Stereochemical courses and mechanisms of ring-opening cyclization of donor-acceptor cyclopropylcarbinols and cyclization of 7-benzyloxy dibenzyl lignan lactones

Article abstract of DOI:10.1246/cl.170081

Lewis acid-mediated ring-opening cyclization of trans- and cis-cyclopropanes 1a and 1b afforded the same trans-dihydronaphthalene 2a. Moreover, Lewis acid-mediated cyclization of 7R- and 7S-benzyloxy dibenzyl lignan lactones 5a and 5b furnished trans-tetr

Full text of DOI:10.1246/cl.170081

Advance Publication Cover Page
Stereochemical courses and mechanisms of ring-opening cyclization of donor-acceptor
cyclopropylcarbinols and cyclization of 7-benzyloxy dibenzyl lignan lactones
Kazuya Sasazawa, Seijiro Takada, Toshihide Yubune, Naoya Takaki,
Ryotaro Ota, and Yoshinori Nishii*
Advance Publication on the web February 8, 2017
doi:10.1246/cl.170081
© 2017 The Chemical Society of Japan
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Publication manuscripts.

1
Stereochemical courses and mechanisms of ring-opening cyclization of donor-acceptor
cyclopropylcarbinols and cyclization of 7-benzyloxy dibenzyl lignan lactones
Kazuya Sasazawa, Seijiro Takada, Toshihide Yubune, Naoya Takaki, Ryotaro Ota, and Yoshinori Nishii*
Department of Chemistry, Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano 386-8567, Japan.
(E-mail: nishii@shinshu-u.ac.jp)
Lewis acid-mediated ring-opening cyclization of trans-
plausible mechanisms can be proposed. One is Friedel-Crafts
type attack of aromatic ring to the benzyl cation to furnish the
trans-product based on the neighboring chiral center (trans-
selective SN1 pathway via cation A). The other one is the peri-
cyclic reaction-like6 mechanism via transition state B with
retention of the stereochemistry of cyclopropane. In France’s
report, a substrate bearing cyclic cis-2,3-disubstituents was
employed to investigate the diastereoselectivity and afforded
the cis-substituted tetracyclic product (Scheme 2). This result
seems to support the pericyclic reaction-like mechanism.
However, cyclic cation can prevent the construction of the
tetracyclic trans-cyclopentene product due to the high strain
(On the basis of our calculation using Spartan 09 using
B3LYP/6-31G(d), the energy of cis-product is 6.6 kcal/mol
lower than that of trans-product). Here, we report the
diastereoselectivities of the ring-opening cyclization of trans-
and cis-cyclopropanes 1a and 1b along with similar
cyclizations of 7-benzyloxy dibenzyl lignan lactones 4a and
4b. Based on those results, we elucidate the reaction
mechanism.
and cis-cyclopropanes 1a and 1b afforded the same trans-
dihydronaphthalene 2a. Moreover, Lewis acid-mediated
cyclization of 7R- and 7S-benzyloxy dibenzyl lignan lactones
5a and 5b also furnished the trans-tetralin 6a with high
diastereomeric and enantiomeric excess. Based on these
results, we rationalized the mechanisms of the cyclizations via
trans-selective
intramolecular
Friedel-Crafts
alkylation/cyclization via the SN1 pathway.
Cyclization reactions of donor-acceptor (D–A)
cyclopropanes are recognized as versatile protocols for
syntheses of carbocyclic and heterocyclic scaffolds.1,2 As part
of a program of synthetic studies using cyclopropropane
moieties,3,4 we achieved the first asymmetric total synthesis of
(+)-podophillic aldehydes using highly stereoselective Lewis
acid-mediated
ring-opening
cyclization
of
D–A
cyclopropylcarbinols to afford 1-aryl-1,2-dihydronaphthalene
with retention of stereochemistry and high enantiomeric
excess (Scheme 1).4f
O
O
MeO2C
CHO
CO2Me
MeO
O
O
MeO2C
CO2Me
cat. Rh2(esp)2
MeO
MeO
MeO
MeO
OR2
LiBEt3H
MeO
MeO
OR2
Br
CHO
cis
N2
Ph
(95% ee)
Ph
OTMS
2,6-lutidine
MeO
cat.
N
OMe
35%
H
OMe
OH
O
OH
O
CO2Me
O
CO2Me
MeO
MeO
O
OR2
Ca(NTf2)2
Bu4NPF6
R
R
R
MeO
S
OR
O
OMe
O
BF3•OEt2
trans-selective
SN1
A
MeO
C
MeO
OMe
D
O
MeO
OMe
OMe
MeO
MeO
F
(95% ee)
O
OMe
OMe
or
O
CO2Me
or
CO2Me
R
cis
OR
R
O
retention
31%
O
S
O
R
retention
S
H
MeO
MeO
pericyclic
reaction-like
OMe
B
(95% ee)
OMe
O
MeO
MeO
MeO
MeO
OMe
OMe
OMe
E
OMe
(+)-podophyllic aldehydes
High strain
inversion
G
0 %
Scheme 1. Our previously reported asymmetric total
synthesis of (+)-podophillic aldehydes.
Scheme 2. An example of diastereoselective ring-opening
Recentry, France and co-workers improved our method
by using catalytic amount of Ca(NTf2)2 instead of
stoichiometric amount of BF3·OEt2 or Sc(OTf)3.5 Although
the modified method can provide variety of cyclic compounds,
their method deals with racemic substrates. Meanwhile, the
mechanism of the reaction has not been revealed and two
cyclization in France’s report.
Investigation of the diastereoselectivities of the ring-opening
cyclizations of 1a and 1b is key to reveal the reaction
mechanism (Scheme 3). Following our previously reported
transformation4a of dichlorocyclopropane, the desired

