Thermal decarboxylative Nazarov cyclization of cyclic enol carbonates involving chirality transfer

Article abstract of DOI:10.1246/cl.190763

Decarboxylative Nazarov cyclization of chiral cyclic enol carbonates proceeded to afford chiral 2-cyclopentenones with excellent chirality transfer under thermal conditions without any catalyst. Interestingly, the thermal decarboxylative Nazarov cyclization furnished the desired product with better chirality transfer than the Lewis acid-catalyzed reaction.

Full text of DOI:10.1246/cl.190763

CL-190763
Received: October 9, 2019 | Accepted: October 31, 2019 | Web Released: December 5, 2019
Thermal Decarboxylative Nazarov Cyclization
of Cyclic Enol Carbonates Involving Chirality Transfer
Akane Kozuma, Keiichi Komatsuki, Kodai Saito, and Tohru Yamada*
Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
E-mail: yamada@chem.keio.ac.jp
Decarboxylative Nazarov cyclization of chiral cyclic enol
C(2) of the 5-membered enol carbonate is transferred to C(4)
and C(5) of the product.6 The cyclic carbonates were prepared
by silver-catalyzed incorporation of carbon dioxide into chiral
propargyl alcohols. The efficiency of the chirality transfer is
strongly affected by the reaction conditions, such as catalysts and
solvents, which can contribute to the stabilization of the cationic
intermediate 1. Additionally, the introduction of electron-
donating groups on the substrates causes a decrease in chirality
transfer. For example, the reaction of 2b (R = 4-CH3C6H4, 82%
ct) showed lower chirality transfer compared with 2a (R = Ph,
95% ct) (Scheme 2). To examine the effect of the substituent R in
more detail, we newly prepared 2c (R = 4-MeOC6H4) in this
work and employed it in the reaction, which resulted in a drastic
decrease of chirality transfer (21% ct). We hypothesized that
good chirality transfer occurs when O(2) tightly coordinates to
C(2) before the decarboxylation and C(4) and C(5) bond forma-
tion. However, in the case of 2c, by addition of a Lewis acid and
the introduction of an electron-donating group on the substrate,
the contribution of a zwitterionic structure, such as 5c, is not
negligible compared with the suitable structure 4c (Scheme 3).
To improve the chirality transfer, the development of a thermal
decarboxylative Nazarov cyclization for the asymmetric synthe-
sis of 2-cyclopentenones is described in the present report.7
Based on this hypothesis, we initially investigated whether
the reaction proceeds under catalyst-free conditions. The
reaction temperature and solvent were screened first (Table 1).
carbonates proceeded to afford chiral 2-cyclopentenones with
excellent chirality transfer under thermal conditions without any
catalyst. Interestingly, the thermal decarboxylative Nazarov
cyclization furnished the desired product with better chirality
transfer than the Lewis acid-catalyzed reaction.
Keywords: Electrocyclization
| Decarboxylation |
Chirality transfer
Asymmetric construction of cyclopentenone units is highly
desired due to their wide utility as building blocks for the
synthesis of a variety of natural products and biologically-active
compounds.1 Nazarov cyclization, a conrotatory 4π electro-
cyclization reaction, is promoted by a Lewis acid to provide the
stereoselective synthesis of cyclopentenones.2 The consideration
of torquoselectivity,3 i.e., the control of clockwise/counter-
clockwise rotation in electrocyclization reactions, is essential for
the production of chiral cyclopentenones based on the Nazarov
cyclization, because it defines the newly generated stereochem-
istry. Some solutions for this issue, such as a substrate control
strategy using a chiral auxiliary,3 etc.,4 have been reported.
