Gold(I) as an Artificial Cyclase: Short Stereodivergent Syntheses of (−)-Epiglobulol and (−)-4β,7α- and (−)-4α,7α-Aromadendranediols

Abstract

Three natural aromadendrane sesquiterpenes, (−)-epiglobulol, (−)-4β,7α-aromadendranediol, and (−)-4α,7α-aromadendranediol, have been synthesized in only seven steps in 12, 15, and 17 % overall yields, respectively, from (E,E)-farnesol by a stereodivergent gold(I)-catalyzed cascade reaction which forms the tricyclic aromadendrane core in a single step. These are the shortest total syntheses of these natural compounds.

Aromadendranes are a family of hydroazulenes named after (+)-aromadendrene (1, Figure 1), the main component in the essential oil from Eucaliptus trees. The related sesquiterpenoids (−)-globulol (2), (−)-epiglobulol (3), (−)-4α,7α-aromadendranediol (4), and (−)-4β,7α-aromadendranediol (5) are widespread in plant species[1] and display antifungal,[2] antibacterial,[3] antiviral,[4] cytotoxic,[5] and other activities.[6] Interestingly, the antipodes of 1 and other aromadendrenes have been isolated from corals.[7] Aromadendranes with amino, isonitrile, isothiocyano, and urea functionalities at C4 have been found in sponges.[8] Diterpenoids with an aromadendrane structure are also natural products.[9]

Figure 1.

Naturally occurring aromadendranes.

The synthesis of members of this family of tricyclic sesquiterpenes has attracted significant interest.[10] (−)-Epiglobulol (3), isolated in hop[11] and many essential oils,[12] was prepared from 1 or the corresponding ketone (apoaromadendrone).[13] A first total synthesis of 3 from the chiral pool was accomplished in eight steps (4 % overall yield).[14] A recent synthesis of (±)-epiglobulol in 18 steps used a rhodium(I)-catalyzed hydroacylation/cycloisomerization as the key step.[15]

(−)-4α,7α-Aromadendranediol (4) was isolated from a marine coral Sinularia may[7] and the leaves of the Amazonian tree Xylopia brasiliensis.[2] A semisynthesis of 4 from (+)-spathulenol[7] and one total synthesis have been reported.[16] This total synthesis involved a three-reaction sequence in a three-component reaction to generate four stereogenic centers in one step and required ten steps to produce 4 in 23 % overall yield. (−)-4β,7α-Aromadendranediol (5) has been isolated from the leaves of Chloranthus glaber.[17] A semisynthesis of 5 from (+)-spathulenol has been reported.[7]

We developed a gold(I)-catalyzed cascade cyclization of the dienyne 6, a cascade consisting of a cyclization, 1,5-migration of the propargylic OR group, and intramolecular cyclopropanation, thus leading to tricyclic structures closely related to the aromadendrene sesquiterpenes (Scheme 1).[18] This reaction is stereospecific since (E)-6 gave the tricyclic product 7 having the relative configuration of 3 and 5, whereas the geometrical isomer of 6 led to 8, the C4 epimer of 7, having the configuration of 2 and 4. We recently applied a strategy based on a gold(I)-catalyzed cyclization/1,5-OR migration/intermolecular cyclopropanation for the first total synthesis of (+)-schisanwilsonene A. As part of our program on the synthesis of terpenoids by using new gold-catalyzed cyclization cascades,[19] we decided to target 3, 4, and 5, each of which present six stereogenic centers in a tricyclic skeleton. In principle, 3 and 5 could be synthesized from the dienyne (S,E)-6 (Scheme 1), whereas 4 would be prepared from geometric isomer (S,Z)-6. However, although enantioenriched (E)-6 could be readily prepared from (E,E)-farnesol (9), the starting material, (E,Z)-farnesol, required for the synthesis of (Z)-6 is not commercially available.[20]

Scheme 1.

Gold-catalyzed formation of tricyclic cores of the aromadendranes by cyclization/1,5-OR migration/intramolecular cyclopropanation.

