Spirocycles Containing All-Carbon Quaternary Centers Baran Group Meeting Emily Cherney Alkylations Continued Suresh- Synthesis (2008) v. 7, 1065-1068 Ficini- Tetrahedron Lett. (1981) v. 22, 629-632 O CO2Me O Me Me DME, rt H Me Me Me Me Me N H 44% N Ph N CO Me O 2 O MeO2C MgBr2, ACN, 70 °C O O O MeO2C 60-70% O O Ph N O Gravel- Org. Lett. (2010) v. 12, 5772-5775 • Me single diast. "Domino Stetter-Aldol-Aldol reaction" N Ph Br Me O O Et N S (30 mol %) H DBU (1 eq), Tanner- Tetrahedron (1989) v 45, 4309-4316 Me (CH2)2OH Me H H DCM, rt, NaH, DMF, Me 20 min TsHN Ts TsN Ts Stetter 0 to 50 °C O O (2 eq) TfO 71% Me O O O O Me nBuLi, THF, (±)-acoradiene H H HMPA, -20 °C O Aldol O 69% O Ts O HO HN Na(Hg), NaH2PO4, MeOH HO TsN H (+)-nitramine 74% OH O Aldol/ Sum it up! Common Akylation Strategies: J. Chem. Soc., Chem. Commun. (1995) 955-956 Elimination O 1 - double alkylation of bis-halide or other bis- O electrophile !- to ketone, malonate, etc. BF3•OEt2, DCM 2 - intramolecular cyclizations onto epoxides, O halides, or other electrophiles OH 3 - intramolecular Michael or Aldol reactions to HO Me O form quaternary centers 85% ee O 4- intramolecular Sakurai allylations to form OH O quaternary centers 86% 5- use of chiral amines to form chiral enamines for diastereoselective Aldol and Michael 71% reactions 6-I didn't cover oxidative dearom/intramolecular dr 1:1 Prins-type closure. This is included later! Spirocycles Containing All-Carbon Quaternary Centers Baran Group Meeting Emily Cherney Transition Metal-Based Methods Rainey- JACS (2012) v. 134, 3615-3618 Moreto- JACS (1992) v.114, 10449-10461 Pd(OAc)2 (10 mol %) Chiral Bronsted Acid (20 mol %) O O Me 5- Me HO 1,4-benzoquinone (2 eq.) Me Ni Ni(CO)4, exo- PhCF3 MeOH trig i Br 2,4,6-tri PrPh 71% 50% O MeO C Chiral O O 86% ee OH OH 2 P HO Bronsted O OH yield modest b/c 6- Acid: endo competes Mori- JACS (1997) v. 119, 7615-7616 2,4,6-triiPrPh MgCl Stephenson- Org. Lett. (2011) v. 13, 6320-6323 Bu Bu Cp* Cp* HO O ZrCp*, Me Pd(OAc)2 (10 mol%) BuMgCl Zr Zr Authors propose a MgCl Selectfluor(2 eq.) II/IV ACN, rt, 12 h Pd catalytic cycle NBn H H N Me 43% Me N N 46%, Bn Bn Bn 86% ee OH O H Negishi- Tetrahedron Lett. (1996) v. 37, 3803-3806 Note: The first assymetric Heck reactions were described in 1989 by Shibasaki and Overman. We will see many more examples demonstrating the power of the assymetric Heck in Part 2. Overman- JACS (1998) v. 120, 6477-6487 Et2AlCl, Ti(OiPr) (cat.) Et Pd2(dba)3 (5 mol%) 4 M Hexanes Et M (R)-BINAP (11%) Me Ag3PO4 (2 eq), DMA A I Me 49% Me H 99% and MeN 72% ee MeN Me O Et Et Et M O O Busacca developed new phosphine ligands to improve ee for this reaction. See: Org. Lett. (2003) OH 2 v.5, 595-598 OH and B Mikami- JACS (2003) v. 125, 4704-4705 B H 1:1 dr A H H CO2Me [(MeCN)4Pd](BF4)2 (5 mol%) MeO C (S)-BINAP (10 mol%) 2 O Buchwald- JACS (2011) v. 133, 9282-9285 HCO2H (1 eq) O DMSO, 100 °C, 1hr OH O [Pd(cinnamyl)Cl2] (1 mol%) N 99% Ligand (3 mol%) Ts O 99% ee N K2CO3, Dioxane Ts MeO L Toste- JACS (2007) v. 129, 2764-2765 MeO MeO * Pd OTIPS O Ligand = PCy2 ((R)-Binaphane)Pd(OH2)2(OTf)2 73% OMe BnN 100:1 Et2O/AcOH, rt, 20 min BnN Br racemic* 80% 98% ee * Preliminary assymetric results were obtained with chiral phosphine ligands providing up to 74% yield, 81% ee on the substrate shown. Mechanistic studies support Pd-alkyne activation followed by silyl enol ether addition. Spirocycles Containing All-Carbon Quaternary Centers Baran Group Meeting Emily Cherney Rearrangement Methods Hwu- JOC (1992) v. 57, 922-928 Silicon-Facilitated Ring Contraction Me Kita- Tetrahedron Lett. (1995) v. 36, 3219-3222 Epoxide Rearrangement FeBr3, DCM, Me Me "-silicon effect F3B O -60 °C OCOPh OCOPh OCOPh Me stabilizes positive BF3•OEt2, O TMS 54% charge build up during DCM, O °C ring contraction HO O Me rearrangement Me 95% Me Me 91% ee Me Me Me Me Kido- J. Chem. Soc., Perkin Trans. 1 (1992) 229-233 [2,3]-Sigmatropic Rearr. Burnell- JOC (1998) v. 63, 5708-5710 Acyloin Condensation/Ring Expansion Me Me Me Me Me Me O Cl Rh (OAc) , O 2 4 TMSO BCl , DCM, HF, MeOH; O PhH, reflux O 3 B TFA -78 °C O O 87% Me 85% 72% 2 steps EtO2C O TMSO Me O PhS S N2 EtO2C SPh Me Ph EtO2C O Me Kuroda- Tetrahedron Lett. (1994) 6895-6896 Nazarov Tu- J. Chem. Soc., Perkin Trans. 