Stereoselective total synthesis of (3Z)- and (3E)-elatenynes

Abstract

We describe here the highly stereoselective total synthesis of the Laurencia C₁₅ acetogenins (3Z)- and (3E)-elatenynes having a 7,12-dibromo-6,9-cis-10,13-cis adjacent bis-tetrahydrofuran (THF) core. The present synthesis features a highly stereoselective, protecting group-dependent, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 7-hydroxy-6,7-cis-6,9-cis-THF intermediate 10, deployment of the sequential ate complex (n-BuLi/DIBAL-H) reduction/Keck allylation/cross metathesis (CM) protocol for the stereoselective introduction of the C(10)–C(15) unit, a sequential Sharpless asymmetric dihydroxylation (SAD)/intramolecular Williamson etherification for the construction of the 10,13-cis-THF ring, and a modified Nakata chloromethanesulfonate-mediated S_N2 displacement for the 7,12-dibromo functionality. Furthermore, our strategy based on chelate-controlled IAEA methodology would provide access to any member of the C₁₅ adjacent bis-THF acetogenin class.

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Marine algae produce a diverse set of oxacyclic C₁₅ acetogenins, among which some, as shown in Fig. 1, have a 2,2′-bifuranyl (adjacent bis-THF) core structure.¹ (3Z)-Elatenyne (1a) was first isolated from the marine algae Laurencia elata by Hall and Reiss in 1986,^2a and Erickson reported isolating (3E)-elatenyne (1b) from the marine alga Laurencia majuscule in 1989.^2b Later, 1a was re-isolated from Laurencia decumbens by Wang in 2007 (ref. 2c) and from Laurencia elata by Urban in 2011.^2d The isolation of several closely related Laurencia C₁₅ acetogenins has been reported, including notoryne (2),³ chloroenyne (3) from L. majuscule,⁴ laurendecumenyne B (4),⁵ and laurefurenynes A (5a) and B (5b).⁶ It is worth mentioning at this point that the structures depicted in Fig. 1 have been revised or confirmed by total synthesis.^{2h,3c–e,6b,c}

Fig. 1 Laurencia adjacent bis-tetrahydrofuranoid natural products.

Based on extensive ¹H and ¹³C NMR spectroscopic analyses, the structure of (3Z)-elatenyne (1a) was initially proposed by Hall and Reiss to have a pyrano[3,2-b]pyran core (fused bis-THP), as depicted in 1c.^2a However, the 1c structure was shown by Burton, et al., to be incorrect through the total synthesis thereof.^2e,f The Burton and the Goodman groups collaborated to predict the correct 2,2′-bifuranyl skeleton (adjacent bis-THF) structure and relative stereochemistry of 1a through comparison of the ¹³C NMR chemical shifts of 1a with the Boltzmann-weighted GIAO ¹³C NMR chemical shifts determined through DFT methods.^2g Later, a collaborative effort by the Kim and Burton groups achieved the total synthesis of 1a and ent-1a utilizing a modular and biomimetic approach, respectively.^2h Despite the collaborative effort, the unequivocal assignment of the absolute stereochemistry of 1a was still not possible. Eventually, Urban and Fujita confirmed the absolute stereochemistry of 1a as that shown in Fig. 1 using the crystalline sponge method.²ⁱ

The structural features of these C₁₅ adjacent bis-THF acetogenins have received considerable attention from organic chemistry community, culminating to several total syntheses: the modular synthesis on the basis of analysis ¹³C NMR chemical shifts,^2h,e,3e,6b biomimetic approach,^2e,h,3c,e the cyclization of chlorohydrin derived from anti-aldol reaction,^6c the Sharpless asymmetric dihydroxylation (SAD)/Williamson cyclization sequence,^4b and the bromo-etherification.^3d

Based on the insights garnered from our highly stereoselective syntheses of oxylipids^7a and asimitrin,^7b we formulated a synthetic strategy which provides access to any member of this C₁₅ adjacent bis-THF acetogenin class through a highly stereoselective construction of the 2,5-disubstituted-3-oxygenated tetrahydrofuran moiety A (Fig. 1) via intramolecular amide enolate alkylation (IAEA).⁷ In addition, our strategy utilizes Marshall's protocol [cross metathesis (CM)/SAD/Williamson cyclization]⁸ for the efficient construction of 2nd THF skeleton in the adjacent bis-THF unit.

