In situ catalytic generation of allylcopper species for asymmetric allylation: Toward 1H-isochromene skeletons

Article abstract of DOI:10.1002/anie.201302027

Stay active: Allylcopper species can be generated in situ through catalytic intramolecular oxycupration of allenic alcohol. The allylcopper can react with various aldehydes and a ketone to give 1H-isochromene derivatives in an enantioselective manner (see scheme; HMPA=hexamethylphosphoramide, THF=tetrahydrofuran). The protocol is atom-economical, highly regioselective, stereoconvergent, and tolerant to free hydroxy groups. Copyright

Full text of DOI:10.1002/anie.201302027

Angewandte
Chemie
Communications
Asymmetric Catalysis
J. Kawai, P. K. Chikkade, Y. Shimizu,*
M. Kanai*
&&&& — &&&&
In situ Catalytic Generation of Allylcopper
Species for Asymmetric Allylation:
Toward 1H-Isochromene Skeletons
Stay active: Allylcopper species can be
generated in situ through catalytic intra-
molecular oxycupration of allenic alcohol.
The allylcopper can react with various
aldehydes and a ketone to give 1H-
isochromene derivatives in an enantio-
selective manner (see scheme; HMPA=
hexamethylphosphoramide, THF=tetra-
hydrofuran). The protocol is atom-eco-
nomical, highly regioselective, stereo-
convergent, and tolerant to free hydroxy
groups.
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DOI: 10.1002/anie.201302027
Asymmetric Catalysis
In situ Catalytic Generation of Allylcopper Species for Asymmetric
Allylation: Toward 1H-Isochromene Skeletons**
Junya Kawai, Prasanna Kumara Chikkade, Yohei Shimizu,* and Motomu Kanai*
Asymmetric allylation of carbonyl groups has been exten-
sively studied because of the high versatility of enantiomer-
ically enriched homoallylic alcohols.[1] There are four main
methods for catalytic asymmetric carbonyl allylation: a) using
allylmetal species (such as allyl tin, allyl silicon, and allyl
boron reagents),[2] b) using the catalytic variant of the
Nozaki–Hiyama reaction,[3] c) using reductive generation of
nucleophilic p-allyl palladium from allylic alcohols or ace-
tates,[4] and d) using catalytic transfer hydrogenation[5] of
various precursors, such as allyl acetates,[6] allenes,[7] and
dienes[8] in a waste-minimal manner. Those methods are
reliable and widely used in organic synthesis. In contrast,
despite potential utility, in situ generation of nucleophilic
allylmetal species by oxymetallation has been less explored.
Herein we report the sequential intramolecular oxycup-
ration of allenes[9–11] and subsequent asymmetric addition of
the in situ generated allylcopper intermediates to carbonyl
compounds (Figure 1).[12] This method has four characteristic
asymmetric allylation, an additional heterocycle can also be
procured, a heterocycle which is ubiquitous in natural
products. Finally, this transformation does not generate
stoichiometric waste throughout the cascade.
We chose the 1H-isochromene ring formation as the first
target for our reaction development.[14] Initial optimization
for the reaction between the allenic alcohol 1b and benzal-
dehyde (2a) using copper-conjugated Brønsted base catalysts
generated in situ from CuX and LiOtBu is summarized in
Table 1.[15] Preliminary ligand screening suggested that elec-
Table 1: Initial optimization of catalytic asymmetric construction of 1H-
isochromene derivative 3ba.
