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Baran Group Meeting Joel M. Smith Lipids (Fatty Acids) in Organic Synthesis 4/09/15

Definitions Cultural References Focus of This Presentaion – Main focus is on fatty acids and derivatives (nomenclature, , sources, etc.) Lipid (n.) – any of various substances that "Tyler sold his – Functionalization and synthesis of simple fatty acids. are soluble in nonpolar organic (as soap to – Synthesis of natural products derived from long-chain lipids. chloro-form and ether), that are usually department insoluble in water, that with and stores at $20 – Arachidonic Acid and derivatives – CP carbohydrates constitute the principal a bar. Lord – Chlorosulfolpids – Endiandric Acids and Kingianins structural components of living cells, and that knows what – Prostaglandins – include fats, waxes, phosphatides, they charged. Items not covered cerebrosides, and related and derived It was (See GM 2013) compounds. (Merriam-Webster) beautiful." Terpenes (Burns GM 2004, Maimone GM 2005, Michaudel GM 2013, Seiple GM 2007), Lipids – A loosely defined term for substances of biological origin that are Sphingolipids, glyceroolipids, glycerophospholipids soluble in nonpolar solvents. They consist of Saccharolipids, Polyketides. "I love the smell Supramolecular chemistry (micelles, lipisomes, etc.) saponifiable lipids, such as glycerides (fats of...[hexadecanoic and oils) and phospholipids, as well as acid and Nomenclature of fatty acids nonsaponifiable lipids, principally steroids. napthenic acid]... omega (IUPAC Gold Book) O in the morning." 1 6 Etymology (Apocalypse Now) OH Derived from the French lipide which, in turn, 8 5 is derived from the Greek lipos meaning "fat," Common nomenclature – Arachidonic acid alpha or "grease." "I want my baby IUPAC nomenclature – (5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoic acid back baby back Δx nomenclature – cis, cis, cis, cis-Δ5,Δ8,Δ11,Δ14 icosatetraenoic acid Classes of Lipids and Characteristics baby back baby omega – x classification – omega-6 Fatty acids – characterized by having a hydro- back baby back... philic, polar end, and a nonpolar hydrocarbon ribs. I want my lipid numbers nomenclature – 20:4ω6 chain. baby back baby Sources of Fatty Acids (g/100g) Fun Fatty Facts: back baby back – linoleic acid is an ess- Source Saturated Polyunsaturated Cholesterol Glycerolipids – characterized by a glycerol unit baby back baby ential fatty acid and acylacted by three fatty acid sidechains. back... ribs." Lard 40.8 9.6 93 mg must be consumed. (Austin Powers 2) – Omega-3 fatty acids Glycerophospholipids – Similar to Glycerolipids Duck Fat 33.2 12.9 100 mg (α-linoleic acid) must in structure, however, an acyl chain is often sub- be consumed. stituted with a polar head group like a phosphate OH Butter 54 2.6 230 mg – Most trans facts are (common in cell membranes). vitamin A not found in nature, Coconut Oil 85.2 1.7 OH and are artifacts of Sphingolipids – comprised of a serine backbone . conjoined to a fatty acyl side chain. Palm Oil 45.3 8.3 HO – lauric acid (C12H24O2) 12 is converted to sodium Sterol lipids – (poly)cyclic, mostly hydrocarbon NH2 Soybean Oil 14.5 56.5 laureth sulfate, which molecules reponsible for much cell-sginaling and sphingosine is used in everyday membrane structure. Olive Oil 14.0 11.2 cleaning items. – Items like Margarin Prenol lipids – molecules of repeating 5-carbon H Corn Oil 12.7 24.7 and Crisco are derived units (isoprene) and include terpenes. from hydrogenation of H H Canola Oil 5.3 24.8 unsaturated oils. This Saccharolipids – compounds with a sugar back- HO process is called "hard- bone with appended acyl fatty acids. Cholesterol O Hemp Oil 10 75 ening" because they are higher boiling and Polyketides – molecules with repeating acetyl and OH Source: Food Standards Agency (1991). "Fats and Oils". resistant to oxidation. propionyl subunits, and are often cyclic. lauric acid McCance & Widdowson's the Composition of Foods.

