Baran Group Meeting Ruben Martinez Ring Construction via Annulation 01/16/16

What to expect Background and history: What's in a name? The focus of this seminar will be methods for ring construction that can be used as a Annulation has no official (IUPAC) definition until 1994! package (one-pot protocol) rather than a series of reactions ultimately leading to a cyclization. Michael Jung clears the haze around the term: "Annulation, derived from the Latin word annulatus (ringed) means "the formation of Annulation types and varieties rings". In organic chemistry this term is used to describe the process of building a ring onto a pre-existing system, cyclic or non-cyclic... This broad definition includes in a general sense many reactions that are not thought of as annulation reactions, such as Two Carbon Annulation Three Carbon Annulation Diels-Alder reactions, acid catalyzed polyolefinic cyclizations, photochemical, radical and Review: Synthesis 1984, 520. thermal cyclizations." TMS Tetrahedron 1976, 32, 3. O O COCl Rick Danheiser's simplified definition: SnCl4 AlCl3 "We define as annulations those ring-forming processes in which two molecular fragments + E CH3 are united with the formation of two new bonds." J. Am. Chem. Soc. 1982, 104, 7670. E = CO Et J. Org. Chem. 1980, 45, 1046. 2 J. Org. Chem. 1981, 46, 3758. Dennis Curran backs Danheiser "Although it is used very commonly by organic chemists, the word "annulation" has yet to find a standard spelling or meaning. An authoritative review recommends the spelling "annulation", not "annelation". The latter spelling is not listed in any of the dictionaries that we consulted. We subscribe to the definition of Danheiser that an annulation is a Four Carbon Annulation Four Carbon Annulation "ring-forming process in which two molecular fragments are united with the formation of (Robinson type) (non-Robinson type) two new bonds". A ring need not be appended to a preexisting ring to qualify as an O O O O annulation." R J. Am. Chem. Soc. 1989, 111 , 8873. R Gary Molander adds clarity and wisdom + "The condensation of two acyclic units through creation of two bonds in a single process is by far the most efficient means of creating cyclic molecules. Mechanistically such O O conversions may take place in either a concerted manner (like the Diels-Alder cycloaddition reactions) or in a sequential mode that is characteristic of many [3 + 2] Review: Tetrahedron 1976, 32, 3. J. Org. Chem 1984, 49, 4567. annulations for five-membered ring synthesis. From a synthetic point of view, either process is sufficient so long as regiochemistry and stereochemistry can be controlled." Acc. Chem. Res. 1998, 31, 603. Definitions (IUPAC Recommendations 1994) Five carbon annulation Spiroannulation Benzannulation Annulation OH A transformation involving fusion of a new ring to a molecule via two new bonds. Some O O 1 5 authors use the term "annelation" for the fusion of an additional ring to an already existing R R one, and "annulation" for the formation of a ring from one or several acyclic precursors, + but this distinction is not made generally. R2 R4 Annelation E R3 Alternative, but less desirable term for annulatton. The term is widely used in German E= CO Me and French language publications. 