Asymmetric Counter-Anion-Directed Aminomethylation: Synthesis of Chiral β-Amino Acids via Trapping of an Enol Intermediate

Article abstract of DOI:10.1021/jacs.8b12832

A novel enantioselective aminomethylation reaction of diazo compound, alcohol and α-aminomethyl ether enabled by asymmetric counteranion-directed catalysis is disclosed that offers an efficient and convenient access to furnish optically active α-hydroxyl-β-amino acids in high yield with high to excellent enantioselectivities. Control experiments and DFT calculations indicate that the transformation proceeds through trapping the in situ generated enol intermediate with methylene iminium ion, and the asymmetric induction was enabled by chiral pentacarboxycyclopentadiene anion via H-bonding and electrostatic interaction.

Full text of DOI:10.1021/jacs.8b12832

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Communication
Asymmetric Counter-Anion-Directed Aminomethylation: Synthesis
of Chiral #-Amino Acids via Trapping of an Enol Intermediate
Zhenghui Kang, Yongheng Wang, Dan Zhang, Ruibo Wu, Xinfang Xu, and Wenhao Hu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12832 • Publication Date (Web): 09 Jan 2019
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Asymmetric Counter-Anion-Directed Aminomethylation: Synthesis
of Chiral β-Amino Acids via Trapping of an Enol Intermediate
Zhenghui Kang,a,b,† Yongheng Wang,a,† Dan Zhang,a Ruibo Wu,a Xinfang Xu,*,a and Wenhao Hu*,a,b
aSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
bShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and
Molecular Engineering, East China Normal University, Shanghai 200062, China
Supporting Information Placeholder
ABSTRACT:
A
novel enantioselective aminomethylation
Scheme 1. Asymmetric Induction Models in Mannich-type
Aminomethylation Reaction
reaction of diazo compound, alcohol and α-aminomethyl ether
enabled by asymmetric counter-anion-directed catalysis (ACDC)
is disclosed that offers an efficient and convenient access to
furnish optically active α-hydroxyl-β-amino acids in high yield
with high to excellent enantioselectivities. Control experiments
and DFT calculations indicate that the transformation proceeds
through trapping the in situ generated enol intermediate with
methylene iminium ion, and the asymmetric induction was
enabled by chiral pentacarboxycyclopentadiene (PCCP) anion via
H-bonding and electrostatic interaction.
The introduction of an aminomethyl group into small organic
molecules has recently attracted considerable attention due to the
pervasive occurrence of this moiety in a wide variety of natural
products and pharmaceuticals.1 Moreover, the resulting nitrogen-
containing products are versatile synthetic building blocks for the
preparation of biologically active compounds. Thus, methods for
the incorporation of the aminomethyl functional group, such as
nucleophilic displacement and cross-coupling reaction, have been
developed.2,3 However, most of these advances are racemic ver-
sions. To date, only
a handful of catalytic asymmetric
aminomethylation reactions have been reported.3 Seminal works
by Córdova and Gellman have enabled asymmetric
aminomethylation of aldehydes or ketones catalyzed by a chiral
secondary amine.3a,3b Recently, Feng and Luo reported asymmet-
ric aminomethylation of 1,3-dicarbonyl compounds, catalyzed by
chiral Lewis acid3e and chiral primary amine3f catalysts, respec-
tively. In these advances, a precisely designed catalytic strategy of
asymmetric activation of the nucleophiles was employed for the
induction of the chirality. Thus, the substrate scope of these re-
ported reactions is limited to aldehydes, ketones or β-ketoesters
based on the corresponding catalytic model (Scheme 1a), and
asymmetric aminomethylation at the α-position of esters, which is
extremely useful for the synthesis of β-amino acid derivatives,
could not be realized with these methods. In this context, devel-
opment of new approaches via asymmetric activation of
aminomethylation reagent is urgently needed (Scheme 1b); these
approaches will provide a new avenue for the enantioselective
aminomethylation to allow extensive exploration of the substrate
generality, particularly for the nucleophiles that are reactive in-
termediates and for which asymmetric induction is difficult.
In the past decade, chiral Brønsted acid has shown versatile
ability in asymmetric Mannich-type reactions. Generally, direc-
tional H-bonding activation of imine is the common pattern for
the asymmetric induction,4 and the Brønsted acid serves as a pro-
ton shuttle in most of these transformations.5 Recently, we have
realized enantioselective multi-component reactions by trapping
ylide/zwitterionic intermediates with imines in the presence of a
chiral Brønsted acid (Scheme 1c).6-8 However, the electrophiles
are still restricted to the relative stable imines in these reactions.
