Enantioselective Nazarov cyclization catalyzed by a cinchona alkaloid derivative

Article abstract of DOI:10.1016/j.tetlet.2014.12.136

Nucleophilic catalysts for a 1,6 addition/Nazarov cyclization/elimination sequence were evaluated for their ability to induce enantioselectivity in the electrocyclization step. Of the tertiary amines examined, it was found that a cinchona alkaloid derivat

Full text of DOI:10.1016/j.tetlet.2014.12.136

Tetrahedron Letters 56 (2015) 3523–3526
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Enantioselective Nazarov cyclization catalyzed by a cinchona alkaloid
derivative
⇑
Yu-Wen Huang, Alison J. Frontier
Department of Chemistry, University of Rochester, Rochester, NY 14627, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Nucleophilic catalysts for a 1,6 addition/Nazarov cyclization/elimination sequence were evaluated for
their ability to induce enantioselectivity in the electrocyclization step. Of the tertiary amines examined,
it was found that a cinchona alkaloid derivative was able to generate substituted 5-hydroxy c-methylene
cyclopentenones with excellent enantioselectivity. The study results suggest that successful cyclization
depends upon the ability of the dienyl diketone substrate to readily adopt an s-cis conformation.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 14 December 2014
Accepted 26 December 2014
Available online 13 January 2015
Keywords:
Nazarov cyclization
Enantioselective
Cinchona alkaloid
O
OH
Introduction
R1
R2
Lewis acid
(1)
R3
Nu
5-Hydroxycyclopentenones are an important motif in natural
products and other valuable small molecules. For example, stemo-
namide1 is isolated from Stemonaceae that are used in Chinese and
Japanese medicine for cough relief,2 phorbol3 has tumor-promot-
ing activity through the activation of protein kinase C,4 and prze-
walskin B5 has weak anti-HIV-1 activity (Fig. 1).
Nu
2
O
O
OH
tertiary
amine
R1
O
R2
R2
(2)
(3)
R
3 = H
R1
R3
3
1
One method for the synthesis of substituted cyclopentenones is
the Nazarov cationic electrocyclization, which is often initiated by
activation of a carbonyl group, with either protic acid or Lewis
acid.6 It has become possible, using acid catalysis, to achieve enan-
tioselective cyclizations of divinyl ketone derivatives.7 In addition
to these achievements, alternative methods for generating penta-
dienyl cation intermediates have become increasingly common,6f
expanding the utility and convenience of the Nazarov cyclization
as a synthetic strategy. In ongoing studies, we have developed a
Nazarov cyclization variant that is initiated by the 1,6 conjugate
addition of a nucleophile to a dienyl diketone.8 In these reactions,
various neutral nucleophiles (such as malonate derivatives, pri-
mary, and secondary amines)8 and anionic nucleophiles (sodium
alkoxide and sodium thiolate)9 are effective promoters, generating
5-hydroxycyclopentenones 2 with excellent diastereoselectivity
(Eq. 1). In addition, tertiary amines initiate either the addition–
tertiary
amine
R
O
R2
R1
3 = alkyl
O
R3
4
Herein, we describe an asymmetric version of the addition/electro-
cyclization/elimination, catalyzed by a cinchona alkaloid derivative.
The sequence generates 5-hydroxycyclopentenones (cf. Eq. 2 and
Fig. 1) in enantioenriched form.
The mechanism proposed for the Eq. 2 cyclization inspired our
experimental design. As shown in Scheme 1, addition of a tertiary
amine to 5 in a 1,6-fashion, followed by single bond rotation, is
thought to generate intermediate 7. The 4
p electrocyclization of
7, followed by elimination of the tertiary amine, then furnishes
elimination process (Eq. 2) or a 6
p electrocyclic reaction (Eq. 3)
to afford methylene cyclopentenones 3 and 2H-pyrans 4.9
the
c-methylene cyclopentenone 3. This reaction sequence is
similar to the Morita–Baylis–Hillman reaction10 and the Rauhut–
Currier reaction.11 Enantioselective versions of these two reactions
have been achieved with the use of cinchona alkaloids12 and a
chiral guanidine.13 We sought to examine these catalysts in the
⇑
Corresponding author. Tel.: +1 585 275 2568.
E-mail address: frontier@chem.rochester.edu (A.J. Frontier).
http://dx.doi.org/10.1016/j.tetlet.2014.12.136
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

