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

  The Synthesis Chemistry of Alkaloid: Finding a Shortest Route of Important Alkaloids

Masruri, PhD

this was prepared from any sources from internet and detail of material can

be download from a mentioned journals

  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

  

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

resistance-reversing properties Welwitindolinone Alkaloids

  Synthesis of the Building Block

  Me HO Me O H

  Wood et al, JACS, 1999, 121, 6326-6327

  O N Me TBDMSO MeOOC O

  

Konopelshi et al, Org. Lett,

2001, 3, 3001-3004

  N Boc

  H

  Me OCN Me O

  Rawal et al, Org. Lett, 2005, 7, 3421-3424

  N Me O

  

Simpkins et al, Org. Lett,

2005, 7, 4087-4089

  N Me

  Synthesis of the Building Block

  RO RO H Me OCN Me

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

  N Me R= TBS Me H Me Me H Me O H

  Garg et al, Org. Lett, 2009, 11, 2349-2351

  O N Me O H Me H Me O

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

  N Me O H Me MeOOC Me O H

  

Rawal et al, Org. Lett,

2011, 13, 3214-3217

  O N Me

  Rawal retrosynthetic analysis

  N Me O O Me Me H Me O CN H O N Me O O Me Me H Me O

  SCN

  X OH N Me O Me Me H Me TBSO

  OHC

  X N Me O Me Me H Me OTBS

  X Br HO H N Me Me Me Br OTBS Me MeO H O

  N-Methylwelwitindolinone D isonitrile

• HO

  N Me O O Me Me H Me O CN H O

  MgBr -78

  OTBS Me O + OTBS Me OMe H O

  N-Methylwelwitindolinone D isonitrile

2 S,

  Me OTBS O Me 1, CuBr, Me

  o

  C, THF, than TFEF 2, Me

  2 SO

  OHC

  , K

  2 CO

  3

  , DMF 50%, 2 steps 15: 1 N Me Me Me Br HO N Me Br O Me MeMgBr, 0

  o

  C, THF

  TFEF O O F F F : Zayia's reagent

  4

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

  25

  HMDS Si H N Si DBU, toluene OH O 49% OTBS Me OMe H O

  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

  , reflux 87% OTBS O Me

  6

  6 H

  /C 50 psi 76% O O O DBU, TBSCl, C

  2

  , Pd(OH)

  2

  DCM 83% O O O H

  66% O O HO O MsCl,Et

  4

   ,THF 87% OH O O HO HO NaIO

  4

  C 78% OH O O O O LiAlH

  o

3 N

2 CuLi, TMSCl

  F OTBS F OTBS OTBS O O Me CuBr, Me S,

2 MgBr F

  Me Me

  o

  H -78

  C, THF OMgBr OH O O

  o

  1, 1.1eq LDA, Et O, -78 C

  2 o

  2, Zayia's reagent, -78 C

• + o O OH

  3, H ,-78 C O R' R R R' O O OH O OH O 75%

  83% Me Me OTMS O O O OH Me 60% Me 79% OHC

  Zayia, OL, 1999, 1, 989-991

  OTBS Me MeO H O KHMDS, TMSCl -78

  t

  o

  C, 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 -78

  o

   (30 mol %) KHMDS, 80

  3

  Bu

   (30 mol%) P

  o

  2

  78% 2 steps N Me O Me Me H Me OTBS Br HO H Pd(OAc)

  4

  C, THF Then, aq HClO

  o

  C, THF OTBS Me MeO H OTMS N Me Me Me Br HO TMSOTf, -40

  C, THF 91%

  TBSO OTBS Pd(OAc) (30 mol%)

2 Me

  t

  H P Bu (30 mol %) H Me

  3 o

  H Me KHMDS, 80

  C, toluene Me OHC HO Br Me O O Me 73% N N

  Me Me O O Ar PdL

  2 H

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

  Br Pd Ar R'' R R'' O R R' R'

