synthesis of 2,6-dialkyl-1,2,5,6-tetrahydropyridines and their applications in total synthesis

Current Organic Synthesis, 2004, 1, 83-109 83

1570-1794/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd.

Synthesis of 2,6-Dialkyl-1,2,5,6-Tetrahydropyridines and Their Applicationsin Total Synthesis

François-Xavier Felpin and Jacques Lebreton*

Laboratoire de Synthèse Organique, CNRS UMR 6513, Faculté des Sciences et desTechniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France

Abstract: This review focuses on the different approaches to construct the 2,6-dialkyl-1,2,5,6-tetrahydropyridine skeleton and their applications in total synthesis ofalkaloids.

Keywords: Total Synthesis, Alkaloids, Tetrahydropyridines, Piperidines.

It is Our Pleasure to Dedicate this Review to Our Friend and Colleague Dr AndréGuingant in Thanks of his Help and Guidance

INTRODUCTION

The piperidine ring system is one of the most commonmotifs found in numerous natural products, drugs and drugcandidates. It was recently pointed out by Watson et al. [1]that the piperinidinic substructure was mentioned in over12000 compounds in clinical or pre-clinical studies fromJuly 1988 through December 1998. Accordingly, theimportant bioactivities of piperidines have stimulated thedevelopment of new approaches and considerable syntheticeffort has been devoted to the preparation of thesecompounds [2], in particular with respect to enantiomericallyselective synthesis [3]. 2,6-Disubstituted piperidinesrepresent a subclass of naturally occurring alkaloids that havealso been the targets of many synthetic efforts due to theirwide range of pharmacological activities [4]. Notableexamples include (-)-solenopsin A, a constituent of fire-antvenom Solenopsis species, which is characterized by apredominance of 2-alkyl-6-methylpiperidines [5], and (+)-himbacine, a piperidine alkaloid isolated from the bark ofGalbulimina baccata of the magnolia family. These haveappeared as novel drug candidates for the treatment ofAlzheimer’s disease [6] (see Figure 1).

NCH3 C11 H2 3

H

O

O

CH3

H

H

H

H

NCH3

CH3

(-)-Solenopsin A (+)-Himbacine

2 6

Fig. (1).

*Address correspondence to this author at the Laboratoire de SynthèseOrganique, CNRS UMR 6513, Faculté des Sciences et des Techniques, 2rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France; Tel: + 332 51 12 54 03; Fax: + 33 2 51 12 54 02; E-mail: [email protected]

Compared to this class of alkaloid, the 2,6-disubstituted-1,2,5,6-tetrahydropyridine skeleton is present in only a fewnatural products [7]. (+)-Cannabisativine is an unusualmacrocyclic spermidine alkaloid containing a trans-2,6-disubstituted-1,2,5,6-tetrahydropyridine ring, which wasisolated in 1975 from the roots and leaves of the commonmarijuana plant, Cannabis sativa L (see Figure 2) [8].Another member of this class of alkaloids, (-)-palustrine [9],a toxic component of the horsetail plant Equisetum palusterL. found in the meadows of Europe, has been isolated as has(-)-sedacrine [10] a sedum alkaloid.

N

HO

HO

H

OHN

HN

NH H

OHO NH

NH

N

CH3

PhHH

OHO

NR1 R2

H

(+)-Cannabisativine (-)-Palustrine

62

3

4

5

H

(-)-Sedacrine 2,6-disubstituted-1,2,5,6-tetrahydropyridine

Fig. (2).

It is not surprising that these natural products,particularly cannabisativine and palustrine, have been thetarget of different syntheses and have served as usefulmodels to develop a new strategy to construct the 2,6-disubstituted tetrahydropyridine skeleton. Moreover, the 2,6-disubstituted tetrahydropyridine framework should beregarded as a valuable basic unit since the possibility ofmodification and functionalization of the double bondenables the preparation of polysubstituted piperidines.

Mustansir

84 Current Organic Synthesis, 2004, Vol. 1, No. 1 Felpin and Lebreton

N

O

R1

R2

OTIPS-OTf

N

O

R1

R2

OTIPS

Et3NNR1

R2

OTIPS

OH H

TIPS = Si(i-Pr)312

3

Ireland-Claisen

rearrangement

Scheme 1.

O

O

N

O

Ph

H

N

Bn OH H

TIPSO

N

O

BnTIPSO

OTIPS

HO

OH

NH

OPh

N

BnH H

TIPSOOH

N

Bn OH H

OTIPS

TIPSO

HO N

O O

Ph

NHH H

OOH

OMe

a b , c d

e , f , g

h i-p

4 5 6

78

9 10 (-)- Methyl Palus tramate

Scheme 2. Reagents and conditions: (a) DIBAL-H, CH2Cl2, hexane, -78°C, 20 min, then CH2=CHMgCl, -78°C to rt, 13 h, 71%. (b)LiAlH4, THF, 0°C to reflux, 4 h, 76%. (c) BrCH2CO2Ph, EtN(i-Pr)2, CH3CN, 0°C to rt, 66 h, 71%. (d) (i-Pr)3SiOTf, Et3N, benzene, 5°C tort, 4 h, 96%. (e) K2CO3, EtOH, THF, H2O, rt, 5 h. (f) CDI, CH2Cl2, 0°C to rt, 1 h, then imidazole, CH3-NH(OCH3)-HCl, rt, 12 h, 76% from6. (g) EtMgBr, THF, 0°C, 6 h. (h) LiBH4, THF, MeOH, 0°C to rt, 12 h, 81% (2 steps). (i) CH3OCH2Br, EtN(i-Pr)2, CH2Cl2, 0°C to rt, 7 h,83%. (j) Li, (NH2CH2)2, Et3N, THF, rt, 4.25 h, 71%. (k) Cl3CH2COC(O)Cl, pyridine, 0°C to rt, 4.25 h, 93%. (l) HF-pyridine, THF, 0°C tort, 3 h, 98%. (m) PDC, DMF, rt, 30 h, 85%. (n) CDI, CH2Cl2, 0°C to rt, 2 h, 1h, then imidazole, MeOH, rt, 19 h, 70%. (o) Zn, 1M aq.KH2PO4, THF, rt, 15 h, 74%. (p) BuSH, MgBr2, Et2O, rt, 39 h, 76%.

In this review, we will present the recent methodologiesand works concerning the construction of 2,6-disubstituted-1,2,5,6-tetrahydropyridine frameworks.

IRELAND-CLAISEN REARRANGEMENTS

Since its introduction in 1972, the Ireland-Claisenrearrangement has been widely used in synthesis [11]. Angleet al. used it on chiral vinyl morpholinones 1 to form thecis-2,6-disubstituted pipecolic 2 ester derivatives [12] via thesilyl ketene acetal intermediates 3 (see Scheme 1).

Using this methodology, the authors published a set ofelegant total syntheses of alkaloids: (+)-monomorine [12b],(-)-indolizidine 167B [12c], (-)-methyl palustramate [12d](see Figure 3).

The synthesis of (-)-methyl palustramate (a possibleintermediate to reach (-)-palustrine) starting from the lactone4 is presented in Scheme 2 as an illustration of the efficiencyof this rearrangement. Lactone 4 (prepared from L-methionine) was treated with DIBAL-H and the resulting

lactol was trapped with vinylmagnesium chloride to furnishthe amino alcohol 5 in 71% yield as a diastereoisomericmixture in an 11:1 ratio. The amide function of 5 wasreduced with LAH to the corresponding benzylamine, whichwas isolated in a 32:1 ratio and 76% yield afterrecrystallization. Alkylation of this latter amine with phenylα-bromoacetate led to the formation of the six-memberedlactone 6 in 71% yield. Treatment of the lactone 6 withTIPS-OTf in the presence of Et3N at room temperatureafforded the silyl ketene acetal intermediate 7 , whichunderwent Ireland-Claisen rearrangement to give the cis-2,6-disubstituted pipecolic silyl ester derivative 8 in 96% yield.To complete this synthesis, the ethylketone 9, prepared from8 via the corresponding Weinreb amide, was reduced withLiBH4 to afford the desired alcohol 10 in 64% overall yield(from 8) with excellent diastereoselectivity (32:1). At thisstage, protecting group manipulations and oxidation of theprimary alcohol function to carboxylic acid provided (-)-methyl palustramate in 8 steps and with 18% overall yieldfrom alcohol 10.

Synthesis of 2,6-Dialkyl-1,2,5,6-Tetrahydropyridines Current Organic Synthesis, 2004, Vol. 1, No. 1 85

OH

C5H11

O

N O

C5H11

H

COOMeH

TfO NHTs

N N

HN

OTBDMS

C5H11

H O

Ts

OTBDMS

N

H

H

C5H11

COOH

NHTs

O

H2N O

C5H11

O

N O

COOMeH

H

C5H11

O

HN O

C5H11

COOMeOAc

NHN

HN

O

C5H11

H

H O

OTBDMS

NH

H

H

C5H11

COOMe

N NHTs

HN

OH

H O

OTBDMS

C5H11

(±)-15

a b-c d

e-f g-h i-j

k-lm-n o-q

(±)-17(±)-16 (±)-18

(±)-19

(±)-23

(±)-20(±)-22

(±)-24

(±)-anhydrocannabisativine

21

HH

Scheme 5. Reagents and conditions: (a) NaOCN, TFA, Et2O, rt, 24 h, 95%. (b) methyl glyoxylate, acetone, reflux, 3 days, 82%. (c)Ac2O, pyridine, rt, 12 h, 97%. (d) EtN(i-Pr)2, toluene, 215°C, 3 h, 83%. (e) 5% aq. NaOH, MeOH, rt, 2 h, 96%. (f) Cl2(CO), toluene, rt, 3 h,then CH2N2, Et2O, rt, 1 h, then MeOH, Ag2O, rt, 12 h, 78%. (g) Ba(OH)2, glyme, H2O, reflux, 48 h, then, MeOH, SOCl2, reflux, 12 h, 87%.(h) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0°C, 4 h, 91%. (i) 21, EtN(i-Pr)2, CH2Cl2, rt, 4 h, 99%. (j) 1N LiOH, MeOH, 0°C to rt, 15 h, 100%.(k) 2,4,5-trichlorophenol, 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate, CH2Cl2, rt, 45 h. (l) 4-aminobutanol, DMF, -20°C, 18 h, 82% (2 steps). (m) MsCl, Et3N, CH2Cl2, -15°C to 5°C, 1 h, 80%. (n) K2CO3, CH3CN, reflux, 24 h,58%. (o) Na, NH3, THF, -60°C then reflux, 20 min, 90%. (p) BF3-Et2O, CH2Cl2, rt, 1 h. (q) Jones reagent, acetone, rt, 30 min, 54% (2steps).

NH

OH

MeO

O

H H

NN

(-)-Methyl Palustramate

(+)-Monomorine (-)-Indolizidine 167B

Fig. (3).

AZA-DIELS-ALDER REACTIONS

Hetero-Diels-Alder and, in particular, imino-Diels-Alderreactions provide a powerful tool for functionalizedheterocyclic ring constructions, generally with high regio-and diastereo-control [13]. Imino-Diels-Alder reactions havegenerally been performed with electron-deficient dienophile11 and activated diene 12, such as Danishefsky’s diene, togive tetrahydropyridinone 13 (see Scheme 3).

OMe

OTMS

N

R2OOC

R1 N

O

R1

R2OOC

(±)-131211

Scheme 3.

However, when non-activated dienes, such as butadienewere used, the tetrahydropyridine core 14 could be directlyobtained (see Scheme 4).

N

R2OOC

R1

+

11 (±)-14

N

R2 OOC

R1

Scheme 4.