2 Cycloaddition Tetrahedron. Lett. 1990, 31, 5985. A reaction in which two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity. Some well known annulations not covered Cyclization Dotz These well known, powerful transformations are deserving Formation of a ring compound from a chain by formation of a new bond. Pictet-Spangler of their own group seminar to showcase the synthetic utility Glossary of terms used in physical organic chemistry Larock indole synthesis and potential of each . Pure Appl. Chem. 1994, 66, 1107. Baran Group Meeting Ruben Martinez Ring Construction via Annulation 01/16/16 Robinson Annulation Antibody-catalyzed enantioselective Robinson annulation O O O Initial report Robinson, J. Chem. Soc. 1935, 1285-1288. Ab 38C2 Ab O O General note NH O The Robinson annulation is useful only in simple 1) NaNH2 O O cases, or where the availability of starting Ph 2) Ph materials compensates for the low yield of O O desired product. The reactions is typically low O O O yielding due to polymerization of Michael Ab 38C2 3) acidic work-up acceptor by strongly basic enolates. + (43%) O O α-silyl enone stabilization and shielding 95% ee Lerner, Danishefsky, Barbas J. Am. Chem. Soc. 1997, 119 , 8131. SiEt SiEt 3 KOt-Bu SiEt3 3 + A proline-catalyzed asymmetric Robinson annulation reaction t-BuOH O O O O O O J. Am. Chem. Soc. 1973, 95, 6152. O L-proline (35 mol %) Stork-Jung modification + Me DMSO, 35 °C, 89 h O Me TMS Me O Me TMS 1)m-CPBA (49%) 76% ee + 2) KOH Barbas Tetrahedron Lett. 2000, 41, 6951. OLi O O I J. Am. Chem. Soc. 1974, 96, 3682. Total synthesis of hispidospermidin J. Org. Chem 2005, 70, 739. O Functionalized Products 1) O TMS O O O O Me LiCuMe2 2 2 2) MeOH, + KOH Et2O, O 4% KOH (aq.) Me MeOH O OMe O Me single diast. (70%) OMe H R N J. Org. Chem. 1973, 38, 3663. Me Cl O O O steps R = (CH2)4NMe(CH2)3NMe3 NaOEt Me O + + Me EtOH hispidospermidin O O O O O HO Danishefsky, J. Am. Chem. Soc. 2000, 122, 6151-6159. Cl Cl (43%) (11%) Some important masked Michael acceptors J. Chem. Soc. D, Chem. Commun. 1971, 367. O O O O Me TMS O TMS I Et2N Me NaH I + Et Et Et O N N Et N I O 2 O Me Me 2 Et Et J. Am. Chem. Soc. 1950, 72, 494. Baran Group Meeting Ruben Martinez Ring Construction via Annulation 01/16/16 Danheiser benzannulation Hauser Annulation OH 2 O 2 R OH O O R R R1 R4 O 80 - 160 °C O + LDA 2 2 R 3 O + R R4 R3 R X R3 X 1 R4 2 1 R R SO Ph R X = OR, OSiR3 2 O O OH SR, NR2 J. Org. Chem. 1984, 49, 1672. R2 O R O R1 O O R1 R2 R1 R4 SO2Ph J. Org. Chem. 1978, 43, 178. 3 R X 2 X R3 X R R4 Synthesis of aquayamycin R4 R3 R2 O O OMe O R R Use of siloxyacetylenes 1) Lit-BuO O + O O OH 2) Me2SO4, sugar O sugar O 1) O C5H11 K2CO3 OBn SO2Ph OBn OMe 2) HCl/EtOH O OTIPS O C5H11 O TMSO HO OH Δ-6-tetrahydrocannabinol J. Am. Chem. Soc. 1988, 110, 3693. OH steps HO O Danheiser cyclopentene annulation HO OH O Genenral reaction scheme TiCl3 aquayamycin Tetrahedron Lett. 2000, 41, 8393. O R6 TMS O O R1 R6 Weiss-Cook annulation 1 1 6 Tetrahedron Lett., 1968, 4885. R TiCl4 R R X + X X 3 E R R3 SiMe3 TMS E 2 3 4 2 O MeOH R R R5 R R R2 MeO2C R4 R5 R4 R5 citrate phosphate buffer O X = alkyl, -OR + O 4-5 days O O (79%) E Reaction with aldehydes MeO2C E = CO Me Me Me 2 E H Me O O TBS E TiCl4 TBS E CHO + + O (97%) Me Me TBS Me AcOH/10% HCl 7 : 1 O E J. Am. Chem. Soc. 1981, 103, 1604. E J. Am. Chem. Soc. 1985, 107, 7233. (73%) Paquette, J. Org. Chem. 1995, 60, 353. Baran Group Meeting Ruben Martinez Ring Construction via Annulation 01/16/16 Prins—pinacol aza-Cope-Mannich J. Am. Chem. Soc. 1993, 115 , 9293. Total Synthesis of (±)-kumausallene Total synthesis of (–)-strychnine J. Am. Chem. Soc. 1995, 117 , 5776. Overman, J. Am. Chem. Soc. 1993, 58, 2468.

