Pd(II)Pd(II)--Catalysed CyclisationsCatalysed Cyclisations in in thethe

Total Synthesis of Natural Total Synthesis of Natural ProductsProducts

Dr. Peter SzolcsányiDr. Peter SzolcsányiDepartment of Organic ChemistryDepartment of Organic ChemistrySSlovak lovak UUniversity of Technologyniversity of Technology

BratislavaBratislava, Slovak Republic, Slovak Republic

XII. Blue Danube Symposium on Heterocyclic ChemistryXII. Blue Danube Symposium on Heterocyclic ChemistryJune 10June 10thth - 13 - 13thth, 2007, 2007 Tihany, Hungary Tihany, Hungary

Pd(II)-activation of C=C bond and subsequentPd(II)-activation of C=C bond and subsequenttransformationstransformations

YH

Y=O, NPG

YH

PdX2L2+ PdX2L2

- HX

YPdXL2

-Pd-complex

-Pd-complex

+ CO

Y

-Pd-CO-complex

PdXL2

O

(T < -20°C)

R R

R

R

+ CuX2

- PdX2Y

X

R

Y=NPG, X=Cl, Br

+ MeOH

Y OMe

OR

R=OH

Y

O

O

-H--elim.

Y

R

Versatility of Pd(II)-catalysed cyclisationsVersatility of Pd(II)-catalysed cyclisationsof aminoalkenesof aminoalkenes

Pd(II)/CuCl2

NH

PG

R2

N

PG

ClN

O

PG

Pd(II)/C

uCl 2

R 2=OH

R1

CO/Pd(II

)

MeOHN

PG

CO/Pd(II)R1 =OH

N

PG

O

O

OMe

O

Synthesis of (un)natural piperidine alkaloidsSynthesis of (un)natural piperidine alkaloids

(+)-EPIPINIDINONE

(defense alkaloid and deterent ofC. montrouzieri and E. varivestis)

(+)-CALVINE

(defense alkaloid and deterent ofC. 10-guttata and C. 14-guttata)

NH

OH

homo-1-DNJ

OH

HO

OH

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

NH

OH

Cl

6-Cl-L-ido-1-DNJ

OH

HO

NH

O

NC5H11

OO

TTotal synthesis of otal synthesis of unnaturalunnaturalanalogues of 1-deoxynojirimycinanalogues of 1-deoxynojirimycin

1-Deoxynojirimycin1-Deoxynojirimycin

White mulberry(Morus alba)

Inhibition: Ki = 32 nM (-D-glucosidase)Activity: anti-diabetes, anti-HIV, ...Applications: Tay-Sachs, Gaucher, ...

NH

1-Deoxynojirimycin(1,5-dideoxy-1,5-imino-D-glucitol)

OH

OH

OHHO

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

Retrosynthetic analysisRetrosynthetic analysis of new analogues of 1 of new analogues of 1--DNJDNJ

NH

OH

homo-1-DNJ

OH

HO

OH NPG

OPG

PGO O

O

NHPG

OH

OPG

PGO

NH

OH

Cl

6-Cl-L-ido-1-DNJ

OH

HO

NHPG

OH

OPG

PGO

SUGAR

SSubstrateubstrate p preparationreparation

Pd(II)-catalysed aminocarbonylation & Finalisation

P. Szolcsányi et al.: Tetrahedron: Asymmetry 2000, 11, 2579.

OH

OBn

OBn

NHBnNBn

OBn

BnO

CO (balloon)0.1 eq. PdCl2

1 eq. BQ

2 eq. LiCl2 eq. AcONa

THF, r.t.17 hrs, 66%

D-gluco L-ido(4 : 1)

O

O

NBn

OBn

BnO O

O+

NBn

OBn

BnO O

O

1. LiBH4, THF 0°C - r.t., 64%

2. H2 (balloon) 10% Pd/C, HCl

MeOH, r.t., 90%

N

H.HCl

OH

homo-1-DNJ

OH

HO

OH

Pd(II)Pd(II)//CuClCuCl22-catalysed chlorocyclisation-catalysed chlorocyclisation

OH

OBn

OBn

NHBnNBn

OBn

BnO OH

ClNBn

OBn

BnO OH

Cl

0.1 eq. PdCl23 eq. CuCl2

3 eq. AcONaglacial AcOH

r.t., 2 days, 70%

+

L-ido D-gluco(19 : 1)

OH

OBn

OBn

NHBn

NBn

OBn

BnO OH

Cl

0.1 eq. PdCl23 eq. CuCl2

3 eq. AcONar.t., DMF, 53%

NBn

OBn

BnO OH

Cl+

L-altro D-galacto

+

NBn

BnO OH

O

(11%)(15 : 1)

P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498.