2
substrates 1a and 1b were obtained in good yields. However,
cyclopropanations of (E)- and (Z)-1-phenyl-1-propenes using
-diazo--ketoester in the presence of the Rh2(esp)2 catalyst
used in France’s report5, or other catalysts such as Rh2(OAc)2,
Cu(acac)2, and Cu(OTf)2, all failed to afford desired
cyclopropanes due to the stereocongestions.7,8
substrates was as follows (Scheme 6): i)4h the Cu(OTf)2-
mediated oxy-homo-Michael reaction of bicyclic donor-
acceptor cyclopropanes 3, which was prepared via asymmetric
cyclopropanation9 using Hayashi-Jørgensen catalyst,10 with
1.0 equiv. of BnOH gave a 1:1 mixture of lactones 4a and 4b
(If 2.0 equiv. of BnOH is used, lactone 4a can be obtained
with a high stereoselectivity.), ii)13 benzylation of the resulting
1:1 mixture of lactones 4a and 4b using K2CO3 and
benzylbromide afforded the corresponding benzylated
lactones, and iii) finally, decarboxylation of the lactones with
LiCl at 189˚C yielded a 1:1-mixture of 5a and 5b. Lactones
5a and 5b were each isolated by silica gel column
chromatography.14
OH
OH
MeO
MeO
CO2Me
Me
MeO
MeO
CO2Me
Me
1b
or
1a
– OH–
– OH–
CO2Me MeO
– OH–
MeO
CO2Me
MeO
CO2Me
OH
MeO
MeO
CO2Me
Me
MeO
MeO
CO2Me
MeO
pericyclic
Me
Me
MeO
trans-selective
Me
or
MeO
H
H
or
BF3·OEt2
Me
pericyclic
reaction-like
reaction-like
SN1
SN1
B1
B2
A
A
1a
BF3·OEt2
OH
MeO
MeO
MeO
MeO
CO2Me
Me
CO2Me
Me
MeO
MeO
CO2Me
Me
MeO
MeO
CO2Me
Me
2a
trans-selective
?
2b
2a
1b
Scheme 3. Speculated mechanisms for the ring-opening
cyclizations of substrates 1a and 1b
Scheme 5. Mechanisms for the ring-opening cyclizations of
donor-acceptor cyclopropyldarbinols 1a and 1b.
MeO
MeO
CO2Me
Me
BF3·OEt2
O
O
O
H
1a
H
MeO2C
MeO2C
MeO2C
Ar1
BnOH (1.0 equiv.)
Cu(OTf)2
O
+
O
R
R
O
BnO
H
R
H
BnO
Ph
2a

