Selective Ring-closing Metathesis Research Articles

E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids.

We present an E-selective ring-closing metathesis reaction in α-helical stapled peptides at positions i and i + 4. The use of two chiral carbocyclic α,α-disubstituted α-amino acids, (1S,3S)-Ac5c3OAll and (1R,3S)-Ac5c3OAll, provides a high E-selectivity of a ≤59:1 E:Z ratio, while mixtures with E:Z ratios of 2.1-0.5:1 were produced with standard acyclic (S)-(4-pentenyl)alanine amino acids. A stapled octapeptide composed of (1S,3S)- and (1R,3S)-Ac5c3OAll amino acids showed a right-handed α-helical crystal structure.

Cis Selective RCM Study to the 14-Membered Cyclic Subunit of Bielschowskysin.

A concise, (Z)-selective ring-closing metathesis (RCM) route to the 14-membered carbocycle of bielschowskysin is detailed using naturally occurring chiral starting materials. Unproductive RCM substrates were attributed to alkyne chelation of the ruthenium catalyst and steric disadvantages within the cembranoid precursors, which was eventually circumvented by using cyclic diol benzylidene protection involving a C8-quaternary carbinol center.

Total synthesis and cytotoxic activity of dechlorogreensporones A and D

The first and convergent total syntheses of polyketide natural products dechlorogreensporones A and D have been accomplished in 17 longest linear steps with 2.8% and 5.4% overall yields, respectively, starting from known methyl 2-(2-formyl-3,5-dihydroxyphenyl)acetate and commercially available R-(+)-propylene oxide and 1,2-epoxy-5-hexene. Our synthesis exploited key Mitsunobu esterification and (E)-selective ring-closing metathesis (RCM) to assemble the macrocycles as well as a Jacobsen hydrolytic kinetic resolution to install the stereogenic centers. Both synthetic compounds were found to display significant cytotoxic activity against seven human cancer cell lines with the IC50 ranges of 6.66–17.25 μM.

Stereoselective Access to Z and E Macrocycles by Ruthenium-Catalyzed Z-Selective Ring-Closing Metathesis and Ethenolysis

The first report of Z-selective macrocyclizations using a ruthenium-based metathesis catalyst is described. The selectivity for Z macrocycles is consistently high for a diverse set of substrates with a variety of functional groups and ring sizes. The same catalyst was also employed for the Z-selective ethenolysis of a mixture of E and Z macrocycles, providing the pure E isomer. Notably, an ethylene pressure of only 1 atm was required. These methodologies were successfully applied to the construction of several olfactory macrocycles as well as the formal total synthesis of the cytotoxic alkaloid motuporamine C.

Gram‐Scale Synthesis of Iejimalide B

Iejimalide B (2) is the most promising member of a small family of marine polyene macrolides endowed with remarkably selective activity against human cancer cell lines. As this product, however, is hardly available from the natural sources, a detailed evaluation requires the development of an efficient and practical synthetic approach. This challenge has now been met by adapting the first total synthesis of 2 previously reported by our group to the needs of high material throughput. Redesigning the access routes to the five required building blocks in combination with a careful optimization of the fragment coupling processes provided gram amounts of this valuable compound in a sequence of no more than 16 linear steps with an overall yield of about 7%. Key elements of the successful strategy include: i) three hydrostannylation processes of elaborate terminal alkynes with "lower order" stannyl cuprates, ii) a Brown allylation, a Noyori transfer hydrogenation, and a Marshall propargylation to set the chiral centers at C9, C17, C22 and C23, and iii) a modified Takai-Utimoto olefination for the preparation of the very labile skipped 1,4-diene flanking the ester group. The assembly process benefited from a particularly mild protocol for the Stille cross-coupling previously developed in this laboratory, which clearly outperformed the alternative Suzuki reaction in terms of yield and scalability. The 24-membered macrocyclic frame was forged by a remarkably selective ring-closing metathesis reaction (RCM), in which two out of the ten double bonds present in the cyclization precursor were selectively activated with the aid of a second-generation Grubbs catalyst.

ChemInform Abstract: Cyclic 1,2‐Diketones as Core Building Blocks: A Strategy for the Total Synthesis of (‐)‐Terpestacin.

