(S)-4-Benzyl-2-oxazolidinone

(1; R1 = H, R2 = &wbond;Bn) (S)

[90719-32-7]  · C10H11NO2  · (S)-4-Benzyl-2-oxazolidinone  · (MW 177.20) (Li salt)

[123731-35-1] (2; R1 = H, R2 = &wlbond;Bn) (R)

[102029-44-7]  · C10H11NO2  · (S)-4-Benzyl-2-oxazolidinone  · (MW 177.20) (Li salt)

[128677-61-2] (3; R1 = H, R2 = &wbond;i-Pr) (S)

[17016-83-0]  · C6H11NO2  · (S)-4-Isopropyl-2-oxazolidinone  · (MW 129.16) (Li salt)

[96021-69-1] (4; R1 = &wlbond;Ph, R2 = &wlbond;Me) (4R,5S)

[77943-39-6]  · C10H11NO2  · (S)-4-Benzyl-2-oxazolidinone  · (MW 177.20) (Li salt)

[92061-65-7] (5; R1 = &wbond;Ph, R2 = &wbond;Me) (4S,5R)

[16251-45-9]  · C10H11NO2  · (4R,5S)-4-Methyl-5-phenyl-2-oxazolidinone  · (MW 177.20) (Li salt)

[127882-97-7] (6; R1 = H, R2 = &wbond;Ph) (S)

[99395-88-7]  · C9H9NO2  · (S)-4-Phenyl-2-oxazolidinone  · (MW 163.18) (7; R1 = H, R2 = &wlbond;Ph) (R)

[90319-52-1]  · C9H9NO2  · (S)-4-Benzyl-2-oxazolidinone  · (MW 163.18) (8; R1 = H, R2 = &wbond;t-Bu) (S)

[54705-42-9]  · C7H13NO2  · (S)-4-t-Butyl-2-oxazolidinone  · (MW 143.19)

(chiral auxiliaries used in asymmetric alkylations,1 acylations,2 halogenations,3 aminations,4 hydroxylations,5 aldol reactions,6 conjugate additions,7,8 Diels-Alder reactions,9 acyl transfer,10 and sulfinyl transfer11)

Physical Data: (1) mp 87-89 °C; (2) mp 85-87 °C; (3) mp 71-72 °C; (4) mp 118-121 °C; (5) mp 118-121 °C; (6) mp 130-132 °C; (7) mp 130-132 °C; (8) mp 118-120 °C.

Solubility: sol most polar organic solvents.

Form Supplied in: white crystalline solid; commercially available.

Analysis of Reagent Purity: 99% purity attainable by GLC.

Handling, Storage, and Precautions: no special handling or storage precautions are necessary. There is no known toxicity. It may be harmful by inhalation, ingestion, or skin absorption and may cause skin or eye irritation.

Synthesis of the Chiral Oxazolidinone Auxiliaries.

(S)-4-Benzyl- (1), (R)-4-benzyl- (2), (S)-4-i-propyl- (3), (4R,5S)-4-methyl-5-phenyl- (4), (S)-4-t-butyl- (8), and (S)-4-phenyl-2-oxazolidinones (6) are commercially available. Typical procedures to form these chiral auxiliaries involve the reduction of a-amino acids to the corresponding amino alcohols or the purchase of amino alcohols, followed by formation of the cyclic carbamate (eq 1). A number of high-yielding methods of reduction have been employed for this transformation, including Boron Trifluoride Etherate/Borane-Dimethyl Sulfide,12 Lithium Aluminum Hydride,1,6,13,14 Sodium Borohydride/Iodine,15 and Lithium Borohydride/Chlorotrimethylsilane.8 Selection among these methods is largely based upon cost of reagents and ease of performance. Reagents for effecting the second transformation include Diethyl Carbonate/Potassium Carbonate12 or Phosgene,16 -18 with the former being preferable for large-scale production. Ureas,19,20 dioxolanones,21 chloroformates,22 trichloroacetate esters,22,23 N,N-Carbonyldiimidazole,24 and Carbon Monoxide with catalytic elemental Sulfur25 or Selenium26,27 provide alternatives for the transformation of amino alcohols to the derived oxazolidinones.