1 Baran Group Meeting Joel M. Smith Lipids (Fatty Acids) in Organic Synthesis 4/09/15

Dijkstra, Hamilton, and Hamm. Synthetic Manipulation of Arachidonic acid: Corey, Tetrahedron Lett. 1982, 23, 2351. Fatty Acid Biosynthesis (via FAS I and II): "Fatty Acid Biosynthesis." Trans Fatty Acids. O Corey, J. Am. Chem. Soc., 1980, 102, 1435. Oxford: Blackwell Pub., 2008. O HO C O O O2C 2 1. KI , KHCO ACP O O NADPH + H 3 3 1. Et3N, MeOH THF/H O, 0 °C O SCoA 2 2. MsCl, Et3N SACP SACP NADP 2. DBU, PhH HS ACP 3. H2O2, Et2O –110 °C CO2 3 OH O (73%, 2 steps) 3 (41% yield) as above O O – H O CO Me NADPH + H 2 OOH 2 SACP O CO2Me Tf O, PMP, SACP SACP 2

NADP CH2Cl2,–78 °C; – Fatty acid synthase II is mainly in Et N, hexane O prokaryotic organisms. Capable 3 + H O O 3 (33% yield) 3 2 of performing anaerobic oxidation SACP via not performing 2nd reduction 13 OH Corey, J. Am. Chem. Soc. 1979, 101, 1585; Corey, J. Am. Chem. Soc. 1980, 102, 1433. 13 – FAS I is common to all life. HS ACP palmitic acid Capable of making medium chain H O fatty acids in addition to palmitic HO2C O 1. (imid)2CO, CH2Cl2 4. CH N acid. O 2 2 2. H2O2, Li(imid) Chemistry on Fatty Acids and Derivatives: Hosmane, Organometallics, 2012, 31, 2589. 3. KHSO4, CH2Cl2 (>98%)

MeO C [Ir(coe)2Cl]2 (2.5 mol%) MeO C 3 3 2 dppf, pinBH 2 – For a review, see: Mecking, ACS Catal. MeO2C MeO2C MeO2C Bpin aq. KBr, CH Cl , [THTdP][DBS] 2015, 5, 5951. 6 5 2 2 6 5 AcOH (47% yield) – For hydroformyl- ation, see: Westfechtel, + THF Cole-Hamilton, Inorg. Chem. Commun. 2005, 8, 878. Eur. J. Lipid Sci. 2005, 107 , 213. 3 3 (95%) 3 MeO2C MeO C HO Br Br OH O (dtbpx)Pd(OTf)2 (1 mol%) 2 2 : 1 MeO C MeO2C MeO2C CO/MeOH 2 6 VO(acac)2, TBHP, 5 > 95% selectivity 6 5 PhH; 1. Tf2O, pyr., CH2Cl2 Meier,Eur. J. Lipid Sci. Technol. 2013, 115 , 76. Me2S 2. HMPT, CH2Cl2 Pd(OAc) (10 mol%) 2 (63% yield) 3 3 1,4-BQ (2 equiv) O Br (85% yield) O CO2Me CO Me OH AcO 2 6 1:1 AcOH/DMSO, 50 °C 5 Corey, J. Am. Chem. Soc. 1982, 104, 1750. (81%, 18/1 E/Z) O MeO2C MeO2C 1. TsNHNH tBu 2 HO2C F3C Alexanian and Vanderwal, CrO3, AcOH, N J. Am. Chem. Soc. 2016, 138, 696. H SO Cl 2 4 CH2Cl2, HQ

Cl , 2. LiOH, CF MeO C 3 + regioisomers 3 –20 °C 3 DME/H O 2 MeO2C Br OH Br O 2 3 hv, Cs CO , 55 °C 2 3 (82%) (48% yield) + regioisomer + regioisomer (52% yield)

