Iridium-catalyzed direct asymmetric vinylogous allylic alkylation

Article abstract of DOI:10.1039/c8cc07249c

The catalytic asymmetric vinylogous allylic alkylation of α,β-unsaturated lactones (including coumarins) was achieved with excellent regio- and enantioselectivity. Transformations of the product were carried out by means of the versatile terminal olefin and lactone moieties. The synthetic application of the present methodology was showcased by the asymmetric synthesis of an advanced synthetic Merck intermediate toward a new drug candidate.

Full text of DOI:10.1039/c8cc07249c

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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Iridium-Catalyzed Direct Asymmetric Vinylogous Allylic Alkylation
Chang-Yun Shi,a Jun-Zhao Xiao a and Liang Yin*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The catalytic asymmetric vinylogous allylic alkylation of α,β- bulkiness of organocatalyst (a prolinol derivative).
unsaturated lactones (including coumarins) was achieved with An indirect but effective method to achieve asymmetric
excellent regio- and enantioselectivity. Transformations of the allylic alkylation is to employ a sequential combination of
product were carried out by means of the versatile terminal olefin and catalytic asymmetric -allylic alkylation and Cope
γ
-
α
lactone moieties. Synthetic application of the present methodology rearrangement, which was reported by Tunge group and Cossy
was showcased by the asymmetric synthesis of an advanced synthetic group.6 In 2016, Stoltz and co-workers disclosed an elegant
Merk intermediate toward new drug candidate.
catalytic asymmetric vinylogous allylic alkylation of
unsaturated malonates or ketoesters, involving iridium-
catalyzed -allylation of -unsaturated malonates or
ketoesters and following Cope rearrangement at 100 oC
(Scheme 1c).7 In 2018, Peters group reported an similar
strategy by using isoxazolinones as the pronucleophiles and
finally accomplished asymmetric N-allylation through an aza-
Cope rearrangement.8 It is evident from the literature that a
α,β-
Catalytic asymmetric vinylogous reactions have gained a
preeminent position in organic synthesis due to its extensive
application in the synthesis of complex natural products and
biologically active pharmaceuticals.1 Although transition metal-
catalyzed asymmetric allylic alkylation of carbonyl compounds
is identified as one of the most fundamental strategies to
α
α,β
construct chiral
vinylogous version leading to synthetically valuable chiral
substituted
-unsaturated carbonyl compounds3 was not
α
-substituted carbonyl compounds,2 its
direct catalytic asymmetric vinylogous allylic alkylation of
unsaturated compounds is not easy to achieve.
α,β-
γ
-
α,β
Scheme 1 Prior Arts in Ir-Catalyzed Asymmetric Vinylogous
studied extensively. Catalytic asymmetric vinylogous allylic
Allylic Alkylation and Our Work
(a) Hartwig's Mukaiyama-Type Vinylogous Allylic Alkylation
alkylation is challenging due to some concerns, such as
regioselectivity (α- vs γ-allylic alkylation, γ- vs γ'-allylic
alkylation), chemoselectivity (C- vs O-allylic alkylation) and
R2
O
O
[Ir]
O
O
R2
+
ref 4
OLG
OTMS
O
R3
LG = Troc or P(O)(OEt)2
remote control of enantioselectivity.