We have recently developed an asymmetric synthesis of
cyclopentenones based on chirality transfer through decarboxyl-
ative Nazarov cyclization of cyclic enol carbonates by using a
Lewis acid catalyst.5 In a general Nazarov cyclization, the forma-
tion of the pentadienyl cation intermediate 1 involving the loss of
chirality at C(2) (Scheme 1) is inevitable. However, in the
decarboxylative Nazarov cyclization, cleavage of the C(2)-O(2)
bond and subsequent bond formation between C(4) and C(5)
occur before racemization, and therefore the stereochemistry at
O
O
O
O
B(C6F5)3 (10 mol%)
Me
Ph
Ph
Me
t-Butylbenzene
-40 °C, 12 h
R
3
Decarboxylative Nazarov cyclization
LA
R
2
R = Ph (3a); 90%, 95% Ct
O
(>99% ee)
O
R = 4-CH3C6H4 (3b); 94%, 82% Ct
R = PMP (3c); 72%, 21% Ct
O
O
LA
(cat.)
O
O
R1
R1
Ct: Chirality transfer
PMP = 4-methoxyphenyl
R5
R5
R4
2
5
R3
R4
R3
4
Scheme 2. Initial examination of the substituent effect.
R2
[E/Z]
R2
Cyclic carbonates
-
-
1
LA
LA
O
LA
O
O
O
O
O
R1
R3
O
R5
R4
Nazarov
cyclization
5
4
2
O
Me
O
Me
O2
2 Me
R'
R'
R'
5
- CO2
- LA
R2
4
2-Cyclopentenones
[trans/cis]
Features: (1) Stereospecific and regiospecific reaction
(2) Catalytic reaction
OMe
OMe
OMe
5c
(3) Chirality at C(2) transfers into C(4) and C(5)
4c
Scheme 1. Decarboxylative Nazarov cyclization.
Scheme 3. Plausible intermediates.
60 | Chem. Lett. 2020, 49, 60–63 | doi:10.1246/cl.190763
© 2020 The Chemical Society of Japan

Table 1. Examination of reaction conditions
Table 2. Substrate scope
O
O
O
O
O
O
R1
R3
O
R5
R4
O
Optimized conditions
R1
Me
Ph
R5
Ph
Me
Solvent
Temp, Time
R3
R4
PMP
R2
R2
PMP
3c
2
3
2c
Entry
Product
Conditionsa Yield/Ct (%)b,c
80 °C, 12 h 84%, 81% Ct
Entry
1c
2
3
4
5
6
7
Solvent
Temp/°C Time/h Yield/%a Ct/%b
O
t-butylbenzene
t-butylbenzene
t-butylbenzene
t-butylbenzene
benzene
¹40
40
60
80
60
70
80
60
80
70
12
96
72
12
30
72
12
30
12
90
72
n. r.
80
84
83
81
87
84
74
86
21
®
79
81
71
75
75
77
81
69
Me
Ph
1
PMP
3c
L. A.
72%, 21% Ct
C6F6
mesitylene
toluene
trimethylphenylsilane
cyclohexane
O
60 °C, 72 h 80%, 73% Ct
Me
Ph
MeO
8
9
10
2
MeO
aIsolated yields. bOptical purity was determined by HPLC on a
chiral stationary phase. Chirality transfer was calculated using:
Ct (%) = ee of 3c (% ee)/ee of the corresponding propargyl
alcohol 6c (% ee). cB(C6F5)3 (10 mol %) and MS 5¡ was used.
n. r. = no reaction.
L. A.
88%, 32% Ct
OMe
3d
O
80 °C, 12 h 81%, 88% Ct
Me
Ph
3
Although the reaction of 2c8,9 did not proceed at 40 °C (Entry 2),
it was fully converted into 3c at 60 °C in 80% yield with 79% ct
(Entry 3).10,11 At higher temperatures, 2c was consumed faster
and the selectivity was maintained (Entry 4). When the reaction
was carried out in benzene or hexafluorobenzene, a decrease in
ct was observed (Entries 5 and 6). Alkyl-substituted benzenes,
such as mesitylene and toluene, were employed for this reaction
to give 3c with 75% ct and 77% ct, respectively (Entries 7 and
8). The use of trimethylphenylsilane showed good chirality
transfer (81% ct), but with a slight decrease in the yield of 3c
(Entry 9). Hydrocarbon solvents, such as cyclohexane, did not
have a favorable effect on the selectivity of this reaction
(Entry 10). Based on the above results, it was found that
benzene derivatives bearing a bulky substituent were suitable as
solvents for this reaction in terms of the chirality transfer, with
tert-butylbenzene being the optimal solvent.
