Natural Product Chemistry II 1 Natural Product Chemistry II Four Lectures

OH MeO O OMe N MeN O MeO O Ph OMe Me N OH H O H H OMe

Synopsis: Recap of pyridoxal phosphate and biosynthesis of some amino acids; lysine and ornithine in biosynthesis of pyrrolidine and piperidine alkaloids; alkaloids derived from phenylalanine and tyrosine; benzylisoquinoline alkaloids; phenol oxidaon in the biosynthesis of complex alkaloids; classic examples of biomimec synthesis

︎ Chemical Aspects of Biosynthesis, Oxford Chemistry Primer no. 20, John Mann

The Organic Chemistry of Biological Pathways, John ︎ McMurry, Tadhg Begley

︎ Organic Chemistry, Jonathan Clayden, Nick Greeves, Stuart Warren, Peter Wothers, 1st Edion, Chapters 49, 50 and 51

︎ Medicinal Natural Products – A Biosynthec Approach, 2nd Edion, Paul Dewick

︎ Biomimec Organic Synthesis, Vols 1 & 2, Eds Erwan Poupon and Basen Nay [email protected] handout available at: hp://burton.chem.ox.ac.uk/teaching.html Natural Product Chemistry II 2

︎ Alkaloids

︎ Nitrogen containing secondary metabolites – non-pepdic – non-nucleoside Me O N ︎ Named by Meissner as they were ‘like alkali’ H2N OH NH2 ︎ Mostly derived from α-amino acids ornithine O tropinone ︎ ornithine and lysine - aliphac alkaloids O H N O 2 OH ︎ phenyl alanine and tyrosine – aromac alkaloids NH N and aromac compounds in general 2 H lysine'('Lys'('K pelle$erine ︎ tryptophan – indole alkaloids

O O OH MeO OH HN NH2 NH N HO 2 MeO tryptophan)*)Trp)*)W tyrosine)*)Tyr)*)Y OMe O OMe OH papaverine NH2

phenyl'alanine'*'Phe'*'F Natural Product Chemistry II 3

︎ Biosynthesis of amino acids – amine transfer using pyridoxamine / pyridoxal phosphate and an aminotransferase Enz$B H R R CO H H O CO H 2 O R CO2H 2 Enz$B H H N H N P OH O O HO O NH2 O P OH P OH HO O HO O N Me O O H N Me N Me H H pyridoxal phosphate

O R' CO2H R CO2H R' OH NH2 H N O O P OH NH2 H O HO O O O O P OH P OH HO O HO O N Me O O as lysine imine H N Me N Me H H hydrolysis O HO C HO C CO H 2 OH 2 2 O NH NH 2 O 2 α+ketoglutarate glutamic)acid P OH HO O R CO2H O + ︎ Overall transaminaon N Me O H ︎ Glutamate acts as nitrogen source – pyridoxamine phosphate nitrogen inially introduced by reducve aminaon of α-ketoglutarate ︎ Pyridoxal phosphate carried around as the lysine imine Natural Product Chemistry II 4

︎ Pyridoxal phosphate mediates a number of other transformaons including racemisaon and decarboxylaon Enz$B Enz$B H H Me CO H 2 Me CO2H H O Me CO H O 2 H N H N P OH NH O O HO O 2 O P OH P OH HO O HO O N Me O O H N Me N Me natural (S)-L-alanine H H pyridoxal phosphate

H Me CO2H H O O H N O P OH Me CO H hydrolysis HO O + 2 P OH O HO O N Me NH2 O H N Me H unnatural (R)-D-alanine Natural Product Chemistry II 5

︎ Decarboxylaon O Enz$B H B-Enz R H R H H O O O R CO2H !"CO H N 2 H N P OH O O HO O NH2 O P OH P OH HO O HO O N Me O O H N Me H N Me pyridoxal phosphate H

R H

H O R H N O hydrolysis O + P OH NH P OH HO O 2 HO O O O N Me N Me H H

O O NH 2 H N H2N NH2 H2N OH H2N 2 OH NH 2 NH2 ornithine putrescine lysine'('Lys'('K cadaverine

As their names suggest, putrescine and cadaverine smell of rong flesh ︎ ︎ Other reacons mediated by pyridoxal phosphate include C-C bond formaon, substuon at the β-posion of α- amino acids, internal redox reacons between Cα and Cβ and between Cα and Cγ, oxidaon of a primary amine Natural Product Chemistry II 6