Conversion of the appropriate a-amino acids to oxazolidinones may also be performed as a one-pot procedure, obviating the need to isolate the intermediate amino alcohols (eqs 2 and 3).28,29 Overall isolated yields for these procedures are 70-80%.

Carbamate-protected amino alcohols also yield oxazolidinones upon treatment with base (eq 4)30,31 or p-Toluenesulfonyl Chloride (eq 5).32 The latter reaction requires the protection of the amino group as the N-methylated carbamate for selective inversion of the hydroxyl-bearing center.

Resolution of racemic oxazolidinones affords either enantiomer of the auxiliary and provides a versatile route to unusually substituted derivatives (eq 6).33

Methods of N-Acylation.

Lithiated oxazolidinones add to acid chlorides (eq 7)6,34 and mixed anhydrides (eq 8)35,36 in high yields to form the derived N-acyl imides. In the latter case the anhydride may be formed in situ with Trimethylacetyl Chloride, and then condensed with the lithiated oxazolidinone selectively at the less hindered carbonyl moiety.

Acryloyl adducts cannot be formed through traditional acylation techniques due to their tendency to polymerize. These adducts may be obtained through reaction of acryloyl chloride with the bromomagnesium salt of the oxazolidinone auxiliary9,37 or the N-trimethylsilyl derivative in the presence of Copper(II) Chloride and Copper powder.38 These methods yield products in the range of 50-70%.

Methods of N-Alkylation.

In analogy with acylation techniques, metalated oxazolidinones add to alkyl halides to afford the N-alkylated products in high yields.39-42

Enolization of N-Acyloxazolidinones.

Various methods have been developed to effect the enolization of chiral N-acyloxazolidinones. In alkylation reactions, both Lithium Diisopropylamide and Sodium Hexamethyldisilazide deprotonate these imides to provide the (Z)-enolates in >100:1 selectivity.1

Di-n-butylboryl Trifluoromethanesulfonate with a tertiary amine also provides the (Z)-enolates of chiral acyl oxazolidinones in >100:1 selectivity for use in subsequent aldol additions.6,14 With Triethylamine, Diisopropylethylamine (Hünig's base), or 2,6-Lutidine the order of addition is of no consequence to enolization.43 Triethylamine has traditionally seen the greatest utilization in these reactions based upon cost considerations; however, with certain sensitive aldehyde substrates, lutidine provides milder reaction conditions.44

The (Z)-enolate is also accessed exclusively using titanium enolization procedures.45,47 Irreversible complexation of Titanium(IV) Chloride with tertiary amine bases demands complexation of the substrate with the Lewis acid prior to treatment with either triethylamine or Hünig's base. Reactions using Hünig's base occasionally display higher diastereoselectivities, particularly in Michael additions.7,45 Of the alkoxy titanium species employed in imide enolization, only TiCl3(O-i-Pr) is capable of quantitative enolate formation. In these reactions, order of addition of reagents is not significant. These enolates demonstrate enhanced nucleophilicity, albeit with somewhat diminished diastereoselectivity.

Other Lewis acids have been demonstrated to provide moderate levels of enolization, including Aluminum Chloride, Magnesium Bromide, and Tin(II) Trifluoromethanesulfonate.45,46 However, SnCl4, Me2AlCl, and ZrCl4 failed to provide detectable enolization.45

Enolate Alkylation.

Alkylation of chiral N-acyloxazolidinones by simple alkyl and allylic halides occurs through the chelated lithiated (Z)-imide enolates to afford products in greater than 93:7 diastereoselectivities (eqs 9 and 10).1 For small electrophiles such as Iodomethane and Ethyl Iodide, NaHMDS proved to be the enolization base of choice. On selected substrates, alkyl triflates also demonstrate promise as alkylating agents.34

For benzyloxymethyl electrophiles, titanium enolates are superior to the corresponding lithium enolates in both yield and alkylation diastereoselectivity (eq 11). Unfortunately, the analogous p-methoxybenzyl-protected b-hydroxy adducts cannot be obtained by this method. In other cases the titanium methodology complements the corresponding reactions of the lithium and sodium enolates for SN1-like electrophiles.47 It is noteworthy that imides may be selectively enolized under all of the preceding conditions in the presence of esters (eq 12).