With the optimized reaction conditions in hand, the scope of
the thermal decarboxylative Nazarov cyclization was examined
and compared with the results under Lewis acid-catalyzed con-
ditions. The reactions of 2d and 2e bearing a 2,4,6-trimethoxy
group and a 4-methylthiophenyl group at R2, respectively,
proceeded to provide 3d and 3e in good yields with a large
improvement in the chirality transfer (Entries 2 and 3). Next,
introduction of an electron-donating group on R1 was attempted.
Substrates 2f and 2g substituted with the PMP group and the
MOM-protected phenolic group were tolerant to the conditions,
and the corresponding cyclopentenones 3f and 3g were obtained
in 85% and 93% yields with 98% ct and 79% ct, respectively
(Entries 4 and 5). The reaction time was shortened and the yield
of 3f was further improved to 87% by microwave irradiation.
Substrates containing 3,4-dimethoxyphenyl (2h) and 4-methyl-
thiophenyl (2i) groups at R1 were also applicable and a signi-
ficant improvement of chirality transfer was observed under
thermal conditions (Entries 6 and 7). The thermal reaction of 2j
L. A.
84%, 14% Ct
MeS
PMP
3e
O
85%, 98% Ct
87%, 98% Ctd
Me
80 °C, 12 h
L. A.
4
5
6
80%, 69% Ct
3f
O
MOMO
80 °C, 24 h 93%, 79% Ct
Me
L. A.
83%, 66% Ct
3g
O
O
MeO
MeO
60 °C, 72 h 83%, 90% Ct
Me
Me
L. A.
73%, 51% Ct
3h
MeS
80 °C, 24 h 90%, 98% Ct
7
8
L. A.
86%, 65% Ct
3i
O
60 °C, 24 h 83%, 99% Ct
Ph
PMP
Me
Me
L. A.
92%, 99% Ct
3j
Continued on next page:
Chem. Lett. 2020, 49, 60–63 | doi:10.1246/cl.190763
© 2020 The Chemical Society of Japan | 61

Supporting Information is available on https://doi.org/
10.1246/cl.190763.
Continued:
Entry
Product
Conditionsa Yield/Ct (%)b,c
60 °C, 24 h 86%, 98% Ct
O
References and Notes
1
Reviews of the synthesis of cyclopentenones, see: a) R. A.
Ellison, Synthesis 1973, 397. b) G. Piancatelli, M. D’Auria,
F. D’Onofrio, Synthesis 1994, 867. c) S. E. Gibson, S. E.
Lewis, N. Mainolfi, J. Organomet. Chem. 2004, 689, 3873.
d) S. P. Simeonov, J. P. M. Nunes, K. Guerra, V. B. Kueteva,
C. A. M. Afonso, Chem. Rev. 2016, 116, 5744.
PMP
Ph
Me
9
Me
L. A.
82%, 71% Ct
3k
O
150 °C, 12 h 75%, 45% Ct
Me
Me
2
Reviews of Nazarov cyclization, see: a) A. J. Frontier, C.
Collison, Tetrahedron 2005, 61, 7577. b) M. A. Tius, Eur. J.
Org. Chem. 2005, 2193. c) H. Pellissier, Tetrahedron 2005,
61, 6479. d) T. N. Grant, C. J. Rieder, F. G. West, Chem.
