Chiral acid-catalyzed asymmetric nazarov reaction: Nucleophilic construction of a quaternary asymmetric center at the a-position of the keto function

Article abstract of DOI:10.1055/s-0029-1217823

A chiral Lewis acid catalyzed enantioselective Nazarov reaction affording -alkoxy cyclopentenones has been developed. This is the first example for construction of an asymmetric quaternary center by using the monodentate coordinated divinyl ketones via th

Full text of DOI:10.1055/s-0029-1217823

2524
LETTER
Chiral Acid-Catalyzed Asymmetric Nazarov Reaction: Nucleophilic
Construction of a Quaternary Asymmetric Center at the a-Position of the
Keto Function
A
symmetric
Nazar
e
ov
R
eactio
n
n
taro Yaji,a Mitsuru Shindo*b
a
Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, Kasuga-koen, Kasuga 816-8580, Japan
Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga-koen, Kasuga 816-8580, Japan
Fax +81(92)5837875; E-mail: shindo@cm.kyushu-u.ac.jp
b
Received 11 June 2009
Nazarov reaction of monodentate-type divinyl ketones
has been limited (Figure 1).
Abstract: A chiral Lewis acid catalyzed enantioselective Nazarov
reaction affording a-alkoxy cyclopentenones has been developed.
This is the first example for construction of an asymmetric quater-
nary center by using the monodentate coordinated divinyl ketones
via the interrupted Nazarov reaction, which involves a nucleophilic
attack of an alcohol on the a-position of the keto function.
O
O
O
O
OR
Key words: asymmetric catalysis, asymmetric synthesis, electro-
cyclic reactions, ketones, Lewis acids
1
2
Figure 1 The bidentate-type substrates
Recently, we have developed an acid-catalyzed high
speed Nazarov reaction of b-alkoxy divinyl ketones giv-
ing a-alkoxy cyclopentenones, which have a quaternary
carbon at the a-position of the keto function.8 Mechanisti-
cally, this quaternary center is constructed by attack of the
alkoxy group on the cationic site at the a-position. Al-
though West9 and Tius10 reported the interrupted Nazarov
reaction, no publications on catalytic enantioselective
variants have yet appeared. In this communication, we de-
scribe a catalytic asymmetric Nazarov reaction providing
a-alkoxy cyclopentenones having a chiral asymmetric
carbon center (Scheme 2).
The Nazarov reaction is a classic electrocyclization medi-
ated by acids to give cyclopentenones.1 Although regio-
controlled acid-catalyzed Nazarov reactions under mild
conditions have appeared in the literature in recent years,2
only a few examples of asymmetric variants using chiral
catalysts have been reported. Since the conventional
Nazarov reaction consists of a 4p-electrocyclization,
deprotonation, and reprotonation, two methods for cata-
lytic asymmetric induction are possible. One is an asym-
metric torquoselective 4p-electrocyclization as the key
step (Scheme 1, a), reported by Aggarwal,3 Trauner,4
Togni,5 and Rueping6 using chiral Lewis or Brønsted ac-
ids. The other is an enantioselective protonation of enols
or metal enolates in the final step of the Nazarov reaction
(Scheme 1, b), described by Trauner4 and Rueping.7 Most
of these successful results used bidentate-type substrates
bearing an a-oxy group (mostly dihydropyran-2-yl, 1) or
a b-carbonyl unit (e.g., 2) for fixing the metal ternary
complex by chelation as well as for stabilizing the inter-
mediates. Consequently, the use of the asymmetric
*
M
O
O
O
chiral acid (M*)
catalyst
RO
*
OR
OR
3
4
5
monodentate
substrates
Scheme 2 Chiral acid-catalyzed asymmetric Nazarov reaction
M*
M*
O
O
O
O
torquoselective
4π-electrocyclization
diastereoselective
protonation
chiral acid (M*)
*
*
(a)
(key step)
*
(M = H, Mtl)
M*
O
M*
O
O
O
enantioselective
protonation
chiral acid (M*)
4π-electrocyclization
*
(b)
(key step)
