Masruri, PhD this was prepared from any sources from internet and detail of material can be download from a mentioned journals

(1)

The Synthesis Chemistry of Alkaloid:

Finding a Shortest Route of Important Alkaloids

Masruri, PhD

(2)

N R O O Me Me H Me Cl SCN Welwitindolinone B isothiocyanate R=H, Me N Me O O Me Me H Me Cl R H N-Methylweltindolinone C R= NCS, NC

N Me O O Me Me H Me Cl R H OH 3-hydroxy-N-methylwelwitindolinone C R= NCS, NC

N Me O O Me Me H Me O CN H O N-Methylwelwitindolinone D isonitrile N H Me Me O H Cl Me CN Welwitindolinone A isonitrile N H H Cl Me CN H Fischerindole G

Moore et al, published welwitindolinone alkaloids isolated from a series of marines and

terrestrial cyanobacteria (Moore et al,

JACS

,

1994

,

116

, 9935-9942)

Total synthesis of Welwitindolinone A isonitrile and Fischerindole G,see: Baran et al,

JACS

,

2005

,

127

,15394-15396

Wood et al,

JACS

,

2006

,

128

, 1448-1449

JACS

,

2008

,

130

,2087-2100

Isolated also from blue-green algae. N-Methyl Welwitindolinone may have some multiple drug

resistance-reversing properties

(3)

Konopelshi et al,

Org. Lett

,

2001

,

3

, 3001-3004

N Me O

Me Me OCN

H

Rawal et al,

Org. Lett

,

2005

,

7

, 3421-3424

N Boc O MeOOC

TBDMSO

N Me

O

Simpkins et al,

Org. Lett

,

2005

,

7

, 4087-4089

N

Me O O

Me Me HO

H

Wood et al,

JACS

,

1999

,

121

, 6326-6327

(4)

N Me O O Me Me H Me Me H

H

Garg et al,

Org. Lett

,

2009

,

11

, 2349-2351

N Me O Me Me H H O

Martin et al, Org. Lett, 2010, 12, 2492-2495

N Me O O Me Me H MeOOC H O

Rawal et al,

Org. Lett

,

2011

,

13

, 3214-3217

N Me Me Me OCN RO RO H R= TBS

Funk et al, Org. Lett, 2006, 8, 2643-2645

(5)

(6)

N Me O O Me Me H Me O CN H O N-Methylwelwitindolinone D isonitrile OTBS Me O + OTBS Me OMe H O OHC Me OTBS O Me

1, CuBr, Me2S, MgBr

-78oC, THF, than TFEF 2, Me2SO4, K2CO3, DMF

50%, 2 steps

15: 1 N Me Me Me Br HO N Me Br O

Me MeMgBr, 0oC, THF

TFEF F O O

F F :

(7)

OH HOOC HO OH OH D-(-)-Quinic Acid cas: 77-95-2 TCL, 25g 560

dry HCl, acetone 25o_C

78% OH O O O O

LiAlH4 ,THF

87% OH O O HO HO NaIO4 66% O O HO O

MsCl,Et3N

DCM

83% O O O

H2, Pd(OH)2/C

50 psi

76% O O O

DBU, TBSCl, C6H6, reflux

87%

OTBS O

Me2CuLi, TMSCl

OTBS O DDQ, HMDS

OTBS OTMS

rf: JOC, 1986, 51, 2332-2342

rf: JOC, 1989,54, 3738-3740

rf: JOC, 2007, 72, 6885-6890 50% 2 steps

(8)

Zayia,

OL

,

1999

,

1

, 989-991

CuBr, Me2S, MgBr

-78oC, THF OTBS O Me OTBS Me OH H O O O F F F OTBS Me OMgBr R O R'

1, 1.1eq LDA, Et₂O, -78o_C

2, Zayia's reagent, -78oC 3, H+,-78oC

R O

R' OH

O _O _OH

(9)

OTBS Me MeO H O KHMDS, TMSCl -78oC, THF

OTBS Me MeO H OTMS N Me Me Me Br HO

TMSOTf, -40oC, THF Then, aq HClO4

78% 2 steps

N Me O Me Me H Me OTBS Br HO H

Pd(OAc)2 (30 mol%)