Herein we report a simple solution to this problem and it allows general access to this class of sesquiterpenes from (S,E)-6 as a common precursor by means of a stereodivergent gold(I)-catalyzed cascade process. The reaction can take place intramolecularly by 1,5-migration of OR in A and in the presence of an external nucleophile (via B), thus leading to 7 and 8, respectively, having opposite configurations at C4 (Scheme 1). Starting from (R,E)-6, enantiomeric aromadendranes can be similarly obtained. This proposal is based on our initial mechanistic study in the Z series, in which we found that the cyclopropyl gold(I) carbene intermediate could be trapped with methanol to form an epimeric compound as a minor product.[18] In these transformations, gold(I) acts as an artificial cyclase,[21] thus mimicking the action of terpene cyclases forming polycyclic skeletons by the selective activation of the alkyne terminus of a dienyne, to readily build a tricyclic skeleton with exquisite stereocontrol.[22, 23]

The dienyne (S,E)-6 (R=Bn) was prepared in four steps and 62 % overall yield by using a route similar to that used in the transformation of the lower homologue geraniol.[19a, 24] the transformation involved the known Sharpless asymmetric epoxidation of (E,E)-farnesol (9) to give the epoxide (S,S)-10 (88 % yield, 91:9 e.r.)[25, 26] (Scheme 2). Substitution of the primary alcohol by chloride with CCl₄ and PPh₃ gave 11, which was treated with nBuLi to yield the propargylic alcohol 12. Finally, benzylation under standard reaction conditions gave (S,E)-6.

Scheme 2.

a) l-(+)-DIPT, Ti(OiPr)₄, tBuOOH, 4 Å M.S., CH₂Cl₂, −48 °C, 88 %, 82 % ee;[25] b) PPh₃, NaHCO₃, CCl₄, reflux, 6 h, 94 %; c) nBuLi, THF, −40 °C, 2 h, 82 %; d) BnBr, NaH, Bu₄NI, THF, 23 °C 12 h, 91 %. DIPT=diisopropyl tartrate, M.S.=molecular sieves, THF=tetrahydrofuran.

Exposing (S,E)-6 to the cationic gold(I) complex [(JohnPhos)Au(MeCN)]SbF₆ (13) for 5 minutes at room temperature gave 7 in 60 % yield (Scheme 3). Other gold(I) catalysts were also screened for this reaction, but the best results were obtained using complex 13.[27] The relative configuration of 7 (racemic series) was confirmed by X-ray diffraction.[28, 29] Debenzylation of 7 with H₂ (1 atm) and Pd(OH)₂/C gave the alcohol 14 (79 % yield), which was hydrogenated with [Ir(cod)(PCy₃)py]BAr_F catalyst[30] under high pressure of H₂ to give 3 in 40 % yield (95:5 e.r.). The synthesis 3 from 9 required seven steps and proceeded in 12 % overall yield.

Scheme 3.

Reagents and conditions: a) [(JohnPhos)Au(MeCN)]SbF₆ (13; 2 mol %), 23 °C, 5 min (60 %); b) H₂, Pd(OH)₂/C, 1:1 MeOH/THF, 23 °C, 4 h (79 %); c) [Ir(cod)(PCy₃)py]BAr_F (15 mol %), H₂ (80 atm), CH₂Cl₂, 40 °C, 4 days (40 %); d) oxone, NaHCO₃, 18-crown-6, 1:1:2 acetone/CH₂Cl₂/H₂O, 23 °C, 1 h (51 %); e) Li, EDA, 50 °C, 1 h (78 %); f) allyl alcohol (20 equiv), 13 (2 mol %), −30 °C, 15 min (56 % + 21 % 7); g) [Pd(PPh₃)₄] (5 mol %), K₂CO₃, MeOH, reflux 72 h (72 %); h) mCPBA, CH₂Cl₂, 0 to 23 °C (83 %); i) Li, EDA, 50 °C, 1.5 h (62 %). BAr_F=3,5-bis(trifluoromethyl)phenylborate, cod=1,5-cyclooctadiene, EDA=ethylenediamine, JohnPhos=(2-biphenyl)-di-tert-butylphosphine; mCPBA=m-chloroperbenzoic acid.