O Ot-Bu H O H N OH O O BF OEt OBz 3 steps OBz OBz 3 2 + H (CH2O)n, DCM O O steps N OH (49%) Na2SO4 —23 °C H H H Me O (71%) N O N t-BuO NaOMe HO MeCN, 80 °C (83% yield) N NMe (98%) MeN NMe HO H O H O 1) ArSO2Cl, O O DMAP 9 steps MeO H H OH N N 2) LiCuBr2 O (32%) O (73%) H H OTBDMS H H NaOAc, H CH2(CO2H)2 H steps H H O O N Ac2O, AcOH N H H H Br H 2 steps Br H O O HO O O H H H H O H OTBDMS H H H (–)-strychnine (21%) Br Wieland–Gumlich (±)-kumausallene aldehyde

Total Synthesis of (–)-magellanine and (+)-magellaninone Total synthesis of (±)-actinophyllic acid J. Am. Chem. Soc. 2008, 130, 7568. J. Am. Chem. Soc. 1993, 115 , 2992. H H H 1) t-BuLi HO 6 steps HO H steps HO BOC N N i) TFA H O OTPDPS steps O H OTPDPS I ii) (CH2O)n 2) 2 N N E CO2H CHPh2 E H H E = CO2t-Bu N H H 1)OsO4/ H NaIO O H SnCl TESO H O H 4 4 HO H OMe HN H 2) reductive (57%) iii) 0.5M HCl OMe OMe N OMe amination MeOH HO2C N H Me H Me Me N N N N CO H O (62%) H 2 H H H steps Jones O H O H [O] O H 1) LDA, CH O HN + 2 H H H 2) 4M HCl HO2C OH OH O (50%), 2 steps N O H H H magellanine magellaninone OH actinophyllic acid Baran Group Meeting Ruben Martinez Ring Construction via Annulation 01/16/16 Aza-Annulation in Total Synthesis Total synthesis of aspidophytine Tetrahedron Lett. 2006, 47, 7711. Synthesis of (±)-Strychnofoline Chem. Eur. J. 2006, 12, 8208. 1) t-BuLi, CuBr DMS Fragment A synthesis OMe OMe then p-Tol OMe 1) BnNH2 OMe O O R S Zn(Cu), O OMe 2) O N O Cl3CCOCl NBn 6 steps NBoc 3 steps NBoc2 NBoc2 Cl MeO NBoc 2) MeLi, THF, —45 °C Cl H R Cl OMe Boc2O R (84%) 3) Pd/C, H2 Marino H PGO (71%, 2 steps) S p-tolS O O OMe OPG O O p-Tol O annulation O (PG = TBDPS) R = BnO Fragment B synthesis 3 2 Cl OH 5 steps 1) Cl MeO NH2 Cl OH O MeO 6 steps O H2NO HCl N MeO MeO 2) polyphosphoric MeO N O BnO N O 7 steps N O acid H Bn N NaH N O Boc2 H OMe Boc2 MeO N O DMF, 0 °C HN convergent annulation 3 H (88%) N OPG MeO Me Cl O 2 N OPG MgI2 aspidophytine OBn + O OBn THF, 80 °C H BnO N O Total synthesis of (–)-cylindricine C Org. Lett. 2006, 8, 777. Bn (55%) BnO N O O CO2Et 9-BBN, THF then OAc O N NBoc PdCl2(dppf) DCM (cat.) 5 steps N 2 3 steps 5 steps O K3PO4 Br n-Bu 2 5 steps CO2Et BocN EtOH, pyridine H H H NH N from L-serine O 2 HO N O MeN BnO N O CH(OMe)2 OTf OP (±)-strychnofoline PO PO OAc n-Bu O 1) K CO , Diastereoselectivity Protonated type normal B benefits NH2 2 3 H H H H O from a stabilizing H-bond N O OAc MeOH 2 O Keq > 1 RN 1 N O N R1 N R Na2SO4, EtOAc 2) TPAP, 2 O N O RN R2 R The position of the equilibrium 4 steps 150 °C O NMO is correlated to the protination n-Bu H H H (68%) n-Bu (85%, 2 steps) OP H H state of the alkaloid. In acidic O medium the type normal B type normal A type normal B stereoisomer dominates. Under alkaline conditions the type normal H PO O 1) NaCNBH , Na(OAc) BH O H A stereoisomer dominates. 3 HO O 3 HO N R1 Keq < 1 MeOH, AcOH AcOH (cat.) H O RN N R1 O RN R2 Non-protonated form suffers from N R2 O 2) TBAF N N H H electrostatic repulsion between the H n-hex H H (85%, 2 steps) H n-hex (83%) H O nitrogen and carbonyl lone pairs n-Bu (–)-cylindricine Baran Group Meeting Ruben Martinez Ring Construction via Annulation 01/16/16 Total synthesis of murrayamine-D Chem. Eur. J. 2014, 20, 8536. Hagiwara annulation reagent: vinylcyclopropanation and beyond J. Chem. Soc., Perkin Trans. 1 1980, 964. 1) Pd(OAc) (cat.) 2 O J. Org. Chem. 1986, 51, 4746. rac-BINAP, Cs CO CO Et OP Me 2 3 Me HO 2 2) Pd(OAc) (cat.) citral, cyclohexenone/ OBn 2 Br CO2Et LDA then Br Cu(OAc)2, AcOH PhB(OH)2 (cat.) LDA solution cyclohexanone + PO OH 3) Pd/C, H Me Br 2 N Me H NH (76%, 3 steps) P = TIPS 2 CO2Et LDA then Me cyclopentenone general mechanism Me OH O HO PO O O 1) TFA Me O + N O N H H TMSI, O 2) TBAF 1) TMSI HMDS Me R = prenyl R 2) NaH CO2Et PhB(OH)2 CO2Et CO2Et H H Ph Ph O O O O B B OH OH exo vs endo O O HO O O B O O O CO2Et Ph CO2Et CO2Et Total synthesis of (±)-clusianone J. Am. Chem. Soc. 2007, 129, 12682. CO Et exo Br Br endo 2

