Direct Enantioselective and Regioselective Alkylation of β,γ-Unsaturated Carboxylic Acids with Chiral Lithium Amides as Traceless Auxiliaries

Article abstract of DOI:10.1021/acs.orglett.9b00587

Efficient asymmetric alkylation of β,γ-unsaturated carboxylic acids without prior functionalization is enabled by chiral lithium amides. Enantioselectivity is imparted by a putative mixed lithium amide-enediolate aggregate that acts a traceless auxiliary formed in situ, allowing for a direct asymmetric alkylation and a simple recovery of the chiral reagent.

Full text of DOI:10.1021/acs.orglett.9b00587

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Enantioselective and Regioselective Alkylation of β,γ-
Unsaturated Carboxylic Acids with Chiral Lithium Amides as
Traceless Auxiliaries
Kai Yu, Bukeyan Miao,† Wenqi Wang, and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: Efficient asymmetric alkylation of β,γ-unsatu-
rated carboxylic acids without prior functionalization is enabled
by chiral lithium amides. Enantioselectivity is imparted by a
putative mixed lithium amide−enediolate aggregate that acts a
traceless auxiliary formed in situ, allowing for a direct
asymmetric alkylation and a simple recovery of the chiral
reagent.
Scheme 1. Approaches to the Enantioselective Synthesis of
α-Substituted β,γ-Unsaturated Carboxylic Acids
he enantioselective alkylation of enolates is a fundamental
and broadly utilized transformation in stereoselective
T
organic synthesis. Chiral auxiliary-based methods for alkylation
of carboxylic acids in which the auxiliary is covalently bound
have gained widespread application in both industrial and
academic settings.1,2 Chiral lithium amides, which form mixed
aggregates with organolithium and other organometallic
reagents,3 offer an alternative approach to asymmetric
alkylation of enolates.4,5 Within the context of these complex
aggregates, chiral lithium amides in effect function as
noncovalent, or traceless, chiral auxiliaries. Formed in situ,
they provide a chiral environment enabling asymmetric
transformations. Some of the practical advantages of the chiral
lithium amide-based approach6,7 are (1) eliminating the need
for prederivatization of carboxylic acid substrates, (2) simple,
high-yield recovery of the amine reagent by acidic extraction,
and (3) high reactivity of enediolates used in direct alkylation
of carboxylic acids.
Previously, we demonstrated that C2-symmetric chiral
lithium amides enable highly enantioselective alkylation and
conjugate addition of enediolates derived directly from aryl-
and heteroarylacetic acids.6 However, other types of carboxylic
acids are also highly valuable substrates in organic synthesis.
Specifically, we became interested in β,γ-unsaturated aliphatic
acids because of their appeal as starting materials and the
potential for further elaboration of the double bond. In
addition, a new challenge with this class of substrates is the
question of α versus γ regioselectivity during the reaction of
the electrophile with the enediolate intermediate (Scheme 1c).
While other approaches for the stereoselective synthesis of α-
substituted 3-alkenoic acids have been reported on the basis of
kinetic resolution8 or covalent chiral auxiliaries9 (Scheme 1),
the enantioselective alkylation of β,γ-unsaturated aliphatic
acids is still underdeveloped.10 Previously, poor regioselectiv-
ities have been observed in the reaction of enolates derived
from 3-alkenoic acids with electrophiles.11 Here, we report that
chiral lithium amides are effective reagents for highly enantio-
and regioselective direct α-alkylation of β,γ-unsaturated
carboxylic acids.
Ethylation of (E)-4-phenyl-3-butenoic (1a) and (E)-4-
cyclohexyl-3-butenoic (1b) acids with iodoethane provided a
platform to test the feasibility of this approach and to identify
the most effective chiral lithium amides from a set of readily
available amines5 (R)-1TA−5TA and (R)-DA (Table 1).
Received: February 15, 2019
© XXXX American Chemical Society
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Comparable levels of enantio- and regioselectivity and
comparable yields were observed for ethylation of (E)-4-
cyclohexyl-3-butenoic acid 1b (Table 1, entries 8−13).
Optimal aggregation now required 45 min at 23 °C with this
fully aliphatic substrate. Tetraamine (R)-1TA again proved to
be the most effective, giving α-ethylation product 2b in 71%
yield, 92:8 er, and >20:1 regioselectivity (entry 8). With LDA,
a lower regioselectivity of 6:1 was observed, highlighting the
impact of the lithium amide structure on regiocontrol (entry
14).
