Journal of Synthetic Organic SYNTHESIS Chemistry REPRINT With compliments of the Author Thieme SHORT REVIEW ▌2551 short review Conhydrine: An Account of Isolation, Biological Perspectives and Synthesis l ChinmayConhydrine: A Short Review Bhat,*a Sandesh T. Bugde,b Santosh G. Tilve*b a Centre for Nano and Material Sciences, Jain Global Campus, Jakkasandara Post, Kanakapura Road, Ramanagara District, Karnataka 562 112, India b Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India Fax +91(832)6519317; Fax +91(965)7962641; E-mail: [email protected]; E-mail: [email protected] Received: 23.05.2014; Accepted after revision: 06.08.2014 Abstract: Conhydrine is a naturally occurring 2-substituted piperi- dine alkaloid from the plant Conium maculatum L that exists in four different forms and is known for its high toxicity. This article focus- es on the synthesis of conhydrine as its medicinal applications are limited due to its high toxicity. The various asymmetric methods de- veloped for the synthesis of conhydrine are classified based on the methodology: the chiral pool method, the chiral auixiliary method, and asymmetric catalysis. A brief overview of the complete synthet- ic coverage of conhydrine (1948–2014) in different isomeric forms is given. Dr. Chinmay Bhat was born in Sirsi, Karnataka, India. He moved to 1 Introduction the Department of Chemistry, Goa University in 2006 for his M.Sc. 2 Isolation and Biological Perspectives in chemistry. After qualifying CSIR-NET-JRF in 2007, he joined the 3 Synthesis group of Prof. Santosh Tilve in 2008 in the doctoral programme and 3.1 Chiral Pool Methods worked on the asymmetric synthesis of natural products. After obtain- 3.2 From Achiral Starting Material ing his Ph.D. in 2013, he joined IISER Mohali in the postdoctoral pro- 3.3 Chiral Auxiliary Mediated Synthesis gramme. At present he works in the Centre for Nano and Material 3.4 Catalysis Approach (Organo and Metal Catalysis) Science (CNMS), Jain University, Bangalore in the group of Dr. Amit 4 Conclusion and Outlook Kumar. His research interests include asymmetric synthesis, synthe- sis of heterocycles, inorganic metal complexes, and nano chemistry. Key words: conhydrine, organocatalysis, enantioselective, synthe- Mr. Sandesh Bugde was born in 1986, in Goa, India. After obtaining sis, piperidine alkaloid his bachelor’s degree at St. Xavier’s college, Goa in 2007, he moved to Goa University for his master’s degree and completed this in 2009 in organic chemistry. He qualified UGC-NET-JRF and joined the group of Prof. Santosh G. Tilve. Currently in the doctoral programme, 1 Introduction he is studying asymmetric organocatalysis and natural product syn- thesis. 1,2-Amino alcohols are ubiquitous among various natural Prof. Santosh G. Tilve was born in 1959 at Usgao, Goa, India and received his B.Sc. and M.Sc. degrees from Bombay University. He products and they have attracted considerable synthetic This is a copy of the author's personal reprint obtained his Ph.D. in 1989 from Pune University under the supervi- l interest due to their interesting medicinal and pharmaco- l 1,2 sion of Prof. R. S. Mali. After working in the chemical industry for six logical applications. Many of these compounds are cy- months, he began his academic career as a lecturer at Goa University. clic pyrrolidine and piperidine ring structures with a 1- He was promoted to associate professor in 1999 and to full professor hydroxyalkyl side chain at the 2-position, and these have in 2007. He has also been a visiting fellow with Prof. I. Blair at the wide medicinal relevance for the treatment of various dis- Pennsylvania University (USA) in 2000–2002. At present, he is head eases.3 The piperidine nucleus with a hydroxylated side of the Chemistry Department, Goa University. His current research interests include asymmetric synthesis, heterocycles, green chemis- chain has special synthetic interest due to its anti-HIV, an- try, domino reactions, and nano composites as catalyst. tiviral, and antitumor activity.2,4 Moreover, these mole- cules are basically small organic compounds that have facile synthetic approaches and, hence, they are highly beneficial from industrial and practical points of view. Most of these appendages are derived from easily avail- Conhydrine is one such alkaloid comprising of a simple able starting materials, and various unnatural analogues of piperidine unit tethered to 1-hydroxyalkyl side chain that such entities have been synthesized and in clinical trials in finds special synthetic interest due to its unique biological recent years. The design and synthesis of such natural and properties and vicinal chiral hydroxy and amino function- unnatural components has been a formidable challenge alities. for chemists due to difficulties in isolation, global scarci- ty, and high pharmacological demand. 