In the course of their studies toward the total synthesis ofspermidine alkaloids such as (±)-anhydrocannabisativine,Weinreb et al. [14] envisaged the construction of thetetrahydropyridine core using an intramolecular imino-Diels-Alder reaction (see Scheme 5). The synthesis of the Diels-Alder precursor 15 began with the diene 16, available in 2steps with 69% yield from pentadienyllithium. The alcohol16 reacted with sodium cyanate to give the corresponding


OBn

N

BuOOC

Ts

OBnBnO

C5 H1 1

N

BuOOC

Ts

N

COOBu

Ts

OBn

H

H

N

COOBu

Ts

OBnBnO

H

C5H11

H

+

+

a

b

25

26

27

27

28

29

Scheme 6. Reagents and conditions: (a) neat, 40°C, 48 h, 83%; (b) neat, 40°C, 6 days, 81%.

carbamate 17 in high yield (95%). This carbamate 17 wastreated with methyl glyoxylate and the generated methylolacetate was then acetylated with acetic anhydride to affordthe precursor for the Diels-Alder reaction 15 in 97% yield forthis process. Upon heating in a sealed tube at 215°C,compound 15 in toluene solution containing an equivalentof Hünig’s base was converted stereo- and regioselectively totetrahydropyridine 18 in 83% yield with a trans relationshipof hydrogens α to nitrogen. After mild saponification of themethyl ester, the resulting acid was homologated by theArndt-Eistert procedure to yield ester 19 in 75% yield overtwo steps. The cyclic carbamate 19 was opened with bariumhydroxide then the resulting amino acid was re-esterified andthe hydroxyl function was protected as silyl ether to giveamine 20 in good yield (79%, two steps). The secondaryamine 20 was alkylated with compound 21 and the esterfunction was saponified to give the corresponding acid 22 inquantitative yield over two steps. After activation of thecarboxylic acid function as the 2,4,5-trichlorophenyl ester,the latter was treated with 4-aminobutanol to afford amide-alcohol 23 in 82% yield over two steps. The activation ofthe alcohol function of 23 as a mesylate under classicalconditions and the subsequent treatment with K2CO3 inacetonitrile afforded the expected cyclized product 24 (46%,two steps). The final steps resulted in cleavage of the N-tosyl and the O-TBDMS protecting groups followed by theJones oxidation to give (±)-anhydrocannabisativine (49%,three steps).

In their initial investigation of the synthesis of naturalproducts related to palustrine and cannabisativine, Hamada etal. [15, 16] reported the formation of the functionalizedtetrahydropyridine core by an aza-Diels-Alder reaction.Starting from dienes 25 or 26 (the latter chiral diene isprepared in 12 steps and 21% yield from n-hexanal), theDiels-Alder reaction with the imino-ester dienophile 27 gavewith good yields (83% and 81% respectively) the expectedcyclo-adducts 28 and 29 in a regio- and stereoselectivemanner (see Scheme 6).

With cycloadduct 29 in hand, these authors [15] reportedthe total synthesis of (-)-cannabisativine (see Scheme 7). Thehomologation of the ester function of 29 via a Wittigolefination of the aldehyde intermediate withmethoxymethylene phosphorane gave, in a few steps, the

tetrahydropyridine 30 (62%, four steps). From thisintermediate 30, subsequent cleavage of the N-tosyl group,acylation of the liberated amine function with acid chloride31, and reduction of the resulting amide with LAH furnishedcompound 32 in 76% yield over three steps. The tosylaminogroup of 32 was alkylated with N - (4-bromobuty l )phthalimide and the phthaloyl group of the primary aminewas replaced with a trifluoroacetyl-protecting group tofurnish 33 in 78% yield over three steps. The acetal functionwas subjected to acidic media to give the correspondingaldehyde, which was readily epimerized by treatment withK2CO3 in MeOH. This aldehyde intermediate was thenoxidized with sodium chlorite and immediately esterifiedwith diazomethane to afford 34 (68%, four steps). Treatmentof 34 with Ba(OH)2 resulted in the hydrolysis of the methylester and N-trifluoroacetyl group to give the expected aminoacid, which was cyclized using the Mukaiyama reagent (2-chloro-1-methylpyridinium iodide) and DMAP to afford 35(60%, two steps). Finally, removal of the protecting groupsof 35 with sodium-naphthalenide afforded (-)-cannabisativine(non-natural enantiomer) in 83% yield. The synthesis of thisenantiomer assigned the absolute configuration of (+)-cannabisativine.

Bailey et al. [17] have developed an aza-Diels-Alderreaction using a chiral imino-ester 36 as dienophile with thechiral auxiliary branched on the imino nitrogen. The aza-Diels-Alder carried out with the latter dienophile 36 and 1-methylbutadiene gave the expected cis cyclo-adduct 37 withmodest yield and asymmetric induction (see Scheme 8).

To improve their results, these authors [18] studied thereactivity of the dienophile 38 (prepared in three steps fromfumaric acid), which combined two chiral auxiliaries,namely 1-phenylethylamine on the imino nitrogen and 8-phenylmenthol on the ester function (see Scheme 9). Due tothe presence of the two chiral auxiliaries, they distinguisheda matched and a mismatched process depending on theconfiguration of each one. As an example of the efficiency ofthis process, when matched auxiliaries were used with 1-methylbutadiene in the cycloaddition reaction, the resultingcyclo-adduct 39 was isolated with complete diastereo-selectivity. As a limitation, 8-phenylmenthol is expensiveand only one enantiomer is readily accessible (prepared from(R)-pulegone).


N

COOBu

Ts

OBnBnO

H

C5 H11

HN

OBnBnO

H

C5 H11

CH(OMe)2

NHTsH

N

OBnBnO

H

C5H11

COOMe

N

Ts

NHCOCF3

H

N

OHHO

H

C5 H1 1

HN

O

HN

H

NTs

OBnBnO

C5H11

CH(OMe)2

H

H

Cl NHTs

O

N

OBnBnO

H

C5 H11

HN

O

N

Ts

H

N

OBnBnO

H

C5 H1 1

CH(OMe)2

N

Ts

NHCOCF3

H

a-d e-g

29 30

32

33 34

35

(-)-cannabisativine

31

h-j k-n

o-p q

Scheme 7. Reagents and conditions: (a) LiAlH4, Et2O, 92%. (b) (COCl)2, DMSO, Et3N, CH2Cl2, -60°C. (c) MeOCH=PPh3, THF, 72% (2steps). (d) CSA, MeOH, 93%. (e) Na, naphthalene, THF, 86%. (f) 31, K2CO3, benzene, toluene, H2O (3/1/1), 94%. (g) LiAlH4, THF, reflux,94%. (h) PhthN(CH2)4Br, K2CO3, DMF, 95%. (i) NH2NH2, EtOH. (j) TFAA, CH2Cl2, 82% (2 steps). (k) TsOH, acetone. (l) K2CO3, MeOH.(m) NaClO2, 2-methyl-2-butene, t-BuOH. (n) CH2N2, Et2O, 68% (4 steps). (o) Ba(OH)2, MeOH, H2O (3/1). (p) 2-chloro-1-methylpyridinium iodide, DMAP, CH2Cl2, 63% (2 steps). (q) Na, naphthalene, THF, 83%.

Me

N

Me

Ph

O

O

Me

Me MePh

N

Me

Ph

Me

O

Me MePh

Me

+a

38 39

O

Scheme 9. Reagents and conditions: (a) CF3CH2OH, MS 4Å, TFA, rt, 24 h, 53%, >95% de.

Me

+EtOOC

N Ph

Ph

N

COOEt

Ph

PhMe40

a

(+) - 41

Scheme 10. Reagents and conditions: (a) CF3CH2OH, MS 4Å, TFA, -40°C, 20 min, 62%.

Me

N

EtOOC

Me

Ph N

COOEt

Me

Ph

Me

+a

36 37

Scheme 8. Reagents and conditions: (a) DMF, TFA, H2O, 35%,36% de.

The same authors have reported a highly diastereo-selective aza-Diels-Alder reaction in the racemic series, usingan imino ester generated from benzhydrylamine and ethylglyoxylate [19]. Indeed benzhydrylimine 40 reacted with 1-methylbutadiene with total regio- and diastereo-control toafford in 62% yield the cycloadduct (±)-41 (see Scheme 10).

Recently Yang, Wu et al. [20] reported the first exampleof an antibody-catalyzed aza-Diels-Alder reaction. Indeed, the


N

MeO

NH

OH

O

O

Me

PhN

MeO

NH

HN

O

O

Me

Ph

BSAa

42 43

Scheme 11. Reagents and conditions: (a) Bovin Serum Albumin (BSA), EDCI, DMF, 10 mmol/L PBS buffer (pH 7.2), rt, 5 h.

+EtOOC

N Ph

Me

N

COOEt

Ph

Me

36

a

OH OH

4544

Scheme 12. Reagents and conditions: (a) polyclonal antibody, 10 mmol/L PBS buffer (pH 7.0), 37°C.

AcO

OBn

Ru

PCy3

PCy3

Ph

Cl

Cl

OBnAcO

CCl3

NTs

N

AcO

Ts

CCl3BnO

+

a b46

47

4 9 50 51

48 Grubbs' catalyst

Scheme 13. Reagents and conditions: (a) Grubbs’ catalyst 48, CH2Cl2, rt, 36h, 80%, E/Z : 0.8. (b) 50, CH2Cl2, 70°C, 12 kbar, 40 h,90%, isomer ratio: 1.3.

authors demonstrated that hapten 42 coupled with carrierprotein Bovine Serum Albumin (BSA) providedimmunogen 43. Immunization of rabbits with 43 providedpolyclonal antibodies, Aza-BSA-3, which catalyzecycloaddition between diene 44 and dienophile 36 (seeSchemes 11 and 12). The trans adduct 45 was isolated asthe major product with high diastereoselectivity (trans/cis:13/1). The originality of this process is demonstrated by thefact that under classical acidic catalysis (without polyclonalantibodies) the selectivity was reversed with the cis adductas the major product (trans/cis: 1/4).

A versatile synthesis of substituted tetrahydropyridinesusing a combination of an enyne cross metathesis (CM)reaction and an aza-Diels-Alder reaction under high pressurewas reported by Blechert and Schürer [21]. To demonstratethe efficiency of this methodology, alkynes and alkenes witha variety of functionalities were used to give highlysubstituted tetrahydropyridines as a diastereoisomericmixture (in a ratio varying from 0.8 to 1.5) as described inScheme 13.

AZA-[2,3]-WITTIG REARRANGEMENTS

The sigmatropic oxy-[2,3]-Wittig rearrangement ofsecondary allylic ethers (see Scheme 14, X = O) has becomean important tool for the construction of complexfunctionalized acyclic and cyclic natural products [22].However, the aza version (X=NR3) has been the focus of lessattention and only a few successful examples have beenreported in the literature [23].

XG

R1R2

HX

R1

G

R2

1) base

2) H2O

X = O, NR3,

G = Ph, CO2R, C CTMS, CN

* *

*

Scheme 14.

In this context, Somfai et al. [24] published a conciseand elegant methodology to synthesize cis-2,6-disubstituted


NR1

CO2tBu

R2

1) LDA

2) H2O NR1

H

R2

CO2tBuNR1

CO2tBu

1) LDA

2) H2O NR1

H

R2

CO2tBu

R2

(E) (Z)

Scheme 15.

NR1

CO2 tBu

R2N

LiO

OtBu

H

R2

R1

H

H

H2O

NR1

H

R2

CO2tBu

LDA

Scheme 16.

OH

C5H11

O

OTBDMS

C5H11

N

CO2 tBu

NH

Me

C5H11 CO2tBu

NH

Me

C5H11

CO2Et

OH

C5H11 OH

N3

C5H11

N

CO2tBu

Me

OH

C5 H1 1 N3

HO

N

Me

C5 H1 1

O

NH

Me

C5H11

OH

OTBDMS

C5H11

NH

NH

Me

C5H11 CO2tBu

NH

Me

C5H11

CO2Et

N

Me

C5H11

a b, c d

(-)-indolizidine 209B

e, f, g h

j

52 53 55

56

54

+

57

i k

58

l m n

59 60 61

62 63

23

Scheme 17. Reagents and conditions : (a) NaN3, NH4Cl, MeOCH2CH2OH, H2O, reflux, overnight, 89%. (b) TBDMSCl, CH2Cl2, Et3N,DMAP, rt, overnight, 90%. (c) PPh3, toluene, reflux, overnight, 90%. (d) t-butyl bromoacetate, K2CO3, 18-crown-6, THF, rt, 40 h, 60%.(e) n-Bu4NF, THF, rt, 30 h, 81%. (f) DMSO, (COCl)2, Et3N, CH2Cl2, -78°C, 40 min. (g) Ph3P=CHMe, THF, -20°C to rt, 30 min, 80% (twosteps). (h) LDA, THF, -78°C, 10 min, 97%. (i) H2, 5% Pd/C, EtOH, rt, overnight, 55%. (j) LiAlH4, THF, 0°C to rt , 30 min, 90%. (k)DMSO, (COCl)2, Et3N, CH2Cl2, -78°C, 20 min, then Ph3P=CHCO2Et, 75%. (l) H2, 4kg/cm2, 5% Pd/C, EtOH, rt, overnight, 84%. (m)Me3Al, benzene, rt, 2 h, then reflux, overnight, 88%. (n) LiAlH4, THF, reflux, 2 h, 70%.

tetrahydropyridines in stereo and enantiospecific mannerfrom aza-[2, 3]-Wittig rearrangement of chiral trans-2,3-disubstituted vinylaziridines (see Scheme 15).