R1
R3
R1
In 2014, Hartwig and co-worker disclosed an iridium-
catalyzed highly selective asymmetric vinylogous allylic
alkylation of silyl dienolates derived from dioxinones (Scheme
1a).4a Later, the scope of allylic electrophiles was successfully
expanded from disubstituted allylic carbonates to
trisubstituted allylic phosphates (Scheme 1a).4b In 2015,
(b) J rgensen's Direct Vinylogous Allylic Alkylation via Dual Catalysis
CHO
CHO
[Ir]
OH
+
ref 5
Ar
Ar
enamine catalysis
X
X
(c) Stoltz's Reaction Sequence Involving -Allylic Alkylation and Cope Rearrangement
Ar
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
MeO2C
[Ir]
Jørgensen group reported an asymmetric γ-allylation of α,β-
ref 7
Ar
100 o
C
Ar
OCO2Me
unsaturated aldehydes through combined organocatalysis and
transition-metal catalysis (Scheme 1b).5 The key to perfectly
control the regioselectivity was mainly ascribed to the
n
n
X
X
n
X
(d) Krische's Catalytic Asymmetric Vinylogous Aldol Reaction
O
OH
R'
O
[Ir]
+
ref 14
R'
OH
BocO
OEt
OEt
(e) Our Work: Direct Vinylogous Allylic Alkylation
O
O
O
O
'
[Ir]
'
EWG
R2
+
OCO2Me
EWG
high regioselectivity
*
high enantioselectivity
R2
EWG = CN, COMe, CO2Et, CONH2
Coumarins
1 are selected as pronucleophiles because
coumarin structures are not only frequently found in natural
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Journal Name
products, but also serve as “privileged” scaffolds of biological
and pharmaceutical interests.9 Coumarins
The classical bidentate phosphine ligand, (R)-BINAP, was
1 have been proved to be unproductive (entry 9). Ligand L1 and L2,
successfully applied in catalytic asymmetric vinylogous possessing only axial chirality, were found to be not effective
alkylation,10 vinylogous allylic alkylation,11 vinylogous ring- either (entry 10-11). Carreira ligand17 was also investigated,
opening,12 and vinylogous propargylation.13 Inspired by above affording the corresponding vinylogous allylic alkylation
mentioned seminar works with iridium catalysts and Krische’s product 3aa in 30% yield with 51% ee (entry 12). It was found
extinguished iridium-catalyzed asymmetric vinylogous aldol that You ligand18 was slightly superior to Feringa ligand in this
reaction (Scheme 1d),14 we achieved a high regio- and reaction, leading to 3aa in excellent yield with -96% ee (entry
enantioselective vinylogous allylic alkylation of cyclic
unsaturated compounds (including coumarins and ) with mol % without compromising both yield and enantioselectivity
iridium catalyst (Scheme 1e), which followed our research (entry 14). (Ra,R)-You ligand resulted in the same yield and
interest in catalytic asymmetric vinylogous reactions.15
enantioselectivity excess for 3aa as (Sa,S)-You ligand did (entry
α
,
β
-
13). The loading of [Ir(COD)Cl]2 was successfully decreased to 1
1
4
Table 1 Optimization of the Reaction Conditions with 1a and 15).
2aa
Table 2 Substrate Scope of Catalytic Asymmetric Vinylogous
Allylic Alkylation of
and 2a
[Ir(COD)Cl]2 (5.0 mol %)
ligand (11.0 mol %)
base (1.0 equiv)
O
O
1
O
O
CN
+
Ph
OCO2Me
CN
THF, rt, t h
, >20/1; b/l, >20/1
Ph
1a, x equiv
x
2a, y equiv
3aa
entry
1
y
ligand
base
Et3
t
yield (%)b
22
ee (%)c
96
95
94
92
93
94
94
94
-
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
(Sa,S,S)-Feringa ligand
(Sa,S,S)-Feringa ligand
(Sa,S,S)-Feringa ligand
(Sa,S,S)-Feringa ligand
(Sa,S,S)-Feringa ligand
(Sa,S,S)-Feringa ligand
(Sa,S,S)-Feringa ligand
(Sa,S,S)-Feringa ligand
(R)-BINAP
N
24
24
24
24
24
24
24
24
24
24
24
24
10
24
10
2
1.0
Cy2NMe
TMG
16
3
1.0
61
4
1.0
LiOtBu
NaOtBu
KOMe
TMG
40
5
1.0
33
6
1.0
23
7
1.0
44
8
2.0
TMG
91
9
2.0
TMG
trace
trace
trace
30
10
11
12
13
14d
15e
2.0
L1
TMG
-
2.0
L2
TMG
-
2.0
(Sa)-Carreira ligand
(Sa,S)-You ligand
(Sa,S)-You ligand
(Ra,R)-You ligand
TMG
51
-96
-94
95
2.0
TMG
99
2.0
TMG
89
2.0
TMG
99
a1a: 0.10 mmol or 2a: 0.10 mmol. THF: 1 mL. bDetermined by 1H NMR analysis of reaction crude mixture
using mesitylene as an internal standard. cDetermined by chiral-stationary-phase HPLC analysis. d1.0 mol %
[Ir(COD)Cl]2 and 2.2 mol % ligand employed. e2.0 mol % [Ir(COD)Cl]2 and 4.4 mol % ligand employed. TMG =
tetramethyl guanidine.