Pt_Bu

3 (30 mol %)

KHMDS, 80oC, toluene

N Me O Me Me H Me TBSO OHC 73%

1, HF, DCM 2, DMP, DCM

91%, 2 steps

N Me O Me Me H Me O OHC KHMDS, NBS -78o_{C, THF}

(10)

N Me O Me Me H Me OTBS Br HO H

Pd(OAc)2 (30 mol%)

Pt_Bu

3 (30 mol %)

KHMDS, 80oC, toluene

N Me O Me Me H Me TBSO OHC 73% O R'' R R'

H ₊ _ArBr PdL2

Base O R'' R R' Ar ArBr Pd(O) Pd Ar Br O R'' R R' H + Base O R'' R R' Pd Ar O R'' R R' Ar O R'' R R' Pd Ar

(11)

N Me O Me Me H Me O OHC Br DMDO, acetone NaHCO3 41% N Me O O Me Me H Me O OHC H O

NH2OH*HCl

Py, 45o_{C, MeOH}

94% N Me O O Me Me H Me O _H O N HO NCS, DMF;

then 0oC THF, NEt3

N Me O O Me Me H Me O SCN H O N H NH S 65% MeN P O Ph

110oC, toluene 54% N Me O O Me Me H Me O CN H O N-Methylwelwitindolinone D isonitrile

(12)

N Me O O Me Me H Me O _H O N HO NCS, DMF;

then 0oC THF, NEt3

N Me O O Me Me H Me O SCN H O N H NH S 65% R

N OH NCS

R N OH

Cl

thiourea

Et3N _R

N S O

NH2

NH2 rt

R-NCS R N S O NH2 NH2

-H2N NH2

O

(13)

N Me O O Me Me H Me O SCN H O MeN P O Ph

110oC, toluene

54% _N Me O O Me Me H Me O CN H O N-Methylwelwitindolinone D isonitrile R-NCX + MeN P O

Ph R-NC +

N P O Ph X Me X= O X= S R N C X _N P O Ph Me R N C

-_X _N+

P O Ph Me X P O N N R Me Ph _N P O Ph X Me R-NC +

(14)

N Me O O Me Me H Me Cl SCN H Electrophilic chlorination N Me O Me Me H Me N OHC NH2 N Me O Me Me H Me O OHC

Rawal retrosynthetic analysis

N Me O O Me Me H Me Cl SCN H N Me O O Me Me H Me Cl CN H N Me O O Me Me H Me Cl SCN OH

(15)

N Me O Me Me H Me O OHC

THF/EtOH, 0oC 89% N Me O Me Me H Me O HO

N2H4, AcOH

EtOH, 70o_C

N Me O Me Me H Me N HO N Me O Me Me H Me Cl HO NH2 NCS Pyridine 61% 2 steps

MMPP TFA, AcOH 72% N Me O Me Me H Me Cl HO O H Dess-martin periodinane, NaHCO3

DCM 99% N Me O Me Me H Me Cl OHC O H

NH₂OH*HCl, pyridine MeOH, 45oC

97% N Me O Me Me H Me Cl O H N HO

NCS, DMF, THF, 40oC then Et3N, 23oC

N NH SH 83% N Me O O Me Me H Me Cl SCN H N-Methylweltindolinone C-NCS

(Dr= 4.4: 1 ) 1.1 equiv NaBH(OMe)₃ COOH O O O -2 Mg2+

6H2O

*

(16)

N Me O Me Me H Me O HO

N2H4, AcOH

EtOH, 70oC

N Me O Me Me H Me N HO N Me O Me Me H Me Cl HO NH2 NCS Pyridine 61% 2 steps

N NH2 NCS _N N H Cl N+ N --HCl N+ N Cl

+_Cl H _Cl

O N2H4 N

NH2

NCS

Cl

NCS

Chem. Phram. Bull

.