Epoxidation of 7 with dimethyldioxirane yielded 15 stereoselectivily. Epoxide opening and ether cleavage with Li in ethylenediamine[31] yielded 5 in 78 % (96:4 e.r.), which gave enantiopure material after crystallization. The synthesis of 5 from 9 was accomplished in seven steps with 15 % overall yield.

When the gold-catalyzed reaction of dienyne (S,E)-6 was performed in the presence of allyl alcohol as an external nucleophile, the allyl ether 8 was obtained with the opposite configuration at C4 compared to that of 7 (Table 1). While lowering the reaction temperature to −30 °C led to a 1:1 mixture of 7 and 8 (Table 1, entry 3), increasing the concentration of allyl alcohol to 20 equivalents favored the intermolecular pathway (Table 1, entry 5). Similar results were obtained with using only 1 mol % gold(I) catalyst (Table 1, entry 5). Under the optimized reaction conditions, 8 was obtained in 56 % yield, along with 7 (21 % yield; Scheme 3). Removal of the allylic ether with [Pd(PPh₃)₄] in MeOH gave the alcohol 16, whose structure was confirmed by X-ray crystal diffraction[29] in the racemic series (Figure 2).[26] Although 4 could be synthesized from 16, a more direct synthesis was completed from 8 by selective epoxidation with mCPBA from the convex face (83 % yield), followed by opening of the epoxide and allyl cleavage with Li in ethylenediamine to give 4 in 62 % yield (87:13 e.r.), yielding enantiopure 4 after crystallization. Spectral data and optical rotation of synthetic 4α,7α-aromadendranediol matched those reported for the natural compound. The relative and absolute configuration of 4 were confirmed by X-ray diffraction (Figure 2).[29] The synthesis of (+)-4α,7α-aromadendranediol was similarly carried out from (R,R)-10.[27]

Table 1.

Gold(I)-catalyzed addition of allyl alcohol to (S,E)-6.^[a]

Entry	AllylOH (equiv)	T [°C]	t [min]	7/8[b]
1	10	23	5	75:25
2	10	0	10	55:45
3	10	−30	15	50:50
4	20	−30	20	27:73
5[c]	20	−30	30	33:67

[a] 0.05 m. [b] Determined by GC-MS. [c] 1 mol % 13.

Figure 2.

X-ray structures for (±)-16 and 4. Thermal ellipsoids are shown at 50 % probability.

The stereochemical divergent synthesis of 3 and 4 from (S,E)-6 confirms the proposal that this cascade cyclization process proceeds by intra- or intermolecular reactions of cyclopropyl gold(I) carbene-like intermediates such as A or B.[18, 32] The enantioselectivity is fully preserved in the formation of 3 and 5 via 7 by an intramolecular gold(I)-catalyzed 1,5-migration of a propargylic group. The intermolecular reaction of (S,E)-6 with allyl alcohol occurs with high enantioselectivity (ca. 96 %). In this case, the slight racemization is due to the competitive formation of a propargyl carbocation, presumably facilitated by the higher polarity of the reaction medium.

In summary, we have completed highly concise syntheses of three representative aromadendranes from a single precursor by a stereodivergent gold-catalyzed reaction which establishes four new stereogenic centers from a single one. The three natural sesquiterpenes (−)-epiglobulol (3), (−)-4α,7α-aromadendranediol (4), and (−)-4β,7α-aromadendranediol (5) have been synthesized in seven steps in 12, 17, and 15 % overall yields, respectively, from commercially available (E,E)-farnesol (9), and constitutes the shortest total syntheses of these natural compounds. This route could be extended for the enantioselective synthesis of any enantiomer of other aromadendranes and non-natural analogues.

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