Branchpoints

Greatest simplification (in middle of molecule, at branchpoint, rings from chains. 

The synthesis of the natural product citronellol (1) (used in perfumery) shows guidelines 1 and 4 in action. Disconnection at the branchpoint is possible (la) and the required alcohol (2) comes from available ketone (3) (p Tl) by reduction. 

AnBwep Disconnection back to the first branchpoint ( in 14a) requires formaldehyde and halide (15) which comes from alcohol (16). Disconnect ion back to the second branchpoint ( in 16) gives two available starting materials. 

Example As part of a programme to screen for new perfumery compounds, alcohol (17) was wanted. This has two branchpoints ( in 17) and disconnection between them simplifies the problem a great deal. Ketone (IS) is an available natural product (thujaketone) and halide (19) can be made via a Grignard reaction. 

Answer We obviously want to discontioct on the more substituted side and (a), (b) and (c) are all possibi Disconnection (c) has the advantage that it is betweer two branchpoints and so gives two simple starting materials. 

Optically active ketone (6) was needed for a study of asymmetric induction It could be made from acid (7) by a Friedel Crafts route or from nitrile (8) by Grignard addition, but neither of these compounds could be made by alkylation as the branchpoint is on the 3 carbon ( in each). The 1,3 C-C disconnection, e.g. (6b) is not good as it destroys the chiral centre. 

Answer Tho dlsconnccLion must he of a bond S,, y to the carbonyl group. It is best to Inavt the ring intact and disconnect at a ring-chain Junction (a-c) or at a branchpoint (d). 

Answer The OH group is best placed at the branchpoint to give alcohol (8) any arm of this symmetrical alcohol can now be disconnected. 

An uer Disconnection at the branchpoint is best giving acry.late (15) and specific enol (14),... 

Answer The better Michael disconnection is (19a) (branchpoint and more stable anion) and the intermediate (20) can be made by direct formylation of cyclohexanone. 

Answer Comparison with dimedone (p T 177) suggests a similar analysis, starting with the 1,3-dicarbonyl disconnection to give keto-ester (33), and then disconnecting next to the branchpoint to give enone (34). Anatysis... 

Opening the anhydride and writing the enol as a ketone reveals that we are trying to make an a-ketoacld (51), The best disconnection Is (51a) which uses the 1.3-dlcarbonyl relationship, Is next to a branchpoint, and produces a symmetrical starting material (52), Ana lysis... 

Hydrogenation of an alkene such as (42) or (43) is a good irtethod, and these could both be derived from branchpoint alcohol (44). 

Alkenes (46) or (47) could be hydrogenated to (45) and these could be made by Wittig reactions or from the three branchpoint alcohols (48 - 50). 

Lactone (13) is clearly derived from (14) branchpoint disconnection gives acid (15) and synthon (16). Epoxide (17) has the right regloselectivity for this synthon. 

The diketo-ester (1) has 1,4 1,5 and 1,6-dicarbonyl relationships. Both the 1,4 and 1,5 relationships can be disconnected at the branchpoint in the middle of the molecule, to give sensible intermediates such as (3) and (4), but difficult synthons (2) and (5). The 1,6 reconnection requires symmetrical Diels-Alder adduct (6). 

Enone disconnection gives ketoaldehyde (2) as the key intermediate. Cyclisation of (2) to (1) will be unambiguous as no other stable ring can be formed. Disconnection ol (2) is more of a problem. The branchpoint suggests two possibilities (a) and (b). 

From the topology of branched systems with trifunctional branchpoints, for any given molecule the number of branched units is equal to the number of terminal unit minus one. Thus, Eq. 1 can be further simplified to... 

Although NMR experiments afford a conclusive measurement of the degree of branching for lower y values, the low concentration of branchpoints in the... 