1) KHMDS, Synthesis of retigeranic acid J. Am. Chem. Soc. 1989, 111 , 6691. AcO O O O OH O CHO Me O Me LDA, 1 step Br HMPA + H H (prenylation) O OMe (56%) 2) TMSCHN2, H HO OH OHC CO Et Me H i-PrEtN Me 2 Me EtO2C Me Me Me exo/endo (40/60)

16 steps 7 steps Δ (51%) O O limonene pulegone OH O R 5 steps O Me Me 4 steps Me Me O OMe H O O H AcO Me R Me H Me CO2H H R = prenyl Me Me CO2H CHO Me (±)-clusianone retigeranic acid Baran Group Meeting Ruben Martinez Ring Construction via Annulation 01/16/16 Radical-Mediated Annulations [3+2] radical annulation strategy Barton, Zard, J. Chem. Soc., Chem. Commun. 1988, 285. Radical annulation defined: EWG S "A radical annulation involves an intermolecular addition onto a radical acceptor, followed EWG by intramolecular trapping of the radical intermediate onto another radical acceptor O hν H EWG N functionality present on the initial radical-bearing molecule." C6H6 Synthesis 2003, 6, 803. O H S Radical annulation basics Once formed, radical intermediate C can: EWG O EWG N 1) Reat with initial rad. precursor H H + 2) React with H atom source O n n 3) β-fragmentation (requires design) EWG EWG 4) Add to another equiv. of rad. acceptor H H A B C SPyr EWG = SO2Ph (74%) EWG = CO2Me (43%) Bicyclic systems Rates matter Curran's logic for radical reaction design E H Me Me 1) Barton ester Radical annulation is a highly complex When designing a radical annulation sequence, it is CO H Me formation reaction that requires careful planning advantageous to permit long lifetimes for the Me 2 and consideratin of all of the rates of 1) Barton ester Me 2) hν, intermediate radicals so that desired reactions Me CO H each of the steps involved in order to can occur. The chain transfer step should be as rapid formation 2 C8H8O2S Me design a viable annulation strategy. as possible to prevent diversion of the final radical 2) hν, 3) DBU EWG Me EWG Synthesis 2003, 6, 803. along undesired pathways. methyl acrylate Me E E = CO2Me EWG = SO2Ph Me See J. Lo H-atom transfer GM J. Am. Chem. Soc. 1987, 109, 6658. 3) DBU Atom transfer radical annulation Total synthesis of matrine Zard, Angew. Chem. Int. Ed. 1998, 37, 1128. Curran, J. Am. Chem. Soc. 1987, 109, 6658. The term "atom transfer" ephasizes the method of control of the radical CO2t-Bu E E O R I R reaction. In the tin hydride method, O the chain is transfered by H atom 1 Bu SnSnBu 3 steps 3 steps H R EWG 3 3 abstraction from the reagent. In the N + N + EWG S N C6H6, 70 °C atom transfer method the chain is 1 H H H sunlamp R transfered by halogen atom abstraction O I from the starting halide. EtO S D 5-exo Luperox® E = CO2Me C H N Curran's "atom transfer cycloaddition" 6 6 I matrine R R I R R E E E E E E R1 EWG EWG + EWG EWG + O O EtO O EtO 1 1 R1 R EtO O H R R N N S N S R S S S CO2t-Bu + H H + H CO2t-Bu CO2t-Bu 6 steps Application of method to synthesis of albene 1) Bu SnSnBu , D N N N 3 3 5 steps O 2) NaOH O (30%) O (18%) O 3) CH N O 2 2 CO2Me Me 4) Bu SnH O 3 CO2Me Me Luperox® (55%, 4 steps) albene C6H6 Baran Group Meeting Ruben Martinez Ring Construction via Annulation 01/16/16 Radical annulation cont. Total synthesis of epimeloscine and meloscine Radical annulation strategy to bicyclo[3.3.1]nonanes enabled by a cascade radical annulation

