P -Chiral, N -phosphoryl sulfonamide Br?nsted acids with an intramolecular hydrogen bond interaction that modulates organocatalysis

Article abstract of DOI:10.1039/c9ob01774g

Br?nsted acids exemplified by OttoPhosa I (5c) were designed and evaluated in the asymmetric transfer hydrogenation of quinolines. Their catalytic properties are modulated by an intramolecular hydrogen bond that rigidifies their catalytic cavity, accelerates the reaction rate and improves enantioselectivity.

Full text of DOI:10.1039/c9ob01774g

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DOI: 10.1039/C9OB01774G
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P-Chiral, N-Phosphoryl Sulfonamide Brønsted Acids with an
Intramolecular Hydrogen Bond Interaction that Modulates
Organocatalysis
Received 00th January 20xx,
Accepted 00th January 20xx
Minglei Yuan,a† Ifenna I. Mbaezue,a† Zhi Zhou,a Filip Topic,a Youla S. Tsantrizos*a
DOI: 10.1039/x0xx00000x
For example, List reported that direct asymmetric N,O-acetalization
of aldehydes with Brønsted acids 1e and 1g resulted in products
with 61% ee and 14% ee, respectively.19a Similarly, asymmetric
methanolysis of cis-1,2-cyclohexanedicarboxylic anhydride with a
phosphinic acid and its corresponding phosphoramide led to 22%
ee and 0% ee, respectively.19b Recently, Han reported the synthesis
of P-stereogenic analogs 3 (e.g. 3a,b) and observed that these
compounds catalyzed the transfer hydrogenation of 2-
phenylquinolines in only 30-36% enantiomeric excess.20
Based on the collective knowledge in this field, we decided to
explore the impact of an intramolecular non-covalent interaction
that could potentially participate in stabilizing the reaction
intermediates in the transfer hydrogenation of heterocyclic
compounds. We aimed to combine the higher catalytic activity of
phosphoramides with the steric effect of t-butyl-substituted P-
chiral phosphines into a new class of Brønsted acids, typified by
analog 5c (Fig. 1). In the design of these compounds, we presumed
that a hydrogen bond between a heteroatom attached to the
backbone of the catalyst and the acidic NH could (a) further increase
the acidity of the catalyst, (b) rigidify the catalytic cavity, (c) stabilize
the transition state of the reaction, and (d) potentially recruit the
Hantzsch ester, thus leading to faster conversion at RT and good
enantioselectivity. Herein we report the properties of a prototype,
analog 5c (OttoPhosa I) having a strategically placed phenolic
moiety, as a key structural element (Fig 1).
Recently, we reported a library synthesis of structurally diverse
t-butyl-substituted P-chiral secondary phosphine oxides (SPOs) in
high enantiomeric purity, starting from precursor 6 (Scheme 1).21
Preparation of analogs 7a, 7c and 7d was reported and the same
methodology was used for the synthesis of 7e and 7f in good yield
and high enantiomeric purity.21 In order to probe the impact of the
intramolecular hydrogen bond characterizing Brønsted acids 5 in a
head-to-head comparison with analogs missing only that feature,
we also synthesized the previously disclosed SPO 7b (the precursor
to Brønsted acids 3b) using the method previously reported.22
Intermediates 7 were treated with aqueous ammonia in the
presence of Et3N and CCl4 to obtain the phosphinamides 8 via an
Atherton-Todd-type reaction.23 These intermediates were treated
with the 2,4,6-triisopropylbenzenesulfonyl chloride under basic
conditions to give the P-chiral, N-phosphoryl sulfonamides 3b and
4. Finally, analogs 3b and 4b-e were treated with BBr3 to cleave the
methyl ether and obtain the phenolic Brønsted acids 5a-e (Fig. 1).
Brønsted acids exemplified by OttoPhosa I (5c), were designed and
evaluated in the asymmetric transfer hydrogenation of quinolines.
Their catalytic properties are modulated by an intramolecular
hydrogen bond that rigidifies their catalytic cavity, accelerates the
reaction rate and improves enantioselectivity.
Phosphorus-based Brønsted acids have emerged as a highly
promising class of organocatalysts. Many molecular designs have
