biomimetic organic synthesis (poupon:biomim.synth. 2v o-bk) || biomimetic synthesis of manzamine...

181

6

Biomimetic Synthesis of Manzamine Alkaloids*

Romain Duval and Erwan Poupon

6.1Introduction

Since the isolation of manzamine A (1) in 1986 [1] the manzamine group of alka-loids1) has been enriched continuously by the discovery of novel marine compoundswith unprecedented molecular architectures (Figures 6.1 and 6.2). Nearly 100 ofalkaloids have been isolated to date from sponges of the order Haplosclerida andDictyoceratida. This apparently heterogeneous family of alkaloids2) encompasses:

1) 3-Alkylpyridines and 3-alkylpyridinium salts (see the examples of monomerictheonelladin A (2) [2], oligomeric cyclostellettamine A (3) [3], and niphatoxin B(4) [4], and also polymeric structures such as halitoxins (5) [5]–Figure 6.1);

2) Elaborated and sometimes highly complex structures; see the examples ofmanzamine A (1) [1], sarain A (6) [6], keramaphidin B (7) [7], halicyclamine A(8) [8], manadomanzamine A (9) [9], nakadomarine A (10) [10], madangamineC (11) [11], misenine (12) [12], and upenamide A (13) [13] (Figure 6.2).

Despite their high structural diversity and variable sponge origin, the manzaminealkaloids exhibit common structural features, such as polycyclic bis-nitrogenatedcores and macrocyclic alkyl loops, suggesting a common biosynthetic origin.This led to the proposal of ‘‘universal’’ biogenetic hypotheses for these com-plex secondary compounds, and motivated their biomimetic synthesis by severalresearch groups.3)

∗ In memory of the late Dr ChristianMarazano whose creativity and humanitywill always inspire us.

1) The term ‘‘manzamine alkaloids’’ will beused throughout the chapter, as recom-mended by Marazano and colleagues, in-stead of less specific ‘‘3-alkylpiperidine al-kaloids.’’

2) Although identical alkaloids were some-times isolated from different sponges, only

the one organism from which the moleculewas first characterized is given in thischapter.

3) Of particular interest and with importantconsequences among sponge-derived sec-ondary metabolites is the real origin of themolecules. Whether they are produced bythe sponge itself or by associated symbiontsraises exciting questions (who possess thegenes?).

Biomimetic Organic Synthesis, First Edition. Edited by Erwan Poupon and Bastien Nay. 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

182 6 Biomimetic Synthesis of Manzamine Alkaloids

cyclostellettamine A 3[Stelletta maxima]N N

theonelladin A 2 [Theonella swinhoei ]

N NH2monomers:

dimersand oligomers:

polymers:

N

N

N

Me

NMe

Men

n

nn = 2-5

halitoxins 5[Haliclona spp.]

N N

N

6

Cl

5

niphatoxin B 4[Niphates sp.]

("C-C" connection)

("C-N" connection)

Figure 6.1 Examples of simple ‘‘manzamine alkaloids’’:3-alkylpyridines and pyridinium salts.

While numerous articles have already reviewed these fascinating alkaloidsand their total syntheses [14], to the best of our knowledge none has yetconcentrated on comparing their perceived biogenesis and biomimetic synthe-sis. This chapter reviews several possible biogenetic relationships (mapped inSchemes 6.1, 6.24, 6.34, 6.36, and 6.38 and, mainly, Scheme 6.42) between themost representative members of the manzamine alkaloids. This tree-like, ‘‘fromsimple to complex,’’ description integrates biomimetic chemistry studies to illus-trate how, and to what extent, some hypotheses were validated or invalidated byexperimental synthesis. Comprehensive reviews on the structure and sources ofmanzamine alkaloids as well as their total synthesis and biological activities willbe found elsewhere [14]. From the discovery of manzamine A to the brilliant in-tuitions of Baldwin and Marazano and to the latest development in total synthesiswe will embark on a journey that covers 25 years of discoveries of fascinatingnatural substances and biosynthetically driven chemical endeavors (see timescaleon Figure 6.3).

6.2Two Complementary Hypotheses: An ‘‘Acrolein Scenario’’ and a ‘‘MalondialdehydeScenario’’

6.2.1From Fatty Aldehydes Precursors to Simple 3-Alkyl-Pyridine Alkaloids

The manzamine alkaloids, which feature large alkyl chains or loops, must at leastpartly originate from polyacetate metabolism. In a memorable paper entitled ‘‘Onthe biosynthesis of manzamines’’ published in 1992, this observation led Bald-win and Whitehead from the University of Oxford to propose fatty dialdehydes

6.2 Two Complementary Hypotheses: An ‘‘Acrolein Scenario’’ and a ‘‘Malondialdehyde Scenario’’ 183

O

N

OH

N

NH

HNO

man

adom

anza

min

e A

9[A

cant

host

rong

ylop

hora

sp.

]

N

N

NN H O

H

H

H

man

zam

ine

A 1

[Hal

iclo

na s

p.]

N

N

H

HH

halic

ycla

min

e A

8[H

alic

lona

sp.

]

NO

NH

naka

dom

arin

e A

10

[Am

phim

edon

sp.

]

O HO

ON

HH

ON

upen

amid

e A

13

[Ech

inoc

halin

a sp

.]

N

N

H

x

y

mis

enin

e12

[Ren

iera

sp.

]

N

N

mad

anga

min

e C

11

[Xes

tosp

ongi

a in

gens

]

mac

rocy

clic

com

plex

alk

aloi

ds:

NNO

sara

in A

6[R

enie

ra s

arai

]H

O

HO

kera

map

hidi

n B

7[A

mph

imed

on s

p.]

NN

H

Figu

re6.

2Ex

ampl

esof

com

plex

man

zam

ines

:m

acro

cycl

icpo

lycy

clic

alka

loid

s.


theo

nel

lad

ine

A t

ype

NN

NN

H2

NH

2

OO

tran

sam

inat

ion

NH

2NH

2O

dim

eriz

atio

n or

olig

omer

izat

ion

H2N

O "NH

3"

fatty

aci

dca

tabo

lism

X =

H: a

crol

ein

16X

= O

H: m

alon

dial

dehy

de 1

7

cycl

ost

elle

ttam

ine

A t

ype

NN

X=

OH

(17

)

O

OXO

XO

X O

and

oxid

atio

n if

X=

H

−2 H

2O

−2 H

2O

−2 H

2OX

=H

(16

)

oxid

atio

n

mon

omer

form

atio

n

exis

tenc

e of

abi

osyn

thet

ic Z

inck

e-ty

pere

actio

n?

3

33

NN

OO

xest

osp

on

gin

typ

e −2 H

2Oan

d re

duct

ion

see

sche

me

6.11

for

deta

ils

see

sche

me

6.2

for

deta

ilsse

e sc

hem

e 6.

2fo

r de

tails

see

sche

me

6.2

for

deta

ils

14 15

1515

18

XO

Sche

me

6.1

Prop

osed

bios

ynth

esis

of3-

alky

lpyr

idin

eal

kalo

ids:

(i)

mon

omer

s:ne

edfo

ran

exog

enou

sni

trog

enso

urce

(am

-m

onia

equi

vale

nts)

and

(ii)

dim

ers

(and

olig

omer

s):

self-

amin

atin

gpr

oces

s,th

atis

,on

eam

ino-

alde

hyde

part

ner

isth

eni

tro-

gen

sour

cefo

rth

eot

her.

Lipo

phili

cch

ains

and

mac

rocy

cles

ofth

ena

tura

lal

kalo

ids

are

depi

cted

bylo

ops

inSc

hem

es6.

1,6.

11,

6.25

and

6.30

,al

-lo

win

ga

visi

onof

the

poss

ible

rela

tions

hips

betw

een

hete

rocy

clic

core

sof

repr

esen

tativ

eal

kalo

ids,

irre

spec

tive

ofsp

ecifi

cst

ruct

ural

diffe

renc

es(s

uch

asch

ain

leng

th,

unsa

tura

tions

,et

c.).


N

N

N NH

OH

H

H

1980 1990 2000 2010

1986: discovery ofmanzamine A byHiga and coll. 1992: the "acrolein scenario"

by Baldwin andWhitehead

O

1998: a unified alternative"malonaldehyde scenario"

by Marazano and coll.1998: first total synthesis of

manzamine A by Winkler and coll.

OO

N N

1998: biomimetic synthesis ofkeramaphidin B by Baldwin and coll.

2006: total synthesis ofsarain A by Overman and coll.

N N

O

HO

HO

N

N

HH

H

H

2010: total synthesis ofhaliclonacyclamine C bySulikowski and coll.

Figure 6.3 Selected milestones in 25 years of manzamine alkaloid chemistry.

(possibly coming from fatty acid catabolism) as universal, bifunctional precursorsof what would become the ‘‘manzamine family’’ [15]. According to this seminalhypothesis, dialdehydes in C8 –C16 such as 14 would be monoaminated with eitherpyridoxamine (via transamination) or ammonia (via reductive amination) to yieldamino-aldehydes 15 (Scheme 6.1). Also plausibly produced by fatty acid degrada-tion (see below), acrolein 16 (the original C3 species hypothesized by Baldwin) ormalondialdehyde 17 (alternative C3 species proposed by Marazano in 1998 at theInstitut de Chimie des Substances Naturelles in Gif-sur-Yvette [16]) would reactwith 15 and a source of ammonia, furnishing pyridine alkaloids of the theonelladinA type. On the other hand, dimerization of amino-aldehydes 15 in the presenceof two equivalents of acrolein 16 or malondialdehyde 17 would furnish alkaloidsof the cyclostellettamine type via dihydropyridiniums 18. Formation of alkaloidsof the xestospongin type would occur in the case of alkyl chains β-hydroxylatedrelative to the nitrogen (Section 6.3.2). Scheme 6.2 presents detailed mechanismsfor pyridine ring formation according to both scenarios. Importantly, late oxidationof dihydropyridine species would be required to yield the final pyridine/pyridiniumskeletons when acrolein 16 is incorporated, contrary to malondialdehyde 17.Also important and central to the modified hypothesis involving 17 is the pos-tulate of the existence of two types of C5 reactive units: glutaconaldehydes andaminopentadienals.

