Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives through Iridium-Catalyzed Allylic Alkylation

Article abstract of DOI:10.1002/anie.201707015

The first highly enantioselective iridium-catalyzed allylic alkylation that provides access to products bearing an allylic all-carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one-pot preparation of α-quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations.

Full text of DOI:10.1002/anie.201707015

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Accepted Article
Title: Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic
Acid Derivatives via Iridium-Catalyzed Allylic Alkylation
Authors: Samantha Shockley, John Caleb Hethcox, and Brian Stoltz
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707015
Angew. Chem. 10.1002/ange.201707015
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10.1002/anie.201707015
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic
Acid Derivatives via Iridium-Catalyzed Allylic Alkylation
Samantha E. Shockley,‡ J. Caleb Hethcox,‡ and Brian M. Stoltz*
Dedicated with admiration and respect to Professor Günter Helmchen on the 20th Anniversary of his seminal report on iridium-
catalyzed asymmetric allylic alkylation.
Abstract: The first highly enantioselective iridium-catalyzed allylic
alkylation providing access to products bearing an allylic all-carbon
quaternary stereogenic center has been developed. The reaction
utilizes a masked acyl cyanide (MAC) reagent, which enables the
one-pot preparation of α-quaternary carboxylic acids, esters, and
amides with a high degree of enantioselectivity. The utility of these
the electrophile.5,11,12 Herein, we unlock this heretofore
unreactive class of electrophiles to achieve the first example of
an enantioselective iridium-catalyzed allylic alkylation reaction
forming a quaternary stereocenter at the allylic position.
a) Limitations in Enantioselective Iridium-Catalyzed Allylic Akylation
products is further explored via
transformations.
a series of diverse product
[L*Ir]
[L*Ir]
R2
R
R1
Nuc
Nuc
Nuc
R1 R2
R
all reports
zero reports
The field of enantioselective iridium-catalyzed allylic
alkylation has flourished in the 20 years since the seminal report
by Helmchen.1 Over these two decades, the substrate scope
with respect to the nucleophile has expanded significantly to
encompass a vast array of both carbon2 and hetereoatom3
nucleophiles.4 Conversely, the scope of the electrophiles has
remained largely unchanged, being limited to those that produce
products bearing a tertiary allylic stereocenter (Figure 1a, left).5
Despite the longstanding interest in the synthesis of
enantioenriched quaternary stereocenters within the synthetic
community as well as the development of other transition metal-
catalyzed processes to access all-carbon quaternary allylic
stereocenters,6,7,8 iridium-catalyzed allylic alkylation reactions
that furnish products possessing such a stereocenter remain
conspicuously absent from the literature (Figure 1a, right).
As part of our ongoing program in developing iridium-
catalyzed allylic alkylation technology and our continued interest
in the catalytic, asymmetric synthesis of quaternary
stereocenters,9 we were attracted to this unmet challenge.
Moreover, we imagined that an umpolung strategy iridium-
catalyzed allylic alkylation reaction of a trisubstituted allylic
electrophile with a masked acyl cyanide (MAC) nucleophile
would not only give rise to products containing an
enantioenriched allylic all-carbon quaternary stereocenter, but
also provide access to highly valuable acyclic α-quaternary
carboxylic acid derivatives (i.e., acids, esters, amides) upon
unmasking of the MAC functionality (Figure 1b).8,9e,10 However,
success of this strategy hinged upon the implementation of a
trisubstituted allylic electrophile, which were predicted to be
unreactive in an enantioselective iridium-catalyzed allylic
alkylation reaction. It is known that the reaction rates of these
processes decrease with increasing substitution on the olefin of
b) This Research
O
R2
i. [IrL*]
OMOM
δ
δ
X
+
R1
OCO2Me
NC
CN
ii. H+, HX
R1 R2
X = OH, OR, NR2
Figure 1. Synthesis of allylic all-carbon quaternary stereocenters via
enantioselective iridium-catalyzed allylic alkylation.
