Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Searching reductive coupling on Scifinder will lead to two major classes of reactions: Classes of Reductive Coupling 1) to carbonyl compounds (aldehydes, imines and ketones): carbonyls lead to allylic 1) Coupling of two carbonyl-type species to form pinacol type products . - why is this good? no need for multistep functionalization to form an organometallic species, also Example: McMurry coupling in Nicolau's synthesis of taxol more ammenable to asymmetric transformations.

O HO OH 1 O R R (O-i-Pr)2 OBn OBn Ti(O-i-Pr) 1 4 then 1 Ti i-PrMgCl O-i-Pr R TiCl (DME) , Ti O 3 1-5 R2 O-i-Pr O R4 Zn-Cu, DME R2 R2 3 o R O 70 C, 23% O H O H O R3 R4 O O O O O O behaves as a vincinal quench with use H2O Nicolaou Nature 1994, 367, 630 dianion equivalent for reductive R1 OH Other C=X (X = heteroatom, ex. nitrones, oximes) etc can be used. SmI2 is frequently employed 1 in the literature to induce this transformation TMS R3 R R3 yields 47-90% 4 + 4 rr 86:24 to >96:4 R2 R R 2) Transition metal catalyzed C-C bond forming event where a hydrogen (reductive coupling) is alkyne used in many cases 2 transferred instead of an group (alkylative coupling) in the reductive elimination step OH R

- addition of two molecules of aldehyde to titanocyclopropane not observed R4 hydrogen introduction H onto metal either from Sato Tetrahedron Lett. 1995, 36, 3203 LnNi -hydride elimination from LnNi 3 R3 β R R1 R1 R5 ligand/reducing agent or 1) Ti(O-i-Pr)4 / i-PrMgCl NH 4 4 3 R ZnO introduced H2 gas R ZnO R 1 4 + R 3 R 5 2 R R R2 1 2 2) R R R1 R H N R4 H 2 R NH 2 key catalytic cycle R5 R R3 R4 intermediate yields 48-94% then H O rr >20:1 in most cases - many factors influence the reductive 2 direct pathway taken such as; elimination Sato Tetrahedron Lett. 1995, 36, 5913 reductive ligand, reductant, solvent elimination Use of Ni to induce RC. ZnEt2 is the reducing agent so run risk of alkylative coupling (Et transfer) 4 OH H OH R H 1 1 R1 R3 R1 R3 O R ZnEt2 HO R H H yields 62-74% R2 R2 X H Ni(COD)2 : PBu3 alkylative coupling product reductive elimination product 1:4 X Montgomery J. Am. Chem. Soc. 1997, 119, 9065 Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Mechanism OH O CH3 MOMO O CH3 L L 3 R2 R3 R O large substituent O O LnNi(0) Ni O R1 HO MOMO H H 2 R H R 1 small substituent OH O (or tether chain) aigialomycin D OH OTBS

Et3SiH (5.0 equiv) 4 use of NHC carbene ligand Ni(COD)2, IMes HCl H R L L t-BuOK (25 mol% each) Me Me LnNi 3 LnNi 3 R R Ni 3 Cl L = PBu3 4 R N N ZnR 2 O MOMO O CH3 R4ZnO R4ZnO Me Me R2 R2 1 Me Me O 1 1 R 2 R H R H H R IMes HCl MOMO L = THF - terminal known to give poor dr as observed, OTES but reaction of internal alkynes did not yield desired product 61% OH H 4 OTBS OH R 1:1 dr Reductive coupling would only R1 R3 1 3 occur on intramolecular Montgomery Org. Lett. 2008, 10, 811 H R R substrates with phosphine ligands 2 H R 2 - inter always led to alkylative with R First Catalytic in Nickel, also first intermolecular example using Ni these coditions (intramolecular variant only)

Ni(COD)2 (10 mol%) OH Applications to Natural Product Synthesis O Bu3P (20 mol%) Et B (200 mol%) 1 3 R1 R2 3 R R Me diethyl zinc adds to carbonyls 3 H R 2 CH3 in comples substrates Me toluene or THF R Me yield = 45-89% 1) Et3SiH, Ni(COD)2 Jamison Org. Lett. 2000, 2, 4221 rr = 92:8 to 98:2 PBu3, THF 95% N 2) HF pyridine 92% Asymmetric Variants By Jamison N H OH .. o H 3) Li , NH3, THF 88% Me O Me OH P H Et3SiH also eliminates Ph Me H3C OBn alkylative coupling allopumiliotoxin 267A Me Fe Me PPh2 - cyclization step assembles six-membered ring, controls the relative stereochemistry adjacent to a quaternary center and assembles the alkylidene unit (each event occuring in a highly selective manner up to 67% ee (+)-NMDPP, up to 96% ee Montgomery J. Am. Chem. Soc. 1999, 121, 6098 J. Org. Chem. 2003, 68, 156 J. Am. Chem. Soc. 2003, 125, 3442 Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Applications to natural product synthesis catalytic cycle H OSiMe3 O Me Ph O Ph Ph O Ph O I Me Me Rh Ln H D HO Me Ph O + Me OTBS Ph Ph O Me H HO LnRhID Me OH Me Me Ph terpestacin alkyne/aldehyde D O Ph Ph O I coupling Ni(cod)2 (20 mol%) Rh Ln ligand (40 mol%) Ph Ph O Jamison J. Am. Chem. Soc. 2003, 125, 11514 Et B (150 mol%) Ph 3 D2 OSiMe ethyl acetate 3 D OH Ph .. H D O O 81% III P OH Rh (D)2Ln Fe Me Ph OTBS H Me Me BnO Me HO Me Me ligand 2 OAc MeO2C O OTBS Me could envision forming the macrocycle regioselectivity = 2.6:1 O O Me by this method but wrong regioisomer was diastereoselectivity = 2:1 the only formed product (14 membered ring) 41% yield desired compound OH O O