In vivo, malondialdehyde (17) results mainly from the catabolism and per-oxidation of polyunsaturated fatty acids such as arachidonic or linolenic acid(Scheme 6.3). Different mechanisms have been proposed, some involving radicalreactions with reactive oxygen species (ROS) [17]. The existence of an acroleinradical (19) has been postulated, which could react with a hydroxyl radical to givemalondialdehyde 17. From this hypothesis, a simple reduction of 19 would explainthe formation of acrolein 16.


O

ONH2 HN

N

−H2O

OO

HN O

or+ HX

aminopentadienals

O

O

glutaconaldehyde

NH2

2 types of C5 units

reactive C3units

aza-aldol

O

NH2

N

O

N

OH

N

Baldwin's hypothesis (1992): a dihydropyridine chemistry

general scheme for theformation of heterocycles

O

NH2

X

O

OX=H: acrolein 16

X=OH:malonaldehyde 17

X

oxidation

Marazano modified hypothesis (1998): a pyridinium chemistry

type 2type 1

Scheme 6.2 Detailed pyridine ring formation according to both scenarios.

poly-unsaturatedfatty acids

(e.g. arachidonic acid)

O

OOH

OO

OH

O

O Omalonaldehyde 17

OH

R H O

acrolein 16?

lipidic peroxidation 19

Scheme 6.3 Plausible origin of C3-reactive units from lipidic peroxidation.

Alternative biosynthetic pathways have been proposed. To date, they have notbeen corroborated by biomimetic chemical synthesis but they merit attention.Amade, Thomas, and colleagues founded their hypothesis for the biosynthesis of3-alkylpyridiniums when they isolated pachychalines A (20) and B (21) from aCaribbean Pachychalina species [18] and pachychaline D (22) from a Callyspongiaspecies [19]. Given the presence of a homospermidine fragment on pachychalineB (21) and D (22), the authors proposed this diamine as a possible C3 unit providerand put together a unified scenario for both C-N and C-C connection patternsnecessitating oxidation steps of primary amines into the corresponding imines(Scheme 6.4).

Imines/enamines cascades could be responsible for the formation of pyridiniumswith a C3 diamine acting as a leaving group. Whatever the biosynthetic schemedevised by chemists, it is striking that it is impossible to avoid some kind of C3

unit.


N12

8

N

12

pach

ycha

line

A 2

0[P

achy

chal

ina

sp.]

N12

N8

N H10pa

chyc

halin

e B

21

[Pac

hych

alin

asp

.]

HN

hom

ospe

rmid

ine

C-C

con

nect

ion

C-N

con

nect

ion

N

N H

12

10N H

pach

ycha

line

D 2

2[C

ally

spon

gia

sp.]

NN HN

H2

NN

NNN

H2

NH

2

NH

2

NH

2

NH

2

NH

2

NH

2

NH

2N

H2

NH

2

NH

2

NH

2

NH

2

NH

2

NN

HN

H

"C-C

con

nect

ion"

-see

abo

ve-

N

N HH

N

"C-N

con

nect

ion"

-see

abo

ve-

oxid

atio

n

N

N

=

N

R1

R1

R1

R1

R1

R1

R1

R1

R1

R1

R2

R2

R2

R2

R2

R2

R2

R2

R2

N

=

N H

O

Ore

duct

ive

amin

atio

n

23

C3

unit

oxid

atio

ns

R2

Sche

me

6.4

Alte

rnat

ive

bios

ynth

etic

hypo

thes

esfo

r3-

alky

lpyr

idin

ium

sba

sed

onth

epa

chyc

halin

ese

ries

.


6.2.2Biomimetic Synthesis of Dihydropyridines and Dihydropyridinium Salts

The order of events in this postulated biosynthesis of pyridine rings, involvingimine/enamine formation, Michael reaction, and aldol/aza-aldol reaction, is un-known. To our knowledge, its closest synthetic equivalent is the Chichibabinsynthesis of pyridines, where ammonia or primary amines and aliphatic alde-hydes in excess react at elevated temperatures to yield 3,4,5-trisubstituted di-hydropyridines/dihydropyridinium salts that spontaneously oxidize to pyridines/pyridinium salts (Scheme 6.5) [20]. This reaction cannot be exploited when pyridinessubstituted with different groups, or dihydropyridine intermediates, are desirable.However, Marazano and colleagues developed a versatile strategy related to theChichibabin synthesis to by-pass these limitations and access Baldwin’s interme-diates, based on the coupling of Strecker (intermediate 24), Michael (intermediate25 formed with 16), and aza-aldol reactions. This ‘‘one-pot’’ procedure capitalizeson the particular reactivity of zinc triflate and directly furnishes 1,3-disubstituteddihydropyridiniums masked under the form of α-aminonitriles 26 (Scheme 6.5)[21]. Those stable equivalents favorably compare to dihydropyridinium 27 obtainedfrom pyridinium salts 28, following the classical reduction-modified Polonovskireaction sequence developed by Husson and colleagues (via tetrahydropyridine 29and N-oxide 30) [22]. Dihydropyridinium 27 can in turn be formed from 25 upon

R

O

KCNR

CN

HN

Ph

O

R

CN

N

Ph

O

AgBF4

RN

Ph

RN

Ph CN

NaBH4 KCN

Zn(OTf)2

R

O

RN

Ph

R

N

Ph

RN

Ph

R

NaBH4, EtOH

N

Ph

RO

mCPBA

O

O

biosyntheticintermediates

NH2

NH2

Ph

TFAA

Marazano biomimetic synthesis of dihydropyridine:

Husson's strategy (modified Polonovski reaction):

NH2

Ph

R

O

RO

RN

Ph

R

R

Historical Chichibabin synthesis of pyridines (1906):

TFAA: trifluoroacetic anhydridemCPBA: meta-chloroperbenzoic acid

R

spontaneousoxidation

24

1625

26

27

29 3028

Scheme 6.5 Syntheses of biomimetic equivalents of dihydropyridines.


treatment with a silver salt and be reduced to 29 with sodium borohydride, usuallywith high selectivity, or trapped with cyanide ions to yield 26.

Conditions for deprotonating stable salts such as 31, prepared in situ by heat-ing masked dihydropyridinium 32, to give the corresponding dihydropyridine33 (that was unstable but could be trapped), were disclosed by the Marazanogroup (Scheme 6.6) [23]. The possibility of favoring one isomer over the other(dihydropyridinium 34) soon appeared to be a challenging problem in gainingchemoselectivity (see the following sections).

N

Ph

MeX N

Ph

Me

OMe

N

Ph

Me

MeO

H

N

Ph

Me

HX

dihydropyridinium salts dihydropyridine

34 3132 33

Scheme 6.6 Isomerization of dihydropyridinium salts to dihydropyridine.

6.2.3A Tool Box of Biomimetic C5 Reactive Units from the ‘‘Old’’ Zincke Reaction

Marazano et al. revisited the century-old Zincke reaction, a nucleophilic ringopening of electron-deficient pyridinium (‘‘Zincke salts,’’ easily prepared frompyridines and electrophiles such as cyanogen bromide or 2,4-dinitrochloro-benzene) [24].

Scheme 6.7 presents the mechanism generally admitted for the Zincke reaction[25]. Ring opening of pyridinium 35 occurs with the first equivalent of amine(usually accompanied by a dark red coloration of the reaction mixture). A sec-ond equivalent of amine then reacts with 36 to provide 37 with extrusion of a2,4-dinitroaniline moiety. In solution, 37 is in equilibrium with two aminopentadi-enimines (38 and 39). Upon heating, intermediate 37 may cyclize into pyridiniumsalts 40 with elimination of one amine moiety [26].

Aminopentadienimines of type 38 and 39 are of particular interest for accessingbiomimetic equivalents of postulated intermediates, namely aminopentadienalsand glutacondialdehydes (Scheme 6.2) [27]. Convenient and scalable accesses tosubstituted glutacondialdehyde salts from the corresponding pyridinium Zinckesalts were recently disclosed4) [28]. Specifically, in these cases, a secondary aminesuch as dimethylamine is employed for the ring-opening to afford firstly salts 42,then biomimetic equivalents 43 of biosynthetic aminopentadienals. These lattercan be hydrolyzed into glutacondialdehyde salts 44 when treated with potassiumhydroxide (Scheme 6.8).

4) Overcoming thereby some drawbacks ofthe ‘‘classical’’ Zincke reaction, such as theuse of two equivalents of amine and the

propensity of aminopentadienals to formpyridinium salts.


N

DNP

R2

R2 R2

R2

R2R2

R2R2

R2

R1

R1

R1

R1

R1

R1R1

R1

R1

DNP= 2,4-dinitrophenyl

RH2N

H2N

N

DNPHNCl

HCl

NHDNP

NR R

N

DNP HN

R

HCl HCl

NR H

NR

HCl

RH2N

DNP NH2NR

pyridinium salts

N NH

RRNH

NRR

aminopentadieniminiums

NR H

NR

R

3536

373839

40

(or other deactivating group)

Scheme 6.7 Mechanism of the Zincke reaction.

N

DNP

R

NMe

Me RO

O

OO

aminopentadienalO

O

glutaconaldehydeNH2NH2

postulated biosynthetic intermediates

HN O

MeHN

Me

ROOK

NMe

Me RN

Me

Me

NaOH"Zincke salts"

"Zinckealdehydes"THF/MeOH

(65-93%)

KOH

glutaconaldehyde salts

41

51-91% from 41

44 43

42EtOH, reflux

Scheme 6.8 Glutacondialdehydes and aminopentadienals asbiosynthetic intermediates and biomimetic equivalents.

RO N N

t-Bu

R

Et

Et

KO OR

RN

t-But-BuNH2

quant.

i-LDA

Et2N NEt2ii -

iii -HCl

RO

O

O

>90%

biosynthetichypothesis

KOH

50-80%2

HCl46 48

44

O OOBn

K 45

LDA: lithium diisopropylamide

47

Scheme 6.9 Alternative synthetic pathway towards substi-tuted glutacondialdehyde salts, using vinamidinium salts asbiomimetic equivalents of malonodialdehyde.