Entry Cu cat. Solvent
T [8C] t [h] Yield [%][a] ee [%][b]
1[d]
2[d]
3[d]
4[d]
5
CuCN
CuCl
CuBr
CuPF6
NMP
NMP
NMP
NMP
RT
RT
RT
RT
RT
24 33
24 33
22 23
28 77
16 71
20 89
3
14
38
74
74
85
[g]
Figure 1. Catalytic intramolecular oxycupration of allenes and subse-
quent asymmetric carbonyl allylation toward 1H-isochromene deriva-
tives
CuOtBu NMP
CuOtBu HMPA/THF (1:9) RT
CuOtBu HMPA/THF (1:19)
MesCu HMPA/THF (1:19)
6
7[e,f]
8[e,f]
0
0
2
4
97 (87)[c] 92
98 (92)[c] 92
features compared to current catalytic asymmetric allylation
chemistry. First, a nucleophilic allylcopper species is gener-
ated from stable organic molecules, allenes. Second, the thus
generated chiral allylcopper species is used for catalytic
[a] Determined by 1H NMR spectroscopy using tBuOMe as an internal
standard. [b] Determined by HPLC using a chiral stationary phase.
[c] Yield of isolated product given within parentheses. [d] LiOtBu
(10 mol%) was added. [e] 0.3m. [f] Used 2 equiv of 2a. [g] Used
CuPF6(CH3CN)4. HMPA=hexamethylphosphoramide, NMP=N-meth-
ylpyrrolidone, THF=tetrahydrofuran.
[13]
À
asymmetric C C bond formation.
Third, along with
[*] J. Kawai,[+] Dr. P. K. Chikkade,[+] Dr. Y. Shimizu, Prof. Dr. M. Kanai
Graduate School of Pharmaceutical Sciences
The University of Tokyo
tron-rich aliphatic diphosphine ligands were suitable and Ph-
bpe was proven to be the best for the desired transformation.
Among the copper sources screened (entries 1–4), cationic
copper (CuPF6) markedly improved the yield and enantiose-
lectivity (entry 4) compared with those obtained using CuCN
or copper halides. The addition of in situ generated allylcop-
per species to aldehydes proceeded with exclusive regiose-
lectivity at the terminal position of the allene, rather than at
the benzylic position, to give the desired 3ba. The possible
regioisomeric isobenzofuran product, generated through the
5-exo-trig cyclization of 1b, was not detected for any of the
reactions.[16] In contrast, when the yield was moderate, one of
the major side products was 4b, which was generated by
oxycupration and subsequent protonation of the resulting
allylcopper species from the substrate alcohol.[17] To reduce
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: y-shimizu@mol.f.u-tokyo.ac.jp
kanai@mol.f.u-tokyo.ac.jp
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/e_index.html
Dr. P. K. Chikkade,[+] Prof. Dr. M. Kanai
JST, ERATO, Kanai Life Science Catalysis Project
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
[+] These authors contributed equally to this work.
[**] This work was supported by ERATO from JST (M.K.) and Grant-in-
Aid for Research Activity Start-up from JSPS (Y.S.). We thank Dr.
Hiroyasu Sato (Rigaku Corporation) for helpful suggestions about
X-ray analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302027.
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Table 3: Substrate scope.
the undesired protonation pathway, the possible effects of
lithium salts generated in the catalyst preparation step were
assessed using salt-free CuOtBu[18] (entry 5). However, the
results did not change much, thus indicating that the lithium
ion did not play a key role. In contrast, solvent screening
revealed that the use of a HMPA/THF mixed solvent
profoundly reduced the formation of 4b and enhanced the
enantioselectivity of 3ba (entries 6 and 7).[19] Finally, 3ba was
obtained in excellent yield and enantioselectivity using
mesitylcopper (MesCu)[20] as the catalyst (entry 8).
The thus developed reaction conditions, however, were
not suitable for the primary allenic alcohol 1a. Therefore, we
investigated the reaction conditions again using 1a and
cyclohexanecarboxaldehyde (2c) as substrates (Table 2).
Table 2: Optimization of the reaction between 1a and cyclohexane-
carboxaldehyde (2c).
Entry
x
T [8C]
t [h]
37
37
>37
15
Yield [%][a]
ee [%][c]
1
2
0
2
2
5
5
RT
RT
RT
RT
15
25
70
0
88
89
n.d.