  H R'' R R' + Base

  Buchwald, JACS, 1997, 119, 11108-11109

  Hartwig, JACS, 1997, 119, 12382-12383 Buchwald, JACS, 1998, 120,1918-1919

  O O O H

  H Br NH OH*HCl

  2 H o

  H DMDO, acetone H Me Me Me

  Py, 45

  C, MeOH O O NaHCO Me Me

  Me

3 OHC

  OHC Me Me

  Me O O O

  HO N 94% 41% O O N N

  N Me Me Me O O

  H H MeN H Me H NCS, DMF; Me O Me O P O

  o

  Me Ph then 0 C THF, NEt CN

3 SCN

  Me

  o

  O Me O 110

  C, toluene NH O O 54% N 65% N N S

  Me Me H

  N-Methylwelwitindolinone D isonitrile Rawal et al, JACS,

  2011, 133, 5798-5801

  O O H H

  H NCS, DMF; Me H Me O

  o

  Me O then 0 C THF, NEt

3 Me

  SCN Me O Me O N NH HO O O

  N N S N Me H Me 65% OH OH

  O NCS rt N thiourea NH N

  2 N

  R-NCS Et N

3 S NH

  R Cl R

  2 R

  O

• H N NH

  2

  2 O

  NH N

  2 S

  NH

  2 R Ryu, TL,

  1993, 34, 8283-8284 Kim, TL, 1997, 38, 1597-1598

  O O H H MeN H Me H Me

  O P O Me O Me Ph CN SCN Me

  o

  Me O O 110

  C, toluene O O 54% N N Me Me

  N-Methylwelwitindolinone D

isonitrile

  Me MeN N R-NCX

  X R-NC + P O + Ph P O Ph X= O X= S R R R-NC R N N N Me C

  Me Me C

• + + -

  X N

  X X N N P P Me P Ph Ph N Ph O O O

  X P O Ph

Mukaiyama et al, Bull. Chem. Soc. Jpn.

  1965, 38, 858-859

  N Me O O Me Me H Me Cl SCN H

  Electrophilic chlorination N Me O Me Me H Me N OHC NH

  2 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 N-Methylweltindolinone C-NCS N-Methylweltindolinone C-NC 3-hydroxy-N-methylwelwitindolinone C

  O NH

  2 N Cl

  O H 1.1 equiv Me H H Me H NaBH(OMe)

  Me Me OHC

  3 Me NCS Me

  Me N H , AcOH

  2

  Me O

  4 Me

  o

  Me Me

  o O O

  HO HO THF/EtOH, 0 C Me Pyridine HO O EtOH, 70 C 61% 2 steps N 89% Me

  N N N Me Me Me Cl Cl

  Cl H NH OH*HCl, pyridine

  2 Me

  H H Dess-martin Me

  o

  Me Me MMPP Me periodinane, NaHCO MeOH, 45 C Me

3 N

  OHC HO Me Me TFA, AcOH O

  Me HO O

  O DCM H H 97% H (Dr= 4.4: 1 ) O

  O 72% O 99% N

  N N Me

  Me Me

  Cl o H

  NCS, DMF, THF, 40 C

  Me Me o SCN

  then Et N, 23 C

3 Me O H

  NH

  O

  O

  N

  N SH

• - Me

  O O

  2+

  83% Mg

  N-Methylweltindolinone C-NCS

   6H O *

  2 COOH

  2 MMPP

  N Me O Me Me H Me O HO N

  2 H

  4

  , AcOH EtOH, 70

  o

  C N Me O Me Me H Me N HO N Me O Me Me H Me Cl HO NH

  2 NCS

  Pyridine 61% 2 steps N NH

• +

  N
• - -HCl N
• + N Cl
• + Cl H Cl O N N

  2 NCS

  N N H Cl N

  2 H

  4 NH

  2 NCS

  Cl NCS Chem. Phram. Bull.

