Smith synthesis subunit

Smith and co-workers reported their second-generation approach to discodermolide in 1999, which was now performed in the correct enantiomeric series [46—48]. By carefully redesigning the route, the overall number of steps was significantly reduced and, importantly, it enabled a gram-scale synthesis. As outlined in Scheme 7, the key bond constructions at C8-C9 and C14-05 were retained, while strategic modifications involved the earlier introduction of the terminal (Z)-diene unit in 44 and a revised C1-C8 subunit 45. 

The animal fatty acid synthase (FAS EC 2.3.1.85) is one of the most complex multifunctional enzymes that have been characterized, as this single polypeptide contains all the catalytic components required for a series of 37 sequential transactions (Smith, 1994). The animal FAS consists of two identical polypeptides of approximately 2500 amino acid residues (MW, ca. 270 kDa), each containing seven catalytic subunits (1) ketoacylsynthase, (2) malonyl/acetyl transferase, (3) dehydrase, (4) enoyl reductase, (5) (3-kcto reductase, (6) acyl carrier protein (ACP), and (7) thioesterase. Although some components of the complex are able to carry out their respective catalytic steps in the monomeric form, only in the FAS dimer do the subunits attain conformations that facilitate coupling of the individual reactions of fatty acid synthesis to occur (Smith et al., 2003). 

In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired xyn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 1 mixture of diastereomers, which was purified to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9-C14 subunit of the TBS ether of (+)-trienomycinol. 

The spongistatins are a family of architecturally complex bisspiroketal macrolides, which display extraordinary cytotoxicity. During the second generation synthesis of the ABCD subunit of spongistatin 1, A.B. Smith and coworkers utilized the Keck allylation to construct the Kishi epoxide. The allylation was carried out under standard conditions, using tributyl-(2-ethylallyl)-stannane as the allylstannane reactant. The desired product was formed in high yield and a diastereomeric ratio greater than 10 1. 

Rangan, V. S., Joshi, A. K. and Smith, S., Fatty acid synthase dimers containing catalytically active beta-ketoacyl synthase or malonyl/acetyltransferase domains in only one subunit can support fatty acid synthesis at the acyl carrier protein domains of both subunits, J Biol Chem 273 (1998) 34949-34953. 

Smith AB III, Lin Q, Doughty VA, Zhuang L, McBriar MD, Kerns JK, Brook CS, Murase N, Nakayama K. The spongistatins architecturally complex natural products - part two synthesis of the C29 51 subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew. Chem. Int. Ed. 2001 40 196 199. 

Smith AB HI, Tomioka T, Risatti CA, Sperry JB, Sfouggatakis C. Gram-scale synthesis of (+)-spongistatin 1 development of an improved, scalable synthesis of the F-ring subunit, fragment imion, and final elaboration. Org. Lett. 2008 10 4359 362. 

It may be important to note that there seems to be a dissociation between the synthesis of FceRI subunits and the cell surface expression of this receptor in human eosinophils. Indeed, Smith et al. (52) confirmed the presence of intracellular FceRla protein, using flow cytometry to analyze permeabilized cells as well as immunohistochemistry to directly visualize cytospin preparations, but negligible FceRla protein was detectable on the cell surface. Furthermore, Semi-... 

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