On the other hand, asymmetric counter-anion-directed catalysis
(ACDC) has been demonstrated to be an effective asymmetric
induction strategy,9,10 and the first proof-of-concept example for
highly enantioselective ACDC was reported by List et al.10a In-
spired by these works, we envisioned that by applying the ACDC
concept,10 the in situ generated tight ion pair of methylene
iminium ion with corresponding chiral counter anion may enable
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Table 2. Substrate Scopea
the trapping of the nucleophile intermediate and realize
enantioselective aminomethylation via a novel catalytic strategy
(Scheme 1b vs 1a). However, the asymmetric aminomethylation
reaction catalyzed by a chiral Brønsted acid has never been re-
ported, possibly due to the inherent lability and the absence of a
handle for the methylene iminium ion species to interact with the
catalyst.9,11 Herein, we report the first example of an
enantioselective counter-anion-directed aminomethylation reac-
tion, and the envisioned asymmetric induction step proceeds via
the trapping of the in situ generated enol intermediate with meth-
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ylene
iminium
ion
in
the
presence
of
pentacarboxycyclopentadiene (PCCP) acid 6 (Scheme 1d). This
method not only provides a novel catalytic pattern for the asym-
metric aminomethylation but also reveals an effective strategy for
the interception of reactive intermediates with substrate compati-
bility and offers convenient access for furnishing chiral α-
hydroxy-β-amino acids with an α-quaternary stereocenter.12
We initially test our studies by employing α-aminomethyl ether
3a as methylene iminium ion precursor13 to react with diazo 1a
14
and benzyl alcohol 2a in the presence of [PdCl(η3-C3H5)]2 and
BINOL-derived phosphoric acid 5 in dichloromethane at 0 °C.
Gratifyingly, the desired product 4a was obtained in 89%-95%
yields (Table 1, entries 1-6). Further extensive evaluation of
Table 1. Condition Optimizationa
3
Bn
Bn
-
[PdCl( C3H5)]2
N2
Bn
N
N
BnO
Ph
(5.0 mol %)
+
BnOH +
Ph
CO2Me
Bn
MeO2C
S, 0 oC
OMe
Å M
acid, 4
1a
2a
3a
4a
6a
, R =
i-Pr
R
O
O
H
RO
Me
5a: R= 9-Phenanthryl
5b: R= 3,5-Cl2C6H3
5c: R= 2,4,6-iPr3C6H2
5d: R= SiPh3
5e: R= 4-OMeC6H4
5f: R= 3,5-(CF3)2C6H3
O
O
O
P
RO
OR 6b
, R =
O
R
OH
OR
H
O
OR O
6c
, R = Me
yield (%)b
ee (%)c
entry
solvent
acid
1
2
3
DCM
DCM
DCM
93
89
95
<5
5
5a
5b
5c
5d
5e
5f
51
4
5
6
DCM
DCM
DCM
92
90
89
27
<5
15
7
8
DCM
DCM
DCM
CHCl3
90
90
88
92
-
6c
88
84
96
6a
6b
6a
9
10
aAll reactions were conducted on a 0.2 mmol scale: 1:2:3 = 1.5:1.5:1, acid
c
(5.0 mol % 5 or 3.0 mol % 6). bIsolated yield. Determined by chiral
HPLC analysis.
different chiral phosphoric acids and investigation of the effects of
the solvent and temperature did not provide any improved results
(see Table S1). Considering the fact that the weaker and less di-
rectional nature of electrostatic ion-pairing interaction between
methylene iminium ion and chiral counter anion may be the main
reason for the low enantioselectivity in this reaction,9c a chiral
counter anion with larger steric hindrance may be required to
enhance the directionality of the methylene iminium ion for
enantiodiscrimination. Recently, Lambert reported a novel chiral
pentacarboxycyclopentadiene (PCCP) acid.15 The acidity of this
catalyst results from the aromatic nature of the cyclopentadienyl
aReactions were conducted on a 0.2 mmol scale: 1:2:3 = 1.5:1.5:1.
bRh2(OAc)4 was used as catalyst.