We report a full account of our work towards the total synthesis of (−)-terpestacin (1), a sesterterpene originally isolated from fungal strain Arthrinium sp. FA1744. Its promising anti-HIV and anti-cancer activity, as well as its novel structure, make terpestacin an attractive synthetic target. A strategy based on the unique reactivity of cyclic 1,2-diketones (diosphenols) was developed and total synthesis of 1 was achieved in 20 steps, in the longest linear sequence, from commercially available 2-hydroxy-3-methyl-2-cyclopenten-1-one. The key feature of our synthesis is the double usage of a “Pd AAA-Claisen” protocol (AAA=asymmetric allylic alkylation), first in the early stages to generate the C1 quaternary center and then in the late stages to install the side chain. In addition, a rather unusual ene-1,2-dione moiety was synthesized and utilized as an excellent Michael acceptor to attach the C15 substituent. Several possible routes towards the total synthesis have been examined and carefully evaluated. During our exploration many interesting chemoselectivity issues have been addressed, such as a highly selective ring-closing metathesis and a challenging oxidation of a disubstituted olefin in the presence of three trisubstiuted ones.

Cyclic 1,2‐Diketones as Core Building Blocks: A Strategy for the Total Synthesis of (−)‐Terpestacin

We report a full account of our work towards the total synthesis of (-)-terpestacin (1), a sesterterpene originally isolated from fungal strain Arthrinium sp. FA1744. Its promising anti-HIV and anti-cancer activity, as well as its novel structure, make terpestacin an attractive synthetic target. A strategy based on the unique reactivity of cyclic 1,2-diketones (diosphenols) was developed and total synthesis of 1 was achieved in 20 steps, in the longest linear sequence, from commercially available 2-hydroxy-3-methyl-2-cyclopenten-1-one. The key feature of our synthesis is the double usage of a "Pd AAA-Claisen" protocol (AAA=asymmetric allylic alkylation), first in the early stages to generate the C1 quaternary center and then in the late stages to install the side chain. In addition, a rather unusual ene-1,2-dione moiety was synthesized and utilized as an excellent Michael acceptor to attach the C15 substituent. Several possible routes towards the total synthesis have been examined and carefully evaluated. During our exploration many interesting chemoselectivity issues have been addressed, such as a highly selective ring-closing metathesis and a challenging oxidation of a disubstituted olefin in the presence of three trisubstituted ones.

Total Synthesis of Cyclic Diterpene Tonantzitlolone Based on a Highly Stereoselective Substrate‐Controlled Aldol Reaction and Ring‐Closing Metathesis

The total synthesis of the cyclic diterpene ent-tonantzitlolone (ent-1) is presented. Key steps for assembling the macrocyclic core structure of 1 are a highly selective aldol reaction and an E selective ring-closing metathesis reaction. A detailed investigation of these two steps and the final transformations towards the completion of the synthesis is disclosed.

Total Synthesis of (+)-Phomopsolide C by Ring-Size Selective Ring-Closing Metathesis/Cross-Metathesis

[reaction: see text]A new strategy for the synthesis of chiral 6-substituted 5,6-dihydro-5-hydroxypyran-2-ones by ring-size selective ring-closing metathesis (RCM) and its application to a short total synthesis of (+)-phomopsolide C are described. The key bond-forming reactions in this approach are a chemoselective cross-metathesis (CM) and RCM.

Diversity‐Oriented Synthesis of Azaspirocycles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The migrastatin family: discovery of potent cell migration inhibitors by chemical synthesis.

The first asymmetric total synthesis of (+)-migrastatin (1), a macrolide natural product with anti-metastatic properties, has been accomplished. Our concise and flexible approach utilized a Lewis acid-catalyzed diene aldehyde condensation (LACDAC) to install the three contiguous stereocenters and the trisubstituted (Z)-alkene of migrastatin (2 + 3 --> 21). Construction of the two remaining stereocenters and incorporation of the glutarimide-containing side chain was achieved by an anti-selective aldol addition of propionyl oxazolidinone 28 to angelic aldehyde 27, followed by a Horner-Wadsworth-Emmons (HWE) coupling of 32 with glutarimide aldehyde 5. Finally, the assembly of the macrocycle was realized by a highly (E)-selective ring-closing metathesis (35 --> 37). Utilizing the power of diverted total synthesis (DTS), a series of otherwise inaccessible analogues was prepared and evaluated for their potential as tumor cell migration inhibitors in several in vitro assays. These studies revealed a dramatic increase in activity when the natural motif was considerably simplified, presenting macrolactones 45 and 48, as well as macrolactam 55, macroketone 60, and CF(3)-alcohol 71 as promising anti-metastatic agents.

