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

725

3. Using baker’s yeast

Baker’s yeast reduction of organic compounds, especially carbonyl compounds, is an extremely useful method of obtaining chiral products255 257. Recently, much effort has been expended to improve the ee obtained in this process. In one very useful example, 1-acetoxy-2-alkanones have been reduced enantioselectively into (S)-1-acetoxy-2-alkanols in 60 90% yields and with 95 99% ee258. The reaction readily occurs in a variety of solvents, both aqueous and nonaqueous. The reduction is fairly selective and so may be brought about in the presence of ˛-amide, ether, ester and other acid functional groups, in reasonable yields and with excellent ee (equation 65)259 261. Thus, in the synthesis of the C-13 side chain of taxol, the key step was the reduction of a ˛-ketoester to the corresponding alcohol in 72% overall yield (equation 66)262.

O						O
R1				R1						(65)
R2									R2
O					OH
NH2	O								NH2	O
					baker’s					(66)
		OCH3
					yeast
										OCH3
	O									OH

-Ketoacids263 and ˇ-ketoesters264 273 have also been reduced enantioselectively by baker’s yeast, in good to excellent ee (It seems that pretreatment of the yeast may improve the stereochemical control of the reaction274.) In this case a chiral lactone is usually formed. Nitro-containing ketones275 277, epoxyketones (equation 67)278 280 and acetophenones281 may also be reduced in a similar fashion. Also, in the case of diketones

it is sometimes possible to obtain selective reduction of just one ketone group282 284 (equation 68)285.

	O		OH			OH
Ph		Ph		+	Ph	(67)
	Me	H		Me	H	Me
			O			O
	O
O	O	H	OH	O
						(68)
	H			H

˛-Hydroxyketones (and other oxygenated groups) are also readily tolerated by the reaction conditions, giving very good to excellent yields of the corresponding diols, with one alcohol as part of a chiral center (equation 69)286 288. Whether the stereocenter is

726	Jeff Hoyle

R or S is very much dependent upon the reaction conditions and upon the substrate structure289. This is probably due to the several dehydrogenase enzymes that are present in baker’s yeast.

R			R
	OH	baker’s	OH	(69)
O		yeast	OH

Fluorinated ˛-diketones are reduced by baker’s yeast in a regioselective fashion giving reduction chiefly at the ketone which is adjacent to the fluorine atoms (equation 70)290. The enantiomer in excess can be selected by manipulation of the rest of the molecular structure.

CF3		R		CF3	R
			baker’s	*	(70)
O	O		yeast	OH	O

Finally, (S)-coriolic acid (a metabolite of linoleic acid) has been synthesized, in an enantiospecific fashion, by the use of the alcohol dehydrogenase enzyme from baker’s yeast in the presence of NADPH. In the key step of this synthesis, the supported enzyme/NADPH was used to reduce a bromovinyl ketone enantiospecifically (equation 71)291.

	O			H
				HO
H	R		H	R
Br			Br	(71)

4. Other methods

Some other methods used for the stereocontrolled reduction of aldehydes and ketones are discussed below. Catalytic hydrogenation, under mild conditions using rhodium-based catalysts, is a very facile means of reducing a wide range of aldehydes and ketones292. Asymmetric reduction of ˛-dicarbonyl compounds may be performed selectively at a ketone in the presence of an ester or amide, by hydrogenation using achiral binaphthalene (BINAP) ruthenium complex. The resulting 2-hydroxy ester (amide) is typically obtained in excellent yield and in high ee293 295. Similar catalysts may be used to reduce ˇ-ketoesters296 and cyclic alkanones and ˇ-thiacycloalkanones (equation 72)297, with hydrogen, in the same controlled fashion.

O	OH
	(72)
(CH2 )n	(CH2 )n
S	S

Catalytic reduction of unsymmetrical ketones into alcohols by concomitant oxidation of 2-propanol to acetone (Meerwein Ponndorf Verley reduction, MPV), with rhodium

14. Some synthetic uses of double-bonded functional groups

727

catalysts, has been a very successful methodology that has resulted in excellent selectivity (equation 73)298,299. Recently, this selectivity has been improved by the use of C2- symmetric 1,2-diamines as chiral ligands300,301. This reaction may also be brought about using trivalent lanthanide compounds, with chiral ligands, as catalysts302 305. Other improved MPV reductions have been performed using either hydrous zirconium oxide306, or a new silica-supported zirconium complex307 as the catalyst. These reactions result in excellent yields of the corresponding alcohol, under mild and neutral conditions.