  1963, 684-685

  O O OH OH H HO

  Me H Me Me H Me O

H

OHC

4 A mol, toluene Me Me O

  Me O o O Me 100 C O O N 57% N Me N Me Me (not observed) O O Me O

  Me CHO H CHO Me Me rearomatization Cope OHC Me O O

  O H N Me N N Me Me O H OH O H H Me O O OH O O Me O

  Me H Aldol H Me O

  Me O O N N N Me Me Me N Me

  E-olefin to Z-olefin

  N Me O O Me Me H Me Cl SCN H

  MeN P O Ph 110

  o

  C, toluene 65%

  N Me O O Me Me H

Me

Cl

  

CN

H N-Methylweltindolinone C-NC

  KHMDS, THF, -78

  o

  C then Ph NSO

  O 67 %

2 Ph

  N Me O O Me Me H Me Cl SCN OH 3-hydroxy-N-methylwelwitindolinone C Rawal, JACS, 2012, 134, 1392-1395

  

Garg’s Retrosynthetic Analysis

Cl

  Cl RO

  H

  H H

  Me Me

  Me Me Me Me

  SCN

  H H

  Me O

  Me Me O O

  H

  H

  O

  O

  N

  N N

  Me

  Me Me OR OR OR Me Me H Me Me Me O O O Br + Br N N Me Me N Me

  OPiv Me O Me Me Me O Me s-carvone 1, K

  

3

  , MeOH, 60

  o

  C 2, I

2 CO

  , MeOH, 23

  o

  C N Me Br OH Me O Me N Me Br Me H TBSCl, imidazole DMAP, Bu

  2

  DMF, 100

  o

  C 54% 2 steps 90% OTBS Me O Me N Me Br Me H NaNH

  2

   (10.5 equiv) t-BuOH (3.5 equiv) THF, 23

  o

  C N Me O Me Me H Me H TBSO + OTBS Me O Me N Me Me H 2.5 : 1 46%

  Cas:2240-16-8 25mL 556

  4 NI

  O OPiv Me Me Me Me O Me s-carvone OPiv OPiv O Me NaOMe PivCl CrO LiAlH Me

  3 Me

4 Pyridine

  MeOH O Me N Me Me N H OPiv OPiv MgBr Me Me

  O Me PivCl = Me CuBr Cl O Me O Me OPiv OPiv Me CrO Me

3 O Me

  N Me N H H H NH N

  O O

• +

  H +

  CrO

  Cr N :

3 Cr O

• - O : N N N O

  Cr HO OH HO N N O HO

  Chem.pharm.bull. 1994, 42, 1393-1398

  TBSO O

  Me Sn

  3 o

  1, KHMDS, THF, -78 C H H

  H

  o

  Me Me 1, TBAF, THF, 60 C comins's reagent Me

  Me Me Me H

  H H

  o

  Me Me 2, Dess-Martin,DCM,23 C O

  O Me 2, (Me Sn) , Pd(PPh )

  3

  2

  3

  4 O o

   LiCl, dioxane, 110 C 95% 2 steps N N

  N Me 74% 2 steps Me

  Me Cl Cl Cl H o H

  

o HCl, 80

  C, EtOH Me H NBS, 0

  C, DCM Me Me Me CuCl , dioxane

2 Me

  H Me H Me

  o

  Me H O O 23-80 C Me

  H O 89%, 2 steps Br O 75%

  N N Me N Me Me

  F F O S F N N O S O O F F F

  C 33% 25% N Me Me Me O H Me Cl H O O HN 1, Ba(OH)

  N Me O Me Me H Me H Cl O H 1, i-Bu

  2 AlH,DCM, -78 o

  C 2, Cl

  3 CC(O)NCO

   DCM, 0--23

  o

  C K

  3

  , MeOH 86% 2steps N Me Me Me O H Me Cl H H O O H

  2 N

  AgOTf, PhI(OAc)