contributed to this field, including the most valuable BINOL-based
Brønsted acids 1 and 2 (Fig. 1).1 Brønsted acids 1 were first reported
by Akiyama2 and Terada,3 and have been shown to efficiently
catalyse a plethora of asymmetric reactions, including Mannich-
type2a,3,4 and Diels-Alder reactions,5 the enantioselective
hydrophosphonylation of imines,6 reductive aminations,7 imine
transfer hydrogenations,8 Friedel-Crafts alkylations,9 intramolecular
Michael additions,10 the N,O-acetalization of aldehydes11 and the
transfer hydrogenation of various heterocyclic compounds.12 These
Brønsted acids were also reported to catalyse metal-free asymmetric
6π-electrocyclization reactions, leading to enantiomerically enriched
1,4-dihydropyridazines.13 Recently, List reported the design of
BINOL-based
dimeric
and
sterically
highly
confined
imidodiphosphorimidate analogs (IDPi; 2, Fig. 1).14 IDPi were shown
to catalyse the protonation of olefins, which then react with
intramolecular hydroxyl groups to form chiral 5- and 6-membered
ring ethers.14a Additionally, they can catalyse enantioselective C-C
bond formation in Mukaiyama Aldol-type reactions at remarkably
low concentration of the catalyst.14b
N-phosphoryl sulfonamide derivatives of 1 (e.g. 1f), were first
introduced by Yamamoto and shown to provide greater ability to
activate substrates with low reactivity, such as aldehydes, ketones
and silyl enol ethers.5,15 This observation is consistent with the
higher acidity of the N-triflyl Brønsted acid;16 the pKa values of
many analogs of 1 have been determined in acetonitrile17 and
DMSO.18 However, the higher reaction rates observed with the N-
triflyl Brønsted acid, as compared to the corresponding phosphoric
acids, were often also associated with lower enantioselectivity.4b,4c
a. Department of Chemistry, McGill University, 801 Sherbrooke Street West,
Montreal, Quebec, Canada H3A 0B8. Email: Youla.tsantrizos@mcgill.ca
b. † Authors contributed equally
c. Electronic Supplementary Information (ESI) available: Synthesis and X-ray
crystallography data. See DOI: 10.1039/x0xx00000x
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Journal Name
Due to the polarity of these compounds (4 and 5), chiral HPLC
analysis proved to be very challenging. Consequently, the reported
enantiomeric purities of analogs 4 were based on the enantiomeric
purity of the corresponding phosphinamides 8. However, in cases
where both compounds 8 and the corresponding analogs 4 could be
analyzed by chiral HPLC, a negligible difference in enantiomeric
excess was observed (e.g. for 8a and 4a a 96.6% ee and 96.0% ee,
respectively).
As a proof-of-concept, we decided to study theVaiebwilAitrtyicleofOnoliuner
compounds to catalyze the asymmetric transfer hydrogenation of
DOI: 10.1039/C9OB01774G
quinolines, which is an extensively investigated reaction with many
BINOL-based Brønsted acids 1. Rueping first reported using Brønsted
acids 1 (Fig. 1),24 as a greener approach to the preparation of chiral
1,2,3,4-tetrahydroquinolines (as compared to classical metal-
mediated hydrogenation under high pressure of H2). The hydride
source for these reactions is derived from the Hantzsch ester 9 (Table
1), a bioisostere of NADH/NADPH.25 Chiral tetrahydroquinolines are
valuable scaffolds for the synthesis of many biologically active
compounds, including natural products26,27 and human therapeutics
Previous Work
This Work
R1
O
O
O
S
P
N
H
(Fig. 2).28
X
O
O
R
P
R2
Natural Products
R1
NH
R2
OR'
R1OC
, R1 = H, X = O, R2 = OH
, R1 = Ph, X = O, R2 = OH
, R1 = 9-phenanthryl, X = O, R2 = OH
, R1 = 4-NO2C6H4, X = O, R2 = OH
, R1 = 2,4,6-(i-Pr)3C6H2; X = O, R2 = OH
, R1 = Ph; X = O, R2 = NHTf
, R1 = 2,4,6-(i-Pr)3C6H2; X = O, R2 = NHTf
, R1 = 2,4,6-(i-Pr)3C6H2; X = S, R2 = NHTf
, R1 = 3,5-(CF3)2C6H3; X = O, R2 = OH
, R1 = 3,5-(CF3)2C6H3; X = O, R2 = NHTf
, R1 = [H8]-SiPh3; X = O, R2 = OH
OR'
1a
N
N
H
1b
1c
1d
1e
1f
HO2C
N
H
H
A
B
C
D
OR'
N
NH
NH
OCH3
N
H
; R1 = OH, R2 = Cl
; R1 = NH2, R2 = OH
Benzastatin D
Viratmycin
OR'
OR'
(-)-Martinellic acid