anion as the conjugate base16 and the propeller-like steric chiral
structure shows obvious advances for the enantioselectivity con-
trol with challenging substrates.17 Significant increases in the
enantioselectivity with excellent yield were observed in the pres-
ence of chiral PCCPs 6 (entries 8-9). Upon examining the solvents
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and temperature with 6a as the cocatalyst (see Table S2), 4a was
operation, which is the core skeleton in many bioactive mole-
cules.23
To gain insight into the reaction mechanism, control experi-
obtained in 92% yield with 96% ee, when chloroform was used as
the solvent (entry 10).18
With the optimal conditions, the scope of this asymmetric
aminomethylation reaction was investigated (Table 2). A series of
aryl diazoesters 1 were subjected to the current conditions with 2a
and 3a to afford the corresponding products in excellent yields
with high enantioselectivities. Aryl diazoacetates bearing either
electron-withdrawing or electron-donating substituents on the
phenyl ring reacted smoothly, leading to the desired products 4a-
4h in high yields (78-96%) with 90%-96% ee.19 Diazo com-
pounds with di- or tri-substitutes on the aryl ring all gave the cor-
responding products (4i-4k) in good yields with comparable
enantioselectivities. Various diazo compounds, including α-styryl
diazoacetate 1l, benzyl diazoacetate 1m, and diazoketone 1n,
delivered the corresponding products 4l-4n in high yields with
72%-94% ee. The α-alkyl substituted diazoacetates performed
well to afford the aminomethylation products (4o-4r) in high
yields with moderate to high enantioselectivities.20 Further opti-
mizations of α-alkyl diazoacetate (see Table S3 and S4) found that
with the steric bulky 9-fluorenol, the reactions of diazopropanoate
1p gave the corresponding products with 90%-92% ee (4s-4u).
Then, the scope with respect to the alcohols was examined.21 Var-
ious substituted benzyl alcohols provided the corresponding α-
benzyloxy β-amino esters (4v-4x) with 78%-91% yields and 93%-
94% ee. Furfuryl alcohol gave 90% yield and high
enantioselectivity (4y). Subsequently, different alkyl alcohols also
gave good results, furnishing 4z-4C in 85%-92% yields with
87%-96% ee. Alcohols bearing the alkynyl and alkenyl species
were also well-tolerated in this reaction and afforded 4D-4G in
82%-90% yields with high selectivity. Notably, biomolecules,
epiandrosterone, dehydroepiandrosterone, and testosterone, were
tested in this reaction, and the corresponding products were
formed in > 92% yields with > 95:5 dr (4H-4K). These results
have shown the potential of this aminomethylation process for the
selective modification of bioactive molecules that bear a hydroxyl
group. In addition, the α-aminomethyl ether derivatives with sub-
stituted benzyl groups gave the comparable results with >92%
yields and 90%-94% ee (4L-4N).22
ment of O-H insertion product with 3a under the standard condi-
tions gave no desired product 4a, excluded the possibility that the
reaction goes through a stepwise process. Moreover, control ex-
periment by adding varying stoichiometric amounts of acid 6c to
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1
3a was conducted, with monitoring by H NMR spectroscopy.
Formation of the conjugate base of 6c and MeOH were detected
simultaneously, indicating the generation of an ion pair (see Fig-
ure S2). Furthermore, the generated methylene iminium ion in-
termediate from 3a in the presence of 6c was also detected by
HR-MS (see Figure S3). Methylene iminium chloride underwent
anion exchange with chiral silver complex Ag-6a to form the
chiral ion pair 3a-6a24 that was then employed for the reaction of
1a with 2a in the absence of additional 6a, and 4a was isolated in
40% yield with essentially the same enantioselectivity as that of
the model reaction (Scheme 3). These results indicate that the
Scheme 3. Control Experiments
contact ion pair may be the key intermediate in this reaction, and
the chiral counter anion is responsible for the asymmetric induc-
tion.
On the basis of the aforementioned insights and density func-
tional theory (DFT) calculation results, the mechanistic rationale
for this reaction is proposed in Figure 1. Tight chiral ion pair V is
To demonstrate the synthetic potential of this strategy, a gram-
scale reaction was conducted, affording 4a with comparative re-
sults (5.0 mmol scale, 2.07 g, 89%, 95% ee). Moreover, these
products could be readily converted into synthetically useful
building blocks (Scheme 2). The α-hydroxyl-β-amino ester 7a
Scheme 2. Synthetic Utility
Figure 1. Proposed reaction mechanism.
generated through MeOH elimination from 3a in the presence of
chiral PCCP. In the parallel transition-metal catalysis cycle (left
cycle), palladium carbenoid species I is generated from diazo 1 in
the presence of [PdCl(ƞ3-C3H5)]2 that further reacts with alcohol 2
to form palladium-associated oxonium ylide II. This active ylide
II may either undergoes a 1,3-Pd transfer to give an enolate spe-
cies III through a transition state TS1 or a 1,4-proton transfer to
was generated in 96% yield with 95% ee via a one-pot operation.
