Peptide-Catalyzed Fragment Couplings that Form Axially Chiral Non-C2-Symmetric Biaryls

Article abstract of DOI:10.1002/anie.201913563

We have demonstrated that small, modular, tetrameric peptides featuring the Lewis-basic residue β-dimethylaminoalanine (Dmaa) are capable of atroposelectively coupling naphthols and ester-bearing quinones to yield non-C₂-symmetric BINOL-type scaffolds with good yields and enantioselectivity. The study culminates in the asymmetric synthesis of backbone-substituted scaffolds similar to 3,3′-disubstituted BINOLs, such as (R)-TRIP, with good (94:6 e.r.) to excellent (>99.9:0.1 e.r.) enantioselectivity after recrystallization, and a diastereoselective net arylation of the minimally modified nonsteroidal anti-inflammatory drug (NSAID) naproxen.

Full text of DOI:10.1002/anie.201913563

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Accepted Article
Title: Peptide-Catalyzed Atroposelective Fragment Couplings that
Form Axially Chiral Non-C2-Symmetric Biaryls
Authors: Gavin Coombs, Marcus Hao-Yi Sak, and Scott J. Miller
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913563
Angew. Chem. 10.1002/ange.201913563
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10.1002/anie.201913563
Angewandte Chemie International Edition
COMMUNICATION
Peptide-Catalyzed Fragment Couplings that Form Axially Chiral
Non-C2-Symmetric Biaryls
Gavin Coombs, Marcus H. Sak, and Scott J. Miller*
Previous Work
Abstract: We have demonstrated that small, modular, tetrameric pep-
A. Chiral Phosphoric Acid Catalyzed Coupling
tides featuring
a Lewis-basic residue, β-dimethylaminoalanine
R2
HO
(Dmaa), are capable of atroposelectively coupling naphthols and es-
ter-bearing quinones, yielding non-C2-symmetric BINOL-type scaf-
folds with good yields and enantioselectivities. The study culminates
in the asymmetric synthesis of backbone-substituted scaffolds similar
to 3,3ʹ-disubstituted BINOLs, such as (R)-TRIP, with good (94:6 e.r.)
to excellent (>99.9:0.1 e.r.) enantioselectivity after recrystallization,
and a diastereoselective net arylation of a minimally modified, non-
steroidal anti-inflammatory drug (NSAID), naproxen.
PA*
O
O
O
P
O
OH
PA*
OH
OH
OH
R2
+
R1
*
up to 95% yield
up to >99:1 e.r.
O
R1
B. Cinchona Alkaloid Catalyzed Coupling
R2
HO
O
OH
OH
OH
cinchona alkaloids
R2 = Br, Cl
R2
+
R1
up to 99% yield
up to 93:7 e.r.
R1
O
Approaches for the synthesis of enantioenriched biaryl atro-
pisomers are often divided into several categories.[1] Perhaps the
most well-developed method is direct atroposelective coupling of
two arene units.[2] A second method involves a preformed, but ste-
reochemically ambiguous, axis that is kinetically resolved, as pio-
neered by Bringmann,[3] and for which a number of catalytic in-
stances have now been demonstrated,[4] including several pep-
tide-catalyzed atroposelective bromination reactions.[5] Indeed, a
now-burgeoning series of chiral axis-forming bond constructions
exploit a range of chiral catalysis approaches.[6] Atroposelective
biaryl construction via coupling of one arene to a second partner,
which then aromatizes to reveal a newly-formed axis of chirality is
also a contemporary approach.[7] Recently, our group has contrib-
uted to this category with a peptide-catalyzed cyclodehydration,
transforming a pre-existing C–N bond into an axis of chirality.[8]
Also within this third category is the innovative work of Tan and
co-workers who demonstrated that BINOL-derived chiral phos-
phoric acids (BINOL-CPAs), such as (R)-TRIP, can catalyze the
addition of naphthols to quinones, affording enantioenriched non-
C2-symmetric biaryls in good yields and selectivities (Scheme
1A).[9] Complementary to this approach is the excellent work by
Salvio and Bella who showed that cinchona alkaloids were also
effective in atroposelectively coupling naphthols to halogenated
quinones (Scheme 1B).[10] Inspired by these studies, and realizing
the potential for site- and diastereo-selective arylation of phenol-
containing natural products, we wondered if we could effect a sim-
ilar transformation utilizing a tetrameric peptide featuring a Lewis-
basic catalytic residue as shown in Scheme 1 (bottom). Herein,
we present our work on the first peptide-catalyzed,[11] atroposelec-
tive carbon-carbon bond-forming reaction between two independ-
ent fragments: an ester-bearing quinone and a naphthol, yielding
non-C2-symmetric BINOL-type scaffolds.[12]
This Work: Lewis-Base Peptide-Catalyzed Coupling
R2
HO
O
O
O
OH
+
Alkyl
catalyst
Alkyl
OH
OH
R2 = Br, H
O
R1
R2
O
up to 99% yield
up to 93:7 e.r.