To rationalize the exclusive formation of cis-2,6-disubstituted tetrahydropyridines, the authors proposed thetransition state depicted in Scheme 16.

A limitation became apparent when cis-2,3-disubstitutedvinylaziridines were used. The rearranged compounds wereisolated as a mixture of cis- and trans-2,6-disubstitutedtetrahydropyridines or exclusively as the cis-isomersdepending on the substrates. Nevertheless, the readyavailability of chiral trans-2, 3-disubstituted vinylaziridines,prepared from the corresponding epoxyalcohols obtained by


N

TMS

Me

Ph

O

N

TMS

Me

Ph

O

TMS

A B

N

TMS

Me

Ph

O

TMS

NMe Ph

OH

NMe Ph

OH

+

(±)-anti-64 (±)-cis-65 (±)-trans-66

a

Scheme 18. Reagents and conditions : (a) 1.0 eq TMSOTf, CH2Cl2, -40°C, 8 h, 91%.

C

N

TMSO

Me Ph

TMS

N

TMS

Me

Ph

OTMSD

E

F

N

TMSO

Me Ph

TMS

N

TMS

Me

Ph

OTMS

+

+

trans-66

cis -65

Scheme 19.

Sharpless epoxidation of allylic alcohols, makes thismethodology very attractive. Somfai et al. [25] haveexploited this aza-[2,3]-Wittig rearrangement as a key step toconstruct the piperidine ring in the synthesis of indolizidinealkaloids. For example, starting from chiral 2, 3-epoxyalcohol 52, they achieved a 14-step synthesis of (-)-indolizidine 209B [25b] as presented in Scheme 17.

Bimolecular nucleophilic ring-opening of the chiral 2,3-epoxyalcohol 52 with excess of sodium azide afforded amixture of substituted compounds at the C-2 and C-3positions, 53 and 54 respectively. The use of the mixture ofazidoalcohols 53 and 54 has no consequence on theformation of the chiral aziridine 55 and no attempt was madeto separate these compounds [26]. After selective silylationof the primary alcohol, the resulting mixture was treatedwith triphenylphosphine in refluxing toluene to give thedesired aziridine 55 as a single isomer in 72% overall yieldfrom 52. N-Alkylation of the aziridine 55 with t-butylbromoacetate was carried out with potassium carbonate inthe presence of 18-crown-6 to furnish the N-alkylatedcompound 56 in 60% yield. The aza-Wittig substrate with(Z) double bond 57 was synthesized in 65% yield fromcompound 56 following a three-step sequence involving thecleavage of the silyl protecting group, a Swern oxidation ofthe resulting primary alcohol and a Wittig olefination. Thetreatment of the aziridine 57 with LDA at low temperatureled to the rapid formation of the cis-2,6-disubstitutedtetrahydropyridine 58 as the sole diastereoisomer in 97%yield. The cis-2,6-disubstituted tetrahydropyridine 58 wassuccessfully transformed to (-)-indolizidine 209B via a 6-step sequence using known procedures.

INTRAMOLECULAR ALLYLSILANE-NITRONECYCLOADDITIONS

A comparative study between thermal and TMSOTf-induced intramolecular allylsilane-nitrone cycloaddition has

been reported by Wuts et al. [27]. This work has beensuccessfully used to build either racemic cis- or trans-2,6-dialkyl tetrahydropyridine motifs.

Thus, treatment of the racemic anti-nitrone 64 with oneequivalent of trimethylsilyl triflate (TMSOTf) in methylenechloride at low temperature afforded a mixture of the N-hydroxylamines cis-65 and trans-66 in 91% yield as a 1 to 1mixture, without formation of [3+2] dipolar cycloadducts(see Scheme 18). The anti-nitrone 64 was prepared byreaction of benzaldehyde with the corresponding anti-hydroxylamine, which was isolated from an anti/syn (3.8/1)mixture obtained by condensation of acetaldehyde oximewith γ-(trimethylsilyl)allylboronate.

The formation of the racemic tetrahydropyridines cis-65and trans-66 could be explained by the fact that thestoichiometric amount of TMSOTf leads to the formation ofan electrophilic N-siloxyiminium intermediate A, whichreacts in intramolecular fashion with the allylsilane moietyto generate a cation B stabilized by the neighboring Si-Cbond (see Scheme 18). The formation of cis-65 and trans-66adducts arises from the boat C and chair D transition states,in which the silyl group adopts an axial position to allow aσ-π stabilization of the β-silyl cation intermediates E and F(Scheme 19).

This methodology was used for the synthesis of racemicsolenopsin A from the anti-nitrone 67 as depicted in Scheme20.

In contrast with the results above, thermal intramolecularallylsilane-nitrone [3+2] dipolar cycloaddition of anti-nitrone 64 conducted in refluxing toluene proceeded in theusual way to afford a diastereoisomeric mixture of bicyclicisoxazolidines 70, 71 and 72 in 79/17/4 ratio (compounds70 and 71 are inseparable but could be separated from 72)(see Scheme 21).


N

TMS

Me

C11H23

O NMe C11H23

OH

NMe C1 1H23

OH

NMe C11H23

H

+

(±)-anti-67 (±)-trans-68

trans-68/cis-69 : 68/32

(±)-cis-69 (±)-Solenopsin A

a b, c

Scheme 20. Reagents and conditions : (a) 1.0 eq. TMSOTf, CH2Cl2, -40°C, 8 h, 58% of trans-68, 27% of cis-69. (b) Zn, AcOH, H2O,60°C, 4 h, 97%. (c) PtO2, H2, EtOH, rt, 100%.

N

TMS

Me

Ph

O

N

O

Me Ph

TMS

N

O

PhTMS

Me

N

O

Me

TMS Ph

(±)-anti-64

70

+ +

71 72

70/71/72 : 79/17/4

a

Scheme 21. Reagents and conditions : (a) Toluene, reflux, 2 h, 87%.

N

O

Me Ph

TMS

N

O

PhTMS

Me

N

O

Me

TMS PhNH

Me Ph

N

OH

Me Ph NH

Me Ph

(±)-70

+

(±)-71

(±)-72

+a b

a, b

(±)-75 (±)-cis-73

(±)-trans-74

(±)-71

Scheme 22. Reagents and conditions : (a) 1.0 eq TMSOTf, CH2Cl2, rt, 2.5 h. (b) Zn, AcOH, H2O, 60°C, 4 h, 82% cis-isomer 73 over 2steps and 76% trans-isomer 74 over 2 steps.

N

HO

HO

H H

OHN

HN

N

HHO

HO

H H

OBn

N

HHO

HO

HH

OBn

(±)-Cannabisativine

(±)-77

(±)-76

Fig. (4).

The cis- and trans-2,6-dialkyl-tetrahydropyridines 73 and74 could be selectively obtained from the inseparablemixture of isoxazolidines 70 and 71 or from isoxazolidine72 respectively, as described in Scheme 22. The TMSOTf-induced cleavage occurs only on the endo-isoxazolidine 70,leading to the formation of a carbo-cation intermediate,which is then stabilized by a maximum overlap with theTMS group in the axial position (as previously presented inScheme 19) to afford the cis-N-hydroxyl tetrahydropyridine

75. The exo-isomer 71 was recovered unchanged in thereaction mixture. The intermediate 75 was reduced with zincto afford the cis-2,6-disubstituted tetrahydropyridine 73. Thesame sequence was run on isoxazolidine 72 to afford theracemic trans-isomer 74.

This methodology was successfully applied to thesynthesis of the two racemic tetrahydropyridine carbonskeletons 76 and 77 of cannabisativine (see Figure 4) [27b].


H11 C5 N

TMS

O

O

H OH

N

O

TMS

OBn

O

O

H1 1C5

OBn

OHC

N

OTMS

OBn

H1 1C5

O

O

H11C5

NO

O

OBn

O

TMS

H

N

OHH H

H11C5

O

OOBn

NH H

H11C5

OO

OHTMS

H

OBn

NH

H11C5

HO

HO

H H

OHTMS

OBn

NH

H1 1C5

HO

HO

H H

OBn

H11C5

NO

O O

TMS

H

OBn

NH

H11C5

HO

HO

H H

OBn

+

+

a

+

e f

b

c, d

(±)-78 79 (±)-80

(±)-85 (±)-77

(±)-76(±)-84(±)-83

(±)-81 (±)-82

(±)-80

(±)-78

14.8:1

Scheme 23. Reagents and conditions : (a) toluene, CaCl2, -20°C, 8 h, then reflux, 2 h, 100%. (b) Zn, AcOH, H2O, 60°C, 4 h. (c) APTS,toluene, reflux, 3 h. (d) TFA, THF, H2O, rt, 36 h, 61% (three steps). (e) 79, CH2Cl2, CaCl2, -20°C, 14 h, then 1.0 eq TMSOTf, -40°C, 18 h,79%. (f) Zn, AcOH, H2O, 80°C, 4 h, then TFA, THF, rt, 20 h, 73%.

The hydroxylamine 7 8 was reacted with 3-(benzyloxy)propanal 79 in toluene at low temperature toafford the nitrone 80, which was then refluxed to give aninseparable mixture of the isoxazolidines 81 and 82 as a14.8 to 1 ratio in quantitative yield (see Scheme 23). Thehydroxylamine 78 was synthesized by condensation of thecorresponding oxime (prepared in 6 steps from commerciallyavailable materials) with γ-(trimethylsilyl)allylboronate.

The isoxazolidines 81 and 82 were treated with zinc togive the piperidinol 83 accompanied by the compound 84resulting from the hydrolysis of the acetonide. This mixturewas submitted to Peterson olefination followed by completeremoval of the acetonide to afford the desired (±)-cis-2,6-disubstituted-tetrahydropyridine 76 in 61% overall yield forthe three steps. Cyclization of the nitrone 8 0 indichloromethane at low temperature with TMSOTf led to theformation of trans-tetrahydropyridine 85 as the solediastereoisomer in 79% yield. Reduction of thehydroxylamine 85 and acidic cleavage of the acetonide groupgave the desired trans-2,6-disubstituted-tetrahydropyridine77 in 73% overall yield for the two steps.

Thermal or TMSOTf-induced intramolecularcycloadditions of allylsilane-nitrone afford stereoselectively

either cis- or trans-2,6-dialkyl-tetrahydropyridines asillustrated by the synthesis of two tetrahydropyridine carbonskeletons (±)-76 and (±)-77 of (±)-cannabisativine. It shouldbe noted that the use of chiral oximes as substrate and/orchiral tartrate ester γ-silylallylboronates [28] could lead tothe synthesis of chiral molecules.

IMINIUM ION–VINYLSILANE CYCLIZATIONS

Iminium ion-vinylsilane cyclization reactions introducedby Overman et al. [29] appear very attractive for thepreparation of chiral 2,6-dialkyl tetrahydropyridines. Chiralsilicon-containing iminium ions are readily available fromamino acids and the initial stereogenic center at C-6 in theiminium intermediates could induce chirality to the newlyformed stereogenic center at C-2 (see Scheme 24).

Unfortunately, earlier mechanistic studies, particularlyfrom Overman et al. [30] have shown that the reaction mayoccur following two different pathways. In the first one, thecyclization of the iminium A gives the β-silyl carbo-cationintermediate B, which subsequently loses the trimethylsilylgroup to afford C (see Scheme 24). Alternatively, prior tocyclization, iminium A undergoes a [3,3]-sigmatropic aza-


D

A

N R2R3

Me3Si

R1

N R2R3

Me3Si

R1

B

N R2R3

Me3Si

R1 C

N R2R3

R1

***

* *

2 6

Scheme 24.

Me3Si

HN

Ph

Me

Me3Si

N

Ph

MePh

CN

N

Ph

MePh

86 87 88

a b

Scheme 25. Reagents and conditions : (a) PhCHO, TMSCN, ZnI2, MeOH, 65°C, 21 h, 43%. (b) AgBF4, CH3CN, 100°C, 45-55% yield,79-83% ee.

H2N

Me3Si

Me N

Me3Si

MePh

N

Me3Si

MePh

OEt

CO2Et

N Me

Ph

Ph

N Me

CO2Et

Ph N Me

CO2 Et

Ph

N Me

Ph

Ph+

(1:1)

+

(1:1)

a b

c

d

89 90

92

91 85% ee

93 95% ee

88 85% ee

94 95% ee

Scheme 26. Reagents and conditions : (a) PhCHO, MgSO4/Na2SO4 (1/1), CH2Cl2, 0°C to rt, 1 h, 62%. (b) CF3CO2H, CH3CN, 60°C, 3 h,50-70% crude yield. (c) Diethyl pyrocarbonate, toluene, reflux, 20 h, 71%. (d) BF3-OEt2, CH2Cl2, 0°C, 5 h, 71% crude yield.

