Organic Synthesis II: Selectivity & Control 8 lectures, TT 2011

Transcription

1 rganic Synthesis II: Selectivity & Control 8 lectures, TT 2011 andout 1 andouts will be available at: Dr Martin Smith ffice: CL 1 st floor Telephone: (2) [email protected]

2 ! rganic Synthesis II: Selectivity & Control. andout 1! Selectivity and Control! Definitions: Chemo- and egio-selectivity! ecap of selective reactions: reductive amination 1,4 vs 1,2 addition Electrophilic aromatic substitution ucleophilic aromatic substitution! Stereoselectivity: definitions and recap! Selectivity and disconnection! The finished product: total synthesis of (+-) methyl homosecodaphniphyllate! Chemo- and egio-selectivity in oxidation of alcohols! xidation as a common functional group interconversion! xidation of alcohols: Cr(VI) oxidants! Activated DMS oxidants: Swern, Moffatt and Parikh-Doering procedures! Application to the generation of bis-aldehydes : (+-) methyl homosecodaphniphyllate! ypervalent iodine: Dess-Martin periodinane! Mn 2 and ppenauer xidations! Catalytic xidants: TPAP and TEMP! Chemo- and egio-selectivity in reduction of carbonyl derivatives! Selectivity in DIBAL reductions: stopping reactions half-way! Selectivity in (general) hydride reductions! Using amides as electrophiles: Weinreb amides and examples; the problem of C-acylation! An aside: acylation at carbon - kinetic and thermodynamic control! Kinetic control: use of methylcyanoformate! Selectivity in hydride reducing agents: Lithium Aluminium ydride Lithium Borohydride Borane (and related complexes) ab 4 ; modified borohydrides & the Luche reduction! rganic Synthesis II: Selectivity & Control. andout 1!Stereoselectivity in hydride reductions: 1,2 stereoinduction (Felkin models and variants) 1,3 stereoinduction (1,3-syn and 1,3-anti diols Additions to cyclohexanones (torsional control) Enantioselectivity in hydride reduction A catalytic asymmetric hydride reduction! ecap: reduction of alkynes! Dissolving metal reductions: the Birch reduction! Dissolving metal reductions of!,"-unsaturated ketones (and esters)! ydrogenation! xidation reactions involving alkenes! ecap: dihydroxylation and allylic alcohol reactions! smium-mediated hydroxylation! Allylic alcohol mediated alkene functionalization! Titanium mediated epoxidation: the Sharpless Epoxidation! The Wacker oxidation! Epoxidation vs Baeyer-Villiger! ucleophilic epoxidation of electron deficient alkenes! Books & other resources: 1. xidation & eduction in rganic Synthesis (T. J. Donohoe, UP) 2. rganic Chemistry (ayden, Greene, Wothers & Warren, UP) 3. Professor Andrew Myers website (arvard) Molecular rbitals and rganic Chemical eactions (I. Fleming, Wiley, 2nd Edn.) chanisms for many oxidation reactions (even well-known ones) are significantly more complex than drawn throughout this course (and in many cases are not known or understood). Some are based on factual mechanistic data; some should be treated more as a mnemonic than explanation.

3 ! What is Selectivity & Control? (and why do we need it?)! Chemo-selectivity Selectivity between two functional groups with nucleophiles or reducing agents Which group reacts?! egio-selectivity Selectivity between different aspects of the same functional group reaction with peroxy-acids Where does it react? direct or conjugate addition with nucleophiles or reducing agents X ortho-, para- or metawith electrophiles and selectivity between o- and p-! Chemoselectivity: reactions you have already seen! Functional groups have different kinds of reactivity ab 4 2 Pd/C C=C weaker #- bond than C= use nucleophilic reagent ketoneelectrophilic alkene- not electrophilic use catalytic hydrogenation! Functional groups have similar reactivity ab 4 use selective reagent ketone- more electrophilic ester- less electrophilic protect more reactive group