Treatment of the silyl enol ethers of N-acyloxazolidinones with selected electrophiles that do not require Lewis acid activation similarly results in high induction of the same enolate face (eq 13).48 The facial bias of this conformationally mobile system improves with the steric bulk of the silyl group.

Chiral oxazolidinones have also been used to induce chirality in TiCl4-mediated allylsilane addition reactions to a-keto imides (eq 14).49

Enolate Alkylations with Transition Metal Coordinated Electrophiles.

Coordination of various transition metals to dienes and aromatic compounds sufficiently activates these compounds to nucleophilic addition, resulting in high asymmetric induction at the a-center. However, the manganese complexes of various benzene derivatives couple with lithium enolates in low selectivity at the nascent stereogenic center on the ring (eq 15).50

In contrast, molybdenum and iron diene complexes undergo the same type of reaction with chiral lithium imide enolates, with moderate to good induction at the b-position (eq 16).51-53

Dicobalt hexacarbonyl-coordinated propargyl ethers also combine with imide boron enolates through a kinetic resolution of the rapidly interconverting propargylic cation isomers to afford a 92:8 mixture of isomers at the b-center in 80% yield (eq 17). Stereocontrol of the a-center is 97:3.54

Enolate Acylation.

Acylation of these enolates provides a direct route to b-dicarbonyl systems. Acylations generally proceed with >95% diastereoselection in 83-95% yields, with the valine-derived auxiliary providing slightly higher selectivity (eq 18).2 The sense of induction is consistent with reaction through the chelated lithium (Z)-enolate, and the newly generated stereocenter is retained through routine manipulations.

An alternate approach to these useful 1,3-dicarbonyl substrates may be achieved through enolate orthoester acylation. Titanium enolates have been employed to effect this transformation (eq 19).45,47 Similarly, treatment of the titanium enolate of b-ketoimide with dioxolane orthoesters results in the formation of a masked tricarbonyl compound (eq 20). Trimethyl orthoacetate and Triethyl Orthoacetate are not appropriate partners in these coupling reactions.45,47

Michael Addition.

Titanium imide enolates are excellent nucleophiles in Michael reactions. Michael acceptors such as ethyl vinyl ketone, Methyl Acrylate, Acrylonitrile, and t-butyl acrylate react with excellent diastereoselection (eq 21).7,45 Enolate chirality transfer is predicted by inspection of the chelated (Z)-enolate. For the less reactive unsaturated esters and nitriles, enolates generated from TiCl3(O-i-Pr) afford superior yields, albeit with slightly lower selectivities. The scope of the reaction fails to encompass b-substituted, a,b-unsaturated ketones which demonstrate essentially no induction at the prochiral center. Furthermore, substituted unsaturated esters do not act as competent Michael acceptors at all under these conditions.

Various chelated lithium imide enolates have also served as nucleophiles in Michael additions to 3-trifluoromethyl acrylate, favoring the anti isomer (eq 22).55

Enolate Hydroxylation.

Treatment of the sodium enolates with the Davis oxaziridine reagent affords the hydroxylated products with the same sense of induction as the alkylation products (eq 23).5,35 Although high diastereoselectivity may be achieved with Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) (MoOPH), such reactions proceed in lower yields.

Enolate Amination.

Amination likewise can be effected using Di-t-butyl Azodicarboxylate (DBAD).4,56 Despite the excellent yields and diastereoselectivity obtained using this methodology (eq 24), the harsh conditions required for further transformation of the resultant hydrazide adducts (Trifluoroacetic Acid and hydrogenation at 500 psi over Raney Nickel catalyst) limit its synthetic utility.

