C5 Stereocenters

The key step in the synthesis of A-ring fragment 50 [56] is the chelation-controlled addition of allylstannane 53 to aldehyde 52, which sets the C7 stereocenter and introduces the C8 gem-dimethyl moiety. Aldehyde 52 is itself prepared from 1,3-propanediol using the author s protocol for titanium-catalyzed enantioselective allylstannation [57], which sets the C5 stereocenter, followed by chelation-controlled Mukaiyama aldol addition [58] to establish the C3 stereocenter (Scheme 5.6). 

The extension of the above radical intramolecular cyclization of /V-haloaryl-p-lactams to 2-azetidinones bearing the proradical center at C3 was also explored. The treatment of haloarenes 109a-c under similar conditions for the preparation of benzocarbapenems and benzocarbacephems 104—108 gave the fused tricyclic (1-lactams llOa-c (Scheme 37, Table 2). Compounds 110a and 110b were obtained as mixtures of diastereomers, which are epimers at the newly formed C5 stereocenter, while the amino derivative 110c could be prepared as a single isomer. 

The use of a,y -chiral ketones has been studied (Scheme 9-11). In general, the a-stereocenter of the ketone controls the sense of addition and this can be seen in the boron-mediated anti aldol reaction of ketone 30 where the configuration of the C5 stereocenter makes little difference to the selectivity of the reaction [15]. 

The synthesis of the C1-C7 fragment, which corresponds to the lactone, starts with the homoallylic alcohol 2 which was prepared from 1. The existing stereocenter and the conjugate addition method of Evans [21] allow the control of the C5 stereocenter. The homoallylic alcohol 2 was oxidatively cleaved and homologated to the trans enoate 3 by a Wittig olefination. Treatment of 3 with benzaldehyde and a catalytic amount of KHMDS provided acetal 4. The internal Michael addition of the hemiacetal intermediate proceeds with complete stereoselectivity [22]. After deprotection and oxidation, the corresponding aldehyde was treated with Amberlyst-15 and then with camphor sulfonic acid (CSA), to yield pyrane 5 as a mixture of (3- and a-anomers (1.8/1). This compound was converted to the thiophenyl acetal 6 (4 steps) as this compound can be hydrolyzed later under mild conditions (Hg +) with subsequent oxidation of the lactol to the desired lactone. Compound 6 represents the C1-C7 fragment of discodermolide (Scheme 1). 

Much to our surprise (but not Rich s), this reaction generated isoxazoline 2 6 as a single chemo- and regioisomer in 3 1 diastereoselectivity Since the identity of the myriaporone 1 C5 stereocenter was unknown, an unselective cyclization was an ideal solution to this problem. 

Deslongchamps applied the equatorial selective Ireknd-Claisen rearrangement described previously (cf. Scheme 4.41) in a formal synthesis of erthyronoHde A (Scheme 4.119) [43]. The rearrangement of the Z-silyl ketene acetal proceeded via a chair transition state to establish the C4 and C5 stereocenters of erythronolide A. 

Johnson and coworkers have also applied their cycloaddition chemistiy to the synthesis of (+)-virgatusin (Scheme 26) [26]. From enantiomericaUy pure trani-cyclopropane 93, treatment with piperonal 94 in the presence of AICI3 gave 2,5-c -tetrahydrofuran 95. Interesting was that 95 resulted from retention of the stereochemistry on the cyclopropane which, in a similar fashion to the Yang et al. observation (Scheme 19), is a consequence of reversible tetrahydrofuran formation. As a result of this, the benzyl ester stereochemistry on the cyclopropane was what ultimately dictated the C2 and C5 stereocenters. 

Our spectroscopic data for (+)-lepadin F matched those reported by Carroll and coworkers [155] for the natural (+)-lepadin F and Blechert s synthetic sample [162], thereby allowing us to claim a completed total synthesis. Yet we believe there is a high margin of error in determining the C5 stereochemistry, since not only was the C5 stereocenter never defined in the isolation report, but also the C5 stereocenter is acyclic and highly insulated on the side chain. Consequentiy, we synthesized the C5 epimer of (+)-lepadin F commencing with advanced intermediate aldehyde 339 and sulfone (E)-340 in the requisite Kocienski-modified Julia olefination (Scheme 12.84) [166]. Spectroscopic comparisons of both H- and C-NMR data sets of our synthetic (+)-lepadin F and (+)-5 -epi-lepadin F with the natural (+)-lepadin F of Carroll and coworkers enabled us to confirm the correct relative stereochemistry at C5 in (+)-lepadin F as S. 

Scheme 2.6 provides an overall view of our strategy towards solving this problem. As depicted, our late generation synthesis embraces three key discoveries that were crucial to its success. We anticipated that the difficult Cl-Cll polypropionate domain could be assembled through a double stereodifferentiating aldol condensation of the C5-C6 Z-metalloenolate system B and chiral aldehyde C. Two potentially serious problems are apparent upon examination of this strategy. First was the condition that the aldol reaction must afford the requisite syn connectivity between the emerging stereocenters at C6-C7 (by uk addition) concomitant with the necessary anti relationship relative to the resident chirality at C8 (by Ik diastereoface addition). Secondly, it would be necessary to steer the required aldol condensation to C6 in preference to the more readily enolizable center at C2. 