2 Baran Group Meeting Joel M. Smith Lipids (Fatty Acids) in Organic Synthesis 4/09/16

Chlorosulfolipids (a neglected family, until recently) Cl OH Cl OSO 1. ICl, 1.8:1 dr Cl OH 3 Cl Cl Cl Cl OSO C6H13 Cl Cl C H 3 2. Bu SnH, C H 6 13 Cl Cl OTBS 3 6 13 7 BEt , O Cl Cl Cl Cl OSO 3 2 Cl Cl Cl OTBS danicalipin A 3 Cl 7 (30%, 2 steps) Cl Cl Cl OSO3 Cl 2 steps Cl Cl Cl danicalipin A C8H17 mytilipin A Malhamensilipin A: Vanderwal, J. Am. Chem. Soc. 2010, 132, 2542. Cl Cl Cl OSO3 as malhamensilipin A C8H17 OH Et NCl Cl OH Me Cl OSO Cl OH Cl OH X Cl 4 3 above 3 CO2Et CO2Et C8H17 palmityl CH2Cl2, –78 °C O OH ONs (83%, >10:1 dr) Cl ONs Cl Cl Cl Cl Cl Cl Cl OH X = OH, mytilipin B Et NCl Cl OH Cl OH Cl Cl 4 3 X = H, mytilipin C Cl C6H13 Cl Cl Stereoselective Chlorination: Vanderwal, J. Am. Chem. Soc. 2008, 130, 12514. C6H13 CH2Cl2 7 –78 °C to 0 °C Cl Cl OTBS OX Cl OX Cl Cl Cl Cl OTBS OX Bu Et4NCl3 (97%, 8:1 dr) 7 + Ph Bu Ph Bu Ph CH2Cl2, temp. 2 steps malhamensilipin A A Cl B Cl X temp dr (A/B) Carriera's Approach to the Chlorosulfolipids: Carreira, Nature, 2009, 457, 573. TCAO Cl TCAO Cl H –78 1:1 Cl Cl OTBS Me –78 2:1 tBu Bu 1. DIBAL-H (72%) Ph CO2Et TBS –78 2:1 Me Me OTBS Cl Cl 1. OsO4, NMO CO Me –78 5:1 2. TBSCl (87%) 2 70%, 10.9:1 dr 77%, 8.6:1 dr Cl Cl 2. DABCO, Tf2O Boc –78 5:1 TCAO Cl 3. CSA, MeOH Ac –78 5:1 TCAO Cl OMe PPh3Br OTBS (50%, 3 steps) Piv –90 7.7:1 Cl 6 Bu O A Cl CCO –90 6.5:1 OMe TMSCl Cl 3 OBn Cl 1. Swern O F3CCO –90 7.0:1 Cl Me 78%, >20:1 dr 67%, 4.6:1 dr Me CH2Cl2, EtOAc Cl OTBS 2. A, nBuLi of Danicalipin A: Vanderwal, J. Am. Chem. Soc. 2009, 131, 7570. Cl mechanism? 6 THF, –78 °C OH Cl OH (62%, 2 steps) Cl OH 3 1. Et4NCl3 Cl steps Me Cl OSO Cl CO2Me CO2Me O 5 steps 3 C6H13 C6H13 Cl Cl OTBS Cl 2. OsO4, NMO C6H13 * * Cl OH 6 (major Me * (47%, 2 steps) Cl CHO Cl Cl (43%, 9.8:1 dr) isomer) Cl Cl Cl Ph P OTBS Does not match isolation 1H spectrum 3 Cl BF Et O O 3 2 7 Et NCl Cl Cl KHMDS 4 mCPBA O steps C6H13 Cl Cl Me OH Me OH (E)-mityllipin A THF, –78 °C to 0 °C Cl OTBS (48% from E/Z misture) CH2Cl2 Cl 7 Cl (95%, 1:1 dr) (63%, 2.5:1 Z/E) change stereochem!