H
Ar1
H
Ar1
(0.5 equiv.)
3 (95% ee)
Ar1 = trimethoxyphenyl
72%
4a
85% (1:1) 4b
MeO
MeO
CO2Me
O
1)
O
K2CO3
O
O
O
1b
2a
H
H
O
Me
0%
Br
64%
O
O
R
O
R


BnO
H
7
H
7
2b
O
+
Ph
BnO
H
Ar1
5a
34%
R
H
Ar1
5b
34%
2)
S
LiCl, 189ºC
(95% ee)
Scheme 4. Ring-opening cyclizations of 1a and 1b.
Treatment of 1a with BF3·OEt2 produced 2a in 72 % yield as
a single isomer (Scheme 4). During the reaction with
retention, the trans-conformation of cyclopropane 1a was
preserved in the trans-conformation of 2a. Remarkably, the
same reaction of 1b also afforded 2a in 64% yield as a single
isomer, resulting in an inversion at the donor site; this result is
the first example of a formal homo-Nazarov-type ring-
opening cyclization with complete inversion. Thus, the same
trans-product 2a was obtained from the reactions of both
Scheme 6. Preparations of 7R and 7S-benzyloxy dibenzyl
lignan lactones 5a and 5b.
O
O
O
H
H
O
O
O
BnO
O
R

BF3·OEt2
O
 R
R
H
R
H
H
H
5a
(95% ee)
OMe
6a
MeO
MeO
OMe
diastereomers.
These results undoubtedly support the
OMe
84 %
(95% ee)
OMe
O
O
stepwise mechanism including the F-C type attack to the
cation A to furnish the trans-product 2a based on the
neighboring chiral centre (Scheme 5). Thus, we verified the
proposed mechanism in our previous report.4f The mechanism
distinguishes the ring-opening cyclization of D–A
cyclopropylcarbinols (formal homo-Nazarov cyclization11-
type reaction) from concerted reactions or pericyclic reactions
such as the original Nazarov cyclization.12
H
O
BnO
O

R
BF3·OEt2
H
6a
93 %
(95% ee)
H
5a + 5b
(95% ee)
dr = 5a/5b = 1/1
OMe
MeO
OMe
As a similar cyclization, we investigated the Lewis acid-
mediated cyclization of 5a and 5b. The synthesis of these
Scheme 7. BF3·OEt2-mediated cyclizations of 7-benzyloxy
dibenzyl lignan lactones 5a and a 1:1 mixture of (5a and 5b).

