Catalytic Enantioselective Birch-Heck Sequence for the Synthesis of Tricyclic Structures with All-Carbon Quaternary Stereocenters

Article abstract of DOI:10.1021/acs.orglett.8b00196

A new enantioselective desymmetrizing Mizoroki-Heck reaction is reported. The process affords high yields and enantioselectivities of tricyclic structures containing all-carbon quaternary stereocenters. The substrates for the reaction are efficiently synt

Full text of DOI:10.1021/acs.orglett.8b00196

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Enantioselective Birch−Heck Sequence for the Synthesis of
Tricyclic Structures with All-Carbon Quaternary Stereocenters
Andrew T. Krasley, William P. Malachowski,* Hannah M. Terz,† and Sabrina Tran Tien†
Department of Chemistry, Bryn Mawr College, 101 North Merion Avenue, Bryn Mawr, Pennsylvania 19010, United States
S
* Supporting Information
ABSTRACT: A new enantioselective desymmetrizing Mizoroki−Heck reaction is reported. The process affords high yields and
enantioselectivities of tricyclic structures containing all-carbon quaternary stereocenters. The substrates for the reaction are
efficiently synthesized from Birch reduction−alkylation of benzoic acid and benzoate esters.
Scheme 1. Catalytic Enantioselective Heck Reactions
ecent structural analysis of drug candidates has discovered
3
Rthat successful drugs have a higher percent of sp carbons
and are more likely to contain stereogenic centers. In a series of
articles entitled “Escape from Flatland,”1,2 Lovering and
colleagues analyzed drug development candidates since 1980
and discovered a higher frequency of sp3 carbons and chiral
centers in successful drugs. Two reasons have been advanced to
explain the better pharmaceutical profile of sp3-rich and chiral
molecules: improved solubility2 and less promiscuous binding
behavior.1
In contrast to the apparent need for drug candidates with sp3
carbons and chiral centers, the three most commonly used
reactions by medicinal chemists remain amide bond formation,
the Suzuki−Miyaura reaction, and nucleophilic aromatic
substitution.3 These sp2 carbon-focused methodologies in
combination with other popular and efficient cross-coupling
synthetic tools have likely contributed to the preponderance of
flat aromatic structures in compound screening libraries. To
overcome this limitation and assist in the development of better
drug candidates, there is a pressing need for more efficient tools
to construct chiral, nonplanar structures.
One of the most challenging sp3 stereocenters to construct is
the all-carbon quaternary center,4−7 and one popular and
efficient method for creating quaternary all-carbon stereocenters
is the Mizoroki−Heck (Heck) reaction.8 Many elegant
enantioselective applications of the Heck reaction have been
described,9−11 but the full substrate scope of the asymmetric
Heck reaction has yet to be explored, and important tools for the
construction of complex bioactive structures remain to be
developed. A recent popular approach to more general
enantioselective Heck reactions involves desymmetrization
reactions.5,12−14 Scheme 1 illustrates a collection of examples
related to the current work, including desymmetrization
examples by Shibasaki15,16 and Feringa.17,18 These procedures
demonstrated modest to good yields and high enantioselectiv-
ities to polycyclic ring structures, which are common
components of successful drugs.19,20
Herein, we report a new desymmetrizing enantioselective
Heck reaction, which has high yields and high enantioselectiv-
ities. The method complements recent work by Tang21 and
Feringa and expands the scope of the Shibasaki work being both
more efficient and more stereoselective. In the process, a tricyclic
Received: January 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ring system is generated with an all-carbon quaternary
stereocenter. In addition, the substrates are produced through
an efficient Birch reduction−alkylation process with inexpensive
benzoic acid or benzoate esters. Although this process is perfectly
suited to the facile generation of cyclohexadiene desymmetriza-
tion substrates, previous work has almost exclusively used
alkylation of the considerably more expensive 2,5-cyclo-
hexadiene-1-carboxylic acid15 or a 5−6 step sequence starting
with cyclohexenone derivatives.22−25
Table 2. Aryl Iodide Heck Reaction Optimization
entry
solvent
base
Ag2CO3
time (h) result
er
1
2
3
DMF
118
137
280
no rxn
2a
toluene
Ag2CO3
Ag2CO3
79:21
84:16
Our study began with the synthesis of various substrates using
the Birch reduction−alkylation reaction (Table 1).26 Both
1,4-dioxane
(0.05 M)
2a
4
1,4-dioxane
(0.2 M)
Ag2CO3
Ag2CO3
67
2a
81:19
88:12
Table 1. Birch Reduction−Alkylation Reaction
5
6
1,4-dioxane
1,4-dioxane
137
2a
Ag2CO3
(1.0 equiv)
1000
a
7
1,4-dioxane
Ag2CO3
87
2a
87:13
(4.0 equiv)
b
8
9
1,4-dioxane
1,4-dioxane
Na2CO3
153
87
2a
2a
75:25
81:19
88:12
b
Cy2NMe
entry
R1
Et
X
Y
R2
yield (%)
compound
c
10
1,4-dioxane
Ag2CO3
137
2h
1
2
3
4
5
6
7
8
9
I
Br
Br
Br
Br
Br
Cl
Br
Br
Cl
H
85
54
18
78
77
28
96
79
57
1a
1b
1c
1d
1e
1f
a
b
c
Incomplete. 2.0 equiv Ag3PO4 added as halide scavenger. t-Bu ester
Et
OTf
OTf
OTf
OTf
OTf
I
H
used.