Diversity-oriented synthesis of azaspirocycles.

Multicomponent condensation of N-diphenylphosphinoylimines, alkynes, zirconocene hydrochloride, and diiodomethane provides a rapid access to omega-unsaturated dicyclopropylmethylamines. These novel building blocks are converted into heterocyclic 5-azaspiro[2.4]heptanes, 5-azaspiro-[2.5]octanes, and 5-azaspiro[2.6]nonanes by means of selective ring-closing metathesis, epoxide opening, or reductive amination. The resulting functionalized pyrrolidines, piperidines, and azepines are scaffolds of considerable relevance for chemistry-driven drug discovery.

Directed ring-closing metathesis of trienes by silyl substitution

A synthetic strategy for ‘disarming’ a terminal alkene by substitution with a bulky silyl blocking group has been developed. In a series of model studies, sequential selective ring-closing metathesis of trienes followed by selective mono-hydrogenation of the resulting diene is described. The bulky silylated alkene is activated for a subsequent cross-metathesis reaction with a range of diverse alkenes by protodesilylation.

The Total Synthesis of (+)‐Migrastatin.

The first total synthesis of (+)-migrastatin, a macrolide natural product with interesting antimetastatic properties, has been accomplished. Our concise and flexible approach utilizes a Lewis acid-catalyzed diene aldehyde condensation to install the three contiguous stereocenters and the trisubstituted (Z)-alkene of migrastatin. Construction of the two remaining stereocenters and incorporation of the glutarimide-containing side chain have been achieved via an anti-selective aldol reaction, followed by a Horner-Wadsworth-Emmons olefination. Finally, the assembly of the macrocycle has been realized by a highly (E)-selective ring-closing metathesis.

The total synthesis of (+)-migrastatin.

The first total synthesis of (+)-migrastatin, a macrolide natural product with interesting antimetastatic properties, has been accomplished. Our concise and flexible approach utilizes a Lewis acid-catalyzed diene aldehyde condensation to install the three contiguous stereocenters and the trisubstituted (Z)-alkene of migrastatin. Construction of the two remaining stereocenters and incorporation of the glutarimide-containing side chain have been achieved via an anti-selective aldol reaction, followed by a Horner-Wadsworth-Emmons olefination. Finally, the assembly of the macrocycle has been realized by a highly (E)-selective ring-closing metathesis.

Total Synthesis of Prelaureatin.

Total synthesis of prelaureatin, which is an 8-membered cyclic ether isolated from red alga Laurencia nipponica, has been achieved through a process including stereoselective introduction of two allyl groups starting fromgalactose pentaacetate, cleavage of the hexose ring, and transformation of an acyclic triene into an oxocene by selective ring-closing metathesis.

Total Synthesis of Proposed Amphidinolide A via a Highly Selective Ring‐Closing Metathesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of the macrolide core of migrastatin

A concise and efficient synthesis of the macrolactone core of migrastatin, a new natural product with potent anticancer properties, has been achieved. The key features of our synthetic strategy encompass a Lewis acid catalyzed diene aldehyde condensation (LACDAC) to install the three contiguous stereocenters and the trisubstituted ( Z)-double bond of migrastatin, and a ( E)-selective ring-closing metathesis (RCM) to construct the macrocycle.

Total synthesis of proposed amphidinolide A via a highly selective ring-closing metathesis.

[structure: see text] A highly convergent synthesis of the proposed structure of amphidinolide A is reported. Instructive applications of several organometallic processes are illustrated, including a highly selective ring-closing metathesis reaction.

Total Synthesis of Prelaureatin

Total synthesis of prelaureatin, which is an 8-membered cyclic ether isolated from red alga Laurencia nipponica, has been achieved through a process including stereoselective introduction of two allyl groups starting from galactose pentaacetate, cleavage of the hexose ring, and transformation of an acyclic triene into an oxocene by selective ring-closing metathesis.