Part I Biomimetic Total Synthesis of Alkaloids - Wiley-VCH

60 Pages·2011·0.7 MB·English

1
PartI
BiomimeticTotalSynthesisofAlkaloids
BiomimeticOrganicSynthesis,FirstEdition.EditedbyErwanPouponandBastienNay.
2011Wiley-VCHVerlagGmbH&Co.KGaA.Published2011byWiley-VCHVerlagGmbH&Co.KGaA.

3
1
BiomimeticSynthesisofOrnithine/ArginineandLysine-Derived
Alkaloids:Selected Examples
ErwanPoupon,RimSalame,andLok-HangYan
1.1
Ornithine/ArginineandLysine:MetabolismOverview1)
1.1.1
Introduction:ThreeImportantBasicAminoAcids
• l-Ornithine(l-1)(l-Orn,Figure1.1)isanon-proteinogenicaminoacidproduced
froml-glutamicacid(4)inplantsandfroml-arginine(2)inanimals.l-Ornithine
playsacentralroleintheureacycleinterrestrialvertebrates[1].
• l-Arginine:Withitsguanidineresidue,l-Arginine(l-2)(l-Arg,R)isahighlybasic
aminoacid.ItisencodedbyDNAandisthedirectprecursorof l-ornithine(l-1),
urea, and also nitric oxide. It is also be encountered in some natural products
(seebelow)[1,2].
• l-Lysine(l-3)(l-Lys,K):istheonlyaminoacidtohavetwodifferentbiosynthetic
pathways.Oneistheaspartate(5)pathwaypresentinbacteria,plants,andalgae.
Theotherstartsfromα-ketoglutarate(6)andispresentinfungi[3,4].Lysineis
anessentialaminoacidforhumans.
Scheme 1.1 reflects some of the biochemical relations between l-ornithine
(l-1)/l-arginine(l-2)andl-lysine(l-3).Itisofcoursenottheaimofthischapterto
providefurtherdetailsconcerningtheirrespectivebiosynthesis.2) Onlyimportant
metabolic intermediates, helpful for a better comprehension of the following
sections,havebeenstressed.
1)Thesethreeaminoacids(Figure1.1)share lysine and arginine/ornithine derived
commonchemicalreactivityandareimpli- naturalsubstancesinasinglechapter.
catedinmoreorlesssimilarbiosynthetic 2)Theinterestedreaderisreferredtoclassi-
pathways.Wethusdecided,inaneffortto calbiochemistrytextbooks.
establish useful comparisons, to garner
BiomimeticOrganicSynthesis,FirstEdition.EditedbyErwanPouponandBastienNay.
2011Wiley-VCHVerlagGmbH&Co.KGaA.Published2011byWiley-VCHVerlagGmbH&Co.KGaA.
4 1 BiomimeticSynthesisofOrnithine/ArginineandLysine-DerivedAlkaloids:SelectedExamples
"C N" units
4
NH pK 1.8
pK 13.2 a
aH2N NH CO2H pKa 10.7 H2N d a CO2H pKa 1.7
L-arginine 2 (R) NH2 pKa 9 L-ornithine 1 NH2 pKa 8.7
(encoded by DNA) (not encoded by DNA)
nitrogen of the derived alkaloids
"C5N" units pKa 10.5 H2N e a CO2H pKa 2.2
NH
L-lysine 3 (K) 2 pKa 8.9
(encoded by DNA)
Figure 1.1 Structure of the amino acids.
COH COH
HO2C 2 HO2C 2 COH
oxaloacetic acid O NH2 2
Asp 5 NH2 NH2
L-Lys L-3
citric acid cycle H
HOC N
(Krebs cycle) 2
NH L-pipecolic
acid L-9
HO2C CO2H HN N CO2H L-Arg L-2
2 H
O NH2
2-ketoglutarate 6
urea cycle H2N
(animals) NH
H2N urea
HOC COH COH
2 2 HN 2
2
NH NH
L-Glutamic acid 2 2
(Glu) 4 L-Ornithine 1
NH2
HN
H 2
HO2C N L-proline L-8 putrescine 7
Scheme 1.1 Place of the three amino acids in primary metabolism.
1.1 Ornithine/ArginineandLysine:MetabolismOverview 5
1.1.2
FromPrimaryMetabolismtoAlkaloidBiosynthesis
Theparallelbetweenl-ornithine(l-1)andl-lysine(l-3)metabolismconcerningtheir
catabolism/biotransformationandsubsequentchemicalreactivitytoformalkaloids
isobvious(eveniftheincorporatednitrogenatomisdifferent,thatis,incorpora-
tion of the α-amino group for ornithine and ε-amino group for lysine). Mainly,
both amino acids will be able to undergo decarboxylation to the corresponding
diamine[putrescine7(C )andcadaverine10(C ),respectively]andthenoxidative
4 5
deaminationintoaminoaldehydes(seebelow).Thereby,ratherstableaminoacids
areturnedintohighlyreactiveunitssuitablefornaturalorganicchemistry.