1963

, 684-685

(17)

N Me O Me Me H Me O OHC HO OH 4 A mol, toluene

100oC

57% N Me O Me Me H Me O O O (not observed) N Me O Me Me H OH O H N Me O Me Me H Me O OHC Cope N Me Me O CHO O N Me Me O CHO O H rearomatization N Me Me O O O H N Me O O H Me OH N Me O O H Me O Aldol N Me O Me Me H OH O H

(18)

N Me O O Me Me H Me Cl SCN H MeN P O Ph

110oC, toluene

65% _N Me O O Me Me H Me Cl CN H N-Methylweltindolinone C-NC

KHMDS, THF, -78oC then

Ph NSO₂Ph O 67 % N Me O O Me Me H Me Cl SCN OH 3-hydroxy-N-methylwelwitindolinone C

(19)

(20)

OPiv Me O Me Me Me O Me s-carvone

1, K2CO3, MeOH, 60oC

2, I₂, MeOH, 23o_C

N Me Br OH Me O Me N Me Br Me

H TBSCl, imidazole_{DMAP, Bu}

4NI

DMF, 100oC

54% 2 steps

90% OTBS Me O Me N Me Br Me

H NaNH2 (10.5 equiv)

t-BuOH (3.5 equiv) THF, 23oC

N Me O Me Me H Me H TBSO + OTBS Me O Me N Me Me H

2.5 : 1 46%

(21)

Chem.pharm.bull

.

1994

,

42

, 1393-1398

JOC

.

1978

,

43

, 2057-2059

OPiv Me O Me Me Me O Me s-carvone Me O Me

LiAlH₄ Me

OPiv

Me PivCl

Pyridine

PivCl = O Cl CrO3 Me OPiv Me O NaOMe MeOH Me OPiv Me Me O N H N MgBr CuBr Me OPiv Me Me O Me OPiv Me

CrO₃ Me

OPiv Me O N H N NH N

+ _CrO₃

N N Cr O OH O H

: _N H

(22)

N N S S O O O O F F F

F _FF comins' reagent N Me O Me Me H Me H TBSO

1, TBAF, THF, 60oC 2, Dess-Martin,DCM,23oC

95% 2 steps _N Me O Me Me H Me H O

1, KHMDS, THF, -78oC comins's reagent

2, (Me₃Sn)₂, Pd(PPh₃)₄ LiCl, dioxane, 110oC

74% 2 steps N_Me O Me Me H Me H Me3Sn

CuCl2, dioxane 23-80 oC

75% N Me O Me Me H Me H Cl

NBS, 0oC, DCM HCl, 80oC, EtOH 89%, 2 steps

(23)

N Me O Me Me H Me H Cl O H

1, i-Bu2AlH,DCM, -78oC

2, Cl3CC(O)NCO

DCM, 0--23oC K₂CO₃, MeOH

86% 2steps N Me Me Me O H Me Cl H H O O H2N

AgOTf, PhI(OAc)2

bathophenanthroline CH3CN, 82oC

33% 25% N Me Me Me O H Me Cl H O O HN

1, Ba(OH)2* 8H2O

H2O, dioxane,110oC

2, IBX, TFA DMSO, 23oC

48% 2 steps N_Me O

Me Me H Me

H2N

Cl

O H

N O O N S

DMAP, DCE, 90oC

N Me O Me Me H Me SCN Cl O H N-Methylweltindolinone C-NCS bathophenanthroline N N

(24)

N Me O Me Me H Me H Cl O H

1,LiEt3B-D,THF,-78--0oC

2, Cl₃CC(O)NCO DCM, 0--23oC K2CO3, MeOH

100% 2steps N Me Me Me O H Me Cl H H O O H2N

D N Me Me Me O H Me Cl H H O O H2N

R

AgOTf, PhI(OAc)2

bathophenanthroline CH3CN, 82oC

+ N Me O Me Me H Me H Cl O H N Me Me Me O H Me Cl H O O HN R

R= H 33% 25%

(25)