R1
O
H
R3
R4
N
N
catalyst:
O
O
O
HN
R5
Me2N
NH
O
O
R6
O
Scheme 1. Approaches toward construction of enantioenriched atropisomers
via naphthol-quinone coupling.
CPAs developed by Krische and co-workers for the enantioselec-
tive C–H crotylation of alcohols,[15] and approaches preparing ra-
cemic NOBIN- and BINOL-type biaryls by Gao et. al. and Kamit-
anaka et. al. using quinone monoacetals as coupling partners.[16]
As we will detail below, these important examples are now
complemented by the chemistry presented herein, including the
backbone-substituted adducts shown in Scheme 2: we success-
fully synthesized a highly enantioenriched non-C2-symmetric 3-
bromo-substituted biaryl (>99.5% ee post-recrystallization,
Scheme 3A) and a 3,3ʹ-dibromo-substituted biaryl with good e.r.,
which affords the opportunity for their use as ligands or for further
derivatization. The demonstration that peptide-based catalysts
may chaperone highly atroposelective coupling of fragments rep-
resents a significant advance for this emerging class of catalysts,
with ramifications for complex molecule diversification.
Our investigation commenced with interrogation of a peptide
sequence best suited for inducing enantioselectivity in the model
reaction shown in Table 1. We believe that the amine on β-dime-
thylaminoalanine (Dmaa), the catalytic residue, interacts initially
with the naphthol –OH group to promote a close interaction be-
tween the substrate and catalyst. While the i+1 residue is gener-
ally a proline of either stereochemistry to encourage the formation
of a β-turn via the indicated cross-strand hydrogen bonds,[17]
amino acids at i+2 and i+3 are often quite diverse. Positing that
an aromatic residue at i+3 would enforce potential p-p interactions
Notably, related to the pioneering work of Tan, and Salvio
and Bella,[9-10] few other examples exist for the organocatalyzed
construction of non-C2-symmetric BINOL-type catalysts or ligands
with substituents decorating the backbone, a feature that often
imparts high enantioselectivity.[13] Important examples include the
3,3ʹ-disubstituted BINOL carboxylic acids developed by Terada
and co-workers for hetero-Diels–Alder reactions,[14] H8-BINOL-
A
B
O
HO
HO
Br
[*]
G. Coombs, M. Sak, Prof. S. J. Miller
Department of Chemistry, Yale University
225 Prospect Street, New Haven, CT 06511 (USA)
E-mail: scott.miller@yale.edu
O
O
OH
OH
OH
OH
O
O
Br
Br
>99:1 e.r. after two recrystallizations 94:6 e.r. after one recrystallization
(200 mg scale)
(200 mg scale)
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Showcase examples of BINOL-type brominated biaryls synthesized
via peptide-catalyzed quinone arylation.
This article is protected by copyright. All rights reserved.