Cope rearrangement to give the more reactive allylsilane D,which then cyclizes leading to C with concomitant loss ofthe trimethylsilyl group. It is obvious that if the aza-Copeprocess occurs more rapidly than the cyclization reaction, thepotential of this methodology in total synthesis will beruined by the partial to complete racemization of the chiralmaterial A.

Synthesis of chiral 2,6-dialkyl tetrahydropyridines byvinylsilane-iminium ion cyclization was first reported by

Overman, Mariano et al. [31] from the chiral amine 86 (>96% ee) (prepared from L-alanine in 9 steps, 23% overallyield) as presented in Scheme 25. Treatment of the α -cyanoamine 87 (derived from 86) with AgBF4 promoteddecyanation leading to the iminium intermediate, whichcyclized to furnish only the trans-2,6-dialkyl isomer 88 withsome racemization during the process (79-83% ee).

Others conditions to form the iminium intermediateswere also studied by the same authors as reported in Scheme


HN

Me3Si

Ph

OBn

Ph N

Me3Si

CN

Ph

OBn

NC6 H13

Ph

OBn

NPh

Ph

OBn

a

b

c

(±)-95 (±)-96

(±)-97 (±)-98

Scheme 27. Reagents and conditions : (a) n-C6H13CHO, CSA, CH3CN, 120°C, 29%. (b) PhCHO, CSA, CH3CN, 120°C, 10%. (c) AgBF4,CH3CN, 100°C, 46%.

NC NBn

nPr

H

NBn

nPr

H

Me3Si

NBn

nPr

Me3Si

MeCN

NnPr Me

H

NnPr Me

Bn

(±)-100 (±)-101 (±)-99 (±)-102 (±)-epi-dihydropinidine

a b c d

Scheme 28. Reagents and conditions : (a) s-BuLi, AllylSiMe3, THF, rt, 85%. (b) KCN, CH3CHO, 6N HCl, MeOH, rt, 85%. (c) 1M TiCl4,CH2Cl2, rt, 80%. (d) H2, Pd/C, MeOH, rt, 95%.

HN

HOPh

Me3Si

N

O

O

Ph

Me3Si

B

N

Me3Si

O

O

Ph

N

O

O

Ph

N

Me3Si

O

O

SPh

Ph

NH

O

HO

N

O

O

Ph

Me3Si

A

a b c

d

103 104 105

107

c

106

Scheme 29. Reagents and conditions : (a) CHOCHO, EtOH, reflux, 2 h, 78%. (b) LiHMDS, THF, -45 °C, 15 min, then, PhSSPh, 73%. (c)ZnCl2, CH2Cl2, rt, 1.5 h, 78%. (d) H2, Pd(OH)2/C, EtOH, rt, 4-6 h, 98%.

26. The results were disappointing: no diastereoselectivitywas noted.

More recently, Tanner et al. [32] have reported hightrans-diastereoselectivity with low yields on differentexamples in racemic series (see Scheme 27).

A stereoselective TiCl4 induced iminium ion cyclizationof α -cyanoamine 99 was used by Yang et al. [33] in the

total synthesis of racemic epi-dihydropinidine, as depicted inScheme 28.

More recently, Kadouri-Puchot et al. [34] have describeda highly stereoselective synthesis of 6-substituted pipecolicacids as presented in Scheme 29. Treatment of β-aminoalcohol 103 (prepared in 2 steps from (S)-phenylglycinol)[35] with glyoxal gave the corresponding morpholinone 104,


BocN

SiMe3

H

N

H

a

108 109

Scheme 30. Reagents and conditions : (a) 2-methylpropanal, TiCl4, CH2Cl2, 0°C to rt, then addition of 108, 3 min, rt, 51%.

A

B

N

R2

R1

H

N R2

H

R1N

R2

SiMe3

R1

H

A

(ii)(i) protodesilylation

Scheme 31.

NH

OH

Ph

SiMe3

N

O

O

Ph

A

NO

Ph

Me3Si

OH

NH

HO2 C

ONPh

HMe3Si

OH

B

N

O OH

Ph

a

b

111 112

110 (S)-Baikiain acid

Scheme 32. Reagents and conditions : (a) CHOCHO, THF/H2O (1/1), rt, 48 h, 71%. (b) DMSO, (COCl)2, CH2Cl2, - 60°C, 10 min., then112, -60 °C, 30 min, NEt3, -60 °C to rt, 1 h, 70%.

which was alkylated with PhSSPh in the presence of base toafford the thioether derivative 105. Treatment of the lattercompound 105 with ZnCl2 induced the formation of theiminium ion A, which underwent cyclization with attack tothe allylsilane moiety from the less hindered face (oppositephenyl) to give the trans-2,6-disubstituted-tetrahydro-pyridine system 106 with an excellent diastereoselectivity(up to 95%). Upon treatment with H2 in the presence ofPearlman catalyst, the compound 106 was converted into 6-substituted pipecolic acid 107.

IMINIUM ION-ALLYLSILANE CYCLIZATIONS

A highly diastereoselective intramolecular iminium ion-allylsilane cyclization was reported by Taddei et al. [36].The chiral allylsilane 108 (prepared in 4 steps from N-Bocleucine) was added to a solution of 2-methylpropanal andTiCl4 to afford the cis-2,6-dialkyl-tetrahydropyridine 109 in51% yield (see Scheme 30). Under these conditions, the Bocprotecting group was cleaved and the Lewis acid promotedthe formation of the iminium species A (see Figure 31). Theauthors proposed two possible mechanisms via the iminiumA: (i) intramolecular attack to the allylic carbon close to thesilicon, (ii) a protodesilylation to give intermediate Bfollowed by an intramolecular ene-iminium reaction.

In connection with their work on iminium ion-vinylsilane cyclization (see above), Kadouri-Puchot et al.[34] reported a stereoselective synthesis of a protected trans-6-substituted baikiain acid 110. The condensation of the β-amino alcohol 111 (prepared in two steps from (S) -phenylglycinol) [35] with glyoxal led to the formation of theiminium ion A, which then cyclized leading to the stabilizedβ-silyl cation intermediate B to afford, after elimination ofthe axial TMS group, the hemiketal 112 in 71% yield. Thislatter compound 112 was converted into the lactone 110using Swern oxidation conditions.

Very recently, Panek et al. [37] have reported a highlystereoselective methodology for the preparation of bothpossible cis-2,6- and trans-2,6-trisubstituted tetrahydro-pyridines. In a one-pot procedure, the silanes anti-113 orsyn-113 were condensed with different aldehydes to form thecorresponding imines. These were treated with an excess ofTiCl4 to afford, in a highly diastereo- and enantioselectiveprocess, the tetrahydropyridines (isolated as trifluoro-acetamides) as outlined by the two representative examplespresented in Scheme 33. It should be emphasized that thepreparation of both enantiomers of the silanes anti-113 andsyn-113 have previously been described by Panek et al. [38],giving access to the four possible cis-2,6- and trans-2,6-tetrahydropyridine stereoisomers.


CO2Me

NH2

SiMe2Ph

H

O

NO2

CO2Me

NH2

SiMe2Ph

H

O

Br

NMeO2C

Me

F3C O

NO2

NMeO2C

Me

F3C O Br

+dr > 30:195% ee90% yield

+dr > 30:195% ee82% yield

anti-113 95% ee

syn-113 95% ee

trans-114

cis-115

a, b, c

a, b, c

Scheme 33. Reagents and conditions : (a) MgSO4, CH2Cl2. (b) TiCl4, -78°C to rt. (c) TFAA, pyridine, CH2Cl2.

CO2Me

NH2

SiMe2Ph

O OAc

H

N

MeH

OMe

N

MeH

TMS

NMeO2C

Me

Cbz

OAc

N

MeH

N

MeH

CO2Me

+ syn-117

cis-116

a, b, c d, e, f

g, h i, j k

(-)-217A

118

119

121120

Scheme 34. Reagents and conditions : (a) MgSO4, CH2Cl2, rt, 0.5 h. (a) TiCl4, CH2Cl2, -78°C to rt, 12 h. (c) CbzCl, Na2CO3, CH2Cl2,0°C, 4 h, 60% (three steps). (d) H2, PtO2, NaNO2, MeOH, rt, 12 h. (e) H2, Pd/C, K2CO3, MeOH, rt, 6 h, 90% (two steps). (f) CBr4, Et3N,PPh3, CH2Cl2, 0°C, 30 min, then Et3N, 0°C, 10 min, 98%. (g) DIBAL-H in hexane, Et2O, -78°C, 1 h. (h) Ph3P=CHOMe, THF, -78°C to rt,overnight, 67% (two steps). (i) 6 N aq HCl, Et2O, rt, overnight. (j) Me3SiC≡CCH2TBS, t-BuLi, Ti(Oi-Pr)4, THF, Z/E : 5/1,-78°C to rt, 3 h,60% (two steps). (k) K2CO3, MeOH, rt, 1.5 h, 95%.

OMe

Ts

MeO

NTs

Ts

N

Ts

N

Ts

Ts

MeO

MeONH

Ts

a b+

122 123

c

124125 cis-126

Scheme 35. Reagents and conditions : (a) n-BuLi, THF/TMEDA (4/1), -78°C, 20 min then addition of 123, -78°C to rt, 30 min, thenAcOH 1M in THF, 85%. (b) TMSCl, NaI, MeCN, rt, 20 min, 74%. (c) AllylSiMe3, SnCl4, CH2Cl2, 99%.

It is notable that the resulting diastereoselectivity ofthese cyclizations is dictated by the silyl group. This groupalso plays a crucial role in terms of reactivity and selectivity,which may once again be attributed to its ability to stabilizethe emerging carbo-cation at the β position in the transitionstate. This methodology has been applied to the firstenantioselective synthesis of the quinolizidine alkaloid (-)-217A isolated from the Madagascan frog Mantella baroni aspresented in Scheme 34. Following this methodology, thecis-2,6-N-Cbz-protected tetrahydropyridine 116 is isolated as

a sole diastereoisomer in 60% yield from silane syn-117 andaldehyde 118. This intermediate 116 was converted into thenatural product in an 8-step sequence, involving anolefination using Yamamoto’s method [39], in 32% overallyield. This synthesis enabled the absolute stereochemistry of(-)-217A to be assigned.

This new methodology should be regarded as aparticularly powerful tool for the synthesis of both chiralpossible cis-2,6- and trans-2,6- 3-trisubstituted tetrahydro-


HN CO2Me

Ns

o

OBn

N

Ns

CO2Me

B

NH

CO2 H

N CO2 Me

Ns

BnO

N

Ns

CO2Me N

Ns

CO2Me

N

Ns

CO2MeBnO

a b+

127 128

c

129 130

+

d, e

132131

133

98:2

Scheme 37. Reagents and conditions : (a) Pd(OAc)2, dppp, Et3N, CH3CN, 1 h, rt, 84%. (b) Grubbs’ catalyst 48, rt, 90%. (c)Allyltributyltin, BF3-Et2O, CH2Cl2, -78 °C to rt, 94%. (d) PhSH, K2CO3, DMF, rt. (e) LiOH, MeOH, H2O, 61% (2 steps).

pyridines, valuable key intermediates for the total synthesisof alkaloids.

IMINIUM ION-MEDIATED C-C BOND FORMATION

An new route to chiral 1,2,5,6-tetrahydropyridines wasreported by Craig et al. [40] using an N-sulfonyliminiumion-mediated C-C bond formation. A representative exampleof this methodology is described in Scheme 35.

Lithiation of the β-sulfonyl acetal 122 (obtained in athree-step sequence from acrolein and thiocresol) followed byaddition of enantiomerically pure 2-substituted N -tosylaziridine 123 (prepared by a three-step sequence from L-valine) gave the compound 124. Treatment of 124 withTMSI (formed in situ from TMSCl and NaI) afforded thecyclized product 125 in 74% yield, isolated as a 2:1 mixtureof 4S and 4R diastereoisomers. This mixture was convertedupon treatment with allylsilane in the presence of SnCl4 intothe chiral cis-2,6-disubstituted-1,2,5,6-tetrahydropyridine126, isolated as the unique diastereoisomer in 99% yield.

N

Ts

A

N

R

S

OO

cis-126

2

6

Nu

Nu

β-attack

α-attack

Scheme 36.