Et
4-Me
5-Me
6-Me
4-Cl
H
Et
Table 3. Aryl Triflate Heck Reaction Optimization
Et
Et
t-Bu
t-Bu
H
1g
1h
1i
OTf
OTf
H
H
catalyst
time
(h)
a
t-BuOH added with benzoate ester substrates.
entry
(mol %)
temp (°C)
result
no rxn
er
1
2
10
23→100
23
229
215
21
benzoic acid and benzoate ester substrates were used. With
benzoate esters, t-BuOH is added as a proton source to protonate
the radical anion intermediate. In all cases, a 2-iodo or 2-triflate
group was incorporated in the alkylating agent for later use in the
Heck reaction. The Birch reduction−alkylation yields generally
ranged from good to excellent, with the 2-iodo derivatives
affording the highest yields (entries 1 and 7). The lowest yielding
examples involved alkylating agents with 2-triflate and
substituted benzene rings (entries 3 and 6). In these cases,
there was considerable decomposition, including, not surpris-
ingly, from cleavage of the triflate group. Although benzyl
bromides were the alkylating agent of choice, we found the
benzyl chloride better in some cases, including with benzoic acid
reductive alkylations (entry 9) or in cases where the triflate
alkylating agent proved unstable as a benzyl bromide derivative
(entry 6). Notably the benzyl halides used in the Birch reaction
are some of the most complex used to date and the first example
of an alkylating agent with an aryl triflate.
Initial Heck reaction studies were conducted with the 2-iodo
substrates (Table 2), as they were more readily synthesized
through the Birch reduction−alkylation. Extensive reaction
screening was conducted to optimize ligands, bases, solvents,
and temperatures. Table 2 illustrates modifications to solvents,
bases, Ag2CO3 equivalents, and reaction concentration, which
lead to some of the more successful efforts. The Supporting
Information (SI) has a complete account of the reaction
screening. The reactions did afford efficient conversions (50−
90% yield), and the use of toluene or 1,4-dioxane with Ag2CO3
afforded the 1,3-diene product exclusively (cf. Table 3 products).
This was critical as, not surprisingly, the diene isomers had
almost identical chromatographic properties, and therefore, the
presence of both made enantioselectivity evaluations difficult. An
10
2a/3a (68:32)
3
10
23
no rxn
4
10
40
593
593
162
428
593
39
a
5
5 + 5 (24 h)
40
a
6
20
40
2a
97:3
7
10
60
a
8
5 + 5 (24 h)
60
a
9
20
60
2a
97:3
10
11
12
10
80
39
2a
82:18
66:34
5 + 5 (24 h)
20
80
39
2a
80
39
2a/3a (81:19)
a
Incomplete.
additional challenge was found with incomplete reactions as the
iodo starting materials had similar chromatographic properties to
the cyclized products. Nonetheless, despite significant optimiza-
tion efforts, the best enantioselective ratio achieved was 88:12
(entries 5 and 10). It should be noted that in this and all
subsequent examples, the cis ring junction isomers were
presumed to be formed, but the exact enantiomer has not been
determined.
Although aryl halides have been successful in affording
enantioselective Heck reactions (Scheme 1, Feringa and Tang
work), there is good evidence that the most reliable path to high
enantioselectivities in asymmetric Heck reactions is via a cationic
palladium complex pathway.10,11 Cationic palladium complex
formation was promoted with the aryl iodides through the use of
silver salts (Table 2); however, we had reached a limit to the
enantioselective gains from the silver. Consequently, we turned
to aryl triflates, whose counteranion is much weaker than the
halides and does not require silver salt sequestration to provide
B
DOI: 10.1021/acs.orglett.8b00196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
greater amounts of cationic palladium complex. Table 3 details
the exploratory work with aryl triflates which lead to the first
reaction examples with enantioselectivities exceeding 90%.
