Negishi E. 2002 Handbook of organopalladium chemistry for organic synthesis / 0863 942

	[184]			[177]
	66			89
	3
	PPh
				4
	2			)
				3
	Pd(dba)						Pd(PPh
OMe	Cl				Cl
MeO
			O								O
				2
					AlMe
	TMS
O			OH
	Sn
	3
	Bu
	(E)-neomanoalide					menaquinone-3
	25			26

	[185]
	100
			LiCl
	2
			Pd(dba)
	OAc
			H
				H
				BnO
OMOM				OMOM
	Sn
	3
	Me
		−)-stypoldione
	(
	27

	[42]					[186]
	−50					68
	45
	PPh					3
							AsPh
	3
	3					3
	CHCl						CHCl
	.					.
	3					3
	(dba)						(dba)
	2					2
	Pd						Pd
							O
	O	O							MeO
					O		N
	O
		Br		3
				SnBu	OMOM				Br
OMOM						ZnCl
OTBS	O
TBSO	B2
	vineomycinone	methylester					hennoxazole		(cf.below)
	27					29

Me

2

OH CO

B2

Me

O OH vineomycinone methylester

OH O

OH

O

HO

Me

O

O

H

H

stypoldione-

O

−)

(

HO

menaquinone-3

O

O

OH

O

OH

O

2

CH

neomanoalide

(E)-

(Continued )

913

TABLE 7. (Continued )

Catalyst Additive Yield (%) Reference

R′X

RM

Name

n C

	[187]			[188],[189]
	47			98
	3
	AsPh			LiCl
	3
	CHCl
.				3
	3
	(dba)			(dba)
	2			2
	Pd			Pd
				COOMe
		O
O		N	MeO
			Br
	3		OSEM	AcO
		SnBu		SnMe		OTHP
				3
	hennoxazole			lurlene	(lurlenicacid)
	29			31

COOH

			OH	lurlene (lurlenicacid)
O
O
O		H
HO

	N	O	hennoxazole
	O	N
OH	OMe
	O

914

III.2.18 SYNTHESIS OF NATURAL PRODUCTS VIA CROSS-COUPLING

915

G. SYNTHESIS OF NATURAL PRODUCTS VIA Pd-CATALYZED ALKYLATION, HOMOALLYLATION, HOMOPROPARGYLATION, AND HOMOBENZYLATION

Until recently, cross-coupling between alkylmetals and aryl, alkenyl, and alkynyl halides was achieved mostly with alkylcoppers. Over the past two decades, however, the Nior Pd-catalyzed reaction of alkylmetals with the unsaturated organic halides mentioned above has been developed as a viable alternative, as detailed in Sect. III.2.11. The Cubased methodology still remains highly competitive. So, it is advisable to consider both options for finding the method for a given case.

Unlike the cases discussed earlier in this section, the current range of metal countercations in Pd-catalyzed alkylation is practically limited to Zn and B, although Mg has been satisfactory in some cases. The scope of Pd-catalyzed alkylation with alkylmetals containing other metals, such as Al, Si, Sn, and Zr, is severely limited at present. Of the two widely used metals, that is, Zn and B, Zn is significantly more reactive than B, and less elaborate and less vigorous reaction conditions are required. However, in those cases where alkylboranes are readily available via hydroboration, this and the higher level of chemoselectivity make B an attractive and competitive alternative. Here again, the general lack of comparative data does not permit a critical comparison of the two metals. As a crude guideline, it is not unreasonable to consider Zn in cases where alkylmetals containing Li, Mg, or Zn are some of the most readily available alkylmetals. In cases where alkenes are to be covnerted to alkylmetals, however, B may be considered first.

The currently available results of the synthesis of natural products via Pdcatalyzed alkylation are shown in Table 8, which is indeed dominated by the reactions of alkylzincs and alkylboranes. It is noteworthy that homoallyl-, homopropargyl-, and homobenzylzincs are readily generated by (i) indirect zincation, (ii) oxidative magnesiation followed by metathetical zincation, and, most cleanly, (iii) lithiation of primary alkyl iodides followed by zincation, and that the resultant alkylzincs very cleanly and selectively undergo Pdor Ni-catalyzed cross-coupling with unsaturated organic electrophiles. The synthesis of 1,5-dienes via Pd-catalyzed reaction of homoallyland homopropargylzincs detailed in Sect. III.2.11.2 is particularly noteworthy.

The currently available examples of the synthesis of natural products via Pd-catalyzed alkylation are summarized in Table 8.

