Lactate derivatives

Preliminary investigations into the generality of this synthesis of lactate-derived ketones using other alkyl lithium reagents including butyllithium and phenyllithium have not been as successful. Product mixtures were typically contaminated with significant amounts of both the tertiary alcohol and the starting ester. 

S)-2-/-Butyldimethylsilyloxypentan-3-one (46), a lactate-derived chiral ketone, undergoes titanium-mediated aldols giving all-vyn products in high de.121 Low-temperature (g) H and 13C NMR evidence suggests a likely TS to account for the selectivity. 

Ethyl lactate was used for diastereocontrol and asymmetric transmission in a sequential 2,3-Wittig-oxy-Cope rearrangement, affording product in 91% ee (eq 9). - 4 Excellent asymmetric induction has also been noted in the Lewis acid-mediated ene reaction of (5)-ethyl lactate-derived intermediates (eq 10). ... 

Several alternative auxiliaries for obtaining anti aldol products are available [26]. For example, the lactate-derived ketone (R)-39, as developed in our laboratories, displays high levels of stereocontrol in boron-mediated anti aldol reactions (Scheme 9-14) [27]. Simple manipulations of the aldol product 40 allows the gen-... 

The related lactate-derived ketones, 44 [27] and 45 [29], are useful auxiliaries for boron- and titanium-mediated syn aldol reactions, respectively (Scheme 9-14). The effect of the protecting group in both cases is notable. For ketone 44, the use of the boron chloride reagent unexpectedly afforded the syn adduct with good control... 

At the time, many unsuccessful attempts were made to improve the selectivity of the mismatched anti aldol reaction mentioned above, outlining the limitations of some chiral ligands or auxiliaries at overcoming inherent substrate bias in anti aldol reactions. Since the completion of this work, we have introduced the lactate-derived ketones (/ )- and (S)-39, which should now allow the stereoselective synthesis of the ebelactones. As shown in Scheme 9-75, each enantiomer of the parent ketone acts as a propionate equivalent with a covalently attached auxiliary which will overturn the facial bias of most aldehydes [27, 28]. 

The synthesis of 16 starts using a lactate derivative and makes cunning use of a lithium-binding chain to achieve the selectivity required in producing intermediate 17.11 The even better catalyst 18 was prepared from the same key intermediate 17. 

Scheme 18 Intramolecular [2+2] photocycloaddition of a substrate with a lactate-derived tether.

Magnesiocuprates react with lactate derivative 189 to give the corresponding (S)-2-methylalkanoic acids (202) in moderate yield, however, optical yields are quite impressive, with enantiomeric excesses ranging from 95 to 99% [74]. This is superior to reactions with corresponding tosylates or mesylates where highly competitive reduction or elimination processes predominate. 

Benzyl-protected ( S)-lactaldehyde (464) can be prepared from either the methyl or ethyl lactate derivative 271 by reduction of the ester with lithium aluminum hydride followed by oxidation of 276 under Swem conditions (83% yield) [92,148] or with PCC in methylene chloride [149]. Aldehyde 464 can also be obtained directly from 271 by partial reduction with diisobutylaluminum hydride at —78 °C [117,150]. 

Cycloaddition of chiral imines with diketene allows one to gain access to chiral lactams. An interesting example of this is the reaction of lactate-derived imine 573 with diketene, which produces a 7.3 1 mixture of 574 and 575 [117]. Chromatographic separation of the major isomer furnishes 574 with an enantiomeric excess of 96%. 

The synthesis of (-h )-polyoxamic acid (435), the unusual amino acid component of polyoxin B, incorporates backbone assembly via a Homer- Emmons olefination of L-tartrate-derived aldehyde 430 with (i )-lactate-derived jS-ketophosphonate 914 [101] (Scheme 122). The key introduction of the chiral amine stereocenter is accomplished by a trifluoroacetimidate rearrangement, outlined in Scheme 60 (Section 1.4.7.2). 

Lactate-Derived Phenyl Ether Complexes of Osmium(II). 122... 

The oxylactonization of ort/io-alkenylbenzoates with lactate-derived optically active hypervalent iodine(III) reagents proceeds with a high degree of regio-, diastereo- and enantioselectivity leading to the asymmetric synthesis of 3-alkyl-4-oxyisochroman-l-ones [263]. A specific example - the enantioselective oxylactonization of substrate 202 with reagent 203 - is shown in Scheme 3.83. 

Ac2-L-Lys-D-Ala-D-Ala, but still 100-fold greater than that for Ac2-L-Lys-D-Ala-D-Lac, indicating that the lone pair repulsion is the principal contribution to the low affinity of the lactate derivative. 

In recent years, chiral hypervalent iodine(III) reagents have received immense attention and have been applied extensively in the stereoselective synthesis of heterocycles. In 2010, Fujita et al. [53, 54] documented an enantiodifferentiating ewiio-selective oxylactonization of ort/io-alkenylbenzoates 55 by using a series of optically active lactate-derived iodine(III) reagents such as 57 (Scheme 14). This stereocontrolled transformatirai allowed efficient access to optically active 4-oxyisochromanones 56. 

Deoxy-sugars have also been constructed from noncarbohydrate starting materials. One-carbon extension of the L-lactate derivative (59) gave dithioacetal (60) from which various 4-deoxy-L-threose and -erythrose derivatives were synthesised. Tetramethylammonium triacetoxyborohydride has been used to selectively reduce -hydroxy-ketones to anti-1.3-diols. as in the conversion of ketones (61) and (62) to diol (63) and triol (64),... 

Scheme 4-56. Synthesis of enantiomerically enriched (ethylidene)iron complexes using chiral lactate-derived acyliron complexes.

The aldol reaction with the lactate derivative was applied to the synthesis of citreoviral 78 (Scheme 8.12). The enolate of 72 was reacted with unsaturated aldehyde 73 to yield a,(3-dihydroxy-7,8-unsaturated imide 74 in a stereoselective manner. Adduct 74 was subjected to iodolactonization to accompany the removal of the chiral auxiliary to give 75 as a single isomer. Debenzylation was followed by etherification with the tertiary alcohol to provide the highly substituted furan 77 having all the chiral centers of the target molecule. The additional four-step sequence afforded citreoviral 78. 

SCHEME 8.11. The titanium-mediated aldol reactions of lactate derivatives. 

FIGURE 10.7. Patersons et al. lactate-derived ketones 156/157 versus other ketones possessing... 

SCHEME 10.33. Diastereoselectivity of aldol reactioDS using Paterson s lactate-derived ketones. 

Paterson I, Wallace DJ, Velazquez SM. Studies in polypropionate synthesis high -rr-face selectivity in syn and anti aldol reactions of chiral boron enolates of lactate-derived ketones. Tetrahedron Lett. 1994 35 9083-9086. 

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