︎ Biosynthesis of some amino acids O O O ATP HO C CO H HO C CO H P CO H NADH CO H 2 2 2 2 O O 2 H 2 NH2 O α!ketglutarate O O glutamate NH NH NH P OH 2 2 2 HO O spontaneous O O N Me SCoA H HO C CO H 2 2 N CO2H O HN O O P O NADH O ATP O P O O O O O P O N CO2H O P CO H O O 2 H O proline()(Pro()(P HN O NH R O 2 P OH ATP NADH HO O O O N Me CO H H CO H H 2 2 H2N HN O HN O H H O

NH2 NH N CO H CO H urea H N 2 R H N N 2 2 2 cycle NH H NH 2 NADH 2 ornithine arginine'('Arg'('R Natural Product Chemistry II 7

︎ Urea Cycle O

H2N NH2 O O urea 2 HCO +)NH +)2ATP H N OPO 3 3 H2N OH 2 3 NH2 ornithine

H2O O O H2N O H N N OH HN N OH 2 citrulline H NH H 2 NH2 arginine ATP

HO2C CO2H fumarate HO2C O O%AMP O HN OH O HN N OH HN N OH H NH₂ H NH 2 O O NH H 2 N OH NH HO O O N N O aspar*c,acid H H uric(acid Natural Product Chemistry II 8

︎ Biosynthesis of some amino acids

O HO CO2H HO2C CO2H SCoA HO2C CO2H HO2C HO C CO2H 2 O CO2H citrate α!ketoglutarate and hydrolysis HO CO2H citric acid dehydraon CO2H cycle + H2O O O O HO C + OH SCoA 2 CO H HO C NAD 2 2 CO H HO C acetyl/CoA oxaloacetate 2 2 CO H CO H 2 (from/glycolysis) 2 NH2 O CO2H P OH -CO2 HO O ︎ Lysine is an essenal amino acid O O N Me NH2 H HO2C HO C CO2H 2 CO2H ︎ Pathway from α-ketoglutarate is unique to fungi α!aminoadipate

NH O 2 ATP P OH NADH HO O H O O O N Me NH H N O NH2 2 2 OH H H CO H N NH2 2 R lysine'('Lys'('K NAD+ Natural Product Chemistry II 9

︎ Biosynthesis of some amino acids

HO CO2H HO2C CO2H HO2C CO2H citrate α!ketoglutarate O citric acid NH O 2 cycle P OH HO O O O O NH2 ATP N Me HO C HO C NADH O NH2 2 H 2 CO H SCoA CO2H 2 H CO H acetyl/CoA oxaloacetate aspartate'('Asp'('D 2 (from/glycolysis) O

O CO2H O O HO C SCoA 2 CO H CO H HO OH succinyl(CoA 2 NADH 2 O HN O N N NH O 2 P OH CO2H CO2H HO O O CO2H N Me H then hydrolysis H O O P OH O O HO O O O HO OH N Me H N H 2 OH NH NH 2 2 NH -CO2 2 meso!2,5!diaminopimelate lysine'('Lys'('K Natural Product Chemistry II 10

︎ Aliphac alkaloids H O O H2N O H2N putrescine P OH HO O ︎ O Enz H ︎ O H2O CO2H N Me N N H2N ︎ H O O H N NH2 P OH P OH 2 HO O HO O ornithine O O ︎ N Me N Me N H H O MeHN P OH NMe HO O ︎ ︎ O NH H Enz N N Me O O H H -pyridoxamine P OH NMe HO O P OH ︎ HO O SAM O O N Me N Me Me SCoA H H CO H O O 2 acetoacetyl CoA H2N S R Me Me NMe NMe S!adenosyl*methionine ︎ ︎ N water -CO2 ︎ O SAM Me SCoA Me OH Me O O O O hygrine

NH2 ︎ Also possible is methylaon of the cyclic imine formed aer release of pyridoxamine H2N putrescine ︎ In this example the reacon does not proceed by way of symmetrical putrescine ︎ However, symmetrical putrescine is an intermediate in some plants (but not others) Natural Product Chemistry II 11