H. SYNTHESIS OF NATURAL PRODUCTS VIA Pd-CATALYZED CROSS-COUPLING INVOLVING -HETERO-SUBSTITUTED

ORGANIC ELECTROPHILES

Of various types of Pd-catalyzed cross-coupling reactions involving -hetero- substituted organic electrophiles discussed in Sect. III.2.12, the Pd-catalyzed carbonylative and noncarbonylative acylation as well as selective alkenylation with 1,1-dihaloalkenes have attracted the special attention of synthetic chemists. Along with several other organometallic reactions with acyl halides and related electrophiles involving Cu, Mg, Al, and Mn, Pd-catalyzed acylation with organometals containing Zn and Sn has emerged as a competitive and complementary alternative. It should be noted that the high reactivity of organozincs does not readily permit the desired

TABLE 8. Alkylation, Homoallylation, Homopropargylation, and Homobenzylation (cf. III.2.11)

Catalyst Additive Yield (%) Reference

R′X

RM

Name

n C

[190]		[191]			[192]
58		75			55
K						DIBAH
4
PO
3
					2
Pd(dppf)		3			)
						Pd(PPh
		4			3
		)
Cl			Pd(PPh			Cl
2					2
						O
	O
Br			Cl		Br
						ZnBr
B			ZnCl
OTHP
(E)-1-ethyl-5- methyl- 4-heptenylacetate (quadrilure)		β-bisabolene				dendrolasin
12		15			15

[193]			[194]			[194]			[194]
90			84			78			86
							TFP
3			Pd(dppf)			(dba)			3
4						3			4
)									)
Pd(PPh			Cl			Pd			Pd(PPh
			2			2
					I			I			OH
											I
I			I
						TMS			ZnBr
		ZnBr			ZnBr
						BrZn
			TMS
TMS
(2E,6E)-farnesol			(2E,6Z)-farnesol			(2Z,6Z)-farnesol			(2Z,6E)-farnesol
15			15			15			15

OH

(2E,6E)-farnesol

O

dendrolasin

-bisabolene

OAc	quadrilure

916

[195]

[196]

[197]

[198]

NA

60

70−80

70

3

3

CO

AsPh

Cs

2

3

3

Pd(dppf)

3

4

4

4

)

)

)

Pd(PPh

Pd(PPh

Cl

Pd(PPh

2

I

3

OBn

O

OTBS

OCH

CO

I

I

3

I

H

ZnI

ZnCl

OTBDMS

2

ZnCl

B

B

6

)

Me

N

Me

C(CH

H

2

O

Cl

MeO

O

A

yellowseale

pheromone

-(+)pumiliotoxin

PGE

(cf.[197])

-(+)casbene

1

17

19

20

20

77 [199],[200]		COOH HO						(+−)-dihydroxy- serrulaticacid
				HO
3
CO
2
K
Pd(dppf)								casbene-
Cl
2
3								(+)
OCH		O
Br			OH					A
		Me					Me	pumiliotoxin-
							OH
				N			H	(+)
		OAc

S

S
		OAc
(+−)-dihydroxy- serrulaticacid		yellowseale pheromone
20

(Continued )

917

TABLE 8. (Continued )

	Reference	[194],[204]
	Yield(%)	81
	Additive		DIBAH
	Catalyst	Pd(dppf)
		Cl
		2
					I
	R′X
		I
		TMS
	RM
		TIPS
		BrZn
	Name	(2E,6Z,10E)- geranylgeraniol
	C	20
	n

[194],[204]

DIBAH 67

Pd(dppf)

2

Cl

I

ZnBr

TMS

84 [201]

	4
	)
	3
	Pd(PPh
	OTBDPS
SEMO		I
ZnCl	OTHP
	(+)-amphidinolideJ
	24

[202]	[202]				[203]
68	66				64
					3
					CO		3
					Cs		AsPh
					2
Pd(dppf)	Pd(dppf)				Pd(dppf)
2	2				2
Cl	Cl				Cl
I	OBn					N
			S
							O		O
	Br		I
ZnCl	ZnI		B				OCH		OCH
							3
									3
									O
BnO					TBSO
(+)−-agelineA	(+)−-agelineA				epothiloneA
26	26				26

			O OH				O OH	A
			O					epothilone
					O
S		N
			Cl		Me		N N
					NN
			−
							N	agelineA
							2
							H
								(+)−-

Me HO	OH			O Me O Me		(+)-amphidinolideJ
					(2E,6Z,10E)-	geranylgeraniol
			HO

918

62 [192]

2 ) 3 Pd(PPh 2 Cl

3 O O

ZnBr

Br

30 mokupalide

			[205]
			83
			LiCl
			2
			)
			3
			Pd(PPh
			2
			Cl
OCH	OTf		CH				H
3			3
	MOMO	OH	N		N		O	OTBDPS
		H					CN
		H					H
							O
			C
			3
			H
			Sn
			4
			Me

ecteinascidin	(cf.[205])
39

[206]	[105]−[109]
91	94

4 ) 3 Pd(PPh

OTBS		O OMOP
O	H
Ph	O	TfO

MgCl 2 TMSCH

47 taxol[206])(cf.

4
)
3
Pd(PPh
OTBS			OBn
H			H
O			H
			BnO
TfO
ZnI
	MeOOC
brevetoxinA		(cf.[105])
49

O

O

mokupalide

919

920	III Pd-CATALYZED CROSS-COUPLING

oxidative addition–CO insertion–reductive elimination cascade, since they tend to cross-couple without incorporation of CO.

The trans-selective cross-coupling of 1,1-dihaloalkenes exhibiting 98% stereoselectivity has found various interesting and attractive applications in natural products synthesis, as represented by those of lissoclinolide,[46] ( )-chlorothricolide,[78] and kijanolide.[88] These and other examples are summarized in Table 9.