O
O
O
O
R
R
O
O
O
O
Ph
Ph
PPh2
PPh2
P
N
P
N
P N
P
N
(Sa,S,S)-Feringa ligand
(Sa)-Carreira ligand
(Sa,S)-You ligand
(R)-BINAP
R = Et, L1; R = Ph, L2
The reaction between coumarin 1a and allyl methyl
carbonate 2a was studied as a model reaction (Table 1).
Phosphoramidites, privileged chiral ligands in asymmetric
catalysis,16 were selected as the ligand in this iridium-catalyzed
vinylogous allylic alkylation. Fortunately, in the presence of 5.0
mol % [Ir(COD)Cl]2, 11.0 mol % (Sa,S,S)-Feringa ligand16 and 1.0
Considering the easy manipulation and commercial
availability of (Ra,R)-You ligand, 2 mol % [Ir(COD)Cl]2 and 4.4
mol % (Ra,R)-You ligand were employed in the following
equiv Et3N, the reaction proceeded smoothly to afford
γ
-allyl
substrate investigation (Table 2). The products (3aa-3ja) were
coumarin 3aa in excellent regioselectivity
(γ/α, >20/1;
isolated in good to high yields with uniformly excellent
enantioselectivity. Furthermore, product 3ka containing a
naphthyl moiety was generated in good yield and high
branched/linear, >20/1) (entry 1). Although the yield was low,
the enantioselectivity of 3aa was satisfactory. Among other
common organic bases, TMG outperformed to furnish 3aa in
61% yield with 94% ee (entry 2-6). Increasing the amount of
electrophilic 2a was not helpful and the yield even decreased,
possibly due to the double vinylogous allylic alkylation in the
presence of 2 equiv 2a (entry 7). Changing the ratio of 1a to 2a
from 1/2 to 2/1 was proved to be effective to enhance the
yield as the partial decomposition of 1a was compensated by
the excess amount of 1a in reaction mixture (entry 8).
enantioselectivity. Interestingly, isocoumarin
(
1l
)
was
successfully utilized as a vinylogous pronucleophile in the Ir-
catalyzed asymmetric allylic alkylation for the first time, which
afforded 3la in 48% yield with 95% ee. The gram-scale reaction
of 3aa was successfully performed with constant yield and
enantioselectivity. As for allyl methyl carbonates (2b-2m), a
number of aryl groups with electron-rich or electron-deficient
2 | J. Name., 2012, 00, 1-3
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substituents, as well as heteroaromatic groups (3-pyridinyl, 2-
furanyl and 2-thienyl), was accepted. The R2 group was were also tolerated under the present reaction conditions. By
successfully extended to 2-methyl vinyl and alkyl substituents using 4a as the vinylogous pronucleophile, the substrate scope
(including alkyls with functional groups, such as benzyloxy or of allyl methyl carbonates was studied. As for R group, aryls
COMMUNICATION
α,β,γ,δ-Unsaturated 1,3-dicarbonyl compounds (4g and 4h)
chloride) (3an
determined to be S by comparison of its optical rotation value groups), heteroaryls, substituted vinyls, 1,3-dienyl and alkyl
with reported data (for details, see SI).13 For other products, are acceptable substituents (5af
5ai 5ak 5am 5ao and 5at
the absolute configurations were tentatively assigned by 5av). More interestingly, complex allyl methyl carbonates
analogy. generated from natural products (2w is derived from farnesal;
Table 3 Substrate Scope of Catalytic Asymmetric Vinylogous 2x is derived from (-)-citronellal; 2y is derived from (-)-
-3as). The absolute configuration of 3aa was (with electron-donating group or electron-withdrawing
,
,
,
-
-
Allylic Alkylation of
4
and 2a
myrtenal; for details, see SI) were applicable in the present
reaction protocol.