Commun. 2009, 5676. e) N. Shimada, C. Stewart, M. A.
Tius, Tetrahedron 2011, 67, 5851. f) T. Vaidya, R.
Eisenberg, A. J. Frontier, ChemCatChem 2011, 3, 1531.
g) W. T. Spencer, III, T. Vaidya, A. J. Frontier, Eur. J. Org.
Chem. 2013, 3621. h) M. A. Tius, Chem. Soc. Rev. 2014, 43,
2979. i) M. J. Di Grandi, Org. Biomol. Chem. 2014, 12,
5331. j) D. R. Wenz, J. Read de Alaniz, Eur. J. Org. Chem.
2015, 23.
a) W. Kirmse, N. G. Rondan, K. N. Houk, J. Am. Chem. Soc.
1984, 106, 7989. b) K. N. Houk, in Strain and Its
Implications in Organic Chemistry, ed. by A. de Meijere,
S. Blechert, Kluwer Academic, Dordrecht, 1989, Vol. 273,
pp. 25-37. doi:10.1007/978-94-009-0929-8_2. c) K. N.
Houk, Y. Li, J. D. Evanseck, Angew. Chem., Int. Ed. Engl.
1992, 31, 682.
a) G. Metha, N. Krishnamurthy, J. Chem. Soc., Chem.
Commun. 1986, 1319. b) S. E. Denmark, K. L. Habermas,
G. A. Hite, Helv. Chim. Acta 1988, 71, 168. c) S. E.
Denmark, M. A. Wallace, C. B. Walker, Jr., J. Org. Chem.
1990, 55, 5543. d) L. N. Pridgen, K. Huang, S. Shilcrat, A.
Tickner-Eldridge, C. DeBrosse, R. C. Haltiwanger, Synlett
1999, 1612. e) D. J. Kerr, C. Metje, B. L. Flynn, Chem.
Commun. 2003, 1380. f) C. Prandi, A. Ferrali, A. Guarna, P.
Venturello, E. G. Occhiato, J. Org. Chem. 2004, 69, 7705.
g) R. D. Mazzola, Jr., T. D. White, H. R. Vollmer-Snarr, F. G.
West, Org. Lett. 2005, 7, 2799. h) D. J. Kerr, M. Miletic,
J. H. Chaplin, J. M. White, B. L. Flynn, Org. Lett. 2012, 14,
1732. i) B. L. Flynn, N. Manchala, E. H. Krenske, J. Am.
Chem. Soc. 2013, 135, 9156. j) N. Manchala, H. Y. L. Law,
D. J. Kerr, R. Volpe, R. J. Lepage, J. M. White, E. H.
Krenske, B. L. Flynn, J. Org. Chem. 2017, 82, 6511.
a) K. Komatsuki, A. Kozuma, K. Saito, T. Yamada, Org.
Lett. 2019, 21, 6628. b) K. Komatsuki, Y. Sadamitsu, K.
Sekine, K. Saito, T. Yamada, Angew. Chem., Int. Ed. 2017,
56, 11594.
Examples of asymmetric Nazarov cyclization based on a
chirality transfer, see: a) X. Shi, D. J. Gorin, F. D. Toste,
J. Am. Chem. Soc. 2005, 127, 5802. b) O. N. Faza, C. S.
López, R. Álvarez, A. R. de Lera, J. Am. Chem. Soc. 2006,
128, 2434. Asymmetric Nazarov cyclization based on
chirality transfer of chiral allene, see: c) H. Hu, D. Smith,
R. E. Cramer, M. A. Tius, J. Am. Chem. Soc. 1999, 121,
9895. d) M. A. Tius, Acc. Chem. Res. 2003, 36, 284.
Examples of catalyst-free Nazarov cyclization, see: a) F.