4 ! Chemoselectivity: reactions you have already seen! Functional group may react twice (is the product more reactive than the SM?) control? Br Br 2 2 Chemoselectivity needed between Starting Material and Product 2! Solution: use reductive amination (more on reduction later) ab(c) 3 or 2, Pd/C 2 Chemoselectivity: ab 3 C only reduces imine, not aldehyde starting material [ab 3 C is a less nucleophilic source of hydride than ab 4 due to the electron-withdrawing nature of the cyanide ligand. As a consequence it will generally not reduce aldehydes and ketones at neutral p]! egioselectivity: reactions you have already seen! Conjugate and Direct Addition to Enones kinetic product Direct u Conjugate [Michael] u thermodynamic product u hard nucleophiles u the enone is electrophilic at two different sites soft nucleophiles! Electrophilic Aromatic substitution X and/or X E E X E X E E choose 'ortho, para-'directing group X: Alk,, F etc choose 'meta- 'directing group X C, 2 etc

5 ! What is Selectivity & Control? (and why do we need it?)! Stereo-selectivity Selectivity between two (or more!) possible stereochemical outcomes Examples you ve already seen: (I) reduction of cyclohexanones (see course from Dr E. Anderson, T 2011) " - " Which face is attacked? t Bu " - " 'ydride' t Bu equatorial attack t Bu axial attack Examples you ve already seen: (II) Additions to chiral aldehydes & ketones (Felkin-Anh model) LiB(s-Bu) 3 [bulky hydride] 1. eactive conformation 2. Bürgi-Dunitz trajectory 3. Attack away from L and over S 4. TS is SM-like u M S L! Selectivity defines strategy in disconnection! eminder of basic principles: where and when to disconnect? (i) branch points (ii) heteroatoms (iii) functional groups (iv) simplifying transformations (v) the order of events (see 1st year course from Prof Gouverneur)! Disconnections that require selectivity: simple aromatic derivatives 2 2 C- Esterification 2 2 directs orthoand para- for nitration Dinocap - fungicide C- Friedel Crafts (issues?) C-C directs orthofor C-C bond formation itration 2 2 para- position blocked rder is important (the alternative C- disconnection prior to the C-C disconnection would not lead to appropriate selectivity)

6 ! Selectivity defines strategy in disconnection! The 1,2 difunctional disconnection 2 S! Two group disconnections: Fluconazole 2 1 F C- 1,2 di-x 2 sulfur ylid F 1 F F F Deactivating: only monoacylation F is o-, pdirecting F X- least hindered end attacked F + 1,2 di-x 2 X F C-C Friedel Crafts C- 1,2 di-x F F! Complex molecule synthesis! We need to exert control to be able to construct complex molecules efficiently! Selectivity - as defined by disconnection - offers an opportunity to do this C2 thyl homosecodaphniphyllate! Isolated from the bark of Daphiphyllum macropodum! Structure confirmed by X-ray crystallography! Complex architecture contains five fused rings

7 ! Selectivity defines strategy in disconnection! Starting at the end: the same disconnections work regardless of complexity 2 C Bn Bn Bn 1 FGI (ox) 2 x C-C redrawn 1,1 C-X (Prins) Diels Alder thyl homosecodaphniphyllate 2 x C- imine formation Bn C-C (1,4 addition) Bn FGI (ox) Bn 2 C C-C (enolate alkyation) 2 C I =! Synthesis of (+/-) methyl homosecodaphniphyllate (I)! An elegant, selective and controlled approach: Bn Bn 1. LDA Generate lithium enolate Li Amide gives predominantly Z enolate egioselective 1,4 addition Li Bn I S 2 alkylation [on carbon, not oxygen] Bn 1. K, 95 C 2. + Amide hydrolysis and lactonization Bn DIBAL Chemoselective reduction (ester vs amide) 2 C Bn eathcock et al., J. Am. Chem. Soc., 1988, 10, 8734

8 ! Synthesis of (+/-) methyl homosecodaphniphyllate (II)! An elegant, selective and controlled approach: Bn Bn Bn 1.LiAl 4 Chemoselective reduction of lactone to diol (C) 2, DMS Et 3, C 2 2 Swern xidation Chemoselective oxidation to bis-aldehyde 3 Imine formation Bn Ac Bn 3 Bn -protonation Enamine formation! Synthesis of (+/-) methyl homosecodaphniphyllate (III)! An elegant, selective and controlled approach: Bn Bn!2s redrawn as: Ac, 25 C egioselective and Chemoselective intramolecular Diels Alder reaction!4s!4s +!2s Bn Bn Bn - + Ac, 75 C Prins reaction Electron rich alkene traps electron poor iminium cation (to give a tertiary carbocation)