N Me Me Me O H Me Cl H O O HN D

1, Ba(OH)₂* 8H₂O H2O, dioxane,110oC

2,Dess-martin, TFA DCM, 23oC

66% 2 steps N_Me O

Me Me H Me

H₂N Cl

O H

1,HCO₂H, Ac₂O THF, 0--23oC 2, Burgess reagent THF, Benzene, rt

100% N_Me

O O Me Me H Me Cl CN H N-Methylweltindolinone C-CN N Me O O Me Me H Me Cl CN H NaH, air THF, 23oC

N Me O O Me Me H Me Cl CN OH N Me O O Me Me H Me Cl SCN H NaH, air THF, 23oC

47% 48% N Me O O Me Me H Me Cl SCN OH 3-hydroxy-N-methylwelwitindolinone C-NCS 3-hydroxy-N-methylwelwitindolinone C-NC O

Garg et al,

JACS

,

2012

,

134

, 1396-1399

(26)

Synthesis Important Piperidine

(27)

Synthesis of ( un) natural piperidine alkaloids

(+)-EPIPINIDINONE

(defense alkaloid and deterent of

C. montrouzieri and E. varivestis)

(+)-CALVINE

(defense alkaloid and deterent of

C. 10-guttata and C. 14-guttata)

N

H

OH

homo-1-DNJ

OH

HO

OH

(analogues of glucosidase inhibitor 1-deoxynojirimycin from Morus sp.)

N

H

OH

Cl

6-Cl-

L-ido

-1-DNJ

OH

HO

N

H

O

N

C

₅

H

₁₁

O

(28)

T

otal synthesis of

unnatural

analogues of 1

(29)

1

-

Deoxynojirimycin

White mulberry

(

Morus alba

)

Inhibition

: K

i

= 32 nM (

α

-D-glucosidase)

Activity

: anti-diabetes, anti-HIV, ...

Applications

: Tay-Sachs, Gaucher, ...

N

H

1-Deoxynojirimycin

(1,5-dideoxy-1,5-imino-

D

-glucitol)

OH

HO

(30)

Retrosynthetic analysis

of new analogues of 1

-

DNJ

N

H

OH

homo-1-DNJ

OH

HO

OH

N

PG

OPG

PGO

O

NH

PG

OH

OPG

PGO

N

H

OH

Cl

6-Cl-

L-ido

-1-DNJ

OH

HO

NH

PG

OH

OPG

PGO

(31)

S

ubstrate

p

reparation

O

HO

OMe

OH

O

HO

BnO

OMe

BnO

OH

O

HO

OMe

OH

O

Ph

OH

OBn

NHBn

O

HO

BnO

OMe

BnO

Br

O

BnO

OMe

BnO

O

Ph

PhCH(OEt)

2

cat.CSA

CHCl

₃

, reflux

3 hrs, 81 %

BnB r, N aH

D MF, 0°C

3 hrs, 75 %

2 % H

2

SO

4

MeOH, 23°C

3 hrs, 97 %

Ph

3

P, CB r

4

pyridine

0°C - 3 hrs

60°C - 30 m in

79 %

Zn, BnNH

2

NaB H

3

CN

n

PrOH/H

₂

O

reflux, 2 hrs

64 %

(32)

Pd( I I ) - catalysed aminocarbonylation & Finalisation

P. Szolcsányi

et al.

:

Tetrahedron: Asymmetry

2000,

11

, 2579.

OH

OBn

NHBn

N

Bn

OBn

BnO

CO (balloon)

0.1 eq. PdCl

₂

1 eq. BQ

2 eq. LiCl

2 eq. AcONa

THF, r.t.

17 hrs, 66%

D-gluco

L-ido

(4 : 1)

O

N

Bn

OBn

BnO

O

+

N

Bn

OBn

BnO

O

1. LiBH

₄

, THF

0°C - r.t., 64%

2. H

2

(balloon)

10% Pd/C, HCl

MeOH, r.t., 90%

N

H

.