I. SYNTHESIS OF NATURAL PRODUCTS VIA Pd-CATALYZED CROSS-COUPLING OF -HETERO-SUBSTITUTED ORGANOMETALS

Pd-catalyzed cross-coupling of -hetero-substituted organometals with various types of electrophiles is discussed in detail in Sect. III.2.13. Several representative examples of natural product syntheses are shown in Table 10.

J. SYNTHESIS OF NATURAL PRODUCTS VIA Pd-CATALYZED CROSS-COUPLING INVOLVING -HETERO-SUBSTITUTED COMPOUNDS

Pd-catalyzed cross-coupling of -hetero-substituted organometals and/or electrophiles is wide-ranging, as discussed in Sect. III.2.14.2. However, the following four topics are particularly noteworthy from the viewpoint of their applications to natural product syntheses:

1.Use of 1,2-dihaloethylenes as (E)- or (Z)-ethylene and ethyne synthons.

2.-Substitution of carbonyl compounds by use of -haloenones and related derivatives.

3.Use of aryl electrophiles hetero-substituted in a position that is to the leaving group for the synthesis of heterocycles including pyrroles, indoles, furans, thiofurans, lactones, and lactams.

4.Use of -hetero-substituted allylic electrophiles for the synthesis of ketones and other functional derivatives.

Most of the six possible 1,2-dihaloethylenes, especially the (E)-isomers, containing I, Br, and/or Cl have been used in the synthesis of natural products via Pd-catalyzed cross-coupling. Some details of the synthesis of lipoxin B (Scheme 6) and xerulin (Scheme 11) are presented in Sect. III.2.14.2. The scheme numbers above correspond to those in Sect. III.2.14.2.

-Substitution of -haloenones catalyzed by Pd complexes has also been widely applied to natural product syntheses. Some details of the syntheses of ( )-methyl shikimate (Scheme 23), ( )-tricholomenyn A (Scheme 24), prostaglandins (Scheme 28), savinin (Scheme 43), gadain (Scheme 43), and strobilurin A (Scheme 49) are presented in Sect. III.2.14.2. The scheme numbers indicated in parentheses are those in Sect. III.2.14.2. Some related examples including the syntheses of nakienones A and B (Scheme 33) and carbacyclin (Scheme 34) are also discussed in some detail.

Some representative examples of natural product syntheses are shown in Table 11.

III.2.12)Sect.

OrganicSubstituted (cf.Electrophiles

-Hetero-

-Cross InvolvingCoupling

9.TABLE

Additive Yield (%) Reference

Catalyst

R′X

RM

Name

n C

62 [207]

	2
	)
	3
	trans-Bn(Cl)Pd(PPh
	Me
	2
	CO
			O
	Cl
	3
	SnBu		O
			O
	MeO
	(+)−-carolinicacid
	9

	[208]
	56
	CO
	2
	)
	3
	trans-Bn(Cl)Pd(PPh
	Me
	2
	CO
			O
	Cl
	3
	SnBu		O
			O
	MeO
	dimethyl(+)−- carolinate
	11

[46]

DIBAH 91

2 ) 3 Pd(PPh 2 Cl

OTBS

Br

Br

Cl

2

ZrCp

TBSO

Table(cf. lissoclinolide3)

11

[209]	[191]
45	75

4			4
)			)
3			3
Pd(PPh			Pd(PPh
NHTROC
ClOC		O			Cl
3
SnBu			ZnCl
		O
Bu
(+)-monomorineI			-bisabolene (cf.Table8)
13			15

LiCl

CO 86 [210]

4 ) 3 Pd(PPh

H

TfO

3 SnBu

TMS

capnellene- 9(12)

15 -(+)−

Me H

HH

H

N

Me

COOMe	OMe				O
	O			O

COOH	OH				O
	O			O

(Continued )

capnellene- 9(12)

-(+)−

-(+) Imonomorine

dimethylcarolinate -(+)−

(+)− -carolinic acid

921

TABLE 9. (Continued )

Catalyst Additive Yield (%) Reference

R′X

RM

Name

n C

80 [170]

	2
	)
	3
	Pd(PPh
	2
	Cl
OTBDPS			COCl
O			CO
	3
			H
	3
	SnBu
	TMS
	PsiAβ (cf.Table6)
	18

[211]

[212]

[213]

[213]

85

76

53

24

NEt

3

CO LiCl

LiCl

2

i-Pr

PPh

CO

CO

3

CN)

CN)

CHCl

2

2

(dba)

.

3

3

(dba)

Pd(CH

Pd(CH

3

3

2

2

2

2

Pd

Pd

Cl

Cl

OBnOTIPS

Me Me

O

Cl

3

Cl

Me

OTBS

TfO

TfO

SnMe

SnMe

O

O

Bu

O

O

Bu

3

Sn

Sn

3

3

O

O

Ph

Me

O

Me

O

X

TBSO

q

(+)−-epi-jatrophone (cf.below)

oleandolide

(cf.below)

(+)-(2′S,3R)-

zoapatanol

(cf.below)

(+)−-jatrophone (cf.below)

20

20

20

922