9 ! Synthesis of (+/-) methyl homosecodaphniphyllate (IV)! Final steps: Bn 2, Pd-C 1. Cr 3, 2 S 4, 2, Acetone 2., + C 2 emoves benzyl protecting group and reduces alkene Chemoselective oxidation to acid; Esterification! A series of simple but selective steps! Chemo-selectivity, regio-selectivity (and stereoselectivity) are exploited throughout the synthesis to great effect.! verall: nine steps - a spectacularly elegant and efficient approach We will cover the details of many of these steps throughout the course! xidation is a very common synthetic transformation! Many functional group transformations are redox reactions electrophilic attack bromonium cation Br Br Br S 2 inversion Br Enters as Br + dibromide product Leaves as Br - Br Br Base -2Br elimination 2 electron oxidation xidation = Electrophilic attack = emoval of electrons So functional groups that react readily with electrophiles are easily oxidized This includes: alcohols, alkenes, amines and phenols! Common 2-electron transformations: -2e -2e -2e -2e 2 alcohol aldehyde acid amine imine nitrile

10 ! Selectivity in oxidation of alcohols! Selective oxidation is a challenging transformation [ox] [ox] primary alcohol aldehyde hydrate acid Generally use Cr(VI), Mn(VII), high oxidation state Sulfur or Iodine Problems: aldehydes are reactive so over-oxidation can be a problem - avoid water!! eagents you ve seen: Cr(VI) oxidation to generate ketones (idealized mech.) Cr(VI) Cr(IV) Cr Cr DS Chromate Ester! Selectivity: variants of chromium oxidants! Common Cr reagents: 2 Cr 2 7 Jones reagent Chromic acid in 2 S 4 Usually acetone co-solvent xidizes 1 alcohols to carboxylic acids; 2 alcohols to ketones. ot suitable for acid sensitive substrates Bn Bn Jones reagent C 2 TBS C 2 C 2 Acid-mediated desilylation and subsequent oxidation TBS = t butyldimethylsilyl Bn = benzyl 2 Cr Pyridinium dichromate (PDC) PDC in dry DCM works well for 1 alcohol to aldehyde oxidation. In DMF oxidation to acids occurs Cr 3 - Pyridinium chlorochromate (PCC) PCC will oxidize 2 alcohols to ketones and 1 alcohols to aldehydes (if kept dry!) Selective oxidation can be problematic with these reagents & stoichiometric chromium can create waste disposal problems - so many alternatives.

11 ! Selectivity in oxidation of alcohols! The Swern oxidation: (i) activation of DMS S DMS xalyl chloride -78 C DCM Chlorosulfonium - salt S + C + C Chlorosulfonium salt is effectively the oxidant - unstable above approx -60 C! The Swern oxidation: (ii) activation of the alcohol S - S Et 3 S + 2 S primary alcohol alkoxysulfonium salt alkoxysulfonium ylide aldehyde 1. Effective for primary and secondary alcohols 2. Amine base is necessary to facilitate breakdown of alkoxysulfonium salt This is an excellent method for the selective oxidation of primary alcohols to aldehydes! Selectivity in oxidation of alcohols! The Swern oxidation: (i) activation of DMS S DMS xalyl chloride -78 C DCM Chlorosulfonium - salt S + C + C Chlorosulfonium salt is effectively the oxidant - unstable above approx -60 C! The Swern oxidation: (ii) activation of the alcohol S - S Et 3 S + 2 S primary alcohol alkoxysulfonium salt alkoxysulfonium ylide aldehyde 1. Effective for primary and secondary alcohols 2. Amine base is necessary to facilitate breakdown of alkoxysulfonium salt This is an excellent method for the selective oxidation of primary alcohols to aldehydes

12 C! Swern oxidation: methyl homosecodaphniphyllate! evisit complex example: the order of addition is important Key: never unmask aldehyde in the presence of reactive functional groups Bn (C) 2, DMS, C 2 2 S Bn then add Et 3 Bn -78 C S bis-alkoxysulfonium salt mono-oxidation [generates mono-aldehyde] in situ Bn hemiacetal formation Bn further oxidation Bn There is no control over which alcohol is oxidised first in the lower route.! Alcohol oxidation: other DMS-based reagents! Parikh-Doering oxidation (S 3.pyridine is the DMS activator) S S TBS S 3. py, Et 3 C 2 2 /DMS, rt S S TBS S 3.pyr is a crystalline solid Mild and scaleable oxidation Selective for 1 alcohol ^ aldehyde o diol cleavage! Pfitzer-Moffat oxidation (DCC is the DMS activator) t Bu DMS, DCC +, pyridine t Bu Possible side reactions: Pummerer rearrangement, and acid-induced problems for sensitive substrates DCC = Dicylclohexylcarbodiimide [the dicylohexylurea biproduct of this reaction can be difficult to remove from the reaction mixture] chanisms are essentially the same as the Swern, but with the electrophilic DMS activator being S 3 or DCC