︎ Aliphac alkaloids

O SCoA [O] NMe NMe NMe NMe MeN SCoA SCoA SCoA O O SCoA O O O O O O O O SCoA hydrolysis malonyl'CoA O O decarboxylaon malonyl'CoA Me N O SCoA O MeN Me O hygrine hydrolysis

O OMe O O OMe O OMe O OH CoAS MeN O Ph MeN NADH SAM OH MeN MeN H O H O O cocaine Natural Product Chemistry II 12

︎ Aliphac alkaloids – tropinone and tropine

[O] hydrolysis NMe NMe NMe NMe NMe

SCoA SCoA SCoA O O SCoA O O O O O O O O O O SCoA hydrolysis malonyl'CoA O O decarboxylaon malonyl'CoA Me O O N O MeN MeN OH H Me O O hygrine P-450 O NADH (-)-hyoscyamine OH CoAS MeN NADH MeN H OH O H NADH MeN HO OH O OH O RO O H V tropine tropinone liorine O Fe Enz O IV Enz Fe OH

• OH HO OH RO RO • RO O O O• Natural Product Chemistry II 13

︎ Robinson’s synthesis of tropinone – R. Robinson, J. Chem. Soc., 1917, 762. Sir Robert Robinson (1886-1975)

Waynflete Professor of Organic Chemistry 1930-1954

Nobel Prize 1947 for “invesgaons on plant products of biological importance, especially the alkaloids” MeN O Inventor of the ‘curly arrow’ CHO MeNH2 O CHO

J. Chem. Soc, 1922, 121, 427. Natural Product Chemistry II 14

︎ Robinson’s biomimec synthesis of tropinone – R. Robinson, J. Chem. Soc., 1917, 762.

O CO2H MeN H pH#7,#water + MeNH + O O H 2

O CO2H as calcium salt O HO2C CO2H Me CO2H N Mannich N Me H O N Me

O OH CO2H OH

O O HO2C HO2C MeN CO2H CO2H CO2H O CO2H N Me N Me

-2CO2

MeN

O Natural Product Chemistry II 15

︎ Biomimec synthesis of tropinone by pyrrolidine oxidaon: E. Leete, S. H. Kim, J. Chem. Soc., Chem. Commun. 1989, 1899. O O MeN Hg(OAc)2 O N Me + NMe

Hg OAc OAc

O O O

MeN

N Me N Me N Me O O Hg H O OAc

O

O O O O H H

N Me N Me NMe Hg

OAc Natural Product Chemistry II 16

︎ Biosynthesis of pyrrolizidine alkaloids H2N H2N + CO2H NH NAD H2N 2 N H2N H O NH H2N H NH2 O H2N P OH ornithine HO O putrescine O NH2 N Me H2N H putrescine imine O exchange

H O H2N NADH H2N N N N N O H H2N H H2N H homospermidine

OH OH OH HO H H CHO H 2 x [O] H NADH N N N N trachelanthamidine retronecine

︎ Biomimec synthesis of pyrrolizidine alkaloids OEt OCHO H EtO H H N N N O O O Natural Product Chemistry II 17

︎ Biosynthesis of piperidine alkaloids ︎ In a similar manner to ornithine, lysine gives rise to piperidine alkaloids H O O O P OH HO O O O N Me O H2N CO2H H O SCoA water N N NH2 N H H O OH lysine H O SCoA

- CO2

O ︎ Not all piperidine alkaloids are derived from lysine – some are acetate derived N O O H 3"x O O O O pelle$erine HO SCoA [O] SCoA SCoA SCoA

fa&y"acid"synthesis H O O NADPH P OH HO O O O O O N Me H N NH H coniceine 2

Me CO H NADPH 2 Me CO2H

N O NH2 H coniine pyruvate alanine Natural Product Chemistry II 18

Glycolysis Natural Product Chemistry II 19

Citric acid cycle Natural Product Chemistry II 20

︎ Biosynthesis of benzylisoquinoline alkaloids isoquinoline MeO ︎ Biosynthesised from tyrosine O O N CO2H O MeO N CO2H OMe

HO OH OMe OH OH papaverine shikimic'acid NAD+ prephenate benzyl

O O O NH2 O CO2H CO2H CO2H

O phenylalanine NH H O O 2 O P OH P OH HO O HO O O O N Me N Me

O NH2 H H O CO2H CO2H HO C HO C CO H 2 OH 2 2

O NH2 α+ketoglutarate glutamic)acid OH OH tyrosine Natural Product Chemistry II 21

︎ Tyrosine can also be biosynthesised directly from phenylalanine by oxidaon (and NIH shi) ︎ Hydride (deuteride) transferred to caon followed by enolisaon ︎ Hydride transfer mechanism discovered the Naonal Instute of Health, Bethesda, USA.