These rhodium procedures requires the alkyne to be conjugated for increased reactivity Me OH O O Rh(COD) OTF (5 mol%) (Krishce Work, uses hydrogen as the reductant) 2 Me c (R)-Tol-BINAP (5 mol%) Ph3CO2H (1.5 mol%) O Rh(COD)2OTf (5 mol%) Bryostatin 1 O Me OH H (1 atm), ClCH CH Cl) R1 R1 Ph O 2 2 2 O (R)-Cl-MeO-BIPHEP (5 mol%) 65 oC R2 C H O CO Me DCE (0.1 M), 25 oC R2 7 15 2 Ph H2 (1 atm) OH BnO BnO OMe 1,3-diynes and glyoxals: J. Am. Chem. Soc. 2003, 125, 11488 O O OTBS 1,3-enynes and glyoxals: J. Am. Chem. Soc. 2004, 126, 4664 Me 4-steps Me conjugated alkynes and ethyl (N-sulfinyl)iminoacetates: J. Am. Chem. Soc. 2005, 127, 11269 Me c Me bryostatin C-Ring conjugated alkynes and α-ketoesters: J. Am. Chem. Soc. 2006, 128, 718 silyl substituted diynes to control regioselectivity: Org. Lett. 2006, 8, 3873 O HO intramolecular acetylenic aldehydes cyclizations: J. Am. Chem. Soc. 2006, 128, 10674 heteroaldehydes and chiral Bronstead additived: J. Am. Chem. Soc. 2006, 128, 16448 C7H15 O CO2Me in situ generation of enynes and coupling to carbonyls: J. Am. Chem. Soc. 2006, 128, 16061 in situ generation of enynes and coupling to imines: J. Am. Chem. Soc. 2007, 129, 7242 conjugated alkynes and α-ketoesters: Org. Lett. 2007, 9, 3745 Krische Org. Lett. 2006, 8, 891 application to the synthesis of hexoses: Org. Lett. 2008, 10, 4133 Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Reaction of alkynes with epoxides - first example of coupling to sp3 center (yields homoallylic alcohols) Me TBSO + 3 O Ni(cod)2 (10 mol%) cat. Ni(cod)2 R Me Ph >99% ee 3 1 Bu3P (20 mol%) 1 2 R Bu3P R yield up to 85% R R + Et3B O 2 >99% ee Et3B R OH enatiomerically pure Me TBSO

Ph cat. Ni(cod)2 OH O Ph Me OH Bu3P yields up to 88% Ph X > 20:1 endo closure benzylidene group is ozonized to produce the carbonyl n Et3B n group found in the natural product X 81% yield 99% dr Jamison J. Am. Chem. Soc. 2003, 125, 8076

Mechanism - endo opening suggests a different reaction mechanism than alkyne/aldehyde steps