13 ! Dess-Martin Periodinane ( DMP )! ypervalent iodine oxidant: mild, reliable and works at T (stylized mech.) Ac Ac I Ac eq DMP DCM, T 2 Ac I Ac biproduct can be buffered for very sensitve substrates! Examples (often used for complex, highly functionalized materials) Ac I 2 TBS I 1.5 eq DMP DCM, T TBS I DMP T Selective for oxidation of 1 alcohols to aldehydes with no overoxidation! Dess-Martin Periodinane ( DMP )! chanistically, the first step is ligand exchange so we would expect to be able to kinetically discriminate between primary and secondary alcohols: TBS TBS TBS TBS DMP DCM, T TBS TBS TBS TBS 1 alcohol oxidized preferentially; 2 alcohol left untouched! Allylic and benzylic alcohols oxidized faster (but can & will oxidize 2 alcohols) DMP DCM, T 2 allylic alcohol oxidized faster than normal 2 alcohol Limitations: can cleave diols (like periodate, another hypervalent iodine oxidant)

14 ! Mn 2 : a selective oxidant for allylic and benzylic alcohols! Selective for allylic and benzylic alcohols (will not usually oxidize 2 alcohols) Mn 2 DCM Allylic alcohol oxidized selectively! Selectivity is probably a consequence of a radical mechanism Mn Mn(IV) Mn(IV) Mn(III) Mn(II) Mn Mn Mn allylic/benzylic alcohol Manganate ester aldehyde/ketone ydrogen abstraction is faster for allylic/benzylic alcohols (the radical that is produced is delocalized and hence more stable)! Mn 2 : a selective oxidant for allylic and benzylic alcohols! Selective for allylic and benzylic alcohols (will not usually oxidize 2 alcohols) Mn 2 Bu 3 Sn C 2 2 Bu 3 Sn Mild conditions; can retain vinyl stannane group! The aldehyde products can be used in-situ with other reagents (Mn 2 is v. mild) xidant (Mn 2 ) compatible with reductant (ab 4 ) in same vessel Mn 2, C 2 2 ab 4, 4Å sieves amine [red] then methanol aldehyde formed in-situ, condenses with amine to form intermediate imine ab 4 reduction of imine faster in polar protic solvent () Mn 2 is a heterogeneous oxidant: workup is generally just filtration

15 ! A Catalytic xidant: Tetra--Propyl Ammonium Perruthenate TPAP! u(vii) with organic-soluble counterion is a selective oxidant and can be used catalytically with a co-oxidant (mechanistically complex!) u u(vi): active u u(vii) Pr Pr Pr Pr +2e u u(iv): inactive 2 1 /2 alcohol Co-oxidant M disproportionation u u(v) 2 Aldehyde/ketone Selective for oxidation of 1 alcohols to aldehydes with no overoxidation! A Catalytic xidant: Tetra--Propyl Ammonium Perruthenate TPAP! chanism: consistent with ruthenate ester (though complex & unproven!) u(vii) u(vii) u(v) 2 u 2 u 2 u 1 /2 alcohol uthenate ester aldehyde/ketone! Examples (4A sieves remove water to prevent hydration and overoxidation) TBS TPAP (10 mol%) M, DCM 4Å sieves TBS TBS TBS Limitations: Can cleave diols (like high valent Manganese and periodate)

16 ! A Catalytic xidant: Tetra--Propyl Ammonium Perruthenate TPAP! Can use in conjunction with the Wittig reaction for reactive aldehydes TPAP (10%), M DCM, 4Å sieves 3 P C 2 Et C 2 Et Stabilized ylide; E/Z >20:1! Steric selectivity can be exploited: generation of lactones (compare Swern) TPAP (10%) M [ox] DCM 4Å sieves 1 alcohol Lactol readily oxidized Lactone TPAP will also oxidize sulfur but not other heteroatoms! Thermodynamics in xidation: the ppenauer reaction! The reverse of the erwin-pondorrf-verley reduction (see Dr E. Anderson course, T 2011) tal 3 L Alkoxide 2 M L xidant educed xidized M = Al, Zr, B, u,! Very mild, uses non-toxic reagents and can be employed on a large scale 3 C Al( i Pr) 3 Zr( t Bu) 4 Generally superceded by other oxidants, but inexpensive and non-toxic.