1.1.2.1 L-OrnithineEntryintoSecondaryMetabolism3)
The diamine putrescine (7) can be formed directly from the decarboxylation of
l-ornithine (1) (Scheme 1.2); it can also be derived from l-arginine (2) [6] after
decarboxylationandtransformationoftheguanidinefunctionalgroup.Putrescine
(7) is then mono-N-methylated4) by putrescine N-methyltransferase (PMT). This
reactionisthefirstpurely‘‘secondarymetabolite’’stepand11isthefirstspecific
metabolite towards alkaloids. N-Methylputrescine (11) may then be oxidatively
deaminatedbydiamineoxidaseto4-methylaminobutanal(12),whichgeneratesthe
N-methyl-(cid:3)1-pyrroliniumcation 13,acornerstoneelectrophilicintermediate and
acentralprecursorofnumerousalkaloidsbelongingtothepyrrolidineortropane
groupswhenthereactionwithanappropriatenucleophileoccurs.
Me
COH decarboxylation NH N-methylation NH
H2N 2 H2N 2 H2N
L-ornithine L-1NH2 –CO2 putrescine 7 11
+CH3 −Nu –H2O Me doexiadmatiinvaetion
Me N NH
paylrkraolloididinse N Nu 13 O 12
N tropane
Me
alkaloids
Scheme 1.2 Key elements of ornithine metabolism towards alkaloids.
1.1.2.2 L-LysineEntryintoSecondaryMetabolism5)
Decarboxylation of l-lysine (l-3) into the diamine cadaverine (10) (Scheme 1.3)
followed by oxidative deamination leads to aminopentanal 14, which can cyclize
into tetrahydropyridine 15.6) This latter is most likely the universal intermediate
3)Thefundamentalfirststepsofornithine(or 5)Theinterestedreaderisreferredtoclassical
lysine) catabolism towards alkaloids now biochemistrytextbooks.
constitute a classic in biosynthesis text- 6)Synonymousterms:2,3,4,5-tetrahydropyri-
books.See,amongothers,Reference[5]. dine=(cid:3)1-piperideine(imineform);1,2,3,
4)This important step has been widely 4-tetrahydropyridine = (cid:3)2-piperideine
studied. PMT is closely related to (enamineform).
spermidinesynthase.SeeReference[7]for
avaluablereview.
6 1 BiomimeticSynthesisofOrnithine/ArginineandLysine-DerivedAlkaloids:SelectedExamples
O
NH NH oxidative NH
HO 2 –CO 2 deamination 2
2
NH2 NH2 O
L-lysine 3 cadaverine 10 5-aminopentanal 14
H −
H N Nu
N
H
N N –H2O
H
15
tetrahydroanabasine
lupine alkaloids
16
H
Nu N
piperidine alkaloids
Scheme 1.3 Key elements of lysine metabolism toward alkaloids.
to lysine-derived piperidine alkaloids. This imine is too unstable and reactive to
be isolated as such from plant material. Nucleophilic addition reactions at the
imine function with suitable nucleophiles help stabilize 15 and are at the origin
of various piperidine alkaloids. Dimerization into tetrahydroanabasine (16) is an
importantalternativeinthelysinemetabolism(theenamineformof15beingthe
nucleophile). This latter reaction is spontaneous at physiological pH (vide infra)
though stereospecific coupling involves an appropriate enzymic intervention in
plants[8].Tetrahydroanabasine(16)(whichisprobablyalsoquiteunstableassuch
in vivo) can then undergo various transformations and is at the origin of a class
ofalkaloidsknownas‘‘lupinealkaloids’’(Section1.4.2).
1.1.3
CloselyRelatedAminoAcids
• l-Proline:(l-8)(l-Pro,P,Scheme1.1)isoneofthe20aminoacidsofthegenetic
codebuttheonlyonewithasecondaryaminefunction.Itisbiosynthesizedfrom
l-glutamicacid[9].l-Prolinerecentlyincreasedinimportancewiththesuccessful
developmentoforganocatalysis.