R PBu3 PBu3 O Me Ni O R H Ni O R O O O H L Ni PBu n 3 Me O Ph Ph Me Me anti-Bredt olefin accomadated by longer Et3B Ni(cod)2 (20 mol%) Ni-O and Ni-C bonds Bu3P (40 mol%) alkyne/ Et3B reductive β−hydride Et PBu3 epoxide Me Ni Me H elimination H Ni PBu3 elimination coupling Ph OX OX OX Me CH2 R R R Me HO O HO X= BEt2 O Jamison Me alkyne/ O O Me Applications to Natural Product Synthesis aldehyde O Me n-Bu macro- lactonization O Ph O N Ni(COD)2 (20 mol%) 44% yield n-Bu PMe2Ph (40 mol%) N >10:1 dr Et3B (150 mol%) Me H Amphidinolide T1 Me O Me toluene, 65 oC Me H pumiliotoxin 251D 82% yield Me OH (5 steps) Jamison J. Am. Chem. Soc. 2004, 126, 998 Jamison J. Org. Chem. 2007, 72, 7451 Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Example to Show Fine Balance Between Alkylative and Reductive Coupling Development of NHC Ligands (allow for efficient intermoleuclar RC with triethylsilanes) Ni(COD) - desired reaction is three-component alkylative coupling (RC was a competing problem) O 3 2 Et3SiO H R (10 mol%) - imines less electrophilic - need hydroxylic solvent and organoboron reagent + yield = 56-84% - methanol occupies coordination site, hindering β-hydride elimination + 1 3 H R1 R2 R R rr = >98:2 N N R R Et3SiH Mes Mes R2 R1 R2 4 4 .. Ni(COD)2 (10 mol%) H HN R5 HN Cross Over Experiment to Show that Ligand Identity Affects Mechanism (c-C5H9)3P (20 mol%) X R5BX2 + R1 R3 R1 R3 R4 O Ph + Et3SiD Ni(COD) R3SiO Ph N MeOAc/MeOH 2 o R2 R2 0 C, 20 h ligand H + Pr3SiH reductive coupling alkylative coupling H R3 (undesired) (major product with MeOH) yields 30-98% R X From NHC From PBu3 Jamison Angew. Chem. Int. Ed. 2003, 42, 1364 rr = > 10:1 alk:red = > 10:1 Et H <2 25 Et D 55 34 Pr H 41 23 Mechanism demonstrating competing pathways Pr D <2 18 Montgomery J. Am. Chem. Soc. 2004, 126, 3698 Me Me alkylative coupling PR3 N reductive coupling using as a regioselective director Ni + 3 Me L Me R3 R aldehyde (n=0) R H Ar or Et N BEt2 Me H N BEt n R4 2 epoxide (n=1) 2 R2 R BEt Et3B Me Ar 3 1 Me Ar R1 R R OH Ni(cod) /Cyp P (cat) Me Me 2 3 reference alkynes effect of alkene-directed PR3 (not alkene-directed) alkenyl group Me reductive reductive Ni Me elimination elimination reverses N BEt2 regioselectivity Me Me Me 1 >20 Ar PR3 Me H >20 1 increases reactivity R3P OH Me Ni N BEt Et 2 t-Bu t-Bu and controls Ni N BEt2 regioselectivity H Me Ar (does not couple) Me Ar 1 >20 Me Me PR3 Me circumvents poor Ni N BEt β-H elimination 2 regioselectivity

MeOH Me Ar 2 1 1 >20 >20 1 Me Jamison J. Am. Chem. Soc. 2004, 126, 4130 Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009 directing effect of remote alkene and impact of phosphine application of synthetic approach: reaction doesn't work with 1,2,4 carbon spacer 1 OMs R Pd(PPh3)4 Ni(COD) Et2Zn + 2 R1O O Me R1 O OH Me Me or 2 * Et2BO R L H * with without OBEt2 SiMe3 Ni Me Me Me Me Cyp3P Cyp3P C TiCl 2 H 4 R R1 R R Me i) n-BuLi regioselective 1 ii) ClTi(Oi-Pr) , R diaseteroselective 3 reductive R1 propargylation C5H9MgCl iii)BF OEt , then coupling (yields 60-82%) 3 2 yields 42-71% (d.r. 5:1 - >20:1) O r.s. 3:1 - 19:1 R2 d.s. 1.5:1 to 4:1 H 2 Me R -CHO Cyp3P Et B R2 CHO 3 - two steps Et3B 1 - two C-C bonds formed R O OH OH - three new stereocenters ( ) 2 * * * R - stereodefined trisubstituted double bond (*) * BEt2 O * Ni Ni 2 - no protecting group manipulations H R Me Me Me Me

R1 R1 applications to total synthesis

- degree of regioselectivity influenced by remote alkene - sense of regioselectivity controled by additive O - with directing alkene and ligand combined, completely different mechanism Me Me Me Me Me 9 MeO Jamison J. Am. Chem. Soc. 2004, 126, 4130 HO OH OH Me OR Me Me OMe two step general strategy: alkynation followed by alkyne/aldehyde reductive coupling Me O O O Me O OH OH O O H O Me 15 Me 1 R1 R2 R " " R2 O 1 O HO NMe NH H H 2 MeO Me Me Me Me Me Me Me Me Me O Me Me R = CONH2 ene-1,5-diol Me O macbecin 1 MeO erythromycin A very substrate for polyols (hydration/dihydroxylation), epoxides (olefin epoxidation Total Synthesis valuable and 1,5-diols (hydrogenation) synthesis of the C-1 to C-15 fragment Micalizio Org. Lett. 2006, 8, 1181 Micalizio Angew. Chem. Int. Ed. 2008, 47, 4005 Micalizio J. Am. Chem. Soc. 2005, 127, 3694. Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Catalytic Version Mechanism Iridium - non-conjugated alkynes can now be coupled H Ir(COD)2BARF (2 mol%) R1 R2 R2 O Et3Si DPPF (2 mol%) Ni O R1 OR yields: 73-99% O H Ph3CCO2H (2 mol%) 4 R3 rr usually > 20:1 OR4 H2 (1 atm) R3 OH PhCH , 60 oC OBn O 3 Alkynes and ketones: Krische J. Am. Chem. Soc. 2007, 129, 280. Alkynes and imines: Krische J. Am. Chem. Soc. 2007, 129, 8432. O H Ni SiEt3 O Mechanism O insertion Me Et Et Ph IrIln OEt OBn Et O OBn O Et Si Ni H Et Et 3 OEt Et oxidative reductive III Et Et LnIr O elimination elimination IrIIILn OSiEt3 LnIrI Ni(0) HO2CR Et3SiH Me