Preliminary studies focused on identifying a combination of
ligand and additive to promote the reaction of MAC 1 and
trisubstituted allylic electrophile 2 (Table 1). Application of our
standard conditions for iridium-catalyzed allylic alkylation
reactions of [Ir(cod)Cl]2, L1, and LiBr returned only starting
material (Table 1, entry 1).9a,e A brief ligand screen revealed that
while ligand L2 also resulted in no reaction (entry 2), the
phosphoramidite L3 developed by Carreira provided desired
product 3 in 13% yield with a moderate 79% ee (entry 3).3b
Attempts to further increase yield and selectivity via an extensive
evaluation of additives known to promote iridium-catalyzed allylic
alkylations proved ineffective.2–4,9 As we hypothesized that the
oxidative addition process is slow for trisubstituted allylic
electrophiles, we reasoned that the inclusion of a strong Lewis
acid would facilitate the ionization of the carbonate during the
insertion event, leading to improved reactivity of these
recalcitrant electrophiles. Toward this end, we substituted LiBr
for triethylborane and were pleased to find that the yield nearly
tripled and the enantioselectivity rose to 93% ee (entry 4).13
Upon varying the stoichiometry of nucleophile 1 to electrophile 2,
we observed a dramatic increase in yield to 74% with no erosion
of enantioselectivity (entry 5). Ultimately, we discovered that
exposure of a mixture (1:2) of MAC 1 and trisubstituted allylic
electrophile 2 afforded MAC adduct 3 in nearly quantitative yield
and in 94% ee (entry 6).14
[a]
S. E. Shockley,‡ Dr. J. C. Hethcox,‡ Prof. Dr. B. M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology
1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
E-mail: stoltz@caltech.edu
‡These authors contributed equally.
Supporting information for this article can be found under:
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10.1002/anie.201707015
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of reaction parameters.a
that hydrolysis of the MAC functionality of product 3 could be
performed in the same reaction vessel as the iridium-catalyzed
allylic alkylation reaction to provide direct access to the
OMOM
[Ir(cod)Cl]2 (2 mol %)
(4.2 mol %), TBD (10 mol %)
OMOM
CN
NC
NC
L
corresponding carboxylic acid in
procedure.10 Moreover, we envisioned that these carboxylic acid
products would be amenable to purification by simple
a
one-pot, two-step
+
Ph
OCO2Me
THF (0.1 M), 60 °C, 18 h
NC
Ph
1
2
3
a
acid/base extraction. To this end, we subjected the crude allylic
alkylation mixture to hydrolysis with 6M HCl at 80 °C and were
pleased to find that pure carboxylic acid 7a was obtained after
an aqueous work-up with no need for column chromatography
(Table 3).
ee
(%)c
Additive
(200 mol %)
Yield
(%)b
Entry
L
1:2
1
2
3
4
5
6
L1
L2
L3
L3
L3
L3
2:1
2:1
LiBr
LiBr
LiBr
BEt3
BEt3
BEt3
0
0
–
–
2:1
13
34
74
99
79
93
92
94
2:1
1:1.2
1:2
Table 3. Aryl Substituent Substrate Scope.a
i. BEt3 (200 mol %)
[Ir(cod)Cl]2 (2 mol %)
L3 (4.2 mol %), TBD (10 mol %)
THF (0.1 M), 60 °C, 18 h
Ph
O
O
O
O
P
OMOM
P
N
P
N
N
O
O
O
Ar
OCO2Me
HO
+
NC
CN
Ph
Ar
ii. 6 M HCl (0.05 M), 80 °C, 18 h
1
6
7
(S,Sa)-L1
(S,S,Sa)-L2
(Sa)-L3
O
O
O
O
[a] Reactions performed on 0.1 mmol scale. [b] 1H NMR yield based on internal
HO
HO
HO
HO
standard. [c] Determined by chiral HPLC analysis. [d] TBD
= 1,3,5-
triazabicyclo[4.4.0]dec-5-ene.
Cl
F
F3C
During the course of our optimization studies, we
discovered both the surprising necessity of the guanidine base
TBD as well as the importance of electrophile stereochemistry in
our newly developed reaction. Though previously reported
conditions for the use of L3 in iridium-catalyzed allylic alkylations
do not require a base additive,15 we found the inclusion of TBD
during the catalyst prestir to be critical to the success of the
reaction. We hypothesize that TBD may be serving as either a
placeholder ligand to prevent the formation of an inactive
catalyst16 or as a base to promote the formation of an active
iridicycle.2a,c Additionally, we noted that use of the E-
trisubstituted allylic electrophile was required, as Z-olefin isomer
4 led to markedly decreased yield and selectivity (Table 2).17
Moreover, neither a kinetic nor a dynamic kinetic resolution
occurs under the reaction conditions with the use of terminal
olefin rac-5 (Table 2).