Scheme 1 The two possible methods for the catalytic asymmetric Nazarov reaction
SYNLETT 2009, No. 15, pp 2524–2528
x
x
.x
x
.2
0
0
9
Advanced online publication: 17.08.2009
DOI: 10.1055/s-0029-1217823; Art ID: U06409ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Nazarov Reaction
2525
Having found that this Nazarov reaction was catalyzed by We next examined the ratio of the Sc(OTf)3 and the
metal triflates or super acids,8 we initially surveyed metal pybox–Ph ligand (8). First we prepared the complex by
triflate complexes containing a chiral bisoxazoline adding 1.8 equivalents of pybox to Sc(OTf)3, based on
ligand11,12 as chiral catalysts. Numerous combinations Trauner’s protocol.4 When the ratio [Sc(OTf)3/8] was
were tested, including the triflates of Cu(II), Ni(II), Zn(II), changed to 1:1.5 and 1:1.1, the stereoselectivity was
Fe(II), In(III), Sn(II), Yb(III), La(III), and Pr(III), which greatly decreased to 21% ee and 0% ee, respectively
did not induce any enantioselectivity. Only the pyridine (Table 2, entries 1–3), due to the generation of trifluo-
2,6-bisoxazolines (pybox)–Sc(OTf)3 complexes showed romethanesulfonic acid (TfOH) which catalyzed the race-
effective asymmetric induction. This preliminary result mic Nazarov reaction. This strong acid might be
prompted us to optimize the reaction conditions and generated from Sc(OTf)3, when the side products 15 and
ligands. As shown in Table 1, the aromatic ring, especial- 16 are generated. If an excess amount of 8 was successful
ly a phenyl group, turned out to be the best substituent on in inactivating TfOH, conceivably an inexpensive achiral
the two oxazoline rings inducing up to 51% ee (entries 1– base might work in place of the expensive chiral ligand
3), but alkyl and indanyl substituents significantly de- bases. If so, theoretically only 1 equivalent of 8 would be
creased the enantioselectivity and the reaction rates (en- needed. As expected, the reaction using 0.7 equivalents of
tries 4–7). Owing to the bulkiness of the substrate, some triethylamine or diisopropylethylamine in the presence of
limited coordination space would be required for effective the chiral complex [1:1.1 ratio of Sc(OTf)3/8] realized the
chiral complexation. Among the reaction solvents, di- same stereoselectivity and good yield (Table 2, entries 4
chloromethane gave the best results (entries 8–10), and and 6) as was the case for entry 1. The addition of 0.9
decreasing the temperature did not affect the stereoselec- equivalents of triethylamine or 0.7 equivalents of pyridine
tivity but only reduced the reaction rate (entry 11). Never- retarded the reaction rate (entries 5 and 7), probably due
theless, ca. 10–20% of the a-exo-methylene to the coordination to the metal.
cyclopentenone 15 and a trace amount of the a-hydroxy
cyclopentenone 16 were generated as side products.
Table 1 Asymmetric Nazarov Reaction Catalyzed by Sc(OTf)3–Pybox Complexes
R3
Sc(OTf)3-pybox
O
O
O
O
complex
EtO
HO
Ph
(10 mol%)
O
O
N
R2
R2
OEt
N
N
Ph
R1
R1
Ph
15
16
Ph
6
7
8 R1 = Ph, R2 = H, R3 = H
9 R1 = 4-MeOC6H4, R2 = H, R3 = HH
10 R1 = Ph, R2 = H, R3 = Br
11 R1 = i-Pr, R2 = H, R3 = H
12 R1 = Ph, R2 = Me, R3 = H
13 R1, R2 = indanyl, R3 = H
14 R1 = Bn, R2 = H, R3 = H
Entry
Chiral ligands
Conditions
CH2Cl2, r.t.
CH2Cl2, r.t.
CH2Cl2, r.t.
CH2Cl2, r.t.
CH2Cl2, r.t.
CH2Cl2, r.t.
CH2Cl2, r.t.
THF, r.t.
Time (h)
Yield of 7 (%)a
ee of 7 (%)b
1
2
8
9
1.5
2
65
56
57
37
69
59
46
39
50
66
58
51
46
46
9
3
10
11
12
13
14
8
1.5
12
0.5
5
4
5
8
6
0
7
24
1
0
8
55
44
38
44
9
8
CH3CN, r.t., 4 Å MS
EtOH, r.t.
2
10
11
8
6
8
CH2Cl2, 0 °C
1
a Ca. 10–30% of the a-exo-methylenecyclopentenone 15 and the a-hydroxycyclopentenone 16 were generated as side products.
b The ee was determined by HPLC analysis using a Chiralpak OJ-H column.