6.3 Biomimetic Synthesis of Pyridinium Marine Sponge Alkaloids 191

More elaborated glutaconaldehyde salts of type 44 (as exemplified by compound45, Scheme 6.9) can also be prepared starting from various aldehydes and vinami-dinium salts 46 (via 47 and 48) [29]. Interestingly, this strategy is reminiscent ofthe first fundamental step in Marazano’s hypothesis of pyridine ring formation,that is, the reaction of a fatty aldehyde with malondialdehyde 17 (see Scheme 6.2for details).

6.3Biomimetic Synthesis of Pyridinium Marine Sponge Alkaloids

6.3.1Biomimetic Total Synthesis of Cyclostellettamine B and Related 3-Alkylpyridiniums

To test their ‘‘malondialdehyde’’ scenario and to demonstrate the suitability ofZincke chemistry toward this end, the access to cyclostellettamine B (49) [3] wasstudied by Marazano and colleagues [16a]. They performed a pseudo-dimerizationof two 3-aminoalkylpyridines (50, 51) of different chain lengths,5) using sequen-tial pyridinium N-activation (via 52 and 53). Cyclostellettamine B (49) was thuselegantly obtained in a biomimetic ‘‘domino-Zincke’’ reaction (Scheme 6.10). Asimilar philosophy permitted the total synthesis of haliclamine A (54) [30, 31] andniphatoxin B (4) [32], and also that of two original molecules isolated and synthe-sized by the Kock group, that is, viscosamine (55) (a trimeric 3-alkylpyridinium)[33] and a monomeric but cyclic 3-alkylpyridinium alkaloid (56) (Scheme 6.10) [34].

6.3.2Biomimetic Synthesis of Xestospongins and Related Structures

Xestospongins are macrocyclic bis-1-oxaquinolizidine alkaloids isolated fromXestospongia exigua (syn. Neopetrosia exigua) [35]. Many other structures are closelyrelated to xestospongins such as araguspongins, and the interested reader is re-ferred to general review articles [14]. We focus herein on the biomimetic synthesisof xestospongins A (57) (Scheme 6.11) and C (58) [35] as well as (+)-aragusponginB (59) (Scheme 6.12) [36] by the Baldwin group in 1998, which also permitted theestablishment of their correct absolute configurations [37].

Biosynthetically, starting from bis-hydroxypyridinium dimer 60 or the corre-sponding dihydropyridinium salt 61, intramolecular trapping of the iminiumswould explain the formation of the oxaquinolizidine ring systems and the naturalsubstances after a reduction step on 62 (Scheme 6.11).

Conformational and configurational differences and/or equilibria between natu-ral substances in this series can be seen to occur via iminium/enamine epimerizingequilibrium, involving ring opening/reclosure to cyclic aminals. The biomimetic

5) The incorporation of chains of variouslengths is of course a critical point in thetotal synthesis of such molecules.


N

NHBoc

NH2N

DNP

Cl N

NHBoc

NCl

N

NH2

NCl DNP

ClNN

cyclostellettamine B 49 [Stelletta maxima]

13 carbons

12 carbons

n-BuOH

reflux

n-BuOH

reflux

Cl-DNP then HCl

N

Nhaliclamine A 54[Haliclona sp.]

N N

N

6

Cl

5

niphatoxin B 4

N

N

N

9

99

viscosamine[Haliclonaviscosa]

55N

4cyclic monomeric

alkaloid 56[Haliclona viscosa]

50

51

52

53

Scheme 6.10 Biomimetic synthesis of cyclostellettamine Band the structure of alkaloids synthesized using a similarphilosophy.

NO

NO

(+)-xestospongin A 57*[Xestospongia exigua]

O O O

see scheme 6.1

NO

N

O5

H H

or

NO

NO

NOH

N

HO

reduction

reduction

oxidation

*absolute configuration as corrected by Baldwin and coll.

5

60

61 62

17 16

Scheme 6.11 Biosynthetic proposal for xestospongin A and related structures.

synthesis of ent-xestospongins A (ent-57) and C (ent-58) and ent-araguspongin B(ent-59) from ent-60 and ent-62 as depicted in Scheme 6.12 probably proceeds viathis pathway, and implicates intermediate ent-61. Two distinct reaction conditionspermitting a reduction of the unsaturated piperidine without reduction of themasked iminium were studied (i.e., hydrogenation with catalytic rhodium or Raneynickel), and gave different ratios of the three natural substances ent-57 and ent-58

6.3 Biomimetic Synthesis of Pyridinium Marine Sponge Alkaloids 193

10 steps

N O

NO

ent-62

DEAD

A

B

N O

NO

N

O

NO

(+)-xestospongin C 58(unnatural isomer)

(−)-xestospongin A 57(unnatural isomer)

+

N OH

N

OH5 A

B

N

O

N

O

(+)-araguspongine B 59(unnatural isomer)

+

conditions

23%17%9.5%77% 7%

Rh on alumina, MeOH, H2;-

N ON

O

N

HO

H

N

OH

fast fast

slow

H

ent-60

DEAD: diethyl azodicarboxylate

O

OEt

O

Raney Ni, MeOH, H2

12

12

Scheme 6.12 Biomimetic synthesis by the Baldwin group.

O

HO

ON

H

H

O N

upenamide 13[Echinochalina sp.]

MeH

H

O N

Me63

H

H

O N

ICHO 64

Figure 6.4 Selected synthetic approaches to upenamide.

and ent-59. Clear establishment of the absolute configurations of (+)-xestosponginA (57) and (−)-xestospongin C (58) and questions concerning those of araguspongin(59) alkaloids were also discussed by Baldwin and colleagues [37].

Similar stereoelectronic outcomes, which we will not discuss here, were studiedduring the synthesis of the octahydropyrano-pyridine ring system of upenamide(13) by the Marazano [38] and Sulikowski groups [39]. The fragments (63 and64) prepared by each group are presented in Figure 6.4. To date, this fascinatingalkaloid has resisted total synthesis.

6.3.3Is the Zincke-Type Pyridine Ring-Opening Biomimetic?

To the best of our knowledge, Zincke-type pyridine or pyridinium ring forma-tions are poorly documented in biochemistry. As an example (Scheme 6.13), thebiosynthesis of quinolinic acid (65)–a direct precursor of nicotinamide adeninedinucleotide (NAD)–from tryptophan-derived 66 was proposed to take place viaacyclic 67 followed by a 6π -electrocyclization (demonstrated with model systems)


L-tryptophanCO2H

NH2

OH

oxidation,isomerization

H2N CO2H

CO2H

CO2H

CO2H

CO2H

CO2H

O NHO

H

N

[6p]

66 67 65

Scheme 6.13 Biosynthesis of quinolinic acid.

(Scheme 6.13) [40]. If discovered in secondary metabolism, such a transformationwould putatively connect theonelladine-type and cyclostellettamine-type alkaloidsvia a biosynthetic Zincke-type reaction (cf. Scheme 6.1).

6.3.4Alkylpyridines with Unusual Linking Patterns

6.3.4.1 Biomimetic Synthesis of Pyrinodemin AWith a cis-cyclopent[c]isoxazolidine ring system linking two alkylpyridine chains,pyrinodemin A (68) (Scheme 6.14), the first representative of a small group offour alkaloids [41], has been the subject of several publications [42]. In fact, onlythe total synthesis in combination with degradation experiments of 68 permittedestablishment of the correct structure of this intriguing natural product as faras the position of the side-chain double bond is concerned. In 2005 [43], theKobayashi group put forward clear conclusions establishing the position of thedouble bond and the racemic character of the central core–despite a (−) reportedoptical rotation in the original paper [41a]. We will, in this section, primarily dealwith the biomimetic access to the central bicyclic system of 68, which was logicallyproposed to biosynthetically arise from a [3 + 2] cycloaddition between a nitroneand a (Z)-alkene, which in turn arise from two precursors (aldehyde 69 and amine70 sharing the same number of carbons and a similarly positioned cis-double bond).The key cycloaddition was exploited in most total syntheses of 68 and resulted in astereocontrolled formation of the bicyclic system in good yields.

ON

N

N

HH

H16' 15'

14

1516

3 3'

pyrinodemin A 68[Amphimedon sp.]

ON

H2N

NO

N16' 15'

15 16

69 70

oxidation

conditions for the biomimetic cycloadditionstep (various substrates): Ph or PhCH3, reflux

Scheme 6.14 Biosynthetic considerations for pyrinodemin A.

6.4 Development of Baldwin’s Hypothesis: From Cyclostellettamines to Keramaphidin-Type Alkaloids 195

6.3.4.2 Biomimetic Synthesis of Pyrinadine A

Another intriguing linking pattern is the one observed in pyrinadine A (71) isolated

from a Cribochalina sp. by Kobayashi and colleagues (Scheme 6.15) [44]. It consists

of an uncommon in Nature diazoxy group, presumably resulting from the oxidative

dimerization of a hydroxylamine such as 72 (obtained from the oxidation of the

corresponding amine 73).

NN

O

N

N

pyrinadine A 71[Cribochalina sp.]

NH2

N

NHOH

oxidativedimerization

biomimetic conditions:CH2Cl2, air (76%) [45]

73 72

reduction (Zn, AcOH)[44(a)]

NO

HN

HO

NNOH

OH

NN

O

N

N

OHdehydro-72

Scheme 6.15 Pyrinadine A: plausible biosynthetic origin and biomimetic access.

In 2009, Lee and colleagues [45] successfully mimicked the process in the

laboratory with a clean and spontaneous conversion of synthetic precursor 72 into

71 under simple aerial conditions according to the mechanism proposed in the box

in Scheme 6.15. Keeping in mind that plausible precursor dehydro-72 is a known

natural product [41b], the exact role of enzymes is clearly questioned in such cases

and an artifactual origin cannot be ruled out.6)

6.4Development of Baldwin’s Hypothesis: From Cyclostellettamines toKeramaphidin-Type Alkaloids

6.4.1Linking Pyridinium Alkaloids and Manzamine A-Type Alkaloids

Competitive to the redox processes that may take place between cyclostelletta-

mine-related alkaloids 74 and postulated dihydropyridinium salts counterparts

such as 75, intramolecular Diels–Alder cycloaddition of bis-dihydropyridinium

75 might occur as represented in Scheme 6.16, yielding a bridged pentacyclic

6) The existence of unsymmetrical mole-cules such as pyrinadines C–G, see

Reference [44], adds further credence tothis statement.