3 Baran Group Meeting Joel M. Smith Lipids (Fatty Acids) in Organic Synthesis 4/09/16

Me Me Vanderwal's approach to mytillipin A: Vanderwal, Angew. Chem. Int. Ed. 2013, 52, 10052. Me Me O O Cl OH O O O O Cl OH Cl2, Et4NCl Cl OH1. DMP Cl 4 steps Ph O N S CH Cl , 0 °C AlEt N O 2 2 2. 2 Cl Cl Cl Cl (89%) BnO Cl OH N N Cl O Cl Cl Me Br ; TBSO Fragment B Me NaOH, 98:2 dr Et NCl, H O TBSO Cl Me Me 4 2 O NaHMDS, (52%, 2 steps) BnO O O Cl Fragment A 30 mol% Grubbs Cl 1. Mg, THF, then DMF cycloadamantyl catalyst Cl Cl O PhMe, –78 °C to rt Br 5 (67%, Z/E = 3:1) 5 2. CrCl , CHCl DCE, CH Cl Cl Cl Cl O 2 3 Cl 2 2 Me (79%, 93:7 E/Z) (32% yield, > 20:1 Z/E) 1. Ph3PCl2 TBSO Me CH2Cl2, 0 °C TBSO Cl OH Me Me Cl OH Cl 2. Et4NCl3 2 steps BF Et O, Et NCl O BnO Cl 3 2 4 CH2Cl2, 0 °C Cl O O Cl (45%, 2 steps) Cl (72% yield) Cl Cl Cl Cl Cl O Cl Cl C15H31OC 5 O Cl Cl Cl Cl O mytilipin A 5 M O SO Cl OH Mee Carraira's approach to mytilipin B: Carreira, Angew. Chem. Int. Ed. 2011, 50, 7940. 3 OTBS Cl Me TBSO Cl Cl OH OH Cl OH 6 steps Me 8 steps O O Cl Cl 3PPh3 Cl O CO Et 2 OBn Cl Cl O Cl Cl Cl OH OAc KHMDS Assigned Structure of mytilipin B (spectra did not match original data) TBSO 1. Et NCl , THF, –78 °C 4 3 (55% yield) Enantioselective Halogenation: Burns, J. Am. Chem. Soc. 2016, ASAP CH2Cl2 TBSO TBSO Cl –78 °C (71%) R R O TBSO Cl 1 1 Cl tBu BnO tBuOCl, TiCl(OiPr)3 Cl 2. K CO O HO 2 3 OBn R2 OH R OH OH MeOH 10-30 mol% (R,S)-L 2 Cl Cl R O 3. DMP Cl 3 hexanes, –20 °C R3 Cl N Fragment A OAc Ph tBu OH 1. RedAl Cl Ph OHC BnOCH2CCH 2. V(O)(acac)2, TBHP Cl OTBS 3 OTBS Me OH deschloro- 3 danicalipin A Cl Cl (–)-N-Methylephedrine Cl Cl 3. DMP Cl mytilipin A Me OH 4. ZrCl 4 Zn(OTf)2, Et3N, PhMe, rt OBn 4 64% yield, 80% ee Cl (70%, 92% ee) 5. NaBH4 86% yield, 83% ee Me Me 1. DIBAL-H Cl Cl OH OH 2. Ti(OiPr)4, tBuO2H, Cl O O (+)-diethyl L-tartrate malhamensilipin A 4 steps Me OH Cl Ph OH OTBS CH2Cl2, -20 °C 6 OH 3 Cl Ph Cl Cl Cl BnO Cl Cl Cl BnO Cl CO2Me 3. TiCl(OiPr)3, PhH 64% yield, 81% ee 61% yield, 90% ee 61% yield, 90% ee (33%, 3 steps) 4 Baran Group Meeting Joel M. Smith Lipids (Fatty Acids) in Organic Synthesis 4/09/16

