Stereodivergent and Protecting‐Group‐Free Synthesis of the Helicascolide Family: A Rhodium‐Catalyzed Atom‐Economical Lactonization Strategy

Abstract

Natural products of polyketide origin, in particular small-sized lactones often possess a very broad range of impressive biological activities. An efficient way to demonstrate the concise access to six-membered lactones was emphasized as part of a stereodivergent and protecting-group-free synthesis of all three representatives of the helicascolide family. This strategy features an atom-economical and highly diastereoselective rhodium-catalyzed "head-to-tail" lactonization by an intramolecular addition of ω-allenyl-substituted carboxylic acids to terminal allenes, including the selective construction of a new stereocenter in the newly formed core structures. The excellent selectivities with which the helicascolide precursors were obtained are remarkable, thus resulting in an expeditious and highly efficient natural product synthesis.

Rhodium-Catalyzed Allylation Reactions

“…The Breit group reported the diastereoselective Rh-catalyzed lactonization by an intramolecular addition of -allenyl-substituted carboxylic acids 178 to terminal allenes; 65 the strategy involved the construction of the new stereogenic center in the newly formed core in only one step (Table 4, entry 2). As a result of this discovery, they have explored this methodology to design a new route for the stereodivergent total synthesis of the helicascolide family without protecting groups and chiral auxiliaries.…”

“…In 2016, the Breit group utilized the Rh-catalyzed lactonization strategy for the synthesis of helicascolide family members containing this six-membered lactone core (Scheme 88). 65 Rh(I)/DPEphos-catalyzed hydro-oxycarbonylation of 307a generated an allylic lactonized product 308a in good yield (78%) and excellent diastereoselectivity (dr >95:5). In contrast, 307b showed very poor reactivity with the same reaction conditions, changing the ligand to (S,S)-DIOP forced 307b to undergo intramolecular hydro-oxycarbonylation affording the desired product 308b in a moderate yield and good diastereoselectivity.…”

The Total Synthesis of Epothilone D as a Yardstick for Probing New Methodologies

“…For the further synthesis of 4 , a Tsuji–Wacker‐type oxidation was chosen to install the required ketone on the allylic site. Using reaction conditions recently reported by our group, 23 was smoothly oxidized to the corresponding ketone in the presence of PdCl 2 and benzoquinone. Subsequent Wittig olefination, reported by Altmann and co‐workers for the synthesis of related compounds, and a final overall deprotection led to 4 , which exhibited spectral properties identical in all respects to those reported for the natural product…”

Six-Membered Ring Systems

“…New approaches for the synthesis of naturally occurring bioactive pyran derivatives have appeared. Different routes have been established for the total synthesis of tetrahydropyran-containing natural compounds brevisamide (16EJO2300, 16JOC3799), (±)-centrolobine (16SL2221), (−)-clavosolide A (16AGE2498), (+)-decarestrictine L (16TL4368), decytospolide A, B, and their C-3 epimers (16S765), goniodomin A (16JOC2213), herboxidiene (16OBC6212), irciniastatins (16JOC1930), (−)-lasonolide A (16JA11690), (−)-luminacin D (16JOC3818), (−)-mandelalide A (16JA770, 16JA3675), isomandelalide A (16JA770), thailanstatin A (16JA7532); of the 2H-pyran-2-ones sibirinone, (E)-6-(pent-1-en-1-yl)-2H-pyran-2-one and (E)-6-(hept-1-en-1-yl)-2H-pyran-2-one (16JOC10357); of the 5,6-dihydropyran-2-one derivatives cryptomoscatone F1 (16S1561), cryptorigidifoliol B (16TL2100), cryptorigidifoliol E (16S4213), 8-methoxygoniodiol (16S4300), pectinolides A, C, and H (16HCA247); and of the tetrahydropyran-2-one derivatives (−)-(S)-goniothalamin and (−)-leiocarpin (16SC187), helicascolides A, B, and C (16AGE5765), isodaphlongamine H (16AGE2577), and (−)-malyngolide and its C-5 epimer (16HCA267).…”