Table 1: Reaction scope of substituted 2-naphthols.
Despite existing strategies for the synthesis of chiral
molecules through oxidative dearomatization/nucleophilic
addition,[12] to the best of our knowledge, this is the first
method to use the enolate intermediate of a catalytic
asymmetric conjugate addition of Grignard reagents.[13]
Our initial investigations focused on 2-naphthol-based
substrate 4 (Scheme 3). We first needed to optimize the
reaction conditions for the copper-catalyzed conjugate addi-
tion of EtMgBr to 4. Under slightly modified conditions, 5 was
isolated in 84% yield and 88% ee, with an S configuration at
the stereocenter (see below).[14–16]
Entry[a] Substrate R2
Product (d.r.[b]) Yield [%][c] ee [%][d]
1
2
3
4
5
6
7
8
9
4
4
4
4
4
4
4
13
15
17
Et
hexyl
6 (>20:1)
7 (>20:1)
69
84
51
70
20
32
8
63
63
13
88
80
80
54
87
82
0
83
89
94
CH2CH2Ph 8 (>20:1)
iPr 9 (>20:1)
but-3-enyl 10 (>20:1)
Me
Ph
Et
11 (>20:1)
12 (>20:1)
14 (>20:1)
16 (>20:1)
18 (>20:1)
Scheme 3. Optimized conditions for the conjugate addition of EtMgBr
to substrate 4. binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl.
Et
Et
10
[a] Reaction conditions: 4 (0.25 mmol) in CH2Cl2 (0.8 mL) was added
over 1 h to a solution of CuI (5 mol%), (R)-binap (7.5 mol%), and
Grignard reagent (2.5 equiv) in CH2Cl2 (0.4 mL) at À408C. The reaction
mixture was stirred at À408C for 4–12 h, and solid copper(II) 2-
ethylhexanoate (2.5 equiv) was added to the reaction mixture and
warmed to RT. [b] Determined by 1H NMR analysis of the crude reaction
mixture. [c] Yield of isolated product. [d] Determined by HPLC on a chiral
stationary phase.
Our preliminary experiments for the sequential conjugate
addition/oxidative cyclization reaction gave highly promising
results (Scheme 4).
which is common for this particular Grignard reagent in the
copper-catalyzed asymmetric conjugate addition reaction
(entry 4). Electron-withdrawing (entry 8) or electron-donat-
ing (entry 9) groups in the 6 position of the naphthol core
were both compatible under the reaction conditions, and gave
the cyclized products in good yields and enantioselectivities.
The use of a Grignard reagent bearing a terminal olefin
(entry 5), MeMgBr (entry 6),[18] and PhMgBr (entry 7)[19]
afforded the products in lower yields either as a result of
the reactivity of the Grignard reagent (entries 6 and 7) or
instability towards the oxidative conditions (entry 5). Low or
no enantioselectivity with PhMgBr in conjugate addition
reactions is also common.[1] Finally, cyclization of substrate 17
to afford a six-membered spirocyclic ring proceeded in a
lower yield than the formation of a five-membered ring, but
with the highest enantioselectivity (94%) achieved with this
method (entry 10). Although it would appear at first glance
that yields could be improved in a few cases, the high degree
of structural and stereochemical complexity introduced in a
single-pot operation makes this method highly valuable.
Furthermore, current oxidative dearomatization processes
are difficult, prone to side reactions, and are generally lower
yielding.[20]
Scheme 4. Initial result for the sequential conjugate addition/oxidative
cyclization reaction.
Under racemic reaction conditions, the conjugate addition
of EtMgBr to 4 was followed by the addition of copper(II) 2-
ethylhexanoate as an oxidant,[13a–d,17] in the same pot
(Scheme 4). The desired spirocyclic product 6 was obtained
in 59% yield upon isolation, as a single diastereomer. Under
the asymmetric reaction conditions employing (R)-binap as
the chiral ligand, the same transformation afforded product 6
with high yield (69%) and 88% ee. Further screening of
oxidizing reagents (other sources of CuII, FeIII, phenyliodine-
(III) diacetate, and phenyliodine (III) bis(trifluoroacetate))
did not improve on these results. The enantiomeric excess of 6
matches exactly that of 5 obtained under the same reaction
conditions for the conjugate addition (see Scheme 3). The
high diastereoselectivity (> 20:1 d.r.) achieved in the cycliza-
tion to 6 suggests that once the first stereocenter is established
during the conjugate addition, it controls the formation of the
two subsequent stereocenters.
To explore the synthesis of different spirocyclic architec-
tures using this method, we employed 1-naphthol substrate
19, with the pendant a,b-unsaturated ester in the 2-position.
The desired product 20 was obtained in 41% yield and with a
diastereoselectivity of 8:1 (Scheme 5). The enantioselectivity
toward the major isomer was 89% ee.[21]
We next focused our efforts on the scope of the reaction
(Table 1). Linear alkyl Grignard reagents provided the
desired products in good to excellent yields (entries 1–3)
and good ee (entries 1–3, 5, and 6). The addition of iPrMgBr
proceeded in good yield, but with lower enantioselectivity,
Angew. Chem. Int. Ed. 2011, 50, 5834 –5838
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5835