1 (2000) 3791-3794 Semipinacol Rearr. TMS O HO O FeCl , DCM, -60 °C ZnBr2 (4 mol%) -bond that shifts should be 3 DCM, rt anti to the alcohol from the 67% O epoxide opening 91 % O OH >99:1 dr For enantioselective version of semipinacol shift onto enone instead of epoxide with chiral iminium Frontier- JACS (2011) v. 133, 6307-6317 Nazarov/ Wagner Meerwein Shifts catalysis see: Tu- JACS (2009) v. 131, 14626-14627 O Marshall- JOC (1970) v. 35, 192-196 Dienone Ring Contraction CO2Me LA O O CO2Me [Cu(II)(box)](SbF6)2 DCM, rt, 5 hrs O Me Me Me h!, AcOH, Ac2O, dioxane H2SO4 79% OMe Me Ar H Ar O 66% O Me Me O Ar=2,4,6-triMeO-Ph Ar Me Me Me Conversion of Bridged Systems Trost- JACS (1996) v. 118, 12541-12554 Vinylcyclobutane Rearrangement Marshall- Tetrahedron Lett. (1969) 1387-1390 Grob on [3.2.1]bicycle JACS (1988) v. 110, 6556-6558 Vinylcyclopropane Rearrangement OMs O TMSOTf (1 eq.) O OTMS pyridine (0.7 eq) -free OH can be OH tBuOK OMe DCM OMe used for the vinyl- 60% OMe 64% cyclobutane Me Grob Fragmentation rearrangements Me Spirocycles Containing All-Carbon Quaternary Centers Baran Group Meeting Emily Cherney Conversion of Bridged Systems-Continued 2: Don't be a Whimp- If you have set yourself up with proper functionality Make that Quat. Center! on your ring, this should be a piece of cake. You Sakai- J. Chem. Soc., Chem. Commun. (1990) 1778-1779 Grob on Bicycle have many reaction to choose from--here are the OH most popular: HO OH O O H HO (5 eq.) O H O BF3•OEt2 (7 eq.) - Alkylation with an Electrophile: deprotonate at the future spirocarbon (or go DCM through an enamine) usually works (unless you are dealing with maoecrystal V) - Allylation: assymetric or not, there are a methodologies devoted to doing just (80%) HO HO Me this. It is sort of under the category of alkylation, but so much work has been Me Me Me done in this area, it get's its own line. O Me Me - Addition of a Nucleophile: if you are adding to a Michael acceptor you are all Janaki- J. Chem. Soc., Perkin Trans. 1 (1997) 195-200 Ox. Cleavage set, if you are adding to a ketone you still have work to do - Claisen Rearrangement: works in tough situations to make sterically hindered O OH O quaternary centers O 3. Follow through and All you have to do is make one last bond--it doesn't RuCl3, NaIO4 Close the Second Ring! even necessarily have to be a C-C bond. Did I mention that everything is intramolecular? As they 75% - Dieckmann Condensation - Acyloin Condensation say, "it's like falling off a log." Common reactions are listed along with the following "bold" disconnection: Me Me -Wittig olefination, etc. Iyer- Tetrahedron Lett. (1985) 5393-5396 Ozonolysis of Bicycle -RCM CHO -Aldol Condensation LiH, DMF, hydroquinone, O -Lactonization !, 69% nBu N, 190 C O3, DCM; DMS 3 ° O 78% 68% F N H2N O H Husson- ACIE (1998) v. 37 104-105 Reduction of Hemiaminal Fleming- Letrahedron Lett. (1982) v. 23, 2053-2056 Cycloaddition Methods OH Ph OH NaSO2Tol, HO Norman- JOC (1975) v. 40, 1602-1606 Diels-Alder on Exocyclic Olefins CHO CHO N O LAH ZnBr2 N 82% SnCl4•5H2O, 51% Ts Ts Me Me O Ph NH2 O Ph rt Me O Ring Closure of Geminially Disubstituted Cyclic Systems 48% Rather than showing a bunch of boring transformations I will sum up this section visually: Me 1: Start with a Ring Your functional group handle can be many things--anything that has a handle! that you can form a quaternary center from. Some popular Smith- JOC (1984) v. 49, 832-836 Intramolecular [2+2]/cleavage choices in the literature are: FG RuO4, NaIO4, n NR2 OR OR O h , ACN H O, CCl FG " 2 4 O 23% nBu O n FG R 2 steps CO2H FG MeO OMe R O nBu nBu O O O O O O issue with this approach: always have to cleave the cyclobutane to get to the FG S n R spirocycle. The same is true for intramolecular cyclopropanations. For examples see: J. Chem. Soc., Chem. Commun. (1976) 978 and Can. J. Chem. (1970) 3273-3274 Spirocycles Containing All-Carbon Quaternary Centers Baran Group Meeting Emily Cherney Cycloaddition Methods Continued Oppolzer- Helv. Chim. Acta (1977) v. 60, 2388-2401 Ene Reaction Me Me Tokunaga- J.