Table 1. Chiral Lithium Amides for Enantioselective and
Regioselective Ethylation of 4-Phenyl-3-butenoic Acid and
4-Cyclohexyl-3-butenoic Acid
a
With the optimal reaction parameters for both type of
substrate established, we first explored alkylation of various 4-
aryl-3-butenoic acids shown in Scheme 2. A strong preference
Scheme 2. Scope of Aryl-Substituted β,γ-Unsaturated
a
Carboxylic Acids
entry
acid (R)
amine
yield (%)
er
α:γ ratio
b
1
2
3
4
5
6
7
8
1a (Ph)
(R)-1TA
(R)-2TA
(R)-3TA
(R)-4TA
(R)-5TA
(R)-DA
i-Pr2NH
(R)-1TA
(R)-2TA
(R)-3TA
(R)-4TA
(R)-5TA
(R)-DA
i-Pr2NH
95
74
67
25
75
30
88
71
47
39
16
37
11
71
96:4
>20:1
>20:1
>20:1
15:1
>20:1
>20:1
6:1
>20:1
>20:1
>20:1
14:1
82:18
34:66
54:46
26:74
76:24
−
c
d
1b (Cy )
92:8
9
75:25
71:29
50:50
15:85
47:53
−
10
11
12
13
14
6:1
11:1
6:1
a
Experiments were performed on a 0.50 mmol scale; all results
normalized to bases with the R configuration. (R)-TA/DA (1.03
equiv), n-BuLi (4.0 equiv), C2H5I (4.0 equiv), and THF (4.0 mL).
b
c
Aggregation performed at 0 °C for 45 min with 1a. Aggregation
d
performed at 23 °C for 45 min with 1b. Cy = cyclohexyl.
Because aggregation conditions are known to have a
profound influence on the outcome of organolithium
reactions,6 they were examined first. For 1a, optimal
aggregation was achieved upon treatment of an equimolar
mixture of chiral tetraamine (R)-1TA and acid 1a with 4.0
equiv of n-BuLi at 0 °C for 45 min in THF. Addition of
iodoethane at −78 °C resulted in 95% yield of (S,E)-2-ethyl-4-
phenyl-3-butenoic acid (2a) with a 96:4 enantiomeric ratio
(er)12 and a >20:1 preference for α-alkylation (Table 1, entry
1). High regioselectivity was maintained with other chiral
amines tested (entries 2−6). Notably, with LDA there was a
reduction of regioselectivity, with a 6:1 ratio of α- and γ-
alkylation products (entry 7). Enantioselectivity was similar
with pyrrolidine-derived tetraamine (R)-2TA but generally
lower with other chiral amines studied. Interestingly, an
inversion in the enantioselectivity was observed with more
hindered amine (R)-5TA.
a
Experiments were performed on a 0.50 mmol scale unless stated
otherwise.
for α-alkylation and enantioselectivity and practical yields were
general for most substrates bearing aryl and heteroaryl
substituents. While para substitution in the Ph group had
little impact on reaction outcome (3a and 3d−3f), ortho
substitution resulted in a moderate reduction of α-
regioselectivity from >15:1 to 8:1 (3g and 3k). Naphthyl
B
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a
and heteroaryl substituents were compatible, giving excellent
regio- and enantioselectivity and good yields in the alkylation
reaction (3b, 3c, and 3m−3o). Notably, ethylation of 3-
phenyl-3-butenoic acid also occurred at the apparently more
hindered α position with good regioselectivity (10:1) and
excellent enantioselectivity in 77% yield (3p). Although the
4Z-methyl substituent had no detrimental effect on the
reaction outcome (3o), alkylation of (Z)-4-phenyl-3-butenoic
acid,13 while highly regioselective (>20:1), resulted in
substantially lower yield and er values (3q). A test of the
alkylation procedure on a 1 g scale was performed with (E)-4-
(naphthalen-2-yl)-3-butenoic acid, which afforded 3b in
excellent yield and excellent enantio- and regioselectivity. In
this case, we demonstrated the simple recovery of tetraamine
auxiliary (R)-1TA in 98% yield by aqueous acid−base
extraction.
Scheme 4. Scope of Alkylating Agents
3-Butenoic acids substituted with alkyl groups at position 4
generally afforded >20:1 α-regioselectivity in the alkylation
reaction (Scheme 3). Ethylation on long-chain (E)-3-octenoic
Scheme 3. Scope of Aliphatic β,γ-Unsaturated Carboxylic
a
Acids
a
b
Experiments were performed on a 0.50 mmol scale. With (S)-5TA.
acid gave a 67% yield of 4a with an 88:12 er (4a). The er with
γ,γ-disubstituted 4-methyl-3-pentenoic acid increased to 93:7
(4b). (E)-4-Isopropyl-3-pentenoic acid afforded the corre-
sponding alkylation product in 71% yield and 92:8 er (4c).