As a method for the synthesis of a-amino acids, the hydrazide methodology has now largely been supplanted by direct enolate azidation (eq 25).4,57 These adducts are susceptible to mild chemical modification to afford N-protected a-amino acid derivatives. Under optimal conditions, yields range from 74-91% and selectivities from 91:9 to >99:1. Imide enolization can be carried out selectively in the presence of an enolizable t-butyl ester and suitably protected amino groups.

Hydrogenation of the azide moiety readily provides the amine using Palladium on Carbon and H2 or Tin(II) Chloride. This methodology has been extended to the synthesis of arylglycines (eq 26).58

Failure to use 2,4,6-Triisopropylbenzenesulfonyl Azide results in substantial diazo imide formation. However, optimization for the formation of the a-diazo imide compounds can be achieved with NaHMDS and p-nitrobenzenesulfonyl azide, followed by a neutral quench (eq 27).4 These diazo compounds, however, have failed to demonstrate utility in asymmetric carbenoid chemistry.59

Enolate Halogenation.

Enolate halogenation is achieved by reaction of the boryl enolate with N-Bromosuccinimide, affording configurationally stable a-bromo imides in >94:6 diastereoselectivity in 80-98% yield (eq 28).3,4 The sense of induction suggests halogenation of the chelated (Z)-enolate. Introduction of an a-fluoro substituent can be effected by the treatment of imide enolates or a,b-unsaturated enolates with N-fluoro-o-benzenedisulfonimide (eq 29).60

Displacement of a halide at the a-position with tetramethylguanidinium azide (TMGA) introduces nitrogen functionality with inversion of the original halide configuration and <1% epimerization (eq 30).3,4

In those transformations where other stereogenic centers reside proximal to the prochiral center, auxiliary control is dominant in most cases (eq 31).61

Aldol Reactions.

The dibutyl boryl enolates of chiral acyloxazolidinones react to afford the syn-aldol adducts with virtually complete stereocontrol (eq 32).6,13,14,43,61-64 Notably, the sense of induction in these reactions is opposite to that predicted from the analogous alkylation reactions. This reaction is general for a wide range of aldehydes and imide enolates.36,65-69 Enolate control overrides induction inherent to the aldehyde reaction partner.

Titanium enolates of propionyloxazolidinones also undergo aldol reactions with the same sense of induction as the boryl counterparts, but require two or more equivalents of amine base to afford adducts in marginally higher yields but diminished selectivity (eq 33).45

A second entry to dicarbonyl substrates utilizes the aldol reaction to establish the a-methyl center prior to oxidation of the b-hydroxyl moiety. Commonly, this oxidation is performed using the Sulfur Trioxide-Pyridine complex, which results in <1% epimerization of the methyl-bearing center (eq 34).2 Interestingly, this procedure procures the opposite methyl stereochemistry from that obtained through enolate acylation of the same enantiomer of oxazolidinone.

Non-Evans Aldol Reactions.

Either the syn- or anti-aldol adducts may be obtained from this family of imide-derived enolates, depending upon the specific conditions employed for the reaction. Although the illustrated boron enolate affords the illustrated syn-aldol adduct in high diastereoselectivity, the addition reactions between this enolate and Lewis acid-coordinated aldehydes afford different stereochemical outcomes depending on the Lewis acid employed (eq 35).70 Open transition states have been proposed for the Diethylaluminum Chloride mediated, anti-selective reaction. These anti-aldol reactions have been used in kinetic resolutions of 2-phenylthio aldehydes.71

Enolates derived from a-haloimides also exhibit metal-dependent syn/anti-aldol diastereoselection. The derived Li, SnIV, and Zn enolates afford the anti isomer in reactions with aromatic aldehydes, while the corresponding B and SnII enolates lead to the conventional syn products.72,73 The non-Evans syn adducts have also been observed in reactions organized by Chlorotitanium Triisopropoxide.74,75

Crotonyl Enolate Aldol Reactions.

