Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 0705 780

	14. Some synthetic uses of double-bonded functional groups				735
X		B(OH)2 TfO	Pd(PPh3 )4	X	NR
		+	DME		(103)
			LiCl	N
	N	N	Na2 CO3
	Ts	R		Ts

In a similar fashion, vinyl halides have been used in C C bond formation, giving good to excellent yields in the synthesis of prostaglandins, as exemplified in equation 104406. Other similar syntheses have been performed with great success407 411. A similar coupling reaction may also be performed by using vinylzinc and vinyltin reagents412 414.

O				O
I				(CH2 )6 CO2 Me
+	B(CH2 )6 CO2 Me	PdCl2	(dppf)
				(104)
TBDMSO			TBDMSO

C. Reactions with Organometallic Reagents

The formation of new C C bonds by reaction of double-bonded functional groupcontaining compounds with organometallic reagents is a useful method in organic synthesis. Alkylation at an anionic center adjacent to a CO group is a very useful means by which more complex organic compounds may be synthesized. However, this reaction is not covered in the present work and the reader is referred to the excellent Annual Reports in Organic Synthesis series for recent advances in this area.

1. With alkenes

In a useful intermolecular carbozincation process, a vinylzinc reagent reacts with allyl halides to give good to excellent yields of the unconjugated 1,4-diene (equation 105)415. The reaction is highly regioselective and occurs at room temperature in 10 20 minutes.

ZnEt

+ X	R	DMF	(105)
		R

Carbozincation of alkenes is a very facile method for the formation of new C C bonds. A smooth intramolecular reaction occurs when functionalized 5-hexenyl iodides are treated with diethylzinc in ether, followed by acid work-up (equation 106)416.

			Me
X			(106)
I	1. Et2 Zn	X
	2. H3 O+

736	Jeff Hoyle

1,5- and 1,6-Dienes may be cyclized in high yields by reaction with dialkylaluminum compounds. The reaction is catalyzed Ti(OiPr)4 and proceeds via carboalumination and surprisingly occurs in a trans-selective manner for 5-membered rings and in a cis-selective manner for 6-membered rings (equations 107 and 108)417. Trienes are also cyclized to give bicyclic products, however the mixtures formed are not synthetically very useful.

R

R2 A lCl

(107)

Ti(OPr-i)4

OH

R

(108)

R2 A lCl

Ti(OPr-i)4

OH

Conjugate addition of organocopper reagents (generated in situ) to cycloalkeneones, using a bound, chiral amidophosphine ligand, allows for the high-yield preparation of 3- substituted cycloalkanones in 68 95% ee (equation 109)418,419. This type of asymmetric reaction may also be performed using CO compounds with chiral auxiliaries420,421, or metal thiolates and amides as chiral components of the organometallic reagent422 426. This whole area of synthesis has been recently reviewed427,428.

O		O
	RLi	(109)
		(CH2 )n
(CH2 )	CuCN/LiBr
n	ligand

R

Alkene cyclozirconation is a really useful means by which 1,2-trans difunctionalized cyclopentane rings can be produced. The initially formed cyclometallic species is decomposed in the presence of oxygen and aqueous acid to give the desired product (equation 110)429 433.

Cp2 ZrCl2

Cp

Zr

BuLi/THF

Cp

HO

O2

H3 O+

(110)

OH

14. Some synthetic uses of double-bonded functional groups

737

Finally, C C bond formation occurs through regioand stereospecific reaction between allyl alcohols and ethyl magnesium chloride, in the presence of complex zirconium catalysts, followed by treatment with oxygen (equation 111)434. In this reaction the alkene functionality is lost.

		Me
	1. EtMgCl	(111)
R	R
	2. O2
OH	OH	OH

2. With carbonyl compounds

The catalytic asymmetric synthesis of -hydroxy ketones and aromatic hydroxy ketones by alkylation of keto aldehydes with dialkylzincs is a very useful method of obtain these target molecules (equation 112)435,436. The reaction requires a chiral amine437, such as N,N-dibutylnorephedrine, as catalyst. Chiral diols438 440 and other bidentate441 443 and tridentate444 ligands have also been successfully used as the catalyst. Reaction yields are very good and ee is typically 85%. This is a much more versatile route to -hydroxy ketones than the asymmetric aldol reaction. If the zinc reagent contains an alkene moiety, then asymmetric alkenylation may be easily accomplished445. Other functional groups, such as esters, halides, silanes, stannanes and protected amines and alcohols, may also be present in the dialkyl zinc reagent446 449. These organozinc compounds are readily available via hydroboration of the corresponding alkene followed by transmetallation.