10.1002/anie.201913563
Angewandte Chemie International Edition
COMMUNICATION
between catalyst and substrate, we initially evaluated catalysts
with a phenylalanine at this position and chose to vary residues
at i+2 (Table 1, entries 1–5). Our group previously demonstrated
in several enantioselective bromination reactions that this position
is particularly important in inducing enantioselectivity,[11e] however
in this reaction it proved not to be influential. Replacing phenylal-
anine with non-aromatic leucine at i+3 and exchanging D-proline
for L-proline at i+1 resulted in significantly lower enantioselectivity
(Table 1, entry 6); reinstalling the D-proline residue in catalyst P7
did not rescue the enantioselectivity (Table 1, entry 7). We sus-
pected that a tertiary amide at the C-terminus (Table 1, entries 8–
9) might enhance the donor capabilities of the i+3 carbonyl, thus
increasing the strength of the cross-strand hydrogen bond and af-
fording a more rigid solution-phase conformation. Using identical
conditions from Table 1, entry 8, but with an additional phenylala-
nine at i+2 (P9) resulted in higher yield, but only a marginal de-
crease in enantioselectivity (Table 1, entry 9). Considering our hy-
pothesis regarding p-p interactions, we incorporated naphthylala-
nine (Nal) (Table 1, entries 10–12) and O-benzyltyrosine (Table
1, entry 13) at i+3. Retaining the C-terminal dimethylamide
(Scheme 4, entries 10–13), we found that P10 provided the high-
est enantioselectivity observed thus far with 92:8 e.r. (Table 1,
entry 10). Using 2Nal at i+3, we again probed the effect that sub-
stituents at the C-terminus have on selectivity while varying i+2
between aminoisobutyric acid (Aib) and aminocyclopropane car-
boxylic acid (Acpc) (Table 1, entries 14–19). Catalyst P16 with a
C-terminal methyl ester afforded product in similar enantioenrich-
ment as the dimethylamide(P10) and diethylamide (P13) analogs,
but with consistently higher yield over three trials and three hour
reaction time. Further attempts to increase the enantioselectivity
by incorporating α-methyl valine at i+2 (P19) failed, as did ap-
pending substituents at the 4-position of the proline (P20 and P21).
Catalyst P22 displays a L-proline/D-valine-induced β-turn and a
chiral C-terminal substituent which reversed the enantioselectivity
(Table 1, entry 23). Interestingly, this reversal is not observed us-
ing catalysts P6 and P21 where L-proline is positioned at i+2 (Ta-
ble 1, entries 6 and 22).
With optimal catalyst P16 in hand, we addressed the reac-
tion conditions to increase enantioselectivity and yield. Our stand-
ard catalyst screening conditions resulted in the highest enanti-
oselectivity observed (Table 2, entry 1) but with moderate yield.
Increasing the catalyst loading to 10 mol% increased the yield, but
lowered enantioselectivity (Table 2, entry 2). Further increasing
the catalyst loading resulted in decreased enantioselectivity with-
out a substantial change in yield (Table 2, entries 2–4). Running
the reaction at a lower concentration markedly improved the yield,
perhaps by attenuating side reactivity (Table 2, entries 5–6); how-
ever, the enantioenrichment was not restored to the initial result in
entry 1. Extended reaction time using 5 mol% catalyst over 24
hours afforded product in good yield, but lower selectivity once
again (Table 2, entry 7), and lowering the catalyst loading to 2
mol% did not meaningfully alter these results (Table 2, entry 8).
Over the course of optimizing the catalyst and the reaction condi-
tions, we were able in some instances to detect by LC-MS the
presence of two side products, one originating from oxidation of
the desired hydroquinone product (3) to quinone, and the other
from intramolecular cyclization, presumably leading to a Bring-
mann-type lactone (see Supporting Information for details).[1a, 3b]
Table 1. Dmaa[a] Catalyst Screen.
i + 1
H
R1
R2
i + 2
HO
N
O
N
CO2Bn
MeO
OH
O
BnO2C
MeO
OH
OH
catalyst (5 mol%)
O
+
O
i
H N
-78 ºC, 3 h
DCM (0.048 M in 2a)
R3
Me2N
i + 3
N H
O
O
O
PG
1a
2a
O
3a
1.2 equiv
1 equiv
Yield
(%)[b]
Entry
1
Cat
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
i+1
i+2
Aib
i+3 – PG
Yield (%)[b]
e.r.
Entry
13[c]
14[e]
15
Cat
P12
P13
P14
P15
P16
P17
P18
P19
P20
P21
P22
i+1
i+2
Aib
i+3 – PG
e.r.