	OH	Rh cat	OH		O
	+		*	+	(73)
		KOH
R1	R2		R1	R2

Metals in protic solvents have also been used to reduce ketones to alcohols. One such process employs cadmium chloride and magnesium in THF water. This reagent efficiently (85 95%) reduces aldehydes and ketones to their corresponding alcohols308. Sodium supported on alumina has also been used as an excellent means of ketone reduction309. In this reaction a proton donor such as isopropanol is employed. This reaction gives good yields and affords a moderate selectivity in the case of ketones containing chiral centers in close proximity. The synthetic utility of this reagent is due to the ease by which the sodium-supported reductant may be prepared and wax-coated, thus allowing the material to be stored ready for use at a later date.

Reduction of benzaldehydes with Raney nickel, under alkaline conditions, gives good to excellent yields of the corresponding alcohol310. Reduction of the same substrates under acidic conditions, using an amine-cyanoborane complex as the reducing agent, also gives very good yields311.

B. Reduction of C=N Containing Compounds

The reduction of imines to the corresponding amino compounds is a synthetically useful and very important means of introducing this latter group into organic compounds312,313.

Aromatic aldoximes have been smoothly reduced to their corresponding acylamides by ammonium formate-palladium-carbon catalyzed hydrogenation, in either ethanoic or propanoic acid solution in 65 85% yield (equation 74)314. Catalyzed hydrogenation has also been successful for the formation of amines from cyclic ketimines315. In this reaction a highly enantiomerically enriched cyclic amine, an important functionality in natural products316, is produced by the use of a chiral titanocene catalyst. The reaction occurs in good yields and is general for 5- to 7-membered cyclic imines (equation 75). Other asymmetric hydrogenations have also led to enantiomeric amines317 323.

ArCH		NOH			H2		ArCH2 NHCOR
				HCO2 NH4 , Pd/C			(74)
					RCO2 H
							H
	N						N
R						R	(75)
		(CH )					(CH2 )
	2		n				n

n = 1−3

728	Jeff Hoyle

Reduction of dihydropyrimidines by the use of excess sodium borohydride in methanol, at 60 °C, has been used as a route to substituted polyamines (equation 76). The reaction occurs in a stereocontrolled fashion and gives reasonable yields. These latter molecules are synthetic targets due to their potential in chemotherapy.

	R1
		NBu	R1	R2	(76)
			NaBH4
R2	N	NHBn	BuHN	NH	NHBn

Imidoylstannanes may also be cleanly reduced to ˛-stannylamines in good yields by the use of sodium borohydride in ethanol at ice temperatures (equation 77)324. The same reagent may be used to reduce ˛,˛-dihalo ketimines (equation 78) to ˇ,ˇ-dialkoxyamines

(which are ˛-amino keto acetals)325. The intermediates for the synthesis of a wide

products from this reaction are extremely useful variety of heterocyclic molecules.

R
N		NaBH4		NHR
				(77)
SnBu3		EtOH		SnBu3
N				NH
	NaBH4			(78)
	EtOH
X X				EtO OEt

Chiral sulfoxides are useful both as intermediates and target molecules of synthetic elaboration. The ˇ-amino- -hydroxysulfoxide moiety is one type of chiral sulfoxide which is the intermediate target in the synthesis of (S)-(C)-sparsomycin. In the key step in this synthesis, the sought after moiety was produced by asymmetric reduction of an oxazoline using DIBAL, in the presence of zinc chloride and at 78 °C (equation 79)326.

	N	Ar		RHN	O ••
	S		DIBA L		−	(79)
				HO	S
O	−
			ZnCl2
	•• O				Ar

Lithium aminoborohydrides, which are readily obtained by reaction of n-BuLi with amine-boranes327,328, are excellent reagents for the reduction of imines to their corresponding secondary amines (equation 80)329. If the substrate possesses chirality, then there is considerable diastereoselectivity in this reaction (up to 90%).

N	Ph	LiEt2	NH	Ph	(80)
			NBH3

THF	H

14. Some synthetic uses of double-bonded functional groups

729

O,O-Dialkyl 1-aminoalkanephosphonates, which are moieties in peptide analogues, with antibacterial activity, and important inhibitors of aminopeptidases330 have been synthesised from oximes in THF (equation 81)331.

O R′

(RO)2 P

OH

N

O R′

LiBH4	(RO)2 P	(81)

Me3 SiCl

NH2

Asymmetric reduction of aryl ˛-ketoimines, by the use of oxazaborolidine catalysts, gives a good ee of the resultant alcohol (equation 82)332. The product is an arylethanolamine which is a synthetic target (e.g. ˇ-blockers) and a useful intermediate.

O

H3 B − SMe2

NR

Ar	cat.

OH

(82)

NHR

Ar

Catalytic reduction of chiral 2-(2-pyridyl)-1,3-oxazolidines and of 2-pyridyl imines, which are easily produced by standard synthetic means, followed by oxidation, results in the formation of chiral secondary amines as shown in equation 83333. The reaction occurs with a reasonable diastereoselectivity.