Synlett 2009, No. 15, 2524–2528 © Thieme Stuttgart · New York

2526
K. Yaji, M. Shindo
LETTER
Table 2 Addition of Bases for Trapping of TfOH
NOE
O
HO
EtO
H
Entry Ratio
Additives
Time
(h)
Yield
(%)
ee
(%)
EtO
Sc(OTf)3/8 (equiv)a
NaBH4, CeCl3⋅7H2O
MeOH, 0 °C, 1 h
1
2
3
4
5
6
7
1:1.8
1:1.5
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
–
1.5
1
65
64
71
71
55
69
30
51
21
0
–
7
17 (dr 9:1)
Ph
Ph
–
1
+0.023
H+0.04
RO
(R)- or (S)-MTPA
EDCI, DMAP
O
Et3N (0.7)
Et3N (0.9)
i-Pr2NEt (0.7)
pyridine (0.7)
2
54
56
46
54
–0.064
+0.031
CH2Cl2, r.t., 24 h
+0.116
20
1.5
20
H
–0.021
+0.0215
H
(R)-18
(S)-18
–0.0245
–0.015
Ph
(R = MTPA, Δδ = (δS–δR) value)
a This equivalent was based on Sc(OTf)3.
Scheme 3 Synthesis of (R,S)-MTPA ester 18 and NOE experiments
of secondary alcohols
The absolute configuration of the product was determined
by the Kusumi–Mosher method.13 The enantiomerically
enriched 7 (87% ee) was reduced with NaBH4–CeCl3, fol-
lowed by methoxytrifluoromethylphenylacetyl (MTPA)
esterification to give 18 (Scheme 3). Comparison of the
1H NMR spectra of the (R)-MTPA and (S)-MTPA esters,
along with NOE experiments on 17, revealed that the qua-
ternary center was in the S-configuration.
1) did not proceed in the presence of EtOH. A larger neo-
pentyl substituent at R2 resulted in moderate yield and no
stereoselectivity along with much more of the a-exo-
methylene cyclopentenone 21 (entry 6). A phenyl substit-
uent at R1 did not give good results (entry 7).
We have already shown that intermolecular alkoxy migra-
tion can occur using crossover experiments.8 In order to
confirm the intermolecular migration in this case, we tried
the Nazarov reaction in i-PrOH-d8 as the solvent. As a
result, the deuterium-labeled isopropoxy product was
obtained (Scheme 4), indicating the intermolecular migra-
tion of the alcohol, that is, the asymmetric center is pre-
sumably constructed by attack of the external alkoxide or
alcohol, not by the intramolecular 1,3-shift of the b-alkox-
ide. Therefore, the torquoselectivity of the electrocyclic
reaction might not contribute to the enantioselectivity.
Based on these results, several kinds of b-alkoxy divinyl
ketones were subjected to the asymmetric Nazarov reac-
tion under the conditions described above, as shown in
Table 3.14 Higher enantioselectivity was obtained since
the substituents at R2 were sterically larger (entries 1–4).
Furthermore, when i-PrOH was used as a solvent in order
to accelerate the addition of i-PrOH, the highest stereo-
selectivity of 91% ee and a relatively good yield were
achieved (entry 5). This alcohol effect was limited to the
case of entry 5, because the reaction of the substrate (entry
Table 3 Catalytic Asymmetric Nazarov Reaction
Sc(OTf)3–pybox
complex
(10 mol%)
O
O
O
O
R2O
HO
+
+
Et3N, CH2Cl2, r.t.
R1
OR2
R1
R1
R1
19
20
21
22
Entry
R1
R2
Time (h)
Yield (%)
ee of 20 (%)
20
21
22
6
1
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph
Et
2
1
4
7
3
2
8
71
53
41
38
55
34
40
9
20
14
20
14
41
5
54
65
80
84
91
0
2
Bn
15
18
7
3
i-Pr
i-Pr
i-Pr
t-BuCH2
Me
4a
5b
6
4
15
21
7
12
a Sc(OTf)3/8 = 1:1.8 without use of Et3N.
b The solvent was i-PrOH.