N

N

N NH

OH

H

H

keramaphidin B 7

NNX

NH

N

O

HN

N

CHOH

N

N

X

N

N

NN

NN

X

N

N

redoxinterconversion

X

X

pyridinium alkaloids

keramaphidin-type alkaloids

manzamine A type alkaloids

dismutation

reduction

NH

NH2

Pictet-Spenglerand oxidations

H2O

manzamine A 1

N

N

CHOH

OH

ircina l A 79[Ircinia sp.]

oxidations

H

74

75

76

77 78

80

−

−

−

−

−+

+

+

+

+

+

Scheme 6.16 Baldwin’s hypothesis: the missing link be-tween pyridinium alkaloids and manzamine A.

intermediate (76). Dismutation7) reaction would give rise to a new iminium

(77), which upon hydrolysis would provide 78 as a direct precursor of ircinal

A (79), a natural substance isolated for the first time in 1992 from Ircinia sp.

(notably, after Baldwin’s proposals) [46]. Formation of manzamine A (1) through a

Pictet–Spengler reaction with tryptamine (80) followed by oxidation into the final

β-carboline would then be easily explained.

The pertinence of Baldwin’s proposal comes from the fact that key pentacyclic

intermediate 76 was postulated in 1992 for the biogenesis of manzamine A (1),

before its natural occurrence became apparent some time later with the isolation of

keramaphidin B (7) (1994) and related analogs. In fact, simple iminium reduction

of 76 can explain the biosynthesis of keramaphidin B-type alkaloids, placing thereby

7) This term will be used cautiously in thepresent chapter, regarding the absence of

knowledge of the precise redox mecha-nisms involved biosynthetically.


76 as a cornerstone in the general biosynthetic mapping of manzamine alkaloids.This example is probably one of the most brilliant demonstrations of the power of‘‘retrobiosynthesis’’ as it beautifully paved the way to rich biomimetic endeavors.

6.4.2Biomimetic Total Synthesis of Keramaphidin B

6.4.2.1 Model Studies (1994)To validate their hypothesis, Baldwin and colleagues successfully carried out modelreactions that permitted the synthesis of the central core of keramaphidin B (7) byintermolecular Diels–Alder reaction between two molecules of dihydropyridiniumsalts 81, prepared from picoline via N-oxide 82 (Scheme 6.17) [47]. Incubation of81 in an aqueous buffer at pH 8.3 for 18 h followed by treatment with sodiumborohydride yielded mainly unsaturated piperidine 83 but also 84 (10% yield basedon N-oxide 82), the awaited polycyclic core reminiscent of that of keramaphidin B(7), probably formed via iminium 85.8)

N

N

Me

MeNN

Me

Me

N

Me

3 steps

N

Me

NN

Me

Me

N

Me

X

N

Me

+NaBH4

NaBH4

84, keramaphidincentral core

major compound

N

Me

O(CF3CO)2O

8281

85

10%83

+

+

+−

+

−

Scheme 6.17 Baldwin’s hypothesis: model studies toward keramaphidin B.

6.4.2.2 Total Synthesis of Keramaphidin B (1998)Four years later, the Baldwin group made a significant contribution to the art of total(biomimetic) synthesis (Scheme 6.18). They first obtained cyclostellettamine-type74 by dimerization of 3-tosyloxyalkenyl pyridine 86, which was converted intopostulated biosynthetic intermediate 75, via intermediate 87, using the classi-cal reduction/modified Polonovski reaction sequence (vide supra Schemes 6.5and 6.17). Following equilibrium of bis-dihydropyridinium 75 in aqueous medium

8) The publication ended with:

‘‘investigations into an intramolecularvariant of the cycloaddition [ . . . ] are

in progress with the aim of accom-plishing the total biomimetic synthesesof manzamines and ingenamine viakeramaphidin B.’’


keramaphidin B 7

NN

X

N

N

N

O

N

N

N

X

X

N

N

N

N

X

X

TsO

H

X

NN

MeOH, H2O then NaBH4

(0.2-0.3%)

3 steps

1 - mCPBA2 - (CF3CO)2O

NaBH4

biosyntheticintermediate 76

NaBH4

86 74

8775

56% from 86

98%

60-85%

+

+−

−

+

+

−

+

−

− +

+−

Scheme 6.18 Validation of Baldwin’s hypothesis: total synthesis of keramaphidin B.

and reduction, the authors were able to isolate keramaphidin B (7) in 0.2–0.3%overall yield [48]. As already pointed out in the model studies (Scheme 6.17), themajor compound resulting from this last reaction was recyclable bis-tetrahydro-pyridine 87.

6.4.3Drawbacks of the ‘‘Acrolein’’ Scenario

While this total synthesis achievement clearly demonstrated the validity of themodel, the extremely low yield of keramaphidin B (7) became the subject of puzzlinginvestigations. This result was explained by important side-reactions (mainlydismutation of dihydropyridines via intermolecular hydride transfer), and by thehigh energy barrier of the macrocyclic cycloaddition. The experimental drawbacksobserved with this pioneering model are detailed below and were part of the reasonwhy a modified scenario was concomitantly proposed by the Marazano group.

6.4.3.1 Very Low Yield of the Endo-Intramolecular Diels–Alder ReactionThis is obviously the major drawback of Baldwin’s total synthesis of keramaphidinB (Scheme 6.19). This key step could benefit in vivo from the intervention of a


NN

X

N

N

X

low yield

endo intramolecular Diels-Alder

- transition state energetic reasons?- in vivo Diels-Alderase?

7576

++

−−

Scheme 6.19 Low yield of the Diels–Alder reaction.

‘‘Diels–Alderase’’ that could limit the conformational mobility of the transitionstate, thereby minimizing the entropic factor.

However, molecular modeling studies conducted on intermediate 75 revealedthe existence of conformations close to the required transition state [48b]. Thekinetic preference of 75 to disproportionate was thereby put forward as the mainreason for the low yield of the synthesis.

6.4.3.2 Undesirable Transannular Hydride TransfersOne of the reasons why the above Diels–Alder reaction was not as efficient asexpected is probably the existence of a favorable transannular dismutation, leadingafter reduction to �3-piperidines. This disproportionation phenomenon, whichwas observed on model systems with dihydropyridinium salt 81 [47], occurred toa greater extent with 75 in the natural product synthesis (Scheme 6.20). Severalexperimental evidences suggested that the isolation of reduced 87 after treatmentof the reaction mixture with sodium borohydride resulted from the reduction of 88(arising from spontaneous dismutation), and not from the reduction of biosyntheticintermediate 75. The intervention of a putative ‘‘Diels–Alderase’’ could also excludeor limit this disproportionation reaction.

N

N

N

N

X

X

87

75

N

N

X

88

spontaneous dismutation

disproportionation

NaBH4 NaBH4

+

+

+−−

−

Scheme 6.20 The disproportionation issue.


6.4.3.3 Conversion of a ‘‘Keramaphidin’’ Skeleton into an ‘‘Ircinal/Manzamine’’Skeleton Was Not Experimentally PossibleAccording to Baldwin’s biogenetic hypothesis, alkaloids of the keramaphidin Btype are the immediate precursors of ircinal type and manzamine A type alkaloids,following regioselective oxidation and iminium hydrolysis (cf. Scheme 6.16). Totest this hypothesis, the Marazano group synthesized aminonitrile 89, whichwas submitted to decyanation–hydrolysis using tetrafluoroboric acid in aqueousmedium. Although the N2-iminium 90 was clearly observed by NMR, aldehyde91 could never be obtained even under various forcing hydrolytic conditions(Scheme 6.21) [49]. This result disfavors the perception that manzamine aldehydesoriginate from the hydrolysis of keramaphidin-type iminium as proposed by J.E.Baldwin [15]. However, one should keep in mind that this hydrolysis equilibriumcould be driven biosynthetically by a connected equilibrium (e.g., proton shift toαβ-unsaturated aldehyde), or any irreversible transformation (e.g., Pictet–Spenglerreaction).

H2O

NH

N

Me

Me

Me

H

Me

O

keramaphidin B skeleton ircinal/manzamine skeleton

HBF4

NMe

CHO

Me HN

Me Me

H

NN

Me

Me

Me

H

Me

2 BF4

NN

Me

Me

Me

Me

CN

H2O

89

90

91

Scheme 6.21 Failure to convert a keramaphidin skeletoninto a ircinal/manzamine A skeleton on a model system.

6.5‘‘Malondialdehyde Scenario:’’ A Modified Hypothesis Placing Aminopentadienals asPossible Precursors of Manzamine Alkaloids

6.5.1Keramaphidin/Ircinal Connection

The modified hypothesis, based on the intervention of malondialdehyde C3-reactiveunits to explain the formation of pyridinium salts, sets the stage for a universalmodel of biosynthesis for the manzamine alkaloids. Armed with a long experiencein the pyridinium chemistry, the Marazano group turned its attention to themanzamine alkaloids in the mid-1990s. In their 1998 and 1999 papers [16], for thefirst time the pyridinium/aminopentadienal chemistry was put forward to explainthe divergent formation of ircinal/manzamine and halicyclamine alkaloids.

Whereas polycyclic intermediate 76 (resulting from the intramolecular Diels–Alder reaction between dihydropyridinium salts, cf. Scheme 6.16) was central inBaldwin’s hypothesis, intermediate 92 featuring (i) a dihydropyridinium moiety

6.5 Aminopentadienals as Possible Precursors of Manzamine Alkaloids 201

manzamine A 1

keramaphidin B 7 NH

N

O

HN

N

CHOH

HN

NH

O

O

O

O

O

O

NH3

NH3

NH3

O

O

N

N

O

O

N

NH

O

O

O

O

O

O

O

O

reduction

X

X

X

HN

N

CHO

pyridinium salts alkaloids

reduction

reduction

−H2O

9374

see scheme 6.2

NH3

see scheme 6.2

NN

aminopentadienal

aminopentadienal

92

78

1716

17

type (see scheme 6.2)

1

1

2

Scheme 6.22 Biosynthetic scheme towards manzamine Aand keramaphidin B according to Marazano’s hypothesis.