  2

  bathophenanthroline CH

  3 CN, 82 o

2 CO

• * 8H

  2

  2 O

   H

  2 O, dioxane,110 o

  C 2, IBX, TFA DMSO, 23

  o

  C 48% 2 steps N Me O Me Me H Me H

  2 N

  Cl O H N O O N S DMAP, DCE, 90

  o

  C

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

  bathophenanthroline N N

  Garg et al, JACS, 2011, 133, 15797-15799

  Cl Cl Me D H o 1, LiEt

  B- D ,THF,-78--0 C

  3 Me

  Me H H

  H Me Me H N

  2 O 2, Cl CC(O)NCO

  3 O

  H

  o Me

   DCM, 0--23 C O O H K CO , MeOH

  2

3 O

  N Me N 100% 2steps Me Cl

  Cl Cl Me R Me R H

  H AgOTf, PhI(OAc)

  2 H

  H Me Me

  Me bathophenanthroline H N HN Me

  2 H

  O O + Me

  Me

  o Me O

  O H CH CN, 82 C O H

  3 H

  O O O N

  N N Me Me Me 33% 25% R= H R=D

  8% 60%

  Cl

  Cl Cl Me D 1,HCO

  H, Ac O

  2

  2

  1, Ba(OH) * 8H O

  2

  H H o

  2 H

  o

   THF, 0--23 C Me Me

  Me

   H O, dioxane,110 C HN Me

  2 Me CN

  H N O

  2 Me

  Me Me 2, Burgess reagent O 2,Dess-martin, TFA O O

  H

  H H

  o THF, Benzene, rt O

   DCM, 23 C O O

  N

  N N 100% 66% 2 steps

  Me

  Me Me

  N-Methylweltindolinone C-CN

  O O

  Cl

• + Cl

  N S O N O

  H H Me Me Me Me CN NaH, air CN

  Burgess reagent

  Me O o Me O

  THF, 23 C

  H OH O

  47%

  O N N Me Me 3-hydroxy-N-methylwelwitindolinone C-NC Cl Cl H H Me

  NaH, air

  Me Me Me o SCN

  THF, 23 C

  SCN Me O Me O H

  48%

  OH O O N N Me Me 3-hydroxy-N-methylwelwitindolinone C-NCS

  

Alkaloids

  

Synthesis of ( un) natural piperidine alkaloids

Synthesis of ( un) natural piperidine alkaloids

  OH OH HO OH HO OH Cl N

  N OH H H homo-1-DNJ

  6-Cl-L-ido-1-DNJ

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

  O C H N

  5

  11 N O H

  O (+)-EPIPINIDINONE (+)-CALVINE (defense alkaloid and deterent of (defense alkaloid and deterent of

  C. montrouzieri and E. varivestis)

  C. 10-guttata and C. 14-guttata)

  T T otal synthesis of otal synthesis of unnatural unnatural analogues of 1 analogues of 1 - - deoxynojirimycin deoxynojirimycin

  1 Deoxynojirimycin - -

  1 Deoxynojirimycin OH OH HO OH N H 1-Deoxynojirimycin (1,5-dideoxy-1,5-imino-D-glucitol) Inhibition: K

  White mulberry = 32 nM (α-D-glucosidase) i Activity: anti-diabetes, anti-HIV, ... (Morus alba) Applications: Tay-Sachs, Gaucher, ...

  Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond, Ed. A. E. Stütz, Wiley, 1999.

  Reference:

  Retrosynthetic analysis DNJ - of new analogues of 1 - Retrosynthetic analysis of new analogues of 1 DNJ OPG OPG OH

PGO OH PGO HO OH

  O O NH

N

N OH

  PG PG H homo-1-DNJ

OPG OH PGO OH HO OH

  SUGAR Cl NH N PG H 6-Cl-L-ido-1-DNJ

  S S ubstrate ubstrate p p reparation reparation O HO HO OMe OH OH O HO BnO OMe BnO OH O HO OMe OH O O Ph OH OBn OBn NHBn O HO BnO OMe BnO Br O BnO OMe BnO O 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 % 5 steps 30 % overall yield