Triterpenoid saponins are synthesized via the isoprenoid pathway.4 The first committed step in triterpenoid saponin biosynthesis involves the cyclization of 2,3-oxidosqualene to one of a number of different potential products (Fig. 5.1).4,8 Most plant triterpenoid saponins are derived from oleanane or dammarane skeletons although lupanes are also common 4 This cyclization event forms a branchpoint with the sterol biosynthetic pathway in which 2,3-oxidosqualene is cyclized to cycloartenol in plants, or to lanosterol in animals and fungi. 

Fig. 10.3 Reaction catalyzed by the cytochrome P-450-dependent oxidase berbamunine synthase (CYP80A1). This enzyme creates a branchpoint in the (5)-reticuline biosynthetic pathway to form the bisbenzylisoquinoline alkaloids.

BAK, S., TAX, F.E., FELDMANN, K.A., GALBRAITH, D.A., FEYEREISEN, R, CYP83B1, a cytochrome P450 at the metabolic branchpoint in auxin and indole glucosinolate biosynthesis in Arabidopsis thaliana, Plant Cell, 2001,13, 101-111. 

Ortiz de Montellano PR, Komives EA. Branchpoint for heme alkylation and metabolite formation in the oxidation of arylacetylenes by cytochrome P-450. J Biol Chem 1985 260(6) 3330-3336. 

Figure 14. Principle for measuring bidirectional fluxes by 13C metabolic flux analysis. In a carbon labeling experiment, 1 13C glucose is provided in the medium, and the culture is grown until a steady state is reached. Glucose can either go directly via the hexose phosphate pool (Glu 6P and Fru 6P) into starch, resulting in labeling hexose units of starch only at the Cj position, or it can be cleaved to triose phosphates (DHAP and GAP), from which hexose phosphates can be resynthesized, which will result in 50% labeling at both the Ci and the C6 position (assuming equilibration of label by scrambling at the level of triose phosphates). From the label in the hexose units of starch, the steady state fluxes at the hexose phosphate branchpoint can be calculated for example, if we observe 75% label at the Ci and 25% at the C6 position, the ratio of vs to V7 must have been 1 to 1. All other fluxes can be derived if two of the fluxes of Vi, V6, and V7 are known (e.g., V2 vi V3 V5 + v6).

Fig. 18a-c. Tube-model diagrams of the low-frequency model for the pom-pom architecture a the unstretched molecule b under deformation such that the cross-bar has been stretched by a factor less than the number of arms c under deformation such that the backbone has been stretched by a factor greater than the number of arms, initiating branchpoint-withdrawal ... 

EDITING MECHANISMS BRANCHING ENZYME BRANCHPOINT BREATHING Bredt s Rule,... 

In Tabernaemontana divaricata treatment of plant cell suspension cultures with an elicitor cause inhibition of CS activity [24,25]. This response is accompanied by stimulation of activity of constitutive enzyme activities of the isoprenoid pathway leading to 2,3-oxidosqualene (squalene synthase and squalene oxidase), and induction of enzymes required for biosynthesis of pentacyclic triterpenoid phytoalexins (/lAS and aAS). Thus inhibition of the branchpoint enzyme CS results in increased flux through the triterpenoid pathway. 

These methods give a number-average estimate of the end-groups or branchpoints, and correspondingly the number-average DP must be known before the... 

The synthesis of adrenal steroids is illustrated in Fig. 5.3.1. Cortisol, corticosterone, and aldosterone are formed by sequential hydroxylations and oxidoreductions from pregnenolone and progesterone. 17a-Hydroxypregnenolone (17HP) is a branchpoint constituent because it can be converted to cortisol or adrenal androgens. All of the components of this pathway can be quantified by MS/MS. The steroids around the periphery are urinary metabolites and these are measured by GC-MS following hydrolysis of conjugates and derivatization. 

A NoineiuTaiiue of Junctions and Branchpoints In Nucleic Acids hup //ww w.clieiu. qiiiLil.ac.Lik/iubiiib/iiiisc/bian.liliiLl... 

Synthetic reactions, such as the biosynthesis of amino acids in the bacterium Escherichia coli, are similarly organized into pathways (fig. 1.20). Frequently pathways have branchpoints. For example, the synthesis of the amino acids threo-... 

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