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. 2021 Mar 16;54(6):1360-1373.
doi: 10.1021/acs.accounts.0c00858. Epub 2021 Feb 23.

Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis

Affiliations

Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis

Sara E Dibrell et al. Acc Chem Res. .

Abstract

With complex molecular architectures, intriguing oxidation patterns, and wide-ranging biological activities, diterpene natural products have greatly impacted research in organic chemistry and drug discovery. Our laboratory has completed total syntheses of several highly oxidized diterpenes, including the ent-kauranoids maoecrystal Z, trichorabdal A, and longikaurin E; the antibiotic pleuromutilin; and the insecticides ryanodol, ryanodine, and perseanol. In this Account, we show how analysis of oxidation patterns and inherent functional group relationships can inform key C-C bond disconnections that greatly simplify the complexity of polycyclic structures and streamline their total syntheses. In articulating these concepts, we draw heavily from the approaches to synthetic strategy that were codified by Evans, Corey, Seebach, and others, based on the formalism that heteroatoms impose an alternating acceptor and donor reactivity pattern upon a carbon skeleton. We find these ideas particularly useful when considering oxidized diterpenes as synthetic targets.In the first part of the Account, we describe the use of reductive cyclizations as strategic tactics for building polycyclic systems with γ-hydroxyketone motifs. We have leveraged Sm-ketyl radical cyclizations as "reactivity umpolungs" to generate γ-hydroxyketones in our total syntheses of the Isodon ent-kauranoid diterpenes (-)-maoecrystal Z, (-)-longikaurin E, and (-)-trichorabdal A. Following this work, we identified the same γ-hydroxyketone pattern in the diterpene antibiotic (+)-pleuromutilin, which again inspired the use of a SmI2-mediated reductive cyclization, this time to construct a bridging eight-membered ring. This collection of four total syntheses highlights how reductive cyclizations are particularly effective umpolung tactics when used to simultaneously form rings and introduce 1,4-dioxygenation patterns.In the second part of the Account, we detail the syntheses of the complex and highly oxidized ryanodane and isoryanodane diterpenes and present the oxidation pattern analysis that guided our synthetic designs. We first discuss our 15-step total synthesis of (+)-ryanodol, which incorporated five of the eight oxygen atoms in just two transformations: a dihydroxylation of (S)-pulegone and a SeO2-mediated trioxidation of the A-ring cyclopentenone. This latter transformation gave rise to an independent investigation of SeO2-mediated peroxidations of simple bicyclic cyclopent-2-en-1-ones. The syntheses of (+)-ryanodine and (+)-20-deoxyspiganthine are also presented, which required modified end-game strategies to selectively incorporate the key pyrrole-2-carboxylate ester. Finally, we describe our fragment coupling approach to prepare the isoryanodane diterpene (+)-perseanol. Using a similar oxidation pattern analysis to that developed in the synthesis of ryanodol, we again identified a two-stage strategy to install the five hydroxyl groups. This strategy was enabled by a Pd-mediated carbopalladation/carbonylation cascade and leveraged unexpected, emergent reactivity to sequence a series of late-stage oxidations.While each of the diterpene natural products discussed in this Account present unique synthetic questions, we hope that through their collective discussion, we provide a conceptual framework that condenses and summarizes the chemical knowledge we have learned and inspires future discourse and innovations in strategy design and methodology development.

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Figures

Figure 1.
Figure 1.
(a) Oxidized diterpene targets completed by the Reisman laboratory. (b) Difunctional relationships guide key C–C bond constructions. (c) Carbon framework topology guides early vs. late stage C–H oxidation.
Figure 2.
Figure 2.
Retrosynthetic analysis of ent-kauranoid diterpenes.
Figure 3.
Figure 3.
Retrosynthetic analysis of (+)-pleuromutilin (4) and 12-epi-4.
Figure 4.
Figure 4.
Retrosynthetic analysis of ryanodane diterpenes.
Figure 5.
Figure 5.
Retrosynthetic analysis of (+)-perseanol (6).
Scheme 1.
Scheme 1.
12-step total synthesis of (−)-maoecrystal Z (1).
Scheme 2.
Scheme 2.
Total synthesis of (−)-longikaurin E (3) and (−)-trichorabdal A (2).
Scheme 3.
Scheme 3.
18-step total synthesis of (+)-pleuromutilin (4).
Scheme 4.
Scheme 4.
18-step total synthesis of (+)-12-epi-pleuromutilin (12-epi-4).
Scheme 5.
Scheme 5.
15-step total synthesis of (+)-ryanodol (43).
Scheme 6.
Scheme 6.
18-step total synthesis of (+)-ryanodine (5).
Scheme 7.
Scheme 7.
19-step total synthesis of (+)-20-deoxyspiganthine (44).
Scheme 8.
Scheme 8.
(a) Dioxidation of bicyclic cyclopent-2-en-1-ones with aqueous SeO2. (b) Trioxidation of bicyclic cyclopent-2-en-1-ones with anhydrous SeO2.
Scheme 9.
Scheme 9.
(a) Preparation of the C-ring fragment (92). (b) Preparation of the A-ring fragment (91).
Scheme 10.
Scheme 10.
16-step total synthesis of (+)-perseanol (6).

References

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      The synthesis of ent-kauranoid diterpene maoecrystal Z leveraged a SmI2-mediated reductive cascade cyclization to quickly forge the tricyclic core from a spiro-lactone intermediate accessed via reductive epoxide coupling

    1. Farney EP;‡ Feng SS; Schäfers F;‡ Reisman SE Total Synthesis of (+)-Pleuromutilin. J. Am. Chem. Soc 2018, 140 (4), 1267–1270.

      Access to the central eight-membered ring of pleuromutilin was enabled by a SmI2-mediated reductive cyclization of a bifunctional hydrindane fragment, formed via a modular crotylation that also allowed synthesis of natural product analogs.

    1. Chuang KV;‡ Xu C;‡ Reisman SE A 15-Step Synthesis of (+)-Ryanodol. Science 2016, 353 (6302), 912–915.

      The oxidative complexity of ryanodol guided its expedient synthesis, which hinged on a strategic Pauson–Khand reaction of a pulegone-derived intermediate and unique SeO2-mediated oxidative transposition to quickly install challenging patterns of oxidation.

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