NH2 NH2 NH2 NH2 NH2

CO2H CO2H CO2H CO2H CO2H [O] D H H D O D D O D O OH phenylalanine tyrosine

Biosynthesis of ︎ L-dopa and adrenaline H O O P OH HO O O CO H HO CO H HO NH 2 2 N Me 2 [O] H NH NH HO 2 HO 2 HO tyrosine L"dihydroxyphenylalanine dopamine L'DOPA

OH OH HO NHMe HO NH2

HO HO adrenaline noradrenaline Natural Product Chemistry II 22

︎ The related ephedrine, from a number of Ephedra species, has a very different biogenesis involving pyruvate

O using&dehydroalanine&in& O O enzyme&ac2ve&site OH OH SCoA

NH2

phenylalanine O OH

O OH OH O O Me SAM

NHMe NH2 NH2 O

ephedrine norephedrine

OH OH SAM

NHMe NH2

pseudoephedrine norpseudoephedrine

R N thiamine pyrophosphate S R' Natural Product Chemistry II 23

︎ Retrosynthec analysis of a benzylisoquinoline alkaloid.

MeO MeO MeO NH2

NH N O MeO MeO H MeO

MeO MeO MeO OMe OMe OMe N!norlaudanosine Pictet Spengler

MeO MeO NH2 MeO MeO NH O acid N NH MeO MeO MeO H MeO H

MeO MeO MeO MeO OMe OMe OMe OMe N!norlaudanosine

POCl3 HN R NH N N Cl H O R R R Bischler Napieralski Natural Product Chemistry II 24

︎ Biosynthesis of papaverine. MeO H O O P OH N HO O MeO tyrosine O OMe CO2H N Me CO2H H NH O HO 2 HO HO papaverine OMe H O O N P OH HO H HO O HO2C O N Me H HO NH HO NH2 2 [O]

HO HO tyramine H O O P OH HO O HO O HO N Me HO NH H NH H HO HO NH H -CO2 HO2C HO HO2C

OH OH OH (S)#norcoclaurine Natural Product Chemistry II 25

︎ Biosynthesis of papaverine – a recent study reveals the following plausible biosynthesis – Phytochemistry, 2010, 71, 1305. HO MeO MeO

NH SAM NH SAM NMe HO HO HO H H H

OH OH [O] OH (S)-norcoclaurine

MeO MeO MeO

NMe NMe NMe MeO HO HO H SAM H SAM H

OMe (S)-reculine OMe OH (S)-laudanine OH OH OH

SAM

MeO MeO MeO MeO

NMe NH NH N MeO demethylaon MeO [O] MeO [O] MeO H H H OMe

OMe OMe OMe OMe OMe OMe OMe (S)-laudanosine tetrahydropapaverine dihydropapaverine papaverine Natural Product Chemistry II 26

︎ Complex alkaloids can be readily formed biosynthecally and in the laboratory by oxidave radical coupling. MeO MeO MeO MeO

NMe NMe Enz'B H NMe NMe HO [O] O O HO H • H H H H H

OMe MeO MeO MeO re#culine isoboldine OH O• O OH H B'Enz ortho/para coupling

MeO MeO MeO MeO

NMe • NMe Enz)B H NMe NMe HO [O] O O HO H H H H H H O O HO •

OMe MeO MeO MeO re#culine OH ortho/ortho coupling

ortho︎ or para couplings to phenols are acceptable mechaniscally and biosynthecally O

O NMe H HO

bulbocapnine MeO Natural Product Chemistry II 27

︎ Pummerer’s ketone and its relaon to biosynthesis ︎ Inial incorrect structure assignment based on reasonable mechanism Me OH O• O• O O Me K3Fe(CN)6 Me Me Me Me X Me O H