7a
7c
90% yield
90% ee
7b
80% yield
93% ee
7d
83% yield
92% ee
77% yieldb
95% eec
O
O
O
O
HO
HO
HO
HO
Br
NO2
OH
7h f
93% yield
d
7f
7g e
69% yield
92% ee
7e
65% yield
94% ee
51% yield
95% ee
87% ee
O
O
O
O
HO
HO
HO
HO
7i g
66% yield
7j g
68% yield
7kg
32% yield
7l
Table 2. Electrophile Isomers.a
0% yield
–% ee
92% ee
85% ee
93% ee
BEt3 (200 mol %)
[Ir(cod)Cl]2 (2 mol %)
L3 (4.2 mol %), TBD (10 mol %)
OMOM
OMOM
CN
NC
NC
[a] Reactions performed on 0.2 mmol scale. [b] Isolated yield. [c] Determined
by chiral HPLC or SFC analysis. [d] Electrophile 6f used as the bis-carbonate
which was deprotected during hydrolysis. [e] Reaction run for 48 h. [f] Absolute
stereochemistry determined via single crystal X-ray analysis, the absolute
stereochemistry of all other compounds has been assigned by analogy. [g]
Reaction performed with double catalyst loading.
+
2, 4, or 5
THF (0.1 M), 60 °C, 18 h
NC
Ph
1
3
Ph
OCO2Me
Ph
OCO2Me
OCO2Me
Ph
With the optimized protocol in hand, we first explored the
effect of substitution on the aryl moiety of electrophile 6 (Table
3). We were pleased to find that para-substitution was well
tolerated to provide acids 7b–f in consistently high
enantioselectivities, though electron-rich substrates provided
decreased yields. Meta-substituted products 7g and 7h were
obtained in similarly high enantioselectivites (92% and 87% ee,
respectively), and bulky naphthyl-substituted acid 7i was
furnished in 92% ee, albeit in a moderate 66% yield. Further
2
4
18% yield
16% ee
5
99% yield
1% ee
99% yieldb
94% eec
[a] Reactions performed with 1 (0.1 mmol) and 2, 4, or 5 (0.2 mmol). [b] 1H
NMR yield based on internal standard. [c] Determined by chiral HPLC analysis.
Before substrate scope exploration commenced, we
identified an additional opportunity for innovation. We imagined
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10.1002/anie.201707015
Angewandte Chemie International Edition
COMMUNICATION
exploration of steric effects using methyl-substituted derivatives
demonstrated that while a single meta-substituent is tolerated to
access 7j in 68% yield with 93% ee, the bis-meta-substituted
derivative 7k was afforded in a drastically lower 32% yield but
with good enantioselectivity (85% ee). Finally, we discovered
that ortho-substitution was not tolerated and only starting
material was recovered from the reaction.18
access to both tertiary amide 12 in 61% yield and secondary
amide 13 in 63% yield.
O
O
MeO
O
a
b
OMOM
10
11
Cl
Cl
NC
NC
Table 4. Non-Aryl Substituent Substrate Scope.a
i. BEt3 (200 mol %)
[Ir(cod)Cl]2 (4 mol %)
L3 (8.4 mol %), TBD (20 mol %)
R2
O
OMOM
O
O
Cl
c
THF (0.1 M), 60 °C, 18 h
R1
OCO2Me
HO
O
+
NC
CN
N
H
N
R1 R2
d
ii. 6 M HCl (0.05 M), 80 °C, 18 h
1
8
9
13
12
Cl
Cl
O
O
HO
HO
HO
Figure 2. (a) i. CSA, AcOH/DME, 60 °C, 6 h, ii. MeOH, Et3N, –40 °C → 23 °C,
18 h, 88% yield; (b) i. CSA, AcOH/DME, 60 °C, 6 h, ii. allyl alcohol, Et3N, 0 °C
→ 23 °C, 18 h, 74% yield; (c) CSA, AcOH/DME, 60 °C, 6 h, ii. pyrrolidine, Et3N,
–40 °C → 23 °C, 18 h, 61% yield; (d) i. CSA, AcOH/DME, 60 °C, 6 h, ii. allyl
amine, Et3N, 0 °C → 23 °C, 18 h, 63% yield.
