Table 1. Box Ligand Screen for Bn Insertion in Cyclohexanonea
Scheme 1. Varied Strategies for Alicyclic and Linear Ketone
Synthesis by Catalytic Diazoalkane-Carbonyl Homologation
screening chiral ligands for enantioselective reactions. Asym-
metric strategies8 for Roskamp β-keto ester synthesis with R-
alkyl diazoacetates have been reported, including a catalytic
one8b based on the use of chiral N,N0-dioxide-Sc3þ salts.
Herein, we report a direct approach to nonracemic 2-aryl
cycloalkanones with bis- and tris(oxazoline) ligands.
entry T (°C) ligand
linker (G)
2,6-pyridyl
CH2
CH2
C(CH3)2
C(CH2)2
C(CH3)2
C(CH3)2
R1
R2
erb
1
2
3
4
5
6
7
8
-60
-78
-78
-78
-78
-78
-78
þ4
3
4
5
6
7
8
9
8
Ph
Bn
Ph
Ph
Ph
Bn
H
H
57:43
55:45
Ph 75:25
Ph 84:16
Ph 87:13
H
91:9
TertiaryR-aryl ketones are an ideal proving ground for the
method, since they are not accessible by cross-coupling
strategies9 due to facile racemization. The only workable
approach to these synthons is based on enantioselective
protonation.10 In advance of our experiments, we prepared
authentic optically active 2-phenyl cycloheptanone (1) by the
three-step sequence shown in Scheme 2 to test its con-
figurational stability under the reaction conditions. After
catalytic benzyl insertion with cyclohexanone and 0.5 mol %
Sc(OTf)3 to access racemic 1 and careful trimethylsilylation
of its thermodynamic enolate (f2), a face-selective protona-
tion with BINAP•AgF as the catalyst gave (S)-1 in 95:5 er.10c
Upon exposure of this material to phenyldiazomethane,
Sc(OTf)3, or a combination of the two (toluene, 0 °C, 6 h)
no loss in enantiopurity was observed (95:5 er by chiral SFC).
- indanyl - 91:9
C(CH3)2
Bn
Ph
Ph
H
H
H
53:47
93:7
91:9
9
10
11
-78
-78
-78
10
11
12
C(CH3)(Ph-ox)
C(CH3)[(Ph-ox)CH2]
C(CH3)[(indanyl-ox)CH2] - indanyl - 95:5c
a 0.2 M toluene and 25 mol % THF as cosolvent; >98% conv in each
entry. b By chiral SFC analysis. c Without THF.
Our study continued with an evaluation of [Sc(R,R)-Ph-
pybox](OTf)3 as the catalyst for enantioselective homo-
logation of cyclohexanone with phenyldiazomethane. As
shown in entry 1 of Table 1, measurable stereoinduc-
tion is observed at -60 °C with the catalyst prepared from
Sc(OTf)3 in situ with a slight excess of the ligand. We
therefore tested13 other box derivatives, judging that the
nature of the linker could affect the Lewis acidity of the
trication and its proximity to the blocking groups. Biden-
tate ligands with a CH2 spacer (4, entry 2) gave higher reac-
tivity, allowing >98% conversion in <10 min at -78 °C.
Ligand 5, derived from a diphenyl amino alcohol, was
particularly effective (entry 3). It was then observed that
geminal substitution on the linking carbon was helpful
(entry 4). High crystallinity in the tetraphenyl series facili-
tated the study of bite angle effects in the context of
cycloalkyl linkers.14 Bis(oxazolinyl)-cyclopropane 7 was
superior to its 4-, 5-, and 6-C ring variants (entry 5, other
data not included).13 Reaction with 8, containing a di-
methyl linker and benzyl blocking groups, further improved
the enantiomer ratio to 91:9 in a result curiously matched
by the rigid hexacycle 9 (entries 6 and 7). Warming of the
reaction mixture gave poor selectivity (entry 8), and a
solvent screen showed that toluene was optimal. Premixing
the substrate with catalyst was also critical for high
Scheme 2. Efficient Benzyl Insertion with Cyclohexanone and
Its Potential to Streamline Access to Homochiral Aryl Ketones
These results support the mildness of our strategy and
underscore the benefits of eliminating the arylation and
enolsilylation steps that must precede protonation.
Among the multidentate ligands for catalytic asym-
metric synthesis with the lanthanides,11 those based on
pyridylbis(oxazoline) are the most well characterized.12
(8) (a) Hashimoto, T.; Miyamoto, H.; Naganawa, Y.; Maruoka, K.
J. Am. Chem. Soc. 2009, 131, 11280–11281. (b) Li, W.; Wang, J.; Hu, X.;
Shen, K.; Wang, W.; Chu, Y.; Lin, L.; Liu, X.; Feng, X. J. Am. Chem.
Soc. 2010, 132, 8532–8533.
(11) Reviews: (a) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002,
102, 2187–2210. (b) Mikami, K.; Terada, M.; Matsuzawa, H. Angew.
Chem., Int. Ed. 2002, 41, 3554–3572.
˚
(9) (a) Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J. M.; Buchwald,
(12) As a lead reference, see: Evans, D. A.; Fandrick, K. R.; Song,
H.-J.; Scheidt, K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129, 10029–10041.
(13) Salen, bipyridine diol, and other ligand constructs were also
tested. Full details are available in the Supporting Information.
(14) (a) Davies, I. W.; Gerena, L.; Castonguay, L.; Senanayake,
C. H.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Chem. Commun.
1996, 1753–1754. (b) Davies, I. W.; Deeth, R. J.; Larsen, R. D.; Reider,
P. J. Tetrahedron Lett. 1999, 40, 1233–1236.
S. J. Org. Lett. 2001, 3, 1897–1900. (b) Chae, J.; Yun, J.; Buchwald, S. J.
Org. Lett. 2004, 6, 4809–4812. (c) Liao, X.; Weng, Z.; Hartwig, J. F. J.
Am. Chem. Soc. 2008, 130, 195–200.
(10) (a) Ishihara, K.; Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J.
Am. Chem. Soc. 2003, 125, 24–25. (b) Cheon, C. H.; Yamamoto, H. J.
Am. Chem. Soc. 2008, 130, 9246–9247. (c) Yanagisawa, A.; Touge, T.;
Arai, T. Angew. Chem., Int. Ed. 2005, 44, 1546–1548. A review: (d)
Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nat. Chem. 2009, 1, 359–369.
Org. Lett., Vol. 13, No. 8, 2011
2005