K3Fe(CN)6 O

• • O O O O H O Me Me Me ✓ Me Me Me Me Me O O O ︎ Sir Derek Barton (1918-1998) incorrect original O assignment for ︎ Professor of Organic Chemistry, Pummerer’s ketone Me O Imperial College, London 1957-1970 Me

+ ︎ Hofmann Professor of Organic Ac2O, H Chemistry, Imperial College, London correct structure of 1970-1978 Pummerer’s ketone OAc + O Ac2O, H Me ︎ Nobel Prize 1969 with Odd Hassel Me for ‘development of the concept of Me O conformaon and its applicaon in Me chemistry’ OAc

Natural Product Chemistry II 28

︎ Biosynthesis of the opium alkaloids

MeO MeO MeO ◾ + NMe NADP NMe NADPH NMe HO HO HO H H

◾ (S)-reculine OMe OMe (R)-reculine OMe OH OH OH

MeO MeO MeO MeO

HO O •O H •O ◾ NMe NMe NMe H •O H H H ◾ NMe MeO MeO MeO MeO O salutaridine O O• NADPH HO MeO MeO MeO ◾ O O HO HO NMe O ◾ OH NMe SCoA NMe NMe H H H H H HO ◾ O MeO MeO MeO ◾ OH OAc thebaine Me N OH H salutaridinol morphine H H Natural Product Chemistry II 29

︎ Biosynthesis of the opium alkaloids MeO MeO MeO MeO

O [O] O NADPH NMe NMe O O NMe NMe H H H H H H MeO HO O H B#Enz O HO thebaine codeinone [O] codeine

HO AcO

O O NMe NMe OH H H H H HO AcO O heroin Me N OH H morphine H H Natural Product Chemistry II 30

︎ Biomimec synthesis of codeine White et. al. Tetrahedron 1983, 39, 2393.

MeO MeO O O MeO O Br ,%AcOH F C O CF NH 2 NH 3 3 N CF HO HO Br HO Br 3 H 88% H 80% H

OMe OMe OMe (R)-norreculine OH OH OH O

MeO Br MeO Br MeO Br O CF3 MeO Br I O HO CF O HO HO O 3 H F3C O H N NCOCF NCOCF HO 3 3 N CF H O H H 21% 3 MeO MeO MeO MeO O O O O CF I 3 O K2CO3, MeOH

O H Me N MeO Br MeO Br 2 MeO Br MeO O O + H i)#H ,#H2O HO NaBH ,'H O HO ii)#LiAlH 4 2 O 4 O NH N Me N Me NMe H H H H H MeO MeO MeO HO O OH codeine Natural Product Chemistry II 31

︎ To solve a ‘meta’ coupling, do an ortho/para coupling and a dienone-phenol rearrangement

MeO MeO MeO MeO [O] NADPH NMe • NMe NMe NMe HO O HO HO H H H MeO H MeO MeO (S)-orientaline OH •O O HO OMe (S)-orientalinone Enz%B H [O]

MeO MeO MeO NMe NMe NMe HO HO HO H H H H (R)-orientaline MeO MeO

[O] OH isothebaine OMe

MeO MeO MeO O NMe NMe NMe NMe O HO HO HO H H H H MeO H OMe OMe OMe HO stephanine Enz%B H Natural Product Chemistry II 32

︎ Biosynthesis of erythrina alkaloids: Zenk, Phytochemistry, 1999, 52, 373. Enz%B H O• O• O MeO MeO MeO MeO NH HO [O] H H H •O NH NH NH H H OMe (S)-norreculine MeO MeO MeO OH O• O

O O O O OH O O O O MeO

NH NH NH NH NH H H MeO MeO MeO MeO MeO OH OH OH O O Enz%B H [O]

O O O O O O O O [O] NH NH NH N N • O O

MeO MeO MeO MeO MeO • O O O O erythraline Natural Product Chemistry II 33

︎ Biomimec synthesis of galanthamine. Barton, J. Chem. Soc., 1962, 806; Chaplin & Tiffin, Tet. Le., 1997, 38, 7931; Node, Angew. Chem., Int. Ed., 2001, 40, 3060. HO

OH O O OH tyramine

O O HO HO N Me NMe NMe NMe NMe

MeO MeO MeO MeO

(-)-narwedine (-)-galanthamine HO OMe OH OH O O i)#Br2,#AcOH i) H N MeO ii)#48%#HBr HO 2 H H reduc(ve*amina(on 63% H HO MeO MeO Br ii) O NMe H reduc(ve*amina(on 77% MeO R