Douelle, L. Tal, M. F. Greaney, Chem. Commun. 2005, 660.
b) M. Miao, H. Xu, Y. Luo, M. Jin, Z. Chen, J. Xu, H. Ren,
10
11
Ph
L. A.
63%, 0% Ct
3l
O
150 °C, 12 h 83%, 62% Ct
Ph
Ph
L. A.
85%, 51% Ct
3m
O
89%, 99% Ct
92%, 99% Cte
Ph
Me
100 °C, 12 h
L. A.
12
13
3
4
92%, 99% Ct
3n
O
Br
80 °C, 12 h 65%, 99% Ct
Me
L. A.
80%, 99% Ct
3o
aL. A.: B(C6F5)3 (10 mol %), ¹40 °C, MS 5¡, 12 h. Isolated
b
c
yields. Optical purity was determined by HPLC on a chiral
stationary phase. dMicrowave (80 W) was irradiated for 9 h.
eIsolated 2n was used as the substrate. Chirality transfer was
calculated using: Ct (%) = ee of 3 (% ee)/ee of 6 (% ee).
bearing a tri-substituted olefin with a PMP group at R2
proceeded as successfully as the reaction under Lewis-acid
conditions (Entry 8). On the other hand, a large difference in
chirality transfer was observed depending on the reaction
conditions in the case of the synthesis of tetrasubstituted 2-
cyclopentenone 3k having a PMP group at R1 (Entry 9). The
conversion of 2l derived from a terminal alkyne showed lower
reactivity and the corresponding 3l was obtained with much
better chirality transfer than under Lewis acid conditions
(Entry 10). When substrates 2m-2o were employed under the
thermal conditions, the efficient construction of the correspond-
ing cyclopentenones 3m-3o was accomplished (Entries 11-13).12
In summary, the asymmetric synthesis of 2-cyclopentenone
derivatives based on decarboxylative Nazarov cyclization
involving chirality transfer under thermal conditions was
achieved using chiral cyclic carbonates, which were prepared
by silver-catalyzed incorporation of carbon dioxide into a chiral
propargyl alcohol. The substrate scope was successfully ex-
tended by the development of catalyst-free conditions. Further
investigation of the reaction mechanism and application of the
reaction to the synthesis of more complex molecules are
underway.
5
6
7
62 | Chem. Lett. 2020, 49, 60–63 | doi:10.1246/cl.190763
© 2020 The Chemical Society of Japan

Synthesis 2018, 50, 349.
and it was confirmed that the present reaction also proceeded
through a clockwise rotation as well as the reaction of Lewis
acid conditions.
8
As previously reported in ref 5, 2c was prepared by the
silver-catalyzed CO2 incorporation reaction into optically-
pure propargyl alcohol 6c.
11 Although the driving force of this reaction is unclear so far,
the decarboxylation might be triggered by a polarization of
C(2)-O(2) bond in the transition state under thermal
conditions.
12 Among substrates employed for this reaction, some sub-
strates showed a better chirality transfer in the Lewis acid
conditions as follows.
CO2 (1 MPa)
OH
AgOAc (10 mol%)
DBU (1 equiv)
Ph
Me
2c
Toluene
25 °C
PMP
6c
9
a) W. Yamada, Y. Sugawara, H. M. Cheng, T. Ikeno, T.
Yamada, Eur. J. Org. Chem. 2007, 2604. b) K. Sekine, T.
Yamada, Chem. Soc. Rev. 2016, 45, 4524.
O
90%, 95% Ct (LA)
R2 = Ph;
78%, 79% Ct (100 °C, 20 h)
Me
Ph
83%, 97% Ct (LA)
80%, 70% Ct (100 °C, 72 h)
R2 = C6H4CO2Me;
10 The correspondence of absolute configurations of a propar-
gyl alcohol and a 2-cyclopentenone was determined by the
comparison with 1o and 3o in the previous report (ref 5a)
R2
Chem. Lett. 2020, 49, 60–63 | doi:10.1246/cl.190763
© 2020 The Chemical Society of Japan | 63