89
3[d]
4
79
5
24
66[b]
91
[a] Determined by 1H NMR spectroscopy using tBuOMe as an internal
standard. [b] Yield of isolated product. [c] Determined by HPLC using
a chiral stationary phase. The absolute configuration of the product 3ac
was estimated from that of 3aa. [d] Neither mesitylcopper nor ligand was
added as a control experiment. n.d.=not determined.
DTBM-segphos was found to be superior, in terms of
enantioselectivity, to other ligands examined.[21] The reactiv-
ity was not satisfactory (entry 1) despite further screening of
catalysts. To improve the reactivity, we studied additive
effects. Pleasingly, the addition of 2 mol% of Al(OtBu)3
dramatically improved the reactivity without affecting the
enantioselectivity (entry 2). Al(OtBu)3 alone in the absence
of the copper catalyst promoted no reaction at all (entry 3).[22]
Finally, the reaction proceeded at 158C to give the desired
product 3ac in 66% yield with 91% ee (entry 5).
[a] Conditions A: Using 2.0 equiv of aldehyde in the absence of Al-
(OtBu)3. Ligand=(S,S)-Ph-bpe. Conditions B: Using 1.5 equiv of alde-
hyde and 5 mol% Al(OtBu)3. Ligand=(R)-DTBM-segphos. See the
Supporting Information for more details. [b] Yield of the isolated
product. [c] Determined by HPLC using a chiral stationary phase.
[d] HMPA/THF (1:4) was used as a solvent. [e] Used 5 mol% of CuOtBu
instead of MesCu. [f] Used 1.5 equiv of aldehyde. [g] Added 2 mol% of
Al(OtBu)3. [h] Added 5 mol% of Al(OtBu)3. [i] Diastereomeric ratio was
1
determined from H NMR analysis of the crude reaction mixture.
With the optimized reaction conditions in hand, we
studied the substrate scope of this asymmetric carbonyl
allylation (Table 3). Both aromatic and aliphatic aldehydes
were competent (entries 1–16). Excellent enantioselectivity
was generally produced, especially for the combination of
aliphatic aldehydes with 1a (entries 2–6) and aromatic
aldehydes with 1b (entries 8–16). The catalyst loading could
be reduced to 5 mol% in an ideal case without decreasing
enantioselectivity (entry 9). Heteroaromatic aldehydes can
also be utilized (entries 13 and 14). The a,b-unsaturated
aldehyde 2m exclusively produced the corresponding 1,2-
adduct (entry 15), thus implying that the addition of allyl-
copper to aldehydes proceeds via a six-membered transition
state. The reaction with the aldehyde 2n, possessing an
additional unprotected hydroxy group, was noteworthy as it
afforded the target product 3bn in 79% yield and 89% ee
(entry 16). Moreover, acetophenone (2g), a significantly less
reactive electrophile than aldehydes, also gave the desired
product in 77% yield, albeit with moderate enantioselectivity
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(76% ee; entry 7). Together, the allylcopper
species was tolerant to protic functional groups,
and still exhibited high nucleophilicity to
carbonyl groups.
As for the scope of the allenic alcohols, the
substrates 1c–e having an electron-withdraw-
ing halogen substituent at the meta- or para-
position to the allene moiety had good reac-
tivity and afforded the desired products in good
yield with high enantioselectivity (Table 3,
entries 17–20). The electron-donating group
at the para-position of the allene moiety in
the substrate 1 f led to a slower reaction, but
the product was still obtained with excellent
enantioselectivity (entry 21). Next we exam-
ined the reaction with the racemic, disubsti-
tuted allenic alcohols 1g and 1h and the results
obtained were also noteworthy (entries 22 and
23). Although the methyl-substituted substrate
1g had lower reactivity (entry 22) than 1b
(entry 8), the reaction proceeded in the pres-
ence of Al(OtBu)3 as a cocatalyst and the
product 3ga was obtained in high yield (98%)
as a mixture of diastereomers (79:21) with high
enantioselectivity (97% ee/82% ee). X-ray
Figure 2. Proposed catalytic cycle of 1H-isochromene-constructing asymmetric allylation
between 1 and 2.