D2 Mori J. Am. Chem. Soc. 1994, 116, 9771 Et O Et O Et O OBn Et Et Et OEt OEt OEt Applications to total synthesis III D OH LnIrIII OH LnIr OH O H D O2CR Me 94%, 95% D 20 mol% Ni(cod)2 DO2CR H 40 mo% PPh3 OH N CHO Et3SiH (5 equiv) Coupling of Other π-Components to Carbonyls N O THF

100 mol% Ni(acac)2 elaeokanin C 200 mol% PPh3

DIBAL-H (2 eq to Ni) H H Me OSiEt OSiEt OH 3 3 1 1 R3 + O R Ni complex R 3 or R = N N OBn Mori Tet. Lett. 1997, 38, 3931 OBn 1.5 eq Et3SiH 37% O O 36% n toluene n >2:1 ratio of double bond position isomers (also works catalytic) (internal usually favoured) Mitsunobu Reaction yield 52-86% 81% (4 steps) Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

CO2Me silylethylene-titanium alkoxide complex - reagent originally developed by Kulinkovich. Addition HO to an makes cyclopropanols. Utility expanded by Sato. O H 100 mol% Ni-complex CO2Me O 1,3-CHD (150 mol%) 53% (15% rcvd sm) THF, rt R H H+ Me3Si O O O O Me OH 34-87% Me Me Me R1 N R Me Si HO H+ 3 1,3-CHD is important to obtain double bond Me3Si R2 in the desired position. If it is not included it CO2H 1 48% it migrates one position closer to the newly Ti(O-i-Pr)2 NHR formed C-C bond. SiMe2 R2 + HO Total Synthesis by Mori, Synlett 1997, 734 H Me3Si OH PGF2α OEt

SiMe 75% ketones and - stated as the first catalytic for alkene/alkyne with heteroatom 2 containing DB. Mori did it with dienes and aldehydes in 1994...? Sato J. Org. Chem. 2000, 65, 6217 OEt

OH OH O 1) 10% Cp2Ti(PMe3)2 Me Me coupling of allenes / alkynes with chiral imines silyl hydride + OMe X - reverse order, Ti reagent is complexed CH3 CH3 Me 2) workup X X to imine instead of alkyne/allene R major HN Ph (from more stable metallocycle) Ar R Buchwald J. Am. Chem. Soc. 1995, 117, 6785 H Mechanism Crowe J. Am. Chem. Soc. 1995, 117, 6787 O OMe MeO yield = 28-84% Cp Ti(PMe ) X d.r. >98:2 Ph2(H)SiO 2 3 2 Me Ti(O-i-Pr)4 Ph N Ph 2 i-PrMgCl N H Ti(O-i-Pr)2 CH3 -2PMe3 +2PMe3 H3C Ar H Ph OMe X CH3 O 2 R HN Ph H+ Cp2Ti X C R1 X Ar R2 Ph2(H)SiO H H HO R1 H CH CH3 3 H - chiral group can be removed to produce chiral primary yields = 45-74% H3C H d.r. >98:2 TiCp X 2 X Sato Org. Lett. 2003, 5, 2145 Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

homo-allylic alcohols and imines Allenes and Transfer hydrogenation: - more complex RC as you generate two new stereocenters. 1 3 R Ti(O-i-Pr) R PPh / CCl OH R3 4 3 4 R [Ir(BIPHEP)(cod)]BARF (5-7.5 mol%) OH 1 c-C H MgCl OH HN reflux 1 O R + N 5 9 C R3 2 cyclization 2 Cs2CO3 (5-7.5 mol%) 2 yields 61-83% 1 R N R R H R R R2 3 DCE-EtOAc (1:1), 75 oC R1 R2 r.r. > 20:1 76-85% R3 i-PrOH (200 - 400 mol%) d.r. = 4:1 to >20:1 yields: 50-90%

(i-PrO)n R3 - transfer hydrogenation must be used since H2 over reduces all products besides reverse prenyl O N Ti Micalizio J. Am. Chem. Soc. 2007, 129, 7514 - basic additive Cs2CO3 also helps to inhibit over-reduction R2 - no stoichiometric by products produced 1 H R - in many cases 4 to 8 equivalents of allyl source is required (no mention of this!)