3
Y.; Yoshida, T.; Asano, H.; Wakasugi, K.; Morita, J.; Aso, Y.;
Yoshida, E.; Motoyoshiya, J.; Aoyama, H.; Tanabe, Y. J. Org.
Chem. 2005, 70, 2667.
Treatment of 5a with BF3·OEt2 afforded trans-tetralin 6a as
a single isomer in 84% yield (Scheme 7).15 Notably, the same
reaction of a 1:1 mixture of 5a and the other diastereomer 5b
also furnished the same isomer 6a in 93% yield as a sole
product. Hence, both diasteremers 5a and 5b provide the
same cation A and highly trans-selective F-C cyclization
proceed through the SN1 pathway utilizing the neighboring
chiral centre (Scheme 8). Thus, optically active tetralin 6a
(95% ee) was obtained from enantioenriched dibenzyl lignan
lactones 5a and 5b (95% ee).
4.
a) Nagano, T.; Motoyoshiya, J.; Kakehi, A.; Nishii, Y. Org.
Lett. 2008, 10, 5453.
b) Yoshida, E.; Nagano, T.;
Motoyoshiya, J.; Nishii, Y. Chem. Lett. 2009, 38, 1078 (open
access). c) Yoshida, E.; Yamashita, D.; Sakai, R.; Tanabe, Y.;
Nishii, Y. Synlett, 2010, 2275. d) Yoshida, E.; Nishida, K.;
Toriyabe, K.; Taguchi, R.; Motoyoshiya, J.; Nishii, Y. Chem.
Lett. 2010, 39, 194. e) Sakuma, D.; Ito, J.; Sakai, R.; Taguchi,
R.; Nishii, Y. Chem. Lett. 2014, 39, 194 (open access). f) Ito,
J.; Sakuma, D.; Nishii, Y. Chem. Lett. 2015, 44, 297 (open
access). g) Sakuma, D.; Yamada, Y.; Sasazawa, K.; Nishii, Y.
Chem. Lett. 2015, 44, 818 (open access). h) Takada, S.; Iwata,
K.; Yubune, T.; Nishii, Y. Tetrahedron Lett. 2016, 57, 2422. i)
Takada, S.; Saito, T.; Iwata, K.; Nishii, Y. Asian J. Org. Chem.
2016, 5, 1225.
O
O
O
H
H
O
O
BF3·OEt2
O
O
O
5.
6.
Sandridge, M. J.; France, S. Org. Lett. 2016, 18, 4218.
Nazalov cyclization is a pericyclic reaction that belongs to the
class of 4-electrocyclization, which undergoes conrotatory
ring closure.
BnO
H
5a
7.
8.
González-Bobes, F.; Fenster, M. D. B.; Kiau, S.; Kolla, L.;
Kolotuchin, S.; Soumeillant, M. Adv. Synth. Catal. 2008, 350,
813.
In the Rh-catalyzed cyclopropanation of (E)- and (Z)-1-
phenyl-1-propenes, dimethyl -diazo-malonate narrowly
furnish the tetrasubstituted cyclopropanes, whereas more
bulky methyl -diazo-benzoylacetate did not afford desired
cyclopropanes.
MeO
MeO
OMe
OMe
OMe
OMe
H
BF3·OEt2
O
trans-selective
O
O
O
O
O
O
BnO
O
H
H
H
9.
Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc.
2007, 129, 10886.
5b
6a
MeO
OMe
10. References for the original Hayashi-Jørgensen catalyst, see: a)
Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. b) Hayashi, Y.; Gotoh,
H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44,
4212. c) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T.
C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 18296.
MeO
OMe
OMe
OMe
Scheme 8. Mechanisms for the cyclizations of benzyloxy
dibenzyl lignan lactones 5a and 5b.
11. a) De Simone, F. Andès, J.; Torosantucci, R.; Waser, J. Org.
Lett. 2009, 11, 1023. b) Patil, D. V.; Phun, L. H.; France, S.
Org. Lett. 2010, 12, 5684-5687. c) Phun, L. H.; Patil, D. V.;
Cavitt, M. A.; France, S. Org. Lett. 2011, 13, 1952–1955. d)
Patil, D. V.; Cavitt, M. A.; Grzybowski, P.; France, S. Chem.
Commun. 2011, 47, 10278-10280. e) Shenje, R.; Williams, C.
W.; Francois, K. M.; France, S. Org. Lett. 2014, 16, 6468-
6471. f) Cavitt, M. A.; France, S. Synthesis, 2016, 48, 1910-
1919.
12. Some reviews for Nazarov cyclization, see a) Santelli-Rpuvier,
C.; Santelli, M.; Sntheis, 1983, 429. b) Krohn, K. Org. Syn.
Highlites, 1991, 137. c) Habermas, K. L. Denmark, S. E.;
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14. Absolute configuration of 4a was determined by X-ray
crystallographic analysis (see supplementary information of
ref. 4h). Based on the comparison of the spectral data, stereo
structures of 4a and 4b were also determined. Therefore,
absolute configurations of C-7 of 5a and 5b were
characterized the same as those of 4a and 4b.
In conclusion, Lewis acid-mediated ring-opening cyclization
of cyclopropylcarbinol and simple cyclization of 7-benzyloxy
dibenziy lignan lactones respectively provided trans-isomers.
Based on the results, we verified the mechanism of those
cyclizations via trans-selective F-C reaction on SN1 pathway.
This research was partially supported by Grant-in-Aids
for Scientific Research on Basic Areas (A) ‘15H01789’, Basic
Areas (B) ‘26288089’ and (C) ‘15K05420’ from JSPS. We
thank Mr. Morikawa and Dr. Nomura (Shinshu university) for
their calculation of energies of cis-and trans-products in
scheme 2.
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