OH O K3Fe(CN)6; R = H, 1.4%

K3Fe(CN)6; R = Br, 30%

O PhI(OCOCF3)2 BnO NCHO BnO NCHO 85% MeO MeO O OBn OBn NMe

MeO R Natural Product Chemistry II 34

︎ Biomimec synthesis of galanthamine crystallise*from* O O basic*ethanol O OH seed*with* Pd(OAc)2,*PPh3, (4)4narwedine LiAlH4 O O O O O NMe H ONa NMe NMe NMe

MeO Br MeO MeO MeO (-)-narwedine (-)-galanthamine Natural Product Chemistry II 35

︎ Biosynthec overview of amaryllidaceae alkaloids from the daffodil family OH CO H HO H2N 2 + HO N NH H HO/H 2 HO OH H HO O OH OH

HO OH MeO N MeO MeO H HO norbelladine N N HO NH HO HO H H MeO

OH O

HO OH

O O O via NMe O NH O N O N lycorine crinine MeO MeO O galanthamine via O via MeO MeO N N O O H H Natural Product Chemistry II 36

︎ Biosynthesis as a guide for retrosynthesis ︎ Carpanone; Chapman, J. Am. Chem. Soc., 1971, 93, 6696 – see Dr Robertson’s opon course

Me Me • Me Me • H O O O O O O H O O O O O O O O O O O O

O O PdCl2 O O

O O O O O OH HO O Pd

Me Me Me Me H O O O O H O O O O O O O O Natural Product Chemistry II 37

︎ Alkaloids from Yuzuriha – Clayton Heathcock Review, Angew. Chem. Int. Ed., 1992, 31 665-681; Classics in Total Synthesis, K. C. Nicolaou, E. J. Sorensen, Chapter 26.

︎ Professor Clayton Heathcock

︎ Professor of Organic Chemistry, UC Berkeley

︎ Natural product synthesis

︎ Stereochemistry of the aldol reacon

CO2Me

H H H H

HN HN HN

methyl homosecodaphniphylate ‘protodaphniphyllin’ 1st pentacyclic intermediate in biosynthesis?

squalene Natural Product Chemistry II 38

︎ Plausible biogenesis / retrosynthesis - high molecular complexity reduced to linear precursor

R R R

H H H H H aza-Prins

HN HN N H

‘protodaphniphyllin’ 1st penatcyclic intermediate in Diels Alder biosynthesis?

R R R

H H Michael condensaon

O NH N 2 H R R O O

squalene Natural Product Chemistry II 39

︎ Plausible retro-biosynthesis / retrosynthesis - high molecular complexity reduced to linear precursor R R R R NH O 2 P OH HO O O N Me H [O] O Me O Me O H OH H OH H BEnz R R N R N R O N N

squalene H H O BEnz O OH OH P P O O O O

R R R R

H hydrolysis

N OH O Me O H H OH R R R N R NH2 NH2 N H O OH P O O squalene Natural Product Chemistry II 40

︎ Biomimec synthesis of methyl homosecodaphniphylate OBn OBn OBn H (COCl) , DMSO H HO 2 O H then Et3N NH3 HO O then AcOH N

5 steps from ‘simple’ OBn OBn OBn starng materials

H H H H

H

HN N N H H

OBn OH

H H CO Me H H 2 i) CrO3, H2SO4 H H2, Pd ii) MeOH, H2SO4 H HN 96% HN 89% HN 77% Natural Product Chemistry II 41

︎ Biomimec synthesis of methyl homosecodaphniphylate OBn OBn OBn H (COCl) , DMSO H HO 2 O then Et3N MeNH2 H HO O then AcOH, NH4OAc N Me 5 steps from ‘simple’ starng materials OBn OBn OBn

H H H hydride H H transfer

N N N H Me

hydrolysis OBn 75%

H CO2Me H

H H

HN HN Natural Product Chemistry II 42

︎ Biomimec “one step” synthesis of dihydro ‘protodaphniphyllin’ Me O N O NHMe R O MeNH2 OH then AcOH, R NH4OAc R R

