Lactacystin synthesis

Lactacystin synthesis 196 Lasubine synthesis 134 Lepadin synthesis 142... 

The methyl ester of the wrong diastereoisomer of 3-hydroxyleucine 183 required merely deprotection of 182 and ester exchange best catalysed by Ti(IV). Incorporation into the oxazoline 184 prepares the way for the aldol reaction with formaldehyde that inverts the stereochemistry at the ester centre and leads to their lactacystin synthesis.27... 

Both the benzylic C-O and the C-N bonds were cleaved during the synthesis of (4)-lactacystin. The hydrogenolysis of the oxazoline moiety on Pd/C, Pd(OH2)/C, or Pd black in MeOH proved unsuccessful, but catalytic transfer... 

Several groups employed this strategy for the synthesis of lactacystin analogues, an important class of nonprotein neurotrophic factors. For example, in their total... 

Synthesis of the Proteasome Inhibitors Salinosporamide A, Omuralide and Lactacystin... 

The structurally-related 7-lactams salinosporamide A 1, omuralide 2 and lactacystin 3, of bacterial origin, inhibit proteasome activity, and so are of interest as lead compounds for the development of anticancer agents. Barbara . M. Potts of Nereus Pharmaceuticals in San Diego has reported (J. Med. Chem. 2005,48,3684) a detailed structure-activity studies in this series, and E.J. Corey of Harvard University has prepared (J. Am. Chem. Soc. 2005,127, 8974, 15386) several interesting structural analogues. Susumi Hatakeyama of Nagasaki University, building on previous work in this area, has reported (J. Org. Chem. 2004, 69,7765) a synthesis of 2 and 3 from Tris. 

Shibasaki M, Kanai M, Fukuda N (2007) Total Synthesis of Lactacystin and Salinosporamide A. Chem Asian J 2 20... 

Ohfune and co-workers have developed several methodologies involving an asymmetric version of the Strecker synthesis called asymmetric transferring Strecker synthesis (ATS) which has been successfully applied to the synthesis of optically active / -hydroxy-a-substituted a-amino acids [20]. This technique was further applied toward the synthesis of the Corey intermediate of lactacystin [21]. 

Hydroxyalkanoic acids are easily dehydrated to either spiro or fused /3-lactones. Sulfonyl chlorides have been the traditional reagents employed for this transformation <1996S586, 2001CC753>. However, as illustrated in Equation (38) for a cyclization used as part of a synthesis of lactacystin/omuralide (see also Section 2.06.12.4), bis(oxazolidi-none) phosphinyl chloride (BOP-C1) has proven an effective agent for application in sensitive structures note also the selectivity for introduction of the fused (vs. spiro) lactone <2006JOC1220>. 

Chida, N, Takeoka, J, Tsutsumi, N, Ogawa, S, Total synthesis of (4-)-lactacystin from D-glucose, J. Chem. Soc., Chem. Commun., 793-794, 1995. 

A variety of complex natural compounds are synthesized by using monosaccharides as chiral starting materials. Exemplifying eight representative natural products, i. e., erythromycins, elaiophilin, herbimaycins, calbistrin A, lactacystin, tautomycin, FK-506, and halichondrin B, the methodology how monosaccharides are incorporated into natural product synthesis as chiral pools is described. 

Lactacystin (108) is the first nonprotein neurotrophic factor (O Fig. 9). Chida and coworkers achieved the total synthesis of lactacystin (108), whose central core 109 was prepared from l,2 5,6-di-0-isopropylidene-Q -D-glucofuranose (2) [61,62]. 

The groups of Corey [63,64,65,66], Omura and Smith [67,68], and Baldwin [69] have reported the total synthesis of lactacystin (108) the starting materials of their syntheses are amino acids. The groups of Panek [70], Hatakeyama [71], Kanai and Shibasaki [72], and Jacobsen [73] have also reported the total synthesis of lactacystin (108). 

Many of the application of AA have used conjugated alkenes but simple, even mono-substituted alkenes such as 179 can be used providing there is some definite difference between the ends - here with this naphthalene compound 180 between no substituent and an aromatic ring. The synthesis of lactacystin using AA is described in chapter 31. 

A tetrahydropyran that inhibits leukotriene biosynthesis Asymmetric synthesis of2-methyl-tetrahydropyran-4-one by kinetic resolution Part VI - Asymmetric Desymmetrisation of a Diels-Alder Adduct Ifetroban sodium a thromboxane receptor antagonist A laboratory synthesis starting with a Diels-Alder reaction Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent Laboratory and process routes compared Part VII - Asymmetric Synthesis of A Bicyclic 3-Lactone Lactacystin a naturalproteasome inhibitor... 

A chiral pool synthesis of lactacystin from glucose... 

Strategies used in the synthesis of lactacystin, the P-lactone, and analogues... 

An early synthesis of lactacystin, not via the P-lactone, used glucose as starting material.20 Disconnection to 115 (the vinyl group can be converted into COzH and the benzyl ether into CHO) gives a structure that can be redrawn as 116 and then, with incorporation of an extra C atom (to be removed in the synthesis by diol oxidation) derived from 117. 

We move into approaches that are more sophisticated in several ways. The synthesis by Omura and Amos B. Smith23 was partly inspired by the biosynthesis of lactacystin and partly by an attempt to make other diastereoisomers. Their key intermediate is the non-proteinogenic amino acid hydroxyleucine 147 and they were able to make both enantiomers of both diastereoisomers of this compound by asymmetric synthesis. 

Many developments have come from Corey s laboratories in the lactacystin area since the synthesis described above.24 One strategy we have not mentioned before is the use of an enzyme, pig liver esterase (chapter 29) in the selective hydrolysis of one of two enantiotopic ester groups in the malonate 161. An MeS group is used to block enolisation and prevent racemisation of the product 162. The mono ester 162 is initially formed in 67% ee improved by one crystallisation of the quinine salt to 95% ee. The pyrrolidine ring 164 is made in an unusual way by first forming the amide 163 and then cyclising the diester by carbonyl condensation. The new chiral centre in 164 is not controlled but disappears in the next step. 

A large-scale synthesis of lactacystin analogues using AD and an asymmetric aldol reaction... 

The oxazoline 184 provides an attractive approach to lactacystin as it is a protected form of 3-hydroxyleucine. The other half of the molecule was made in the LeukoSite synthesis by a very different method the alkylation of an Evans chiral auxiliary. This was chosen partly because they wished to vary the alkyl group on the pyrrolidone ring and we use the propyl compound as example. The phenylalanine derived oxazolidinone 193 (chapter 27) was acylated and then the titanium enolate of 194 was alkylated to give 195 with very high selectivity and the chiral auxiliary removed to give the simple acid 196. 

Bond insertion. A gainful application of the intramolecular Rh-carbenoid insertion into a C—H bond is described in a synthesis of ctoto-lactacystin 3-lactone. ... 

The total synthesis of (-l-)-lactacystin (1) has been achieved via Overman rearrangement of allylic trichloroacetimidate derived from D-glucose as an effective method for chiral synthesis of a,a-disubstituted amino acid derivatives (Schemes 1 and Selective... 

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