Total synthesis of (.+-.)-dactylol and related studies

Abstract

The marine sesquiterpene (f)-dactylol was prepared from 2,S-dimethyl-7-(3-methyl-4-pentenyl)tropne in six steps.Salient features of the synthesis include: (1) a sterm and regioselective intramolecular troponealkene [6r + 2r] photocyclization to furnish the dactylol carbocyclic skeleton, (2) a regioselective Baeyer-Villiger oxidation of a bisneopentyl ketone, and (3) a chemoselective 1 ,4-reduction of a cyclocta-l,3-diene moiety A concise and stereoselective synthesis of the cyclopentannelated cyclooctanoid natural product (*)-dactyl01 (l),I which features a novel [6r + 2 r ] intramolecular photocycloaddition2 of a methylated alkenyltropone, is described hereha This irregular marine sesquiterpene has been isolated both from the sea hare Aplysia dactylomelaiR and its putative food source the red seaweed Lourencia poitei,Ib although a relevant biological role for dactylol in either organism has yet to be established. The unusual methylatior, pattern (methyl at C(3) instead of the expected C(2)) is believed to arise biogenetically through a series of alkyl shifts via carbocationic intermediates which originate from a humulene-derived africanyl (e.g., bicyclo[5.1 .O]octanyl) ~a t i o n .~ This biosynthetic hypothesis was probed initially by Shirahama et al.,3a and later by Paquette? through preparation of the africanyl cation precurser 3 followed by Lewis acid-mediated conversion into dactylol (Scheme 1). An alternative nonbiogenetic strategy for the synthesis of dactylol was demonstrated by Gadwood,$ who converted poitediol (6), itself available from the cyclohexenone 5, to 1 via reductive deoxygenation at C(4). Both the Paquette and Gadwood studies featured a [3,3] sigmatropic rearrangement to construct crucial carbon-carbon bonds and establish product stereochemistry. In the Paquette route, the stereochemistry at C(9) (relative to the cyclooctane ring) was set in a Johnson orthoester-type Claisen rearrangement, while the Gadwood route featured an anionic oxy-Cope rearrangement of an alkynyl alkenylcyclobutanol to deliver the intact cyclooctadiene ring. In both apprmches, difficulties in achieving stereoselective functional group transformations late in the syntheses led to production of undesired isomers.Distinct from these approaches cited above, the cornerstone of our approach for the synthesis of (*)-dactyl01 (1) was a cycloaddition strategy for preparation of the core eight-membered ring.The particular cycloaddition used, the [ 6 r + 2271 photocyclization of alkenyltropones,* has been demonstrated to occur through a series of discrete intermediates, including a hydroxy(or alkoxy)tropylium ion photochemical precursor (e.g., 14), and a diradical (or zwitterionic) species in which one of the two new carbon-carbon bonds has been formed.2c With respect to the dactylol skeleton, this key transformation offers the potential economies of (1) construction of the cyclooctanoid ring in a single step, (2) relative asymmetric induction from C(9) to C ( l ) and ( I ) (a) Schmitz, F. J.; Hollenbeak, K. H.; Vanderah, D. J. Tet...

Bicyclo [6.3.0] Undecane Sesquiterpenoids: Structures, Biological Activities, and Syntheses

“…On the other hand, in the Paquette route, a cycooctadiene ring was built from cycloheptane precursors by Friedel–Crafts cyclization, while the Gadwood route featured an anionic oxy–Cope rearrangement. Later, to solve the undesired isomer problem, originatingthe stereoselective functional group transformations, Feldman et al developed concise and stereoselective novel [6π + 2π] intramolecular photocycloaddition to synthesize dactylol in 1989 and 1990 [13,14]. Then, in 2000, intramolecular 4 + 3 cycloaddition was achieved in the synthesis of dactylol by Harmata’s group [15,16].…”

“…Structurally, precapnellane (Figure 1a), asteriscane (Figure 1b), dumortane (Figure 1c), toxicodenane (Figure 1d), and capillosane (Figure 1e) featured four methyl groups on the 5-8 ring moiety, while jasionane (Figure 1f) and sinulane (Figure 1g) decorate the core with an isopropyl group. As the cyclooctanoid core represents an important and challenging target for the development of the methodology, necessary to prepare the eight-membered ring-containing compounds, some total syntheses of precapnellane-sesquiterpenoid [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29], asteriscane-sesquiterpenoid [30,31,32,33,34,35,36], and jasionane-sesquiterpenoid [37] have been achieved. However, so far, no comprehensive review of these molecules has been published.…”

m-Chloroperbenzoic Acid

“…When 1,2,3,8,9,9a-hexahydro-1-methyl-3a,8-methano-3aHcyclopentacycloocten-10-one, which has double bonds as well as a keto group, was treated with m-CPBA, exclusive alkene epoxidation was observed. 46 Ketones having stannyl groups on the β-carbon undergo a tin-directed Baeyer-Villiger reaction. 47 Oxidation of Nitrogen-Containing Compounds.…”

“…m-CPBA with the isoxazole(46) furnishes the nitrone (47) (eq 15). 55 m-CPBA oxidation of (−)-isoxazole(48) and subsequent workup results in the formation of the (−)cyclopentanone (49) (eq 16); 56 the initially formed nitrone is hydrolyzed during workup.…”

Ni(NHC)]-Catalyzed Cycloaddition of Diynes and Tropone: Apparent Enone Cycloaddition Involving an 8π Insertion

“…This resonance structure explains the dipolar nature of tropone 3a and the large LUMO coefficients at the alpha-positions (Figure 1 c). 5 Therefore, tropone cycloaddition reactions usually lead to bond formations at the α-positions as in (6 + 2), 6 (6 + 3), 7 and (6 + 4) 8 cycloaddition reactions or in one α-position and the oxygen atom as in (8 + 2) 9 and (8 + 3) 10 cycloaddition reactions (Figure 1 a). 11 …”