R R

Diels- R Me H H Me N Alder N R

Me N Me N O R aza-Prins R

R R

H H hydride H H H H water transfer one pot H N N HN 5-rings 4-C-C bonds 65% 2-C-N bonds 7 stereocentres Natural Product Chemistry II 43

︎ Manzamine alkaloids - cytotoxic ︎ Sir Jack Baldwin Isolaon of manzamine A, J. Am. Chem. Soc., 1986, 108, “Moreover, its provenance is problemacal as there appears ︎ Waynflete Professor of Organic to be no obvious biogenec path.” Chemistry 1978-2005

︎ ︎ Biogenesis of the manzamine alkaloids, Baldwin’s Rules J. E. Baldwin, R. C. Whitehead, Tetrahedron Le., 1992, 33, 2059 ︎ “In fact the structural analysis of these substances Biosynthesis of penicillins reveals that they may be derived in vivo from three building blocks…..

HO2C

NH2 N N N N H N N N O H H H H H H H H OH H O N N N

NH3 N HN H H H

O O

manzamine A manzamine B manzamine C

︎ “Biogenecally an aldehyde funcon is equivalent to an α-ketoacid or an α-amino acid. The simplest of these has been used in this treatment.” Natural Product Chemistry II 44

︎ Biogenesis of the manzamine alkaloids, J. E. Baldwin, R. C Whitehead, Tetrahedron Le., 1992, 33, 2059

H O N N H H N N HO2C H H + H H H H H NH2 N N H O H H N N HN HN HN N N

manzamine B N N

CHO N HN N N reduce N N N

N

keramaphidin F O O

O H H H N N N H NH3 NH3 N O H H

O O Natural Product Chemistry II 45

︎ Biosynthec synthesis of keramaphidin B, J. E. Baldwin, T. D. W. Claridge, A. J. Culshaw, F. A. Heupel, V. Lee, D. R. Spring, R. C. Whitehead, Angew. Chem. Int. Ed., 1998, 37, 2661. O ,"TsOH KHMDS&then Ph3P OH Ph3P O O O O O 93% I I H i) HCl, MeOH N I N 83% ii) TsCl, Et3N 89%

N NaI,%heat N N TsO N N

NaBH4, MeOH I i)#mCPBA ii) O O MeOH, N F C O CF pH 7.3 N 3 3 N N N 100% H N 56% from tosylate

N N

then%NaBH4

N 0.2-0.3% N

keramaphidin F Natural Product Chemistry II 46

︎ FR-901483 – potent immunosuppressant; Snider, J. Am. Chem. Soc., 1999, 121, 7778; Sorensen, Angew. Chem. Int.. Ed., 2000, 39, 4593. OMe OMe OMe

N H N H N H MeHN HO MeHNMeHN HO MeHN HO H H H OH H H O P OH O OH O aldol

OMe OMe OMe

N H MeHN O N CO Me N CHO MeHN 2 MeHN O O O oxidave cyclisaon OMe

tyrosine O H MeHN OH N CO2Me NH HO 2

OH Natural Product Chemistry II 47

︎ FR-901483 – potent immunosuppressant; Sorensen, Angew. Chem. Int.. Ed., 2000, 39, 4593.

OMe OMe OMe

Ns O Ns OAc Ns H I H MeN NaBH(OAc)3 MeN OAc MeN H H2N CO2Me N CO2Me N CO2Me reducve aminaon OAc I OH OH O

OMe OMe OMe

i)#PhSNa Me H2,$Raney Me ii)#Boc2O, Ns N CO Me Ni N CO Me pyridine N CO Me BocN 2 BocN 2 MeN 2

OH O O

i)#LiAlH4 ii)#(COCl)2,#DMSO OMe then#Et3N N H OMe OMe MeHN HO H NaOMe,' H OH Me Me O P N H MeOH N H O O OH BocN O BocN O HO S aldol H O N O O 2 Ns#=#p%nitrobenzenesulfonyl Natural Product Chemistry II 48

︎ FR-901483 – potent immunosuppressant; Sorensen, Angew. Chem. Int.. Ed., 2000, 39, 4593.