2 Isolation and Biological Perspectives SYNTHESIS 2014, 46, 2551–2573 Conhydrine is a piperidine alkaloid from the hemlock Advanced online publication: 11.09.20140039-78811437-210X DOI: 10.1055/s-0034-1379023; Art ID: ss-2014-m0315-sr family first isolated by Wertheim from the leaves and © Georg Thieme Verlag Stuttgart · New York 2552 C. Bhat et al. SHORT REVIEW HO l N N N N H H H Me coniine pseudoconhydrine N-methylconiine 2-pentylpiperidine HO H N N N N H H OH O Me conhydrinone coniceine N-methylpseudoconhydrine conhydrine Figure 1 Alkaloids isolated from Conium maculatum L H N HO COOEt O H O OH HO COOEt HO H HO OH TBSO metal- N OH H mediated chiral pool N Ts organo- catalysis method chiral pool chiral pool catalysis OH method TBSO OH N metal- method N mediated OH achiral starting H2N COOH OMe chiral pool H catalysis achiral starting material method OTBS material SAE SAE OMe chiral auxiliary chiral auxiliary TIPS method H chiral pool method H N method N chiral pool H O H N OH O H OH method OTBS O CHO achiral starting (+)-α-conhydrine chiral auxiliary (–)-α-conhydrine material chiral pool method O method achiral starting chiral pool COOMe organo- material H N method chiral pool catalysis SAD O OH achiral O method (Henry chiral pool chiral pool starting reaction) method CHO method chiral pool material SAD method NO2 SAD N COOH Boc NH HOOC COOH O OH NH2 N COOH H O H N Boc O This is a copy of the author's personal reprint This is a copy of the author's personal reprint l l Ph Ph O N D-mannitol NC N O Me OH O O O O CHO N chiral pool O N chiral pool H method CHO H method chiral pool chiral pool method H method metal- metal- N O mediated mediated D-mannitol chiral pool O catalysis catalysis method chiral pool BnO OTBS chiral pool H method OH H method O chiral auxiliary N N H O H OH method OH chiral pool OBnOH (+)-β-conhydrine method (–)-β-conhydrine O chiral auxiliary O chiral pool D-mannitol method method chiral pool CHO method MeOOC achiral starting SAD chiral material auxiliary chiral pool method method Cl N COOH HOOC H COOH NH2 OMe TIPS N O O Boc N N N OMe Boc Me Figure 2 The different methods of chiral induction for conhydrine Synthesis 2014, 46, 2551–2573 © Georg Thieme Verlag Stuttgart · New York SHORT REVIEW Conhydrine: A Short Review 2553 seeds of plant Conium maculatum L in 1856;5 its structure auxiliary mediated synthesis, and using the catalysis ap- was elucidated in 1933.6 Conium maculatum L is a highly proach (organo and metal catalysis). l poisonous hemlock that belongs to the family of Apiace- ae, which is widespread throughout the world, including 3.1 Chiral Pool Methods Australia, New Zealand, North America, and different parts of Asia. In ancient Greece, an extract of hemlock This method mainly involves multistep synthesis using was used for the execution of criminals; the Greek philos- amino acids and sugar-derived compounds like mannitol opher Socrates was condemned to death in 399 BC and as the starting chiral pool material. After the first synthesis drank hemlock. The seeds of Conium maculatum are rich of racemic conhydrine by Galinovsky and Mulley using in alkaloids and different piperidine-based alkaloids have the high pressure hydrogenation of a pyridine derivative,9 been isolated and identified (Figure 1).7 Among them its synthesis remained untouched for a period of 37 years. coniine and γ-coniceine are the most abundant and they Husson and co-workers undertook the first enantiospecif- are hemlocks chronic and acute toxicity is attributed to ic synthesis of (+)-β-conhydrine by illustrating the poten- them. The consumption of this plant affects the central tial application of chiral synthon 1 (Scheme 1).10 nervous system (CNS), causes depression, paralysis, hy- 7 The generation of the anion next to the nitrogen atom fol- perventilation, coma, and even death. lowed by alkylation using propionaldehyde delivered the Clinical studies show that the presence of an aliphatic side single isomer 2. Subsequent complete reduction of inter- chain in the 2-position consisting of at least three carbons mediate 2 produced (+)-β-conhydrine. is responsible for the enhanced toxicity of these alkaloids. The copper-catalyzed three-component reaction of These alkaloids have been screened for various other bio- alkyne–dibenzylamine–α-oxyaldehyde permit the con- logical applications, but their medicinal application is lim- struction of α-oxyamines with very high diastereoselec- ited due to closeness of their therapeutic and poisonous tivity. The methodology was initially used by Haung et al. values. However, hemlock has found useful medical ap- for the construction of syn-α-oxyamines11 and further ex- plications in homeopathic medicine with the name coni- tended to the synthesis of 1,2-amino alcohol (+)-β-conhy- um, and it is best utilized for the treatment of various 12 8 drine by Talukdar and co-workers (Scheme 2).