  Pd( I I ) - catalysed aminocarbonylation & Finalisation P. Szolcsányi et al.: Tetrahedron: Asymmetry 2000, 11, 2579. OH OBn 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 O N Bn OBn BnO O O + N Bn OBn BnO O 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 OH

• - Pd( I I ) / CuCl catalysed chlorocyclisation Pd( I I ) / CuCl catalysed chlorocyclisation -

  2

  2 OBn OBn BnO OH BnO OH 0.1 eq. PdCl

  2 OH OBn 3 eq. CuCl +

  2 NHBn Cl Cl N N 3 eq. AcONa Bn Bn OBn glacial AcOH

  L-ido D-gluco

r.t., 2 days, 70% (19 : 1)

OBn

  OBn BnO OH BnO OH BnO OH 0.1 eq. PdCl OH OBn

  2 O 3 eq. CuCl + +

  2 NHBn Cl Cl

  N N N 3 eq. AcONa Bn Bn Bn OBn r.t., DMF, 53%

  (11%) (15 : 1) L-altro D-galacto P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498.

BICYCLE CHLORIDE

  NHBn BnO OBn OH H Cl

  2 CHLOROCYCLISATION BICYCLISATION D-galacto

  2 PdCl

  2 L

  2 PdCl

  Cu Cl Pd Cl Cl L

  2 NBn BnO OBn OH PdCl N Bn BnO OBn OH σ -Pd/Cu-complex II

  2 Pd NBn BnO OBn OH Pd Cl NBn BnO OBn OH Pd Cl Cl Cu Cl NHBn BnO OBn OH H PdCl

  2 σ -Pd/Cu-complex I

  Mechanistic proposal of the Pd( I I ) / CuCl Mechanistic proposal of the Pd( I I ) / CuCl

  2 CuCl

  CuCl

  σ -Pd-complex I σ

  BnHN BnO BnO OH

HCl HCl

  Si-attack Re-attack

  2 - - catalysed catalysed

chloroaminocyclisation and bicyclisation

chloroaminocyclisation and bicyclisation

  2

• -Pd-complex II

  Synthesis of new analogues of Synthesis of new analogues of iminoalditols iminoalditols 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 C

  4 (J 3,4 = 2.3, J 4,5 = 6.7 Hz)

  2

  Formal t Formal t otal synthesis of otal synthesis of alkaloid ( + ) alkaloid ( + ) - -

  2 -

• -

  e

  e pi pi pinidinone pinidinone N H (2R,6R)/(2S,6R)-6-methyl-2-(2 , -oxo-propyl)piperidine O (-)-Pinidinone N H O (+)-2-Epipinidinone

  Ladybird Beetles ( ) Coccinellidae

Mealybug ladybird beetle Mexican bean beetle

(Cryptolaemus montrouzieri) (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 1993, 49, 9333.

  Coniferous Trees ( ) Pinaceae Ponderosa pine Colorado spruce (Picea pungens) (Pinus ponderosa) 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 1994, 35, 951.

  Retrosynthetic analysis Retrosynthetic analysis of of ( + ) ( + ) - -

  2

  2 - - epipinidinone epipinidinone N H O (+)-2-Epipinidinone N PG OMe O

NH PG

  Formal t Formal t otal synthesis otal synthesis of ( + ) of ( + ) - -

  2

  2 - - epipinidinone epipinidinone Substrate preparation: D. J. Dixon, S. V. Ley, W. E. Tate: J. Chem. Soc., Perkin Trans. 1 2000, 2385.

a) Preparation of the substrate and its Pd( I I ) - catalysed methoxycarbonylation

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)

A. Fürstner, K. Langemann: Synthesis 1997, 792. MgBr 0.1 eq. Li

  Formal t Formal t otal synthesis otal synthesis of ( + ) of ( + ) - -

  2

  2 - - epipinidinone 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

b) Deprotection and completion of the formal synthesis

  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 (+)-2-epipinidinone

  

Short t otal synthesis of racemic

Short t otal synthesis of racemic

• - alkaloids c alvine and 2 e picalvine - alkaloids c alvine and 2 e picalvine

  [ 1] [ 1] Ladybird Beetles ( ) Ladybird Beetles ( Coccinellidae ) Coccinellidae 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

  [ 2] knee joints ( so called reflex bleeding ) [1] A. G. King, J. Meinwald: Chem. Rev. 1996, 96, 1105.