Tyr(Bn)-
NMe2
D-Pro
D-Pro
D-Pro
D-Pro
D-Pro
L-Pro
D-Pro
D-Pro
D-Pro
D-Pro
Phe-OMe
Phe-OMe
Phe-OMe
Phe-OMe
Phe-OMe
Leu-OMe
Leu-OMe
Phe-NMe2
Phe-NMe2
2Nal-NMe2
47
51
48
81
71
65
51
54
99
64
88:12
89:11
84:16
83:17
82:18
63:37
65:35
88:12
84:16
92:8
D-Pro
D-Pro
D-Pro
D-Pro
D-Pro
D-Pro
D-Pro
D-Pro
53
62
92
70
76
57
67
76
77
99
80
88:12
91:9
2
Acpc
Gly
Ach
Aic
Aib
2Nal-NEt2
3
Acpc
Acpc
Aib
2Nal-NMe2
83:17
83:17
92:8
2Nal-(R)-
αMBA
4
16
5
17[f]
18
2Nal-OMe
6
Aib
Acpc
Aib
2Nal-NBn2
74:26
85:15
86:14
80:20
63:37
40:60
2Nal-pyrrol-
idine
7[c]
8[c]
9[c]
10
Phe
Aic
19
(αMe)
-Val
20
2Nal-OMe
2Nal-NMe2
2Nal-OMe
D-Pro (4S-
NHCOPh)
Pro (4S-
Phe
Aib
21
Acpc
Aib
22
NHCOCyMe)
2Nal-(R)-
αMBA
11[d]
12[c]
P10
P11
D-Pro
D-Pro
Aib
Aib
2Nal-NMe2
1Nal-NMe2
55
48
91:9
23[f]
L-Pro
D-Val
88:12
A general β-turn catalyst is shown at top left with peptide nomenclature denoted. [a] Boc-Dmaa is the ith residue in all catalysts. [b] Isolated yield of product. [c] 2 hour
reaction time. [d] 2 hour reaction time, 20 mol% catalyst. [e] Yield and e.r. are the average of two trials. [f] Yield and e.r. are the average of three trials.
Uncommon amino acids are highlighted in red within the table and depicted below.
H
H
H
N
N
O
O
N
Me
Me
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
H
N
O
Me
N
H
H
H
H
H
H
Acpc
(R)-MBA
(Me)Val
D
-Pro(4S-NHCOPh)
Pro(4S-NHCOCyMe)
Ach
Aic
2Nal
1Nal
Aib
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10.1002/anie.201913563
Angewandte Chemie International Edition
COMMUNICATION
HO
O
We suspected that perhaps dissolved oxygen in the reaction sol-
vent was responsible for the oxidation and residual acid from di-
chloromethane was catalyzing the reaction non-selectively or pro-
moting the cyclization. For this reason, we employed anhydrous,
oxygen-free dichloromethane that had been filtered through basic
alumina prior to use. These efforts, as shown in Table 2, entry 9,
did not increase the enantioselectivity, though we were able to iso-
late product nearly quantitatively after borohydride reduction. In
this case, while the formation of lactone was not detected, we still
observed the presence of oxidized 3 prior to reductive work up;
attempts to isolate this product were unsuccessful. Rather than
exogenous oxygen, we propose, in agreement with Salvio and
Bella, that in some cases, coupling is followed by rapid oxidation
of 3 by 2.[10] To ensure that all coupled material was in the hydro-
quinone form, we opted to employ a sodium borohydride reduction
as a standard procedure in the work-up of all entries in Table 2.
While evaluating other chlorinated solvents, we observed
that lower temperatures favored higher enantioselectivity (Table 2
entries 10–12). Toluene provided lower yield and enantioselectiv-
ity (Table 2, entry 13), lending evidence to productive p-p sub-
strate-catalyst interactions. Similarly, carbon tetrachloride and di-
ethyl ether both furnished the product in lower e.r. and yield (Table
2, entries 14 and 15); however, it should be noted that the solubil-
ity of 1a in these solvents was poor. Despite presenting the oppor-
tunity to competitively hydrogen bond with the catalyst, propi-
onitrile afforded desired product in good e.r. albeit with low yield
(Table 2, entry 16). With H-bonding donor capabilities, methanol
as a solvent resulted in severe depletion of enantioselectivity and
yield (Table 2, entry 17). We ultimately chose to pursue the con-
ditions in Table 2, entry 18, which allows the use of more concen-
trated reaction conditions, no special treatment of the solvent, and
slightly reduced reaction time.