Although 1,4-dioxane was the optimal solvent for the aryl iodide
reactions, DMF worked best for the aryl triflates and, as a strong
coordinating solvent, could provide cationic palladium complex
stabilization.27,28 Without the need for silver in the Ag2CO3 base,
Cy2NMe was determined to be the optimal base. One additional
fortunate outcome of the aryl triflate substrates was the exclusive
formation of the 1,3-diene product in most cases. As noted for
Table 2 results, incomplete reactions were difficult to analyze due
to the similar chromatographic properties of the triflate starting
materials and the cyclized product. Although efforts were made
to reduce the Pd catalyst equivalents, lower amounts resulted in
slower or incomplete reactions (cf. entries 4 and 5 versus 6).
While increasing the reaction temperature to accelerate the
process degraded the enantioselectivity (cf. entry 9 versus 10 and
11), this is likely because it compromised the stability of the
palladium−BINAP complex. Higher catalyst loadings for aryl
triflate reactions with stable diphosphine bidentate ligands are
relatively common.29−31 These ligands form stable complexes,
which critically and thoroughly control the chiral environment of
the catalytic complex but frequently lead to slow turnover in the
process.
Table 4. Ester Derivative Heck Reactions
entry
1
R
time (h)
yield (%)
er
compd
Me, 1j
Et, 1b
15
39
39
38
44
41
19
76
73
86
74
72
c
98:2
98:2
97:3
97:3
97:3
2j
a
2
2a
2a
2h
2l
b
3
Et, 1b
4
5
6
7
t-Bu, 1h
Bn, 1l
allyl, 1k
OH, 1i
c
a
b
c
0.08 mmol scale. 1.0 mmol scale. Decomposed.
Table 5. Substituted Aryl Group Heck Reactions
entry
R
time (h)
yield (%)
er
compound
With enantioselective ratios over 90%, studies turned to
exploring the substrate scope with the optimal reaction
conditions. Two modifications were explored: alternative ester
derivatives and substituted aryl triflates. The ester derivatives
were synthesized from the benzoic acid Birch reaction product
(Table 1, entry 9), as illustrated in Scheme 2. Substituted aryl
1
2
3
4
4-Me, 1c
5-Me, 1d
6-Me, 1e
4-Cl, 1f
17
219
288
86
72
77
73
75
96:4
98:2
60:40
96:4
2c
2d
2e
2f
Scheme 2. Esterification Reactions
construct the desymmetrization substrate and is the first example
of such an application.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00196.
Experimental procedures and spectroscopic data for all
compounds including 1H, 13C and 2D NMR spectra, GC-
MS, and chiral HPLC; full Heck reaction condition
screening tables (PDF)
triflates were synthesized through the use of appropriately
substituted 2-OTf-benzyl halide alkylating agents. These
alkylating agents were synthesized in three steps from substituted
salicylaldehydes (see SI).
Table 4 shows success with a range of ester derivatives. Methyl,
ethyl, t-butyl, and benzyl all work efficiently. The ethyl derivative
was run at 1 mmol scale and provided an even higher yield than
the smaller-scale exploratory reactions. Allyl and carboxylic acid
derivatives (entries 6 and 7) both decomposed to diphenyl side
product, presumably the result of decarboxylative oxidation of
the cyclohexandiene−carboxylate core.
Substituted benzene rings also afforded high yields and
enantioselectivities (Table 5) for methyl and chloro substitution.
Electron-withdrawing (NO2 and CF3) and electron-donating
(OMe) groups failed to react. Substitution adjacent to the triflate
group created steric hindrance to the process that degraded the
rate and enantioselectivity (entry 3).
In conclusion, a new catalytic enantioselective desymmetrizing
Heck reaction has been achieved, and in most cases, it affords
high yields and enantioselectivities in the construction of tricyclic
rings with an all-carbon quaternary stereocenter. Modifications at
the quaternary center and the aryl triflate ring are permitted. The
process uses a Birch reduction−alkylation reaction to efficiently
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wmalacho@brynmawr.edu.
ORCID
William P. Malachowski: 0000-0003-1215-3808
Author Contributions
†H.M.T. and S.T.T. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A generous award from the National Science Foundation (CHE-
0958996) enabling acquisition of the 400 MHz NMR
spectrometer used in these studies is gratefully acknowledged.
The authors would also like to thank Bryn Mawr College for
financial support of this work. The University of Delaware Mass
Spectrometry Facility is acknowledged for acquiring all HRMS
C
DOI: 10.1021/acs.orglett.8b00196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
data. The authors are also grateful to Haverford College for use of
their polarimeter.
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DOI: 10.1021/acs.orglett.8b00196
Org. Lett. XXXX, XXX, XXX−XXX