• - - 2 e picalvine - S tructure elucidation of ( + ) c alvine and ( + ) - - S tructure elucidation of ( + ) c alvine and ( + ) 2 - e picalvine

  1 0 9 1 1 cis

   (Calvine)

  8

  7

1 N

  2

  3 trans (2-Epicalvine)

  6 O

  4

  5 O

(1S,8S)/(1R,8S)-3-oxo-8-n-pentyl-7-aza-4-oxabicyclo[5.4.0]undecane

  

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

HRMS studies and subsequently confirmed racemic total via [ 3] synthesis. The absolute configuration w as determined by [ 4] enantioselective total synthesis. [3] J.-C. Braekman, A. Charlier, D. Daloze, S. Heilporn, J. Pasteels, V. Plasman, S. Wang: Eur. J. Org. Chem. 1999, 1749.

  Know n total syntheses of ( + ) alvine and ( + ) - c - 2 e picalvine - - - Know n total syntheses of ( + ) c 2 e picalvine - alvine and ( + )

  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 15% total yield over 9 steps P. Dewi-Wülfling, J. Gebauer, S. Blechert: Synlett 2006, 487.

• - c - Know n

  2 e picalvine - formal syntheses of ( + ) alvine and ( + ) - - 2 e picalvine - Know n formal syntheses of ( + ) c alvine and ( + )

  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:

Tetrahedron 2005, 61, 7774.

  Retrosynthetic analysis Retrosynthetic analysis of of calvine and 2 calvine and 2 - - epicalvine epicalvine N C

  5 H

  11 O O NH C

  5 H

  

11

OH OTs C

  5 H

  11 (Epi)calvine

• - R acemic total synthesis of calvine and 2 epicalvine - R acemic total synthesis of calvine and 2 epicalvine

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

  NaBH , MeOH

  4 0°C, 30 min, 77%

Mg, Et O

  2 +

• + Br O

  

r.t. - reflux

OH O C H C H

  5

  11

  5

  11

2 hrs, 3 g scale

16%

  67% (overall 80%) 2 eq. TsCl 15 eq. H N(CH ) OH

  2

  2

2 DCM, py

  47% total yield over 4 steps C H NH

  5

  11 reflux, THF 0°C - r.t. C H OTs

  5

11 OH 18 hrs, 79% 2 days, 75% The identical sequence on analogous compounds: A. Fürstner, K. Langemann: Synthesis 1997, 792.

  R R acemic total synthesis acemic total synthesis of calvine and 2 of calvine and 2 - - epicalvine epicalvine

  rac

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

• aminoalkenitol

  

N C

  5 H

  

11

O 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 O + rac-aminoalkenitol

  (2.2 : 1) 26% total yield over 5 steps

  

ynthesis

S

  Gates Synthesis Gates, M.J. J. Am. Chem. Soc.

  1953, 75, 4340 Gates Synthesis

  Gates Synthesis Gates, M.J. J. Am. Chem. Soc.

  1953, 75, 4340 Rice Synthesis

Rice, C.; Brossi, A. J. Org. Chem. 1980, 45, 592

  Rice Synthesis 16 steps (yield 12%) Grewe cyclization was key disconnection Practical method for conversion of dihydrocodeinone to morphine

  Rice, C.; Brossi, A. J. Org. Chem. 1980, 45, 592

  Evans Synthesis

  Evans Synthesis Evans, D.A.; Mitch,

C.H. Tetrahedron Lett.