Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

A few examples of polyketides: Poly(β-carbonyl)s, intermediates in polyketides biosynthesis O Me This group meeting will mainly focus on poly(β-carbonyl)s with unsubstituted Me methylenes at the α-position: HO OH Me erythromycin A OH Me NMe2 OH OH Me Me HO polyacetates (often macrocyclic) O O O Me MeO n O O Me enzymatic OH O O transformationsenzymatic Me O Me transformations fatty acids n Me Me enzymatic OH transformations O Me O O aromatic polyketides roflamycoin Me OH

OH OH OH OH OH OH OH O Polyketides rapid overview: HO O OH O OH OH O CO Me * name coined in 1907 by John Norman Collie (polyketenes hypothesis) 2 MeO O O J. Chem. Soc. 1907, 91, 1806. β−rubromycin * correct biosynthetic pathway proposed by A. Birch in the 1950s ("head-to-tail" (revised condensation of acetate units Me OH structure) see Renata 6-methylsalicylic acid O OMe O O Me emodin OH O group 4 OH meeting 2008 OH OH Aus. J. Chem. 1955, 8, 539 O

= 14C OH O O O HO O OH * first polyketide synthase (PKS) was isolated in the 1970s HO * secondary metabolites of microorganisms (bacteria, fungi, etc.) OH O * 20 marketed drugs out of some 7000 characterized polyketide structures, HO R "hit rate" of 0.3 % Science 2009, 325, 161. daeschol A R = H, dalesconol A R = OH, dalesconol B JACS doi.org/10.1021/ja110932p (synthesized by S.A. Snyder Angew. Chem., Int. Ed. 2010, 49, 5146)

1 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

Biosynthesis of polyketides: O acyl transfer CoA-SH KS CO2 R S KS ACP condensation CoA-SH S S O O KR DH ER O O OH O O O KS ACP O KS ACP R S ACP R SACP R SACP R SACP SH SH O H CoA CoA SH S S S O O O O O O OH O O R SX OH O O O reduced poly(β-carbonyl)s O R SX R OH n n KS ACP poly(β-carbonyl)s fatty acids

S SH O For a review, see: D. A. Hopwood, Chem. Rev. 1997, 97, 2465. KS: keto-synthase Cycle repeated P. M. Dewick, Medicinal Natural Products, 2002, John Wiley & Sons, Ltd. O ACP: acyl carrier protein n times KR: keto-reductase DH: dehydratase Polyketide bioengineering: ER: enoyl-reductase Two general methods with PKSs:

O O * genetic modifications of enzymatic complexes: lead to "unnatural products" but often decrease productivity. S KS n * recombination of intact modules from the repertoire of PKSs.

2 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

Polyketides bioengineering: LD: loading domain M: module Ectopic expression of polyketide synthase, the TE: thioesterase minimal whiE (Moore et al.)

LD M1 M2 M3 M4 M5 M6 TE OH O Me O S S S S S S S O O O O O O O O HO HO OH HO HO O HO HO O O HO HO O OH HO HO O O OH OH HO HO O TW93c O OH OH O HO HO O OH aglycone of Me HO HO erythromycin HO HO O

HO O

HO O TW93d O Me HO O O M3 + TE OH O O O OH methylmalonyl-CoA H SNAc HO HO M2 (or M5 or M6) + TE OH O H O methylmalonyl-CoA O O O HO O Khosla, Science 1999, 284, 482 TW93h Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 3622

3 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

Total synthesis through in vitro reconstitution of complete biosynthetic pathways: O O O O Ph ketosynthase Favorskii-type OH acyl carrier protein S-EnC EncA-EncB, rearrangement O OH ketoreductase EncD, EncC O ligase EncN transacylase FabD HO O ATP NADPH O O O O O 7 eq. 7 eq. COS-EnC HO SCoA HO S-EnC O

O OH

O O O O

HO Ph Enc-S O O O H Ph O H Ph O O O O O OH methyltransferase O OH 5 EncK HO O Ph OH OH OH OH SAM OH wailupemycin G O O " favorskiiase" flavoprotein MeO O HO O EncM OH OH ferredoxin, ferredoxin-NADP+ + reductase NADP ~ 25% overall yield; Ph EncR formation of 10 C–C, 5 C–O, O O SAM and 7 stereocenters in one–pot O O O H Ph See also Gulder group meeting 2007 HO O O on biocatalysis. O O Ph O OH HO wailupemycin F HO OH See also Harris' biosynthesis of griseofulvin 5 MeO OMe J. Am. Chem. Soc. O OH O 1976, 98, 5380 COS-EnC enterocin O O Moore et al. Nat. Chem. Biol. 2007, 3, 557 O MeO O MeO O Cl Me 4 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

