The important requirement for approval of a
new drug, in case it happens to be chiral, that both enantiomers of the drug be
studied in detail [1], have focused the attention of synthetic organic and
medicinal chemists on the development of new methods for catalytic asymmetric
synthesis especially of relevant saturated N-heterocycles. Despite the success
of chirally modified transition-metal catalysts in asymmetric synthesis, in the
form of the Nobel Prize in Chemistry in 2001, the field of asymmetric organic
synthesis has since then been dominated by organocatalysts due to their ability
to catalyze a variety of fundamentally important transformations in medicinal
chemistry and therefore chemical biology. One example is the Staudinger
synthesis of β-lactams representing one class of saturated N-heterocycles and
continuing to provide unique opportunities for the discovery of new derivatives
with novel pharmacological profiles [2,3]. Specifically, β-lactams have
recently been found to have potential as the basis for treatments for
neurological disorders including amyotrophic lateral sclerosis (ALS), also
known as Lou Gehrig’s disease [4]. Although significant progress has been made
in asymmetric organocatalytic Staudinger synthesis of β-lactams since the
inaugural and pioneering investigations by Lectka and coworkers around the turn
of the century [5,6], the same did not hold true regarding the development of a
novel Gilman-Speeter process for the catalytic enantioselective synthesis of
β-lactams [7]. Efforts directed at this latter goal are ongoing in this
Laboratory.
Since piperazine
derivatives have been reported to elicit a broad spectrum of pharmacological
activities including antidepressant, anticancer, anti-helminthic, anti-bacterial,
antifungal, anti-mycobacterial, anti-malarial, anti-tuberculant, anti-convulsant
[8] and anti-AIDS [17]; one can easily comprehend that the sky will be the
limit, as far as novel drug development is concerned, once this catalytic
enantioselective process will be fully developed [18].
Finally, aziridines
are structurally fascinating, pharmaceutically important, and finding
applications in synthetic organic and medicinal chemistry [19-20]. Thus, they
can be readily converted into a variety of nitrogen-containing compounds due to
the inherent reactivity of the constrained three-membered ring present in biologically
active natural products such as the azinomycins [21] and the mitomycins [22].
Novel catalytic enantioselective synthesis of aziridines as well as their
employment in piperazine syntheses is under active investigation in this
Laboratory [23-25].
1.
Stinson SC
(2001) Chiral Chemistry. Chem Eng News 79: 45-56.
2.
Galletti P,
Giacomini D (2011) Monocyclic β-lactams: New structures for new biological
activities. Curr Med Chem 18: 4265-4283.
3.
Magriotis PA
(2014) Progress in asymmetric organocatalytic synthesis of β‐lactams. Eur J Org
Chem 2014: 2647-2657.
4.
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, et al. (2005)
Beta-lactam antibiotics offer neuroprotection by increasing glutamate
transporter expression. Nature 433: 73-77.
5.
Lectka T, Taggi
AE, Hafez AM, Wack H, Young B, et al. (2000) Catalytic, asymmetric synthesis of
β-lactams. J Am Chem Soc 122: 7831-7832.
6.
Lectka T, France
S, Weatherwax A, Taggi AE (2004) Advances in the catalytic, asymmetric
synthesis of β-lactams. Acc Chem Res 37: 592-600.
7.
Magriotis PA (2001)
Recent progress in the enantioselective synthesis of beta-lactams: development
of the first catalytic approaches. Angew Chem Int Ed Engl 40: 4377-4379.
8.
Alam M, Shaquiquzzaman
M, Verma G, Marella A, Akhter M, et al. (2015) Piperazine scaffold: A
remarkable tool in generation of diverse pharmacological agents. Eur J Med Chem
102: 487-529.
9.
Ye Z, Gettys KE,
Dai M (2016) Opportunities and challenges for direct C–H functionalization of
piperazines. Beilstein J Org Chem 12: 702-715.
10.
Vitaku E, Smith
DT, Njardarson JT (2014) Analysis of the structural diversity, substitution
patterns, and frequency of nitrogen heterocycles among U.S. FDA approved
pharmaceuticals. J Med Chem 57: 10257-10274.
11.
Nelson A, James
T, MacLellan P, Burslem GM, Simpson I, et al. (2014) A modular lead-oriented
synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds. Org
Biomol Chem 12: 2584-2591.
12.
Gettys KE, Ye Z,
Dai M (2017) Recent advances in piperazine synthesis. Synthesis 49: 2589-2604.
13.
Vo CVT, Luescher
MU, Bode JW (2014) SnAP reagents for the one-step synthesis of medium-ring
saturated N-heterocycles from aldehydes. Nat Chem 6: 310-314.
14.
Rinehart KL
(2000) Antitumor compounds from tunicates. Med Drug Rev 20: 1-27.
15.
Nikolaou KC,
Montagnon T (2008) Molecules that changed the World. Wiley-VCH: Weinheim, pp:
241-250.
16.
Magriotis PA (2017)
Synthetic approaches to the stereochemically complex antitumor drug Ecteinascidin-743:
A marine natural product by the name Yondelis® or Trabectidin. In: Stereochemistry
and Global Connectivity: The Legacy of Ernest L Eliel.; Cheng et al. Ed. ACS
Symposium Series, American Chemical Society: Washington, DC, 2: 61-78.
17.
Nathans R, Cao H,
Sharova N, Ali A, Sharkey M, et al. (2008) Small-molecule inhibition of HIV-1
Vif. Nat Biotechnol 26: 1187-1192.
18.
Rathi AK, Syed R,
Shin HS, Patel RV (2016) Piperazine derivatives for therapeutic use: a patent
review (2010-present). Expert Opin Ther Pat 26: 777-797.
19.
Jacobsen EN (1999) Asymmetric aziridination, In:
Comprehensive Asymmetric Catalysis: Jacobsen EN, Pfaltz A, Yamamoto H (Eds).
Springer: New York, Chapter 17.
20.
McCuil W, Davis
FA (2000) Recent synthetic applications of chiral aziridines. Synthesis 2000:
1347-1365.
21.
Hodgkinson TJ,
Shipman M (2001) Chemical synthesis and mode of action of the azinomycins.
Tetrahedron 57: 4467-4488.
22.
Kasai M, Kono M
(1992) Studies on the chemistry of mitomycins. Synlett 1992: 778-790.
23.
Osborn HM, Sweeny
J (1997) The asymmetric synthesis of aziridines. Tetrahedron Asymmetry 8:
1693-1715.
24.
Tanner D (1994)
Chiral aziridines - Their synthesis and use in stereoselective transformations.
Angew Chem Int. Ed 33: 599-619.
25.
Pellissier H
(2014) Recent developments in asymmetric aziridination. Adv Synth Catal 356: 1899-1935.
