Key words
total synthesis - piperine - alkaloid - cyclobutene - pericyclic reaction - stereoselective
- organometallic chemistry
In 1820, the Danish physicist and chemist Hans Christian Ørstedt, pursuing an interest
in the isolation of ‘new alkalis’, reported a new alkaloid from pepper (piper nigrum), which he called piperine.[1] Piperine would ultimately gain the attention of the chemistry and physiology communities[2] mostly due to its wide range of biological activities. This was foreshadowed by
the original communication itself, where Ørstedt noted that an ethanolic solution
of piperine has an ‘exceptionally pungent taste’.[1] The pungency of piperine can be attributed to its agonistic nature towards the heat-
and acidity-sensing TRPV ion channels, which are associated with temperature and pain
regulation in the human body.[2a]
[b] A range of human disorders are linked to the overexpression of TRPV1, including
inflammatory bowel disease (ulcerative colitis and Crohn’s disease) and chronic breast
pain.[2c] Studies have shown that piperine is a potent desensitizer of human TRPV1, rendering
its structure a potent scaffold for the design of improved TRPV1 agonists.[2c]
[d]
Moreover, piperine has been recently identified as an allosteric modulator of the
γ-amino butyric acid type A (GABAA) receptor.[3a] The mode of action of piperine is thus analogous to commonly used drugs such as
benzodiazepines, widely used as sleep-inducing agents. [3b]
[c] In addition, it has been shown that piperine derivatives are efficient inhibitors
of vascular smooth muscle cell proliferation.[4] Antidepressant[5b] and antitumor[5c] activities along with insecticidal properties[5d] are also attributed to this intriguing molecule which can be technically found in
almost every modern kitchen in the world.
Despite the numerous demonstrated beneficial therapeutic properties of piperine, biological
applications are limited by its poor solubility in aqueous media.[6] This implies that new synthetic routes towards piperine analogues are highly desirable.
Piperine can be easily extracted[5] and its basic hydrolysis, yielding piperic acid, opens up the preparation of many
amide analogues for biological evaluation.[7] This approach is unfortunately limited by nonexchangeability of the aryl moiety.
Most approaches for the synthesis of 1-carbonyl-4-aryl-substituted dienes typically
make use of a (2 + 2), (3 + 1), or a (1 + 2 + 1) carbon disconnection. In this regard
Wittig olefination,[8] olefin metathesis,[9] palladium-catalyzed cross-coupling,[10] or ruthenium-catalyzed vinyl–alkyne coupling[11] have been employed as dominant strategies.
Scheme 1 Previous work and this work
A rather unconventional approach is the direct coupling of the aryl moiety with the
diene or a diene precursor. Mihovilovic and coworkers reported an efficient Heck reaction
approach in which an aryl bromide is coupled to a pentadienoic amide (Scheme [1, a]).[4]
[12] Another intriguing, earlier approach, relies on the addition of a Grignard reagent
to a furfural hydrazone, which rearranges to the corresponding pentadienal under the
reaction conditions (Scheme [1, b]).[13]
Herein we would like to present a different strategy towards the synthesis of piperine
analogues. The bicyclo [2.2.0] lactone 2 and its derivatives have been deployed in previous work by our group and others as
a versatile electrophile.[14] In particular, we have shown that copper-mediated nucleophilic addition is a very
robust method for a trans-selective allylic substitution of 2.[14f]
The installation of an electron-rich moiety (such as –OR or –N3) in this position has been earlier shown to facilitate a subsequent, spontaneous
4π-electrocyclic opening. This is likely due to a push–pull relationship between the
carboxylic acid and the electron-donating substituent.[15]
We hypothesized that an aryl moiety might be sufficiently electron donating in order
to induce a similar push–pull effect and enable facile electrocyclic ring opening,
either spontaneously at room temperature or upon mild heating. Importantly, the transient
trans-configured cyclobutene should undergo opening according to a thermally allowed, conrotatory
movement torquoselective for the E,E-diene product.
Lactone 2 was prepared in quantitative yield photochemically, as previously reported.[14f] In the event, we found that addition of the in situ formed cuprate (from its corresponding Grignard reagent 3a) directly led to piperic acid (4a) as the sole product in a single, quantitative step.[16] As expected, 4a was formed exclusively as the E,E-diene isomer in a clean reaction.[17] Straightforward amide formation via acyl chloride substitution with piperidine afforded piperine in more than 95% isolated
yield.[18] Through the route presented herein, this alkaloid was thus available in only three
quantitative steps from pyrone 1 and with full stereoselectivity (Scheme [2]).
Scheme 2 A simple three-step synthesis of piperine
Encouraged by these results, we investigated the synthesis of three different piperic
acid analogues by using different Grignard reagents for the ring opening of bicyclolactone
2. The 5-phenylpentadienoic acid (4b) was prepared in quantitative yield, while the para-methoxyphenyl- and the 2-thiophenyl- analogues were formed in slightly lower yields.
Nevertheless, geometric selectivity was excellent in all cases (Scheme [3]).[19] Finally, the corresponding amides were formed as before via standard acyl chloride substitution (Scheme [4]).[18] It should be noted that amides 5bb and 5cb have been previously reported to enhance GABAA-induced chloride currents more strongly than natural piperine (789% ± 72% and 883%
± 70%, respectively).[12]
Scheme 3 Synthesis of piperic acid analogues 4
Scheme 4 Synthesis of piperine analogues 5
In conclusion, we herein presented a conceptually new approach to the synthesis of
4-aryl-substituted pentadienoic acids and their amides in excellent yield and geometrical
stereoselectivity.[20]
[21]
[22]
[23]
[24]
[25]
[26] This enabled a preparation of the natural product piperine in quantitative yield
over three steps from commercially available 2-pyrone 1. Analogues can be readily synthesized through this modular and operationally simple
procedure.
