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Recent Advances in Alkene Metathesis for Natural Product Aldrichimica ACTA 17 VOL. 50, NO. 1 • 2017 Recent Advances in Alkene Metathesis for Natural Product Synthesis—Striking Achievements Resulting from Increased Sophistication in Catalyst Design and Synthesis Strategy Christopher D. Vanderwal* and Brian R. Atwood 1102 Natural Sciences II Department of Chemistry University of California, Irvine Irvine, CA 92697-2025, USA Email: [email protected] Prof. C. D. Vanderwal Mr. B. R. Atwood Keywords. metathesis; natural product synthesis; strategy; 7. Cross-Metathesis catalysts; stereocontrol. 8. Conclusion 9. References Abstract. Every year, advances in the design of metathesis catalysts and insightful strategic applications of alkene metathesis work in concert 1. Introduction to drive the feld into new and exciting directions. From ring-closing The importance of alkene metathesis to synthetic chemistry cannot be to enyne and cross-metathesis, and from late-stage steps that directly overstated. The pioneering work by Chauvin, Grubbs, and Schrock furnish natural products to early transformations that supply starting on improving our mechanistic understanding of metathesis, on materials, metathesis can play a role at every stage of a synthesis. This developing novel metathesis catalysts, and on developing metathesis review will highlight some of the particularly innovative or surprising applications garnered them the 2005 Nobel Prize in Chemistry.1 ways in which alkene metathesis has been implemented in natural For over two decades, organic chemists have harnessed the power product synthesis. of alkene metathesis in academic and industrial settings, and new applications continue to be reported on a regular basis. In the decade Outline following Nicolaou’s extensive review of the use of alkene metathesis 1. Introduction in natural product synthesis,2 the number of examples of such uses 2. Ring-Closing Metathesis has grown at a dizzying rate. Books3–7 and reviews8–11 have been 3. Tethered Ring-Closing Metathesis written to chronicle the breadth of applications of alkene metathesis. 4. Macrocycles Herein, we aim to provide a structured look at a select group of alkene 4.1. Macrocyclic Ring Closure by Metathesis metathesis reactions that are employed in natural product synthesis. 4.1.1. The Alkylpiperidine Alkaloids We discuss accomplishments from the past ten years that exemplify 4.1.2. The Ansatrienins groundbreaking strategic applications of alkene metathesis and/ 4.1.3. Other Natural Products or a particularly impressive reactivity or selectivity in metathesis 4.1.4. Tiacumicin B Aglycon processes. We have organized the discussion by transformation type: 4.2. Macrocyclic Ring Closure by Other Means (i) ring-closing metathesis for normal- and medium-size rings, (ii) 5. Tandem Metatheses metathesis in the synthesis of macrocycles, (iii) tandem metatheses, 5.1. Enyne Metatheses (iv) ring-opening metathesis, and (v) cross-metathesis. 5.2. Ene-yne-ene Metatheses We note here that our purpose is only to demonstrate the power 6. Ring-Opening Cross-Metathesis of metathesis for complex-molecule synthesis using select examples. Recent Advances in Alkene Metathesis for Natural Product Synthesis—Striking Achievements Resulting from Increased Sophistication in Catalyst Design and Synthesis Strategy 18 Christopher D. Vanderwal* and Brian R. Atwood Furthermore, although closely related, alkyne metathesis12 is not a synthesis of elatol.15 The authors built on Weinreb's earlier work which prime focus of this article, and select examples are provided only had demonstrated the general feasibility and utility of this type of RCM.16 to provide context. In this short review, only a small number of the To access the salient chlorinated cyclohexene of elatol, the researchers myriad and incredibly versatile metathesis catalysts developed to date utilized an RCM between two 1,1-disubstituted alkene groups in 18 are showcased (Figure 1). (Scheme 2), one with two carbon substituents and one bearing an alkyl substituent and a chlorine atom. Substrate 18 underwent RCM in the 2. Ring-Closing Metathesis presence of 3 to provide intermediate 19 containing a tetrasubstituted By the mid-2000s, ring-closing metathesis (RCM) to form unstrained, alkene. Following its introduction, catalyst 3 has become an important normal-size rings was a well-established, reliable tool for synthesis. addition to the arsenal of available metathesis catalysts.3,17 The examples below were selected because they have pushed forward In one of a few reported examples of stereochemical equilibration– the frontiers of what was thought possible in terms of reactivity and/ RCM, Tang, Chen, Yang and co-workers reported the synthesis or