Scheme 2 Vinylogous Allylic Alkylation with
6
and
7
and
Bisvinylogous Allylic Alkylation with 10
[Ir(COD)Cl]2 (5.0 mol %)
(Sa,S,S)-Feringa ligand(11.0 mol %)
TMG (1.0 equiv)
O
O
O
O
EWG
+
Ph
OCO2Me
THF (0.1 M), rt
EWG
, >20/1; b/l, >20/1
Ph
EWG = CO2Et (8) 54%, 99% ee;
EWG = CONH2 (9) 83%, 97% ee;
6-7
2a
8-9
CO2Et
Ph
[Ir(COD)Cl]2 (5.0 mol %)
(Sa,S,S)-Feringa ligand(11.0 mol %)
TMG (2.0 equiv)
O
O
CO2Et
Ph
O
+
Ph
OTroc
O
THF (0.1 M), rt
Troc = 2,2,2-trichloroethoxycarbonyl
Ph
11
, >20/1; b/l, >20/1
27%, 94% ee
10
2b
Coumarins
6
and 7
, less efficient12 or even unreactive13 in
reported asymmetric vinylogous reaction, reacted smoothly
with allyl methyl carbonate 2a to afford the products and
8
9
in good yields with excellent stereoselectivity (Scheme 2).
Moreover, a bisvinylogous allylic alkylation with allyl 2,2,2-
trichloroethoxy carbonate (2b) was carried out in the present
catalytic system (Scheme 2). To our joy, the corresponding
product was obtained in 27 % yield with 94 % ee and excellent
regioselectivity.
Scheme 3 Transformation of Vinylogous Allylic Alkylation
Product 3aa
The product 3aa easily underwent transformations to
generate functionalized molecules (Scheme 3). In the presence
of catalytic Pd/C, a selective hydrogenation occurred to give 12
in 83% yield without touching the unsaturated carbon-carbon
double bond. The basic hydrolysis of 3aa provided chiral
ketone 13 in 53% yield. The functionalization of terminal olefin
with HBPin in the presence of catalytic iridium complex
afforded chiral alkyl borate 14 in 65% yield. Ozonolysis of 3aa
proceeded smoothly to furnish chiral aldehyde 15 in 81% yield.
The present methodology was applied in the asymmetric
synthesis of compound 17, which was identified as an
advanced key synthetic intermediate at Merck & Co. (Scheme
4).19 Catalytic asymmetric vinylogous allylic alkylation of 4f and
2t proceeded nicely to afford 5ft in 50% yield with 91% ee. The
Due to Feringa ligand’s superior performance, it was used
for evaluation of the substrates without a fused benzene ring
instead of You ligand (Table 3, 5aa).
dicarbonyl compounds with a five-member ring and an
exocyclic methyl group (4a 4c) were suitable substrates to
undergo the vinylogous allylic alkylation in excellent regio- and
enantioselectivity. -Unsaturated 1,3-dicarbonyl compounds
with a six-member ring and an exocyclic methyl group (4d 4f
were relatively less efficient as the products (5da 5fa) were
isolated in moderate yields together with lower
regioselectivity in the cases of 4d and 4e. Fortunately, no γ'-
α,β-Unsaturated 1,3-
-
α,β
-
)
-
allylic alkylation was detected in the reactions of 4d and 4e
.
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3
For some selected recent examples involving chiral γ-
substituted -unsaturated compounds as valuable
following one-step alcoholysis of 5ft direct resulted in 16 in 56%
yield. Then, by following the reported procedure,19 the key
intermediate 17 could be accessed.
α,β
synthetic intermediates in the total synthesis of complex
natural products, see: (a) X. Huang, L. Song, J. Xu, G. Zhu, B.
Liu, Angew. Chem. Int. Ed., 2013, 52, 952; (b) X. Zhao, W. Li, J.
Wang, D. Ma, J. Am. Chem. Soc., 2017, 139, 2932; (c) W.
