Organic Process Research & Development 2010, 14, 1457–1463
Green Progression for Synthesis of Regioselective ꢀ-Amino Alcohols and
Chemoselective Alkylated Indoles
Boningari Thirupathi, Rapelli Srinivas, Avvari N. Prasad, J. K. Prashanth Kumar, and Benjaram M. Reddy*
Inorganic and Physical Chemistry DiVision, Indian Institute of Chemical Technology, Uppal Road, Hyderabad - 500 607, India
Abstract:
soluble steroidal intravenous anaesthetics.5 Recently, a steroid
possessing a methylpiperazine nucleus was reported to inhibit
the proliferation of HL-60 or WEHI-3B cell lines and is a
promising potential new drug for the treatment of leukemia.6
The significant biological properties of A-ring amino moiety
have urged medicinal chemists to synthesize and test a great
number of novel molecules. Therefore, insertion of the amino
moiety into new positions of a steroid skeleton is an important
synthetic strategy in drug discovery.
Solid acid catalysts based on zirconia materials were investigated
for the first time as catalysts for regioselective organic synthesis
under environmentally benign and mild conditions. The novel
TiO2-ZrO2 mixed oxide catalyst led to two distinct products by
the formation of an N-C bond (ꢀ-amino alcohols) and a C-C
bond (Friedel-Crafts alkylation).
Amino propanols constitute one of the most common central
units of various protease inhibitors such as ꢀ- or γ-secretase,7
HIV protease,8 cathepsins,9 or plasmepsins.10 The scaffold (3,
Figure 1) is a typical example of the 1,3-diaminoalkan-2-ol-
based structure of inhibitors.11 An intermediate in the preparation
of ꢀ-secretase (4, Figure 1) is used in applications such as the
treatment of Alzheimer’s disease and as peptidomimetic inhibi-
tors of human ꢀ-secretase.12 A notable ꢀ-amino alcohol is
propranolol (5, Figure 1), one of the first nonselective ꢀ-blockers
developed, used extensively in the treatment of hypertension
(6, Figure 1) and as an intermediate in the synthesis of an
antitubercular drug,13 which can be obtained by the reaction of
a chlorohydrin with a nucleophile in the presence of stoichio-
metric amounts of a base or by the ring-opening of an epoxide,
1. Introduction
Green chemistry is an important challenge in the battle to
produce biologically active compounds and to replace current
organic chemical processes with more environmentally benign
alternatives. It is also an important task from an ecological point
of view.1 A great deal of interest has been devoted to the use
of aqueous media in organic transformations because water is
nontoxic, nonflammable, inexpensive, and environmentally
benign.2 Other benefits from the use of water as a medium
include replacement of environmentally unfriendly, potentially
dangerous, and expensive organic solvents, thereby reducing
the volatile organic compounds (VOCs) released into the
atmosphere.
ꢀ-Amino alcohols are known for their biological activity.
They find numerous applications as amino alcohol antibiotics
(1, Figure 1) and antibacterial drugs, which function by
specifically binding to prokaryotic 16S rRNA, causing mis-
translation and premature termination of mRNA translation. The
targeted binding site for aminoglycosides is the A-site decoding
region of prokaryotic 16S rRNA.3 Amino alcohol or amino
steroid motifs could be easily obtained through the ring-opening
of the epoxides by amines. ꢀ-Amino alcohol steroids (2, Figure
1) serve as the basis for a wide range of biologically active
natural and synthetic products.4 A series of 2ꢀ-morpholinyl
steroids have been shown to exhibit anaesthetic activity, and
some have been selected for development as potential water-
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* Corresponding author. Telephone: +91-40-27191714. Fax: +91-40-
27160921. E-mail: bmreddy@iict.res.in; mreddyb@yahoo.com.
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10.1021/op1002177 2010 American Chemical Society
Published on Web 10/05/2010
Vol. 14, No. 6, 2010 / Organic Process Research & Development
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