17 ! xoammonium-mediated oxidations! Most common reagent is TEMP: 2,2,6,6-tetramethyl-1-piperidinyloxy Actual oxidizing agent xoammonium TEMP I 2 2 or 1 /2 alcohol disproportionation Ac I Ac TEMP 2 a or Co-oxidant 'BAIB' Aldehyde/ketone TEMP is used catalytically with a co-oxidant! xoammonium-mediated oxidations! chanism: reoxidation Actual oxidant oxoammonium 1 /2 alcohol aldehyde or ketone! Examples: PMB TEMP a KC 3 PMB TBS TEMP BAIB PMB = TBS Generally: mild, functional group tolerant reagent

18 ! Selectivity in reduction: hydride reducing agents! Functional groups have different kinds of reactivity ab 4 2 Pd/C use nucleophilic reagent ketoneelectrophilic alkene- not electrophilic use catalytic hydrogenation! For chemoselective and regioselective hydride reduction - which reagent? 1. a ab 4 2. B 3 Et Ce 3 Et LiAl 4 Important to use the correct hydride for the correct transformation!! Selectivity: hydride reducing agents (not ALWAYS reliable..)! "! educed ot usually reduced Slow DIBAL (low temp) LiAl 4 (low temp) via Acid Chloride ab 3 C ab 4 LiB 4 LiAl 4 B 3 ' ' ' ' 2 imine aldehyde ketone ester amide acid!!!!!!!! " " "!!!!!!!! " " " "!!! ' ' ' 2 amine 1 alcohol 2 alcohol 1 alcohol amine 1 alcohol

19 ! Selectivity in reduction: hydride reducing agents! DIBAL (Di-Iso-Butyl Aluminium ydride) Al Al Al Exists as -bridged dimer but reacts as monomer. Al has empty p-orbital in monomer so is electrophilic.! DIBAL becomes a good reducing agent after reacting with a nucleophile 2 Al tetrahedral intermediate destroys any excess DIBAL Al 2 Al, 2, 2 DIBAL reduces most nucleophilic C= group stable at low temperatures unstable hemiacetal ester reduced to aldehyde with DIBAL at low temperature! Selectivity in reduction: hydride reducing agents! DIBAL is a powerful and less selective reagent at higher temperatures 2 Al Al tetrahedral intermediate 2 Al aldehyde - much more reactive than ester SM at T this intermediate is T stable rapid reduction to alcohol! ften used at T for reduction of esters to alcohols Selective 1,2- reduction t Bu t Bu DIBAL BF 3. Et 2 C 2 2, T Et Complete reduction of ester to 1 alcohol with excess DIBAL at T TBS TBS DIBAL C 2 2, T

20 ! Stopping reactions half way: reduction! Application: the reduction of lactones DIBAL Al 2, 2 stable cyclic hemiacetal 3 P 2 equivalents The reactive aldehyde is never unmasked in the presence of reactive functionality the tetrahedral intermediate is stable under the reaction conditions! Is this approach a solution to a common problem? 2 MgBr 2 MgBr or 2 Li 2 or 2 Li 2 2 ester ketone product formed less electrophilic more electrophilic BuLi BuLi note regioselectivity too: direct rather than conjugate addition! Stopping reactions half way: Weinreb amides! Solution: use amides as electrophiles Li 2 DMF Li 2 stable under reaction conditions 2 2 As seen in ortho-lithiation! A Weinreb amide is a better solution to this problem 2 Li 2 Li 2 a Weinreb amide 2 decomposes during acidic work-up 2 Li tetrahedral intermediate stabilised by coordination 2 Acceptable nucleophiles: -Li Li -MgX Li Li DIBAL LiAl 4

21 ! Examples of the use of Weinreb amides! Grignard addition TBS Ar MgBr TF, 0 C 99% yield TBS Mg Ar TBS Ar! DIBAL reduction tetrahedral intermediate stabilized by coordination 2 TBS DIBAL TF, -78 C 95% yield 2 TBS! Enolate additions Li t Bu TF, -78 C Li C t 2 Bu 83 % yield t Bu tetrahedral intermediate stabilized by coordination "-keto ester: C-acylation requires control! Stopping reactions half way: Acylation at Carbon! The problem: acylation of ketones can be difficult to control ester 2 ketone 2 2 further reaction? less electrophilic more electrophilic! Solution: Employ kinetic or thermodynamic control in aisen condensation acylation at carbon electrophilic ketone stable, non-electrophilic enolate - the product under the reaction conditions ote: The final enolization is reversible, but the equilibrium lies over to the S