To demonstrate the synthetic potential of this strategy, we describe herein the asymmetric total synthesis of (3Z)-elatenyne (1a) and (3E)-elatenyne (1b) featuring a highly stereoselective and chelate-controlled IAEA for constructing key intermediate 7-hydroxy-6,7-cis-6,9-cis-THF 10. This is followed by a sequential ate complex (n-BuLi/DIBAL-H) reduction/Keck allylation/cross metathesis (CM) protocol for stereoselective introduction of the C(10)–C(15) unit.

As shown in our retrosynthetic plan (Scheme 1), we envisioned that respective total syntheses of (3Z)-elatenyne (1a) and (3E)-elatenyne (1b) could be readily accomplished through stereoselective incorporation of the (Z)- and (E)-enyne units into 7,12-dibromo-adjacent bis-THF 6. This intermediate could be accessed by bis-bromination of the adjacent 7,12-dihydroxy-bis-THF 7, which in turn could be constructed from the tetrahydrofuranyl syn-diol 8 through an intramolecular Williamson etherification. We planned to synthesize 8 from homoallylic alcohol 9 by employing cross metathesis (CM) and Sharpless asymmetric dihydroxylation (SAD) as key steps. By this route, (10S)-9,10-syn homoallylic alcohol 9 could be stereoselectively prepared through application of ate complex (n-BuLi/DIBAL-H) reduction/Keck allylation protocols to yield α-alkoxy amide 10 (vide infra). Based on our previous work,⁷ we were confident that key 6,7-cis-6,9-cis-THF intermediate 10 could be accessed by subjecting 6,7-syn-ω-bromo-α-alkoxy amide 11 to our stereoselective chelate-controlled IAEA reaction. Finally, we imagined that IAEA substrate 11 could be prepared in a straightforward manner from the known 6,7-syn epoxy alcohol 12.

Scheme 1 Retrosynthetic plan.

Our synthesis began with the preparation of IAEA substrate 11, as outlined in Scheme 2. Thus, known epoxy alcohol 12 (ref. 9) was subjected to O-alkylation with N,N-dimethyl chloroacetamide to afford the desired epoxy α-alkoxy amide 13 in 94% yield. The regioselective opening of the terminal epoxide 13 was achieved through the action of (n-Bu)₄NBr in the presence of Mg(NO₃)₂·6H₂O to furnish the 6,7-syn-bromoamide 14 with an excellent 96% yield.¹⁰ Protection of the hydroxyl group in 14 as the PMB ether with 4-methoxybenzyl 2,2,2-trichloroacetimidate in the presence of a catalytic amount of p-toluenesulfonic acid (PTSA)¹¹ gave rise to key IAEA substrate 11 in good yield (88%).

Scheme 2 Stereoselective synthesis of 6,9-cis-THF 10 and 6,9-trans-THF 17 via IAEA.

With IAEA substrate 11 in hand, we proceeded to address the pivotal stereoselective IAEA reaction of PMB-protected bromo α-alkoxy amide 11 for the construction of key intermediate 10. Treatment of 11 with LiHMDS in THF at −78 °C for 1 h led to the desired 6,7-cis-6,9-cis-THF 10 in 97% yield as a single stereoisomer (by ¹H NMR analysis, see ESI† for details), presumably via chelated transition state geometry B. The NOE interaction between protons on [C(6) and C(7)] and [C(6) and C(9)] in 10 was supportive of the assigned cis relative stereochemistry.

To establish the diastereoselectivity of the IAEA reaction in a rigorous manner, we decided to synthesize the corresponding 6,9-trans isomer 17 for comparison purposes as shown at the bottom of Scheme 2. To this end, subjection of TIPS-protected bromo α-alkoxy amide 15 (prepared by TIPS protection of alcohol 14) to KHMDS in THF at −78 °C for 1 h gave rise to the desired 6,9-trans-THF 16 in 80% yield as the major isomer (dr > 41 : 1 by ¹H NMR analysis), presumably via transition state C. Deprotection of the TIPS protecting group in 16 by exposure to TBAF and subsequent protection of the resultant alcohol as the PMB ether provided the 6,9-trans-THF 17 in 59% yield (two steps).