The alkylation of 125 proceeds via the formation of theiminium A (irrespective of the configuration at the C-4position), which adopts, due to stereoelectronic preference, a

more boat-like transition state (see Scheme 36). Tominimize repulsive interactions with the axial C-2substituent, the N -tosyl group adopts a pseudo-axialorientation and consequently hinders the β-face. Thus, thenucleophilic attack occurs by the α -face resulting in theformation of the cis-compound 126.

Rutjes et al. [41] have demonstrated the efficiency andthe flexibility of this strategy through the synthesis ofenantiomerically pure cis-2,6-disubstituted unsaturatedpipecolic acid derivatives. For example, treatment of N-(4-nitrobenzenesulfonyl)-protected allylglycine 127 with benzylpropadienyl ether 128 in the presence of Pd(OAc)2 gave thedesired N,O-acetal 129 in 84% yield as a 1:1 mixture ofdiastereoisomers (see Scheme 37). Ring-closing metathesis(RCM) reaction was performed on this mixture with the useof Grubbs’ catalyst 48 to give cyclic N,O-acetal 130 in 90%yield. The mixture of cyclic N,O-acetals 130 was treatedwith allyltributyltin in the presence of BF3-Et2O to affordthe 1,2-and 1,4-adducts 131 and 132, respectively in 98:2ratio and 94% yield. It should be noted that these twoadducts are in enantiomerically pure form as judged by chiralHPLC analysis. Finally, the sulfonamide and ester functionson 131 were cleaved, affording cis-6-allyl-baikiain 133 in44% overall yield (5 steps). The formation of the cis-compound 131 could be explained using the same transitionstate with N-sulfonyliminium ion B as the one presented inScheme 36.

This approach clearly provides an efficient route to cis-2,6-disubstituted-1,2,5,6-tetrahydropyridines with excellentdiastereo- and enantio-control.

Chiral dihydropyridinium salts 134 formed by alkylationof pyridinium salts 135 have been used with success byMarazano et al. [42] in the synthesis of enantiopurealkaloids and analogs via 2,6-disubstituted-tetrahydro-pyridine intermediates (see Figure 5).


C12H25SO3

N

OHPh

H

NMe

OPh

HCl

NH

Me C11H23

NMe

OPh

N

OMgClPh

H

MeH2O

N

OHPh

H

Me C11H23

N

OHPh

H

Me

134 (R=Me)

N

OHPh

H

Me C11H23

a

+ +

(+)-solenopsin A

b

c

135

136 137138 139

90:10 66:34

Scheme 38. Reagents and conditions : (a) MeMgCl, THF, 0°C, 3 h ; 70%. (b) C11H23MgBr, Et2O, 0°C, 1 h then rt. overnight, 43%. (c)H2, 4.5 bar, Pd/C 10%, EtOH, EtOAc, 3N HCl, 48 h, 60%.

O

OAc

AcO

AcO

N

HO

HO

H

C12H25

N

OAc

AcO

AcO

Fmoc

C9H19

SiMe3

N

AcO

AcO

H

C9H19

D-Glucal 140

11 steps a, b

(+)-deoxoprosophylline

c, d

141

142

10%

Scheme 39. Reagents and conditions : (a) BF3-Et2O, CH2Cl2, 142, -60 to 0°C, 3 h. (b) piperidine, CH2Cl2, rt, 1 h, 78% (2 steps). (c) H2,Pt/C, EtOH, 1.5 h, 60%. (d) LiOH, THF-H2O, 2.5 h, 85%.

N

OHPh

H

R

NH

Me C11H23

NH

Me Me

N

Me

Ph Ph

OOH

N

OHPh

H

X X

(+)-Solenopsin A

(-)-Lupetin

(-)-Lobeline

134 135

Fig. (5).

For example, the chiral pyridinium salt 135 (preparedfrom the N -2,4-dinitrophenylpyridinium salt and (R) -phenylglycinol [43]), with the lipophilic dodecylsulfatecounter anion (X = C12H25SO3

-) to increase the solubility,was treated with methylmagnesium chloride to afford the

mixture of the oxazolidine isomers 136 and 137 in a 90:10ratio in 70% yield (see Scheme 38). Upon addition ofundecylmagnesium bromide, the latter mixture ofoxazolidines 136 and 137 was converted with modestdiastereoselectivity into a mixture of trans- and cis-2,6-disubstituted tetrahydropyridines 138 and 139 in a 66:34ratio. After separation by chromatography, the desired trans-isomer 138 was isolated in 43% yield. Hydrogenation of thedouble bond and hydrogenolysis of the N-benzylic bond wascarried out by treatment with H2 in the presence of Pd/C togive (+)-solenopsin A hydrochloride salt.

Nucleophilic alkylations of chiral pyridinium salts 135proceeded showing good regioselectivity at the C-2 positionand with good diastereoselectivity, however the alkylation ofthe oxazolidine intermediates appeared to be lessdiastereoselective. Nevertheless, in this approach, only a fewsteps are required to reach the target molecule and thechemistry could be carried out under practical conditions ongram quantities with inexpensive chiral auxiliaries.

Shipman et al. [44] reported a total synthesis of (+)-deoxoprosophylline from the 3,4,6-tri-O-acetyl imino D-


NO

O

AcOOAc

A

NO

O

OAc

OAc

B

6

Nu

6

Scheme 40.

glucal 140 prepared from D-glucal in 11 steps using animinium ion-mediated C-C bond formation as outlined inScheme 39.

Reaction of the imino glucal 140 with trimethyl-(1-nonyl-allyl)-silane 142 in the presence of BF3-Et2O affordedafter cleavage of the Fmoc group the cis-2,6-disubstituted-1,2,5,6-tetrahydropyridine 141 as the major diastereoisomer(cis/trans in a 9 to 1 ratio). The alkylation of 140 proceedsvia the formation of an intermediate N-acyliminium ion,which is in conformational equilibrium between A and B(see Scheme 40). Also, steric repulsion between the C-6acetoxymethyl group and the N-Fmoc group disfavours Arelative to B. Stereoelectronically controlled axial attack ofthe nucleophile occurs from the top face to give the cis-isomer 1 4 1 . From this latter intermediate, (+)-deoxoprosophylline was obtained by hydrogenation of thedouble bonds and saponification of the acetate groups.

OLEFIN METATHESIS REACTIONS

During this last decade, RCM reaction has emerged as apowerful method for C-C bond formation as demonstratedby the total synthesis of numerous natural products [45]. Aspart of a continuing program directed toward thedevelopment of an efficient and novel strategy for theconstruction of piperidinic and pyrrolidinic alkaloids [46],we have developed a novel access to enantio-enriched trans-2,6-disubstituted-1,2,5,6-tetrahydropyridines [47]. In thiscontext, it appeared to us that the double bond of thetetrahydropyridine motif A could be generated by an RCMreaction from the corresponding diethylenic amine B (seeScheme 41).

R1 N

PG

R2

RCM

A

R1 N

PG

R2

B

Scheme 41.

Our synthetic route started from the commerciallyavailable Garner aldehyde 143 on which a stereoselectiveolefination, via a Horner-Wadsworth-Emmons (HWE)reaction, introduced the first olefin required for the RCMstep (see Scheme 42) to furnish 144. The cleavage of bothoxazolidine and N-Boc protecting groups of 144 in the samestep afforded the expected amino alcohol 145 in quantitativeyield (97%). Introduction of the second olefin was carriedout by diastereoselective allylation of an imine generated by

condensation of 145 with an appropriate aldehyde. Asexpected, the stereoselectivity in favor of the trans isomer(separated from the cis by flash chromatography) could beexplained by the generally accepted transition state underchelation control (see Figure 6).

OMgBr

NH

R

Disfavored

Favored

Fig. (6).

Next, we turned our attention toward cyclization byRCM. However, it was well established that the rutheniumcatalyst was incompatible with free amine [44e, 44f].Consequently, we decided to transform the amino alcoholfunction of 146 , 148 and 150 as its correspondingoxazolidinone 152-154. Thus, the RCM reaction on theoxazolidinone derivative 152-154 afforded the expectedtetrahydropyridines 155-157 in good yields. Thismethodology was applied to the synthesis of the non-natural(-)-3-epi-deoxoprosopinine, an analog of the Prosopisalkaloid family. Epoxidation of the double bond of 157 withmCPBA afforded a separable mixture of exo-158 and endo-epoxide 159 with good selectivity (respectively 1/9). Thestructure was confirmed by X-ray crystallographic analysis.Finally, the regioselective reduction of 159 with Super-Hydride® and the subsequent hydrolysis of oxazolidinone inbasic media afforded the desired (-)-3-epi-deoxoprosopinine[48].

Recently, Couty et al. [49] have described the synthesisof optically active cis and trans-2,6-disubstituted-1,2,5,6-tetrahydropyridines. Starting from ketone 160, readilyavailable from (S)-phenylalaninol in 3 steps, a stereoselectivereduction with NaBH4/EtOH (76% de) or under Lucheconditions, NaBH4/CeCl3/EtOH (58% de) gave bothstereoisomers 161 and 162, respectively (see Scheme 43).Treatment of 161 with NaH led to an intramolecularcyclization to furnish oxazolidinone 163 . This latterintermediate 163 was reacted with allyltrimethylsilane in thepresence of TiCl4 to afford stereoselectively the transoxazolidinone 164. Next, the oxidation of alcohol withDess-Martin periodinane followed by Wittig olefination gavethe diethylenic amine 1 6 5 . The formation of the


H O

BocN

O

NH

HO

R

C12H25 N

OO

O

NH

HO

R

NH

HO

R

BocN

O

C12H25 N

OO

O

NR

O

O

H2N

HO

NH

OH

OHC12H25

R N

OO

+

1 / 9

+

(-)-3-epi-Deoxoprosopinine

a b c

d e

f g-h

143 144 145

158 1 59

R = PhPhCH2CH2C12H25

trans / cis86 / 14

89 / 1187 / 13

Yield (%) 73 / 1262 / 8

56 / nd

157 R = C12H25

Yield (%) 152 89

153 97154 91

Yield (%)

155 88156 92157 99

Product 146 / 147148 / 149150 / 151


Product 14 614 815 0


R =

PhPhCH2CH2

C12H25

trans cis

Scheme 42. Reagents and conditions: (a) PhCH2P(O)(OEt)2, BuLi, THF, -78°C, 2 h, then rt, 12 h, 75%. (b) 12N HCl, MeOH, 60°C, 4 h,98%. (c) RCHO, THF, MgSO4, rt, overnight, then, allylmagnesium bromide, -78°C to -10°C, 5 h. (d) carbonyldiimidazole, Et3N,CH2Cl2, rt, overnight. (e) Grubbs’ catalyst 48 (5 mol%), CH2Cl2, reflux, 1 h. (f) mCPBA, CH2Cl2, rt, 72 h, 81% of 157. (g) LiBHEt3,THF, 0°C to rt, 2 h, 98%. (h) 8N KOH, MeOH, 100°C, 18 h, 90%.

N

O O

PhBoc

N O

O

HO

Ph

N

O OH

PhBoc

N O

OPh

N

O OH

PhBoc

N

O

Ph

O

O

N O

OPh

a

b c d

e-f g

160

161

162

163

164 165 166

Scheme 43. Reagents and conditions: (a) NaBH4, CeCl3,7H2O, EtOH, -78°C, 30 min, 54%, 58% de. (b) NaBH4, EtOH, -78°C, 30 min,72%, 76% de. (c) NaH, THF, reflux, 2 h, 71%. (d) allyltrimethylsilane, CH2Cl2, TiCl4, -78°C to rt, 85%. (e) Dess-Martin periodinane,CH2Cl2, rt, 1 h. (f) Ph3PCH3Br, nBuLi, THF, -30°C to rt, 1 h, 80% (2 steps). (g) Grubbs’ catalyst 48 (2.5 mol%), CH2Cl2, reflux, 2 h,83%.

tetrahydropyridine ring was finally achieved from 165 byruthenium catalysis to yield cis-2,6-disubstituted-1,2,5,6-

tetrahydropyridine 166. Similar chemistry starting from 162yielded the trans-adduct 167 (see Scheme 44).


N

O OH

PhBoc

O

OPh

See Scheme 43

162 167

Scheme 44.

N

R

Pg

[Ru]Ph

N

[Ru]

R

Pg

[Ru]

N

R

Pg

C

N

[Ru]

R

Pg

Ph

N

R

Pg

AC

D

ARu

PCy3

PCy3

Ph

Cl

Cl[Ru]

Ph

N

R

Pg

B

+

-*

*

*

*

*

*

*

*

*

*

*

*

48 Grubbs' catalyst =

Scheme 45.

