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Advanced

Organic

Synthesis

به نام خدا

Dr M. Mehrdad University of Guilan, Department of Chemistry,

Rasht, Iran

10

2

2.

3

J. A. C. S. 1981, 103(25), ……

4

Cala Ratjada (Mallorca) isolated from soil bacteria

Ratjadone potent cancerostaticum and fungicide

trans,trans-diene

cis,trans-diene

Perhydro pyran

Perhydro pyran with double band

disconnected by a retro-Heck coupling

Wittig reactions Bhatt, U. et al., J. Org. Chem. 2001, 66, 1885-1893

6

hetero-Diels-Alder reaction of an acrolein derivative

retro-opened to a -hydroxy epoxide

antitumor activity

Boger, D. L. et al., J. Am. Chem. Soc. 2001, 123, 4161-4167

Fostriecin

Frondosin B

contains four condensed rings:

phenol

furane cycloheptene

cyclohexene

from a Diels-Alder reaction

from an intramolecular Friedel-Crafts acylation

Inoue, M. et al., J. Am. Chem. Soc. 2001, 123, 1878-1889

isolated from a sponge is anti-inflammatory

9

The rest is Sharpless and phenol chemistry

Furane from a base- and palladium-catalyzed intermolecular addition of a phenolate to an alkyne.

Sonogashira Coupling

Alkyne from a

10 Cohen, F. et al., J. Am. Chem. Soc. 2001, 123, 10782-10783

An alkaloid was isolated from a Jamaican sponge useful to treat autoimmune responses, and inhibits protein-protein interactions two tricyclic

guanidine derivatives

branched octanoic acid chain

was disconnected to give a guanidine hemi-aminal and a chiral alcohol in the side-chain, which could be substituted stereoselectively

attached via a -ketoester carbanion

from a 1,3-diamine and Cbz-protected carbonimidothioate

Batzelladine F

11

A triazacyclophane Tripodal Receptor Molecules (as hinge)

selectively sulfonated and trifluoroacetylated

Acetylation with alkyl chloroformate

i) triflate +methanol ii) Fmoc-N-hydroxy- succinimide

Deprotection O-NBS (thiolysis) Aloc(Pd-catalyzed alkyl transfer to anilinium p-toluenesulfinate)

Opatz, T. et al. J. Comb. Chem. 2002, 4, 275-284

12

3. Tandem Reactions

Tandem reactions form several covalent bonds in one sequence without isolating the intermediates. Also called “domino” or “cascade” reactions "Multistep reaction'' or "one-pot sequence“ (descriptions of the procedure)

The ACS search program produces: 507 “tandem”, 115 “cascade”and 34 “domino”titles

published since 1996-2002

1250 “tandem”, 576 “cascade”and 297 “domino”titles

published since 2008-14

13

Some sterically hindered, SnCl4-catalyzed hetero-Diels-Alder cyclizations of -unsaturated ketoesters with alkene alcohols do not occur intramolecularly.

Large substituents on the ketoester prevent the formation of medium-sized rings and the first reaction is a linear dimerization combined with the formation of one dihydropyran unit. The second reaction then gives a second dihydropyran and produces a macrocyclic oligo-ether with good yield.

14

Acetylacetate reacts with zinc methylene iodide (Furukawa reagent)

zinc enolate add its methylene group to the enolate's double bond

Aldehydes then decompose the cyclopropane formed and undergo a Reformatsky addition.

Chain extension-aldol addition tandem

15

Acetals were then reactive enough to decompose the enolate and form a second CC bond stereoselectively the presence of chiral phosphines

three-step reaction a cyclohexanone derivative underwent zinc enolate formation and Michael addition in one step

16

Dieckmann cyclization with a neighboring benzyl ester

The synthesis of a highly functional arene derivative

coupling of a cyanide Michael addition to propargylic acid

17

4. Green Chemistry

There are U.S. and European Green Chemistry Programs, which try to establish environmentally benign synthetic procedures. Energy requirements, waste, and the number of separation steps are all minimized by increased selectivity of the reactions catalyzed. Heck-, Sharpless- and Noyori-type reactions are successful endeavors. Another approach is to replace solvents by water or by supercritical fluids, in particular CO2. CO2 can replace chlorinated solvents. Replacement of soluble Lewis acids by mesoporous solids containing bound sulfonates or aluminum chloride should also become common practice. The solids can be filtered off and usually reactivated and recycled. This helps to prevent waste.

18

most typical for green chemistry, educts should preferably come from renewable sources, in particular glucose

Furthermore syntheses should be atom-efficient, and reagents as simple as possible. Catalysed reactions are preferable.

19

Household and large-scale industrial chemicals, e.g. chelators, should always be biodegradable, as should the intermediates in their synthesis. Boger's iminodiacetic acids are good examples, because they only use succinic acid derivatives

20

The Sonogashira Coupling

16. L. Cassar, J. Organomet. Chem. 1975, 93, 253 – 259.

17. H. A. Dieck, F. R. Heck, J. Organomet. Chem. 1975, 93, 259 – 263.

18. K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4467 – 4470.

19. For a brief historical overview of the development of the Sonogashira reaction, see: K. Sonogashira, J. Organomet. Chem. 2002, 653, 46 – 49.