bradykinin B1/B2 receptor antagonist
antiviral/neuroprotective activity
1g
E
F
1h
1i
Potential Human Therapeutics
4a
4b
4c
4d
4e
A
5a
, R =
5b
, R =
5c
, R =
5d
, R =
5e
, R =
B
,
, R =
R' = H
R' = H
R' = H
R' = H
R' = H
1j
O
C
C
, R = , R' = CH3
,
,
,
O
1k
H
D
D
E
, R = , R' = CH3
N
H
O
N
N
O
N
O
E
, R = , R' = CH3
O
F2HCO
N
NH
R1
F
F
,
, R =
,
R' = CH3
R1
N
O
O
H
O
OCH3
O
O
F
O
N
P
N
N
O
P
H
NH
R2
R2
TAK-480
Zoliflodacin
(AZD0914, ETX0914)
DNA gyrase inhibitor in Phase II clinical development
for the treatment of N. gonorrhoeae infections
R1
R1
NK2 receptor antagonist
in pre-clinical development
for the treatment of IBS
, R1 = 4-tBuC6H4, R2 = SO2CF3
, R1 = 4-tBuC6H4, R2 = SO2-3,4-(CF3)2C6H3
2a
2b
Fig. 2 Examples of Bioactive Tetrahydroquinolines.
H3CO
OCH3
O
O
O
O
O
O
P
S
S
The transfer hydrogenation of 6-bromo-2-methylquinoline (10a)
to the 1,2,3,4-tertahydroquinoline 11a was first investigated using
the previously reported Brønsted acid 3b (Table 1; entry 3). In
parallel, the same reaction was carried out in the absence of a
catalyst at 60oC, 40oC and 22oC, to exclude the possibility of any
competing reaction. Surprisingly, a significant amount of 11a was
formed at high temperatures even in the absence of a catalyst
(entry 1), which was suppressed at RT (entry 2). To the best of our
knowledge, this observation has not been previously reported.
Although the presence of the 2-methoxy group in Brønsted acid 3b
could potentially hydrogen-bond with the NH, the rate of the
reaction and enantioselectivity was identical to that of the simple
phenyl analog 4a (entry 3 vs 4). In contrast, the corresponding
phenolic Brønsted acid 5a led to quantitative conversion in 2 h and
higher enantioselectivity (entry 3 vs 5). A much slower reaction rate
was observed with the 4-phenol derivative 5b and the
enantioselectivity was also reduced to that observed with 3b and
4a (entries 6 vs 3 and 4, respectively). These results strongly support
P
N
N
R
R
H
H
H3CO
3a
3b
, R = 2,4,6-(i-Pr)3C6H2
, R = 2,4,6-(i-Pr)3C6H2
Fig. 1 Phosphorus-Based Brønsted Acid Organocatalysts.
Me
O
P
Cl
Ts
RMgBr, 2-MeTHF
0oC, 30 min
N
H
H
O
O
R
P
H
7a
A
6
, R =
7b,
B
R = , R' = CH3
7c
7d
7e
C
, R = , R' = CH3
D
, R = , R' = CH3
E
, R = , R' = CH3
7f
F
, R = , R' = CH3
NH4OH, Et3N
CCl4, MeCN
0oC to rt, 16 h
iPr
O
Cl
S
iPr
O
O
O
P
O
iPr
H
N
R3
P
NH2
S
NaH, THF
0oC to rt, 16 h
our hypothesis of
interaction.
a beneficial intramolecular cooperative
O
R
R
4a-f
8
Extension of the π-system to the naphthalen-2-ol derivative 5c
led to further improvement in enantioselectivity, giving a crude
product in 1:9 R:S ratio and quantitative yield after 2 h at RT;
enantiomeric purity was increased to 3.5:96.5 R:S ratio upon
crystallization of the product (entry 7). Furthermore, the same
reaction could be completed in only 30 min if run in CHCl3 without
any loss in enantioselectivity (entry 8). The best enantioselectivity
was observed when the reaction was run in cyclohexane (89% ee),
BBr3
3b 4b-e
or
5a-e
CH2Cl2, -78oC to rt
16 h
Scheme 1. Synthesis of of Brønsted Acids (αPrepared as previously
reported22)
however, the reaction time was
a little longer (entry 9).
Interestingly, the corresponding 5,6,7,8-tetrahydronaphthalen-2-ol
2 | J. Name., 2012, 00, 1-3
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derivative 5d gave very similar results to the simple phenol 5a
(entry 5 vs 10), suggesting that π-stacking interactions between the
catalyst and the substrate play a significant role in this reaction.
Extension of the π-system to the 6-phenylnaphthalen-2-ol analog
5e provided some further improvement in enantioselectivity (entry
7 vs 11); this aspect of our catalyst design merits further
investigation in future studies.
larger) substrate-binding cavities. Although, catalyst optimization is
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often required for each different type of reaction, certain structural
DOI: 10.1039/C9OB01774G
trends are well known about organocatalysts 1.1 For example, large
substituents at the 3,3’-positions of the BINOL-based Brønsted