OAc

O

NO2

O

MeO2C NHTs

OAc

NHTs

CO2Me

NMeO2C

OAc

Ts

N

OAc

OAc

OAc

MeO2C+

a 7 s tepsb

168

169 170 171 172

Scheme 46. Reagents and conditions : (a) Pd(OAc) 2, PPh3, NaH, DMF, 0°C to rt, 15 h, 69%. (b) Grubbs’ catalyst 48 (5 mol%), CH2Cl2,rt, 20 h, 96%.

Blechert et al. [50] have exploited in a beautiful way thehuge potential of olefin metathesis reactions i.e. RCM, CMand ring-opening metathesis (ROM) through varioussyntheses of alkaloids making an important contribution inthis field. In particular, they have combined anintramolecular ring-closing/ring-opening metathesis toefficiently transform a carbocycle A to 2,6-disubstituted-tetrahydropiperidine B with complete transfer of thestereocenters (see Scheme 45). First, the ruthenium catalystreacts with the more accessible terminal double bond of A toform the ruthenium carbene complex C. Intramolecular [2+2]cycloaddition of C and subsequent cycloreversion providesthe carbene complex D which reacts in a CM reaction withone molecule of starting material A to afford the 2,6-disubstituted tetrahydropyridine B and concomitantly theintermediate C.

The authors have reported successful application of thisstrategy to the synthesis of 2,6-disubstituted tetrahydro-pyridines [51]. A representative example of this work isdepicted in Scheme 46. A Pd(0)-catalyzed allylation of (S)-allylglycine ester derivative 168 with p-nitrobenzoate 169(prepared by enzymatic desymmetrization of thecorresponding meso-diol) afforded the metathesis precursor170 in 69% yield. Treatment of this latter intermediate 170with Grubbs’ catalyst 48 in dichloromethane at rt resulted,through RCM/ROM reactions, in the formation of cis-2,6-disubstituted tetrahydropyridine 171 in high yield. Thecompound 171 was converted in 7 steps to the indolizidine172.

It should be pointed out that the use of (R)-allylglycineester derivative 168 in this sequence led to the synthesis ofthe trans-2,6-disubstituted tetrahydropiperidine in the sameyield. Given the availability of the chiral starting materialsand the efficiency of the Pd-catalyzed allylation, this strategyis very attractive to prepare both cis- and trans-2,6-disubstituted tetrahydropyridines in high stereoselectivity.

INTRAMOLECULAR CYCLIZATION REACTIONS

Intramolecular cyclization reactions (ring-opening ofepoxide function, SN2 reaction, conjugate addition) using


N

O NH

N Boc

H

Troc

O

NH

O NH

N Boc

H

O

NH

OHO NH

NH

H

NH

OHO NH

N

H

Boc

NH H

O NH

N Boc

OHN

H HOH

O NH

NH

(±)-173

+

(±)-Palus trine

15

1416

15

(±)-174

(±)-cis -176 41% (±)-trans-177 46%

a

b

175

Scheme 47. Reagents and conditions : (a) Zn, THF/H2O, pH 5.5. (b) HCl, CH2Cl2.

NH

O NH

NH

C5 H1 1

O

NH

O NH

NH

O

C5H11N

H

O NH

NH

HC5H11

O

(±)-(E,E)-179

11

(±)-(Z,E)-178 (±)-anhydrocannabisativine

a

Scheme 48. Reagents and conditions : (a) hν 254 nm, EtOH, rt, 20 h, 93%.

the nucleophilic amine function to constructtetrahydropyridine have been successfully used to synthesizenatural products.

Using an intramolecular ring-opening of epoxide as a keystep, Wasserman et al. [52] published a total synthesis ofracemic palustrine isomer 173, showing that the position ofthe double bond in the six-membered ring was located atC14-C15 and not C15-C16, as previously assigned in thenatural product [53] (see Scheme 47). Starting from theintermediate 174, present as a mixture of diastereoisomers,the selective removal of the trichloroethoxycarbonyl (Troc)protecting group afforded the corresponding secondary amine175. This cyclized in situ by regioselective ring-opening ofthe epoxide to give a mixture of desired c i s -tetrahydropyridine 176 and its trans-isomer 177 in 41% and46% yields, respectively after purification by flashchromatography. Cleavage of the Boc-protecting group oncis-176 under acidic conditions led to racemic palustrineisomer 173.

Following a similar route, the same group completed anelegant total synthesis of racemic anhydrocannabisativine[54] as depicted in Scheme 48.

Stereoselective intramolecular conjugate addition of theN11 secondary amine to the (Z,E)-dienone 178, formed insitu by irradiation of the (E,E)-isomer 179, gave racemicanhydrocannabisativine as unique isomer in high yield. This(E,E)-isomer 179 was inert towards thermal isomerizationand cyclization even at high temperature (up to 260°C) withor without amine catalysts.

An interesting entry to chiral c i s - 2 , 6 - d i a l k y ltetrahydropyridines leading to natural products waspublished by Sato et al. [55] using allyltitanium chemistryto prepare the required substrates for the cyclization step (seeScheme 49). The cyclic carbamates 180a-c (prepared fromchiral aminoacids or from chiral 2,3-epoxy-1-hexanol (for R1= n-Pr) using well known reaction sequences) were reactedwith the (η2-olefin)titanium complex 181 formed in situ by


NO

OBn

R1

R1

R2

NH

OH

Bn NH OHBn

R1 R2Ti(O-i-Pr)2 181a)

b) R2CHO 182

a R2 = Me

b R2 =Et

c R2 =n-Pr

d R2 =(E)-CH3CH=CH-

e R2 =Ph

+

180a R1 = Me b R1 = n-Pr c R1 = CH2OTBS

183

184

Scheme 49.

NO

OBn

R1

NO

OBn

R1

Ti(OR)2

Ti(OR)2 ROMgCl

ON

O

Bn

R1

MgCl

TiOR

OROR

N O

Ti

O

OR

OR

R1

Bn

Ti(OR)2

A

O

Ti

N

O

R2

H

O

H

R1RO

RO

Bn

R1

R2

NH

OH

Bn

B C D

R2CHO

183

180

+

181

+

182

R = i-Pr

E

NO

OBn

R1

Scheme 50.

reaction of Ti(O-iPr)4 with 2 equiv. of iPrMgCl. They werethen treated with aldehydes 182a-e to afford, with goodregio- and high stereoselectivity, the 1,5-amino alcohols 183in 79-83% yields.

In all cases, the 1,5-amino alcohols 183 were isolatedaccompanied with their regioisomers 184 in a ratio of morethan 12 to 1. These two regioisomers 183 and 184 could beeasily separated by column chromatography. Concerning the1,5-amino alcohols 183 only the isomer with a (Z)-doublebond was formed and the level of diastereoselection wasbetter when the bulkiness of R1 in 180 and R2 in 182 wasincreased. Thus a 5 to 1 ratio was obtained with R1 = Meand R2 = n-Pr compared to the 20 to 1 ratio with R1 =TBDMS and R2 = Ph. The regio and stereochemistry of thealdehyde addition to the allyltitanium derived from thecyclic carbamates 180 could be explained according to themechanism proposed by the authors and presented inScheme 50. The olefin exchange between the (η 2-olefin)titanium complex 181 and the allyl carbamate 180afforded the intermediate A, which by β-elimination via a

titanacyclopropane complex B, led to the formation of theallyltitanium C [56]. At this stage, due to the higherstability of the six-membered cyclic structure, theequilibrium was shifted in favor of a cyclic allylic titaniumcomplex D. Then, the reaction of aldehydes 182 with thelatter complex E proceeded via a cyclic six-membered chair-like transition state, shown in Scheme 50, in which thealdehydes R2 group occupies an equatorial position, to givethe syn-adducts 183 with (Z)-double bond.

To convert the 1,5-amino alcohols 183 into thecorresponding cis-2,6-dialkyl-tetrahydropyridine 185 (seeScheme 51) the amine function was protected as N-Boc, thebenzyl protecting group was selectively cleaved, the alcoholfunction was activated as mesylate and, finally, thecyclization reaction was promoted by treatment with t-BuOK. The tetrahydropyridine 185 was hydrogenated to (+)-dihydropinidine as its N-Boc derivative 186.

A highly stereoselective preparation of related 1,5-syn-amino alcohol was published by Thomas et al. [57] basedon allyltin chemistry. As also described by these authors, it


Men-Pr

NH

OH

Bn

NMe n-Pr

Boc

NMe n-Pr

Boc

183 (R1=Me, R2=n-Pr)

a, b, c

d

185

186

Scheme 51. Reagents and conditions : (a) (Boc)2O, Et3N, THF,rt. (b) Na, liq. NH3, -78 to –40°C. (c) MsCl, Et3N, CH2Cl2, rt. (d)t-BuOK, THF, 0°C, 60% overall yield. (e) H2, Pd/C, EtOH, rt,quant.

N N R

Li

B

N R

BN R

B

LiN R

B

CH3OH

NaOH

CH3OH

NH

R

N R

B

H

R-Li

-60 to 0°C

188a R = Meb R = nBuc R = Ph

3

33

2 187a R = Me 52%b R = nBu 56%c R = Ph 53%

189

3

190

191

Scheme 52.

NH

R

B

N RH

B

NH

R

CH3OH

NaOHN R

B

N R

B

3

32

125°C

160 to 195°C

2

overall yields 60-70%

187a R = Me b R = nBu c R = Ph

192a R = Me b R = nBu c R = Ph

193 194

195

Scheme 53.

is possible to invert the alcohol configuration using theMitsunobu procedure to give the corresponding anti-diastereoisomers offering the possibility of synthesizingchiral trans-2,6-dialkyl-tetrahydropyridines.

The efficiency of these intramolecular cyclizationreactions to build the tetrahydropyridine core is potentiallyvery attractive due to easy access to the chiral precursors.

TRIALLYLBORANE APPROACH

Bubnov et al. [58] published an original methodology tosynthesize stereoselectively racemic cis- and trans-2-allyl-6-alkyl(or aryl)-1,2,5,6-tetrahydropyridines from pyridine withtriallylborane. The trans-2-allyl-6-alkyl(or aryl)-1,2,5,6-tetrahydropyridines 187a-c were easily prepared frompyridine via a one-pot procedure. First, pyridine was treatedwith an organolithium reagent (RLi, R = Me, n-Bu or Ph)to afford the corresponding lithium derivatives 188a-cformed by 1,2-addition (see Scheme 52).

Then, the lithium derivative 188a-c was reacted withtriallylborane to give presumably an enamine "ate-complex"189. This latter complex 189 was treated with a slightexcess of methanol leading to the cleavage of the B-N bondand concomitantly migration of the double bond withprotonation of the alcohol at C-3 to afford the iminecomplex 190. Finally, the allylboration of the C=N double


N

H

H

R

B

N

H

R

H

B

2 2

R = Me, al lyl and Ph

194 195

Scheme 54. trans-cis Isomerization.

NH

(±)-Epi-dihydropinidine

NH

(±)-Dihydropinidine

192a 187aa a

71% 70%

Scheme 55. Reactions and conditions : (a) H2, Raney Ni, 100 atm, AcOH, 100°C.

bond in the intermediate 190 gave the corresponding trans-adduct 191. This was submitted to treatment with sodiumhydroxide in methanol to lead to the desired trans-2-allyl-6-alkyl(or aryl)-1,2,5,6-tetrahydropyridines 187a-c in 52 to56% overall yields (GC yields up to 90%). The trans-stereochemical outcome of these allylborations can beexplained by the fact that the substituents on the ring directthe reaction on the least hindered face of the molecule.

To complete this work, the same authors [57b] foundthat upon heating with triallylborane at 140-190°C followedby treatment with sodium hydroxide in methanol, the trans-2-allyl-6-alkyl(or aryl)-1,2,5,6-tetrahydropyridines 187a-cwere isomerized into the corresponding cis-isomers 192a-c(see Scheme 53).

Thus, trans-amine 187a-c reacted with triallylborane toafford the corresponding N-B complex 193, which underheating at 125°C led to the aminoborane 194 with loss ofpropene. At this stage under more drastic conditions (>160to 195°C), isomerization to the cis-isomers 195 occurred dueto the greater thermodynamic stability of these isomers withtwo pseudo-equatorial groups compared to the correspondingtrans-isomers 194 (see Scheme 54). After alcoholysis, thecis-2-allyl-6-alkyl-tetrahydropyridines 192a-c were isolatedin 60 to 70% overall yields, while amines 192a and 192bwere contaminated with less than 3% of trans-isomers.Concerning substrate 192c, the isomerization equilibriumfurnished a mixture of cis-192c and trans-187c in an 80 to20 ratio. No improvement was noted with prolonged heatingtime at higher temperature. However, the two isomers 187cand 192c could be separated by chromatography on Al2O3.