R	H		R	Et
	+ Et2 Zn	chiral		(112)
		cat.
	O			OH

Unsaturated aldehydes undergo catalytic enantioselective addition to give secondary allylic alcohols in good to excellent yields and up to 98% ee. (equation 113)450 456.

R	H	R	Me
	Me2 Zn		(113)
	O		OH

Prochiral CO compounds react with Grignard reagents, in the presence of a chiral diamine, such as (5aS,10aS-octahydro-1H,5H-dipyrrolo[1,2-a:10,20 -d]pyrazine (DPP), to give good to excellent yields of chiral tertiary alcohols in 35 97% ee (equation 114)457. Under chelation conditions, using CuBr, chiral Grignard reagents undergo addition with aldehydes containing a chiral auxiliary, to give good yields of alcohols with excellent diastereoselectivity (equation 115)458 463. This reaction has been used as the key step in the synthesis of the bis-THF moiety in (C)-rolliniastatin464. Use of organozinc reagents, in place of the Grignard, is also stereocontrolled but a different optically active product is realized (equation 116)465.

	O			OH
		R3 MgX
				(114)
R1	R2	DPP	R1	R3
			R2

738				Jeff Hoyle
	H		BrMg
									OH
		+			CuBr
RO			O	O		RO		O	(115)
H	O					H			H
						H
	H		Zn
									OH
RO		+
			O	O		RO	O		(116)
H	O					H			H
						H

Allylbarium reagents (generated in situ from allyl halides and barium salts) have been used to perform stereoselective allylation at a CO group. The reaction occurs in THF at78 °C and the resultant homoallylic alcohols are produced in very good yields with a high degree of regioand stereoselectivity (equation 117)466. A similar product is formed if a CO compound is stirred at room temperature in THF or DMF, with an allylic halide and germanium iodide467 or chromium(II) chloride468.

	1. Ba
Cl
	2. R2 CO

HO

R (117)

R

Aldehydes may also undergo asymmetrical allylation by reaction at room temperature with allylic trichlorosilanes in the presence of chiral phosphoramides. Yields are very good and there is some modest ee (equation 118)469. The yields in this reaction are significantly improved by using DMF at 0 °C, with no added catalyst470. Allylstannanes, in the presence of tin(IV) chloride and other catalysts, may also be used to allylate aldehydes asymmetrically471 474. The reaction has also been carried out with a pentadienyltin reagent and zinc chloride as catalyst. In this case an unconjugated 1,4-diene is selectively produced in almost quantitative yields (equation 119)475. Allylation with stannanes is tolerant of the presence of an epoxy group476.

		OH
Cl3 Si	+ RCHO cat.	(118)
		R
		OH
		R1
O		R2
	+	(119)
R1		SnMe3
	R2

The direct coupling of allenic boranes with aldehydes and ketones affords reasonably good yields of homopropargylic alcohols477 480 (equation 120), which are extremely valuable intermediates in organic synthesis. Enynes and enediynes have been made in this

14. Some synthetic uses of double-bonded functional groups

739

fashion in combination with dehydration processes481.

	O		1. Et2 O		HO
	+	B CH C CH2				(120)
			2. H2 O2	/NaOH
R1	R2
					R1	2
					R

3. With imines

Imines undergo asymmetric addition with organolithium reagents in the presence of catalysts with chiral ligands482 485. In general, these methods are restricted to nonenolizable imines and they require large amounts of expensive catalysts. Recently, a reaction sequence has been developed using bis-oxazoline ligands, which allow the reaction to occur for a wider range of imines (equation 121)486. The reaction occurs in very good to excellent yields and in up to 91% ee.

	Ar		H	Ar
				N
N
		R2 Li
				(121)
1	H		R1	R2
R				H
Imines with an adjacent	chiral auxiliary undergo			diastereoselective addition of

organometallic reagents in a similar fashion, as discussed above (equation 122)487. The products are readily converted into enantiomeric ˇ-amino alcohols, which are useful in further synthetic sequences or the target moiety in some natural products. Other such syntheses have been performed via additions to both imines488 490 and the related hydrazone moiety491 493.

X	H		X	H		HOCH2	H
		R2 M
N	1		R2	NR1		R2	NH2
	R

(122)

H

X =

S

O

D.1,2-Additions to Carbonyl Compounds

Intermolecular aldol-type 1,2-addition reactions are an important means by which stereocontrolled chain elaboration can be performed. Such reactions are widely used in synthesis of complex molecules and some leading examples are herein provided.

Considerable efforts have been directed towards the development of a system to maximize enantiomerically pure diastereomers from aldol reactions. The most effective systems

740	Jeff Hoyle

found to date involve the use of ˛-substituted boryl enolates494,495. Also, the use of chiral, boron-containing Lewis acid catalysts has also shown significant promise496 499. Similar control has also been affected by the careful choice of a chiral carbonyl-containing compound and an achiral boryl triflate (equation 123)500. In this latter reaction the yields are reasonable (50 90%) and the diastereoselectivity is excellent.

X	1. 9-BBN-OTf	R	X
CH3	i-Pr2 NEt
O	2. RCHO	OH	O

(123)

X =

O

N

S

A camphor lactam imide auxiliary has also been used in a similar fashion (equation 124)501. Using this type of protocol, but replacing the aldehyde with an imine, the docetaxel (an important anticancer compound related to taxol) side chain has been prepared in 66% yield and 99% ee, as shown in equation 125502.

					X
		X	1. Et2 BOTf
			i-Pr2 NEt		O
	O		2. i-PrCHO
					OH
							(124)
			O
X =
		N
			X		t-BuOCONH	O
Ph	O				Ph
				t-BuOCON	Ph S	R	(125)
				LiN(TMS)2		X
			O			OCH2 Ph

Quantitative yields are realized when ˛-(N,N-dibenzylamino) ethyl ketones undergo aldol reactions with aldehydes. The reaction proceeds in a highly diastereoselective manner

14. Some synthetic uses of double-bonded functional groups

741

and results in the exclusive formation of the syn adduct (equation 126)503,504.

O									O	OH
R1			1. LDA						R1	R2	(126)
			2
			2. R CHO
NBn2									NBn2
The reaction of N-protected-3-amino-4-phenylbutanoic esters										with aldehydes505,
after lithiation, gives good yields			of			products			which are essentially 2-substituted
1-hydroxyethylene building blocks				the		central			moiety of HIV-1	protease inhibitors
(equation 127)506.
Ph									Ph
										OH
					1. LDA						(127)
R1NH					2. R2 CHO				R1NH	R2
CO2 Me									CO2 Me

1,3-Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with ˇ-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92:8; anti :syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508.

O−	O	O	OH	X
		X
+	H
			1,3-anti
			+	(128)
X = OPMB, OTBS, OAc, Cl		O	OH	X

1,3-syn

The conjugate addition of lithium bis(phenyldimethylsilyl)cuprates to ˛,ˇ-unsaturated esters forms enolates, which readily react with aldehydes to give 2-substituted 3-silyl esters (equation 129)509. The products are useful as intermediates in the synthesis of allylsilanes and natural products. Yields of this reaction may be significantly increased by

742	Jeff Hoyle

replacing the cuprates with ilyl(dialkyl)zincates510.

	O		PhMe2 Si	OLi
		(PhMe2 Si)2 CuCNLi2
R1	OMe		R1	OMe

R2 CHO

(129)

PhMe2 Si

CO2 Me

R1

R2 OH

A novel cyclization, producing a polyfunctional cyclopentane ring system, has been reported to occur starting from a ε-keto-˛,ˇ-unsaturated ester. Reaction with Bu3SnSiMe3, in the presence of fluoride ions, gives a Michael addition product, which then undergoes Dieckmann condensation (equation 130)511. The product is formed in reasonably good yields and bicyclic compounds may be accessed from starting materials which possess a cyclic ketone.