HCl

OH

homo-1-DNJ

OH

HO

(33)

Pd( I I )

/

CuCl

2

-

catalysed chlorocyclisation

OH

OBn

NHBn

N

Bn

OBn

BnO

OH

Cl

N

Bn

OBn

BnO

OH

Cl

0.1 eq. PdCl

₂

3 eq. CuCl

₂

3 eq. AcONa

glacial AcOH

r.t., 2 days, 70%

+

L-ido

(19 : 1)

D-gluco

OH

OBn

NHBn

N

Bn

OBn

BnO

OH

Cl

0.1 eq. PdCl

₂

3 eq. CuCl

₂

3 eq. AcONa

r.t., DMF, 53%

N

Bn

OBn

BnO

OH

Cl

+

L-altro

D-galacto

+

N

Bn

BnO

OH

O

(11%)

(15 : 1)

(34)

Mechanistic proposal of the Pd( I I ) / CuCl

2

-

catalysed

chloroaminocyclisation and bicyclisation

Si-attack

Re-attack

BnHN

BnO

OH

HCl

σ

-Pd-complex I

σ

-Pd-complex II

CuCl

₂

CuCl

₂

σ

-Pd/Cu-complex I

NHBn

BnO

OBn

OH

H

Cl

2

Pd

NBn

BnO

OBn

OH

Pd

Cl

NBn

BnO

OBn

OH

Pd

Cl

Cu

Cl

NHBn

BnO

OBn

OH

H PdCl

2

NBn

BnO

OBn

OH

PdCl

N

Bn

BnO

OBn

OH

σ

-Pd/Cu-complex II

Cu Cl

Pd

Cl

L

2

PdCl

2

L

2

PdCl

2

CHLOROCYCLISATION

BICYCLISATION

D-galacto

BICYCLE

CHLORIDE

(35)

Synthesis of new analogues of

iminoalditols

P. Szolcsányi, T. Gracza:

Tetrahedron

2006,

62

, 8498.

NBn

OH

O

H

₂

(1 atm)

10 % Pd/C

EtOH, HCl

100 %

L-altro

H

₂

(1 atm)

10 % Pd/C

EtOH, HCl

100 %

NH

.

HCl

OH

O

D-galacto

BnO

HO

N

OBn

BnO

Bn

HO

Cl

1

C

₄

(J

_4,5

= 10.4 Hz)

(J

_2,3

~ J

_3,4

= 3.5 Hz)

N

OH

HO

H

.

HCl

HO

Cl

H

₂

(1 atm)

10 % Pd/C

EtOH, HCl

100 %

L-ido

N

OBn

BnO

Bn

Cl

HO

1

C

₄

(J

_4,5

= 3.0 Hz)

(J

_2,3

~ J

_3,4

= 4.8 Hz)

N

OH

HO

H

.

HCl

Cl

HO

1

C

₄

(J

_4,5

= 1.5 Hz)

(J

_2,3

~ J

_3,4

= 3.5 Hz)

1

(36)

Formal t

otal synthesis of

alkaloid ( + )

-

2

-

e

pi

pinidinone

N

H

(

2R

,6

R

)/(

2S

,6

R

)-6-methyl-2-(2

,

-oxo-propyl)piperidine

O

(-)-Pinidinone

N

H

O

(37)

Ladybird Beetles (

Coccinellidae

)

Mealybug ladybird beetle

(

Cryptolaemus montrouzieri

)

Mexican bean beetle

(

Epilachna varivestis

)

Reports on (epi)pinidinone occurrence:

V. W. Brown, P. B. Moore:

Aust. J. Chem

. 1982,

35

, 1255.

A. B. Attygalle, S. Ch. Xu, K. D. McCormick, J. Meinwald, C. L. Blankespoor, T. Eisner:

Tetrahedron

(38)

Coniferous Trees (

Pinaceae

)

Ponderosa pine

(

Pinus ponderosa

)

Colorado spruce

(

Picea pungens

)

Reports on (epi)pinidinone occurrence:

J. N. Tawara, A. Blokhin, T. A. Foderaro, F. R. Stermitz,

J. Org. Chem.

1993,

58

, 4813.