20. R. D. Stephens, C. E. Castro, J. Org. Chem. 1963, 28, 3313 – 3315.

21. a) M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993, 34, 6403 – 6406; b) J.-P. Genet, E. Blart, M. Savignac, Synlett 1992, 715 – 717; c) C. Xu, E. Negishi, Tetrahedron Lett. 1999, 40, 431 – 434;

• The coupling of terminal alkynes with vinyl or aryl halides via palladium catalysis was first reported independently and simultaneously by the groups of Cassar[16] and Heck[17] in 1975.

• A few months later, Sonogashira and co-workers demonstrated that, in many cases, this cross-coupling reaction could be accelerated by the addition of cocatalytic CuI salts to the reaction mixture.[18,19]

• This protocol, which has become known as the Sonogashira reaction, can be viewed as both an alkyne version of the Heck reaction and an application of palladium catalysis to the venerable Stephens–Castro reaction (the coupling of vinyl or aryl halides with stoichiometric amounts of copper(I) acetylides).[20]

• Interestingly, the utility of the “copperfree” Sonogashira protocol (i.e. the original Cassar–Heck version of this reaction) has subsequently been “rediscovered” independently by a number of other researchers in recent years.[21]

R2 Xcat. [Pd0Ln]

base

R1 = alkyl, aryl, vinyl

R2 = alkyl, benzyl, vinyl

X = Br, Cl, I, OTf

R2R1 H R2

Mechanism of the Sonogashira Coupling

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

Ph3P

- PPh3

- PPh3

Pd0

Pd0

Pd0

Br

PdPh3P

Br PPh3

PdII

PdPh3P

PPh3

R1

R1

Cu

CuBr

H

R1

NEt3

PdPh3P

Ph3P

R1

R1

R1

NEt3H

PdII

PdII

K. C. Nicolaou, S. E. Webber, J. Am. Chem. Soc. 1984, 106, 5734 – 5736

The Sonogashira Coupling: Eicosanoid 212

MeBr

OTBS

TMS

SonogashiraCoupling

[Pd(PPh3)4] (4 mol%)

CuI (16 mol%)nPrNH2, C6H6, 25 °C

R

Me

OTBS

AgNO3,KCN

208: R = TMS

209: R = H

210, [Pd(PPh3)4] (4 mol%)

CuI (16 mol%)nPrNH2, C6H6, 25 °C

76% Overall from 208

BrCO2Me

OTBS

Me

OTBS

CO2Me

OTBS

Me

OH

CO2H

OH

SonogashiraCoupling

206

207

210

211212

P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126, 15346 –15347.

The Sonogashira Coupling: Disorazole C1

Me

PMBO

Me

OH

Me

Me

PMBO

Me

OH

Me

MeO O

N

CO2Me

SonogashiraCoupling

218[Pd(PPh3)2Cl2] (4 mol%)

CuI (30 mol%), Et3NMeCN, -20 °C, 94%

220, DCC, DMAP80%

Me

PMBO

Me

O

Me

MeO O

N

CO2Me

O

N

O

I

OMe

218[Pd(PPh3)2Cl2] (5 mol%)

CuI (20 mol%), Et3NMeCN, -20 °C, 94%

SonogashiraCoupling

Me

PMBO

Me

O

Me

MeO O

N

CO2Me

O

N

O OMe

OH

Me Me

OPMB

Me

Me

OH

Me

O

Me

MeO O

N

O

N

O OMe

O

Me Me

OH

Me

O

disorazole

N

O

RO

O

I

OMe

218: R = Me220: R = H

217 219

221

222223: Disorazole C1

The Sonogashira Coupling: Dynemicin

MeO2CN

OMe

Me

O

O

Br

MeO2CN

OMe

Me

O

OIntramolecularSonogashira

Coupling

[Pd(PPh3)4] (2 mol%)CuI (20 mol%)toluene, 25 °C

243 244

MeO2CN

OMe

Me

O

O

244

HH

H

H

MeO2CN

OMe

Me

OH

246

[Pd(PPh3)4] (2 mol %)CuI (20 mol %)toluene, 25 °C

BrCO2Me

1)

2) LiOH, THF/H2O65% overall

SonogashiraCoupling

MeO2CN

OMe

Me

OH

CO2H

Diels-Alder

2,4,6-Cl3C2H2COClDMAP, toluene, 25 °C

50%

248

247

YamaguchiMacrolactonisation/

Diels-Alder

HN

OMe

Me

H

OO

O

OMe

OMe

OMe

CO2Me

dynemicin

249: tri-O- methyl dynemicin Amethyl ester

a) J. Taunton, J. L. Wood, S. L. Schreiber, J. Am. Chem. Soc. 1993, 115, 10 378 – 10379

b) J. L. Wood, J. A. Porco, Jr., J. Taunton, A. Y. Lee, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc.

1992, 114, 5898 – 5900

c) H. Chikashita, J. A. Porco, Jr., T. J. Stout, J. Clardy, S. L. Schreiber, J. Org. Chem. 1991, 56, 1692 – 1694

d) J. A. Porco, Jr., F. J. Schoenen, T. J. Stout, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc. 1990, 112, 7410 – 7411.