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Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis.

Yu M, Wang C, Kyle AF, Jakubec P, Dixon DJ, Schrock RR, Hoveyda AH - Nature (2011)

Bottom Line: Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM.The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity.As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.

ABSTRACT
Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, cyclizations often proceed without control of alkene stereochemistry. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

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Total synthesis of nakadomarin A realized through late-stage tungsten-catalyzed RCM of pentacyclic 13 and comparison with results delivered by Ru catalystsRCM of the strained 13 with tungsten complex 10 affords the natural product in 63% yield (69% based on recovered substrate) and 94% Z selectivity. This is in contrast to previous attempts, the best of which involves 20 mol % of a Ru carbene added slowly to a highly dilute solution (0.2 mM) to generate only 63:37 Z:E mixture.
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Figure 2: Total synthesis of nakadomarin A realized through late-stage tungsten-catalyzed RCM of pentacyclic 13 and comparison with results delivered by Ru catalystsRCM of the strained 13 with tungsten complex 10 affords the natural product in 63% yield (69% based on recovered substrate) and 94% Z selectivity. This is in contrast to previous attempts, the best of which involves 20 mol % of a Ru carbene added slowly to a highly dilute solution (0.2 mM) to generate only 63:37 Z:E mixture.

Mentions: Total synthesis of nakadomarin A might alternatively be accomplished by a late-stage stereoselective RCM (vs. at an earlier point as in the pathway in Table 3); such a plan, however, can present additional complications and a non-selective RCM translates to loss of a more valuable advanced intermediate. One route proceeds through the especially demanding RCM (vs. 5→6) of azacene-containing 13xv (Fig. 2): the higher ring strain within the pentacyclic diene substrate is not only expected to discourage ring closure, it likely lowers the barrier to undesired rupture of the macrocyclic alkene. Accordingly, past attempts at achieving conversion of 13 to nakadomarin A, as shown in Fig. 2, have involved the significantly less reactive ruthenium carbene 2bviii (vs. 2c–d) in order to minimize post-RCM isomerization of the macrocyclic alkene. Use of such a reluctant catalyst, which must be introduced slowly, translates to high loadings and elevated temperatures (20 mol %, 40 °C). Extremely dilute conditions (0.2 mM) are needed as well, since it is unlikely that under such conditions any homocoupled byproducts that would otherwise be formed can be reverted back to the monomeric dienes or converted directly to the desired macrocycle. Additionally, the presence of substantial quantities (300 mol %) of camphorsulfonic acid, a strong BrØnsted acid, is required for achieving 63% Z selectivity (otherwise, slight excess of the E alkene is obtained)xv. In sharp contrast, treatment of 13 with 5.0 mol % 10 at 22 °C affords nakadomarin A in 94% Z selectivity and 63% yield (plus 9% recovered diene). Finally, it should be noted that attempts to effect alkyne RCM of the diyne derivative of 13 (Me-substituted), bearing two Lewis basic tertiary amines, with either Mo- or W-based alkylidynes leads to <5% conversion even with 30–50 mol % of a metal complex and at 80 °C (up to 24 h); this latter approach must therefore involve the use of the derived bisamide (20–25 mol % catalyst, 80 °C, 16–18 h).


Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis.

Yu M, Wang C, Kyle AF, Jakubec P, Dixon DJ, Schrock RR, Hoveyda AH - Nature (2011)

Total synthesis of nakadomarin A realized through late-stage tungsten-catalyzed RCM of pentacyclic 13 and comparison with results delivered by Ru catalystsRCM of the strained 13 with tungsten complex 10 affords the natural product in 63% yield (69% based on recovered substrate) and 94% Z selectivity. This is in contrast to previous attempts, the best of which involves 20 mol % of a Ru carbene added slowly to a highly dilute solution (0.2 mM) to generate only 63:37 Z:E mixture.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3211109&req=5

Figure 2: Total synthesis of nakadomarin A realized through late-stage tungsten-catalyzed RCM of pentacyclic 13 and comparison with results delivered by Ru catalystsRCM of the strained 13 with tungsten complex 10 affords the natural product in 63% yield (69% based on recovered substrate) and 94% Z selectivity. This is in contrast to previous attempts, the best of which involves 20 mol % of a Ru carbene added slowly to a highly dilute solution (0.2 mM) to generate only 63:37 Z:E mixture.
Mentions: Total synthesis of nakadomarin A might alternatively be accomplished by a late-stage stereoselective RCM (vs. at an earlier point as in the pathway in Table 3); such a plan, however, can present additional complications and a non-selective RCM translates to loss of a more valuable advanced intermediate. One route proceeds through the especially demanding RCM (vs. 5→6) of azacene-containing 13xv (Fig. 2): the higher ring strain within the pentacyclic diene substrate is not only expected to discourage ring closure, it likely lowers the barrier to undesired rupture of the macrocyclic alkene. Accordingly, past attempts at achieving conversion of 13 to nakadomarin A, as shown in Fig. 2, have involved the significantly less reactive ruthenium carbene 2bviii (vs. 2c–d) in order to minimize post-RCM isomerization of the macrocyclic alkene. Use of such a reluctant catalyst, which must be introduced slowly, translates to high loadings and elevated temperatures (20 mol %, 40 °C). Extremely dilute conditions (0.2 mM) are needed as well, since it is unlikely that under such conditions any homocoupled byproducts that would otherwise be formed can be reverted back to the monomeric dienes or converted directly to the desired macrocycle. Additionally, the presence of substantial quantities (300 mol %) of camphorsulfonic acid, a strong BrØnsted acid, is required for achieving 63% Z selectivity (otherwise, slight excess of the E alkene is obtained)xv. In sharp contrast, treatment of 13 with 5.0 mol % 10 at 22 °C affords nakadomarin A in 94% Z selectivity and 63% yield (plus 9% recovered diene). Finally, it should be noted that attempts to effect alkyne RCM of the diyne derivative of 13 (Me-substituted), bearing two Lewis basic tertiary amines, with either Mo- or W-based alkylidynes leads to <5% conversion even with 30–50 mol % of a metal complex and at 80 °C (up to 24 h); this latter approach must therefore involve the use of the derived bisamide (20–25 mol % catalyst, 80 °C, 16–18 h).

Bottom Line: Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM.The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity.As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.

ABSTRACT
Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, cyclizations often proceed without control of alkene stereochemistry. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

Show MeSH
Related in: MedlinePlus