MeO2C
HO
A
1) l
2) m
k
opening
11b
RO2C
MeO
OMe
fast
MeO
OMe
MeO
OMe
- OH-
elimination
C
B
major
MeO
OMe
MeO
rotation
on bond a
OMe
MeO
OMe
OMe
13 77%
MeO
14 (R = H)
k
MeO
n
MeO
15 (R = Bn)
O
68% (2 steps from 13)
O
ring
opening
OMe
OMe
R
H
OMe
OMe
R
H
E
Scheme 5. Reagents and conditions: (h) DIBAH, CH2Cl2; (i) 4-
methylbenzoyl chloride, TMEDA, THF; (j) SmI2, HMPA, tetrahy-
dropyran (THP); (k) H2, cat. Pd(OH)2-C, AcOEt; (l) Dess-Martin
periodinane, CH2Cl2; (m) NaClO2, NaH2PO4, 2-methyl-2-butene, t-
BuOH; (n) K2CO3, BnBr, DMF.
D
minor
Scheme 4. Proposed mechanism of ring expansion.
mixture of diastereoisomers). Avoiding the notable steric
repulsion of the aryl group of Sm-enolate, the Reformatsky
type reaction of 9 took place only on the trans-face even though
the R (Me or BnOCH2) substituent was attached on the same
face.3a,8 The Sc(OTf)3-mediated ring expansion4 of alcohol 10
(1/1 mixture of diastereoisomers) afforded the desired dihydro-
naphthalene 11 as the sole product with excellent trans-
selectivity (trans/cis > 99/1). We propose the plausible mecha-
nism of the ring expansion as follows (Scheme 4).9 Sc(OTf)3
chelates with the OH and carbonyl of β-hydroxyester 10 to give
intermediate A. Successive Sc(OTf)3-promoted elimination of
the OH group gives cationic intermediates B and D (the
chelation of Sc(OTf)3 would be advantageous to give the desired
conformer B). The ring opening of intermediate D produces
cation E, but the cyclization of intermediate E cannot proceed.
Finally, the ring opening of B occurs to give cation C, and the
Friedel-Crafts type cyclization sequentially occurs to give
dihydronaphthalene 11 with excellent trans-selectivity.
Further functional transformations leading to target com-
pounds were performed as follows (Scheme 5). The reduction of
11a with DIBAH gave alcohol 12. After the acylation of alcohol
12 with 4-methylbenzoyl chloride and TMEDA, treatment of the
resulting 4-methylbenzoyl ester with SmI2 resulted in reductive
dehydroxylation to give («)-cyclogalgravin.10 The spectroscopic
data of the synthesized («)-cyclogalgravin were consistent with
those of the natural cyclogalgravin.1a,2a,2e On the other hand,
hydrogenation of 11b with H2 and Pd(OH)2 afforded alcohol 13.
Monocarboxylic acid 14 (an analog of cyclogalgravin, trilobatin
A, and trilobatin B) was obtained through the stepwise oxidation
of alcohol 13 under mild conditions (the Dess-Martin oxidation
followed by the Kraus oxidation).11 The benzylation of
carboxylic acid 14 with K2CO3 and BnBr yielded benzyl ester
15 (a synthetic segment for the total synthesis of trilobatins A
and B). We confirmed that the deprotection of benzyl ester 15
with H2 and Pd(OH)2 proceeded to give carboxylic acid 14.
In conclusion, we developed a highly stereoselective
synthesis of trans-1-aryl-2-alkyl-1,2-dihydronaphthalene utiliz-
ing the Sc(OTf)3-mediated ring expansion of cyclopropane 10.
The present method was also applied to the efficient total
synthesis of («)-cyclogalgravin and its dicarboxyl analog.
This research was partially supported by a Grant-in-Aids for
Scientific Research on Basic Area (C) “No. 23550048” from
JSPS. We thank Prof. Y. Tanabe (Kwansei Gakuin University)
for his kind advice and encouragement.
References and Notes
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4
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6
7
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8
9
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Chem. Lett. 2014, 43, 610–611 | doi:10.1246/cl.131179
© 2014 The Chemical Society of Japan | 611