N	Pd/C	NaIO4	(83)
	H2		N
N	Ph

NH2

OH

C. Catalytic Hydrogenation of Alkenes

The reduction of alkenes to alkanes is a reaction that is often used as a key part of a synthetic sequence. In some cases this reaction is performed in an attempt to introduce chirality into a molecule. The emphasis here is on the stereocontrolled reduction of alkenes in complex molecules.

Asymmetric hydrogenation has been reported to occur in excellent yield and ee when a trisubstituted alkene is hydrogenated with a chiral titanocene catalyst (equation 84)334. A similar reaction, but with variable enantioselectivity, may also be obtained with chiral Rh, Ru and Co catalysts335 338. Disubstituted alkenes (mainly 1,1-disubstituted) may also be

730	Jeff Hoyle

asymmetrically hydrogenated with various chiral catalysts339 342.

R1 R1

		H2		(84)
		chiral
R3	R2	titanocene	R3	R2

The rhodium-chiral phosphine catalyzed asymmetric hydrogenation of protected enamides, and other unsaturated amino acid derivatives (equation 85), gave almost 100% ee of the corresponding chiral ˛-amino acid derivative343,344.

COOMe

		H2
	NHAc	chiral
		Rh complex

COOMe

(85)

NHAc

-Hydroxy vinylstannanes also undergo catalytic hydrogenation, using chiral rhodium complexes, in this case giving diastereoselectivities of 60:1 and greater345. The reaction occurs under high hydrogen pressures in dichloromethane for 24 36 hours (equation 86).

OH	R		OH	R
		H2		(86)
		Rh cat.
	SnBu3			SnBu3

Chiral rhodium catalysts have also been used to affect the homogeneous asymmetric hydrogenation of protected 2-aminoacrylates (equation 87)346 350. The chiral protected ˛-amino esters formed are extremely useful for further synthetic elaboration.

CO2 Me

H2

MeOH

Rh cat.

R NHP

CO2 Me

*

(87)

R NHP

Finally, of note is the hydrogenation of ˛,ˇ-unsaturated carboxylic acids. This may be accomplished in a highly diastereoselective manner by the use of ruthenium(II) BINAP complexes (equation 88)351. The chemical yields are high (83 99%) and the reaction occurs in up to 97% ee. This type of hydrogenation has been used as the key step in a synthesis of building blocks for protease inhibitors and has been performed on a 100 g scale352.

*

*

(88)

CO2 H

CO2 H

D. Other Reductions

Baker’s yeast has been used to reduce selectively the thioketone moiety in a ˇ-thioketo ester353. Whilst a mixture of alcohol and thiol containing products are obtained, the ee is

14. Some synthetic uses of double-bonded functional groups

731

up to about 90%, thus making this process a valuable one (equation 89).

	X		X
	CO2 R	baker’s	CO2 R
				(89)
		yeast

X = OH, SH

The enantioselective aldol and Michael additions of achiral enolates with achiral nitroolefins and achiral aldehydes, in the presence of chiral lithium amides and amines, was recently reviewed354. The amides and amines are auxillary molecules which are released on work-up (equation 90 shows an example of such a reaction).

OLi

O

O

O

N

MeHN

+ PhCHO

H OH	H OH
Ph +	(90)
	Ph

30

70

Lastly, 1,2-diamines, which are extremely useful in the synthesis of many natural products, may be readily produced in good yields and with excellent diastereoselectivity via the aza-Claisen rearrangement reaction, catalyzed by palladium(II) chloride355. In this reaction sequence the starting amino-containing, allylic alcohol is converted into the corresponding trichloroacetimidate. Following aza-Claisen rearrangement, the 1,2-diamine is produced by an oxidation reduction work-up (equation 91).

NHBoc

NHBoc

OH

HN O

CCl3

(91)

NHBoc

NH2

COOH

HN CCl3

NH2

O

732	Jeff Hoyle

IV. C−C BOND-FORMING REACTIONS

C C bond-forming reactions using double-bonded functional groups are very facile synthetic processes. In the present work only C C bond formations directly at the carbon atoms of the double bond-containing group are considered.

The subdivision of this topic is somewhat arbitrary, but is used in an attempt to group similar C C bond-forming reactions together.

A. Carbonylation and Related Reactions

Carbonylation is a very useful synthetic process356,357. Synthetically, these reactions are usually high yielding methods for the preparation of a wide range of functionalities, covered below. Palladium acetate catalyzed carbonylation of a wide range of alkenes gives good to excellent yields of the homologous acid, in the presence of a proton donor (equation 92)358 363. Other catalysts have been used, but these tend to give lower yields of the desired products364,365. Further, the carbonylation of appropriately functionalized alkenes, in the presence of transition metal acetates, produces reasonably good yields of multifunctional cyclopentanes (equation 93), which are extremely useful synthetic intermediates366,367.