22 ! Thermodynamic control! Intramolecular (Dieckmann) condensation can offer a solution to C-acylation Et Et Et I C 2 Et C 2 Et C 2 Et C 2 Et Irreversible alkylation! egioselectivity through thermodynamic control Et 2 C Et Et Et Et C 2 Et Et Et Cannot form a stable enolate Can form a stable enolate ote: The final enolization is reversible, but the equilibrium lies over to the S! Acylation at Carbon - Kinetic vs thermodynamic! Enolate stability can control regiochemistry of C-acylation C 2 C Kinetic product LDA, -78 C a, 0 C C 2 Thermodynamic product! With reversible enolization conditions we get equilibration between all species C 2 C 2 This enolate destabilized by interaction with aromatic C- bond - precludes planarity C 2 C 2 o such destabilizing interaction - more stable enolate ote: The final enolization is reversible, but the equilibrium lies over to the S

23 ! Acylation at Carbon - Kinetic vs thermodynamic! Enolate stability can control regiochemistry of C-acylation C 2 C Kinetic product LDA, -78 C a, 0 C C 2 Thermodynamic product! Stabilizing the intermediate precludes proton transfer under reaction conditions 2! Example: LDA 1 2 Li C -78 C fast C LDA, -78 C 2 Li C slow 2 otes: pka = 16, pka C = 9.5! Specific reducing agents: Lithium Aluminium ydride LiAl 4! Powerful and (somewhat) non-selective reducing agent: will reduce aldehydes, ketones, esters and amides (anomalous: see mechanism below) Li counterion important (reaction ineffective without it) Al 2 3! Examples: Li 2 3 All 4 hydrides active in principle Al 2 3 Al is Lewis acidic [Al 4 ] - or [Al (4-n) n ] - Al 2 3 Iminium much more reactive etain C- bond (compare with ester reduction) 2 3 LiAl 4 TF LiAl 4 TF educes amide and leads to 1,2-reduction of!,"-unsaturated ketone (hard nucleophile) Lactone (ester) reduction leads to diol production (note cleavage of C- bond)

24 ! Specific reducing agents: Lithium Borohydride LiB 4! Typically used for the selective reduction of esters in the presence of amides, nitriles and carboxylic acids (will also reduce aldehydes and ketones) F F 2 C 2 TBS LiB 4 TF 2 TBS Ester is reduced (with cleavage of the C- alkyl bond) but amide is left untouched! Examples: C 3 LiB 4 2 C C 2 TF C 3 LiB 4 C 2 2 C C 2 TF C C Ester is reduced (with cleavage of the C- alkyl bond) but acid is left untouched Selective ester reduction; nitrile and amide are left untouched Can be made in situ: LiI or LiBr + ab 4! Specific reducing agents: Sodium Borohydride ab 4! Less reactive (than LiAl 4 & LiB 4 ), more selective. Generally used in or Et & will not usually reduce esters, epoxides, lactones, nitriles. ch: a + counterion less important than solvent 2 B 2 All 4 hydrides active in principle B ab 4 slowly reacts with protic solvents (or alcohol products) to generate alkoxy borohydrides! Examples: I ab 4 I Et 2 1. ab 4, 2. 6M ketone is reduced but ester and vinyl iodide are left untouched aldehyde is reduced but amide left untouched (by reduction, anyway )