Mechanistic proposal of the Pd(II)/CuClMechanistic proposal of the Pd(II)/CuCl22-catalysed-catalysedchloroaminocyclisation and bicyclisationchloroaminocyclisation and bicyclisation

Si-attack Re-attack

BnHNBnO

BnO

OH

HClHCl

-Pd-complex I-Pd-complex II

CuCl2CuCl2

-Pd/Cu-complex I

NHBn

BnO

OBn

OHH

Cl2Pd

NBn

BnO

OBn

OH

Pd

Cl

NBn

BnO

OBn

OH

Pd

Cl

Cl

CuCl

NHBn

BnO

OBn

OHH PdCl2

NBn

BnO

OBn

OHPdCl

NBn

BnO

OBn

OH

-Pd/Cu-complex II

Cu Cl

Pd

Cl

Cl

L2PdCl2 L2PdCl2

CHLOROCYCLISATION BICYCLISATION

D-galacto

BICYCLECHLORIDE

P. Szolcsányi, T. Gracza: Chem. Commun. 2005, 3948.

Synthesis of new analogues ofSynthesis of new analogues of iminoalditols iminoalditols

P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498.

NBn

OHO

H2 (1 atm)10 % Pd/C

EtOH, HCl100 %

L-altro

H2 (1 atm)10 % Pd/C

EtOH, HCl100 %

NH.HCl

OHO

D-galacto

BnO HO

N

OBn

BnO Bn

HO

Cl

1C4 (J4,5 = 10.4 Hz)(J2,3 ~ J3,4 = 3.5 Hz)

N

OH

HO H.HCl

HO

Cl

H2 (1 atm)10 % Pd/C

EtOH, HCl100 %

L-idoN

OBn

BnO BnCl

HO

1C4 (J4,5 = 3.0 Hz)(J2,3 ~ J3,4 = 4.8 Hz)

N

OH

HO H.HClCl

HO

1C4 (J4,5 = 1.5 Hz)(J2,3 ~ J3,4 = 3.5 Hz)

1C4 (J3,4 = 2.3, J4,5 = 6.7 Hz)

Formal tFormal total synthesis ofotal synthesis of alkaloid (+)- alkaloid (+)-2-2-eepipipinidinonepinidinone

NH

(2R,6R)/(2S,6R)-6-methyl-2-(2,-oxo-propyl)piperidine

O

(-)-Pinidinone

NH

O

(+)-2-Epipinidinone

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 1993, 49, 9333.

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, Phytochemistry1994, 35, 951.

Retrosynthetic analysisRetrosynthetic analysis of of (+)-2-epipinidinone(+)-2-epipinidinone

NH

O

(+)-2-Epipinidinone

NPG

OMe

O

NHPG

Formal tFormal total synthesisotal synthesis of (+)-2-epipinidinone 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.

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

Formal tFormal total synthesisotal synthesis of (+)-2-epipinidinone 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.

H2 (balloon)0.15 eq. Pd(OH)2

MeOH, 18 hrs, 62%NBn

OMe

O

NH

OMe

O 1. Weinreb

2. MeMgBr NH

O

(+)-2-epipinidinone

b) Deprotection and completion of the formal synthesis

Short tShort total synthesis of otal synthesis of racemicracemicalkaloids calkaloids calvine and 2-alvine and 2-eepicalvinepicalvine

Ladybird Beetles (Ladybird Beetles (CoccinellidaeCoccinellidae))[1][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.

[2] G. M. Happ, T. Eisner: Science 1961, 134, 329.

SStructure elucidation of (+)-tructure elucidation of (+)-ccalvine and (+)-2-alvine and (+)-2-eepicalvinepicalvine

The relative configuration was established on the basis of NMR and HRMS studies and subsequently confirmed via racemic total synthesis.[3] The absolute configuration was 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.