Having accomplished a highly stereoselective synthesis of the desired 6,9-cis-THF 10, we turned our attention to the construction of the crucial adjacent bis-THF 21 as shown in Scheme 3. This requires the stereoselective synthesis of 9,10-syn homoallylic alcohol 9 from α-alkoxy amide 10 through application of our direct ketone synthesis/L-Selectride protocol.⁷ Thus, the Grignard reaction of 10 with CH₂=CHCH₂MgBr, and the subsequent L-Selectride reduction of the resulting ketone 18, afforded the desired 9,10-syn-homoallylic alcohol 9 in moderate yield (59% for two steps) and good selectivity (dr = 8 : 1 by ¹H NMR analysis). In an alternative approach, 10 was reduced using the ate complex derived from n-BuLi and DIBAL-H¹² and subjected to Keck allylation¹³ to afford homoallylic alcohol 9 in improved yield (75% for two steps) and improved selectivity (dr = 46 : 1 by ¹H NMR analysis)¹⁴ CM reaction of the alcohol 9 with cis-3-hexene in the presence of Grubbs second-generation catalyst [G-II, (H₂IMes)(Cy₃P)Cl₂Ru=CHPh]¹⁵ afforded alkene 20 as an inseparable mixture of stereoisomers (95% total yield, E/Z = 6 : 1 by ¹H NMR analysis). Tosylation of alkene 20 (E/Z = 6 : 1) and subsequent AD-mix β-mediated SAD reaction¹⁶ of the resulting tosylate afforded the pure syn-diol 8 in 57% overall yield from 9 (three steps) after separation. Internal Williamson cyclization of 8 in refluxing pyridine or NaH in THF/DMF (3 : 2) furnished the desired adjacent bis-THF 21 in 86% or 84% yield, respectively.

Scheme 3 Construction of 7,12-dihydroxy adjacent bis-THF 21.

Having acquired adjacent bis-THF 21, we proceeded to introduce the bis-bromide functionality to both the C(7) and C(12) positions utilizing the two-step modified Nakata chloromethanesulfonate-mediated S_N2 displacement protocol^2h,7b,17 (Scheme 4). To this end, treatment of bis secondary alcohol 7, obtained from 21 after PMB deprotection (92%), with chloromethanesulfonyl chloride (McCl) in the presence of 2,6-lutidine and subsequent exposure of the resulting sulfonate to (n-Bu)₄NBr in refluxing THF furnished the desired 7,12-dibromo-bis-THF 6 in an overall yield of 63% from 21 in two steps. It is of note that the two-step Nakata protocol was superior to Hooz bromination in term of yield and purification in our hands [69% vs. 58%; see ESI† for details].¹⁸

Scheme 4 Completion of total synthesis of 1a and 1b.

Having successfully installed both the C(7) and C(12) bromide atoms in 1a and 1b, the remaining task was attaching the C(4) enyne appendages. Catalytic hydrogenolysis of benzyl ether 6, followed by Dess–Martin oxidation¹⁹ of the resultant primary alcohol gave rise to aldehyde 22. The stereoselective Julia–Kocienski olefination²⁰ of aldehyde 22 with benzothiazole sulfone C by treatment with KHMDS in THF at –78 to 0 °C for 0.5 h gave rise to the (3Z)-TMS-enyne (Z/E = 31 : 1 by ¹H NMR analysis), which was desilylated with TBAF to afford (3Z)-elatenyne (1a) in 55% overall yield for the two steps from 22. For the second target, Wittig olefination of aldehyde 22 with Ph₃P=CHCHO [(triphenylphosphoranylidene)acetaldehyde] gave exclusively the (E)-α,β-unsaturated aldehyde, which was then subjected to the condition of Colvin–Ohira homologation²¹ using trimethylsilyldiazomethane and LDA to afford (3E)-elatenyne (1b) in 42% overall yield for two steps. The spectral characteristics of our synthetic material 1a and 1b were in good agreement with those reported for both the natural and synthetic (3Z)-^2a,d,h and (3E)^2b,h-elatenynes, respectively.

Conclusions

In summary, we have accomplished the total synthesis of both (3Z)-elatenyne (1a) and (3E)-elatenyne (1b), featuring the protecting group-dependent chelate-controlled IAEA methodology for a highly stereoselective construction of key intermediate 6,7-cis-6,9-cis-THF 10. Other key features of the synthesis include the sequential ate complex reduction/Keck allylation for stereoselective establishment of 9,10-syn configuration, the CM/SAD/Williamson cyclization sequence for the efficient construction of the bis-THF moiety, and the chloromethanesulfonate-mediated S_N2 displacement for installation of the 7,12-dibromo functionality. Application of our strategy on the basis of chelate-controlled IAEA and the Marshall's protocol to the synthesis of other members of the adjacent C₁₅ bis-THF acetogenin class in Fig. 1 is currently under investigation in our laboratories.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2020R1A2C2010329) and a grant (21153MFDS602 & 21163MFDS369) from the Ministry of Food and Drug Safety.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3ra07741a

‡ These authors contributed equally to this work.

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