selectivity. Reiser’s group reported the frst enantioselective synthesis of the 13 Me complex sesquiterpenoid arglabin (Scheme 1). A challenging RCM AcO AcO 4 H H Me of two 1,1-disubstituted alkenes to forge a tetrasubstituted alkene 2 4 H (3 x 5 mol %) + C-4 epimer within a 7-membered ring serves as a key step. A particularly direct, O o O PhMe, 95 C, 6 h O O 17 stereoselective synthesis of the RCM precursor, 16, set the stage for H H H epi- , 16% this challenging ring closure. This metathesis required three separate Me OPMB Me OPMB 16 17 charges (5 mol %) of the Grubbs second-generation catalyst14 (2) and , 70% inert-gas sparging at 95 oC to successfully provide the tetrasubstituted alkene in 17. Epoxidation of the tetrasubstituted alkene and installation H Me O of the requisite functional groups completed the synthesis of arglabin. At O O the time, and to this day, this RCM is striking for its effcient generation H H of a ring size that can often be slow to form, while simultaneously Me arglabin forging a tetrasubstituted alkene. Stoltz’s group was among the frst to employ the RCM of alkenyl Scheme 1. Efficient Formation by RCM of a Cycloheptene with a Tetrasubstituted Double Bond in Reiser's Enantioselective Synthesis of chlorides in natural product synthesis in the course of their innovative Arglabin. (Ref. 13) N N N N N N P(Cy)3 N N Ar Ar Ar Ar Ar Ar Me Me Cl Cl Cl Cl Cl Ru Ru Ru Ru Ph Ru O Cl Cl Cl Cl P(Cy)3 Cl Ph O O O S NMe2 P(Cy)3 i-Pr i-Pr i-Pr O Grubbs Grubbs Hoveyda-Grubbs first-generation second-generation Stewart-Grubbs second-generation (GI, 1) (GII, 2) (SG, 3) (HGII, 4) Zhan-1B (5) F 1-Ad Et SiO P(Cy)3 3 C6F5 N N N N N Ar N Ar Ar Cl O N Mo R' Ru Mo R' Br O H S Ru F R Br Ru Cl O O O F N O F O S i-Pr – O O Et SiO i-Pr Ph i-Pr 3 6 7 8 9 10 OMe 1-Ad N CF 3 Me Me N Cl Cl Mo R' N N N N N O Mo R' Mo R' N Br W t-Bu Br Ph3SiO OSiPh3 O O Mo Br Br O R N Br Br Ph3SiO Ar' Ar' R R N 11 12 13 14 15 R = TBSO; R' = CMe2Ph; Ar = 2,4,6-Me3C6H2; Ar' = 2,4,6-(i-Pr)3C6H2 Figure 1. Structures of Metathesis Catalysts Featured in This Review. Aldrichimica ACTA 19 VOL. 50, NO. 1 • 2017 of schindilactone A, in which that process provided the central 3. Tethered Ring-Closing Metathesis oxabicyclo[4.2.1]nonane ring system of the target (Scheme 3).18 In the Temporary tethers are enormously useful for increasing the rates of presence of GII (2), the desired RCM gave 21, with in situ epimerization slow bimolecular reactions, and are advantageous with respect to producing a single diastereomer at the hemiketal carbon.19 The resulting both chemo- and stereoselectivity. In Kobayashi’s total synthesis cyclooctene later participated in a Pauson–Khand reaction to annulate of (+)-TMC-151C, a silicon-tethered RCM reaction convergently another one of the rings of the natural product. Other examples of assembled the polyketide natural product from two fragments of similar stereochemical equilibration during RCM mostly involve epimerization complexity in a reaction that would have been virtually impossible of stereogenic centers adjacent to ketones.20 to achieve in a bimolecular setting (Scheme 5).22 Further, the tether In their synthesis of sculponeatin N, a bioactive diterpene, served to reinforce the selectivity of the alkene geometry in forming Thomson and co-workers accomplished the equivalent of a the trisubstituted alkene. The RCM reaction of 25 was effected with butadiene–cyclopentenone Diels–Alder cycloaddition by a sequence the Hoveyda–Grubbs second-generation catalyst (4),23 and global featuring an unusual equilibrating diastereoselective RCM reaction desilylation of 26 afforded (+)-TMC-151C directly. (Scheme 4).21 When 24 could not be made by the more straightforward Diels–Alder approach, sequential alkene installation converted the spiro-cyclopentenone precursor to the triene-containing RCM substrate 22. Subjecting triene 22 to metathesis conditions with GII (2) Me 2 (5 mol %) Me afforded the desired cis-fused cyclohexene-containing 24. The authors Me DCM, rt, 15 h Me commented that spirocyclopentene 23 could be isolated by stopping t-BuPh2SiO O t-BuPh2SiO O the reaction early; however, the trans-fused cyclohexene was never 22 24, 91% observed. This particularly creative workaround to the unsuccessful cycloaddition also sets a key quaternary stereogenic center of the target. Me Me t-BuPh SiO Me 2 O O O Me 23 O 3 (5 mol %) Cl Cl Me PhH, 60 oC i-BuO Me i-BuO Me Me Me Me HO O (–) (+) O 18 19, 97% sculponeatin N Scheme 4. Diastereoselective RCM as a Butadiene–Cyclopentenone 3 steps Me Diels–Alder Equivalent in Thomson's Total Synthesis of Sculponeatin N. (Ref. 21) Cl HO Me Me Br Me Me Me Me Me Me Me Me Me OR OR (+)-elatol O 28% (from 19) Et OR RO OR O O O OR OR O Si RO O Scheme 2.
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