Key words tertiary enamides - 1,2,3,4-tetrahydropyridines - asymmetric catalysis - chiral phosphoric
acid - substrate engineering
Chiral six-membered N -heterocyclic compounds such as functionalized 4-aminopiperidines are used extensively
in the study of synthetic pharmaceutics and drug discovery.[1 ] (2S,4R)-1-(3,5-dimethylbenzoyl)-2-benzyl-4-((quinolin-3-ylmethyl)amino) piperidine
CGP 49823, for instance, is an orally and centrally active nonpeptide NK1 antagonist[2 ] while carmegliptin is a potent and long-acting dipeptidyl peptidase IV inhibitor
for the treatment of type II diabetes.[3 ] Synthesis of functionalized 4-aminopiperidine requires multistep reactions[4 ] or reductive amination of prefunctionalized piperidine-4-one derivatives.[5 ] The documented methods suffer, however, from drawbacks such as tedious stepwise
chemical manipulations or low chemical yields. The development of general and asymmetric
catalytic methods for the synthesis of highly enantiopure diverse 4-aminopiperidine
derivatives is therefore highly desirable.
Tertiary enamides are variants of enamines in which one of the N -alkyl groups is replaced by an electron-attracting moiety such as carbonyl. Various
synthetic methods have been established allowing facile accesses to tertiary enamides.[6 ] Unfortunately, due to the electronic effect of carbonyl group, tertiary enamides
show much diminished enaminic activity and had been noted for a long time as inert
and not useful chemical entities in organic synthesis.[7 ]
[8 ]
[9 ]
[10 ] However, we envisioned that tertiary enamides would be a type of shelf-stable nucleophiles
with tunable reactivity based on the fluxional cross-conjugational system comprising
carbon–carbon double bond, lone-pair electrons on nitrogen atom and carbonyl group
(C=C–N–C=O). We have demonstrated in recent years that tertiary enamides behave indeed
as unique and invaluable synthons in chemical synthesis. They are able to undergo
stereoselective nucleophilic addition reactions to epoxides,[11 ] carbonyls,[12 ] iminiums,[13 ] nitriliums,[14 ] and activated alkynes,[15 ] furnishing diverse nitrogen-containing heterocyclic compounds which are not easily
obtained by other means. To further explore the synthetic applications of tertiary
enamides and to develop new methods for the construction of chiral 4-aminopiperidines,[16 ] we have undertaken the current study of catalytic asymmetric cyclization reactions
of tertiary enamides. We disclose herein a chiral phosphoric acid catalyzed intramolecular
nucleophilic addition of tertiary enamides to imines and a substrate engineering strategy
to achieve high enantioselectivity in the synthesis of diverse 4-aminopiperidine derivatives.
We started our study with the examination of the cyclization of tertiary enamide 3aa , which was obtained quantitatively from the reaction of aldehyde 1a with benzylamine 2a (see Supporting Information for details), under asymmetric catalysis. Chiral Lewis
acids catalysts such as BINOL-Ti/spiro-Ti complex, Salen-AlCl, Pybox/Sn(OTf)2 , Brønsted acids such as camphorsulphonic acid and a chiral thiourea were found to
be able to effect the transformation of 3aa to afford 4-aminopiperide product 4aa in good to excellent yields. Disappointedly, the enantiomeric excess values obtained
were very low in all cases (Supporting Information).[17 ] We then focused on chiral phosphoric acids (CPA) as they were renowned catalysts
to activate imine functionality enantioselectively.[18 ]
[19 ]
[20 ] A series of 17 chiral BINOL-derived phosphoric acids CC1 –CC17 (Supporting Information), which have fine-tuned electronic and steric effects, were
tested as catalysts in the transformation of 3aa into 4ab . All chiral phosphoric acids showed appallingly low activity and enantioselectivity
(Supporting Information) except 2,2′-bis(2,4,6-triisopropylpohenyl)-substituted chiral
phosphoric acid CC8 which produced 4aa in 91% yield with 48.3% ee after 18 h in dichloromethane (DCM, Table [1 ]). Unfortunately, further optimization of reaction conditions by screening reaction
media, temperature, and reaction time did not lead to the improvement of enantiocontrol,
with ee values never exceeding 48.3% (Supporting Information).