Boron enolates of the N-crotonyloxazolidinones have been shown to afford the expected syn-aldol adducts (eq 36).76,77 The propensity for self-condensation during the enolization process is minimized by the use of triethylamine over less kinetically basic amines.

a-Alkoxyacetate Aldol Reactions.

The enolates derived from N-a-alkoxyacetyloxazolidinones also provide good yields of aldol adducts. Proper choice of reaction conditions leads to either the syn (eq 37)78 or anti (eq 38)46 adducts. In an application of this aldol reaction in the synthesis of cytovaricin, a complex chiral aldehyde was found to turnover the expected syn diastereoselectivity of the boron enolate.66

N-Isothiocyanoacetyl Aldol Reactions.

Auxiliary-controlled masked glycine enolate aldol reactions afford the chiral oxazolidine-2-thiones which can be cleaved to provide the syn-aldol adducts regardless of aldehyde stereochemistry (eq 39).79

N-Haloacetyl Aldol Reactions.

N-Haloacetyloxazolidinones form suitable enolate partners in aldol reactions, although complete aldehyde conversion requires the use of a slight excess of imide (eq 40). The products can be chromatographed to diastereomeric purity.4,80 Nucleophilic azide displacement of a-halo-b-hydroxy syn aldol adducts affords the corresponding anti a-amino-b-hydroxy compounds (eq 41).4,80 Intramolecular displacement of the halogen to form the a-amino product is also possible (eq 42).80

Acetate Aldol Equivalents.

In contrast to the reliably excellent selectivities of a-substituted dibutylboryl imide enolates, boron enolates derived from N-acetyloxazolidinones lead to a statistical mixture of aldol adducts under the same reaction conditions. Acetate enolate equivalents may be obtained from these enolates bearing a removable a-substituent. To this end, thiomethyl- or thioethylacetyloxazolidinones (eq 43)13 as well as haloacetyloxazolidinones can be submitted to highly selective boron-mediated aldol reactions. Products can be transformed to the acetate aldol products via desulfurization with either Raney Ni81 or Tri-n-butylstannane and Azobisisobutyronitrile,82 or via dehalogenation with Zinc-Acetic Acid (eq 44).81 This latter procedure provides several advantages over the sulfur methodology, including ease of imide preparation and improved overall yields.

b-Ketoimide Aldol Reactions.

As has been demonstrated, chiral oxazolidinones provide a gateway into asymmetric b-ketoimides via either an aldol-oxidation sequence, or enolate acylation. These substrates can then undergo an iterative aldol reaction, where chirality is induced by the methyl-bearing a-center. To date, three of the four diastereomeric aldol adducts may be selectively obtained with a variety of aldehydes (eq 45).36,83-86

Reformatsky Reactions.

The Reformatsky reaction of a-halooxazolidinones provides an alternative to the more conventional aldol reaction. Although the traditional zinc-mediated Reformatsky using valine-derived compounds proceeds nonselectively,87,88 the SnII modification with 2-bromo-2-methylpropionyloxazolidinone proceeds well (eq 46).89,90 In this particular case, however, the geminal dialkyl substituents favor the endocyclic carbonyl acyl transfer of the auxiliary by the aldolate oxygen.

Acyl Transfer Reactions.

(S)-N-benzoyloxazolidinones have been used as acyl transfer reagents to effect the kinetic resolution of racemic alcohols.10 The bromomagnesium alkoxides formed from phenyl n-alkyl alcohols selectively attack the exocyclic benzoyl moiety to afford recovered auxiliary and the derived (R)-benzoates in >90% ee and >90% yield (eq 47). The scope of this reaction seems to be limited to this class of substrates as selectivity drops with increasing the steric bulk of the alkyl group.

Sulfinyl Transfer Reactions.

