Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke Non-Aromatic Heterocyclic Systems The chemistry of small, strained heterocyclic molecules will be discussed. The course will cover 3- and 4-membered ring systems containing one or more heteroatoms. Synthetic strategies will be outlined for each compound class and illustrated with selected examples from the literature. Examples will include key routes into beta-lactams and multi-ring heterocyclic systems. 1. Hypertensive Molecules (Strain) 2. 3-Membered rings containing one heteroatom 2.1. Epoxides 2.1.1. Preparation (i) Olefin and Peracid (ii) Sulphur Ylides (iii) Cyclisation of Halogenohydrins etc. (iv) Sharpless Enantioselective Epoxidation of Allylic Alcohols (v) Jacobsen-Katjuki Epoxidation 2.2. Aziridines 2.2.1. Preparation (i) (1a) From epoxides (ii) (1b) From azido mesylates (iii) From olefins and iodine isocyanate (iv) Via an azide 2.3. Thioepoxides (Thiiranes) 2.3.1. Preparation (i) Halohydrin Method (ii) From Sulphur Ylides (iii) From epoxides 2.4. Reactions of Epoxides and Aziridines (i) Ring opening to relieve strain (ii) Ring expansion reactions (iii) Intramolecular cyclisation via ring opening 2.5. 3-Membered Rings containing one heteroatom plus unsaturation 2.6. 3-Membered Rings containing more than one heteroatom 1 Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke 3. 4-Membered Rings Containing One Heteroatom 3.1. Preparation (i) Halohydrin Method (ii) Paterno-Büchi Reaction 3.1.1. 4-Membered Rings containing one heteroatom plus unsaturation 3.1.2. 4-Membered Rings containing more than one heteroatom 3.2. ß-Lactam Antibiotics 3.2.1. Synthesis of ß-Lactam (1) Cyclisation of ß-amino acids (2) π2s + π2a cycloaddition (i) ketene plus imine (ii) isocyanates (iii) haloamide cyclisation (iv) ring expansion reaction (v) ring contraction reaction (Wolff-Rearrangement) 3.2.2. Conversion of Penicillins into Cephalosporins (i) Oxidation plus 2,3-sigmatropic shift (ii) Sulfoxide stereochemistry (iii) Stability towards base (iv) Stability towards acid 4. Supported Reagents (if time allows) (i) Epoxidation catalysts 5. ß-Lactam Total Syntheses (if time allows) (i) Selected examples 2 Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke Course Summary (i) To introduce general aspects of reactivity associated with small non-aromatic heterocycles (ii) To present synthetic strategies and appropriate reagents for the synthesis of 3-membered ring systems (iii) To present synthetic strategies and appropriate reagents for the synthesis of 4-membered ring systems (iv) To provide examples which demonstrate the reactivity of 3- and 4- membered non-aromatic rings containing at least one heteroatom (v) To introduce and discuss key elements of the synthesis and reactivity of beta lactams (vi) To exemplify transformations of beta-lactams to cephalosporins (vii) To have been introduced to examples in which synthesis and reactivity of small ring heterocycles is aided through the use polymer supports Aim of the course After this course you are expected: (iv) To explain with examples the special relevance of ring strain in the synthesis and reactivity of small non-aromatic heterocycles. (v) To identify and predict syntheses in which steric and stereoelectronic effects allow the stereoselective synthesis of 3- membered rings as exemplified in cases involving a steroid skeleton. (vi) To apply at least 3 synthetic routes (incl. mechanisms)and the corresponding reagents to the synthesis of nitrogen, oxygen and sulphur 3- and 4-membered non-aromatic heterocycles. (vii) To apply at least 3 synthetic routes (incl. mechanisms) and the corresponding reagents to the synthesis of beta lactams (viii) To illustrate three synthetic approaches used in the synthesis of 3- and 4- membered non-aromatic heterocycles containing two or more N, O, or S heteroatoms. (ix) To discuss possible advantages of solid-phase chemistry in the synthesis of strained non-aromatic heterocycles. 