Enolates, boron

Condensation of the Lithium Enolate Derived from 53 with Representative Aldehydes (eq. [32]) 

Metal-Oxygen and Metal-Ligand Bond Lengths for Metals Commonly Used in the Aldol Condensation  

In the late 1960s, methods were developed for the synthesis of alkylated ketones, esters, and amides via the reaction of trialkyl-boranes with a-diazocarbonyl compounds (50,51), halogen-substituted enolates (52), and sulfur ylids (53) (eqs. [33]-[35]). Only one study has addressed the stereochemical aspects of these reactions in detail. Masamune (54) reported that diazoketones 56 (Ri = CH3, CH2Ph, Ph), upon reaction with tributylborane, afford almost exclusively the ( )-enolate, in qualitative agreement with an earlier report by Pasto (55). It was also found that E) - (Z)-enolate isomerization could be accomplished with a catalytic amount of lithium phenoxide (CgHg, 16 hr, 22°C) (54). 

Brown and co-workers have established the feasibility of the conjugate addition of trialkylboranes to a,jS-unsaturated ketones (eq. [36]) (56), and one investigation has addressed the question of 

Several investigations have addressed the synthesis of boryl eno-lates by carbonyl enolization. Kbster has examined in detail the thermal reaction of triethylborane with substituted ethyl ketones catalyzed by diethylboryl pivalate (58) (eq. [40]) (61). The boryl pivalate 58 is undoubtedly the active reagent in this system, and it is regenerated by the illustrated protonolysis (eq. [41]) (62). The vigorous conditions employed in this procedure probably result in the generation of the equilibrated boryl enolates. The enolate ratios obtained by way of this procedure are summarized in Table 18. 

The Mukaiyama reaction can also be applied to ketene acetals such as 255, derived by trapping the enolate of an ester such as ethyl isobutanoate. Reaction of ketene acetal 255 with phenylacetone and TiCLt produced the condensation product 256.This variation is very useful since esters can be used as ketene acetal precursors, greatly expanding the utility of the reaction. 

The disconnections are identical to those shown for the aldol condensation. 

The diastereoselectivity of the aldol condensation varies with the substituents on the carbonyl precursor to the boron enolate. The boron enolates derived from ketone 274 are shown in Table 9.9.1 1 The lithium enolate of 274 reacted with a boron triflate to give the (Z) enolate 275 and the E) enolate 276. Reaction with an aldehyde gave the syn boron aldolate (277) and the anti boron aldolate (278). The boron aldolates were 

A synthetic example of this reaction is taken from Evan s synthesis of (+)-miyakolide.l 3 Ketone 279 was treated with B-chlorodicyclohexylhorane in the presence of triethylamine, and this generated boron enolate 280. 4-Methylbut-2-enal was also present in the reaction and they condensed to give a 98% yield of 281, with a diastereoselectivity of 88 12. 

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Bernard A, A M CapeUi, A Comotti, C Gannari, J M Goodman and I Paterson 1990. Transltion-St Modeling of the Aldol Reaction of Boron Enolates A Force Field Approach. Journal of Orga Chemistry 55 3576-3581. 

Boron Enolates Comprehensive Organic Synthesis 1991, 2, 239. Organic Reactions 1995, 46, 1 ... 

Diastereoselective Aldol Condensation with Boron Enolates... 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

Enantioselective aldoi condensation by means of a chiral auxiliary and boron enolates... 

Table 8. Aldol Reaction of the Amide Boron Enolates CF3CF=C[0B (C4H9)2]N(C2Hs)2 with Aldehydes [9]...