Biosynthesis of the Prostiglandins: Marnett and Rouzer, Chem. Rev. 2003, 103, 2239. Enantioselective Synthesis of danacalipin A: Burns, J. Am. Chem. Soc. 2016, ASAP TBSO Tyr O H H B(MIDA) Cy Cy Cy Cy 1. ICl, 2,6-lut. 1. LiCHCl2, I O 4 (74%) ZnCl2 7 O O O O O Cl Cl O 4 B Cl B COX B(pin) 2. 1,2-diol, NaOH tBuLi O (85%) Cl MgBr2 Et2O HO C Cl 2 (24%) HO2C i. nBuLi, TFAA arachidonic acid O Cl OH Cl Cl Cl BR * TBSO O 2 O 4 O OTBS 4 O C6H13 7 ii. Cl 7 Tyr OH O O CO H Cl Cl Cl Cl O 2 CHO CO2H (75%) Me CD3OD 4 Cl 1. MeN (Cl Br) O O Cl OD 4 2 4 peroxidase 4 Cl Cl (–)-danacalipin A all other O O OH O OTBS 2. Bu3SnH OH prostiglandins C6H13 CO2H CO H BEt3, air without deuteration, 2 furan formation Cl Cl 3. ClSO3H (21% overall) predominated. PGH2 For other approaches to the chlorosulfolipids, see: yield doubled for cyclooxygenase and peroxidase are T. Yoshimitsu et al. J. Org. Chem.2009 74,696. dihalogenation apart of the same enzyme step with exchange T. Yoshimitsu et al. J. Org. Chem. 2010, 75, 5425. T. Yoshimitsu et al. Org. Lett. 2011, 13, 908. Letter of prostiglandin refers to the structure of the 5-membered ring: F. Matsuda et al. Org.Lett. 2011, 13, 904. O O O OH O OH OH Prostiglandins R1 R1 R1 R1 R1 R1 R1 Fun Facts about Prostiglandins: O HO HO HO – Derived from lipids (see biosynthesis) and responsible for -like cell signaling in animals. R R R R R R R – They are produced throughout the body and can produce similar or opposite effects depending 2 2 2 2 2 2 2 A B D E F F on the tissue they are secreted. This is dependent on the cell receptors in the particular tissue. C α β – Two main derivatives: Prostacyclins: Mainly responsible for preventing blood clots; involved in Prostiglandin arabic numerals refers to degree of sidechain unsaturation. inflammation and regulation of smooth muscle contraction. Thromboxanes: Facilitate platelet aggregation (thrombosis) and blood-clots. First total Synthesis of Prostiglandins: Corey, J. Am. Chem. Soc. 1969, 91, 5675. Cl – Aspirin is an effective inhibitor of prostiglandin synthesis by acylating COX (cyclooxygenase), 1. KOH, MeO MeO which is the enzyme involved in the biosynthesis of prostiglandins. H2O, DMSO – Every parent prostiglandin has 20 carbons and one five-membered ring. CN OMe Cl Cu(BF4)2, 0 °C 2. mCPBA O CN CH Cl CO2H CO2H 2 2 CO H CO H (76%, 3 steps) O HO O O 2 2 O O name? O O 1. NaOH O I PGI2 2. KI3 O PGE2 steps 1. Ac2O (vasodilator) NaHCO3 HO and OH OH 2. Bu SnH H2O HO HO PGF2α AcO 3 HO (72%, PGF2α PGE2 OH AIBN, PhH route used for OMe OMe 2 steps) (labor induction) (labor induction) Thromboxin A2 (99%, 2 steps) HO (thrombosis) therapeutic investigation 5 Baran Group Meeting Joel M. Smith Lipids (Fatty Acids) in Organic Synthesis 4/09/16