The efficiency of this new method has been demonstratedby a short and concise synthesis of (±)-dihydropinidine, adefense alkaloid of the Mexican bean beetle Epilachnavarivestis (Coccinellidae) and (±)-epidihydropinidineisolated from P. engelmannii and other Picea (spruce)species (see Scheme 55).

MISCELLANEOUS APPROACHES

Comins et al. [59] reported an efficient synthesis ofracemic cis-2,6-disubstituted-1,2,5,6-tetrahydropyridine 196,

starting from N-acyl-2,3-dihydro-4-pyridone 197, seeScheme 56.

N OMe

O

CO2Bn

N

CO2Bn

O

(±)-196 (±)-197

Scheme 56.

Dihydropyridone 197 was treated with phenylselenylchloride and the resulting compound then participated in aMukaiyama-Michael reaction with O-silyl ketene acetal 198to give piperidone 199 as the sole diastereoisomer in 82%yield over two steps (see Scheme 57). The presence of aphenylselenyl substituent is required to perform the nexttransformation in a stereoselective manner and it is alsouseful for the double bond formation later on. Piperidone199 was reduced under Luche conditions to furnish amixture of diastereoisomers 200 and 201 in a 1 to 1 ratio.Formation of the double bond of 196 was carried out by afree-radical process following a one-pot procedure. The lattercrude mixture of 200 and 201 was converted into thecorresponding diastereoisomeric mixture of thiocarbamates202, which was then treated with Bu3SnH and AIBN topromote the olefin formation in 69% overall yield. It shouldbe noted that elimination via the formation of the mesylatederivative gave the expected tetrahydropyridine 196 only inthe case of trans isomer 201. The same conditions appliedto the cis isomer 200 gave only the C-4 mesylate withoutolefin formation.

An application of this chemistry to the first asymmetricsynthesis of (+)-cannabisativine (natural enantiomer) [8, 15]has also been reported by the same authors (see Scheme 58)[60]. Stereoselective addition of zinc enolate 203 t oenantiopure 1-acylpyridinium 204 (de > 95%) introduced thefirst substituent α to nitrogen in 85% yield to afford 205.After 7 steps of chemical transformation (50% overall yield),the dihydropyridone 206 was engaged in a similar sequenceas the one previously described. Introduction of a


N

CO2Bn

O

N

CO2Bn

O

PhSe

OMe

O

N

CO2Bn

OH

PhSe

OMe

O

N

CO2Bn

OH

PhSe

OMe

O

N

CO2Bn

OMe

O OTMS

OMe

N

CO2Bn

O

PhSe

OMe

O

NS N

+

a,b c

d e

(±)-197

198

(±)-199 (±)-200 (±)-201

(±)-202 (±)-196

4 4

Scheme 57. Reagents and conditions: (a) PhSeCl, EtOAc, 97%. (b) 198, BF3.Et2O, 85%. (c) NaBH4, CeCl3, 43% of 200 and 43% of 201.(d) 1,1’-thiocarbonyldiimidazole, DMAP, toluene, reflux. (e) Bu3SnH, AIBN, toluene, reflux, 69% over the two steps.

N

OMe

TIPS

COOR*

Cl-

O

O

OZnCl

Et

Et

N

O

OO

C5H11

OBn

H

N

OO

C5H11

OBn

OMe

O

H H

N N

O

OH

Bn

C5H11

OBn

HO

TsHN

H H

N

OH

OO

C5H11

OBn

OMe

O

PhSe

H H

N

O

TIPS

COOR*

O

O O

H

N

OO

C5H11

OBn

N

O

OH

Bn

H H

NC5H11

OH

HO

NH

NH

OH H

N

OH

OO

C5H11

OBn

OMe

O

PhSe

H H

+

(+)-cannabisat ivine

a-c

d e-g

h-i j-l

203

207 208

205

206

+

7 steps85%, > 95% de

204

209 210

211

R* = (+)-trans-2-(a-cumyl)cyclohexyl, (+)-TCC.

Scheme 58. Reagents and conditions: (a) LiHMDS, PhSeCl, 73%. (b) 198, BF3.Et2O, 100%. (c) NaBH4, CeCl3, 65% of 207 and 20% of208. (d) 1,1’-thiocarbonyldiimidazole, DMAP, toluene, then Bu3SnH, AIBN, toluene, 85%. (e) NaOH. (f) (COCl)2. (g) 4-(N-benzylamino)-butanol, 82% (3 steps). (h) KOH, MeOH. (i) iPr2EtN, TsNH-(CH2)3-OTf, 84%. (j) MsCl, Et3N, 95%. (k) K2CO3, CH3CN,reflux, 70%. (l) Na, NH3, 76%.

phenylselenyl substituent, stereoselective Mukaiyama-Michael reaction with O-silyl ketene acetal 198 and Luchereduction gave a mixture of diastereoisomers 207 and 208 in62% overall yield from 2 0 6 . The synthesis of thetetrahydropyridine intermediate 209 was achieved from the

latter mixture in 85% yield following a one-pot two-stepprocedure via the formation of the corresponding thiocarba-mates, which were subsequently treated with Bu3SnH andAIBN. The methyl ester 209 was converted into thecorresponding amide 210 in a three-step sequence:


N

Ts

MeCH3(CH2)10N

Me

(CH2)10CH3

Ts

212 (±)-213

a

Scheme 59. Reagents and conditions : (a) 3 mol% Pd(PPh3) 4, DMSO, 25 min, 50°C, 91%.

NTs

o

CO2EtN

CN

CO2Et

H

214 215

+a

(±)-216 98:2 dr

Scheme 60. Reagents and conditions : (a) 20 mol% PBu3, CH2Cl2, rt, 99%.

saponification and subsequent formation of acid chlorideenabled the addition of the required aminoalcohol underSchotten-Bauman conditions (82% yield over three steps).The oxazolidinone ring of 210 was hydrolyzed under basicconditions and the liberated secondary amine was alkylatedwith the appropriate triflate-amine to give 211 in 74% yieldover 2 steps. Formation of the macrocycle by activation ofthe primary alcohol followed by treatment in basic media(67% yield, two steps) and cleavage of benzyl and tosylgroups using sodium in liquid ammonia achieved the firsttotal synthesis of (+)-cannabisativine (19 steps, 9% overallyield from 204).

A palladium(0) catalyzed rearrangement of 1,3-butadienylazetidines, activated by N-tosyl group, to 2,6-disubstituted-1,2,5,6-tetrahydropyridines has been publishedby Oshima et al. [61]. The 1,3-butadienylazetidine 212

(prepared in a five-step sequence from γ-butyrolactone) wastreated with Pd(PPh3)4 in DMSO at 50°C to furnishtetrahydropyridine 213 in high yield but without anydiastereoselectivity (cis/trans :47/53) (see Scheme 59) .

Very recently a phosphine-catalyzed [4+2] annulationreaction of N-tosylbenzaldimines 214 with 2-benzyl-2,3-butadienoates 215 leading to, in good to excellentdiastereoselectivity, the cis-2,6-disubstituted functionalizedtetrahydropyridines 216 has been published by Kwon et al.[62]. A typical example is described in Scheme 60; this newmethod was exemplified by the preparation of 11 adducts.

Recently, Liebeskind et al. [63] described a particularlyoriginal and concise highly stereo-controlled asymmetricsynthesis of alkaloids based on the chemistry of chiraldihydropyridinyl-molybdenum complexes. Bothenantiomers of molybdenum complex 217 are prepared inexcellent enantiopurity from racemic starting material 218following an eight-step sequence including a lipase-catalyzedtransformation (28% overall yield) (see Scheme 61). Thesequential functionalization of (-)-217 was carried out bymethoxy abstractions and nucleophilic additions: treatmentwith Ph3CPF6 followed by addition of Grignard reagent 219gave the intermediate 220 in high regioselectivity (up to49:1). This sequence was repeated on 220 with HBF4/n-PrMgBr to furnish the (2,3,6-trisubstituted dihydropyri-

dinyl)-molybdenum complex 221 in 67% yield. At thisstage the molybdenum complex 221 offered the possibilityof affording in good to excellent regio and stereoselectivitythe trisubstituted tetrahydropyridines 222, 223 and 224following the 3 different demetalation procedures: (i)reductive demetalation by replacing CO with NO+ followedby nucleophilic attack, (ii) protodemetalation or (iii)photolytic protodemetalation. From the trisubstitutedtetrahydropyridine 224, the completion of the total synthesisof (-)-indolozidine 209B was effected in 2 steps (6% overallyield from 218).

Similar chemistry was successfully applied to chiralmolybdenum complex (-)-225 by the same authors for thetotal synthesis of (-)-dihydropinidine and (-)-andrachcinidine(see Scheme 62) [64].

CONCLUSION

This review has attempted to summarize themethodologies available for the synthesis of 2,6-dialkyl-1,2,5,6-tetrahydropyridines developed by different groupssince 1980’s, as well as their application in total synthesis.2,6-Dialkyl-1,2,5,6-tetrahydropyridine frameworks areimportant synthetic building blocks that allow access tomore complex substituted piperidines and this fact mayprovide a driving force for future development in this field.As widely reported, a particular challenge remaining to besolved is the cis/trans stereocontrol for achieving moreefficient syntheses.

ACKNOWLEDGEMENTS

We thank the ‘Conseil Général de la Loire Atlantique’,the ‘Centre National de la Recherche Scientifique’, the‘Ministère de l’Education Nationale de la Recherche et de laTechnologie’ for a doctoral fellowship for F.-X. F. and the‘Université de Nantes’ for supporting our work in the fieldof total synthesis of alkaloids. We would like to warmlythank Prof. Yannick Landais (Laboratoire de ChimieOrganique et Organométallique, UMR-CNRS 5802, TalenceFrance) for fruitful discussions. We also express our


N

HO

Cbz

Me

N

Cbz

Me

C5H11 OBn

N

Cbz

MeO OMe

TpMo(CO)2

N

Cbz

Me

C5H11 OBn

N

Cbz

Me

C5H11 OBn

N

Cbz

Me

C5H11 OBn

BrMgOBn

N

Cbz

Me

MeO OBn

N

Me

C5H11

a b

(±)-218 217 >99% ee 219

8 steps

221 >99% ee

(-)-Indolizidine 209B

c or d

f

e

222

223

Tp = hydridotris(pyrazolyl)borate

For c 222/223 : 15/1

223/224 : 34/1

g, h

224 >99% ee

220

TpMo(CO)2

TpMo(CO)2

Scheme 61. Reagents and conditions : (a) (i) Ph3CPF6, CH2Cl2, -78 to 0°C, 5 min. (ii) 219, THF, -78°C, 15 min. (b) (i) HBF4 (54 wt%in Et2O), MeOtBu, 0°C to rt, 5 min. (ii) nPrMgBr, THF, -78°C, 15 min, 67%. (c) HCl (37 wt mol%), CH2Cl2, rt, 20 min, 70%. (d) AcOH,CH3CN, hν 350 nm, 24 h, 64%. (e) 30 equiv. HCl (gas), CH3CN, 60°C, 2 h, 56%. (f) NOPF6, DME, -15 to 0°C, 30 min, then NaCNBH3 inTHF, rt, 1 h, 59%. (g) 1 atm H2, Pd/C 10%, EtOH, rt, 24 h, 87%. (h) Ph3P, CBr4, CH2Cl2, rt, 30 min, then Et3N, 0°C, 10 min, 63%.

NMeO OMe

O O

TpMo(CO)2

N Me

HN

H

OHO

(-)-Dihydropinidine

(-)-225

(-)-Andrachcinidine

Scheme 62.

gratitude to Mr. Jullien Drône for useful discussions andtechnical assistance.

REFERENCES[1] Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 23, 3679-3681.[2] For representative papers on the piperidine series, see: (a)

Takahata H.; Kubota, M.; Ikota, N. J. Org. Chem. 1999, 64, 8594-8601. (b) Kumareswaran, R.; Balasubramanian, T.; Hassner, A.Tetrahedron Lett. 2000, 41, 8157-8162. (c) Agami, C.; Couty, F.;Evano, G. Tetrahedron: Asymmetry 2000, 11, 4639-4643. (d)Eskici, M.; Gallagher, T. Synlett 2000, 1360-1362. (e) Cossy, J.;Willis, C.; Bellosta, V.; BouzBouz, S. Synlett. 2000, 1461-1463. (f)Lindström, S.; Ripa, L.; Halberg, A. Org. Lett. 2000, 2, 2291-2293.(g) Cossy, J.; Pévet, I.; Meyer, C. Synlett. 2000, 122-124.

