Aldehydes enantiomerically pure

Enantiomerically pure tetroses, pentoses, and hexoses have been synthesized by the following reaction sequence (A.W.M. Lee, 1982 S.Y. Ko, 1983), which is useful as a repetitive two-carbon hotnologi-.ation in total syntheses of higher monosaccharides and other polyhydroxy compounds (1) Wittig reaction of a protected hydroxy aldehyde with (triphenylphosphor-... 

From intermediate 28, the construction of aldehyde 8 only requires a few straightforward steps. Thus, alkylation of the newly introduced C-3 secondary hydroxyl with methyl iodide, followed by hydrogenolysis of the C-5 benzyl ether, furnishes primary alcohol ( )-29. With a free primary hydroxyl group, compound ( )-29 provides a convenient opportunity for optical resolution at this stage. Indeed, separation of the equimolar mixture of diastereo-meric urethanes (carbamates) resulting from the action of (S)-(-)-a-methylbenzylisocyanate on ( )-29, followed by lithium aluminum hydride reduction of the separated urethanes, provides both enantiomers of 29 in optically active form. Oxidation of the levorotatory alcohol (-)-29 with PCC furnishes enantiomerically pure aldehyde 8 (88 % yield). 

The adjacent iodine and lactone groupings in 16 constitute the structural prerequisite, or retron, for the iodolactonization transform.15 It was anticipated that the action of iodine on unsaturated carboxylic acid 17 would induce iodolactonization16 to give iodo-lactone 16. The cis C20-C21 double bond in 17 provides a convenient opportunity for molecular simplification. In the synthetic direction, a Wittig reaction17 between the nonstabilized phosphorous ylide derived from 19 and aldehyde 18 could result in the formation of cis alkene 17. Enantiomerically pure (/ )-citronellic acid (20) and (+)-/ -hydroxyisobutyric acid (11) are readily available sources of chirality that could be converted in a straightforward manner into optically active building blocks 18 and 19, respectively. 

The synthesis of intermediate 19 commences with aldehyde 33 (see Scheme 5b), a substance readily available in enantiomerically pure form from (+)-/ -hydroxyisobutyric acid (11)20. Exposure of... 

The synthetic problem is now reduced to the development of a feasible, large-scale preparation of enantiomerically pure (/ )-citro-nellal (36), which has a single stereogenic center. One way in which the aldehyde function in 36 could be introduced is through the hydrolysis of a terminal enamine. (/ )-CitronelIal (36) can thus be traced to citronellal ( )-diethylenamine (44), the projected product of an enantioselective isomerization of prochiral diethylgera-... 

The synthesis of the E-ring intermediate 20 commences with the methyl ester of enantiomerically pure L-serine hydrochloride (22) (see Scheme 9). The primary amino group of 22 can be alkylated in a straightforward manner by treatment with acetaldehyde, followed by reduction of the intermediate imine with sodium borohydride (see 22 —> 51). The primary hydroxyl and secondary amino groups in 51 are affixed to adjacent carbon atoms. By virtue of this close spatial relationship, it seemed reasonable to expect that the simultaneous protection of these two functions in the form of an oxazolidi-none ring could be achieved. Indeed, treatment of 51 with l,l -car-bonyldiimidazole in refluxing acetonitrile, followed by partial reduction of the methoxycarbonyl function with one equivalent of Dibal-H provides oxazolidinone aldehyde 52. 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

Oxidation of the methyl substituent in compounds 4 to the corresponding aldehydes and subsequent reaction with ephedrine leads to (V.O-acetals, which can be separated by crystallization into the two diastereomers. Treatment with silica gel then gives the enantiomerically pure aldehydes.17... 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

Enantiomerically pure a-alkoxyallylstannanes also react with aldehydes with excellent diastere-ofacial selectivity, see Section 1.3.3.3.6.3.2. 

The enantiomeric compositions of the titanium reagents are monitored easily by the reaction with enantiomerically pure chiral aldehydes, such as 2-(fer/-butyldimethylsilyloxy)propanal104. Here, the ratio of diastereomeric products reflects the ratio of enantiomers of the reagent, although a small error arises from double stereodifferentiation95 104. 

With C2-symmetric reagents (5,5)-2,5-dimethyl-l-trifluoromethylsulfonylborolane34 and (R,R)-l-chloro-2,5-diphenylborolane , (S)-(3-ethylpent-3-yl) thiopropanoate is added, via the corresponding enolates, to aldehydes with remarkable auxiliary-induced stereoselectivity. Thus, /1-hydroxy thioestcrs arc obtained with 87-94% ee when the borolanyl triflate auxiliary reagent is used. These ee values do not exactly reflect the enantiofacial selectivity since the borolane is not available in enantiomerically pure form (see Section 1.3.4.2.2.2.). Use of the chiral chloroborolane auxiliary gives the thioestcrs with 95-96% cc70,11. o... 