• Known total syntheses of (+)-Known total syntheses of (+)-ccalvine and (+)-2-alvine and (+)-2-eepicalvinepicalvine

a) CN(R,S)-methodology - use of chiral N-cyanomethyloxazolidine12% total yield over 7 stepsP. Laurent, J.-C. Braekman, D. Daloze: Eur. J. Org. Chem. 2000, 2057.

b) CM-strategy - olefin cross-metathesis reaction15% total yield over 9 stepsP. Dewi-Wülfling, J. Gebauer, S. Blechert: Synlett 2006, 487.

• Known Known formalformal syntheses of (+)- syntheses of (+)-ccalvine and (+)-2-alvine and (+)-2-eepicalvinepicalvine

c) Davies‘ Li-amide 1,4- addition & Intramolecular Mannich-type reactionS. Rougnon-Glasson, Ch. Tartrat, J.-C. Canet, P. Chalard, Y. Troin:Tetrahedron:Asymmetry 2004, 15, 1561.

d) Diastereoselective reduction of piperidine -enamino estersS. Calvet-Vitale, C. Vanucci-Bacqué, M.-C. Fargeau-Bellassoued, G. Lhommet:Tetrahedron 2005, 61, 7774.

Retrosynthetic analysisRetrosynthetic analysis of of calvine and 2-epicalvinecalvine and 2-epicalvine

NC5H11

OO

NHC5H11

OHOTsC5H11

(Epi)calvine

RRacemic total synthesisacemic total synthesis of calvine and 2- of calvine and 2-epicalvineepicalvine

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

The identical sequence on analogous compounds: A. Fürstner, K. Langemann: Synthesis 1997, 792.

RRacemic total synthesisacemic total synthesis of calvine and 2-epicalvine of calvine and 2-epicalvine

b) Finalisation - Pd(II)-catalysed carbonylation of rac-aminoalkenitol

NC5H11

OO

NHC5H11

OH

CO (balloon)0.1 eq. PdCl22 eq. CuCl2

2 eq. AcONadioxane, 40°C

7 hrs, 55%rac-calvine rac-2-epicalvine

NC5H11

OO

+

rac-aminoalkenitol (2.2 : 1)

26% total yield over 5 steps

ConclusionsConclusions

• Intramolecular Pd(II)-catalysed methoxycarbonylation and/orIntramolecular Pd(II)-catalysed methoxycarbonylation and/or chlorocyclisation of aminoalkenes represents a novel synthetic approachchlorocyclisation of aminoalkenes represents a novel synthetic approach to (poly)substituted piperidinesto (poly)substituted piperidines

• Such structures may well serve as key building blocks for the totalSuch structures may well serve as key building blocks for the total syntheses of various nitrogen-containing natural productssyntheses of various nitrogen-containing natural products

• Both transformations were developed intoBoth transformations were developed into effectiveeffective synthetic methodsynthetic methodologiesologies that were successfully that were successfully emploemployyeded in the total synthesis of alkaloids as well in the total synthesis of alkaloids as well asas their unnatural analoguestheir unnatural analogues

AcknowledgmentsAcknowledgments

Generous support Prof. Dr. Tibor GraczaCo-workers Ing. Kristína Csatayová

Katarína ReichováTechnical support Mária KrajčírováGC, MALDI Dr. Ivan ŠpánikHPLC Dr. Katarína HroboňováNMR Dr. Nadežda PrónayováIR Silvia MarkusováGrant APVT-20-000904

Known Known precedentsprecedents of Pd(II)/CuCl of Pd(II)/CuCl22-catalysed-catalysedhalhaloaminocyclisationoaminocyclisation yielding 6-membered azacycles yielding 6-membered azacycles

ReportsReports o onn Pd(II)/Cu Pd(II)/Cu(II)(II)--heterobimetallic complexesheterobimetallic complexes

Proposed mechanismProposed mechanism of the Pd(II)-catalysed of the Pd(II)-catalysed carbonylationcarbonylation

Observed interconversion of calvine and 2-Observed interconversion of calvine and 2-epicalvine in protic mediaepicalvine in protic media

But no epimerisation reported with:

Formation of the undesired ketone side productFormation of the undesired ketone side product

viavia MPV-type mechanism MPV-type mechanism

B. G. Kovalev et al.: Zh. Org. Khim. 1975, 11, 1183.

The only literature precedent: