From Metallacycle-Mediated Annulative Cross-Coupling to Steroidal Tetracycles through Intramolecular C9–C10 Bond Formation

Abstract

While semisynthesis is a common platform for medicinal investigation of steroidal systems, varying the nature of substitution and stereochemistry at C9 and C10 remains challenging. It is demonstrated here that de novo synthesis, enabled by a metallacycle-centered annulation reaction, provides a uniquely effective means of addressing this problem. In short, double asymmetric Friedel–Crafts cyclization proved most effective for establishing anti- relative stereochemistry (with respect to C13), while an intramolecular Heck reaction reliably delivered the syn- diastereomers with high selectivity. In addition, these studies reveal that this oxidative rearrangement is effective for establishing a C10 quaternary center boasting variable alkyl or aryl substitution.

HFIP in Organic Synthesis

“…Micalizio and co-workers modified steroid scaffolds in a manner that allowed for diversification of the difficult C9 and C10 positions (Scheme ). HFIP and PIDA allowed for an oxidative dearomatization, and a stereospecific 1,2-shift provided steroid scaffolds with different substitution and stereochemistry at C10.…”

General Enantioselective and Stereochemically Divergent Four-Stage Approach to Fused Tetracyclic Terpenoid Systems

“…This “unified” synthetic pathway (vide infra) to structurally diverse tetracyclic terpenoid systems ( 2 , 3 , 5 , and 6 ), which proceeds through sequential C9–C10 bond formation followed by rearrangement, has grown from our previously reported metallacycle-mediated annulative cross-coupling reaction that enables the union of readily available chiral enynes with trimethylsilyl (TMS)-alkynes and produces stereodefined polyunsaturated hydrindanes ( 11 → 12 ; Figure A). , This annulation reaction, along with subsequent cyclization chemistry, is successful on a multigram scale and has played a prominent role in recent natural product synthesis efforts ( 13–15 ; Figure B); consideration of state-of-the-art strategies for asymmetric de novo synthesis of tetracyclic terpenoid systems led us to contemplate the potential value of this annulative process for the construction of a range of such stereodefined carbocyclic systems.…”

“…The value of this stereodivergent bond construction is further amplified by the ability of each stereodefined system ( 2 and 5 ) to undergo a unique oxidative dearomatization/group-selective Wagner–Meerwein rearrangement that stereospecifically repositions the quaternary center from C9 to C10 in each system ( 2 → 3 , and 5 → 6 ). These latter transformations provide a general synthetic entry to steroidal systems that bear either C10,C13- anti stereochemistry (e.g., limonoids and euphanes), or C10,C13- syn stereochemistry (e.g., androstanes, pregnanes, and cardenolides) . This advance is distinct from the existing technology for forging the steroidal C9–C10 bond that proceeds either without the generation of a quaternary center at C9 ( 7 → 8 ; Figure C) or employs Pd-catalyzed coupling technology that requires the use of a complex chiral ligand to generate systems bearing a quaternary center at C10 ( 9 → 10 ) …”

From an ent-Estrane, through a nat-Androstane, to the Total Synthesis of the Marine-Derived Δ8,9-Pregnene (+)-03219A

“…As depicted in Figure B, the mismatched double asymmetric cyclization of 4 has proven to be wholly unselective with respect to stereochemistry, delivering 7 as a 1:1 mixture of isomers at C9. While recent investigations have led to the discovery that an intramolecular Heck reaction of a related substrate derived from 8 is highly selective for producing the syn -isomer, the product of this reaction similarly lacks C17 substitution to facilitate incorporation of the aforementioned acyl group of (+)-03219A …”

“…While recent investigations have led to the discovery that an intramolecular Heck reaction of a related substrate derived from 8 is highly selective for producing the syn-isomer, the product of this reaction similarly lacks C17 substitution to facilitate incorporation of the aforementioned acyl group of (+)-03219A. 13 Because of these deficiencies in previously established approaches to the asymmetric assembly of tetracyclic terpenoid motifs through metallacycle-mediated bond-construction and subsequent acid-mediated formation of the steroidal C9−C10 bond, we aimed to establish a new approach to the pregnane skeleton, being inspired by the marine natural product (+)-03219A. Our retrosynthetic strategy is illustrated in Figure 3 and involves five key phases: (i) redox manipulation of androstane 10 and installation of the C17 acyl group, (ii) oxidative rearrangement to establish the C10 quaternary center of 10 from estrane 11, (iii) formal "inversion" of C13 and introduction of a C17 ketone from ent-estrane 12, (iv) alkoxide-directed metallacycle-mediated annulative cross-coupling between 13 and TMS-propyne (3), followed by sequential protodesilylation and matched double asymmetric Friedel−Crafts cyclization, and finally, (v) assembly of enantiodefined enyne 13 from epichlorohydrin and simple organometallic reagents.…”