OH - reverse prenylation with allenyl metal reagents R1 OH [Ir(BIPHEP)(cod)]BARF (5-7.5 mol%) C OH R Me O [Ir(BIPHEP)(cod)]BARF (5 mol%) Cs2CO3 (5-7.5 mol%) 3 R2 R3 o C DCE-EtOAc (1:1), 75 C R1 R2 Li CO (35 mol%) R No H Me R 2 3 2 yields: 23-92% DCE-EtOAc (1:1), 60 oC Me Me aryl or activate H2 (1 atm) - serves as hydrogen source and electrophilic substrate alkyl aldehyde yields: 60-95% - eliminates the need for oxidation prior to allyl addition Krische J. Am. Chem. Soc. 2007, 129, 15134. Krische J. Am. Chem. Soc. 2007, 129, 12678 - can also use rhodium based catalysts [RuHCl(CO)(PPh3)] to affect similar transformations Mechanism - prenyl group is necessary to prevent over reduction of double bond but an acid cocatalyst (m-NO2BzOH or CF3CO2H) is required when the alcohol is used as the substrate.

O D OH Me Standard Conditions O Other sources of allyl derivative metal reagents for transfer hydrogenation C O NO2 Me NO D2 (1 atm) Me Me 2 R1 R2 LnIr-D LnIr-D OAc OAc 1,3-cyclohexadiene acyclic dienes D Org. Lett. 2008, 10, 1033 JACS 2008, 130, 6338 2 allyl acetate Me D D D OH JACS 2008, 130, 6340 asymmetric crotylation asymmetric JACS 2009, 131, 2415 LnIr Me LnIr Me O JACS 2008, 130, 14891 Me NO2 Me O Me Me R Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Vinyl pyridines and imines Allene Alkyne Coupling ArSO [Rh(cod)2]BARF (5 mol%) 1 H NSO2Ar 1 2 R 1 R 2 R N (2-Fur)3P (12 mol%) R 2 R 1) N R2 Ti(O-i-Pr)2 yields 45-94% E:Z ration 64:36 to >20:1 N 2 Na SO (200 mol%), 65 oC + R 2 4 Me C 3 DCM, 25 oC 2) H+ R 1 H2 (1 atm) 56-97% yield R3 R 3:1 -13:1 dr - need substitution at 6-position of pyridine, otherwise catalyst binds to Sato Chem. Commun. 1998, 271. nitrogen and no reaction Krische, J. Am. Chem. Soc. 2008,130, 12592 Effect of alkoxide on stereochemistry π-π coulpings where the π-bonds are all carbon C6H13 C6H13 Paper was about alkylative cyclization but they found that use of phosphine led to RC C6H13 1) i-PrMgCl if X = H H+ alkylative vs reductive cyclizaiton XO XO + XO O R2 Bu2Zn / BuZnCl O 2) Me Me Ti(O-i-Pr)2 H Ph H X = TBS 62:38 63% Ni(COD)2, 5 mol% Ph X = TBS PPh3, 25 mol% H H 82:18 69%

SiMe3 SiMe3 SiMe3 1) i-PrMgCl H reduction if X = H H+ + H or alkylation XO Me XO Me NiLn XO BuZnO 2) 2 Ti(O-i-Pr)2 R2 without phosphine R = Bu (51%) R2 = H (11%) X = TBS X = TBS 51:49 73% R1 H H 90:10 70% with phosphine R2 = H (92%) - result explained by the fact that the alkoxide is better at locking the transition state in a chair than the -OTBS even though it is "smaller" phosphine may force alkyl and alkenyl into a trans orientation, thus preventing reductive elimination Sato Tetrahedron Lett. 1998, 39, 7329 Montgomery J. Am. Chem. Soc. 1996, 118, 2099 Montgomery J. Am. Chem. Soc. 1997, 119, 4911 alkyne-alkyne coupling to prepare 1,3-dienes

Allenyne Cyclizations 1 1 R 3 R R1 R3 R3 Ti(O-i-Pr)2 R R3 + 1 Ti(O-i-Pr) 1 2 3 R 2 R yield = 42-98% R1 R R R2 rr 4:1 to >20:1 R2 R2 R2 Ti(O-i-Pr)2 yields 47-93% n C R4 n R2 rr = 60:40 to >20:1 R4 Sato J. Am. Chem. Soc. 1997, 119, 11295 Sato J. Am. Chem. Soc. 1999, 121, 7342 Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Cobalt Becomes Involved - alkyne / activated alkene coupling Proposed mechanism shown for diyne: Ph [CoI (PPh ) ], PPh , Zn 3 1 2 3 2 3 2 3 R Ph MeO C R R + R R1 MeO2C 2 o III CH CN, H O, 80 C 2 Rh LnD 3 3 2 R R = acceptor MeO2C Ph MeO2C Ph mechanism Ph Ph Me D2 MeO2C RhILn Co I I Zn CO -nBu LnRh OTf LnRh D CoII CoI 2 D MeO2C Ph CO - Bu Ph 2 n Ph Zn MeO2C RhIII(D) Ln D2 MeO2C D 2 III H2O Co Ph CO2-nBu D CoIII D MeO2C MeO2C Ph Me Ph CO2-nBu Ph Me Cheng J. Am. Chem. Soc. 2002, 124, 9696 Alkyne-Alkyne Coupling by Micalizio (Similar to Sato) previous Krische examples showed metal adding across C-O π bond, why not C-C π bond?

