Citronellal, chiral aldehyde

A striking example of the power of A -heterocyclic carbene (NHC)-bearing catalysts with sterically demanding substrates was disclosed by Chavez and Jacobsen, " who presented a route to several iridoid natural products, exemplified by the enantio- and diastereoselective synthesis of boschnialactone 31 outlined in Scheme 5. Chiral aldehyde 27, available from citronellal by Eschenmoser-methylenation in a single step, reacted despite the presence of an isoprenyl moiety and a gi OT-disubstituted double bond, in the presence of catalyst C smoothly to form... 

The chiraUy modified cluster HRu3(CO)10(i -OCNCH2CH2CH2CHCH2 OCH3) catalyzes the conversion of the prochiral allylic alcohol nerol (78) into the chiral aldehyde citronellal (79)... 

Enamines of unsaturated aldehydes can be converted into the corresponding dienes for example, citronellal, a chiral aldehyde, gives the chiral non-conjugated diene, /f-citronellene, in 92% enantiomeric excess - (Scheme 172). The combination of the Lewis hydroboration procedure with the thallium acetate acetoxylation of enamines provides a means of converting enamines into acetoxycycloalkenes (Scheme 173). The hydroboration oxidation of enamines to give -aminoalcohols was first reported by Borowitz and Williams . Cw-l,2-addition of BH3 occurs, to give the trans-ji-ammocy-... 

Scheme 13.27. The relationship between the chiral aldehyde isolated on pyrolysis of the cholest-A en-3P-ol ozonolysis product and (l )-(+)-citronellal as demonstrated by the identity of their semicarbazone derivatives. After Comforth, J. W. Youhotsky, I. Popjdk, G. Nature, 1954,173,536 and Cornforth, J. W. Gore, I. Y. Popjak, G. Biochem. J., 1957,65,94.

The reaction is general for various acrylates having or not substituents at the y-position (R = Aryl, C02Me) and aldehydes (R = alkyl, alkenyl, carbamate, acetal, ester), (yield 50-87%, ee 87-98%, syn anti 80 20-94 6). By using chiral aldehydes such as (S)-citronellal, the reaction presented high diastereoselectivity (97 3 dr) for the matched pair. 

The mechanisms of the reactions of the cluster Ru3(CO)i2 with halide ions, alkoxide ions and amines, all of which involve initial rapid nucleophilic addition at a carbonyl hgand, have been reviewed.In a related study, addition of 5-proline methylester or 5-methoxymethyl pyrrolidine to a carbonyl ligand of Ru3(CO)j2 has yielded chiral carbamoyl clusters of the type (84) R = C02Me or CH20Me, Eq. (16). Such chiral clusters may have potential as new enantioselective catalysts, as shown by the observation that cluster (84), R = CH20Me) catalyzes the isomerization of the prochiral allylic alcohol nerol to give the chiral aldehyde citronellal with an enantiomeric excess of 12%. 

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. 

Analogous to the use of chiral acetals one can employ chiral N,O-acetals, accessible from a, -unsatu-rated aldehydes and certain chiral amino alcohols, to prepare optically active -substituted aldehydes via subsequent Sn2 addition and hydrolysis. However, the situation is more complicated in this case, since the N,0-acetal center constitutes a new stereogenic center which has to be selectively established. The addition of organocopper compounds to a, -ethylenic oxazolidine derivatives prepared from unsaturated aldehydes and ephedrine was studied.70-78 The (diastereo) selectivities were rather low (<50% ee after hydrolysis) in most cases, the highest value being 80% ee in a single case.73 There is a strong solvent effect in these reactions, e.g. in the addition of lithium dimethylcuprate to the ( )-cinnamaldehyde-derived oxazolidine (70 Scheme 28) 73 the (fl)-aldehyde (71) is formed preferentially in polar solvents, while the (S)-enantiomer [ent-71) is the major product in nonpolar solvents like hexane. This approach was utilized in the preparation of citronellal (80% ee) from crotonaldehyde (40% overall yield).78... 