crystallographic analysis unambiguously revealed the abso-
lute and relative configurations of the major isomer to be
syn-(S,S).[21] Therefore, this transformation can be regarded as
stereoconvergent. The chirality of the substrate was lost at the
allycopper stage, and enantioselective allylation of the
aldehyde proceeded under chiral ligand control.[21] The
phenyl-substituted allenic alcohol 1h was a highly reactive
substrate, and the product 3ha was obtained at À108C in
almost quantitative yield with 81/95% ee (entry 23). Despite
the nearly symmetric structure of the allene moiety of 1h,
only a single regioisomer was exclusively observed as
a product.
These molecules can be versatile chiral building blocks for
potential drug candidates. Typical synthetically useful trans-
formations of 3aa producing isochroman skeletons[23] are
summarized in Scheme 1. Cyclopropanation of 3aa pro-
ceeded in excellent yield with a 6.7:1 diastereoselectivity,
thus giving the (R,R,S) isomer 5a with a tricyclic scaffold.[24]
The addition of an indole nucleophile to the enol ether moiety
of 3aa proceeded using cationic gold catalysis, and the
coupling product 5b, possessing a tetrasubstituted carbon
center, was generated.[25]
Based on our current observations and previous findings
in the reactions using allylcopper species,[12] we propose
a catalytic cycle as shown in Figure 2. First, the copper allenic
alkoxide 6 is generated through deprotonation of the hydroxy
group by the catalyst. Then, either the allylcopper 7 or 7’ is
formed through oxycupration of the allene.[26] The addition of
the thus generated allylcopper to the aldehyde 2 would
proceed through a six-membered transition state (TS1) to
give the enantiomerically enriched copper alkoxide 8. Ligand
exchange between 8 and 1 yields the product 3, and the active
catalyst 6 is regenerated at the same time. Considering the
fact that enantioselectivity was not affected by the addition of
Al(OtBu)3 (Table 2, entry 1 versus 2), the aluminum additive
would accelerate this ligand exchange step after the enantio-
selectivity was determined, by facilitating liberation of the
copper catalyst from 8.
In summary, we developed an efficient catalytic method to
generate reactive allylcopper species by the intramolecular
oxycupration of allenes. The resulting allylcopper can be used
for subsequent asymmetric carbonyl allylation, thus providing
1H-isochromene derivatives in excellent enantioselectivity.
Three characteristics of this reaction are: 1) tolerance to
existing free hydroxy groups, 2) stereoconvergency when
applied to racemic disubstituted allenes, and 3) no need to
prefunctionalize or preactivate substrates for the generation
of the allylcopper. Application and extension of this minimal-
waste-producing allylcopper generation method to asymmet-
ric synthesis of biologically important molecules are currently
ongoing.
Scheme 1. Derivatizations of 1H-isochromene scaffold. Reagents and
conditions: a) Et2Zn (4 equiv), CH2I2 (4 equiv), TFA (4 equiv), DME,
08C, 5 h; (b) N-methylindole (1.5 equiv), [AuCl(PPh3)] (0.1 equiv),
AgSbF6 (0.1 equiv), toluene, RT, 4 h. DME=1,2-dimethoxyethane,
TFA=tetrafluoroacetic acid.
Received: March 11, 2013
Revised: April 22, 2013
Published online: && &&, &&&&
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[18] Salt-free CuOtBu was prepared in situ from mesitylcopper and
the same molar amount of tBuOH.
[19] Generation of the byproduct 4b was minimized in aprotic polar
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[21] See the Supporting Information for details.
[22] Other additives produced less satisfactory results (see the
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[13] Although similar cascade-type reactions have been reported by
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allylation was reported. F. Meng, H. Jang, B. Jung, A. H.
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[26] When we conducted the reaction with the deuterated substrate
1i in the absence of an aldehyde, oxycupration/deuteration
proceeded to give 4c. This result supports the existence of
equilibrium between 7 and 7’.
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