25 ! The Luche reduction: ab 4 + Ce 3.7 2! ab 4 is not selective for 1,2 vs 1,4 reduction: Ce 3 increases selectivity eductant ab 4 51% 49% ab 4, Ce 3 99% trace 1,2-reduction favored by addition of Ce salt Ce 3 accelerates rate of reaction of protic solvent with ab 4 to generate alkoxyborohydrides ab [4-n] n These are harder reducing agents and favour attack at the hard rather than the soft center! Examples: ab 4 Ce Bn Bn 3 3 ab 4 Ce C 2 C 2 Exclusive 1,2-reduction Exclusive 1,2-reduction o ester reduction! ther modified Borohydrides! ab 3 C and ab(ac) 3 : reagents of choice for reductive amination ab 3 C C 2 p 5 TBS Ac ab(ac) 3 Sn 2 Ac TBS educes intermediate imine/iminium T aldehyde: selective reductive amination educes intermediate imine/iminium T aldehyde. Sn 2 Lewis acid accelerates iminium formation! Super-ydride TM: alkyl groups make it the most nucleophilic hydride source challenging S 2 (neopentyl) Ms, Et 3 Ms LiEt 3 B TF Electron donating groups increase hydride donor ability of B- bond The most nucleophilic hydride: especially effective for S 2 type reactions on activated leaving groups

26 ! Specific reducing agents: Borane B 3! eagent for rapid reduction of acids (compare LiAl 4 ); idealized mechanism: B B is Lewis acidic TF B - 2 B 2 group could be TF or substrate 2 2 B nly 1 eq. B 3 per acid required + workup 2 B is Lewis acidic B B 2 B! Examples Br B 3.TF C 2 Br 2 C C 2 Et B 3.TF C 2 Et Selective acid reduction - no reduction of lactone Selective acid reduction o 1,4-reduction; no ester reduction! Chemoselectivity with hydrides: recap ab 3 C ab 4 LiB 4 LiAl 4 B 3 ' ' ' ' 2 imine aldehyde ketone ester amide acid!!!!!!!! " " "!!!!!!!! " " " "!!! ' ' ' 2 amine 1 alcohol 2 alcohol 1 alcohol amine 1 alcohol What about stereoselectivity in reduction?

27 ! Diastereoselectivity with hydrides: 1,2-stereoinduction! Felkin-Anh model (see Dr E. Anderson course T 2011) LiB(s-Bu) 3 TF 1. eactive conformation 2. Bürgi-Dunitz trajectory 3. Attack away from L 4. TS is SM-like B Felkin product! Felkin Polar model S 1. Electronegative group is treated as large LiB(s-Bu) 3 2. #* C= overlap with $* TF C-S (lower LUM) 3. Forming C-u bond stabilized by C-X $* anti-felkin product S i Pr B! Felkin Chelation model Zn(B 4 ) 2 TF Felkin product 1. Lewis acid metal 2. electronegative group coordinates to metal 3. Controls reactive conformation Zn 2+ B! Diastereoselectivity with hydrides: 1,3-stereoinduction! 1,3 polyols are components of many natural products (+)-oxaticin 1,3-syn 1,3-anti! A disconnection approach indicates how to assemble the 1,3-arrangement FGI FGI 2 [red] 2 [red] 2 2 1,3-syn Can we use the stereochemistry of this product to direct hydride reduction to afford either the syn- or anti- product? 1,3-anti

28 ! Diastereoselectivity with hydrides: 1,3-stereoinduction! 1,3-syn diols may be generated by using a Lewis acid to favor intermolecular hydride delivery from the least hindered face: - 3 B, B 2 ab Boron is Lewis acidic Chair-like TS axial attack of hydride 1,3-syn! 1,3-anti diols may be generated by using intramolecular delivery of the hydride nucleophile 2 4 B(Ac) 3 Boron is Lewis acidic Ac B Ac 2 Chair-like TS put substituents pseudo-equatorial Intramolecular delivery 2 1,3-anti! Diastereoselectivity with hydrides! Size matters: addition to cyclohexanones (see Dr E. Anderson course T 2011) - LiAl 4 Small - 9:1, axial/equat. attack Small ydride 'Axial attack' - Large ydride 'Equatorial attack' a(s-bu) 3 B Big - 96:4, equat./axial attack So equatorial attack appears to be favoured, as it does not require the hydride to approach across the ring (where 1,3-diaxial interactions hinder trajectory)! Why is axial attack then favoured for small hydrides (nucleophiles)? axial Equatorial: moves towards C-, leading to higher torsional strain in the TS equatorial Axial: moves away from C-, leading to lower torsional strain in the TS