More recent approaches to the Corey Lactone: Rokach, Tetrahedron Lett. 1993, 34, 8245. Me Ph Me S OH OH CO H O 5 Bu SnH, AIBN 2 OBn O Me O steps 3 LiHN OLi 3 steps H O O PhH, 80 °C, 1h 2 steps O O CO2Me O Me PhH-THF (38%) 0 °C–rt O Me OH OH O (57%, 95% ee) OH HO OBn O Gibbs, Synlett 1997, 657. O O O Clive, J. Org. Chem. 1999, 64, 2776. Sih synthesis of prostiglandin PGE1: (a) Sih, Chem. Commun. 1972, 240–241. (b) Sih, J. H Bu3SnH, Am. Chem. Soc. 1972, 94, 3643. (c) Sih, Ann. N. Y. Acad. Sci. 1971, 180, 64. O OBn AIBN Si(tBu) HO HO (tBu)2SiO 2 O PhMe OH OH Li Br CO2Et HO OBn CO Et H O , NaOCl CO Et CO2Et (79%) 3 : 1 6 6 2 2 2 6 2 6 OCSOPh MOMO THF, rt + OPIv Ikeda,Synthesis 1998, 973. ("100%") MOMO OPiv mech? O O HO TBAF 4:1 O OH 1. DHP O (88%) CO2Me Li C H (undesired recycled) acid 2 steps O 5 11 O CO2Et Rh2(OAc)2 6 CO2Et OBn N2 OEE 6 TBSO CH Cl MOMO 2 2 C5H11 MOMO 40 °C CuI, PBu OPIv 3 OPiv (50%) HO OH 2. AcOH, H2O, THF 3. baker's yeast THPO O PMBO O O OBPS 3 (28%, 3 steps) 1. RuCl3, NaIO4 steps CO2Me Other "conjugate addtion"-type approaches: Noyori, Tetrahedron Lett. 1982, 23, 4057 2. 10% HCl and 5563. PMBO TBSO (53% 2 steps) TBSO O I C5H11 MO OH CO2Me OTBS OHC CO2H O C5H11 HO AcOK H2O2, AcOH O O O tBuLi, CuI, PBu3 BF3 Et2O O Et O, –78 °C Ac2O, rt; aq. NaS2O6 2 steps TBSO THF, –78 °C, 1h TBSO OTBS 2 (83% yield) then heat (90%) MeO C S (93%) * 2 HO MeO2C OBn HO O 1. , DMAP O OBn OBn OBn PGE Ph Cl Rosini, Org. Lett. 2000, 2, 4145. + epimer 2 2 steps methyl ester C5H11 C5H11 15 Kbar MeO TMS SiH 2. Bu3SnH, DTBP CO Me 3 TBSO K TBSO 2 45 °C AIBN OMe O OTBS (70%, 2 steps) OTBS O O O O 3 days PhSe PhH, reflux Noyori, J. Org. Chem. 1989, 54, 1785. MO CO Me + CO Me 2 MeO2C O 2 O I C5H11 I SePh CO2Me 5 equiv O OMe O OMe K SiO , CH Cl , rt OTBS C5H11 HMPA MeO 2 2 2 O O (78% overall) nBuLi, Me Zn, TBSO Et2O, –78 °C to –40 °C Marko´, Tetrahedron Lett. 2 OTBS THF, –78 °C, 1h (71% yield) 2005, 46, 3895. OAc TBSO 6 Baran Group Meeting Joel M. Smith Lipids (Fatty Acids) in Organic Synthesis 4/09/16