R1 - Micalizio different for two reasons: functionalization of the internal alkyne component has only Rh(COD)2OTf (3 mol%) been achieved with TMS-substituted alkynes and conjugated 2-alkynoates (this introduces limits R1 rac-BINAP or BIPHEP (3 mol%) for polyketide synthesis) X yields 51-90% o X R2 DCE (0.1 M), 25 C - coupling can lead to four possible regioisomers H2 (1 atm)

R2 1 2 R1O OR2 R R O OR Me ClTi(Oi-Pr)3, c-C5H9MgCl Rh(COD)2OTf (3 mol%) -78 to -30 oC 3 R rac-BINAP or BIPHEP (3 mol%) R yields 65-91% X -78 oC then terminal alkyne o X Me Me Me DCE (0.1 M), 25 C Me Me yields = 46-87% H2 (1 atm) CH3 r.r. = 5:1 to 8:1

Micalizio Org. Lett. 2005, 7, 5111. diyne and enyne cyclizations: Krische J. Am. Chem. Soc. 2004, 126, 7875 asymmetric enyne cyclizations: Krische J. Am. Chem. Soc. 2005, 127, 6174 Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

1 alkoxide directed (intramolecular) coupling of alkynes R O OH Me explanation for regioselectivty O Oi-Pr i-PrO Oi-Pr O Oi-Pr n intramolecular Ti 2 Li Ti n R Me Me minimization of steric interactions in approach of second alkyne 1 Ti carbometalation O R + Ti catalyst 2 2 2 2 1 2 R R 1 R R R R then n R R2 + LiOiPr 1 i-Pr O R2 R O OH 2 R2 Ti R H+ R2 OH R2 Me Me Me HO 2 RL Me regioisomer R not formed yields 51-58% Oi-Pr major product n n R1 R1 R2 Micalizio J. Am. Chem. Soc. 2006, 128, 2764 2 R Oi-Pr R1O OH also works with allenes to make skipped 1,4-dienes Ti 3 R Ti(Oi-Pr)4 (2.1 equiv) 4 OH OH R RL Me c-C5H9MgCl (4.2 equiv) Me Me Me 5 C R Oi-Pr 1 R1 R 5 R 2 3 R2 then R R single regioisomer formed in most cases 4 1 2 R i-Pr O R O OH R Micalizio Chem. Commun. 2007, 4531 Ti R2

Me Me Me Application to total synthesis palladium-mediated RL Me coupling Oi-Pr Me

O O H R2 Oi-Pr R1O HO Me R2 OH O Ti Me RL Me alkyne-alkyne Me Me Me Me Me Me Me Oi-Pr reductive coupling callystatin A Micalizio Angew. Chem. Int. Ed. 2008, 47, 7837. Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Me ClTi(OiPr)3 Enones and alkynes (enals cyclize) c-C5H9MgCl TBS O OTMS Me toluene O O OiPr R4 Ni(COD) (10 mol%) 2 H R1 2 O R + 75% yield PBu3 (20 mol%) Me Me yield = 50-90% r.r. 5:1 + 1 4 R R rr usually >20:1 Me Me Me Et3B (3.0 equiv) MeOH, THF (8:1) R3 R2 R3 Me

- can couple enoates with ynoates without any homocoupling, which is surprising Micalizio Angew. Chem. Int. Ed. 2008, 47, 7837. O OiPr H Me TBS O OTMS Mechanism Me O BEt2OMe 1 R4 1 R OBEt2OMe Me Me Me Me 1 R O R Et2BOMe NiLn NiLn + or R4 4 2 Ni(0)Ln 4 4 R R R R 1) carbometallation 1 1 2 3 2 3 R 3 + R R R 2 3 R R MLn R 2) H R4 R R + M H R2 R3 R2 R3 R1 H 3 other possible MeOH regioisomers Micalizio Angew. Chem. Int. Ed. 2007, 46, 1440 OBEt2 (MeO)Et2B Ln OH 4 use remote alkoxide to direct regioselectivity O Ni R R1 = H 4 R R4 iPr O OiPr O OiPr - without alkoxide there O Li n was no reaction 3 R 3 Ti Ti 1 R2 R 2 3 RE + R R R RZ 2 n - only works with allylic and R 2 2 2 2 homo allylic alcohols enal leads to cyclization RZ R R RE R R R1 = aryl or alkyl