Table 1 Development of Catalytic Enantioselective Nucleophilic Addition of Tertiary Enamides
to Imines by Means of a Substrate Engineering Strategy
Entry
2
CC8 (mol%)
Solvent
Temp (°C)
Time
Yield (%)b
ee (%)c
1
2a
10
DCM
rt
18 h
91
48.3
2
2a
10
CCl4
rt
48 h
88
35.2
3d
2a
20
CCl4
reflux
7 h
92
33.1
4
2b
10
DCM
rt
2 h
97
41.1
5
2b
10
CCl4
rt
8 h
99
77.8
6
2b
10
CCl4
0
48 h
trace
n.d.
7
2b
10
CCl4
40
1.5 h
95
80.5
8
2b
10
CCl4
reflux
10 min
98
84.6
9
2b
5
CCl4
reflux
30 min
96
72.9
10
2b
20
CCl4
reflux
5 min
98
87.2
11d
2b
20
CCl4
reflux
10 min
98
88.8
12d
2c
20
CCl4
reflux
10 min
97
87.1
13d
2d
20
CCl4
reflux
5 min
99
94.0
14d
2e
20
CCl4
reflux
5 min
97
60.0
a Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), solvent, rt, 5–10 min, then CPA CC8 , c 10 mM.
b Isolated yield.
c Enantiomeric excess of 4 was determined by HPLC analysis on chiral stationary phase.
d The reaction was carried out in the concentration of c 2.5 mM.
Although extensive examination of catalysts fabricated from different chiral scaffolds
and of various reaction parameters may probably result in a better enantioselective
reaction, we adopted completely a different approach to achieve efficient synthesis
of highly enantiopure 4-aminopiperidine structures. In biocatalysis and biotransformation,
substrate engineering, namely, structural modification of the reactants in order to
best-fit the active site of enzymes, is a powerful strategy to realize high enzymatic
activity and selectivity. In comparison to protein engineering, substrate engineering
is generally easy-to-handle, time-saving, and cost-effective.[21 ] For example, we have demonstrated previously the dramatic improvement of enantioselectivity
in enzyme-catalyzed hydrolysis of β-hydroxy and β-amino nitriles and carboxamides
simply by protecting hydroxyl or amino with a benzyl group.[22 ]
Based on the assumption of effective recognition of a larger chiral pocket of CC8 toward imine moiety through both steric and electronic (π/π and C–H/π) interactions,
imine substrates bearing N -diphenylmethyl (DPM, 3ab ), N -di(4-methoxyphenyl)methyl (DMPM, 3ac ), 10,11-dihydro-5H -dibenzo[a ,d ][7]annulen-5-yl (DHDBA, 3ad ) and 5H -dibenzo[a ,d ][7]annulen-5-yl (DBA, 3ae ) were designed and synthesized from the condensation reaction between aldehyde and
the corresponding amines (Supporting Information). Their intramolecular cyclization
reactions were investigated under the catalysis of CC8 . To our delight, substrate engineering led to significant improvement of both efficiency
and enantioselectivity of the catalytic transformation. As indicated in Table [1 ], under the identical conditions such as using CCl4 as solvent, the ee values obtained from the reaction of 3ab and of 3aa were 77.8% and 35.2%, respectively, although comparable enantioselectivity was observed
when reactions were performed in DCM (Table [1 ], entries 1, 2, 4, and 5). After further examining catalyst loading, reaction temperature
and substrate concentration (Table [1 ], entries 6–10), an ee value of 88.8% was achieved for product 4ab (Table [1 ], entry 11). On contrary, under such optimized conditions, namely, refluxing reactant
(2.5 mM) with chiral catalyst (20 mol%) in CCl4 , reaction of 3aa afforded product 4aa with only 33.1% ee (Table [1 ], entry 3). Increasing the bulkiness of N -substituent by replacing DPM (3ab ) with DMPM (3ac ) caused slight decrease of enantioselectivity (Table [1 ], entry 12). After locking the conformation of two phenyl substituents by forming
a fused carbocyclic structure, the resulting DHDBA-bearing substrate 3ad underwent a remarkably high enantioselective cyclization reaction to afford 4ad in an almost quantitative yield with 94.0% ee (Table [1 ], entry 13). Further rigidification of the carbocyclic ring substituent, however,
had a detrimental effect on enantioselectivity of chiral catalysis. This has been
exemplified by the drastic erosion of ee from 94.0% for the reaction of DHDBA-substituted imine 3ad to 60.0% for the reaction of DBA-substituted imine analogue 3ae (Table [1 ], entries 13 and 14).