Me Me O Me H 1) TFA MeCN steps Bu3SnH CN RN 2) allyl bromide O Me Me AIBN Bu3SnH, AIBN RN O PhMe Me C6H6 O NBoc (55%) R = Bn Br NBoc (62%); 6:1 α:β (38%) R = H Srikrishna, Tetrahedron 1994, 50, 8781.

Ring Opening Induced by Iminyl Radicals O O H O H Me NSPh H H RN RN RN RCM CO2Me KOt-Bu Me Bu3SnH N N N (76%) H CO2Me CN meloscine epimeloscine Curran, J. Am. Chem. Soc. 2011, 133, 10376. Development of a trimethylenemethane dianion equivalent Me N Me CN Me CN H SnF + 2 E O O O TMS I THF, rt (95%); >10:1 dr E = CO2Me H

Zard, J. Am. Chem. Soc. 1991, 113 , 1055. CHO SnF2 Radical ring expansion approach to fused carbocycles + TMS I THF, rt O CHO (43%) O O O MeBr H H Bu3SnH, O AIBN 3 O O n cis:trans n 1 (80%) R R OSnX n = 1, > 97:3 Me Ph Me SnF 3 O 2 n COR1 Ph n = 2, 44:56 TMS n = 1, 42:58 R n TMS I TMS SnX3 n = 1, 2 O O R Me O The resulting products are pseudo- TMS symmetrical. Desymmetrization about the exomethylene en route to a target n Me molecule is significantly challenging. n Me O O R1 n To address this issue Molander Ph R R1 Ph developed a bis(TMS) enol ether to n R OSnX3 R = Ph act as a β-dicarbonyl dianion equivalent n Boger, J . Org. Chem. 1 990, 55, 5442. Molander J. Am. Chem. Soc. 1987, 109, 6877. Baran Group Meeting Ruben Martinez Ring Construction via Annulation 01/16/16 Molander cont. O TMSO OMe O CHO TiCl CO Me + 4 2 O OTMS DCM, – 78 °C n (66%–77%) n = 1, 2 H n Tetrahedron Lett. 1989, 30, 2351. Neighboring group participation O CO2Me TMSO OMe O TMSOTf (cat.) + O OTMS n-Pr CHO DCM, – 78 °C n-Pr H n (80%–90%) n n = 1, 2

TMS TMSO OMe O O TMSO Rs TMSOTf OTf OTf OTMS R R S S O n O n O

RL RL RL

O R O OTMS CO2Me OMe Rs n n R OTMS RL O O J. Org. Chem. 1991, 56, 2617. J. Am. Chem. Soc. 1993, 115 , 830. NHC-catalyzed annulation of enals and aldehydes

Mes Cl N O O O Mes N (cat.) H + O H R1 DBU (cat.) Ar 10:1 THF:t-BuOH 1 Ar 25 °C R

OH Mes OH Mes Ar Ar N N Mes Mes

Bode, J. Am. Chem. Soc. 2004, 126, 14370.