Chemistry of poly(β-carbonyl)s: the 'cyclase phase': O O O O O O HF Poly(β–carbonyl)s are highly reactive (methylenes have a pKa around 13– (anhyd.) O –CO2 14) and cyclize easily due to concomitant aromatization: for a review, see Harris et al., Tetrahedron 1977, 33, 2159. R OH R=Ph Ph O OH Ph O Me OH O

O O NaOH Me O Takeshita, Tetrahedron Lett. O O O O HCl or 1977, 19, 1657. H SO Me Me reflux Me Me 2 4 O R OH R=Ph or Me MeOH OH R=Ph or Me R O OH O O base OH EtO OEt HO OH O O O O Ac2O O R=Ph or Me R OH OH R=Ph or Me R O O ONa ONa O O O 1. COS, Et2O spont. Ph + Ph SH 35% ONa ONa ONa 2. H , H2O Ph O O 1. COS

Harris, Tetrahedron 1969, 25, 2687. R + OH 2. H R=Ph or Me O O O H+ or strong base OH O Me Me HO Me O O O O KOH OMe R=Ph or Me R OMe MeOH O O OH O HO R R=Ph or Me O O O O + OH– O H OH OH O OH O R OH O R HO R KOH OH OMe R R=Ph or Me R=Ph or Me H O 2 HO R HO OH O O O O R=Ph or Me weak acid (pH 5) major R OH resorcyclic acid R=Ph or Me R=Ph or Me

5 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

OH OH O O O O O O Ac O O O O O O O Me 2 OH OH Ph 1 9 OH Ph O O Me HO Me Ph O O O O O LDA 2 1:1 ratio CO silica gel Ph LDA OH O CO C4/C9 Me O O O O 2 OH HO OH O O O O O OH HO Me Me Ph 1 3 9 Ph Me 4 8 OH O Ph OH O KOH O O O O O C3/C8 spontaneous Me HO Ph Me Me HO Me OH O O OH OH O OH O OH O silica gel 10 O O O O Ph Ph base Ph Me O C3/C8 C1/C10 Me Ph HO HO Ph HO Me HO Ph 1 Ph 62% 7% not detected O O O O O O Ph O O Ph OH NaHCO3 or Ph 1 3 7 11 Ph 2 8 weak acid OH OH O OH O O O C4/C9 Ph HO OH HO O O KOH 10 O O Ph

C2/C7 HO Ph HO Ph minor + 1 C1/C6 K CO or 70% Ph OH O 2 3 C1/C10 Ph O O CF3CO2H HO O O O O O Ph KOH O O O OH OH Ph O 3 C3/C8 Ph 9 1 OH HO 8 4 + OH HO OH Ph O (C4/C9) 67% minor HO OH HO Ph 6 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

O O O 1. ONa ONa ONa Me OMe O O O O O O N O O O O O O MeNHOMe H MeO OMe Me 2. H+ Me Me N N Cl O O quant. quant. 30–45% Me Me NH, PhH, OLi OLi i Pr2 O O O Me reflux, 80% t O Bu OtBu O N O O O O OAc O OH O O O O O O MeO OMe OtBu N N Ac O H+, 87% O N Me 2 Me pyr. O Me Me O O 67% AcO O HO O HO Me 1.HCl/Me CO Me Me H SO conc. 2 2 4 OH OH 1:40, rt, 55% 80% Tip: tBu ester is less likely t 2. 4M KOH CO2 Bu to undergo self-condensation rt, 70% Me t than Me ester (27% yield) CO2 Bu OH OH O O 1. Me2SO4, K2CO3 Me O 2. TFA 3. CH3COCl HO Me O Me 92% (3 steps) 6-hydroxymusizin barakol OMe OMe O OLi OMe OMe O Me t OH O OH O O Bu O O OH O Starting with a formal then CDI t O 30% O Bu heptaketone, see also O synthesis of: O N HO Me Li HO Me OLi O 70% emodin eleutherinol N OH OH OH OH O OMe OMe OH O OH J. Am. Chem. Soc. 1975, 97, 3270 HI/P/ AcOH NH2 Synthesis of pretetramides, biosynthetic precursors of tetracycline and 6- O reflux t demethyltetracycline (Harris et al.): J. Am. Chem. Soc. 1988, 110, 6172 OH 74% O Bu J. Am. Chem. Soc. 1988, 110, 6180 pretetramide J. Am. Chem. Soc. 1988, 110, 6186 7 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