Synlett 2009, No. 15, 2524–2528 © Thieme Stuttgart · New York

LETTER
Asymmetric Nazarov Reaction
2527
Based on these results, the proposed reaction mechanism
is shown in Scheme 5. The acid catalyst activates the ke-
tone to give the pentadienyl cation 26, which is in equilib-
rium with the oxyallyl cation 27. Initially, an elimination
reaction would proceed to give the a-exo-methylene eno-
late 31 along with TfOH, which is immediately neutral-
ized by the additional base. The enolate 31 would be
transformed into the side product 32, and the resulting
chiral metal alkoxide 28 [Sc*(OR)(OTf)2] would react
with the cation 27 to give the enolate 29 and the regener-
ated catalyst [Sc*(OTf)3]. The enolate 29 would be con-
verted into the final product 30 and the catalyst 28, which
would be used in the next cycle. The minor pathway gen-
erating the side product 32 (the dashed arrows) would
supply the chiral metal alkoxide 28, which would initiate
the catalytic cycle.
Sc*(OTf)2
O
TfO
O
Sc*(OTf)3
OR
OR
Et3NH OTf
25
26
Et3N
TfOH
Sc*(OTf)2
OR
O
Sc*(OTf)2
OR
TfO
O
Sc*(OTf)3
27
31
Sc*(OR)(OTf)2
Sc*(OTf)2
OR
28
O
O
O
Sc(OTf)3–pybox
complex
RO
i-Pr(d7)O
O
(10 mol%)
Et3N, i-PrOH-d8, r.t.
Oi-Pr
29
O
32
RO
Ph
Ph
24
23
>99% d-labelled
64%
30
Scheme 4 Catalytic asymmetric Nazarov reaction in i-PrOH-d8
Scheme 5 Proposed reaction mechanism
The stereochemical course of the reaction can be rational-
ized by assuming the reacting complex depicted in
Figure 2. In this representation, one of the triflates would
be dissociated from the metal center and the cyclopen-
tenoxide bearing an allylic cation would be bound in the
apical position for steric reasons. Addition of an alcohol
from the Si face would be favored as the Re face is shield-
ed by the phenyl group of the pybox ligand 8. Since the C–
O bond of the cyclopentenoxide would rotate freely, two
conformations (a) and (b) can be considered. In conforma-
tion (b), steric congestion between the substituents on the
cyclopentenoxide and the phenyl group can not be ig-
nored, resulting in both sides of the reactive cation site be-
ing blocked; thus a nucleophile would react with
conformation (a) rather than (b). In particular, a sterically
hindered alcohol would tend to react with (a) more prefer-
entially.
an asymmetric quaternary center using the monodentate
coordinated divinyl ketones via the interrupted Nazarov
reaction, which involves a nucleophilic attack of alcohols
on the a-position of the keto function.
Acknowledgment
This research was partially supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas (19020052) and (B) (19390007).
One of the authors (KY) also acknowledges the support of the JSPS.
References and Notes
(1) For reviews, see: (a) Frontier, A. J.; Collison, C.
Tetrahedron 2005, 61, 7577. (b) Pellissier, H. Tetrahedron
2005, 61, 6479. (c) Tius, M. A. Eur. J. Org. Chem. 2005,
2193. (d) Habermas, K. L.; Denmark, S. E.; Jones, T. K.
In Organic Reactions, Vol. 45; Paquette, L. A., Ed.; John
Wiley and Sons: New York, 1994, 1–158. (e) Santelli-
Rouvier, C.; Asantelli, M. Synthesis 1983, 429.
(2) (a) Jones, T. K.; Denmark, S. E. Helv. Chim. Acta 1983, 66,
2377. (b) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc.
2003, 125, 14278. (c) Liang, G.; Gradl, S. N.; Trauner, D.
Org. Lett. 2003, 5, 4931.
In conclusion, we have developed a novel type of catalytic
enantioselective Nazarov reaction affording a-alkoxy cy-
clopentenones. This is the first example for constructing
R2OH
R2OH
(3) Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075.
(4) Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544.
(5) (a) Walz, I.; Bertogg, A.; Togni, A. Eur. J. Org. Chem. 2007,
2650. (b) Walz, I.; Togni, A. Chem. Commun. 2008, 4315.
(6) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.;
Nachtsheim, B. J. Angew. Chem. Int. Ed. 2007, 46, 2097.
(7) Rueping, M.; Ieawsuwan, W. Adv. Synth. Catal. 2009, 351,
78.
OR2
R1
O
O
OR2
R1
O
O
N
N
N
N
Sc
Sc
N
N
O
O
(b)
(a)
(8) Shindo, M.; Yaji, K.; Kita, T.; Shishido, K. Synlett 2007,
1096.