acids 1 typically provide better enantioselectivity, due to higher
steric bulk and larger substrate-binding catalytic cavities (e.g. Table
2, entry 8 vs 9).24
The absolute stereochemistries of the (S)-6-bromo-2-methyl-
1,2,3,4-tetrahydroquinoline (11a), as well as the Brønsted acids Rp-
5a and Rp-5c were confirmed by their single crystal X-ray structures
(Fig. 3a-c, respectively). The structures of Rp-5a and Rp-5c also
clearly showed the presence of a hydrogen bond between the
phenolic oxygen and the acidic NH and provided a molecular view
of a small substrate-binding cavity (e.g. Fig. 3d; 5c).
Table 2. Substrate Scope and Catalyst Effect
R4
R4
*
R6
R3
R2
R6
R3
R2
Cat.
9b
(5 mol%)
*
(3 equiv.)
N
N
H
*
10
11
Time Yield
11
entry Cat
R2
R3/R4/R6
h
16
5
%
73α
99
99
<5
72
77
95
nd
92
70
nd
71
51δ
nd
71
%eeα
Table 1 Asymmetric Transfer Hydrogenation of Quinolines
1
2
3
4
5
6
7
5c
5c
5c
5c
5c
5c
5c
Me
Me
H/H/H
H/H/Br
88
88 (93β)
RO2C
CO2R
Br
Br
Me H/H/NO2
Me H/H/OMe
3
86 (96β)
9b
(3 equiv.)
N
H
Catalyst (5 mol%)
toluene
168
9
-
75
66
59
5
97
30
35
14
N
N
9a
, R = Me
, R = Et
H
10a
11a
Et
i-Pr
Ph
Ph
Ph
H
H
H
H
H
H/H/H
H/H/H
H/H/H
H/H/H
H/H/H
H/Me/H
9b
9c
, R = t-Butyl
22
12
-
Temp
oC
Time
h
Yield
%
50
-
75
72
99
99
99
99
99
99
99
11a
%eeα
-
-
40
entry Catalyst
8γ 1b
9γ
10
1c
5c
12
96
1
2
3
none
none
3b
60
22
22
22
22
22
22
22
22
22
22
48
48
48
48
2
24
2
0.5
5
2
11γ 1b
12 55c
13 55c
14γ 11c
15ε 55c
H/Me/H 35-60
Me/H/H
Ph/H/H
16
86
4
5
4a
5a
40
58
40
4
Ph/H/H 22-48
racemic
30
6
7
5b
5c
80 (93β)
80
CO2Me H/H/H
4
8γ
9δ
10
5c
5c
5d
5e
Most reaction catalyzed by 5c were run at RT. α %ee of product;
β %ee after crystallization; γ data obtained at 60oC;24,30 δyield based
on recovered starting material; εdata obtained at 50oC.
89
60
84
11
2
%ee of crude product; β%ee of isolated crystalline product;
α
Screening of various substituent at the C-2 position of the
quinoline substrate revealed that substituents with larger steric
bulk led to lower enantioselectivity (Table 2; entries 1 vs 5 and 6).
Substitution with an electron withdrawing group at C-6 accelerated
the reaction rate (entries 2 and 3), whereas an electron donating
groups dramatically reduced the rate of the reaction (entry 4).
These observations are consistent with the general mechanism for
this type of reaction.1,24 Hydrogenation of the 2-phenylquinoline
resulted in lower enantioselectivity than expected (59% ee; entry 7),
suggesting a possible competing π-stacking interaction between the
catalyst and the C-2 phenyl group, instead of the quinoline core. It
is noteworthy that in spite of its small cavity size, compound 5c
catalyzed the transfer hydrogenation of 2-phenylquinoline with
significantly higher enantioselectivity than catalysts 1b (entry 7 vs
8).24 Whereas, hydrogenation of the 4-methylquinoline catalyzed
by 5c results in similar enantioselectivity to that reported with
catalyst 1b29 (entries 10 vs 11). We also examined the
hydrogenation of the 3-methyl and 3-pheny substituted quinolines,
but observed low enantioselectivity and slower reaction rates
(entries 12 and 13, respectively). Our observations are consistent
with those reported by Rueping for the 3-substituted vs the 2-
substituted quinoline. For example, whereas hydrogenation of the
2-phenyl quinoline with catalyst 1c leads to 97% ee of the
tetrahydroquinoline 11 (entry 9),24 the 3-phenyl quinoline was
reported to give the racemic mixture of the corresponding product
(entry 14). However, sterically more conjected catalysts, such as 1k,
were shown to lead to the formation of the 3-phenyl-1,2,3,4-
γreaction run in CHCl3; δreaction was run in cyclohexane.
Fig. 3 X-ray Structures of Tetrahydroquinoline 11a and Brønsted
Acids 5a and 5c
Optimization of the reactions conditions for the solvent and the
Hantzsch esters effects in the presence of catalyst 5c were also
undertaken (SI Table 1 and 2). The effects of the Hantzsch esters
(9a-c) investigated so far did not result in any major differences. The
substrate scope was subsequently explored and the results
