Subtle Variations in the Long-Range Transmission of Stereochemical Information: Matched and Mismatched Aldol Reactions

Abstract

In this paper we describe findings with respect to an important question in stereospecific synthesis, that is, how might remote stereogenic loci influence the diastereofacial sense in which covalent bond formation occurs. To address this type of issue in concrete rather than abstract terms, we focused on the very promising antitumor agents, the epothilones (such as epothilone B (1), shown in Scheme 1). These compounds have stimulated a great deal of research from the point of view of total synthesis. [1±6] In this paper we do not directly address the total synthesis problem per se. Rather, we focus on the construction of the C6ÀC7 bond in the acyl sector en route to the natural products, as a paradigm for accomplishing high orders of selection by long-range induction.By way of background we note that, originally, [1a, 1c] the stereochemical information for building the ªacylº sector of the epothilones (see 2 in Scheme 1) was stored in dihydropyrone 5 which itself arose from a cyclocondensation reaction of enantiomerically pure 3 and diene 4. In our second-generation synthesis, [7] the enantiomerically homogenous 6 reacted with Me O

Insights into Long-Range Structural Effects on the Stereochemistry of Aldol Condensations: A Practical Total Synthesis of Desoxyepothilone F

“…Upon deprotonation and reaction of 45 with 14 , smooth condensation gave rise to a 4:1 mixture of aldol adducts 46a and 47a . While this ratio was somewhat lower than that of our previous route (6.5∼5.5:1), 13e,, the major diastereomer 46a was very easily separated by flash chromatography and protected as a Troc group. Indeed, there was a significant advantage in this route in that the aldol condensation, unlike our earlier cases where C3 corresponded to an enol ether,13e went to completion.…”

“…Taking all ofthese preferences into consideration, we analyzed the structure of transition states leading to the formation of 41a − 44a (Scheme ) . While the relative contribution of each factor to transition state stabilization cannot be weighted, we note the reaction of ( R )- 37 with 14 incorporates each of the energy-lowering elements we propose in the transition state.…”

Combination of Pseudo‐Natural Product Design and Formal Natural Product Ring Distortion Yields Stereochemically and Biologically Diverse Pseudo‐Sesquiterpenoid Alkaloids

“…This task was considered particularly challenging because the complex chiral environment and diverse functional groups of NPs may complicate catalyst‐ and substrate‐mediated control of stereoselectivity. Thus, while stereoselective synthesis of one isomer frequently is achievable, [21] stereodivergent synthesis of all isomers is much more demanding because of match‐mismatch effects [22] and limited availability of catalysts in stereoisomeric forms. [23] For the development of suitable reaction conditions, santonin 1 was selected and converted into the corresponding α‐methylene‐γ‐lactone 7 (see Supplementary Figure S2 and Table 1 ).…”

Probing the SAR of dEpoB via Chemical Synthesis: A Total Synthesis Evaluation of C26-(1,3-dioxolanyl)-12,13-desoxyepothilone B

“…To meet the demands on material for advanced biological testing, an efficient and scalable synthesis of compound 8 was required. The initial planning for the synthesis involved key components previously utilized in the synthesis of dEpoB (Figure ) . The polypropionate segment B would be constructed first from an aldol reaction between the lithium enolate of fragment D and aldehyde E .…”