• l-Pipecolic acid: Unlike l-proline (l-8), l-pipecolic acid (l-9) (Scheme 1.1) is a
non-proteogenic amino acid. It derives from l-lysine and is at the origin of
severalclassesofsecondarymetabolites.Biosyntheticandbiomimeticaspectsof
pipecolicacidarediscussedbelow.7)
7)Othercloseaminoacidsexist;ofparticular Alkaloids); see also Reference [10].
interest are piperazic acids (structure H
shown here). Their biosynthesis from HO2C N NH
lysine is discussed in Chapter 10
(Indole-Oxidized and Complex Peptide
1.1 Ornithine/ArginineandLysine:MetabolismOverview 7
1.1.4
TheCaseofPolyamineAlkaloids
CaseswhereaC N buildingblockisincorporated[i.e.,thepolyamineputrescine
4 2
(7)] include ‘‘polyamine alkaloids’’ (Scheme 1.4). Comprehensive review articles,
especially by M. Hesse and colleagues, have appeared detailing the massive
amountofworkdoneinthefieldofthesesecondarymetabolitesduringthelast20
years[11,12].Essentially,sixbasicbackbonecomponents,namely,putrescine(7),
spermidines(17,18),homospermidines(19,20),spermine(21),andhomospermine
(22),participateintheskeletonofpolyaminealkaloids.Figure1.2givesexamples
of cyclic polyamine alkaloids [piriferine (23), celacinnine (24), aphelandrine (25),
andlipogrammistinA(26)],organizedaccordingtotheclassificationofM.Hesse
andcolleagues(seeReference[11]).Interestingly,cadaverineunitsareveryrarely
present in such cyclic molecules. Despite interesting biomimetic syntheses [13],
polyaminealkaloidswillnotbecoveredinthischapter(exceptforthebiosynthesis
ofpyrrolidinealkaloids;seeSection1.3.1).
CO2H H CH3 H2N
H N N R H2N S Adenosyl N N
2
H C
3
L-ornithine or L-arginine S N N
O
H N HO OH
2
CO H
2
C C C
3 4 3
S-adenosylmethionine
putrescine 7 NH
H N 2
2
H
spermidine 17 N NH
H N 2
2
H
spermine 21 N NH
H N N 2
2 H
H
H N N NH sym-Nor-spermidine 18
2 2
H
H N N NH homospermidine 19
2 2
H
N sym-homospermidine 20
H N NH
2 2
H H
H N N N NH sym-homospermine 22
2 2
Scheme 1.4 Main polyamine backbones encountered in polyamine alkaloids.
8 1 BiomimeticSynthesisofOrnithine/ArginineandLysine-DerivedAlkaloids:SelectedExamples
cyclic putrescine cyclic spermidine alkaloids:
alkaloids:
O O
O
N NH H NH N
O Ph N
H Ph
piriferine 23 celacinnine 24
Ph
[Aglaia pirifera] [Maytenus heterophylla...]
cyclic spermine alkaloids: cyclic sym-homospermine alkaloids:
(rare)
aphelandrine 25 O O
[Aphelandra aurantiaca...]
H O N N
H
O N N N
H H
O O
N lipogrammistin A 26
H [Diploprion bifasciatum]
H NH
HN
Figure 1.2 Representative polyamine alkaloids.
1.1.5
BiomimeticSynthesisofAlkaloids
Ionic iminium/enamine reactions are central to the construction of the title
alkaloids, especially the Mannich reaction. This is probably one reason why
biomimetic strategies have been particularly efficient in this class of secondary
metabolites. We will, of course, approach in this chapter only some of the mul-
tifaceted aspects of the biomimetic chemistry of l-lysine or l-ornithine/arginine
derived secondary metabolites. We will select topics and examples that are not
covered(ornotwiththescrutinywethinkopportune)inotherreviewarticles.This
isespeciallythecasewhendealingwiththemanipulationofsmallreactiveC and
4
C unitsderivedfromthethreeaminoacids.Someselectedexamplesarepresented
5
inthefollowingsectionsandorganizedasfollows:
• biomimeticsynthesesfroml-lysineandl-ornithine/l-arginineorC ,C reactive
4 5
unitspresumablyderivedfromtheaminoacids;
• selectedexamplesofbiomimeticsynthesesofmorecomplexstructures.8)
8)Fortheimplementationofhighlycomplex see Chapter 7 (Biomimetic Synthesis of
metabolisms within marine sponges and Marine Pyrrole-2-aminoimidazole and
involving, according to biosynthetic pro- GuanidiniumAlkaloids).