Figure 2 Proposed model of asymmetric induction
Synlett 2009, No. 15, 2524–2528 © Thieme Stuttgart · New York

2528
K. Yaji, M. Shindo
LETTER
(14) Representative Experimental Procedure for the
(9) Recent examples by West: (a) Rieder, C. J.; Fradette, R. J.;
West, F. G. Chem. Commun. 2008, 1572. (b) Grant, T. G.;
West, F. G. Org. Lett. 2007, 9, 3789. (c) Mahmoud, B.;
West, F. G. Tetrahedron Lett. 2007, 48, 2091. (d) Rostami,
A.; Wang, Y.; Arif, A. M.; McDonald, R.; West, F. G. Org.
Lett. 2007, 9, 703. (e) Grant, T. N.; West, F. G. J. Am. Chem.
Soc. 2006, 128, 9348. (f) Giese, S.; Mazzola, R. D. Jr.;
Amann, C. M.; Arif, A. M.; West, F. G. Angew. Chem. Int.
Ed. 2005, 44, 6546. (g) White, T. D.; West, F. G.
Tetrahedron Lett. 2005, 46, 5629. (h) Browder, C. C.;
Marmsäter, F. P.; West, F. G. Can. J. Chem. 2004, 82, 375.
(10) (a) Basak, A. K.; Tius, M. A. Org. Lett. 2008, 10, 4073.
(b) For a chiral auxiliary-controlled interrupted Nazarov
reaction, see: Dhoro, F.; Kristensen, T. E.; Stockmann, V.;
Yap, G. P. A.; Tius, M. A. J. Am. Chem. Soc. 2007, 129,
7256. (c) Dhoro, F.; Tius, M. A. J. Am. Chem. Soc. 2005,
127, 12472.
(11) (a) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata,
M.; Kondo, M.; Itoh, K. Organometallics 1989, 8, 846.
(b) Nishiyama, H.; Itoh, K. J. Synth. Org. Chem. Jpn. 1995,
53, 500. (c) Nishiyama, H. Enantiomer 1999, 4, 569.
(12) For recent reviews on pybox ligands, see: Desimoni, G.;
Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, 3119.
(13) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
Catalytic Asymmetric Nazarov Reaction
A solution of Sc(OTf)3 (9.8 mg, 0.02 mmol), pybox–Ph (8,
8.1 mg, 0.022 mmol) in dry CH2Cl2 (0.4 mL) was stirred for
3 h. Then, Et3N (2.0 mL, 0.014 mmol) and the (E)-b-alkoxy
divinyl ketone (23, 54 mg, 0.2 mmol) in dry CH2Cl2 (0.4
mL) were added. The mixture was stirred at r.t. for 4 h,
quenched with sat. aq NaHCO3, and extracted with CH2Cl2.
The organic extract was washed with sat. aq NaHCO3 and
brine, dried over MgSO4, filtered, and concentrated in
vacuo. The residual oil was purified over silica gel column
chromatography (hexane–EtOAc, 80:20) to afford the
a-alkoxy cyclopentenone (20).
Compound 20 [R1 = Ph(CH2)2, R2 = i-Pr]: 1H NMR (600
MHz, CDCl3): d = 1.07 (d, J = 6.6 Hz, 3 H), 1.10 (d, J = 6.0
Hz, 3 H), 1.26 (s, 3 H), 1.57 (s, 3 H), 2.40 (d, J = 18.0 Hz, 1
H), 2.64–2.78 (m, 3 H), 2.85 (t, J = 7.2 Hz, 2 H), 3.66 (quint,
J = 6.0 Hz, 1 H), 7.16–7.29 (m, 5 H). 13C NMR (150 MHz,
CDCl3): d = 7.89, 23.2, 24.2, 24.7, 32.6, 33.0, 44.0, 66.8,
78.7, 126.4, 128.2, 128.5, 134.6, 140.3, 168.8, 208.5. IR
(neat): 1706, 1643, 1082 cm–1. MS (EI): m/z = 229 [M+ –
CH(CH3)2]. HRMS–FAB: m/z calcd for C18H25O2 [M+ + H]:
273.1856; found: 273.1855. [a]D –6.7 (c 0.3, CHCl3, 80%
ee). The enantiomeric purity of 20 [R1 = Ph(CH2)2, R2 =
i-Pr] was determined by HPLC analysis [Chiralpak OJ-H,
hexane–i-PrOH (90:10), 1.0 mL/min, 254 nm] in
comparison with authentic racemic material.
Synlett 2009, No. 15, 2524–2528 © Thieme Stuttgart · New York

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