1. KOH, MeOH 85% OMe OLi OLi OMe O O O 2. NaH then CO2Me OMe OMe OLi O O O OH OH OH OH O CO2Me (7 eq) 30% Li OMe N TMS NH2

3. CH2N2 25% (2 steps) 4. HBr, HOAc, 50% OH OMe OMe OMe O O OMe OH OH O Me 6-methylpretetramide 1. MeI, K2CO3 NH2 80% OMe O O 2. OLi OMe OMe See also bio-inspired synthesis of alternariol and lichexanthone Li N J. Am. Chem. Soc. 1977, 99, 1631 HBr, HOAc TMS and bio-inspired synthesis of eleutherin 86% 51% (+17% SM) Tetrahedron Lett. 1977, 24, 2069 Tip #2: made with 2 eq. of LDA, OLi pretetramide soluble in THF, thermally stable, Summary of the 'cyclase phase': 11% overall yield Li more nucleophilic than bis-TMS N monoanion and reacts at the C- * Regio- and chemoselective cyclizations conditions of poly(β- TMS position instead of the N-position. carbonyl)s in the literature are scarce and all of them involve simple J. Org. Chem. 1984, 49, 2015. reagents * The main issue is the synthesis of long poly(β-carbonyl) chains due to their high instability in acidic, basic or oxidative conditions. LDA (2 eq.) OLi OLi OMe O OMe O * Poly(β-carbonyl)s with terminal ketones are more eager to cyclize then ClCO2Me than esters or carboxylic acids, as well as those with terminal methyl then MeI OtBu groups than terminal phenyl groups. O O 70% (one pot) 57% MeO * Some total synthesis of natural products use partially protected poly(β- carbonyl)s, but fully deprotected poly(β-carbonyl)s are never isolated. Me CO2Me

OMe OMe OMe O OMe O OH O

t OMe 1. TFA, Et3SiH O Bu O O 2. Me2SO4, K2CO3 OMe 66% (2 steps) OtBu Me HO Me

8 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

Chemistry of poly(β-carbonyl)s: the 'elongation phase': Aromatic compounds as synthons for 1,3-dicarbonyl derivatives: Direct condensation of poly(β-carbonyl)s (Harris and coworkers): For a review, see Chem. Soc. Rev., 2009, 38, 3082 Me Me ONa O Birch ozonolysis

OLi OLi OLi OLi 1. Ph OEt O O O O O O reduction Me Me Ph Ph Ph 2. additional base O O O O 3. H+ Birch, J. Chem. Soc. 1963, 2209. 19% Me Me

O O O O O O ONa O OLi OLi Me Me 1. n-BuLi Li, NH3 2 + Ph Ph Ph OEt 2. H 86% n=2,3 n=2,3 OMe OMe n=2, 15% made in 15 steps n=3, 3% (14 longest linear)!! O3 then H2, Pd/C J. Am. Chem. Soc. 1973, 95, 6865 42%

J. Org. Chem., 1985, 50, 1319 Me O O O O O O Li O OLi OLi O OLi O O O O Me OMe O N Me H+ MeO N "Comparison of the UV spectrum of [this molecule] with the spectra of R n R n Me R n Me Me other polyketide structures (Table I) was especially informative." n=1-3 Me OH R=Ph n=0 0% Me n=1 86% (56% isolated yield) 1. Li, NH 85% n=2, 80% (75%) 3, O Tetrahedron Lett. 1983, 24, 1851 n=3, 88% (55%) 2. Ac O, Et N R=Me n=2 96% (60%) CO2H 2 3 92% made in 7 steps O

* Yields drop with increasing chain length. O Me 1. O3 * Octaketone is the longest chain reported. then Me2S O O O 60%

O

Tetrahedron Lett. 1993, 34, 4957. O 9 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

O OH O 1. TIPSOTf, Et3N * A major drawback: only few substituents can tolerated Birch reduction and MeO OMe ozonolysis conditions. An alternative to avoid Birch reduction is to use [4+2] or 2. Li/NH3 1,4-hydrovinylation to make the polyene. 3. O3, then PPh3 64% (3 steps) R2 R2 racemic made in 5 steps from R2 Δ CoBr2(diimine) O + + Br and Ar Li Zn, Fe, ZnI rt R1 R1 R1 2, R1 R2 O O OH OTIPSOH O O 1. MeOBEt2, NaBH4 In that case, R can be an aromatic group, that allows to make polyketones with a terminal aromatic group with the Birch/ozonolysis sequence. 2. TBSOTf, Et3N MeO OMe 90% (2 steps) Me Me Me CoBr2(dppe) Me 2 + Me O OTBS OTBS OTIPS OTBS OTBS O Zn, ZnI2, rt Me 90% Me Me MeO OMe