Grignard reagents add to diastereomerically pure N-arylsulfinyloxazolidinones with inversion of configuration at sulfur to afford enantiopure dialkyl or aryl alkyl sulfoxides in excellent yields (eq 48).11 Although broader in synthetic utility than the menthyl sulfinate esters,91,92 this methodology is comparable to Kagan's chiral sulfite substrates as a strategy for constructing chiral sulfoxides.93,94

The N-arylsulfinyloxazolidinone methodology is readily extended to the formation of sulfinylacetates, sulfinates, and sulfinamides with >95% ee and high yields (eq 49).

Diels-Alder Reactions.

Chiral a,b-unsaturated imides participate in Lewis acid-promoted Diels-Alder cycloaddition reactions to afford products in uniformly excellent endo/exo and endo diastereoselectivities (eqs 50 and 51).9,37,95,96 Unfortunately, this reaction does not extend to certain dienophiles, including methacryloyl imides, b,b-dimethylacryloyl imides, or alkynic imides. Cycloadditions also occur with less reactive acyclic dienes with high diastereoselectivity (eq 52). Of the auxiliaries surveyed, the phenylalanine-derived oxazolidinones provided the highest diastereoselectivities. This methodology has been recently extended to complex intramolecular processes (eq 53).68,95,97 In this case, use of the unsubstituted achiral oxazolidinone favored the undesired diastereomer.

Staudinger Reactions.

Chiral oxazolidinones have been employed as the chiral control element in the Staudinger reaction as well as the ultimate source of the a-amino group in the formation of b-lactams.41 Cycloaddition of ketene derived from 4-(S)-phenyloxazolidylacetyl chloride with conjugated imines affords the corresponding b-lactams in 80-90% yields with excellent diastereoselectivity (eq 54). The auxiliary can then be reduced under Birch conditions to reveal the a-amino group.

Conjugate Addition Reactions.

a,b-Unsaturated N-acyloxazolidinones have been implemented as Michael acceptors, inducing chirality in the same sense as in enolate alkylation reactions. Chiral a,b-unsaturated imides undergo 1,4-addition when treated with diethylaluminum chloride (eq 55). Photochemical initiation is required for the analogous reaction with Dimethylaluminum Chloride.96

Organocuprates also undergo conjugate addition with chiral a,b-unsaturated imides.98 Treatment of the imides derived from 4-phenyl-2-oxazolidinone with methyl- or arylmagnesium halides and CuBr affords conjugate addition products in yields over 80% with few exceptions (eq 56).8 Reaction diastereoselectivity appears to be contingent upon the use of the 4-phenyloxazolidinone auxiliary. The preceding methodology has been applied to the synthesis of b-methyltryptophan (eq 57).99

Similar chemistry using chiral sultam auxiliaries demonstrates superior yields and selectivities for specific cases of cuprate conjugate additions, but have not yet been extended to the more complex multistep transformation series illustrated above.100,101 Moderate selectivities have been obtained in alkyl cuprate additions to g-aminocrotonate equivalents where the nitrogen is derived from the oxazolidinone.102

The 4-phenyl-2-oxazolidinone auxiliary has also been employed in the TiCl4-mediated conjugate additions of allylsilanes (eq 58).103 Analogous reactions using the phenylalanine-derived auxiliary with dimethylaluminum chloride afforded lower selectivities.104 In these reactions the oxazolidinones perform better than the sultams.

Nucleophilic addition of thiophenol to chiral tiglic acid-derived imides proceeds in excellent yields and diastereoselectivities (eq 59).105 Complete turnover of both the a- and b-centers results from the use of the (Z) rather than (E) isomer. Poor b-induction was found with the imides derived from cinnamic acid.

Dimethylaluminum chloride also catalyzes the ene reactions of chiral a,b-unsaturated imides with 1,1-disubstituted alkenes in moderate yields and selectivities.104

Oxazolidinone-Substituted Carbanions.

Oxazolidinone-substituted organostannanes readily undergo transmetalation with alkyllithium reagents to the organolithium derivatives which then can undergo nucleophilic addition reactions. N-Substituted oxazolidinones can act in this capacity as both a nitrogen source and source of chirality (eq 60). Although the a-stereoselection in these reactions is excellent, a greater variety of reactant alkylstannanes are available using chiral imidazolidinones in place of oxazolidinones.39,40,42

Synthesis of Cyclopropanes.