F. R. Stermitz, J. N. Tawara, M. Boeckl, M. Pomeroy, T. A. Foderaro, F. G. Todd,

Phytochemistry

(39)

of

( + )

-

2

-

epipinidinone

N

H

O

(+)-2-Epipinidinone

N

PG

OMe

O

(40)

Formal t

otal synthesis

of ( + )

-

2

-

epipinidinone

Substrate preparation:

D. J. Dixon, S. V. Ley, W. E. Tate:

J. Chem. Soc., Perkin Trans. 1

2000, 2385.

A. Fürstner, K. Langemann:

Synthesis

1997, 792.

MgBr

0.1 eq. Li

₂

CuCl

₄

-30°C, THF, 82%

3 eq. BnNH

2

, THF

reflux, 36 hrs, 86%

OH

O

+

2 eq. TsCl, pyridine

0°C-r.t., CH

₂

Cl

₂

, 90%

OTs

NHBn

CO (balloon)

0.1 eq. PdCl

₂

3 eq. CuCl

₂

3 eq. AcONa, MeOH

30°C, 3 days, 58%

N

Bn

OMe

O

+

N

Bn

OMe

O

(4 : 1)

(41)

Formal t

otal synthesis

of ( + )

-

2

-

epipinidinone

Debenzylation:

T. Momose, N. Toyooka, J. Makoto:

J. Chem. Soc., Perkin Trans. 1

1997, 2005.

Finalisation:

M. J. Munchhof, A. I. Meyers:

J. Am. Chem. Soc

. 1995,

117

, 5399.

H

₂

(balloon)

0.15 eq. Pd(OH)

₂

MeOH, 18 hrs, 62%

N

Bn

OMe

O

N

H

OMe

O

1. Weinreb

2. MeMgBr

N

H

O

(42)

Short t

otal synthesis of

racemic

alkaloids c

(43)

Ladybird Beetles (

Coccinellidae

)

[ 1]

Calvia 10-guttata

Calvia 14-guttata

These insects are rarely eaten by predators due to the production

of toxic alkaloids in their haemolymph. When disturbed or

molested, they release small droplets of yellow “blood” at their

knee joints ( so called

reflex bleeding

)

[ 2]

[1] A. G. King, J. Meinwald:

Chem. Rev.

1996,

96

, 1105.

(44)

S

tructure elucidation of ( + )

-

c

alvine and ( + )

-

2

-

e

picalvine

The relative configuration w as established on the basis of NMR and

HRMS studies and subsequently confirmed

via

racemic total

synthesis.

[ 3]

The absolute configuration w as determined by

enantioselective total synthesis.

[ 4]

[3] J.-C. Braekman, A. Charlier, D. Daloze, S. Heilporn, J. Pasteels, V. Plasman, S.

Wang:

Eur. J. Org. Chem.

1999, 1749.

[4] P. Laurent, J.-C. Braekman, D. Daloze:

Eur. J. Org. Chem.

2000, 2057.

N

O

1 2

3 4 5 6 7 8

9 1 01 1

cis

(Calvine)

trans

(2-Epicalvine)

(45)

•

Know n total syntheses of ( + )

-

c

alvine and ( + )

-

2

-

e

picalvine

a) CN(

R,S

)-methodology - use of chiral

N

-cyanomethyloxazolidine

12% total yield over 7 steps

P. Laurent, J.-C. Braekman, D. Daloze:

Eur. J. Org. Chem.

2000, 2057.

b) CM-strategy - olefin

cross

-metathesis reaction

P. Dewi-Wülfling, J. Gebauer, S. Blechert:

Synlett

2006, 487.