3524
Y.-W. Huang, A. J. Frontier / Tetrahedron Letters 56 (2015) 3523–3526
OH
H
O
OH
H
O
Me
HO
O
O
O
R2
Me
Me
O
Me
tertiary
amine
bond
O
R2
O
R2
O
OH
rotation
Me
O
R1
O
O
OMe
R1
R1
H
H
O
HO
Me
5
N
NR3
Me
O
6
7
NR3
O
Me Me
Me
HO
phorbol
π
4
electrocyclization
stemonamide
przewalskin B
Figure 1. Natural products bearing 5–hydroxycyclopentenones.
O
OH
O
R1
R1
O
OH
R1
1,6-conjugate addition sequence, to evaluate whether they could
R2
R2
H
effect the enantioselective 4
p
electrocyclization of intermediate 7.
R2
NR3
NR3
8
3
9
Results and discussion
Scheme 1. Proposed mechanism for the formation of 3.
In the screen of different tertiary amines, we found that either
catalytic or stoichiometric amount of tetramethyl guanidine (TM-
guanidine) led us to 11 (Table 1, entries 1 and 2). The reaction with
a stoichiometric amount of DABCO allowed us to obtain the prod-
uct 11 in 93% yield (entry 3). While trying to use quinidine, no
reaction was observed (entries 4 and 5). In the attempt of using
N-methylephedrine (12), low enantioselectivity was observed
(entries 6–8). Fortunately, with Hatakeyama’s chiral cinchona alka-
loid 13, 88:12 er was obtained with 74% yield with 86% conversion
nucleophilic tertiary nitrogen atom, and that the phenol group of
13 serves as a Brønsted acid. Upon screening different tempera-
tures, we found the enantioselectivity was not affected by increas-
ing temperature to 50 °C which increased the rate of the reaction
from 43 h to 20 h (entry 10). We increased the enantioselectivity
up to 97:3 er when the reaction run at ꢀ20 °C, however, this also
decreased the rate of the reaction (entry 12). In addition, changing
the solvent from THF to DMF dramatically decreased the reaction
time and optimized the enantioselectivity to 99:1 er (entry 15).
We could reduce the catalyst loading to 3 mol % with excellent
selectivity (entries 15–18).
With optimized conditions in hand, we began to examine the
substrate scope. We were pleased to find that both electron-with-
drawing and electron-donating aryl substituents are tolerated in
the addition/electrocyclization/elimination reaction (Table 2, entries
1–3), as well as heteroaromatic substituents (entries 4 and 5). High
enantiomeric ratios were obtained in all cases. When the R2 substi-
tuent was either cyclohexyl or trimethylsilyl (TMS), we also obtained
the desired products with excellent enantioselectivities (entries 6
OMe
OH
N
NH
NMe2
TM-guanidine
Me
NMe2
OH
N-methylephedrine (12)
OH
O
Me2N
N
N
N
quinidine
13
of starting material in 43 h (entry 9).12 Hatakeyama and coworkers
hypothesize that the enhanced reactivity of 13 relative to quinidine
can be attributed to the reduced steric demand around the
Table 1
Asymmetric synthesis of addition–elimination product 11a
O
O
HO
Ph
O
Ph
nucleophile
Ph
Ph
10
11
Entry
Nucleophile (mol %)
Solvent (0.1 M)
Time
Conversion (%)
Yield (%)
erb
1
TM-guanidine (10)
TM-guanidine (130)
DABCO (100)
Quinidine (10)
Quinidine (100)
12 (10)
12 (100)
12 (100)
13 (10)
13 (10)
13 (10)
13 (10)
13 (5)
13 (1)
13 (10)
13 (5)
13 (3)
13 (1)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMF
DMF
DMF
DMF
24 h
2 h
2 h
—
—
—
100
100
100
—
—
—
47
54
93
—
—
—
—
—
—
—
—
—
—
58:42
88:12
89:11
—
97:3
90:10
85:15
99:1
99:1
99:1
97:3
2
3c
4
5
6
7d
8d,e
9
—
—
—
24 h
43 h
20 h
—
4 d
5 d
7 d
1.5 h
2.5 h
4.5 h
21 h
60
86
95
—
82
80
77
100
100
95
86
46
74
85
—
73
74
19
76
80
88
52
10d
11f
12g
13
14
15
16
17
18
a
b
c
d
e
f
Reaction conditions were as described in table.
Enantioselectivities were determined by chiral Super-critical Fluid Chromatography (SFC).
Reaction run at 80 °C.
Reaction run at 50 °C.
Y(OTf)3 (1 mol %) and LiCl (2 equiv) were used.
Reaction run at ꢀ78 °C.
g
Reaction run at ꢀ20 °C.