intramolecular bridged conformation less favoured carbometalation Et H 2 O R2 NiL O R NiLn n 2 R R product 2 1 4 2 O OiPr 1 4 R R OH R H R2 R R R H+ n Ti R2 OiPr H+ 2 3 R2 or Ti HO R3 R O E n RE R RZ RE Z R 2 n n Montgomery J. Am. Chem. Soc. 2007, 129, 8712 RE R Z (major product) RZ R Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Cobalt mediated alkyne-alkene R1 application to total synthesis R1 HO Me Me Me [CoI2(dppe)], ZnI2, Zn X X O Me o n CH3CN, H2O, 80 C n R2 alkyne/allylic alcohol OAc R2 reductive coupling OH Cheng J. Am. Chem. Soc. 2007, 129, 12032 phorbasin C no additional coupling even though key step in total synthesis product is again an allylic alcohol Cobalt mediated alkyne-unactivated alkene coupling Me Me Co 1 2 [CoBr (dppe)] R2 β-hydrogen R1 Me Me R R 2 3 O O Me R elimination Me Ti(Oi-Pr) + R2 R3 O 4 O c-C5H9MgCl, Et2O TMS Zn, ZnI2, CH2Cl2 3 + R R1 -78 oC to rt HO 47% dr > 20:1 Treutwein Angew. Chem. Int. Ed. 2007, 46, 8500 HO TMS OH alkynes and allyl alcohols with transfer of oxygen to catalyst (net allyl transposition) Micalizio J. Am. Chem. Soc. 2009, 131, 1392

4 2 4 Complimentary Claisen-based methods: a stereodivergent product is produced R i) ClTi(Oi-Pr)3, c-C5H9MgCl R R 1 5 3 R R OH R ii) O i) Claisen Li rearrangement 3 1 5 R R1 R3 R OH R 1 3 R R 2 yields 42-79% R2 ii) reduction R 2 rr from 1:1 to >20:1 R typically alkene substitution pattern has a large + > 20:1 then H impact on degree of selectivity intermediate

This work: i) ClTi(Oi-Pr) 1 3 t-BuOOH, R (Oi-Pr) c-C H MgCl CsOH, TBAF 1 3 n + Me Me 5 9 1 3 R R H Me R R DMF Ti workup Si 1 major product by control of Tamao R O R1 R2 Cl ii) O [Si] OH R2 A-1,3-strain Li Oxidation 1 2 R2 R 1 3 R Me H R R typically > 20:1 R2 then 1N HCl Micalizio J. Am. Chem. Soc. 2007, 129, 15112 Micalizio J. Am. Chem. Soc. 2008, 130, 16870 similar results reported by Cha J. Am. Chem. Soc. 2008, 130, 15997 Cha (J. Am. Chem. Soc. 2008, 130, 15997) reported this result first, but allylic alcohols were limited to cyclohexyl derived, except for one case Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Reductive Aldols - no prefunctionalization with stoichiometric reagents Hydrogen as the reductant - All work by Krische

O O OSiMe3 O Rh(COD) OTf (10 mol%) O Me SiH 2 2 3 4 3 R O RhCl 3H O R If R = OMe, no O (p-CF3Ph)3P (24 mol%) OH R3 3 2 R3 R R R5 evidence of silyl yield 64-90% 2 + 4 5 R ketene formation H2 (1 atm), KOAc (30 mol%) syn:anti 5 to 20:1 1 R R R 3 DCE, 25 oC R and then aldol n n Revis Tetrahedron Lett. 1987, 28, 4809 yields = 24-95%

O Rh(COD)2OTf (10 mol%) O OH O OSiMeEt O yield 44-92% O R3 2 (p-CF3Ph)3P (24 mol%) O Rh4(CO)12 (cat.) syn:anti 1.7 to 2.5:1 + R R R Et2MeSiH3 + 1 5 1 H R2 1 2 1 4 R R H2 (1 atm), KOAc (30 mol%) R R 5 o H R 2 4 DCE, 25 C 2 R R R 3 For Ketone Additions to Aldehydes Acceptors:J. Am. Chem. Soc. 2002, 124, 15156 R For For Ketone Additions to Ketone Acceptors: Org. Lett. 2003, 5, 1143 Matsuda Tetrahedron Lett. 1990, 31, 5331 yields - 22-99% For Aldehyde Addition to Glyoxals Acceptors: J. Org. Chem. 2004, 69, 1380 dr 55:45 to 84:16 For Aldehyde Additions to Ketones Acceptors: Org. Lett. 2004, 6, 691 Increase in syn selectivity using tri-2-furylphosphine: Org. Lett. 2006, 8, 519 Unsymmetrical divinyl ketone addition to aldehydes: Org. Lett. 2006, 8, 5657 1) 2.5 mol% [(COD)RhCl]2 5.5 mol% Me-DuPhos OH O Ketone addition to α-amino aldehydes (syn stereotriads): J. Am. Chem. Soc. 2006, 128, 17051 O O Asymmetric ketone additions to aldehydes: J. Am. Chem. Soc. 2008, 130, 2746. Cl2MeSiH + 1 2 1 R OR R H OR2 + Mechanism 2) H3O Me - The KOAc helps prevent conjugate reduction by O did experiements in 192 well plates to determine ideal conditions deprotonating complex A or B O Morken, J. Am. Chem. Soc. 1999, 121, 12202 - treatment of substrate with only phosphine Ph does not lead to Baylis-Hillman Enantioselective Variants III LnRh (H)2 1) 2.5 mol% [(COD)RhCl] A 2 OH O O O 6.5 mol% R-BINAP yields 48-72% H2 H + Et2MeSiH syn:anti 1.8:1 to 5.1:1 1 2 III 1 2 R OR ee (syn) = 45-88% O conjugate LnRh R H OR 2) H O+ O O 3 reduction Me O I Ph LnRh Morken J. Am. Chem. Soc. 2000, 122, 4528 avoid this Ph B

