General Synthetic Approach for the Laurencia Family of Natural Products Empowered by a Potentially Biomimetic Ring Expansion

Abstract

The Laurencia family of C 15 -acetogenins is Nature's largest collection of halogenated natural products, with many of its members possessing a brominated 8-membered cyclic ether among other distinct structural elements. Herein, we demonstrate that a bromonium-induced ring expansion, starting from a common tetrahydrofuran-containing bicyclic intermediate and using the highly reactive bromenium source BDSB (Et 2 SBr•SbCl 5 Br), can lead to concise asymmetric total syntheses of microcladallenes A and B, desepilaurallene, laurallene, and prelaureatin. Key advances in this work include (1) the first demonstration that the core bromonium-induced cyclization/ring-expansion can be initiated using an enyne with an internal ether oxygen nucleophile, (2) that reasonable levels of stereocontrol in such processes can be achieved both with and without appended ring systems and stereogenic centers, (3) that several other unique chemoselective transformations essential to building their polyfunctional cores can be achieved, and (4) that a single, common intermediate can lead to five different members of the class encompassing two distinct 8-membered cyclic ether ring collections. Considering this work along with past efforts leading to two other natural products in the collection, we believe the breadth of structures prepared to date affords strong evidence for Nature's potential use of similar processes in fashioning these unique molecules.

Synthesis, Characterization, and Reactivity of Complex Tricyclic Oxonium Ions, Proposed Intermediates in Natural Product Biosynthesis

“…[15][16] Snyder has proposed that deacetyllaurencin (3E)-3 could be biosynthesized from (3E, R, R)-laurediols (3E,R,R)-1 by two favorable 5-endo bromocyclizations via bromonium ions 8 and 9 to give the bicyclic oxonium ion 10 which undergoes formal loss of positive bromine to give deacetyllaurencin (3E)-3. [17][18] Again, this biomimetic ring expansion of an oxonium ion enjoys experimental support. [17][18]28 In both the Braddock and Snyder proposals the respective oxonium ions can open in other ways to form different ring systems found in other Laurencia natural products.…”

“…[17][18] Again, this biomimetic ring expansion of an oxonium ion enjoys experimental support. [17][18]28 In both the Braddock and Snyder proposals the respective oxonium ions can open in other ways to form different ring systems found in other Laurencia natural products. The focus of the current work is the synthesis and characterization of the tricyclic oxonium ions 13 and 20 that are downstream from deacetyllaurencin on the proposed biosynthetic pathway (Figure 1b).…”

“…In a related manner, the biosynthesis of numerous halogenated acetogenin natural products from Laurencia species have been proposed to proceed via complex bi- and tricyclic oxonium ions (Figure ). − The existence of these trialkyloxonium ions, as with carbocations in terpene biosynthesis, has been implied from the structural and stereochemical diversity of these natural products and initial biosynthetic studies with isolated enzymes ,, as well as from a number of elegant biomimetic syntheses primarily from Kim, Snyder, and Braddock that involve ring opening/expansions of in situ generated oxonium ions to give a host of structurally diverse Laurencia natural products. − ,− However, no direct evidence for the existence of these trialkyloxonium ions has been forthcoming. Herein we report the synthesis and full characterization (both chemically and computationally) of one family of tricyclic trialkyloxonium ionsamong the most structurally and stereochemically complex oxonium ions characterized to date .…”

“…Red algae of the genus Laurencia and organisms that feed on them produce a vast array of structurally diverse C 15 halogenated cyclic ether acetogenin natural products which have stimulated synthetic chemists to develop numerous new methods to gain access to these complex secondary metabolites. , Since Masamune’s ground-breaking synthesis of (±)-laurencin ((±)- 4 , Figure ) reported in the 1970s, − the syntheses of over 50 cyclic halogenated acetogenin natural products from Laurencia spp. have been reported with many targets being synthesized by multiple independent routes. − Hand-in-hand with the development of the synthetic methodology has been the development of biosynthetic postulates toward these natural products with many of these biosynthetic postulates being rich in oxonium ion chemistry including bicyclic oxonium ions derived from epoxides, , oxetanes, tetrahydrofurans, , and oxocenes as well as fused , and bridged tricyclic oxonium ions. − ,, Initial proposals regarding the biosynthesis of C 15 halogenated acetogenin natural products from Laurencia species were put forward by Murai ,, which involved bromocyclizations of the linear laurediols 1 that exist in nature as mixtures of diastereomers (Figure a). , Murai postulated that enzymatic bromocyclization of the (3 E , R , R )-laurediol (3 E , R , R )- 1 gives rise to deacetyllaurencin (3 E )- 3 via bromonium ion 2 ; , indeed, experiments with isolated enzymes yielded deacetyllaurencin (3 E )- 3 in very low yield (0.015%). ,,, More recently, trialkyloxonium ions have been proposed as intermediates in the bromocyclization of linear precursors to give deacetyllaurencins 3 . Braddock proposed that laurepoxides 5 , the potential precursor of the laurediols 1 , undergoes bromocyclization to give the bicyclic oxonium ions 7 via the bromonium ions 6 .…”

Forwards and backwards – synthesis of Laurencia natural products using a biomimetic and retrobiomimetic strategy incorporating structural reassignment of laurefurenynes C–F

“…[20][21][22] Key to correcting many of these structural misassignments have been postulates regarding the biosyntheses of acetogenic Laurencia natural products, many of which have been proposed to proceed through complex oxonium ion intermediates. 15,[23][24][25][26][27][28][29][30][31][32][33] These biogenetic postulates have allowed rational prediction of the likely structures of a number of the natural products 15,21,22,26,34 and in a number of cases the biogenetic arguments have been augmented by DFT calculations of both proton and carbon NMR chemical shis 14,22,34 for a range of candidate structures with ultimately the structure of the natural products being established through total synthesis. 35 Among the acetogenic Laurencia natural products whose structures have been reassigned are laurefucin, 36,37 obtusallenes V, VI and VII, 16,19,26 elatenyne, [12][13][14][15]38 laurendecumenyne B, 15,39,40 aplysiallene, 41,42 a chloroenyne from Laurencia majuscula 13,34,38,43 and laur...…”