Prelog-Djerassi lactonic acid

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

As a model study for this methodology, Evans and Bartroli carried out the synthesis of (+)-Prelog-Djerassi Lactonic acid 47 [14b] [27], which is a degradation product of either methymycin or narbomycin [28] and has some of the important structural features present in macrolide antibiotics. 

Note that aldol condensations I, II and III concern the creation of a relative configuration 2,3-syn, which can be easily achieved starting from the (Z)-enolates 74a-74c. Scheme 9.27 summarises the synthesis of 93 and 95, which are equivalent to fragments B and A, respectively. Compound 88 is the abovementioned Prelog-Djerassi lactonic acid 42 which is obtained in optically pure from (>98% ee). On the other hand, for the stereochemical control of the aldol condensation IV a different methodology is necessary whih involves the coupling of two structurally predefined reactants and which will not be discussed here (Scheme 9.28). An important feature of this reaction is that the coordination of Li" " with the oxygen atom at the P-position of the aldehyde 95 is mainly responsible for the observed stereoselection [22e]. 

Like enamines, dihalocarbenes add smoothly to enol ethers and in many cases it is possible to isolate the dihalocyclopropyl intermediates which are valuable synthons for chloroenones (cf. Section 4.7.3.7.1). The earliest example of the addition of a dihalocarbene to an enol ether was provided by Parham,6,79 who studied the addition of dichlorocaibene to dihydropyran (equation 22). An example which illustrates the synthetic potential of the process is the conversion of the cyclohexanone enol ether (6) to the dichlorocy-clopropane (7 equation 23).80 The latter served as a useful intermediate in a stereospecific synthesis of Prelog-Djerassi lactonic acid. 

Cyclic hydroboration (10, 397). Two laboratories1,2 have reported stereoselective syntheses of the Prelog-Djerassi lactonic acid (4), both of which involve cyclic hydroboration of a slightly different 1,5-diene. One of these syntheses is outlined in... 

The group-selective aldolization/desymmetrization of w -dialdehyde with a boron enolate of TV-propionylsultam yielded lactols with simultaneous generation of four stereogenic centers. Oxidation followed by saponification of the sultam moiety provided the Prelog-Djerassi lactonic acid in 61-71% overall yields (Equation (183)).689... 

The BF,-etherate-catalyzed reaction of 1 with the aldehyde 2 provides a short stereoselective synthesis of the Prelog-Djerassi lactonic acid 3. 

A new approach to the synthesis of Prelog-Djerassi Lactonic acid (1) is reported. A key step in this synthesis involves an Ireland-Claisen rearrangement/silicon-mediated fragmentation sequence to provide the carbon framework in (1). 

With the full complement of stereogenic centres required, the 1,3-diol (11) was then taken through a protection/ deproteclion sequence to afford the corresponding diacetoxy alcohol (13), thereby completing the formal synthesis of (+)-PDLA. The remaining steps in the total synthesis followed the route employed by Yamaguchi and co-workers/ Diacetoxy alcohol (13) was oxidised with RuClj/NalO to provide acid (14), which underwent concomitant lactonisation to (15) under saponification conditions. The primary alcohol (15) was then oxidised to afford (+)-Prelog-Djerassi lactonic acid in an overall 9 % yield, with all spectroscopic data in accord with the literature values. 

For a review concerning the synthesis of Prelog-Djerassi lactonic acid, see S. F. Martin and D. E. Guinn, Synthesis, 1991,245 and references cited therein. 

Synthetic Application ( + )-Prelog-Djerassi Lactonic Acid Methyl Ester. . 25... 

Isobe, M, Ichikawa, Y, Goto, T, Total synthesis of (+)-Prelog-Djerassi lactonic acid. Tetrahedron Lett., 22, 4287-4290, 1981. 

Schlessinger and coworkers have studied the aldol reactions of the dienolates derived from the vinylo-gous carbamate (18) in all cases, reaction occurs solely at the 7-position, as shown in equation (31). Various evidence has been adduced that (18) reacts kinetically at the 7-position, in contrast to the behavior of crotonate enolates (vide supra). The process has been used to synthesize the Prelog-Djerassi lactonic acid and a chiral version of (18) has been used to synthesize a fragment of the antibiotic virgi-niamycin M2 (vide infra). ... 

A related reagent (186) is prepared in three steps from (5)-atrolactic acid. The lithium enolate of (186) reacts with phenylacetaldehyde to give two aldols in a ratio of 94 6 (Scheme 12). [The full relative stereochemistry of aldols (187) and (188) was not rigorously determined, but may be deduced from the stereochemistry of (190). It is surprising that the lithium enolate of (186) has a diastereofacial preference that is opposite that of the related ketone (181).] Compound (186) has been used in a synthesis of the Prelog-Djerassi lactonic acid (191), as shown in Scheme 12. Reagents related to (181) and (186) have been used as their boron enolates for other synthetic purposes (see Chapter 1.7, this volume). 

The facial selectivity of (43) was found to be 1.75 1 from the ratio of aldol products (48) and (49) obtained by the reaction with the achiral boron enolate (50). The latter is structurally similar to reagents (37) and (38). These experiments confirm again the validity of the rule of double asymmetric synthesis. The product (44) can be further converted through a sequence of reactions to provide (+)-Prelog-Djerassi lactonic acid (51 Scheme 27) (i) trimethylsilylation (ii) hydroboration with thexylborane (single asym-... 

The two other aldol products that can be derived via propionate addition to (24) are the Prelog-Djerassi lactonic acid diastereomers, both of which were prepared successfully with the internal chiral boron enolates discussed earlier in this section. Thus this work completes a set of chiral reagents that can control the relative stereochemistry at the 2,3 and 4 positions of aldol products. 

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