Et
n-Bu
i-Pr
9b
9c
9a
61% yieldb
92% eec
14% yield
0% yield
–% ee
95% ee
O
O
O
In order to demonstrate the synthetic utility of the
enantioenriched α-quaternary carboxylic acid derivatives, a
series of transformations were performed to access a diverse
array of chiral building blocks starting from ester derivative 10
(Figure 3). Hydrogenation of olefin 10 delivered ethyl-substituted
14 in 97% yield. Alcohol 15 was accessed via reduction of the
ester moiety in 73% yield. Dihydroxylation of the pendant olefin
proceeded with concomitant lactonization to furnish γ-
HO
HO
HO
Ph
9f
9d/e
trace yield
–% ee
9g
32% yield
63% yield
3% ee
[a] Reactions performed on 0.2 mmol scale. [b] Isolated yield. [c] Determined
by chiral HPLC or SFC analysis.
butyrolactone 16 in 82% yield as
diastereomers. Finally, ozonolysis furnished aldehyde 17 in
moderate yield.
a
mixture (1:1) of
With the general trends in reactivity corresponding to aryl
substitution elucidated, we next turned our attention to the scope
of the reaction with respect to the aliphatic moiety of the
electrophile (Table 4). We found that extension of the alkyl chain
led to decreased yields with ethyl-substituted 9a and n-butyl-
substituted 9b isolated in 61% and 14% yield, respectively,
O
HO
MeO
a
b
though
both
were
obtained
in
similarly
excellent
enantioselectivities.
Furthermore,
branched-substituted
Cl
14
15
O
Cl
electrophiles were unreactive and only starting material was
recovered in attempts to prepare isopropyl-substituted 9c.
We then moved to explore the necessity of the aryl
MeO
10
functionality.
We
hypothesized
that
cyclohexyl-
and
Cl
O
O
cyclohexenyl-substituted electrophiles 8d and 8e would mimic
the sterics of the phenyl moiety of 6a when interacting with the
chiral catalyst, but we found that only trace products 9d and 9e
were observed under our reaction conditions (Table 4). Use of
bis-n-alkyl-substituted electrophile 8f provided the corresponding
acid 9f in moderate yield, though no enantioselectivity was
observed. Finally, we were pleased to find that prenyl methyl
carbonate (8g) was a competent electrophile furnishing acid 9g
in 63% yield.
As MAC adducts can be transformed to essentially any
carboxylic acid derivative,10 we endeavored to develop
additional one-pot transformations to access both α-quaternary
esters and amides. Gratifyingly, we found that alkanolysis of the
crude MAC alkylation product with either methanol or allyl
alcohol provided methyl ester 10 and allyl ester 11 in 88% and
74% yield, respectively (Figure 2). Similarly, aminolysis provided
O
MeO
H
d
c
O
Cl
OH
17
16
Cl
Figure 3. (a) Pd/C, H2 (balloon), EtOAc, 23 °C, 18 h, 97% yield; (b) DIBAL,
Et2O, 0 °C, 2 h, 73% yield; (c) K2OsO4, NMO, THF/H2O (4:1), 23 °C, 18 h,
82% yield (1:1 dr); (d) i. O3, NaHCO3, MeOH/CH2Cl2 (1:5), –78 °C, 0.5 h, ii.
DMS, –78 °C→ 23 °C, 18 h, 50% yield.
In conclusion, we have developed the first synthesis of all-
carbon quaternary allylic stereocenters via enantioselective
iridium-catalyzed allylic alkylation. The unprecedented
combination of triethylborane and a catalyst prepared from
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10.1002/anie.201707015
Angewandte Chemie International Edition
COMMUNICATION
[7]
For selected recent examples of the enantioselective transition metal-catalyzed
synthesis of allylic all-carbon quaternary stereocenters, see: a) A. Zhang, T. V.
RajanBabu, J. Am. Chem. Soc. 2006, 128, 5620–5621; b) C. A. Falciola, A.
Alexakis, Chem. Eur. J. 2008, 14, 10615–10627; c) Y. Xiong, G. Zhang, Org.
Lett. 2016, 18, 5094–5097; d) S. Guduguntla, J.-B. Gualtierotti, S. S. Goh, B.