In a chiral aldehyde or a chiral ketone, the carbonyl faces are diastereotopic. Thus, the addition of an enolate leads to the formation of at least one stereogenic center. An effective transfer of chirality from the stereogenic center to the diastereoface is highly desirable. In most cases of diastereoface selection of this type, the chiral aldehyde or ketone was used in the racemic form, especially in early investigations. However, from the point of view of an HPC synthesis, it is indispensable to use enantiomerically pure carbonyl compounds. Therefore, this section emphasizes those aldol reactions which are performed with enantiomerically pure aldehydes. 

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. 

Lower stereoselectivities arise, however, from the addition of ester enolates to this glyceralde-hyde4. Another highly stereoselective addition is in the synthesis of erythromycin A where a single product results from the addition of lithiated tert-butyl thiopropanoate to the enantiomerically pure aldehyde (2/ ,3/ ,4,S, 6/ ,7/ ,8,S, 9/ ,10.S, 11 / )-7-acetoxy-3,4 9,10-bis(isopropy1-idenedioxy)-11-methoxymethoxy-2,4,6,8,10-pentamethyltridecanal5. 

In a synthesis of maytansinoids, a 10 1 ratio of adducts results from the reaction of ethyl lithiodithioacetate with the enantiomerically pure aldehyde ( + )-(2S, 3S, 4S)-3,4-epoxy-2,4-dimethyl-5-trimethylsilyloxypentanal°. 

Examples of both chelation-controlled and nonchelation-controlled additions of achiral enolates to enantiomerically pure aldehydes are listed in Tabic 1. 

Table 1. Addition of Achiral Enolates to Enantiomerically Pure Aldehydes (Representative Examples)... 

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. 

A similar case of enolatc-controlled stereochemistry is found in aldol additions of the chiral acetate 2-hydroxy-2.2-triphenylethyl acetate (HYTRA) when both enantiomers of double deprotonated (R)- and (S)-HYTRA are combined with an enantiomerically pure aldehyde, e.g., (7 )-3-benzyloxybutanal. As in the case of achiral aldehydes, the deprotonated (tf)-HYTRA also attacks (independent of the chirality of the substrate) mainly from the /te-side to give predominantly the t/nii-carboxylic acid after hydrolysis. On the other hand, the (S)-reagcnt attacks the (/ )-aldebyde preferably from the. S7-side to give. s wz-carboxylic acids with comparable selectivity 6... 

The combination of the enantiomerically pure 7V-methylephedrine derived silylketene acetal l-[(l/ ,2S)-2-dimethylamino-1-phenylpropoxy]-l-triniethylsilyloxy-l-propene with the chiral aldehyde (,R)-3-benzyloxy-2-methylpropanal leads, after reduction with lithium aluminum hydride, to the formation of a single 1,3-pentanediol 9 ( matched pair ). 

Addition of metalated, enantiomerically pure a-sulfinyl dimethylhydrazones (e.g., 9) to racemic a-chiral aldehydes 10 proceeds with good to excellent diastereo- and enantioselectivi-ty12. Diastereomeric ratios increase with increasing steric demand of the acetaldehyde substituent R1 compared to the methyl group, and each diastereomer is obtained with high enantiomeric excess. In the aldol-lype addition to 2-phenylpropanal, one of the four possible stereoisomers is formed selectively. The relative (syn) and absolute (R.R) configuration is in accord with Cram s and related rules as well as H-NMR data of closely related compounds. 

I.3.5.6.4. Stereoselective Addition of Enantiomerically Pure Nitronates to Aldehydes... 

The lithio derivative of Ar,Ar-dicthyl-2-toluamide 1 adds to each enantiomerically pure glycer-aldehyde acetonide 4-methoxybenzyl imine [(7 )-2 or (S)-2] to provide only one diastereomer exclusively or (3/ ,TA)-3, respectively]. The moderate yield (50%) is due. in part,... 

Enantiomerically pure of-dibenzylamino-/V-tosylimines 2 arc accessible from amino acids. Since they are not suitable for storage it is advantageous to prepare them in situ from the corresponding aldehydes 1 and A-sulfmyl-4-toluenesulfonamide immediately before use. Addition of Grignard reagents affords the protected 1,2-diamines 3 in good yields (57-95%) and diastereoselectivities (d.r. 85 15 >95 5)8. Deprotection is achieved without racenuzation by reductive methods, see 4-6. 

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