Chiral imide enolates which contain g-halide substituents undergo intramolecular displacement to form cyclopropanes.106 Halogenation of g,d-unsaturated acyl imides occurs at the g-position in 85% yield with modest stereoinduction. The (Z) sodium enolates of these compounds then cyclize through an intramolecular double stereodifferentiating reaction (eq 61).

Stereoselective Cyclizations.

Sultams have been demonstrated to be superior sources of chirality in selected cases of iodolactonizations,107 oxidative 1,5-diene cyclizations,108 and Claisen-type rearrangements of b-acetoxyl substrates.109

Chiral Ligands.

Bidentate chelation of dirhodium(II) compounds by chiral oxazolidinones creates asymmetric sites on the metal, leading to induction in cyclopropanations and carbon-hydrogen insertion reactions. The oxazolidinones are less effective in this capacity than are the pyrrolidines.110

Removal of the Chiral Auxiliary.

In each of the following transformations, the oxazolidinone auxiliary is recovered in high yields (eq 62).

Conversion to the Acid.

Hydroxide6,111 and peroxide112 conditions saponify acyl imides in excellent yields; however, with sterically hindered acyl groups endocyclic cleavage may predominate upon treatment with Lithium Hydroxide. Lithium Hydroperoxide, however, is highly selective for the exocyclic carbonyl moiety.

Conversion to the Alcohol.

Reduction of acyl imides to their corresponding alcohols is effected by a number of reagents, including Lithium Aluminum Hydride,1 Lithium Borohydride,1 LiAlH4/H2/Lindlar's cat./TFA,113 LiBH4/H2O/Et2O,114 LiBH4/MeOH/THF,36 and Bu3B/HOAc/LiBH4.77 Although the sole use of LiAlH4 or LiBH4 affords product often in low yields, the addition of an equivalent of H2O or MeOH greatly enhances reaction efficiency. The MeOH/THF modification occasionally produces more consistent results. The last of the methods outlined above is effective in preventing retro-aldol cleavage in sensitive substrates such as crotyl or a-fluoro aldol adducts (eq 63).

Conversion to the Aldehyde.

This transformation is accomplished through a two-step procedure. One such variant requires reduction to the alcohol (e.g. LiAlH4, H2O) and subsequent oxidation (e.g. Swern conditions).36,85 Alternatively, Weinreb transamination78,115-117 followed by Diisobutylaluminum Hydride,78 or conversion to the thioester (see below) and subsequent Triethylsilane reduction,86 afford the desired aldehyde in excellent yields. Weinreb transamination proceeds with minimal endocyclic cleavage when there is a b-hydroxy moiety free for internal direction of the aluminum species.

Conversion to Esters.

Ester formation is readily achieved by conventional alcoholysis with alkoxides such as LiOBn,1 NaOMe,6 or ROMgBr (eq 64).76,118 In hindered cases, endocyclic cleavage becomes competitive. Various titanium(IV) alkoxides have also been employed to effect this transformation.4,119

Conversion to Amides.

N-Acyloxazolidinones may be converted to the primary amide via the corresponding hydrazide.120 Alternatively, trimethylaluminum/amine adducts form active transamination reagents,36,117 providing amides of b-hydroxy acyloxazolidinones through intramolecular amine addition of the aminoaluminum species (eq 65).105

Conversion to Thioesters.

The transformation of N-acyl imides into thioesters with lithium thiolate reagents proceeds with exceptional selectivity for the exo carbonyl moiety even in exceptionally hindered cases.121 A recent application of this reaction in a complex setting has been reported (eq 66).68,97 This transformation is significant in that the normally reliable peroxide hydrolysis procedure proved to be nonselective. The recently reported high yield reduction of thioesters to aldehydes86 enhances the utility of these thioester intermediates.


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David A. Evans &

Annette S. Kim

Harvard University, Cambridge, MA, USA



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