29 ! Enantioselectivity with hydrides I! ow does ature perform reductions? * S-(+)-lactate C 2 C 2 2 AD lactate dehydrogenase AD * 2 istidine Enzyme holds groups in appropriate position for reactivity (to stabilize TS) and provide selectivity * Asparagine 2 AD! We can mimic this in the lab by using Mg 2+ to control conformation lactatelike Mg 2+ Mg 2+ - (S)-(+)-enantiomer AD-like Mg activates and controls conformation Aromatic biproduct (a pyridinium salt) Single enantiomer produced! Enantioselectivity with hydrides II! We can put the chiral group on the reagent too ( chiral ab 4 ) 3 B B CBS reagent Chiral reducing agent Made from Proline 3 B B 10 mol% cat. B 3 B B Trivalent boron is lewis acidic ydride delivered from 'top' face verall: boat-like arrangement B 3 used to regenerate active material ()-alcohol, 97% ee! A highly effective reagent for enantioselective reduction of ketones B (1 mol%) B 3, TF 98:2 ratio of enantiomers TBS B Bu (1 mol%) B 3, TF TBS 97:3 ratio of diastereoisomers

30 ! eduction of alkynes (recap of 1st year material)! verall cis- addition of hydrogen across the alkyne: hydrogenation 2 2 (g) 2 Lindlar catalyst hydrogen on catalyst surface cis alkene! verall trans- addition of hydrogen across the alkyne: dissolving metal LUM!* C C 2 a 3 (l) 2 3 (l) 2 Anion adopts transconfiguration a 3 (l) 2 3 (l) 2 Isolated alkenes are not usually reduced under these conditions! Dissolving metal reductions: The Birch reduction! The Birch reduction can be used to partially reduce aromatic rings A range of metals can be used: Li, a, K (sometimes even Ca and Mg) a, 3 (l), Et Kinetic product is nonconjugated diene! The regiochemistry of the reduction depends on substitution a, 3 (l), Et C 2 a, 3 (l), Et C 2 Electron-donating groups (, 2, alkyl) give rise to this orientation of reduction Electron-withdrawing groups (C 2, C 2, C, C 2, C, Ar) give rise to this orientation of reduction

31 ! Dissolving metal reductions: The Birch reduction! chanism: reduction of arenes bearing EDG (, 2, alkyl) Li (or a) 3 (l) Li + e [ 3 ] n A dark blue solution of solvated electrons. This is the actual reducing agent in the Birch reduction Addition of electron into benzene LUM Undergoes orthoprotonation (probably) a, 3 (l) Et "e " Et a, 3 (l) Et DS "e " Delocalized radical anion Et 1. eduction of alkyl benzenes and aryl ethers requires a proton source stronger than ammonia (usually an alcohol). 2. First protonation occurs ortho- as this is the site of highest charge (and gives the most stable intermediate) 3. Second protonation occurs para- to give the non conjugated product: kinetic control and a consequence of the pentadienyl anion M having the largest coefficient in this position Undergoes paraprotonation Isolated C=C are not usually reduced! Dissolving metal reductions: The Birch reduction! chanism: reduction of arenes bearing EWG (aryl, carbonyl, acid, nitrile) C 2 C 2 C 2 C 2 C 2 a, 3 (l) Et "e " Et a, 3 (l) Et "e " Et Addition of electron into benzene LUM Undergoes paraprotonation C 2 1. Carboxylate will be deprotonated under reaction conditions 2. First protonation in para- position: site of highest charge (and most stable intermediate) 3. Kinetic and irreversible protonation to give non-conjugated product.! Examples: Undergoes ipsoprotonation Isolated C=C are not usually reduced a, 3 (l) C 2 a, 3 (l) C 2 Et Both EDG: direct reduction to same orientation Et ne EWG and one EDG: both direct to same orientation

32 ! Dissolving metal reductions: The Birch reduction! The proton source is important a, 3 (l) a, 3 (l) Et more reduction without Et non-conjugated diene (with Et)! 3 functions as a proton source (to make 2 - ) if there is nothing better normal nonconjugated product thermodynamic conjugated product a, 3 (l) functions as proton donor 2 - strong base can isomerize conjugated product: further reduction Some reductions do not proceed without the proton source. Applications of the Birch reduction eductions of conjugated alkenes 3 C 3 C K, 3 TF, -70 C Conjugated alkene is reduced more rapidly than electron-rich arene eductive alkylation: alkylation of the pentadienyl anion intermediate C 2 t Bu 1. K, 3 1eq. t Bu C 2 t Bu i Pr C 1. Li, 3 1eq. t Bu C 2. i PrI Br 2. ne equivalent of t Bu to permit first para- protonation, then kinetic alkylation of pentadienyl anion egiochemistry of reduction a consequence of substitution; note alkylation via displacement of best leaving group