compared to those reported for BINOL-based Brønsted acids 1b and
1c (Table 2); the objective of this study was to simply gain further
insight on the catalytic properties of catalyst 5 in comparison to
BINOL-based Brønsted acids 1 that have similar size (or slightly
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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tetrahydroquinoline in 74% ee, under the same reaction
conditions.30 Finally, we examined the transfer hydrogenation of
methyl quinoline-2-carboxylate (entry 15). A strongly electron-
withdrawing substituent at C-2 is expected to decrease the electron
density on the quinoline nitrogen and significantly decrease the rate
of this reaction.31 In fact, the transfer hydrogenation of methyl
quinoline-2-carboxylate catalyzed by a Brønsted acid has not been
previously reported. We were pleased to see quantitative
conversion in 4 hours, albeit in modest enantioselectivity (the
isolated yield of the pure product was only 71% due to partial co-
elution of the Hantzsch esters with the product during
chromatography). It is reasonable to assume that the high acidity of
Brønsted acid 5c is able to compensate for the electronic effects of
the C-2 carboxylate moietry.
acid organocatalysts. Their catalytic properties compare favorably
View Article Online
with those of BINOL-based Brønsted acids 1 DhOavI:in10g.1a0s3i9m/Cil9aOrlyB0s1m77a4llG
substrate-binding pocket. The synthesis of analogues 5 and fine-
tuning of their catalytic properties for different chemical
transformations can be easily achieved in a modular library mode,21
and is currently in progress.
Conflicts of interest
The authors declare no conflict of interest.
References
Although we have not yet fully explored the mechanistic
differences between catalyst 5c and the BINOL-based Brønsted
acids 1, our current data is generally consistent with the established
mechanism for this reaction.1,24,29 The rate acceleration and
enantioselectivity differences observed between catalyst 3b and 5a
(Table 1; entry 3 vs 5) are consistent with our original hypothesis,
which presumed that protonation of the quinoline by the catalyst
could lead to an intramolecular cooperative ion pair (Fig. 4; II),
stabilizing the conjugate base of the catalyst. Whether the shared
proton in the ionized form II is derived from the OH or the NH of the
original catalyst (I) is inconsequential to the proposed intermediate
II. Additionally, once the protonated quinoline is bound to the
catalyst, it is likely that the OH moiety recruits the Hantzsch ester,
leading to a more stable trimolecular complex (III), and guiding the
delivery of the hydride species from the side of the naphthol ring
(IV). Binding of the 2-methylquinoline to 5c through favorable π-
stacking interactions and placement of the quinoline nitrogen near
the acidic NH of the catalyst necessitates that the 2-methyl group
becomes buried in the catalytic pocket and near the t-butyl
substituent on the phosphorus. Therefore, entrance of the hydride
from the side of the naphthol would simultaneously push the 2-
methyl group away from the steric bulk of the t-butyl.
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i-Pr
O
i-Pr
i-Pr
O
i-Pr

N
N
O
S
S
P
P
OH
O
O
H
i-Pr
i-Pr
H

O
O
H

+
N
H
CH3
I
II
R'O2C
R'O2C
R'O2C
-
O
S
O
S
-
O
O
N
N
H
H
NH
N
P

OH
O
P

HO
O
H
+
H
R'O2C
N
+
N
H-
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H
III
IV
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H
N
CH3
H
Fig. 4 Proposed Catalytic Mechanism of Brønsted Acid 5c
In summary, we aimed to demonstrate that the incorporation
of an intramolecular H-bond between a phenolic substituent on a
P-stereogenic center of a Brønsted acid and the NH of its N-
phosphoryl sulfonamide can stabilize the conformation of the
catalytic cavity, accelerate the reaction rate and increase
enantioselectivity for the transfer hydrogenation of quinolines.
OttoPhosa I (5c) represent a prototype of this new class of Brønsted
4 | J. Name., 2012, 00, 1-3
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