L. Feringa, ACS Catal. 2016, 6, 6591–6595; e) B. M. Trost, C. Jiang, J. Am.
Chem. Soc. 2001, 123, 12907–12908; f) X.-L. Hou, N. Sun, Org. Lett. 2004, 6,
4399–4401; g) P. Zhang, H. Le, R. E. Kyne, J. P. Morken, J. Am. Chem. Soc.
2011, 133, 9716–9719.
[Ir(cod)Cl]2, L3, and TBD was used to coerce reactivity from a
once poorly reactive class of trisubstituted allylic electrophiles.
Furthermore, the use of
a single masked acyl cyanide
nucleophile facilitated the one-pot syntheses of enantioenriched
α-quaternary acids, esters, and amides. The protocol is tolerant
of a wide range of substitution on the aryl moiety to provide the
corresponding products with good yields and excellent
enantioselectivites. This methodology is critical in laying the
groundwork for the future development of technology to access
vicinal quaternary stereocenters via iridium-catalyzed allylic
alkylation of prochiral nucleophiles. Work to elucidate the nature
of this catalyst system and further expand the substrate scope
will be reported in due course.
[8]
For the only enantioselective reports to access acyclic quaternary α-vinyl, α-
aryl carbonyl derivatives, see: a) K. E. Murphy, A. H. Hoveyda, Org. Lett.
2005, 7, 1255–1258; b) Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128,
15604–15605; c) F. Gao, Y. Lee, K. Mandai, A. H. Hoveyda, Angew. Chem.
Int. Ed. 2010, 49, 8370–8374; Angew. Chem. 2010, 122, 8548–8552; d) K.
Hojoh, H. Ohmiya, M. Sawamura, J. Am. Chem. Soc. 2017, 139, 2184–2187.
a) W.-B. Liu, C. M. Reeves, B. M. Stoltz, J. Am. Chem. Soc. 2013, 135,
17298–17301; b) W.-B. Liu, C. M. Reeves, S. C. Virgil, B. M. Stoltz, J. Am.
Chem. Soc. 2013, 135, 10626–10629; c) W.-B. Liu, N. Okamoto, E. J. Alexy,
A. Y. Hong, K. Tran, B. M. Stoltz, J. Am. Chem. Soc. 2016, 138, 5234–5237;
d) J. C. Hethcox, S. E. Shockley, B. M. Stoltz, Angew. Chem. Int. Ed. 2016, 55,
16092–16095; Angew. Chem. 2016, 128, 16326–16329; e) J. C. Hethcox, S. E.
Shockley, B. M. Stoltz, Org. Lett. 2017, 19, 1527–1529.
[9]
Acknowledgements
The NIH-NIGMS (R01GM080269) and Caltech are thanked for
support of our research program. J.C.H. thanks the Camille and
Henry Dreyfus postdoctoral program, and S.E.S. thanks the
NIH-NIGMS for a predoctoral fellowship (F31GM120804). Dr.
Michael Takase, Dr. Lawrence Henling, and Niklas Thompson
are acknowledged for assistance with X-ray analysis. Dr. Mona
Shahgholi and Naseem Torian are thanked for mass
spectrometry assistance. Dr. Scott Virgil is thanked for
assistance with instrumentation.
[10] a) H. Nemoto, Y. Kubota, Y. Yamamoto, J. Org. Chem. 1990, 55, 4515–4516;
b) K. S. Yang, A. E. Nibbs, Y. E. Türkmen, V. H. Rawal, J. Am. Chem. Soc.
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137, 14968–14981.
[12] One report of a trisubstituted allylic electrophile in an enantioselective iridium-
catalyzed allylic alkylation has been disclosed, but the products bear a tertiary
allylic stereocenter: M. Chen, J. F. Hartwig, Angew. Chem. Int. Ed. 2016, 55,
11651–11655; Angew. Chem. 2016, 128, 11823–11827.
Keywords: Iridium • Allylic Alkylation • Umpolung • Quaternary
[13] To the best of our knowledge, only one report of a borane additive (Ph3B) in
iridium-catalyzed allylic alkylation reactions has been disclosed: Y. Yamashita,
A. Gopalarathnam, J. F. Hartwig J. Am. Chem. Soc. 2007, 129, 7508–7509.
[14] It should be noted that excess electrophile 2 is not consumed and can be
recovered following the iridium-catalyzed allylic alkylation reaction.
[15] S. L. Rössler, S. Krautwald, E. M. Carreira, J. Am. Chem. Soc. 2017, 139,
3603–3606.