Allylic double bonds can be isomerized by some transition metal complexes. Isomerization of alkyl allyl ethers 480 to vinyl ethers 481 is catalysed by Pd on carbon [205] and the Wilkinson complex [206], and the vinyl ethers are hydrolysed to aldehydes. Isomerization of the allylic amines to enamines is catalysed by Rh complexes [207]. The asymmetric isomerization of A jV-diethylgeranylamine (483), catalysed by Rh-(5)-BINAP (XXXI) complex to produce the (f )-enaminc 484 with high optical purity, has been achieved with a 300 000 turnover of the Rh catalyst, and citronellal (485) with nearly 100% ee is obtained by the hydrolysis of the enamine 484 [208]. Now optically pure /-menthol (486) is commerically produced in five steps from myrcene (482) via citronellal (485) by Takasago International Corporation. This is the largest industrial process of asymmetric synthesis in the world [209]. The following stereochemical corelation between the stereochemistries of the chiral Rh catalysts, diethylgeranylamine (483), diethylnerylamine (487) and the (R)- and (5)-enamines 484... 

The choice of which way round to do the Wittig may appear arbitrary but it isn t. Pempo and his group7 chose citronellal 47 and citronellol 48, two related natural terpenes from citronella oil, as starting materials with the right stereochemistry at the one chiral centre. If you imagine a Wittig reaction between the phosphonium salt 49 and some suitable aldehyde, you will see that the central part of the molecule would be right. 

With the catalysts derived from (S,S)-l,2-bis(diphenylphosphinomethyl)cyclobutane and [RhH(CO)(PPh3)3] or rhodium carbonyls, the a,3-unsaturated aldehydes, neral and geranial, are hydrogenated to (E)- and (S)-citronellal in 79% and 60% ee, respectively. Cyclic a,3-unsaturated ketones such as isophorone and 2-methyl-2-cyclohexenone have been hydrogenated using ruthenium hydrides coordinated with chiral diphosphines in up to 62% ee to give chiral ketones, though conversions are not satisfactory. ... 

The total synthesis of milbemycin-p developed by Williams et al. [124] involves construction of three units the spiroketal moiety (A), carbon chain with a remote chiral centre at C-12 (B) and the substituted benzoic acid (C). Unit (A) is prepared starting from citronellol (154), while unit (B) was prepared starting from (-)-(3S)-citronellal (162) (Scheme 20). A and B were joined after transmetalation of the tetrahydropyranyl ether 166 to give 167 (Scheme 21), which is allowed to react with the aldehyde A to give 168. Further steps are shown in scheme 22. 

The dienamines derived from enals undergo hydroboration with 9-BBN, with high regio- and chemoselectivity at the enamine carbon-carbon double bond and place the boron atom on a carbon having higher electron density. The high selectivity is confirmed by the hydroboration of a 1 1 mixture of 1-hexene and 1-morpholino-l-octene with 1 equiv of 9-BBN. The reaction mixture affords, after the addition of methanol, a 1 1 mixture of 1-hexene and 1-octene, and no 1-hexanol is detected. Consequently, this process is used to convert unsaturated aldehydes to dienes. Thus, enamine of citronellal on hydroboration-elimination affords a chiral non-conjugated diene, p-citronellene (Scheme 24.5) [1]. 

Apart from certain carbohydrates, the most inexpensive source of chiral compounds is the terpenes. These are readily obtained from plant sources and encompass examples of many important functional groups These include alcohols such as (+)-menthol (22) and (-)-bomeol (23), ketones such as (+)-camphor (24), (+)-pulegone (25), (-)-menthone (26) and (-)-carvone (27), the aldehyde (+)-citronellal (28), (+)-camphor-10-sulphonic acid (29), and alkenes such as (+)-limonene (30) and (+)-a-pinene (31). (a)-Pinene provides a good illustration of the fact that naturally derived chiral compounds are not necessarily enantiomerically pure. Both enantiomers are readily available but the normal samples are only of around 90% e.e. Fortunately this is not a serious problem since procedures have been... 

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