It was anticipated that two of the three stereochemical relationships required for intermediate 12 could be created through reaction of the boron enolate derived from imide 21 with a-(benzyloxy)ace-taldehyde 24. After conversion of the syn aldol adduct into enone 23, a substrate-stereocontrolled 1,2-reduction of the C-5 ketone car-... 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

Scheme 6a presents the synthesis of fragment 15. Intermediate 15 harbors two vicinal stereogenic centers, and is assembled in a very straightforward manner through the use of asymmetric aldol methodology. Treatment of the boron enolate derived from 21 with 3-[(p-methoxybenzyl)oxy]propanal (22) affords crystalline syn aldol adduct 34 in 87 % yield as a single diastereomer. Transamination to the A-methoxy-A-methylamide,20 followed by silylation of the secondary hydroxyl group at C-19 with triethylsilyl chloride, provides intermediate 15 in 91 % yield. 

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

The synthesis of the polyol glycoside subunit 7 commences with an asymmetric aldol condensation between the boron enolate derived from imide 21 and a-(benzyloxy)acetaldehyde (24) to give syn adduct 39 in 87 % yield and in greater than 99 % diastereomeric purity (see Scheme 8a). Treatment of the Weinreb amide,20 derived in one step through transamination of 39, with 2-lithiopropene furnishes enone 23 in an overall yield of 92 %. To accomplish the formation of the syn 1,3-diol, enone 23 is reduced in a chemo- and... 

Ideal starting materials for the preparation of. svn-aldols are ketones that can be readily deprotonated to give (Z)-enolates which are known to give predominantly yyu-adducts. Thus, when (5,)-1-(4-methylphenyl)sulfonyl-2-(l-oxopropyl)pyrrolidine is treated with dibutylboryl triflate in the presence of diisopropylethylamine, predominant generation of the corresponding (Z)-boron enolate occurs. The addition of this unpurified enolate to 2-methylpropanal displays not only simple diastereoselectivity, as indicated by a synjanti ratio of 91 9, but also high induced stereoselectivity, since the ratio of syn- a/.vyn-lb is >97 3. 

The following C2-symmetric bis-sulfonamide is a more efficient controller of stereoselectivity in aldol additions. The incorporation of this ligand into the bromodiazaborolane, subsequent generation of the boron enolate derived from 3-pentanone, and addition to achiral aldehydes preferentially leads to the formation of ijn-adducts (synjanti 94 6 to >98 2) with 95-98% ee. Chemical yields of 85-95% are achieved51. 

Achiral ketones, for example, 3-pentanone, can be converted predominantly into (Z)-boron enolates [(Z)/( )>97 3] by treatment with (- )-diisopinocampheylboron triflate. Subsequent addition to aldehydes, followed by an oxidative workup procedure, delivers /i-hydroxy ketones with a diastcrcomeric ratio of 95 5 to 98 2 (synjanli) and the xpn-products with 66 to 93% ee33. 

Substrate-induced diastereoselectivity is provided by the chlorotitanium enolate of 14a,b47b and the boron enolate of ketone 15S3 to give predominantly. wt-aldols. 

The enantiomeric /1-hydroxy ketones are available in an analogous way using the corresponding enantiomeric borinates. The reaction is plagued by low regioselectivity in the formation of the boron enolates, except when R1 is phenyl or isobutyl53,57. 

Pinacolone (3,3-dimethyl-2-butanone) adds to aldehydes in an enantioselective manner when advantage of the induction by a C 2-symmetric boron enolate derived by addition of (2/ ,5/ )-l-chloro-2,5-diphenylborolane is taken. In this way, /i-hydroxy ketones, whose absolute configuration is unknown, arc obtained with 32- 84% cc58. 

S)-Tricarbonyl(2-methoxyacetophenone)chromium is a starting material which provides remarkable substrate-induced stereoselectivity. Thus, its conversion into a boron enolate and subsequent addition to aldehydes delivers the chromium complexes 7 and 8 with diastereomeric ratios of 92 8 to 95 559. 

Boron enolates containing the chiral information in C2-symmetric ligands of the metal atom, also provide rmt/-/ -hydroxycarboxylic acid derivatives of high optical purity34 -64-70. When 5-(3-cthylpent-3-yl) thiopropanoate is treated with (5,5)-2,5-dimethyl-l-(trifluoromethylsul-... 