O OH O Ln H H 1) 2.5 mol% [(COD)IrCl] 2 III 7.5 mol% ligand O O Rh R H R OMe N O O Et2MeSiH O OH N N + enolate O 2) H3O Me addition yields 47-68% Ph ligand Ph OMe syn:anti 1.7:1 to 9.1:1 ee (syn) = 82-96%

Morken Org. Lett. 2001, 3, 1829 Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Role of aryl halides in Ni-Catalyzed Reductive Aldols Three-Component Coupling via Internal Redox (leads to and malonates!) O O OH O + Et3B Three-Component enal, alkyne, alcohol additions (no reducting agent is necessary, No Reaction it forces reaction to the cycloaddition pathway). Without PhI O-t-Bu H R Ni(COD)2 R O-t-Bu PhI CH 3 O 2 - PhI isn't just serving as a mechanism to generate Ni(II) from Ni(COD) Ni(COD)2, KO-t-Bu OMe R H 2 R1 + R4 - proposed to form a boron enolate which then reacts with aldehyde (metal no longer H MeOH, THF (8:1) O R complexed for this step). R3 4 Montgomery Org. Lett. 2007, 9, 537 R2 R1 R3 Random Reactions N N Intermolecular Enal-Alkyne [3+2] Reductive Cycloadditions (first example of catalytic and intermolecular) -synthesis of carbocyclic 5-membered rings via cycloaddtions difficult (traditional 3+2's need a Cl heteroatom in dipole) Mechanism O - formal solutions is to use strained rings precursors, vinyl carbenoids or dianion equivalents H OMe - the assembly of an odd-membered ring from two even numbered pi systems would require a net O Ln NiLn MeOH O 2 two electron oxidation or reduction or a hydride shift H LnNi(0) Ni R - early stoichiometric work in the field by Sato J. Am. Chem. Soc. 1996, 118, 8729 and R2 J. Am. Chem. Soc. 1997, 119, 10014 R2 H 1 5 HO 1 R O R 5 1 R Ni(COD)2 (10 mol%) R R PBu (20 mol%) yield 58-85% + 3 1 R1 R good dr Et B (4.0 equiv) R3 3 R4 R4 MeOH, THF (8:1) R2 3 H H R2 R OMe H OMe LnNi O MeO NiLn Montgomery J. Am. Chem. Soc. 2006, 128, 14030 2 O R O R2 R2 Original Stoichiometric Protocol (only worked for intramolecular) 1 1 O R R NiL R1 O Ni(COD)2 (1 equiv) Ph H Ph Three-Component Enone, Alkyne, Aldehyde Additions L = Me2N NMe2 R1 H (1 equiv) O R2 5 MeOH 2 O R Ni(COD) , Ligand R + + 2 5 R1 O R need to add 3 OH ONiL O R H R4 toluene R4 co-reductant Ni O R3 Ph Ph + Ph LNi(OMe)2 H H Montgomery J. Am. Chem. Soc. 2008, 130, 469 (doesn't re-enter cycle) Baran Group Meeting I.S. Young Reductive Coupling 3/11/2009

Mechanism O L R2 O R2 n 1 LnNi(0) R R Ni L 5 R 1 + R RS R4

O 1 H R O R1 NiL 3 O O n H R NiLn 5 R R2 R5 R3 R2 4 R R4

H 3 3 R 2 H R Ln Ni R R2 O R5 O R5 R4 R4 O R1 O R1

Reviews on Reductive Coupling

Sato: Bicyclization of dienes, enynes, and diynes with Ti(II) reagetn. New developments towards asymmetric synthesis. Pure Appl. Chem. 1999, 71, 1511.

Sato: Synthesis of organotitanium complexes from alkenes and alkynes and their synthetic applications. Chem. Rev. 2000, 100, 2835.

Montgomery: Nickel-catalyzed cyclizations, couplings, and cycloadditions involving three reactive components. Acc. Chem. Res. 2000, 33, 467.

Montgomery: Nickel-catalyzed reductive cyclizations and couplings. Angew. Chem. Int. Ed. 2004, 43, 3890.

Cheng: Cobalt- and nickel-catalyzed regio- and stereoselective reductive couplings of alkynes, allenes, and alkenes with alkenes. Chem. Eur. J. 2008, 14, 10876.

Krische: Catalytic carbonyl addition through transfer hydrogenation: A departure from preformed organometallic reagents. Angew. Chem. Int. Ed. 2009, 48, 34.

Jamison: Nickel-catalyzed coupling reactions of alkenes. Pure Appl. Chem. 2008, 80, 929.