A
O
O
R
MeO
OH
R
OH
OH
catalyst P16 (5 mol%)
O
O
+
MeO
DCM, –78 °C, 18 h
then NaBH4 (5 equiv)
O
2a-h
1a
3a-h
S
R =
O
CF3
3a
3c
3d
3e
3b
88:12 e.r.
94% yield
90:10 e.r.
50% yield
93:7 e.r.
91:9 e.r.
89:11 e.r.
71% yield
84% yield
93% yield
3f
3g
3h
87:13 e.r.
83% yield
89:11 e.r.
86% yield
88:12 e.r.
99% yield
HO
B
O
O
O
8
1
4
Bn
OH
+
Bn
OH
OH
7
R
6
O
catalyst P16 (5 mol%)
O
DCM, –78 °C, 18 h
then NaBH4 (5 equiv)
3
R
5
O
2a
1i-o
3i-o
7-OiPr
3i
R =
6-CN
3-Br
6-Br
7-Br
H
6-(p-tBuPh)
3j
3k
3l
3m
3n
3o
87:13 e.r. 90:10 e.r.
99% yield 48% yield
75:25 e.r. 89:11 e.r.
89% yield 81% yield
90:10 e.r.
93% yield
91:9 e.r.
99% yield
88:12 e.r.
86% yield
C
X
HO
O
O
O
R2
OH
R2
OH
OH
O
catalyst P16 (5 mol%)
O
X
+
R
DCM, –78 °C, 18 h
then NaBH4 (5 equiv)
R
O
3p-t
Br
HO
HO
Br
HO
Br
HO
Intrigued by the lower selectivity observed when running the
reaction in toluene (Table 2, entry 13) we wondered if appending
an extended aromatic system to the quinone substrate would en-
hance catalyst-substrate recognition (Scheme 3A, 2b). Indeed, we
were able to increase the selectivity slightly, relative to our stand-
ard benzylester-p-quinone coupling partner, 2a. Investigating a
potential correlation between enantioselectivity and electronics on
the phenyl group of the quinone, we synthesized more electron
rich quinone 2c and electron deficient quinone 2d. Both substrates
gave similar e.r. values, and the trifluoromethyl group afforded the
highest e.r. to date at 93:7 e.r (Scheme 3A, 3d). Unfortunately,
O
S
OH
OH
EtO2C
OH EtO2C
OH
OH
OH
EtO2C
MeO
OH
OH
O
MeO
O
Br
3p
3q
3r
3s
88:12 e.r.
22% yield
76:24 e.r.
82% yield
70:30 e.r.
80% yield
59:41 e.r.
72% yield
HO
PMBO
O
O
EtO2C
OH
EtO2C
Br
O
OH
OH
Br
O
O
Br
O
3t
1p
2q
2r
80:20 e.r.
98% yield
Table 2. Conditions Optimization.[a]
Scheme 3. Substrate Scope.[a] [a] Isolated yield; e.r. determined by CSP-HPLC
(254 nm, uncorrected). Average of two trials. Absolute configuration shown as
(S) and assigned in analogy to the data reported by Tan and co-workers[9] (see
Section 6.5 in Supporting Information for details). A. Variations in quinone cou-
pling partner. B. Variations in naphthol coupling partner. Numbering is shown
on the naphthol partner for convenience. C. Variations in both coupling part-
ners. Additional coupling partners are boxed. PMB = p-methoxybenzyl.
HO
O
CO2Bn
MeO
OH
BnO2C
MeO
OH
OH
conditions
+
O
1a
2a
3a
Entry
Solvent
T [ºC]
t [h]
Cat
Yield [%]
e.r.
loading[b]
quinone 2c was a poor coupling partner in the reaction, and we
isolated significant quantities of starting naphthol and hydroqui-
none after work-up. The reaction is also tolerant of aromatic het-
erocycles on the quinone coupling partner (Scheme 3A, 2e), af-
fording product 3e in good e.r.. In addition, both selectivity and
yield remained high when assessing alkoxycarbonyl quinones
(Scheme 3A, 2f–h).