OMe OMe OMe O Me H2,$Raney N OiPr Me Me iPrO N N H N H Ni N H BocN HO BocN HO BocN O HO H OBn OH HO OBn ,"PPh H P 3 O OBn H O H P H O OBn O Mitsunobu reacon i)#H2,#Pd ii)#HCl,#MeOH

OMe

N H MeHN HO H H OH O P OH O Natural Product Chemistry II 49

︎ Tetronasin – ionophore anbioc – biosynthesis – Ley and Staunton, Tetrahedron Le., 1994, 35, 307 (and following papers), synthesis, Ley J. Chem. Soc., Perkin 1, 1998, 2259.

Me Me Me HO O Me H H HO HO Me O Me H H H O Me Me OMe H H ONa Me OMe H O Me O ︎ Professor Steven Ley, FRS O

O O Me ︎ BP 1702 Chair, University of H NaO Cambridge, 1992- HO H Me Me H O ︎ Professor at Imperial College, O Na H Me London, 1983-1992 H Me O O ︎ Natural product synthesis, H methodology: TPAP, supported O Me MeO reagents, flow chemistry

Me oxidise polyacetate/proprionate Me Me Me Me Me Me X

O O OH OH tetronic acid cyclohexane THP formaon THF formaon formaon Natural Product Chemistry II 50

︎ Tetronasin – ionophore anbioc – biosynthesis – Ley and Staunton, Tetrahedron Le., 1994, 35 307 (and following papers), synthesis, Ley J. Chem. Soc., Perkin 1, 1998, 2259.

EtO O H Me Me Me EtO C Me H O 2 HO KHMDS, toluene O K H Me Me H O H H O Me OMe Me H OMe MeO

CO2Me Me Me Me 67%

Me Me O Me Me HO O EtO O H H H H Me Me O O H H H H Me Me OMe Me Me OMe ONa H H Me Me O O OMe O O Natural Product Chemistry II 51

︎ Electrocyclic reacons exemplified – biogenesis of the endiandric acids.

Ph H Ph H H H H H H H H CO2Me H CO Me H CO2Me H 2 H CO2Me H H Ph H Ph H H H H H H endiandric acid A endiandric acid B endiandric acid C endiandric acid D methyl ester methyl ester methyl ester methyl ester

Diels Alder Diels Alder Diels Alder 6π electrocyclic

H Ph H Ph H H H H H CO2Me H CO2Me H CO Me Ph CO Me 2 H H H 2 Ph endiandric acid E endiandric acid F endiandric acid G methyl ester methyl ester methyl ester 8π electrocyclic

6π electrocyclic 6π electrocyclic

H H H H 8π electrocyclic CO Me 2 CO Me Ph Ph 2 CO2Me Ph CO2Me Ph ︎ Biosynthesis proposed by Black J. Chem. Soc., Chem. Commun., 1980, 902. ︎ Biomimec synthesis by K. C. Nicolaou, J. Am. Chem. Soc., 1982, 104, 5558. Natural Product Chemistry II 52

︎ Electrocyclic reacons exemplified – the endiandric acids. π8a H Lindlar 2 HH CO2Me CO2Me CO Me Ph Ph 2 8π electrocyclic ring closure - Ph conrotatory π6s

Ph R H H H H CO Me H H 2 R' H H

H CO2Me 6π electrocyclic CO2Me ring closure - Ph exo-Diels Alder Ph heat, 100 °C endiandric acid E disrotatory π6s reacon methyl ester 6π electrocyclic R Ph H ring closure - H H H disrotatory H R' CO2Me H H H endiandric acid A endiandric acid D H H H H methyl ester methyl ester H CO2Me Ph H CO2Me

Ph Natural Product Chemistry II 53

︎ Electrocyclic reacons exemplified – the endiandric acids. π8a

H2 Lindlar

CO2Me Ph CO2Me Ph 8π electrocyclic Ph CO2Me ring closure - π6s conrotatory R Ph H H H H CO2Me H H R' H H

H CO2Me 6π electrocyclic ring closure - Ph Ph CO Me heat, exo-Diels Alder endiandric acid F disrotatory 2 100 °C reacon methyl ester π6s 6π electrocyclic Ph H ring closure - R H disrotatory H H H CO2Me R' H H H endo-Diels Alder endiandric acid B H H H reacon H H methyl ester H H CO Me H 2 H Ph CO Me Ph H H CO2Me 2 H Ph endiandric acid C endiandric acid G methyl ester methyl ester