(resulting from either the ‘‘acrolein’’ or ‘‘malondialdehyde’’ pathways 1© and 2©,respectively, on Scheme 6.22) and (ii) an open-chain aminopentadienal, is obvi-ously the key element of the modified hypothesis (Scheme 6.22). It should bementioned here that intermediate 78 closely related to ircinal and resulting for-mally from an intramolecular Diels–Alder reaction of 92 is therefore a precursorof the keramaphidin (7) skeleton according to this model. Additionally, an inter-mediate such as 93 could also explain the biosynthesis of cyclostellettamine-relatedpyridinium 74.

6.5.2Halicyclamine Connection

The aim of this model was also to explain the formation of halicyclamine-typealkaloids (Scheme 6.23) from precursor 94, that is, similar to precursor 92 withthe difference that it integrates a type-2 aminopentadienal moiety (according toScheme 6.2). Halicyclamine-type alkaloids would this time be generated by anintramolecular 1,4-addition of the aminopentadienal moiety reacting not as a diene


XN

N

O

H

N

HN

O

N

N

H

H H

halicyclamine A 8

N

N

H

H

X

X

reductions

found to be anatural product in

2004![Amphimedon sp.]

reduction

95

94

−H2O

Scheme 6.23 Biosynthetic scheme towards halicyclamine Aaccording to the modified scenario.

N

N

H

H

HN

N

H

HN

N

HO

O

halicyclamine alkaloids ircinal alkaloids

N

NH

O

NH2

O

O

NH2O O

O

N

HNO

aminopentadienalof type

aminopentadienalof type

type type

N

NH

O

HN

N

NHN

O

O

keramaphidine alkaloids

formal (4+2)

15

16

17

1

1

2

2

Scheme 6.24 The aminopentadienal connection betweenrepresentative manzamine alkaloids.

6.6 Testing the Modified Hypothesis in the Laboratory 203

(Scheme 6.22) but as an enamine. Illustrated in Scheme 6.23 with the biosyntheticproposal for halicyclamine A (8) the scenario was consolidated some years later withthe isolation of postulated pyridinium 95 as a natural substance from Amphimedonsp. [50].9)

When considering only the biosynthesis of the central cores of the differentsub-classes of alkaloids evoked up to now, the homogeneity of the model iseven more striking, as represented in Scheme 6.24. Starting from intermediatesof type 15, access to the halicyclamine, keramaphidin, and ircinal series is ex-plained via the reactivity of the aminopentadienal system (acting as either diene orenamine).

6.6Testing the Modified Hypothesis in the Laboratory

6.6.1Biomimetic Models toward Manzamine A

According to Marazano’s hypothesis, which involves malondialdehyde as thecrucial C3 building-block, aminopentadienal-dihydropyridinium species like 92would undergo intramolecular (4 + 2) cycloaddition to yield an iminium thatalready possesses the main structural features of ircinal alkaloids (Scheme 6.22). Toprobe this hypothesis, Marazano and colleagues reacted dihydropyridinium 34 andaminopentadienoate 96, which unexpectedly furnished amine 97 (Scheme 6.25).This behavior was explained by intramolecular hydride transfer to the formediminium 98, followed by loss of butanal upon hydrolysis of 99 [16b].

N MePh

NHn-BuMe

OEtO

N

Ph

CO2Et

Me

NHMe

H

N

Ph

CO2Et

Me

NH2Me

intramolecularhydride shift

CH2Cl20–4°C N

Ph

CO2Et

MeNMe

H2O

~50%

9734

96

9899

Scheme 6.25 A (4 + 2) cycloaddition strategy towards an ircinal model.

While many strategies relied on the use of the Diels–Alder reaction in thenumerous synthetic approaches to manzamine A [51], this one seems to beamong the most efficient since all crucial functionalities are brought together ina single step. Indeed, the construction of the ABC-ring system of manzamine Awas published soon after by the same team (Scheme 6.26) [52]. The choice of acorrect substitution pattern on the starting dihydropyridinium salt 100 permitted

9) The Marazano group extended theBaldwin hypotheses (based on thedihydropyridinium chemistry) to explainthe biosynthesis of halicyclamine A (and

also sarain A) in a 1995 publication [53]before developing their own modifiedmodel.


the construction of the C-ring with a (4 + 2) cycloaddition from 101, furnishingircinal analog 102 in good overall yield.

NPh

HNMe

OEtO

TBDMSON

Ph

CO2Et

Me

OH

NCbz

CO2Et

N

H

A(4+2)

MeB

C N

NOH

H

H

A B

C

manzamine A 1

96100101

1028 steps, 17% from diene 96

Scheme 6.26 Biomimetic synthesis of the ABC-ring system of manzamine A.

No further developments concerning the biomimetic approach to irci-nal/manzamine A series were published in the following years by the group ofMarazano, until 2008 and the publication of a general approach validated by un-precedented results [21]. The authors combined Zincke-type chemistry, involvingbiomimetic species such as aminopentadienals and glutacondialdehydes, andtheir ‘‘Chichibabin-like’’ synthesis of dihydropyridinium depicted in Scheme 6.5.Thus, Strecker–Michael adduct 103 was reacted with aminopentadienal 104 inLewis acid conditions, yielding in moderate yield bicyclic iminopentadienal 105(Scheme 6.27). This stable compound, when treated with acetic anhydride followedby reduction and final hydrolysis, furnished dienal 106 as a biomimetic model ofircinal alkaloids, following an impressive cascade sequence of rearrangements ofthe aminopentadienal system (Scheme 6.27).

N

N

Ph

Ph Me

O

Me

N

O

Me

Ph CN HN

Me

O

Ph

+ZnBr2

N

N

Ph

Ph

Me

O

Me

N

OAc

Me

NBn

MePh

N

OAcMe

NBn

MePh

Ac

N

OAc

MePh

NAc

PhH

N

OAcMe

Ph

NAc

PhH

N

CHO

MePh

H

AcO

Ac2O

NaBH(OAc)3

HCl

Ac

Me

Me

Me

103104 N Me

Ph

NHBn

HO

Me

N

N

CHOH

OH

Hircinal A

79

A B

A B

105

106(55%)(45% from 105)

(22%)

Scheme 6.27 Aminopentadienal scenario towards the AB-ring system of manzamine A.


6.6.2Biomimetic Models toward Halicyclamines

The first clear link between keramaphidin B (7) and halicyclamine alkaloids wasexperimentally demonstrated in 1995 by the Marazano team [53]. When performinga similar reaction to the one described in 1994 by Baldwin and colleagues [47] (cf.Scheme 6.17), consisting of studying the behavior of dihydropyridinium salt 108in solution (generated in situ from 107), a significant amount of 109 was isolatedalong with awaited 110 and 111 (Scheme 6.28).

N

N

H

H H

N

Me

n-hex

H

H

N

Nn-hex

Me

Hn-hexMe

H HN

H

n-hexMe

Nn-hex

OMe

MeN

n-hex Me

H

Nn-hex Me+

NN

Me

n-hex n-hex

Mekeramaphidin

skeleton (25%)

dismutatedpiperideine (40%)

halicyclamine skeleton (7%)

+107 108 110111

109

halicyclamine A 8

Scheme 6.28 First biomimetic synthesis of halicyclamine-related structures.

Similarly, keramaphidin model 112, when submitted to regioselective photo-oxidative α-cyanation, was turned into halicyclamine model 113 via retro-aza-Mannich fragmentation of iminium 114 and cyanide retrapping (Scheme 6.29)[49]. This result suggests that a regioselective N1-oxidation of keramaphidin B typealkaloids might be implicated in the biogenesis of the halicyclamines.

Further, Marazano and colleagues observed that treating polycyclic aminaladduct 115 resulting from nucleophilic reaction of aminopentadienal 116 withdihydropyridinium salt 34 [16b] in acidic conditions gave pyridinium 117, whichwas directly reduced with sodium borohydride to give a 3 : 1 ratio of compounds

NN

Me

n-hex n-hex

Me

NN

Me

n-hexn-hexMeNN

Me

n-hex n-hex

Me

N

Nn-hex

Me

Hn-hex

Me

H H

CN

CN

N

Nn-hex

Me

Hn-hex

Me

H H

CN

CN

conditions: hn (l>495 nm), TPP, TMSCN, O2

selective oxidation

112 114

113 (15%)TPP: tetraphenylporphineTMSCN: trimethylsilylcyanide

−

Scheme 6.29 Selective oxidation of a keramaphidin model.


118 and 119 (Scheme 6.30a). The main compound (118) was found to possess thehalicyclamine A (8) central core whereas 119, the minor adduct, can be consideredas a halicyclamine B (120) model [54] (despite the opposite stereochemistry ofone stereocenter on the tetrahydropyridine ring). In its recent development ofthe halicyclamine chemistry [21], the Marazano group observed that reactionof Strecker adduct 103 and aminopentadienal 116 in the presence of zinc triflatedirectly furnished pyridinium 121 (Scheme 6.30b). Pyridinium 121 was furtherreduced to the above-described mixture of bis-piperidines 118 and 119 in goodoverall yield. Taken together, these results suggest that dehydrohalicyclaminessuch as 95 (i.e., pyridinium species) could be the actual biogenetic precursors ofhalicyclamine-type alkaloids after reduction, and not the opposite.