Y.-W. Huang, A. J. Frontier / Tetrahedron Letters 56 (2015) 3523–3526
3525
Table 2
In conclusion, we have described a highly enantioselective 1,6
addition/Nazarov cyclization/elimination reaction catalyzed by
cinchona alkaloid derivative 13. In the course of screening sub-
strates, we also found the size of R2 is critical to the efficiency of
the reaction sequence. Further investigations are underway,
including asymmetric 1,6-conjugate addition initiated Nazarov
reaction.
Scope of the addition/enantioselective cyclization/elimination reactiona
O
O
R2
HO
O
13
R1
3 mol%
R2
R1
DMF, temp., time
5
3
Entry
1
Temp (°C)
Time
4.5 h
Product
Yield (%)
88b
ere
Acknowledgments
O
HO
Ph
Ph
25
99:1
We thank Dr. Furong Sun (UIUC) for HRMS analysis. We also
thank the NIH (NIGMS R01: GM079364) and National Science
Foundation (CHE-0849892) for funding this work. We thank Dr.
Steven D. Jacob for performing the reaction in Table 1 entry 3.9
11
O
HO
Ph
2
3
25
25
20 h
1 h
73
98
97:3
OMe
14
O
Supplementary data
HO
Ph
>99:1
NO2
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.12.
136.
15
O
HO
4
5
6
7
25
25
50
25
1.5 h
8 h
Ph
97
84
56
46c
97:3
96:4
96:4
>99:1
O
References and notes
16
O
HO
1. Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat. Prod. 1994, 57, 665–669.
O
Ph
2. (a) Aloise Pilli, R.; da Conceicao Ferreira de Oliveria, M. Nat. Prod. Rep. 2000, 17,
117–127; (b) Alibés, R.; Figueredo, M. Eur. J. Org. Chem. 2009, 2009, 2421–2435.
3. Okuda, T.; Yoshida, T.; Koike, S.; Toh, N. Phytochemistry 1975, 14, 509–515.
4. Hirota, M.; Suguri, H.; Endo, Y.; Shudo, K.; Wongchai, V.; Hecker, E.; Fujiki, H.
Cancer Res. 1988, 48, 5800–5804.
17
O
HO
Ph
7d
5. Xu, G.; Hou, A.-J.; Zheng, Y.-T.; Zhao, Y.; Li, X.-L.; Peng, L.-Y.; Zhao, Q.-S. Org.
Lett. 2007, 9, 291–293.
18
O
6. For recent reviews on the Nazarov cyclization, see: (a) Nakanishi, W.; West, F.
G. Curr. Opin. Drug Discov. 2009, 12, 732–751; (b) Grant, T. N.; Rieder, C. J.;
West, F. G. Chem. Commun. 2009, 5676–5688; (c) Davis, R L.; Tantillo, D. J. Curr.
Org. Chem. 2010, 14, 1561–1577; (d) Vaidya, T.; Eisenberg, R.; Frontier, A. J.
ChemCatChem 2011, 3, 1531–1548; (e) Shimada, N.; Stewart, C.; Tius, M. A.
Tetrahedron 2011, 67, 5851–5870; (f) Spencer, W. T., III; Vaidya, T.; Frontier, A. J.
Eur. J. Org. Chem. 2013, 3621–3633; (g) Tius, M A. Chem. Soc. Rev. 2014, 43,
2979–3002; (h) Di Grandi, M. J. Org. Biomol. Chem. 2014, 12, 5331–5345.
7. (a) Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075; (b) Liang, G.; Gradl, N.;
Trauner, D. Org. Lett. 2003, 5, 4931; (c) Liang, G.; Trauner, D. J. Am. Chem. Soc.
2004, 126, 9544; (d) Nie, J.; Zhu, H. W.; Cui, H.; Hua, M.; Ma, J. Org. Lett. 2007, 9,
3053; (e) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J.
Angew. Chem., Int. Ed. 2007, 46, 2097; (f) Walz, I.; Togni, A. Chem. Commun.
2008, 4315; (g) Yaji, K; Shindo, M. Synlett 2009, 2524; (h) Rueping, M.;
Ieawsuwan, W. Adv. Synth. Catal. 2009, 351, 78; (i) Kawatsura, M.; Kajita, K.;
Hayase, S.; Itoh, T. Synlett 2010, 1243; (j) Cao, P.; Deng, C.; Zhou, Y.; Sun, X.;
Zheng, J.; Xie, Z.; Tang, Y. Angew. Chem., Int. Ed. 2010, 49, 4463; (k) Bow, W. F.;
Basak, A. K.; Jolit, A.; Vicic, D. A.; Tius, M. A. Org. Lett. 2010, 12, 440; (l) Basak, A.
K.; Shimada, N.; Bow, W. F.; Vicic, D. A.; Tius, M. A. J. Am. Chem. Soc. 2010, 132,
8266; (m) Rueping, M.; Ieawsuwan, W. Chem. Commun. 2011, 11450; (n)
Hutson, G E.; Türkmen, Y. E.; Viresh, H.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135,
4988–4991.
8. (a) Brooks, J. L.; Caruana, P. A.; Frontier, A. J. J. Am. Chem. Soc. 2011, 133, 12454–
12457; (b) Brooks, J. L.; Frontier, A. J. J. Am. Chem. Soc. 2012, 134, 16551–16553;