Stereocenter • Carboxylic Acid Derivatives
[1]
[2]
J. P. Janssen, G. Helmchen, Tetrahedron Lett. 1997, 38, 8025–8026.
For selected recent examples, see: a) X. Jiang, J. J. Beiger, J. F. Hartwig, J. Am.
Chem. Soc. 2017, 139, 87–90; b) T. Sandmeier, S. Krautwald, H. F. Zipfel, E.
M. Carreira, Angew. Chem. Int. Ed. 2015, 54, 14363–14367; Angew. Chem.
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You, J. Am. Chem. Soc. 2012, 134, 4812–4821.
[16] TBD is included with ligands L1 and L2 to form an active iridicycle catalyst;
however, Carreira has demonstrated that ligand L3 does not form an iridicycle,
see ref. 15.
[3]
[4]
For selected recent examples, see: a) K. Seehafer, C. C. Malakar, M. Bender, J.
Qu, C. Liang, G. Helmchen, Eur. J. Org. Chem. 2016, 493–501; b) C. Defieber,
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3139–3143; Angew. Chem. 2007, 119, 3200–3204; c) M. Ueda, J. F. Hartwig,
Org. Lett. 2010, 12, 92–94.
[17] We rationalize this difference in reactivity via the preferred conformation of
the reactants. Whereas 2 may exist in a planar conformation, the phenyl group
of 4 likely prefers to rotate out of plane to alleviate A1,3 strain. In adopting this
perpendicular conformation, the phenyl ring has now increased the sterics
above and below the olefin as well as become σ-withdrawing rather than π-
donating.
For selected reviews, see: a) G. Helmchen, A. Dahnz, P. Dübon, M. Schelwies,
R. Weihofen, Chem. Commun. 2007, 675–691; b) J. F. Hartwig, M. J. Pouy,
Top. Organomet. Chem. 2011, 34, 169–208; c) W.-B. Liu, J.-B. Xia, S.-L. You,
Top. Organomet. Chem. 2012, 38, 155–208; d) J. C. Hethcox, S. E. Shockley,
B. M. Stoltz, ACS Catal. 2016, 6, 6207–6213.
[18] Thiophene- and furan-substituted allylic electrophiles were well tolerated in
the iridium-catalyzed allylic alkylation reaction but were not amenable to the
hydrolysis conditions.
[5]
A
singular example of an iridium-catalyzed allylic alkylation reaction
producing product bearing an allylic all-carbon stereocenter has been
a
reported with 11% yield and 21% ee: G. Onodera, K. Watabe, M. Matsubara,
K. Oda, S. Kezuka, R. Takeuchi, Adv. Synth. Catal. 2008, 350, 2725–2732.
a) C. J. Douglas, L. E. Overman, Proc. Natl. Acad. Sci. USA 2004, 101, 5363–
5367; b) J. P. Das, I. Marek, Chem. Commun. 2011, 47, 4593–4623; c) K. W.
Quasdorf. L. E. Overman, Nature 2014, 516, 181–191; d) E. J. Corey, A.
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10.1002/anie.201707015
Angewandte Chemie International Edition
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Samantha E. Shockley, ‡ Dr. J. Caleb
Hethcox, ‡ and Prof. Brian M. Stoltz*
i. BEt3 (200 mol %)
[Ir(cod)Cl]2 (2 mol %)
O
OMOM
CN
L3 (4.2 mol %), TBD (10 mol %)
THF (0.1 M), 60 °C, 18 h
X
Ar
OCO2Me
+
NC
Ar
X = OH, OR, NR2
ii. H+, HX
Page No. – Page No.
Allylic All-Carbon Quaternary Stereogenic Centers
Enantioselective Synthesis of Acyclic
One-Pot • Chromatography-Free for Carboxylic Acids • Up to 93% Yield • Up to 95% ee
α
-Quaternary Carboxylic Acid
Derivatives via Iridium-Catalyzed
Allylic Alkylation
Ir-resistable: The first enantioselective iridium-catalyzed allylic alkylation providing
access to products bearing an allylic all-carbon quaternary stereogenic center has
been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which
enables a one-pot preparation of α-quaternary carboxylic acids, esters, and amides
with a high degree of enantioselectivity. The utility of these products is further
explored via a series of diverse product transformations.
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