More functionalized dienoic acids proved to be particularly
suitable substrates affording better enantioselectivities and
yields (4d and 4e). Similarly, ethylation of 2-(cyclohexen-1-
yl)acetic acid afforded 4f in 94% yield and 95:5 er. Ethylation
of unsubstituted 3-butenoic acid with (R)-1TA afforded 4g
with low enantio- and regioselectivity (56:44 er and 5:1 α:γ).
However, both the er and regiocontrol could be improved with
the bulkier tetraamine (S)-5TA as the stereodirecting reagent,
affording 4g in 81% yield, 84:16 er, and 10:1 α-selectivity.
Next, we examined various alkyl halides as alkylating
reagents with carboxylic acids 1a and 1b as prototypical
substrates (Scheme 4). First, iodomethane and 1-iodobutane
proved to be suitable alkylating agents for 1a, maintaining high
regioselectivity and a slight reduction in the er for iodo-
methane (5a and 5b). Allylation with allyl bromide was also
effective (5c). Alkylation with sensitive (E)-6-iodohexa-1,3-
diene prone to competitive elimination was remarkably
effective, affording highly functionalized product 5d in 87%
yield, 93:7 er, and 7:1 regioselectivity with the typical
preference for α-alkylation. Alkylation with activated halides
like cinnamyl and 3-phenylpropargyl bromides was also highly
selective and efficient (5e and 5f). Surprisingly, alkylation with
a
b
Experiments were performed on a 0.50 mmol scale. The er values
were determined by HPLC analysis of corresponding methyl esters.
c
With (R)-2TA.
readily enolizable functionalized halides like ethyl bromoace-
tate and bromoacetonitrile was high yielding, maintaining high
regiocontrol but affording reduced enantioselectivity (5g and
5h). These halides also showed much higher reactivity,
reducing the reaction time from 90 to <15 min. Alkylation
with 4-(tert-butyldimethylsiloxy)-1-iodobutane14 gave 5i in
63% yield and 89:11 er.
An unexpected reduction in regioselectivity to 2:1 was
observed during benzylation with benzyl bromide or a more
functionalized reagent, 3-(bromomethyl)-2-fluoropyridine15
(5j and 5k). With BnBr, the α-benzylation product was
isolated in 95:5 er, while the γ-benzylation product displayed a
lower er (70:30). Fluoropyridine product 5k was isolated in
66% yield and 87:13 er. No reactivity was observed with a
more hindered 2-iodopropane (5l).
With aliphatic acid 1b, the reactivity and selectivity trends
were generally similar, with some notable differences. First,
secondary alkyl halides like 2-iodopropane now are sufficiently
C
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reactive, affording α-alkylation product 6c as a single
regioisomer in 53% yield and a moderate er of 70:30. Second,
benzylation is now again highly regioselective (>20:1) with
either benzyl bromide (6d, 77% yield, 93:7 er) or 3-
(bromomethyl)-2-fluoropyridine (6e, 81% yield, 86:14 er).
For 6d, we performed the reaction on a >1 g scale and
demonstrated the simple extractive recovery of (R)-1TA in
96% yield.16
In summary, we demonstrated that direct enantioselective
alkylation of carboxylic acids with non-aromatic substituents is
feasible and can provide practical levels of enantiocontrol.
Enantio- and regioselective alkylation of 3-alkenoic acids can
be accomplished effectively with chiral lithium amides as
stereodirecting reagents, providing enantioenriched versatile
products primed for further functionalization. The chiral amine
can be readily recovered by a simple aqueous extraction
simplifying the removal and recycling of the stereodirecting
reagent. The preference for alkylation at the α position with
chiral lithium amides was notably stronger than with simple
bases like LDA. This higher selectivity is likely due to yet
undetermined structural characteristics of the mixed lithium
enolate−chiral lithium amide aggregate involved in the
alkylation reaction. Efforts to define the structure of the
mixed aggregate and applications of this method in complex
molecule synthesis will be the subject of our future research.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00587.
Complete experimental procedures and characterization
data (PDF)
1
Copies of H, 13C, and 19F NMR spectra (PDF)
Copies of HPLC traces (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zakarian@chem.ucsb.edu.
ORCID
Armen Zakarian: 0000-0002-9120-1232
Present Address
†B.M.: Department of Internal Medicine-Hematology/Oncol-
ogy, Medical School, University of Michigan, 930 N.
University Ave., Ann Arbor, MI 48109.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Institutes of Health
(National Institute of General Medical Sciences Grant
GM077379). A.Z. thanks Amgen for generous supplies of
tetraamine reagent (R)-1TA. Dr. Hongjun Zhou [University of
California, Santa Barbara, CA (UCSB)] is acknowledged for
expert assistance with NMR spectroscopy. Dr. Dmitriy
Uchenik and the UCSB mass spectroscopy facility are thanked
for assistance with mass spectral analysis. K.Y. is supported by
the Mellichamp Sustainability Fellowship.
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