		O−	OH
O	CO2 R	O	CO2 R (130)
	Bu3 SnSiMe3	OR
		SnBu3	SnBu3

E. Reductive Coupling of Carbonyl and Related Compounds

The reductive coupling of carbonyl-containing compounds is an important route for the synthesis of vicinal diols and alkenes. In addition, a C C bond is being formed, making this type of reaction one that is much used in the building of complex organic molecules. In particular, there is a continuous search for methodology which gives a stereocontrolled vicinal diol moiety.

The pinacol-type coupling of aliphatic aldehydes, in the presence of niobium(III) salts, occurs, with a high anti diastereoselectivity (equation 131)512. In the case of aromatic aldehydes and ketones the alkene product is sometimes formed513. In both cases the cyclic acetals may also be formed.

			R	H
		NbCl3		OH
	RCHO			(131)
		THF	H
				R
			HO

14. Some synthetic uses of double-bonded functional groups

743

Reductive coupling of dialdehydes may also be accomplished by use of samarium(II) iodide514. The reactions is stereoselective and has been used to prepare myo-inositol derivatives (equation 132)515. The equivalent reaction, using low-valent titanium species as catalysts, results in a mixture of products516. The production of cyclic ˇ-amino alcohols may be accomplished in good yields, and with a high degree of cis selectivity by the treatment of carbonyl hydrazones with samarium(II) iodide (equation 133)517. This reaction is effectively equivalent to an aza-Barbier reaction.

BnO	OBn	SmI2
BnO	CHO
BnO	CHO
Ph2 N

BnO	OH
	BnO
BnO	(132)
BnO	OH

N	O		SmI2		NHNPh2
H	(CH2 )n			(CH2 )n	R
		R			OH
	n = 3 or 4

(133)

NH2

(CH2 )n

OH

In a rather surprising, but synthetically very useful, intermolecular reaction, ketones may be electroreductively coupled with a range of CDN-containing compounds to give very good yields of masked ˇ-aminoalcohols (equation 134)518. If the reaction is performed intramolecularly, then cyclic products are formed with a high degree of stereocontrol, giving the trans product (equation 135).

O	HO
	NHX
H e−	(134)

N

X

O

			OH
OMe	e	−	NHOMe (135)

N

CO2 Et

EtO2 C

744	Jeff Hoyle

F. Coupling of Alkenes and Carbonyl Compounds

Alkenes and carbonyl-containing molecules may be coupled in various ways to give new C C bonds in high yields. Intramolecular hydroacylation is a very versatile method for the production of cyclic ketones. Although many Rh complexes cause a significant yield reduction, due to decarbonylation, chiral Rh(diphosphine) catalysts apparently give good yields of cyclopentanones from a wide range of starting 4-pentenals, with reasonable ee (ca 60%) (equation 136)519.

O

O Rh+, cat

R	(136)

H BINA P

R

Intermolecular coupling of ketones and alkenes, promoted by SmI2, occurs with excellent stereochemical control. In one such reaction, samarium(II) iodide has been used to prepare cyclobutanones and cyclobutanols from chiral, 6-oxohex-2-enoates (equation 137)520. The reaction is performed in THF in the presence of HMPT and occurs in good yield with excellent stereocontrol. If appropriately located carbonyl and alkene moieties are present in a molecule, then SmI2-HMPT can be used to form cyclooctanols by a radical cyclization process; in some cases there is a reasonable degree of diastereoselectivity (equation 138)521,522.

CO2 Me

CO2 Me

		SmI2	(137)
		HMPT
BnO	H	HO	OBn
	O
			OH
O	R		R
			(138)
			SmI2
			HMPT

The intramolecular coupling of an aldehyde and alkene at 78 °C, promoted by SmI2, in the presence of a ketone, has led to a tandem coupling addition process. This reaction has proved to be synthetically very useful for the preparation of poly-oxygenated compounds (equation 139)523. This reductive coupling process may also be promoted in dry methanol,