N Me

Ph

HN

HO

Me

N

N Me

O

Me115

(55%)Me

Me

N

N n-Bu

Me

Me

N

Nn-Bu

Me

HMe

H H

N

Nn-Bu

Me

HMe

H

H

N

N

H

H H

CH2Cl2

116

34

H

+

N

N

H

H

H

possible evolution towardsircinal /manzamine A series

see scheme 6.27

N

N

H

H

dehydrohalicyclamine A 95

3:1 ratio(23% from salt 117)

(40% from pyridinium 121)

N

O

MePh CN NH

Me

O

n-Bu

+Zn(OTf)2

103116 N Me

Ph

NHn-Bu

HO

Me

N

Nn-Bu

Me

Me

CN

NaBH4

NaBH4

121(25%)CN

halicyclamine B 120[Xestospongia sp.]

halicyclamine A 8

117

118 119

Ph Ph

Ph Ph

Ph(b)

(a)

Scheme 6.30 First (a) and second (b) generation approaches to halicyclamines.

The latest developments to tackle the total synthesis of halicyclamine A (8)include the synthesis of a macrocyclic target molecule, demonstrating therebythe feasibility of intramolecular reaction (Scheme 6.31) [55]. Precursor 123 wasprepared in eleven steps from tetradecandioic acid (122). Intermediate 124 waseffectively reached with, now classical in this series, zinc triflate. Compound 124then collapsed in acidic conditions to provide α-aminonitrile/pyridinium 125,which was finally converted into halicyclamine A model 126 during a reductionstep that appeared to be both regio- and diastereoselective (to be compared tothe obtaining of a mixture of regioisomers in the case of intermolecular reaction,


N

N

BnMe

O

N

HN

O

Me

CN

Ph N

HN

O

Me

Ph

CN

N N

PhCN

Me

AcO

N

N

Me

H

H H

PhN

N

H

H H

halicyclamine A 8

HO2C CO2H10

122

11steps

123 124

125126

Zn(OTf)2

KCN, AcOH

NaBH4, MeOH/H2O

(33%)

(27%, 2 steps)

Scheme 6.31 Latest developments toward a biomimetic synthesis of halicyclamine A.

see Scheme 6.30). In view of this achievement, a biomimetic total synthesis ofhalicyclamine A (8) is reasonably within reach.

An alternative pathway, involving a late introduction of the nitrogen atoms,was communicated in 2003 (Scheme 6.32) [56]. Compound 127 was preparedas a stabilized equivalent of biomimetic intermediate 128, itself reminiscentof postulated biosynthetic intermediate 129. The strategy towards 127 firmlyexploited the biosynthetic proposals as it consisted of sequential condensation ofaldehyde and malonaldehyde equivalents. Its reactivity towards primary amineswas then studied and led to the formation–via (among others) pyridinium 130–offour diastereomers, including compound 131, which display the same relativestereochemistry as halicyclamine A. Notably, even if conceivable in principle, nomanzamine A type compounds were formed during these investigations, probablybecause of the irreversibility of pyridinium formation.

Overall, these short and convergent biomimetic syntheses, which rely on iden-tical reactants brought to distinct reaction fates, are based on the fusion ofBaldwin’s seminal hypothesis (dihydropyridinium-based) and Marazano’s modi-fied theory (aminopentadienal-based) (Scheme 6.33). In one of the most excitingrecent achievements in natural product biomimetic synthesis, application of theBaldwin–Marazano concepts delivered core analogs of ircinal/manzamine A andthe halicyclamines, constituting a strong presumption of how those alkaloids relatebiosynthetically. Biomimetically speaking, the most impressive fact is that theentire sequences of reactions are promoted in cascades depending on the Lewisacid; it is therefore difficult to imagine more straightforward ways to access thesecomplex families of molecules.


O

O

OOO

MeO

OEt

Me

OO

MeMe

O

Me

O

O

Me

O

127= stabilized analog of 128

O O

OO

O NaOEt

Si(CH3)3

N

biosynthetic intermediate 129

O

Me

O

OEt

Me

OO

MeMe

NH2

Me

then H

NH2

PhN

Me

Me

MeO

OO

MeMe

N

N

Me

H

Me

H H

Ph Me

2- NaBH4,3- 2N HCl then NaBH4

1- H

127 130 131

conception of a biomimetic equivalent:

reactivity towards primary amines:

(66%)(55%)

Scheme 6.32 Alternative strategy towards halicyclamineswith the late introduction of nitrogens.

N

O

MeR1CN HN

Me

O

R2

+

103

104 or 116 N

N R2

Me

HR

Me

H H

N

CHO

MeR1

H

Me

ircinal /manzamineA model

halicyclamine model

106

118

ZnBr2

Zn(OTf)2

Scheme 6.33 Marazano divergent route to either irci-nal/manzamine A or halicyclamine-type alkaloids.

6.7Biomimetic Approaches toward Other Manzamine Alkaloids

6.7.1Biomimetic Models of Madangamine Alkaloids

Pro-ircinal-type alkaloids could undergo core fragmentation via intracyclic (path A)or pericyclic (path B) vinylogous retro-Mannich reactions (Scheme 6.34). Followingredox transformations, a sequence of enamination and vinylogous aza-Mannichreaction would eventually produce madangamine type alkaloids.

Path (B) was pioneered biomimetically by Marazano and colleagues(Scheme 6.35) in an oxidized version, based on (carboxyethyl)acetoacetate dianion

6.7 Biomimetic Approaches toward Other Manzamine Alkaloids 209

N

Nmadangamine type alkaloids

HN

N

H

H

HN

N

H

N

N

H

O

O

HN

N

HO

Ircinal type alkaloids

retro-Mannichvinylogous

HN

N

O

HN

N

O

NHN

O

HN

N

HO

NHN

O

then H

NN


O

path Apath B

then [O]

aza-Mannich vinylogous

Mannich vinylogous

Mannich vinylogous

imine formation

imine formation

aza-Mannich vinylogousthen [H]

retro-Mannich vinylogous

then [H][H]

[O]

Scheme 6.34 Possible biogenesis of madangamine C type alkaloids.

and quaternarized dihydropyridinium 133 as a biomimetic equivalent of postulatedintermediate 132 (see Scheme 6.34) [57]. Following a double Mannich addition,tricycle 134 was obtained in close analogy with the core of madangamine C-typealkaloids. In 2011, the total synthesis of madangamine type alkaloids remains amountain to climb [58].


NHN

O

NHN

OEt

OO

EtO

O

NHN

BnCOCF3

Me

OEt

OO

EtO

ONa

1-THF, RT

2- K2CO3, EtOH/H2Oreflux N

NBn

HN

N

OO

Me madangamine C 11[Xestospongia ingens]

132

133

133134(50%)

Scheme 6.35 Biomimetic synthesis of the madangamine C core.

6.7.2Biomimetic Model of Nakadomarine A

Alkaloids of the ircinal A type could also undergo intracyclic fragmentation viavinylogous retro-Mannich reaction to give 135 (Scheme 6.36). Subsequently, a viny-logous Mannich reaction would enable ring closure of 135, yielding fused tetracycle136. Final cyclization to furan would produce alkaloids of the nakadomarine A type.Alternatively, furan formation could occur from diketonic 135 to 137, enabling afuran-Mannich intramolecular cyclization to nakadomarine alkaloids.

This last hypothesis was validated in the laboratory by Nishida and colleagues onmodels [59], before their publication of the first total synthesis of (+)-nakadomarine

N

N

H

N

N

HO

Ircinal A 79


O

NO

Nnakadomarine A 10

OH OH

N

OOH

N

H

N

O

NOH

−H2Ofuran

formation−H2Ofuran

formation

Mannichvinylogous

NO

N

Mannichvinylogous

135

136

137

H

H

Scheme 6.36 Possible biogenesis of nakadomarine A from ircinal A.

6.7 Biomimetic Approaches toward Other Manzamine Alkaloids 211

p-TsOH

(+)-nakadomarine A 10

NO

N BocBs

AcO

H

HO

142

NO

N Boc

Bs

AcO

H

THPO

141

NO

N Boc

AcO

H

THPO

138

OAc NO

N

H

H

HN CO2Me

O

HCl

(87%, 2 steps)H H H

N CO2MeBs

Bs=PhSO2

O

O

(R)-(–)-140

19 steps 4 steps

12 steps

139

Scheme 6.37 Focus on the biomimetic key step in the firsttotal synthesis of nakadomarine A.

A (10) (see also Section 6.9.8) in 2003 (Scheme 6.37) [60], featured by a keybiomimetic step. Advanced intermediate 138 was prepared in 23 steps fromracemic 139 (via optically active intermediate 140). The authors made successfulan intramolecular furan-iminium cyclization of spiropyrrolidine 141 into 142, anelegant way of mimicking the presumed core biosynthesis of nakadomarine A typealkaloids.

6.7.3Biomimetic Models of Sarains: A Side Branch of the Manzamine Tree

With its highly intricate diazatricyclic central core and two macrocyclic side chainssarain A (6), isolated from Reniera sarai in 1986 and fully characterized in 1989(X-ray analysis of a diacetate derivative), is one of the most complex manzaminealkaloid (Scheme 6.38), featuring an unprecedented pentacyclic, box-like hetero-cyclic architecture. Inspection of this alkaloid reveals a polyenic 1,2,3-aminodiol,sphingolipid-like moiety, suggesting a distinct biogenetic origin relative to themanzamines previously described in this chapter. Indeed, retro-biosynthetic analy-sis of sarain A type alkaloids10) using iminium-based disconnections provides withkey amino-aldehyde 15 and two C3 synthons [postulated as malondialdehyde (17)according to Marazano’s model], along with cyclic amino acid 144 (that may resultfrom the catabolism of sphingolipid 143) (Scheme 6.38) [61]. From these biogeneticelements, but with a philosophy identical to what we have seen up to now, it thusappears that sarain A type alkaloids are not directly connected to the elaboratedmanzamines presented before, with which they only share simple amino-aldehydeprecursors 15. Alkaloids related to sarain A should thus be regarded as branching

10) So far, sarain A is the only isolated man-zamine alkaloid to possess this unprece-dented polycyclic core.