O3 then Me2S J. Am. Chem. Soc., 1992, 114, 1090. 95%

O O MeO R MeO OMe 1. NaH, 2 Me Me 1 O 2. Zn, 64% O O Synthesis, 2002, 609. O O 1: R=CH SO PH 2 2 1. RuCI [(R)-BINAP]Et N 2: R=OCOtBU 2 3 Isoxazole as synthons for 1,3-dicarbonyl derivatives: 10%, H2 100 atm, 59% + + - O O 2.(EtO)2CHCH3, H , 90% N O Et3O BF4 3. Li/NH ; O 60% 3 3, 1 2 1 2 R R 1. RuCI2[(R)-BINAP]Et3N R R NaOH 10%, H2 100 atm MeO OMe 2.(EtO) C(CH ) H+ 2 3 2, * H2, Raney Ni O O O O O O * Mo(CO) , H O, Δ 3. DIBAL-H, vinyl Grignard 6 2 * Na/NH , tBuOH (1eq) 4. EtO) C(CH ) H+ 3 2 3 2, Me 30% (4 steps) * SmI2, MeOH HCl/H2O

(+)-mycoticin A. O O O O O O NH2 O See also Mitsos group meeting Me Me Me Me Me Me J. Am. Chem. Soc., 1993, 115, 3360. R1 R2 2004 on isoxazoles 10 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

An oxidative ring opening has also been reported recently: Polyisoxazoles as hidden poly(β-carbonyl)s:

Me Me BF4 BF4 N O N O N O Me3OBF4 aq. NaOCl OMe O NOH NCS, DMF NOH N O R1 3 R1 3 R1 3 R DCM, rt, 10h R MeCN, 0°C, R OMe Me 10 min or Cl2 R2 R2 R2 Me H Me Cl ET3N, 70% HCl aq. reflux then HONH3Cl R1 and R3 = Me, Ph... 70% R2 = H, Me, CO Et... 2 O O N Me O N O NOH R1 R3 N O N O Angew. Chem. Int. Ed. 2008, 47, 7446 2 R OH Me Me H N O Isoxazole opening in total synthesis: J. Heterocyclic Chem. 1977, 14, 667 * Bis-, tris- and tetraisoxazoles have been synthesized by Aurrichio et al. O O MeO2C MeO2C * Cleavage of bisisoxazoles have been reported by the same team: O H2, Raney Ni O N NH2 O O NH2 + N N MeOH, pH 7 NH2 H2N N O O H2 H Me O O O O Ph N Raney Ni Ph Me H2N

OH O OH O OH O O OH Made in 5 steps from known starting materials Ph + Me 60% Ph Me (2 steps) J. Am. Chem. Soc. 1975, 97, 5940 HO Me HO Ph 8 : 2 Other notable total syntheses: – N ClO4 controlled N OH NH N N O O garuganin III + O O hydrogenation Ni Ph J. Org. Chem. 1993, 58, 6725 Ph Me Me N then H+ geiparvarin N Tetrahedron Lett. 1985, 26, 5319 OH O H2, Raney Ni vitamin B12 then H+ J. Am. Chem. Soc. 1986, 108, 1039 Tetrahedron Lett. 1974, 33, 2793 Me tetracycline 60% (4 steps) J. Am. Chem. Soc. 2005, 127, 8292 Ni(II) octamethylcorphin HO Ph 11 Baran Group Meeting Q. Michaudel Poly(ß-carbonyl)s 04/02/2011

To conclude, a biomimetic synthesis of (–)–zearalenone: Tetrahedron 2010, 6331 1.PhMe 110°C OH O O OH O Me O O O O O

O Me

HO O "classic" key disconnections O O O biomimetic key disconnection 1) CDI, THF, rt 2. p-TsOH, H2O, 2) EtOAc, LDA Me2CO FVP O THF, –78°C to 0°C O O Me O O 580°C, OEt 3) HOCH2CH2OH, p-TsOH, O O O 0.18 mbar O CO2H HC(OEt)3, PhMe, rt 70% O 1) KOH, EtOH, 45°C, CO2Et 2) EDC HCl, CH2Cl2, rt O O N N 3. Cs2CO3, N MeOH H Me Me Me O 4. AcOH 70% then aq. HCl Me Me O O O O O

O O O Me O O O O O O O LiHMDS, ZnCl2, N Me + THF, –78°C to 0°C N OH O 63% N 46% over 4 steps! O OH O O HO O Me (–)–zearalenone Me Me

O O O Grubbs II OH O O (10 mol%) O O O DCM, 40°C Me 75%, > 20:1 E/Z

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