Chen, X.-D. Yang, W.-Y. Tan, X.-Y. Zhang, X.-L. Liao, H. Zhang,
Angew. Chem. Int. Ed., 2017, 56, 12327; (d) C. Xie, J. Luo, Y.
Zhang, L. Zhu, R. Hong, Org. Lett., 2017, 19, 3592.
Scheme 4 Application of the Present Methodology in Organic
Synthesis
4
(a) M. Chen, J. F. Hartwig, Angew. Chem. Int. Ed., 2014, 53,
12172; (b) M. Chen, J. F. Hartwig, Angew. Chem. Int. Ed.,
2016, 55, 11651.
5
6
L. Næsborg, K. S. Halskov, F. Tur, S. M. N. Mønsted, K. A.
Jørgensen, Angew. Chem. Int. Ed., 2015, 54, 10193.
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Int. Ed., 2013, 52, 1257.
Conclusions
7
8
9
W.-B. Liu, N. Okamoto, E. J. Alexy, A. Y. Hong, K. Tran, B. M.
Stoltz, J. Am. Chem. Soc., 2016, 138, 5234.
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Chem. Int. Ed., 2018, 57, 1404.
For some recent reviews on coumarins, see: (a) F. G. Medina,
In summary, a highly regio- and enantioselective catalytic
asymmetric vinylogous allylic alkylation was achieved by using
α
,
β
-unsaturated lactones bearing an electron-withdrawing
J. G. Marrero, M. Mac
Guerrero, A. G. T. Garc
í
as-Alonso, M. C. Gonz
í
ález, I. Córdova-
a, S. Osequeda-Robles, Nat. Prod.
group at -position and an exocyclic methyl group at β-
α
position (including coumarins). The present methodology was
successfully applied in the asymmetric synthesis of an
advanced synthetic intermediate, which was employed in the
synthesis of an investigational new drug candidate. The further
expansion of pronucleophile types in vinylogous reaction and
application of the present methodology to complex natural
product synthesis are underway.
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Conflicts of interest
11 (a) S. Zhao, Y.-Y. Zhao, J.-B. Lin, T. Xie, Y.-M. Liang, P.-F. Xu,
Org. Lett., 2015, 17, 3206; (b) S. Kayal, S. Mukherjee, Org.
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this manuscript, Mukherjee group published a paper similar
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an Advance Article and published officially in issue 26 (14
July, 2018)), which focused on iridium-catalyzed direct
asymmetric vinylogous allylic alkylation of coumarins, see: R.
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge the financial support from the
“Thousand Youth Talents Plan”, the National Natural Sciences
Foundation of China (No. 21672235 and No. 21871287), the
Strategic Priority Research Program of the Chinese Academy of
Sciences (No. XDB20000000), the “Shanghai Rising-Star Plan” (No.
15QA1404600), CAS Key Laboratory of Synthetic Chemistry of
Natural Substances and Shanghai Institute of Organic Chemistry.
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DOI: 10.1039/C8CC07249C
! ꢀꢁꢂꢁꢃꢄꢂꢅꢀ ꢁ ꢄꢆꢆꢇꢂꢈꢅꢀ ꢉꢅꢊꢄꢃꢋꢌꢋꢍ ꢁꢃꢃꢄꢃꢅꢀ ꢁꢃꢎꢄꢃꢁꢂꢅꢋꢊ ꢋꢏ αꢐβꢑꢍꢊ ꢁꢂꢍꢈꢁꢂꢇꢒ ꢃꢁꢀꢂꢋꢊꢇ ꢓꢅꢂꢔ ꢅꢈꢅꢒꢅꢍꢆ
ꢀꢁꢂꢁꢃꢄ ꢂ ꢓꢁ ꢁꢀꢔꢅꢇꢉꢇꢒ ꢓꢅꢂꢔ ꢇꢕꢀꢇꢃꢃꢇꢊꢂ ꢈꢇꢌꢅꢋꢑ ꢁꢊꢒ ꢇꢊꢁꢊꢂꢅꢋ ꢇꢃꢇꢀꢂꢅꢉꢅꢂꢄꢖ