NH2O

−4 H2O

HN N

O

O

N N

O

sarain typealkaloids

N N

O

H2OMannich

NH2

O

OO

NH

HOOC

ba

NH2

O

Sphingolipid type 143

HOOC

O

ba

a : enamine formation

N N

O

HOOC

b : aldol-crotonization

O

N N

O

sarain A 6

HOHO

144

145

146147

15

pH sensitiveproximity

reduction

Scheme 6.38 Proposed biogenesis of sarain A-type alkaloids.

off early on in the manzamine metabolism, in a case of divergent biosynthesis,with postulated intermediates 145–147 represented on Scheme 6.38.

Marazano et al. pioneered the biomimetic synthesis of the heterocyclic coreof sarain A. In their 1999 paper, a first model, albeit incomplete, gave the firstexperimental evidence that manzamines and sarains are biosynthetically related(Scheme 6.39). A thermodynamic mixture of two aldehydes (148 and 149) wasobtained when reacting dihydropyridinium salt 34 and glutaconaldehyde salt 150.The sequence occurred via the rearrangement of aminal 151 into iminium 152 oncontact with alumina. Compound 148 contains a bicyclic system reminiscent ofthat of sarain A 6.

A few years later [61b], using β-bromoacrylamide 153 as aminated malondialde-hyde equivalent (Scheme 6.40), and benzylidene 154 as an amino acid surrogate,another model study was disclosed. Those reactants were coupled under basicconditions to yield glutarimide 155 after benzylidene hydrolysis. Next, 155 wascoupled with malondialdehyde (17) sodium salt to furnish aminopropenal 156,which was N-alkylated to yield 157. After a series of tedious reductions of theglutarimide moiety, the authors were able to obtain aminal 158, which underwentSakurai-type cyclization under the described conditions to afford tricyclic sarain Amodel 159.

6.8 A Biomimetic Tool-Box for the Synthesis of Manzamine Alkaloids 213

N

MePh

ONaMe

HO

34

NMe

O

MeO

Ph

NMe

O

Ph

Me

O

NMe

O

Ph

Me

O148 149

NMe

O

MeO

Ph

2:3 ratiosarain A 6alternative

representation

N

O

N

HO

HO

150151de: 90% 152

CH2Cl2

(95%)

Al2O3 or SiO2

(33%)thermodynamic

equilibrium

Scheme 6.39 Biomimetic synthesis of a first sarain A model.

NH Br

O

Bn

O

EtON

MePh

N

O

OBn

MeNH2

LDAO ONa

N

O

O

Bn NH

O

Me

N

O

OBn N

O

MeMe

H

NaH

then MeI

N

HO

Ts NMeMe

H

TMS

FeCl3N N

Me

MeTs

154

153

155 156 157

158

159

N N

O

sarain A 6 HO

HO

O

O

R NH2

R'

HN

OR''

biosynthetic analogy

N

HO

R N

O

R'R''

H

biosynthetic analogy

(70%)

10 steps

(61%)

17

17

Scheme 6.40 Biomimetic synthesis of a second sarain A model.

6.8A Biomimetic Tool-Box for the Synthesis of Manzamine Alkaloids: Glutaconaldehydesand Aminopentadienals

As seen above, simple aminopentadienals constitute C5 biomimetic equivalentsof long-chain aminopentadienals (types 1 and 2), regarded as key precursors ofthe manzamine alkaloids. Glutacondialdehydes are hydrolyzed counterparts ofaminopentadienals and can also be seen as equivalents of postulated aldehydeintermediates (refer to Scheme 6.2). Such biomimetic C5 nucleophiles can beobtained in a few steps from simple starting materials, using Mannich additionof imine anions onto vinamidinium salts (cf. Scheme 6.9), or, in a more versatilemanner, using the Zincke opening of N-activated pyridinium salts (cf. Scheme 6.8).In their first model reactions (Schemes 6.25 and 6.26), the Marazano group exploitedthe reactivity of more stable aminopentadienoates (but presenting inappropriate


R''R'''

R'O

NR

PhN

RPh

OMe

NR

Ph

CN

maskeddihydropyridinium salts

O

HN R

Ph

in situ generated-dihydropyridinium salts

"increasing biomim

etism"

HNR'''

OMeO

R''

aminopentadienoates

intermolecular reactions

wrongoxidation state

NR'''

O

R''R''N

O

R''R''

R'''

OKR'''

O

aminopentadienals

equivalentsof type

glutaconaldehydes

intramolecular reactions

NPh

NH

RO

first generations

"increasing biomim

etism"

biomimetic electrophiles biomimetic nucleophiles

latest developments

(see scheme 6.2)

1equivalents

of type 2

Figure 6.5 Evolution of the biomimetic chemical tool-boxused for accessing manzamine alkaloids.

oxidation relative to aldehydes), though those species were rapidly abandoned infavor of more versatile aminopentadienals (Figure 6.5).

On the borderline of the chemistry of manzamine alkaloids, several experimentalstudies were conducted to delimit the scope of reactivity of glutaconaldehydes.More or less biosynthetically related structures were obtained. One of the simplestreactions reported is the self-dimerization of glutaconaldehyde 150 formed insitu from the corresponding sodium salt under acidic conditions (Scheme 6.41)[62]. In fact, according to the mechanism depicted, cinnamaldehyde 160 could beobtained in very good yield. A similar outcome was observed when a monoprotectedmalonaldehyde unit 161 was engaged in the cascade [63]. Formation of the resultingadduct 162, which displays the same aromatic pattern as the one encountered in160, was explained by the loss of a carbon in the form of a formic acid molecule.

The chemistry of glutaconaldehydes was recently explored beyond biomimeticconsiderations, especially by the Vanderwal group. Intramolecular ring openings

O

Me

MeO

ONa

Me

MeO O

O p-TSA, CH2Cl2

p -TSA: p-toluenesulfonic acid

160 (80%)

O

Me

MeO

O

OMe

Me

O

MeMe

OO

NaO

O

O

OMe

Me

O

Me

O

OO

MeMe

OO

MeMe

O

Me

OH

OMe

O

H

OO

MeMe

O

MeOMe

HO OH

Bu4NCl,CH2Cl2

162 (32%)150

150

161 150

–HCO2H

Scheme 6.41 Selected examples of reactivity of glutaconaldehydes.

6.9 Biosynthesis of Manzamine Alkaloids: Towards a Universal Scenario 215

of pyridinium salts (including ‘‘Zincke salts’’) gave easy access to multiple hetero-cycles [64]. Aminopentadienals (‘‘Zincke aldehydes’’) were also shown to undergopericyclic cascades to provide synthetically useful (Z)-α, β, γ , δ,-unsaturated amides[65] or served for the preparation of δ-tributylstannyl-α, β, γ , δ,-unsaturated aldehy-des [66]. Applications to the synthesis of natural products or natural product-likeanalogs include the access to indolomonoterpenic alkaloid cores of the strychnane,aspidospermane, or ibogane types (with a total synthesis of norfluorocurarine), aformal synthesis of porothramycins or the total synthesis of nicotine and analogs[67]. Nuhant, Delpech, and colleagues disclosed a methodology driven study dealingwith the activation of aminopentadienals towards nucleophiles which also enabledcompletion of the synthesis of protoemetinol [68].

6.9Biosynthesis of Manzamine Alkaloids: Towards a Universal Scenario

In the following, we propose a general mapping of the biosynthesis of typicalmanzamine alkaloids, as emerging from presumed biogenetic relationships aswell as biomimetic chemistry evidence. This mapping finds its introduction inSchemes 6.1, 6.24, and 6.38 and is extended in Scheme 6.42. The reader will findadditional details in terms of intermediates and alternative biosynthetic connectionsin the corresponding isolated schemes. To provide the simplest yet broadest visionof the possible relationships between the manzamine alkaloids, we again depictmacrocycles by large loops (see footnote 3).

6.9.1From Fatty Acids to Long-Chain Aminoaldehydes and Sarain Alkaloids

As depicted in Scheme 6.1, fatty acid degradation would produce two kinds ofbiosynthetic reactants: (i) dialdehydes 14 (C8 –C16) that would become monoam-inated to yield amino-aldehydes 15; (ii) acrolein (16) (the original C3 specieshypothesized by Baldwin) or malondialdehyde (17) (alternative C3 species proposedby Marazano in 1998). Incorporation of a sphingolipid moiety to this metabolismwould open the path towards sarain A-type alkaloids (Scheme 6.38), which appearto branch off very early from the biogenetic trunk of the manzamine family.

6.9.2Pyridine Alkaloids: Theonelladine, Cyclostellettamine, and Xestospongin-TypeAlkaloids

Condensation of amino-aldehydes 15 with a source of ammonia would furnishtheonelladine-type alkaloids. Alternatively, dimerization of 15 in the presence of twoequivalents of acrolein or malondialdehyde would give rise not only to alkaloids ofthe cyclostellettamine type but also of the xestospongin-type when the alkyl chainsare β-hydroxylated (Schemes 6.1 and 6.11).


N

N

NN H O

H

H

H

Man

zam

ine

A t

ype

alka

loid

sIr

cin

al A

typ

e al

kalo

ids

mad

ang

amin

e C

typ

eal

kalo

ids

NH

NO

NN

NN

HN

N

HO

N

N

HO

N

NO

H

H

H

O

HN

N

HO

NN

N

NO

H

H

H

O

NN

OH

H

O

NN

H

H

O

nak

ado

mar

ine

A t

ype

alka

loid

s

HN

N

HO

OH

HN

N

H

O

HN

N H

HN

N

H

O

HN

N HO

H

N HN

N

HN

N

HO

O

ON

H

OH

HH

H

O

[O/H

]H

2O

H2O

tryp

tam

ine

80P

icte

t-S

peng

ler

Man

nich

man

ado

man

zam

ine

A t

ype

alka

loid

sM

anni

chvi

nylo

gous

Ret

ro-

Man

nich

viny

logo

us

H2O

H2O

retr

o-M

anni

chH

2O

H2O

tryp

tam

ine

80P

icte

t-S

peng

ler

Man

nich

viny

logo

us

retr

o-M

anni

chvi

nylo

gous

ally

lic a

min

atio

n

Man

nich

viny

logo

us

aza-

Man

nich

viny

logo

us

retr

o-A

za-

Man

nich

viny

logo

us

1- R

etro

-Man

nich

2- o

xida

tion

ally

licam

inat

ion

N HN

N NH

OH

HH

H

181

180

171

176

177

178

179

174

173

172

170

H2O

fura

nfo

rmat

ion

NN

H

H

O

tryp

tam

ine

80P

icte

t-S

peng

ler

[O]

ally

lic a

min

atio

n

[H]

[O]

[O]

[O]

[O]

H

175

viny

logo

us

Sche

me

6.42

Map

ping

ofth

epr

esum

edbi

ogen

etic

rela

tions

hips

betw

een

repr

esen

tativ

em

anza

min

eal

kalo

ids.