A high preference for the formation of. syw-adducts combined with remarkable induced diastereoselcctivity is also obtained with the boron enolate of 1598a and the tin enolate of 1698b. 

An entry to. yyrt-2-methoxy-3-hydroxycarboxylic acids is also opened using similar methodology. Thus the norephedrine derived (4/ ,5S)-3-(2-methoxy-l-oxoethyl)-4-methyl-5-phenyl-1,3-oxazolidine-2-one 23105a, as well as the phenylalanine derived (4S)-4-benzyl-3-(2-methoxy-l-oxoethyl)-l,3-oxazolidin-2-one 25105b, can be added to aldehydes via the boron enolates to give, after oxidative workup, the adducts in a stereoselective manner (d.r. 96 4, main product/sum of all others). Subsequent methanolysis affords the methyl esters. 

Crystalline, diastereomerieally pure syn-aIdols are also available from chiral A-acylsultams. lhe outcome of the induction can be controlled by appropriate choice of the counterion in the cnolate boron enolates lead, almost exclusively, to one adduct 27 (d.r. >97 3, major adduct/ sum of all other diastereomers) whereas mediation of the addition by lithium or tin leads to the predominant formation of adducts 28. Unfortunately, the latter reaction is plagued by lower induced stereoselectivity (d.r. 66 34 to 88 12, defined as above). In both cases, however, diastereomerieally pure adducts are available by recrystallizing the crude adducts. Esters can be liberated by treatment of the adducts with lithium hydroxide/hydrogen peroxide, whereby the chiral auxiliary reagent can be recovered106. 

When the related saccharin derived sultam (R)-29 is converted into the (Z)-boron enolate and subsequently treated with aldehydes,. vy -diastereomers 30 result almost exclusively. Thus, the diasteromeric ratios, defined as the ratio of the major product to the sum of all other stereoisomers, surpass 99 1. Hydroperoxide assisted saponification followed by esterification provides carboxylic esters 31 with recovery of sultam 32106a. 

A somewhat tedious extension of this methodology, which guarantees good induced stereoselectivity, relies on the reversible introduction of an a-substituent which is removed after the aldol addition is performed. For this purpose, the corresponding derivative of (methyl-thio)acetic acid is converted into the boron enolate and subsequently reacted with aldehydes. The... 

I4 Boron enolates derived from oxazolidinone 3 arc reported to give either syn- or imp-adducts depending on the amounl of boryl Inflate and base employed, the character of the base, and the structure of the aldehyde see H. Danda, M. M. Hansen. C. H. Heathcock, J. Org. Chem. 55,173... 

The stereoselectivity is not significantly improved if boron enolates are used instead of lithium enolates. For example, the enantiomerically pure aldehyde (—)-(2S,4/ )-4-methoxycarbonyl-2-methylpentanal delivers the diastereomeric thioeslers in a ratio of 3 2 when treated with the indicated boron enolate29. 

If a chiral aldehyde, e.g., methyl (27 ,4S)-4-formyl-2-methylpentanoate (syn-1) is attacked by an achiral enolate (see Section 1.3.4.3.1.), the induced stereoselectivity is directed by the aldehyde ( inherent aldehyde selectivity ). Predictions of the stereochemical outcome are possible (at least for 1,2- and 1,3-induction) based on the Cram—Felkin Anh model or Cram s cyclic model (see Sections 1.3.4.3.1. and 1.3.4.3.2.). If, however, the enantiomerically pure aldehyde 1 is allowed to react with both enantiomers of the boron enolate l-rerr-butyldimethylsilyloxy-2-dibutylboranyloxy-1-cyclohexyl-2-butene (2), it must be expected that the diastereofacial selec-tivitics of the aldehyde and enolate will be consonant in one of the combinations ( matched pair 29), but will be dissonant in the other combination ( mismatched pair 29). This would lead to different ratios of the adducts 3a/3b and 4a/4b. 

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