[3] For a review on asymmetric synthesis in the piperidine series, see:(a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Comm.1998, 633-640. (b) Laschat, S.; Dickner, T. Synthesis 2000, 1781-1813.

[4] For selected recent work see: (a) David M.; Dhimane H.;Vanucci-Bacqué C.; Lhommet G. Synlett. 1998, 206-208. (b)Craig D.; McCague R.; A. Potter G.; Williams M. R. V. Synlett.1998, 58-60. (c) David M.; Dhimane H.; Vanucci-Bacqué C.;Lhommet G. J. Org. Chem. 1999, 64, 8402-8405. (d) YamauchiT.; Fujikura H.; Higashiyama K.; Takahashi H.; Ohmiya S. J.Chem. Soc., Perkin Trans. 1 1999, 2791-2794. (e) Wilkinson T. J.;Stehle N. W.; Beak P. Org. Lett. 2000, 2, 155-158. (f) Davis F. A.;Zhang H.; Lee S. H. Org. Lett. 2001, 3, 759-762. (g) Takahata H.;Ouchi H.; Ichinose M.; Nemoto H. Org. Lett. 2002, 4, 3459-3462.(h) Amat M.; Llor, N.; Hidalgo, J.; Esclano, C.; Bosh, J. J. Org.Chem. 2003, 68, 1919-1928.


[5] (a) Jones T. H.; Blum M. S.; Fales, H. M. Tetrahedron 1982, 38,1949-1958. (b) Kumareswaran R.; Hassner A. Tetrahedron:Asymmetry 2001, 12, 2269-2276.

[6] Takadoi M.; Yamaguchi K., Terashima S. Bioorg. Med. Chem.2003, 11, 1169-1186.

[7] For some leading references, see: (a) Angle, S. R.;Breitenbucher, J. G. In Studies in Natural Products Chemistry:Stereoselective Synthesis; Atta-ur Rahman, Ed.; Elsevier: NewYork, 1995 ; Vol. 16 , Part J, pp. 453-502. (b) Wang, C. J.;Wuonola, M. A. Org. Prep. Proced. Int. 1992, 24, 583-621.

[8] Lotter, H. L.; Abraham, D. J.; Tuner, C. E.; Knapp, J. E., Schiff,P. L.; Slatkin, D. J. Tetrahedron Lett. 1975, 7, 2815-2818.

[9] Karrer, Von P.; Eugster, C. Helv. Chim. Acta 1948, 31, 1062-1066.

[10] Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957-5978.[11] For a recent review in this field, see: Chai, Y.; Hong, S.; Lindsay,

H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58,2905-2928.

[12] (a) Angle, S. R.; Breitenbucher, J. G.; Arnaiz, D. O. J. Org.Chem. 1992, 57, 5947-5955. (b) Angle, S. R.; Breitenbucher, J. G.Tetrahedron Lett. 1993, 34, 3985-3988. (c) Angle, S. R.; Henry, R.M. J. Org. Chem. 1997, 62, 8549-8552. (d) Angle, S. R.; Henry,R. M. J. Org. Chem. 1998, 63, 7490-7497.

[13] (a) Waldmann, H. Synthesis 1994, 535-551. (b) Buonora, P.;Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099-6138.

[14] Bailey, T. R.; Garigipati, R. S.; Morton, J. A.; Weinreb, S. M. J.Am. Chem. Soc. 1984, 106, 3240-3245.

[15] Hamada, T.; Zenkoh, T.; Sato, H.; Yonemitsu, O. TetrahedronLett. 1991, 32, 1649-1652.

[16] Hamada, T.; Sato, H.; Hikota, M.; Yonemitsu, O. TetrahedronLett. 1989, 30, 6405-6408.

[17] Bailey, P. D.; Brown, G. R.; Korber, F.; Reed, A., Wilson, R. D.Tetrahedron: Asymmetry 1991, 2, 1263-1282.

[18] Bailey, P. D.; Londesbrough, D. J.; Hancox, T. C.; Heffernan, J.D.; Holmes, A. B. Chem. Comm. 1994, 2543-2544.

[19] Bailey, P. D.; Smith, P. D., Pederson, F.; Clegg, W.; Rosair, G. M.;Teat, S. J. Tetrahedron Lett. 2002, 43, 1067-1070.

[20] Shi, Z.-D.; Yang, B.-H.; Wu, Y.-L.; Pan, Y.-J.; Ji, Y.-Y.; Yeh, M.Bioorg. Med. Chem. Lett. 2002, 12, 2321-2324.

[21] Schürer, S. C.; Blechert, S. Tetrahedron Lett. 1999, 40, 1877-1880.[22] (a) Marshall, J. A. In Comprehensive Organic Synthesis; Trost, B.

M., Fleming, I., Eds. Pergamon: Oxford, 1991; Vol. 3, Chapter3.11, p 975-1014. (b) Nakai, T.; Tomooka, K. Pure and Appl.Chem. 1997, 69, 595-600.

[23] Anderson, J. C.; Roberts, C. A. Tetrahedron Lett. 1998, 39, 159-162.

[24] (a) Åhman, J.; Somfai, P. J. Am. Chem. Soc. 1994, 116, 9781-9782. (b) Åhman, J.; Jarevång, T.; Somfai, P. J. Org. Chem. 1996,61, 8148-8159.

[25] (a) Åhman, J.; Somfai, P. Tetrahedron Lett. 1995, 36, 303-306. (b)Åhman, J.; Somfai, P. Tetrahedron 1995, 51, 9747-9756.

[26] Legters, J.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1989, 30,4881-4884.

[27] (a) Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53, 1957-1965. (b) Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53,5989-5994.

[28] Roush, W. R.; Pinchuk, A. N.; Micalizio, G. C. Tetrahedron Lett.2000, 41, 9413-9417.

[29] (a) Overman, L. E.; Malone, T. C.; Meier, G. P. J. Am. Chem.Soc. 1983, 105, 6993-6994. (b) Blumenkopf, T. A.; Overman, L.E. Chem. Rev. 1986, 86, 857-873.

[30] Daub, G. W.; Heerding, D. A.; Overman, L. E. Tetrahedron 1988,44, 3919-3930.

[31] Castro, P.; Overman, L. E.; Zhang, X.; Mariano, P. S. TetrahedronLett. 1993, 34, 5243-5246. It should be noted that the resultsdescribed in this paper are in contrast to an earlier report (see ref30) mentioning total racemization in the cyclization reaction.

[32] Kværnø, L.; Norrby, P.-O.; Tanner, D. Org. Biomol. Chem. 2003,1, 1041-1048.

[33] Yang, T.-K.; Teng, T.-F.; Lin, J.-H.; Lay, Y.-Y. Tetrahedron Lett.1994, 35, 3581-3582.

[34] Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org. Chem. 2002,67, 2424-2428.

[35] (a) Agami, C.; Comesse, S.; Kadouri-Puchot, C. Tetrahedron Lett.2000, 41, 6059-6062. (b) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org. Chem. 2002, 67, 1496-1500.

[36] Franciotti, M.; Mann, A.; Mordini, A.; Taddei, M. TetrahedronLett. 1993, 34, 1355-1358.

[37] Huang, H.; Spande, T. F.; Panek J. S. J. Am. Chem. Soc. 2003,125, 626-627.

[38] (a) Sparks, M. A.; Panek J. S. J. Org. Chem. 1991, 56, 3431-3438.(b) See also: Mohamed, M.; Brook, M. A. Tetrahedron Lett. 2001,42, 191-193.

[39] Furuta, K.; Ishiguro, M.; Ikera, N.; Yamamoto, H. J. Am. Chem.Soc. 1981, 103, 5568-5570.

[40] Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett.1998, 55-57.

[41] Tjen, K. C. M. F.; Kinderman, S. S.; Schoemaker, H. E.; Hiemstra,H.; Rutjes, F. P. J. T. Chem. Comm. 2000, 699-700.

[42] (a) Compère, D.; Marazano, C.; Das, B. C. J. Org. Chem. 1999,64, 4528-4532. (b) Guilloteau-Bertin, B.; Compère, D.; Gil, L.;Marazano, C.; Das, B. C. Eur. J. Org. Chem. 2000, 1391-1399.

[43] Genisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco, D.; Das,B. C. Synlett. 1992, 431-434.

[44] (a) Dransfield, P. J.; Gore, P. M.; Shipman, M.; Slawin, A. M. Z.Chem Comm. 2002, 150-151. (b) Dransfield, P. J.; Gore, P. M.;Prokes,

>

I.; Shipman, M.; Slawin, A. M. Z. Org. Biomol. Chem.2003, 1, 2723-2733.

[45] For general review of RCM, see: (a) Fürstner, A. Angew. Chem.,Int. Ed. Engl. 2000, 39, 3013-3043. (b) Grubbs, R. H.; Chang, S.Tetrahedron 1998, 54, 4413-4450. (c) Armstrong, S. K. J. Chem.Soc., Perkin Trans. 1 1998, 371-388. (d) Grubbs, R. H.; Miller, S.J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-552. For generalreview of RCM reactions in the alkaloids field, see: (e) Phillips,A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75-89. (f) Felpin,F.-X.; Lebreton J. Eur. J. Org. Chem. 2003, 3693-3712.

[46] (a) Felpin, F.-X.; Girard, S.; Vo-Thanh, G.; Robins, R. J.;Villiéras, J.; Lebreton, J. J. Org. Chem. 2001, 66, 6305-6312. (b)Felpin, F.-X.; Bertrand, M.-J.; Lebreton, J. Tetrahedron 2002, 58,7381-7389. (c) Felpin, F.-X.; Lebreton, J. Tetrahedron Lett. 2002,43, 225-227. (d) Felpin, F.-X.; Lebreton, J. J. Org. Chem. 2002,67, 9192-9199.

[47] Felpin, F.-X.; Lebreton J. Tetrahedron Lett. 2003, 44, 527-530.[48] Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem, in press.[49] Agami, C.; Couty, F.; Rabasso, N. Tetrahedron 2001, 57, 5393-

5401.[50] (a) Bushmann, N.; Rückert, A.; Blechert, S. J. Org. Chem. 2002,

67, 4325-4329. (b) Blechert, S.; Stapper, C. Eur. J. Org. Chem.2002, 2855-2858. (c) Blechert, S.; Stapper, C. J. Org. Chem.2002, 67, 6456-6460.

[51] Voigtmann, U.; Blechert, S. Synthesis 2000, 893-898.[52] Wassermann, H. H.; Leadbetter, M. R.; Kopka, I. E. Tetrahedron

Lett. 1984, 25, 2391-2394.[53] (a) Mayer, C.; Green, C. L.; Treub, W.; Wälchli, P. C.; Eugster,

C. H. Helv. Chem. Acta 1978, 61, 905-921. (b) Wälchli, P.;Eugster, C. H. Helv. Chem. Acta 1978, 61, 885-898.

[54] Wassermann, H. H.; Pierce, B. C. Tetrahedron 1988, 44, 3365-3372

[55] Xin, T.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1998, 39, 6927-6930.

[56] Kasatkin, A.; Nakagawa, T.; Okamoto, S.; Sato, F. J. Am. Chem.Soc. 1995, 117, 3881-3882.

[57] Stanway, S. J.; Thomas, E. J. Chem. Comm. 1994, 285-286[58] (a) Bubnov, Y. N.; Klimkina, E. V.; Ignatenko, A. V.; Gridnev, I.

D. Tetrahedron Lett. 1996, 37, 1317-1320. (b) Bubnov, Y. N.;Klimkina, E. V.; Ignatenko, A. V.; Gridnev, I. D. TetrahedronLett. 1997, 38, 4631-4634.

[59] Kuethe, J. T.; Comins, D. L. Org. Lett. 1999, 1, 1031-1033.[60] Kuethe, J. T.; Comins, D. L. Org. Lett. 2000, 2, 855-857.[61] Fugami, K.; Miura, K.; Morizawa, Y.; Oshima, K.; Utimoto, K.;

Nozaki, H. Tetrahedron 1989, 45, 3089-3098.[62] Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716-

4717.[63] Shu, C.; Alcudia, A.; Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc.

2001, 123, 12477-12487.[64] Shu, C.; Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 2878-

2879.

synthesis of 2,6-dialkyl-1,2,5,6-tetrahydropyridines and their applications in total synthesis

Documents