6.9 Biosynthesis of Manzamine Alkaloids: Towards a Universal Scenario 217

kera

map

hid

ine

B t

ype

alka

loid

s

N

N

deh

ydro

hal

icy

clam

ine-

typ

elk

alo

ids

hal

icyc

lam

ine

A/h

alic

lon

amin

ety

pe

alka

loid

s

HN

N

HO

NH

N

O

NN

NN

NN

NN

N

NN

NH

NN

H

H

NN

H

HH

aza-

Man

nich

viny

logo

us

(4+

2)cy

cloa

dditi

on

H2O

H2O

HN

N

HO

retr

o-az

a-M

anni

chaz

a-M

anni

ch

N

N

O

H

HN

N

Ofo

rmal

(4+2

)cy

cloa

dditi

on

H2O

[O]

aza-

Man

nich

viny

logo

us

tryp

tam

ine

80P

icte

t-S

peng

ler

ally

lic a

min

atio

n

168

169

163

166

165

167

164

O

OO

fatty acids catabolism

16 17reduction

oxidation

[O]

[H]

H

[H]

[O]

[H]

[H]

Bal

dwin

's h

ypot

hesi

s

Mar

azan

o's

hypo

thes

is

Sche

me

6.42

(Con

tinue

d)


6.9.3From Cyclostellettamines to Keramaphidin and Halicyclamine/HaliclonamineAlkaloids

Incorporation of acrolein as C3 precursor according to Baldwin’s model implieslate, possibly spontaneous, oxidation of dihydropyridine/dihydropyridinium in-termediates to pyridine/pyridinium. Competitive with these oxidation processes,two kinds of reaction might occur: (i) intramolecular Diels–Alder cycloaddition ofbis-dihydropyridiniums 163 to bridged intermediates 164, which could either be re-duced to keramaphidin B type alkaloids or (ii) undergo retro-aza-Mannich fragmen-tation to afford bis-piperidine skeletons 165 typical of halicyclamine/haliclonaminealkaloids following redox transformation. These alkaloids could also arise directlyfrom bis-dihydropyridinium 163 upon intramolecular vinylogous aza-Mannichcyclization, and also from aminopentadienal-dihydropyridinium 166 if malondi-aldehyde (17) is involved as key C3 unit (Marazano’s model).

6.9.4Spinal Cord of Manzamine Metabolism: The Ircinal Pathway

Aminopentadienal-dihydropyridiniums 166 are the direct precursors of isoquino-line aldehydes 167 following intramolecular [4 + 2] cycloaddition. Such pro-ircinalsrepresent the earliest entry point in the biosynthesis of ircinal alkaloids (168 to irci-nal A type alkaloids), of which they possess most structural features, except for theirpyrrolidine ring. Pro-ircinals 168 could also be accessed by regioselective oxidationof keramaphidin type alkaloids to 169 followed by iminium hydrolysis, althoughthis theory has not been supported experimentally. All pro-ircinals and ircinal inter-mediates should be considered central to the ‘‘manzamine metabolism,’’ and seemto constitute branching points toward the majority of structurally representativealkaloids (Scheme 6.24).

6.9.5From Ircinal and Pro-ircinals to Manzamine A Alkaloids

Although ircinal-type molecules are seen as immediate precursors for manzamineA type alkaloids, it should be kept in mind that β-carboline formation is notthe obligate last step toward these alkaloids. Indeed, pro-ircinals 170 and 171 arecandidates for oxidative allylic amination/β-carboline formation, making them allpotentially direct precursors of manzamine A-type alkaloids.

6.9.6From Pro-ircinals to Madangamine Alkaloids

Pro-ircinal alkaloids 170 could undergo a vinylogous retro-Mannich fragmenta-tion, giving rise to spiro-piperidine 172. Following intramolecular redox trans-fer or sequential oxidoreduction, spiranic tetrahydropyridinium 173 would be

6.10 Total Syntheses of Manzamine-Type Alkaloids 219

produced. Madangamine-type alkaloids would eventually be yielded upon cyclizingenamination (174) and vinylogous aza-Mannich reaction with a final reductionof 175.

6.9.7From Pro-ircinals to Manadomanzamine Alkaloids

Intramolecular epoxidation of pro-ircinals 171 would produce isoquinoline alde-hydes 176, prone to Pictet–Spengler reaction with tryptamine (80). Followingregioselective oxidation, iminium 177 would be hydrolyzed to propionaldehydederivative 178, which is amenable to iminium formation with the neo-formedtetrahydroisoquinoline system. Mannich addition of an acetone equivalent ontothe residual iminium of 179 would eventually produce manadomanzamine-typealkaloids.

6.9.8From Ircinals and Pro-ircinals to Nakadomarine Alkaloids

Ircinal A-type alkaloids could undergo vinylogous retro-Mannich fragmentation,identical to the one undergone by 170 in the supposed biosynthesis of madangaminealkaloids (cf. Scheme 6.34). Subsequently, cyclization of diketone 180 to furan 181would enable intramolecular vinylogous Mannich addition to effect ring closure,yielding the fused tetracyclic system typical of nakadomarine A-type alkaloids. Theimplication of furan nucleophiles in this biosynthesis is directly suggested frombiomimetic experiments (cf. Scheme 6.37).

Approaching the end of this marine story, let us finally emphasize how thechemist’s intuitions proved to be right and were corroborated (sometimes af-terwards) by the isolation and characterization of new informative structures ofnatural products. Bear in mind that the structure of ircinal A (79) and keramaphidin(7) were not yet known when Whitehead and Baldwin proposed their pioneeringbiosynthetic model, and that pyridinium-piperidine intermediates such as 95 werepostulated before being discovered in sponges (cf. Scheme 6.23). As the latestnod from Nature to the chemical community, the manzamine-type alkaloids za-mamidines [69] [see the structure of zamamidine C (182), Scheme 6.43] recentlygave striking presumptive evidence for the C3 (acrolein/malonaldehyde) scenario.In fact, a C3 link such as 16 clearly unifies a tetrahydromanzamine A moleculewith a β-carboline moiety; a plausible biosynthesis from ircinal A (79) is thereforeeasily conceivable with the intervention of two molecules of tryptamine (80).

6.10Total Syntheses of Manzamine-Type Alkaloids

The Baldwin–Whitehead and Marazano’s biosynthetic hypotheses have provideda useful framework to develop synthetic approaches to the manzamines alkaloids.


N

N

N NH

OH

H

H

zamamidine C 182[Amphimedon sp.]

N

NH

ircinal A

O NH

H2NONH

NH2

Pictet-Spenglerand oxidation to b-carboline

Pictet-Spengler

80 80

16

79

Scheme 6.43 Retrobiosynthesis of zamamidine C.

Nevertheless, stepwise strategies have been initiated worldwide over the last 20years toward these remarkable alkaloids. To date, the total synthesis of manzamineA (1) [70], nakadomarine A (10) [60, 71], haliclonacyclamine C [72], and sarainA (6) [73] have been achieved and beautifully illustrate the state-of-the art inmethods for highly complex molecule construction. These total syntheses as wellas the numerous chemical approaches are not included in this chapter. Naturalircinals and manzamines have been subjected to semi-synthetic transformations,especially in the Hamann group, providing a wide range of derivatives for diversebiological screenings and studies [74]. In addition, total synthesis has also enabledthe preparation of various simplified analogs that are unreachable from naturalmaterial [75].

6.11Conclusion

From a biosynthetic standpoint, the most striking observation is that the greatmajority of manzamine alkaloids can be connected by means of reversible reac-tions (such as Mannich, aza-Mannich, Michael, and aldol), and thus be potentiallyinterconvertible at a biochemical level. According to this hypothesis, only a lim-ited number of alkaloids should be considered structurally ‘‘terminal,’’ that is,those few formed by enzymatically irreversible steps (such as Pictet–Spenglercyclization to β-carboline systems). In this general biogenetic proposal, reduc-tions would have the role of freezing reactive intermediates (e.g., iminiumspecies) into stable alkaloids. However, it must be realized that several alter-native reoxidations (i.e., at other levels of the molecule) probably remain feasiblebiochemically, due to similar redox potentials of related iminium alkaloids. More-over, conformation-induced intramolecular electron transfers and dismutationshave the potential to occur spontaneously, as suggested by several observationsin the laboratory (cf. Schemes 6.18 and 6.25). Overall, the conception of ‘‘manza-mines in equilibrium’’ for this rich metabolism of marine alkaloids (that mightbe driven by subtle ecological changes) yields a particularly striking picture ofdynamic chemical evolution and diversity-oriented biogenesis. These latter sug-gestions have been, at least partly, magnificently demonstrated by track records of

References 221

ON

N

H

x

y

misenine 12

N

OH

N

NH

HN

O

manadomanzamine A 9

NO

O H

NOHC

HO

haliclonine A 183 [Haliclona sp.]

Figure 6.6 Challenging manzamines as future synthetic targets.

successful applications at the biomimetic chemistry level (cf. Schemes 6.18, 6.28,and 6.33).

Synthetic effort toward the manzamine alkaloids will certainly continue in thefuture as new exciting structures periodically appear in the literature. Moleculessuch as misenine (12) (for which no logical biosynthetic route can yet be proposed),complex, highly rearranged haliclonine A (183) [76], or indolic manadomanzamine(9), will surely keep stimulating chemists because of their intrinsic beauty andnot only because of interesting biological properties (Figure 6.6). Future syntheticendeavors will most probably be guided by the body of growing biosynthetic studiescurrently performed worldwide with marine organisms.

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