posals, l-lysine, l-arginine, and l-proline
1.2 BiomimeticallyRelatedChemistryofOrnithine-andLysine-DerivedReactiveUnits 9
1.2
BiomimeticallyRelatedChemistryofOrnithine-andLysine-DerivedReactiveUnits
1.2.1
Ornithine-DerivedReactiveUnits
1.2.1.1 BiomimeticBehaviorof4-Aminobutyraldehyde
The Christophersen group studied the evolution of aqueous solutions of
4-aminobutyraldehyde (27) [prepared from aminobutyraldehyde dimethyl acetal
(28),Scheme1.5]by1HNMRoverawidepHrange(1–12)[14].Entropicfactors
explaintherapidformationofcyclicimine29,whichcantrimerizeinto30.When
in aqueous solution, different species are in equilibrium and are depicted in
Scheme1.5.Alongwithaminobutanal27,twoneutral(pyrrolidine29andtrimer
30),andfourprotonatedentities(31–34)weredetectedandtrackedasafunction
of pH. Around physiological pH, the four protonated species predominate.
Owing to the rapid emergence of acid-catalyzed aldol condensation products,
the authors cautiously avoided concentrated solution. As we will detail in a
comingsection,nodimericstructuresuchas35hasbeencharacterizedfromthe
mixtures.
+
HN 33
3 10% at pH 1-4
O
+
OMe 2M HClH2N H3N HO 20% at pH 1-7
O OH
HN
2 28 OMe 27 31 H H
N
50% + OH
at pH 1-6
± HO
2 32
H
+
N N N
N N
H
N
30 29 34 N
100% at pH 9 20% at pH 1-7 35
20% at pH 13 not found
% indicate the highest yield of the entities and the corresponding pH
+ H H H + HO +
6<pH<7 N +N H3N OH H3N O
OH
34 (20%) 32 (50%) 31 (20%) 33 (10%)
Scheme 1.5 Biomimeticreactions from 4-aminobutyraldehyde(27).
With substituted nitrogen atom, for example, with a biosynthetically relevant
aminobutyl side chain (Scheme 1.6), the formation of the pyrrolidinium ring
is nearly exclusive, with 36 predominant among several other entities [15].
10 1 BiomimeticSynthesisofOrnithine/ArginineandLysine-DerivedAlkaloids:SelectedExamples
+ +
N N+H3 N NH2 N NH
36 37
pH 1.1-8 pH 7.2-8 pH 8.0-12.7
± HO
HO N NH pH 9 2
2
Scheme 1.6 Biomimeticbehavior of a substituted pyrrolidiniumion.
Notably, aminal 37 is a bicyclic compound that is formed spontaneously at
basicpH.9)
1.2.1.2 Dimerization
Whereasdimerizationofsix-memberedringenaminesisamajoroutcome(aswe
willdiscussindetailwhendealingwithlysine-derivedunits),thedimerizationofthe
correspondingfive-memberedringsystemssuchas29isbyfarlessdescribedinthe
literature.Thechemistryofthesemoleculesis,correspondingly,simplerthanthatof
lysine,probablybecauseofalesserpropensitytoreactasanenamine(Scheme1.7).
Me Me
+NH NH N ? H MeN Me N Me N Me
29 N N+ N N
35
13 38 39
[Nicotiana tabacum]
Scheme 1.7 Dimerization in the pyrrolidineseries.
The dimer type 35 has never been described, although it has been postulated
in some biosynthesis (Section 1.3.3). In the case of N-methyl substituted 13,10)
dimerization has been observed and dimer 38 characterized. Notably, the cor-
responding reduced dimer 39 has been detected as a mixture of diastereomers
fromtherootsystemofNicotianatabacum,aswellasmonomeric13[18].Infact,
at physiological pH (around 7.2 in a growing tobacco plant), the coexistence of
imine and enamine formsof13shouldprovidetheopportunityformoreor less
spontaneouscondensations.
In the laboratory (Scheme 1.8), starting from N-methyl-4-aminobutanal di-
ethyl acetal(40) in acidic conditions,deprotectionaffords12,which cyclizes into
biosyntheticintermediate13,whichinturncandimerizeinto38.Theproductofa
retro-Michaelreaction,41,hasalsobeenfullycharacterized;itwasusuallyobserved
as an impurity in the course of the synthesis of monomers 13 [19]. Alternative
9)Diazabicyclononane37wasisolatedearlier in fact an early and central precursor of
frominvitrochemicalorenzymicconver- manyalkaloidsasthefirstspecificmetabo-
sion of spermidine with pea seedling di- lite en route to alkaloids such as nicotine
amineoxidase(PSDO);seeReference[16]. ortropanesviaN-methylpyrrolinium (13)
10)Is monomeric 29 too reactive and un- (whichcouldthereforebemorestablethan
stable? N-Monomethylputrescine (11) is 15);seeReferences[5,17].