The general feature of these reactions is as follows When treated with Sml2, a reductive cyclization between the carbonyl compound and the 8-carbon of the olefin of [XHI] derived fi-om sugars [XII] gives the desired polyhydroxylated cyclopentane [XIV], in which a new C1/C5 bond (carbohydrate numbering) is formed between sjp- centers. In the overall sequence, the sp alcohol stereocenter at C5 is destroyed when oxidation occurs to form the carbonyl moieties and subsequently reinstated, upon treatment with Sml2, to form a new hydroxy-... 

The large-scale pilot plant preparation of the chiral aminochroman antidepressant ebaizotan (also known as NAE-086) was developed by H.J. Federsel and co-workers. The structural features of the target included a disubstituted chroman skeleton, a stereocenter, as well as a non-symmetrical tertiary amine moiety at the C3 position and a secondary carboxamide group at C5. The backbone of the target molecule was constructed using the Perkin condensation of 2-hydroxy-6-methoxybenzaldehyde with hippuric acid under mild conditions. 

The key component of the cell wall lipopolysaccharide of Gram-negative bacteria, KDO (3-deoxy-D-manno-2-octulosonic acid), was synthesized by S.D. Burke and co-workers. One of the key transformations in the synthetic sequence was a doubie SAD of a 6-vinyldihydropyran-2-carboxylate template. This 1,4-diene was cleanly converted to a mixture of two C7 epimeric tetraols in a 20 1 ratio. The endocyclic olefin had an intrinsic preference for dihydroxyiation from the 3-face and not from the desired a-face. This stereofacial bias was impossible to override with any ligand normally used in the SAD, so later in the synthesis these two stereocenters had to be inverted in order to give the required stereochemistry at C4 and C5. 

Hoffmann and co-workers completed the first synthesis of both denticulatins via a C9-C10 aldol bond construction (Scheme 9-70) [87], In this case, aldehyde 266 was assembled using asymmetric crotylboration reactions to introduce the C4-CS stereocenters. The (Z)-boron enolate 267 was then reacted with aldehyde 266 to afford the desired anh-Felkin adduct with 80% selectivity where the minor diastereomer resulted from reaction of the enantiomer of the starting ketone. Unfortunately, the C5-PMB ether protecting group could not be removed without epi-merization at C o, and denticulatins A and B were formed in equimolar amounts. 

Citronellol. The COSY spectrum of citronellol (see the structural formula on p. 534) is a third example. The spectrum (Fig. 10.14) is rather complex in appearance. Nevertheless, we can identify certain important coupling interactions. Again, lines have been drawn to help you identify the correlations. The proton on C6 is clearly coupled to the protons on C5. Closer examination of the spectrum also reveals that the proton on C6 is coupled through allylic (four-bond) coupling to the two methyl groups at C8 and C9. The protons on Cl are coupled to two nonequivalent protons on C2 (at 1.4 and 1.6 ppm). They are nonequivalent, owing to the presence of a stereocenter in the molecule at C3. The splitting of the methyl protons at CIO by the methine proton at C3 can also be seen, al-... 

In 2008, the group of Williams [15] reported the first total synthesis of ( )-2-0-methylneovibsanin H (33) (Scheme 14.6). The diterpene, isolated from the leaves of Viburnum awabuki [16], was prepared by employing an acid-catalyzed domino sequence. Thus, the key transformation was the conversion of advanced intermediate 28 to cyclohexene 32 upon treatment with an excess of sulfuric acid in anhydrous methanol. Acid-mediated silyl deprotection first revealed alcohol 29, which readily underwent an intramolecular oxa-Michael addition to yield tricyclic 30. It was postulated that solvolysis and nucleophilic addition of methanol to the intermediary allyl cation then furnished acid 31, which underwent Fischer esterification. The resultant highly functionalized cyclohexene 32 was isolated in 50% yield as a mixture of diastereomers at C2 (diastereomeric ratio (dr) = 85 15). The observed stereochemistry at the newly created stereocenters, i.e., at C2 and C5, was postulated to arise from the preexisting sterically congested stereocenters in the starting material (i.e., 28). Cyclohexene 32 was eventually taken on to provide the natural... 

One of the many attractive features of the Ireland-Claisen rearrangement lies in its abiUty to reUably transfer stereochemistry to one or two newly formed sp stereocenters (C2 and/or C3 of the pentenoic acid) as well as to the resulting C4—C5 alkene. It has been found that the stereochemical outcome of the rearrangement may be governed by a variety of influences, some easily rationaUzed and others more subtle. 

In 1S>93 Ireland et al. reported the total synthesis of monensin A using a modified approach (Scheme4.115) [110]. Rearrangement of the pyranyl propionate as in the tirandamycic add synthesis established the C4—C5 bond with 7 1 diastereoselectivity (Eq. 1). The challenging Cl 6 4° center was installed in high yield, albeit with no stereoselectivity (Eq. 2). Finally, the C12 4° stereocenter was installed in 51% overall yield, but with the desired isomer as the minor product (Eq. 3). 

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