•

Know n

formal

syntheses of ( + )

-

c

alvine and ( + )

-

2

-

e

picalvine

c) Davies‘ Li-amide 1,4- addition & I ntramolecular Mannich-type reaction

S. Rougnon-Glasson, Ch. Tartrat, J.-C. Canet, P. Chalard, Y. Troin:

Tetrahedron:Asymmetry

2004,

15

, 1561.

d) Diastereoselective reduction of piperidine

β

-enamino esters

S. Calvet-Vitale, C. Vanucci-Bacqué, M.-C. Fargeau-Bellassoued, G. Lhommet:

(46)

of

calvine and 2

-

epicalvine

N

C

₅

H

₁₁

O

C

5

H

11

NH

OH

OTs

C

₅

H

₁₁

(47)

R

acemic total synthesis

of calvine and 2

-

epicalvine

a) Preparation of the substrate for the Pd(I I )-catalysed aminocarbonylation

The identical sequence on analogous compounds:

A. Fürstner, K. Langemann:

Synthesis

1997, 792.

O

C

5

H

11

O

+

Br

Mg, Et

₂

O

r.t. - reflux

2 hrs, 3 g scale

2 eq. TsCl

DCM, py

0°C - r.t.

18 hrs, 79%

C

5

H

11

OTs

15 eq. H

₂

N(CH

₂

)

₂

OH

reflux, THF

2 days, 75%

NH

C

₅

H

₁₁

OH

16%

OH

C

₅

H

₁₁

67%

(overall 80%)

+

NaBH

₄

, MeOH

(48)

R

acemic total synthesis

of calvine and 2

-

epicalvine

b) Finalisation - Pd(I I )-catalysed carbonylation of

rac

-aminoalkenitol

N

C

₅

H

₁₁

O

NH

C

₅

H

₁₁

OH

CO (balloon)

0.1 eq. PdCl

2

2 eq. CuCl

₂

2 eq. AcONa

dioxane, 40°C

7 hrs, 55%

rac

-calvine

rac

-2-epicalvine

N

C

₅

H

₁₁

O

+

rac

-aminoalkenitol

(2.2 : 1)

(49)

Morfine

S

(50)

(51)

(52)

(53)

(54)

Gates Synthesis

(55)

Gates Synthesis

(56)

Gates Synthesis

(57)

Rice Synthesis

(58)

Rice Synthesis

Rice, C.; Brossi, A.

J. Org. Chem.

1980

,

45

, 592

16 steps (yield 12%)

Grewe cyclization was key

disconnection

Practical method for

conversion of

(59)

Evans Synthesis

(60)

Evans Synthesis

Evans, D.A.; Mitch,

C.H.

Tetrahedron Lett.

(61)

Evans Synthesis

(62)

Overman Synthesis

(63)

Overman Synthesis

(64)

Overman Synthesis

(65)

Overman Synthesis

(66)

Overman Synthesis

Overman, L.E.

Pure and Appl. Chem.

1994

,

66

, 1423

• 1st enantioselective synthesis that did not contain a resolution

• Natural and unnatural morphine available

(67)

White Synthesis

(68)

White Synthesis

(69)

White Synthesis

White, J.D.

J. Org. Chem.

1999

,

64

, 7871

29 steps (Overall yield of 1.73 %)

(70)

Parker Synthesis

(71)

Parker Synthesis

(72)

Parker Synthesis

(73)

Parker Synthesis

(74)

Lupin

A

(75)

Used in cereals, baby formula, pasta, soups and salads in the United States (22 states,

42,000 pounds/year); Seeds used in traditional Chinese medicine

Cultivated for over 2000 years; over 500 species of the genus Lupinus known

Mildly toxic lupin alkaloids present in the plants causes a bitter taste, and are used as a

defensive mechanism against herbivores

(-)-Cytisine has been identified as a selective partial nicotinic

receptor agonist (nicotinic acetylcholine recepters are affected

by Parkinson's and Alzheimer's diseases) (Nicotine is a full

agonist at neuronal nAChR's, and has additional undesirable

biological effects)

Alkaloid extracts from Lupinus species have recently shown

antimicrobial activity :

L. albus showed inhibitory effects on Gram negative bacteria

L. varius and L. densiflorus strongly inhibited Gram positive

bacteria

(76)

(77)

(78)

E. E. van Tamelen and R. L. Foltz, J. Am. Chem. Soc.

1969

, 91 (26), 7372-7377

Synthesis epilupinine

(79)

(80)

(81)

(82)

(83)

(84)

(85)