R1			R1
	CO			(92)
R2		HO2 C	R2
Z		Z	Z
Z
	CO		CO2 H	(93)

In a similar process, nickel compounds also catalyze the carbonylation of allenyl halides, under phase-transfer conditions (PTC), to give allenyl acids in poor to reasonably good yields (equation 94)368.

CO

	PTC	(94)
X	Ni(CN)2	CO2 H

X = Br, Cl

The carbonylation of functionalized alkenes in the presence of alkyl bromides and iodides under radical producing conditions gives good yields of ˇ-functionalized ketones (equation 95)369,370. These compounds may be formed with cyano, ester and aldehyde groups attached directly to the alkene.

		X	O
	RI +	CO
		rad ical	(95)

R X

X = CN, CHO, CO2 R

14. Some synthetic uses of double-bonded functional groups

733

The Pauson Khand reaction is an extremely useful method of construction of 5- membered rings371,372. The reaction proceeds by carbonyl insertion (mediated by cobaltcarbonyl complexes) into an enyne. The products are usefully functionalized cyclopentenones (equation 96)373 377. The reaction is promoted by the addition of tertiary amine N-oxides378,379, DMSO380 or phosphites381. It has also been reported that appropriately placed sulfur or oxygen moieties, within the alkene, also speed up the reaction382. This reaction has been used as the key step in the total synthesis of ( )-˛-kainic acid, a potent neuronal exitant383, the synthesis of bis-heteroannulated pyranosides384 and also in the synthesis of the D and E rings of xestobergsterol385.

Ph	O
X	Ph
Co2 (CO)8	H
	(96)
Y	Y
	X

Y = CH2 , O, NAc

Upon hydroformylation with carbon dioxide and hydrogen, vinylic sulfoxides and sulfones give reasonable yields of branched-chain aldehydes in a regioselective manner (equation 97)386. This reaction also occurs, with Rh catalysis, for a wide range of substituted alkenes387 392.

		OHC
SOxR	CO	SOxR
	H2	(97)
		Me

x = 1, 2

Direct hydrocarboxylation of conjugated dienes with carbon monoxide and formic acid, using Pd C catalysis and in the presence of triphenylphosphine and 1,4- bis(diphenylphosphino)butane (dppb), gives good yields of what is essentially addition of formic acid to the terminal alkene (equation 98)393. This is an extremely useful synthetic route to ,υ-unsaturated acids.

Pd / C
dppb / PPh3	COOH	(98)
CO, HCO2 H

Lastly, stannylformylation has been used to synthesize both homocyclic and heterocyclic five-membered rings394. The reaction occurs by the treatment of 1,6-dienes with tin hydride and AIBN, under CO pressure at elevated temperatures (equation 99).

X

X	CO	(99)
	Bu3 SnH
	A IBN	SnBu3

CHO

X = CH2 , O, NR

734	Jeff Hoyle

B. Vinylations

The introduction of vinyl groups is described in this section. Palladium(0) catalyzed intermolecular vinylation of a wide range of organic compounds by vinyl halides is an important C C bond-forming reaction395 399. As a key step in the synthesis of retinal, an allylic alcohol has been coupled with a vinyl halide to give excellent yields of the adduct (equation 100)400. The side chains of protected ˛-amino acids have also been extended in a similar way, via Pd catalyzed coupling of a vinyl iodide with an alkene (equation 101)401. In some cases the reaction can be carried out at significantly lower temperatures by increasing the pressure402.

		OR2
R1	+
	X
HO		OR2
	Pd cat.		(100)
	base
		OR2
	R1
	HO	OR2
		CO2 Et
	CO2 Et
	+	NHAc	(101)
	R

I NHAc

R

The equivalent intramolecular Heck-type vinylation of a ω-vinyl-(Z)-iodoalkene has been used as the key step in the synthesis of A-ring synthons for 1˛,25-dihydroxyvitamin D3 and its analogues403. The reaction takes place under reflux in acetonitrile in the presence of one equivalent of triethylamine404 and gives a 81% yield (equation 102).

	OH		OH
	I	Pd(PPh3 )3
			(102)
		Et3 N
TBSO	OTBS	TBSO	OTBS

The palladium catalyzed cross-coupling of vinyl triflates with boronic acids is also a very facile means of introducing a vinyl group into a wide range of molecules. The reaction occurs under mild conditions, is highly regiospecific and requires easily prepared starting materials. Thus, this methodology has been employed to introduce a vinyl group at the 3-position of indoles405, as shown in equation 103.