Variations on the naphthol are also well tolerated (Scheme
3B). The bulky 7-isopropoxy group (Scheme 3B, 1i) affected nei-
ther the yield nor selectivity, unlike the strongly withdrawing cyano
group which did not affect selectivity, but lowered the yield, per-
haps due to decreased nucleophilicity of the naphthol (Scheme
3B, 3j). Substitution at the 3 position of the naphthol significantly
reduced the enantioselectivity, presumably through sterically in-
hibiting interactions between the catalyst and the naphthol sub-
strate (Scheme 3B, 3k). Appending the bromine to a position more
distal from the naphthol –OH restored the enantioselectivity
(Scheme 3B, 3l–m). Unsubstituted 2-naphthol also performed well
in the reaction, retaining good selectivity and yield (Scheme 3B,
3n). Investigations into the ramifications of substituents at the 6
1
2
3
4
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM (dry)
CHCl3
DCE
DCE
PhMe (dry)
–78
–78
–78
–78
–78
–78
–78
–78
–78
–60
rt
–10
–78
–10
–78
–78
–78
–78
3
3
3
3
3
5
10
20
30
30
5
5
2
5
5
5
5
5
5
5
5
5
5
55
74
64
71
99
99
89
92
99
99
52
51
49
52
45
51
8
93:7
91:9
91:9
89:11
88:12
89:11
90:10
90:10
88:12
74:26
50:50
69:31
71:29
61:39
76:24
93:7
5[c]
6[c]
7
3
24
24
24
3
8
9[d]
10[d]
11
12
13
14
15
16
17
18
3
24
24
24
24
16
16
18
CCl4
Et2O
EtCN
MeOH
DCM
58:42
89:11
99
[a] Isolated yield. Employed 1 equiv of naphthol and 1 equiv of quinone in DCM
(0.06 M in naphthol). NaBH4 (5 equiv) used in work-up. [b] Catalyst (P16) loading
in mol%. [c] DCM (0.02 M in naphthol). [d] Solvent filtered through basic alumina
prior to use.
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10.1002/anie.201913563
Angewandte Chemie International Edition
COMMUNICATION
A. Preparation of Near-Enantiopure, 3-Substituted Scaffold, 3t[a]
C. Diastereoselective Functionalization of Naproxen Analog, 3u
HO
O
O
HO
catalyst P16
OH
OH
Br
O
O
OPMB (5 mol%)
PMBO2C
OH
OH
O
+
≡
PMBO2C
OH
OH
DCM, –78 °C
18 h
then NaBH4
(5 equiv)
MeO
HO
Me
O
Me
Br
Naproxen, Aleve®
Desmethyl-naproxen-methylester (1q)
1k
2c
3t[b]
200 mg
244 mg
99:1 e.r. after one
recrystallization
R
HO
33% overall yield (146 mg)
Potential derivatization
opportunity at the 3 position
O
O
catalyst
(5 mol%)
RO
OH
+
OH
OH
99.9:0.1 e.r. after two
recrystallizations
12% overall yield (55.1 mg)
OR
O
DCM, –78 °C
18 h
then NaBH4
(5 equiv)
R
O
1q
R
B. Preparative-Scale Enrichment of 3,3’-Substituted Scaffold, 3s[a]
2d
3u
R
HO
Br
O
HO
O
O
catalyst P16
R =
R =
OH
Br
MeO
(5 mol%)
OEt
EtO2C
OH
OH
EtO2C
OH
OH
+
≡
Me
CF3
DCM, –78 °C
18 h
Br
O
then NaBH4
(5 equiv)
Br
d.r. (3u)[c] Isolated Yield (3u)[c]
Catalyst
R
3s[b]
2r
232 mg
1k
Boc-Dmaa-D-Pro-Aib-2Nal-OMe (P16)
7:1
1:1
96%
14%
94:6 e.r. after one
recrystallization
23% overall yield (98.5 mg)
200 mg
Potential derivatization
opportunity at the
3 and 3’ positions
Triethylamine
Scheme 4. Applications of this method. [a] 1 equiv of quinone and 1 equiv of naphthol were used in the reaction. Reported e.r. and yields are from one trial). [b]
X-ray crystal structures verifying the connectivity of products 3s and 3t (crystallographic data gathered on racemic crystals). [c] Average of two trials; d.r.
determined by 1H NMR integrations (see Section 7.6 of the Supporting Information).