Feringa asymmetric conjugate addition: (a) Feringa, JACS 2001, 123, 5841. (b) Feringa, Aggarwal's organocatalystic approach: Aggarwal, Nature, 2012, 489, 278. J. Org. Chem. 2002, 67, 7244. (b) For transposition: Grieco, J. Am. Chem. Soc. 1980, 102, 7587. OH Ph MeO (S)-proline; O O H2O, 75 °C CO2Me OHC Ph Zn TMS OMe CHO 5 2 HO (69%) then O O Bn2NH2TFA OHC Cu(OTf)2 (3 mol%), L* O Zn(BH4)2 2-thiophenyl MeOH 3 PhMe, –40 °C, 18 h, then Et2O, –30 °C Li2(CN)Cu C5H11 OMe amberlyst 15 O CO2Me O O 5 (38%, 2 steps) MgSO4 O OHC OTBS 3 SiMe3 HO OH TMS (14%, 98% ee) Ph TMSCl, Et3N Ph OHC AcO OAc OMe O O OMe 1. HCl, THF 1. TBAF O 3 2. KOtBu, THF Pd(CH3CN),Cl2 (5 mol%) O Ph P 5 CO2Me O3, then 3 2. Ac O CO2H O 2 Ph THF, 3 h 3 NaBH HO (57%, O CO Me Ph 4 5 2 TMSO (60%, 2 steps) 2 steps) C5H11 C H Ph vinyl Zn not 5 11 Ph compatible with this TBSO TBSO AcO OAc approach O CO Me HO 2 steps 6 2 Ph CP Molecules Biosynthesis: O CO2H O O O C5H11 C H 3 O EnzSOC O 5 11 O CO Me P N 6 2 OH O SEnz HO PGE HO OH Ph 1 succinic methyl ester Ph Ph acid O PGF2α (over 2 g prepared) L* R R O SEnz Wulff's creative approach: Wulff, J. Am. Chem. Soc. 1990, 112 , 5660. O O O O O I O(NBu4) OAc O O O O AcBr SEnz tBuLi (OC)5Cr (OC)5Cr O –CO2 SEnz [O] CH Cl C5H11 Et O, –78 °C; 2 2 R O 2 –40 °C then Cr(CO) ; C H C H O R O OPMB 6 5 11 5 11 SEnz then TBAF O O O SEnz OPMB OTBS OPMB O O OAc O O O AcO O O TBSO O C H 5 11 Bu O, 190 °C 2 –40 °C (38%) –H2O O (85%) TBSO OPMB R O C5H11 R O O SEnz O SEnz 2 steps OPMB HO O PGE2 methyl ester O O HO and C15 epimer First natural product synthesis using a Fischer Carbene as an intermediate! O Spencer, J. Am. Chem. Soc. 2000, 122, 420.

7 Baran Group Meeting Joel M. Smith Lipids (Fatty Acids) in Organic Synthesis 4/09/16

Fukuyama's approach: Fukuyama, J. Am. Chem. Soc. 2000, 122, 7825. Shair's approach: Shair, J. Am. Chem. Soc. 2000, 122 , 7424. Bu2BOTf, Et3N, DCM O O O O SnMe3 5 Me O O O 3 steps Bn O C5H9 O EtS OHC Pd2(dba)3, Ph3P O CO2Me N Bn I EtS 0 °C, (80%) C5H9 DMF, 65 °C C8H15 N 5 O O (80% yield) Me CO2Me 2. SO -pyr, DMSO, 5 MeO C 3 OPMB M 2 DIPEA (75%) O O R C8H15 R e MeO2C CO2Me MOMO MOMO O tBuLi O Me CO allyl allyl- C5H9 Me 2 C5H9 BrMgO BrMgO thioglycolate O 1. ZnCl2 - Et2O O O O O O 5 5 S O LHMDS pyr, CH2Cl2, 1h Br C5H9 CO Me name? 2 CO2Me OMOM Et2O, 0 °C R2N O EtS C8H15 EtS C8H15 OPMB OPMB –78 °C; MgBr2, rt (53%, 2 steps) CO Me name? CO Me MeO2C 2 Endiandric acids: Nicolaou, J. Am. Chem. Soc., 1982, MeO2C 2 5555 and 5557. Danishefsky's approach: Danishefsky, ACIE. 1998, 37, 1880 and 1877; ACIE. 1999, 38, 1485 MOMO and 3197; ACIE, 2000, 39, 4509. O O TBS O O CHO O C5H9 HO Lindlar's cat. OH O TBS 1. LDA, THF, –78 °C H O CH2Cl2, MeOH 2. TBSOTf TBS steps RO H quinoline + O O 3. Pd(OAc)2(PPh3)2 C H I PMBO 8 15 Et3N, THF, 4d (62%, 3 steps) H HO H HO OH OTBS O (CH2)6OBn Nicolaou's approach: Nicolaou, Angew. Chem. 1999, 111 , 1774 and 1781; ACIE. 2002, 41, HO OH disrotatory 6π conrotatory 8π 2678; J. Am. Chem. Soc., 2002, 124 , 2190; J. Am. Chem. Soc., 2002, 124 , 2183. 1. 1. I2, K2CO3 (45 – 55%) TPSO I HO OH CyN PMBO CHCl3 1. LDA, Et2O nBuLi –20 °C; 2. TBSCl OHC OHC 3. Zn, AcOH C H THF, –78 °C (92%) OTBS 3 steps 8 15 (79 – 80%) HO OHC OTBS C9H17CHO 2. pyr-SO3, Et3N O O (60%) DMSO/CH Cl Ph O O 2 2 H 2. KH, PMBCl (76%) Ph Ph PO(OEt)2 (78%) 110 °C LDA OTPS H OTBS O H PhMe THF O H OTBS OTPS H (quant.) (75% yield >20:1 E/Z) RO PMBO endiandric H acid C Me2AlCl MeO C PO(OEt) MeO2C 2 2 110 °C NaH, THF MeO2C CH2Cl2 O C8H15 OTBS C H –10 °C O 8 15 O O endiandric acids PhMe (80%) (90%) (92%) R = PMB A and B TBSO