Scheme 1 Catalytic enantioselective synthesis of 4-amino-1,2,3,4-tetrahydropyridine derivatives
from tertiary enamides. a Reflux in CCl4 . b Room temperature in CCl4 .
Since N- DPM- and N- DHDBA-substituted imines exhibited high level of enantiocontrol under catalysis of
chiral phosphoric acid CC8 , the scope of intramolecular nucleophilic addition of tertiary enamides to imines
was then surveyed on substrates derived from amines 2b and 2d . The reactions were conveniently conducted using imines formed in situ. The results
summarized in Scheme [1 ] show clearly that tertiary enamides undergo generally efficient cyclization reaction
to produce 4-amino-1,2,3,4-tetrahydropyridine derivatives irrespective of the nature
of the substituents. For example, reaction of all aryl-substituted tertiary enamides
in which phenyl group contains either electron-withdrawing or electron-donating group(s)
at different position(s) went completion within 0.5 h to generate heterocyclic products
in high yields. Only in the case of N -acetyl-substituted enamide 3ib and cyclohexanone-derived enamide 3jb , a long reaction time (ca. 24–36 h) was required due to their lower enaminic reactivity.
Good to excellent enantioselectivity was achieved using either DPM or DHDBA substituent
on imine moiety. It is worth noting that, however, DPM outweighed DHDBA in a number
of cases in the control of enantioselectivity of chiral phosphoric acid catalyzed
transformation. It implied that the enantioselectivity of intramolecular nucleophilic
addition of enamide moiety to chiral phosphoric acid activated imine moiety is governed
by both the N -substituent on imine and the variation of steric and electronic effects of substituents
bonded to enamide segment. The outcomes manifested again the potential of substrate
engineering strategy in the synthesis of a targeted enantiopure 4-amino-1,2,3,4-tetrahydropyridine
compound under the catalysis of chiral phosphoric acid.[23 ]
Advantage of substrate engineering protocol was further demonstrated by easy removable
of the N -protection group. Treatment of 4ca with trifluoroacetic acid at ambient temperature thus gave product 5 (Scheme [2 ]). Derivatization of free amino group would therefore feasibly permit the generation
of diverse compounds. To determine the absolute configuration of the product 4 , an authentic sample of (S )-4-hydroxy-1,2,3,4-tetrahydropyridine 6
[11b ] was converted into (R )-4-amino-1,2,3,4-tetrahydropyridine (R )-5 through azide intermediate 7 (Scheme [3 ]). The absolute S -configuration was assigned to products 4ac on the basis of the comparison of specific rotation values between (S)-5 (Scheme [2 ]) and (R)-5 (Scheme [3 ]).
Scheme 2 Synthesis of (S)-5 from 4ac through deprotection of DMPM group
Scheme 3 Synthesis of (R )-5 from authentic sample (S )-6
In conclusion, we have shown a general and efficient method for the synthesis of highly
enantiopure 4-amino-1,2,3,4-tetrahydropyridine derivatives based on intramolecular
nucleophilic addition of tertiary enamides to imines. We have also demonstrated a
substrate engineering strategy enabling significant improvement of the enantioselectivity
of chiral phosphoric acid catalyzed reaction.