position of the naphthol revealed that even sterically encumbered
groups, such as 4-tert-butyl phenyl (Scheme 3B, 1o), do not seri-
ously affect the enantioselectivity or coupling efficiency (Scheme
Experimental Section
3B, 3o); however, substituting methoxy at this position drastically
reduced the reactivity (Scheme 3C, 1p). Substituents on the qui-
none ring itself lowered the enantioselectivity, once again indicat-
ing that perhaps productive catalyst-substrate interactions are in-
hibited by steric bulk at positions near the phenols on the sub-
strates (Scheme 3C, 3q). Product 3r further corroborates this hy-
pothesis, as placement of the bromine substituent even more
proximal to the BINOL-type phenol further reduced enantioselec-
tivity. In the case of 3,3ʹ-disubstitution (Scheme 3C, 3s), enanti-
oenrichment is almost entirely ablated. Product 3t served as a
springboard for our foray into preparative scale synthesis and re-
crystallization of enantioenriched backbone-substituted biaryls, as
it achieved higher selectivity than the benzylester congener (3k).
As shown in Scheme 4A, we succeeded in preparing near
enantiopure 3t on preparative scale after two recrystallizations. It
should be noted that significant product enantioenrichment was
obtained after only one recrystallization (99:1 er). Furthermore, we
were able to obtain 3s in 94:6 er after one recrystallization
(Scheme 4B). We believe these examples represent a significant
advancement towards obtaining optically pure scaffolds of this
type with the opportunity for myriad diversification, particularly us-
ing 3s to modulate the 3 and 3ʹ positions of both arenes.[18]
Concurrently, we explored the possibility of derivatizing a
medicinally interesting compound using our catalytic system. To
that end, we succeeded in diastereoselectively functionalizing a
naproxen analog, as shown in Scheme 4C. Following minimal
modification of naproxen, we obtained 1q, and under our opti-
mized reaction conditions using quinone 2d and catalyst P16,
compound 3u was afforded in excellent yield with 7:1 d.r.; notable
is the lower yield and lack of inherent selectivity when triethyla-
mine is used as a catalyst.
Experimental details can be found in the Supporting Information.
X-Ray crystallographic data for compounds 3s (1906659) and 3t
(1900403) are available free of charge from the Cambridge Crys-
tallographic Data Centre.
Acknowledgements
The authors are grateful to Aaron L. Featherston, Dr. Anna E.
Hurtley, Dr. Anthony J. Metrano, Dr. Jonathan M. Ryss, Dr. Chris-
topher R. Shugrue, and Elizabeth A. Stone for preparation of cat-
alysts. We also acknowledge E.A.S. for invaluable assistance in
manuscript preparation. We also thank Dr. Brandon Q. Mercado
for solving our X-ray crystal structures, and Dr. Eric K. Paulson for
helpful NMR discussions. This work is supported by the National
Institute of General Medical Sciences of the National Institutes of
Health (R35 GM132092). G.C. acknowledges the support of the
NSF Graduate Research Fellowship Program.
Keywords: Atropisomerism • Biaryl synthesis • Chirality • Peptide
catalysis • Quinones
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
O
O
F3C
HO
H
N
Gavin Coombs, Marcus H. Sak, Scott J.
Miller*
HO
PMBO
Alkyl
O
O
N
R1
OH
OH
O
OH
OH
O
catalyst
O
O
HN
O
Me2N
O
2Nal
O
20 examples
up to 99% yield
up to 93:7 e.r.
NH
+
O
O
Page No. – Page No.
MeO
O
Br
OH
O
Me
R2
Select example:
>99:1 e.r.
post recrystallization
Naproxen (Aleve®) analog
catalyst
Peptide-Catalyzed Fragment Cou-
plings that Form Axially Chiral Non-
C2-Symmetric Biaryls
7:1 d.r., 96% yield
Peptide-catalyzed atroposelective naphthol-quinone couplings: A peptide-
based catalytic approach for atroposelective couplings of naphthols and ester-bear-
ing quinones to access non-C2-symmetric BINOL-type scaffolds is presented, achiev-
ing good yields and enantioselectivities. A diastereoselective functionalization of a
naproxen analog highlights the utility of this system.
This article is protected by copyright. All rights reserved.