8 Baran Group Meeting Joel M. Smith Lipids (Fatty Acids) in Organic Synthesis 4/09/15

Total Synthesis of Kingianins A, D, and F Total Synthesis of The Unusual Pentacycloanammoxic Acid For Initial Synthesis, see: Sherburn, Angew. Chem. Int. Ed. 2013, 52, 4221. Initial Racemic Approach: Corey, J. Am. Chem. Soc., 2004,126, 15664. For divergence to endiandric acids, see: Sherburn, Chem. Sci. 2015, 6, 3886. Cbz H Br Br CbzN NCbz N OH TMS 2 1. PBr3, Et2O (96%) CbzN O CH Cl , –15 °C 2 2 Br PhH, 60 °C 2. PdCl2(dppf), O H (95% yield) Br O THF, 66 °C Br TBSO ClZn TMS O 1. hν, cyclopentenone Cbz N 1. H , PtO , NaNO CuCl, dry air N MeCN, 23 °C 2 2 2 (84%, decagram scale) EtOH/THF, 23 °C DMF, 60 °C N (40% bsm) CbzN (40%) O 2. Zn, AcOH, 95 °C 2. H2, Pd-C, EtOH, 23 °C TMS then O2, 23 °C OTBS (3 steps from (80% yield, 2 steps) O 3-butyn-1-ol) (76% yield) Rieke Zn O EtOH/THF, 0 °C 1. HC(OMe)3, p-TSA MeOH, 40 °C (91% yield) 2 steps H H O O O 1. PhMe, 100 °C 2. hν, MeCN, 50 °C then (80% yield) O H H 2. TBAF, THF, rt AcOH-H2O, 23 °C (6% yield) N2 21% yield, 3 steps 1. hν, MeOH, Et N 1. LDA, (Br,Ph P(CH ) CO H 3 OH OH 3 2 6 2 23 °C (72% yield) O THF, –78 °C to 23 °C (67% yield) OTBS O O 2. DIBAL-H, PhMe, –78 °C 1 : 1 O 2. NH NH , CuSO , O O 2 2 4 2 3. Swern EtOH-H O, 23 °C (88% yield) CHO 1. A, CH Cl , 0 °C 2 2 2 3. CH N , Et O, 0 °C (95% yield) H O 1. TPAP, NMO 2. TPAP, NMO 2 2 2 (91% yield, 2 steps) H2O, MeCN, rt H2O, MeCN, rt 2. A, CH2Cl2, 0 *C 3. EtNH , HOBt, H 2 H EtHNOC EDC, 40 °C Second Generation/Asymmetric Approach: MeHNOC 3. EtNH2, HOBt, CO Me EDC, 40 °C (37%, 3 steps) 2 Corey, J. Am. Chem. Soc., 2006,128, 3118. O O (17% yield, 3 steps) O O CONHEt O O H hν kingianin A O 7 steps hν, MeCN, rt O + + 10 : 3 H MeCN, –15 °C H (50%) CONHEt O H (78% yield) SiPhMe2 H H CONHEt MeHNOC H O kingianin D O kingianin F 3 steps 8 steps O N Br O 3 CHO Su GM, Cation-Radical CO Me O 2 A Cycloadditions Me2PhSi

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