3 Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke Non-Aromatic Heterocyclic Systems (a) Small Ring Heterocycles O H H (b) Alkaloids n-C10H21 (CH2)4-CHCMe2 disparlure sex attractant for gypsy moth (c) ß-Lactams 1. Hypertensive Molecules (Strain) 2. 3-Membered rings containing one heteroatom Nomenclature 3 3 4 4 5 5 (tri) (tri) (tetra) (tetra) (tetra) (tetra) ir-ane (-) ir-ene (=) et-ane (-) et ene(=) ol-ane (-) ol ene (=) ir-dine (- + ir-ine (= + et-idine (- + et ene(= + ol-idine (- + ol ene(= + N) N) N) N) N) N) O O NH NH oxirane oxirene azetidine azetene H N S thietane aziridine S O O thiirane dioxetane az = ox = oxygen thi = sulphur nitrogen 4 Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke 2.1. Epoxides • most common • easy to prepare • naturally occuring • very useful synthetic intermediates 2.1.1. Preparation (1) Olefin and Peracid O H O O O O R HO R Mechanism m-chloroperbenzoic acid (mCPBA) is the most commonly used since it is: R H R H mCPBA O (1 equiv.) H R H R • commercially available • crystalline • easy to purify • stable when pure Since epoxides are acid sensitive the reaction may require the addition of a buffer to control pH. Solid NaHCO is often used (alternatively 3 PhCN + H O ) 2 2 Since the reaction is an electrophilic addition the most electron rich olefins react first (subject to steric factors). 5 Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke The order of reactivity R R R R R R R R Ph R R R R This of course results from the inductive effect of the alkyl groups. Example: Limonene O mCPBA mCPBA O (1 equiv.) (1 equiv.) Note ! The reaction is stereospecific. The olefin geometry is always preserved. The peracid approaches the olefin from the less hindered face (STERIC APPROACH CONTROL) This is best illustrated by an example from steroid chemistry: 19 19 H H 14 14 10 10 O major isomer The angular 19ß methyl group shields the top face of the steroid molecule and directs the peracid to the α face. 6 Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke 21 18 20 26 19 17 25 Cholest-5-ene H R 14 27 10 H Attack from the more hindered face can result if NEIGHBOURING GROUP PARTICIPATION is possible: In this case the hydroxyl group is an anchor and forms a hydrogen bond to the incoming peracid! OAc OAc OH OH RCO H RCO H 3 3 O O Electron deficient olefins can be converted into epoxides using basic hydrogen peroxide. Once again the reagent approaches from the less hindered α face 7 Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke HOO- OH O H H H O / OH- 2 2 O O H H O H O H (2) Sulphur Ylides Both dimethyl sulfide and dimethylsulphoxide react with iodide to give salts which on reaction with a strong base give sulphur ylides. Preparation The base used is “dimsyl sodium” prepared by the reaction of DMSO with NaH I Me Me S Me I S Me Me Me I Me Me S O Me I Me S O Me Me 8 Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke H 2 H3CS CH NaH H3CS CH H2 O O Na I Me Me S Me S CH NaI + DMSO 2 Me Me I Me Me Me S O Me S O NaI + DMSO Me H C 2 Both sulphur ylides react with ketones to give epoxides: Mechanism (compare to phosphorus ylides; Wittig Reaction) O O H H The two reagents differ in their behaviour towards α,ß-usaturated ketones Me 2 S O O SMe O O H C SMe 2 2 2 Me S 2 ring energy sulphurane 9 Small Ring Non-aromatic Heterocycles 2001 – Dr. J.H.G. Steinke Me O O S Me O Me O CH S CH 2 2 Me softer reagent 1,4 addition (3) Cyclisation of Halogenohydrins etc. H S 2 A A N A = O, NH, NR, S 1 2 X Inversion at C2 X = Br, Cl, I, OTos This reaction can be used to generate the opposite stereochemistry from peracids BrOH OH Et3N Br Br O OH HO ClOH OH Et3N Cl O Cl Note (i) The bromonium cation approaches from the less hindered α face. (ii) The hydroxide anion attacks to give the trans diaxial product. This choice ensures maximum orbital overlap in the transition state for bromonium ion opening, i.e. STEREOELECTRONIC CONTROL. 10