Brooks, J. L.; Frontier, A. J. J. Am. Chem. Soc. 2013, 135, 19362 (correction); (c)
Brooks, J. L.; Huang, Y.-W.; Frontier, A. J. Org. Synth. 2014, 91, 93–105.
9. Jacob, S. D.; Brooks, J. L.; Frontier, A. J. J. Org. Chem. 2014, 79, 10296–10302.
10. For recent reviews on the Morita–Baylis–Hillman reaction, see: (a) Shi, Y.-L.;
Shi, M. Eur. J. Org. Chem. 2007, 2095; (b) Masson, G; Housseman, C.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 4614; (c) Basavaiah, D.; Venkateswara Rao, K.
V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581; (d) Singh, V.; Batra, S. Tetrahedron
2008, 64, 4511; (e) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1;
(f) Carrasco-Sanchez, V.; Simirgiotis, M. J.; Santos, L. S. Molecules 2009, 14,
3989; (g) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447;
(h) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005; (i) Mansilla, J.; Saa, J. M.
Molecules 2010, 15, 709; (j) Lu, Y.; Wang, S.-X.; Han, X.; Zhong, F.; Wang, Y.
Synlett 2011, 2766; (k) Basavaiah, D.; Veeraraghavaiah, G. Chem. Soc. Rev. 2012,
41, 68; (l) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659–6690.
HO
Ph
4 h
TMS
Bu
19
O
HO
Ph
d
8
9
—
—
—
—
—
—
—
20
O
HO
Ph
—
H
21
a
Reaction conditions: 5 (1 equiv), 13 (3 mol %), DMF (0.1 M) (for detail procedure
see, Ref. 14).
b
5% starting material was recovered.
c
38% of desilylated dienyl diketone was obtained.
A trace amount of product was observed when the temperature was elevated to
80 °C, using 10 mol % of Y(OTf)3 and 2 equiv of LiCl as additives for 7 days.
d
e
Enantioselectivities were determined by chiral Super-critical Fluid Chroma-
tography (SFC).
and 7). Interestingly, when the R2 substituent was either an alkyl
group (butyl, entry 8) or hydrogen (entry 9), only trace amounts
of the product were formed before decomposition of the substrate
occurred. Experiments using malonate as nucleophile did not pro-
duce enantioenriched products.
As shown in Table 2, it was not possible to promote cyclization
of substrate 20 (R2 = n-butyl). Based on these results, we surmise
that successful conjugate addition/electrocyclization depends
upon the steric influence of the R2 group: it must be large enough
to promote isomerization to the s-trans conformer, which is
11. For a review on the Rauhut–Currier reaction, see: Aroyan, C. E.; Dermenci, A.;
Miller, S. J. Tetrahedron 2009, 65, 4069–4084.
required to undergo the 4
p
electrocyclization (Eq. 4).
12. (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.
1999, 121, 10219–10220; (b) Iwabuchi, Y.; Furukawa, M.; Esumi, T.;
Hatakeyama, S. Chem. Commun. 2001, 2030–2031; (c) Iwabuchi, Y; Sugihara,
T.; Esumi, T.; Hatakeyama, S. Tetrahedron Lett. 2001, 42, 7867–7871.
13. Terada, M.; Fukuchi, S.; Amagai, K.; Nakano, M.; Ube, H. ChemCatChem 2012, 4,
963.
O
O
O
R2
O
R1
R3
R1 R2 R3
s-cis
ð4Þ
H
14. Typical procedure for the enantioselective Nazarov cyclization: A solution of
corresponding dienyldiketone (50 mg, 0.17 mmol) in DMF (1.7 mL) in an oven
s-trans

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Y.-W. Huang, A. J. Frontier / Tetrahedron Letters 56 (2015) 3523–3526
dried round bottom flask was added to cinchona alkaloid 12 (1.6 mg,
the organic layers were then pooled and dried over MgSO4, filtered, and the
solvent was removed under reduced pressure. The product was then purified
by silica gel chromatography hexane–ethyl acetate as the eluent to give the
methylene cyclopentenones 3.
0.0513 mmol). The reaction was allowed to stir at room temperature until
the dienyldiketone was completely consumed. The solution was then diluted
with saturated aqueous NH4Cl (10 mL) and extracted with Et2O (3 ꢁ 10 mL),