The β-amino acid 8a, which is an essential secondary structure for
the formation of specific β-peptide foldamers,12 was obtained with
consistent ee through the hydrolysis of 7a. Furthermore, 4a could
be transformed into α-hydroxyl-β-lactam 10a through a two-step
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afford an enol intermediate IV via the transition state TS2.25 DFT
calculations indicated that TS1 is 5.3 kcal/mol higher in energy
than TS2, and IV is 13.8 kcal/mol more stable than III (see Fig-
ure S10). Therefore, enol IV is more likely to be the intermediate
for the next step. The subsequent convergent nucleophilic addition
of IV with methylene iminium ion pair V through a transition
state TS3 led to 4, generating the chiral ion pair V in the presence
of 3a simultaneously (right cycle). A control experiment with a
combination of chiral 4a (96% ee) and PCCP 6a as cocatalyst
gave the identical results in comparison with model reaction under
the standard conditions, further confirming the proposed catalytic
cycle (see Figure S4).
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According to the above mechanism, the stereo-determining step
is the nucleophilic addition of the enol IV with the chiral ion-pair
V via a three-component transition state TS3. To further under-
stand the origin of the enantiocontrol of this reaction, the calculat-
ed electrostatic potential of these three components is shown in
Figure 2.26 The negative charges of the PCCP anion are mainly
Figure 3. DFT-calculated transition states.
In conclusion, we have developed a novel enantioselective
aminomethylation reaction via a convergent addition of two in
situ generated reactive intermediates, enol intermediate and meth-
ylene
iminium
ion
in
the
presence
of
chiral
pentacarboxycyclopentadiene. The generated multi-functionalized
β-amino acid derivatives are useful for further diversifications, as
exemplified by the synthesis of enantiomerically pure α-hydroxyl-
β-amino acid and α-hydroxyl-β-lactam. Control experiments and
detailed DFT calculations indicate that the chiral cyclopentadienyl
anion is responsible for the asymmetric induction due to electro-
static interaction and H-bonding. In addition, the present work is
the only example of asymmetric aminomethylation reaction ena-
bled by asymmetric counter-anion-directed catalysis. This asym-
metric induction strategy opens a new avenue for exploring
enantioselective aminomethylation reactions with challenging and
structure appealing substrates.
Figure 2. DFT-calculated electrostatic potential map.
located at the center of cyclopentadienyl ring and on the carbonyl
groups, contributing to the electrostatic interaction and hydrogen
bond formation, respectively, with the corresponding intermedi-
ates (Figure 2a). Following this way, we have located two transi-
tion states, TS3-Re and TS3-Si that directly lead to (R)-4 and (S)-
4, respectively (Figure 3). Due to the unique helical chirality of
this propeller-like chiral PCCP cocatalyst,15-17 in TS3-Re, the Re-
prochiral face of the enol unit approaches the chiral ion pair V
with the benzyl group residing on the one chiral alcohol group
(Figure 3c). For TS3-Si, the Si-prochiral face of the enol unit
reaches the chiral ion pair V with the benzyl group located in the
cavity between the two chiral alcohol groups (Figure 3d). On the
basis of this steric bias, the distance between the center of the
PCCP anion and the nucleophilic site on the enol TS3-Si is closer
than TS3-Re (black dash line in Figures 3c and 3d, 6.54 Å vs 5.53
Å). Therefore, during the Mannich-type addition, the distance
between the positive iminium and the negative center of PCCP
anion in TS3-Re is longer than that in TS3-Si (green line in Fig-
ures 3a and 3b, 6.06 Å vs 4.78 Å), so that TS3-Si has stronger
electrostatic attraction that TS3-Re, resulting in the free energy
preference for TS3-Si over TS3-Re. The free energy of TS3-Re at
273 K in CHCl3 (ε = 4.71) is 2.9 kcal/mol higher than that of
TS3-Si, predicting good enantioselectivity toward the formation
of (S)-4 and is comparable to the experimental value of 2.1
kcal/mol according to the Boltzmann distribution with 96% ee.27
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI
Experimental procedures, characterizations and analytical data of
products, computational results, NMR, HPLC spectra, and crystal-
lographic data for 4a, Ag-6c, and 7a (CIF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: xuxinfang@mail.sysu.edu.cn.
huwh9@mail.sysu.edu.cn.
Author Contributions
†These authors contribute equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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tions. Chem. Soc. Rev. 2011, 40, 4539. (b) Parmar, D.; Sugiono, E.; Raja,
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21773313) and the Program for Guangdong Introducing Innova-
tive and Entrepreneurial Teams (No. 2016ZT06Y337) is greatly
acknowledged.
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