Structure Determination of a Chloroenyne from Laurencia majuscula Using Computational Methods and Total Synthesis

Abstract

Despite numerous advances in spectroscopic methods through the latter part of the 20th century, the unequivocal structure determination of natural products can remain challenging, and inevitably, incorrect structures appear in the literature. Computational methods that allow the accurate prediction of NMR chemical shifts have emerged as a powerful addition to the toolbox of methods available for the structure determination of small organic molecules. Herein, we report the structure determination of a small, stereochemically rich natural product from Laurencia majuscula using the powerful combination of computational methods and total synthesis, along with the structure confirmation of notoryne, using the same approach. Additionally, we synthesized three further diastereomers of the L. majuscula enyne and have demonstrated that computations are able to distinguish each of the four synthetic diastereomers from the 32 possible diastereomers of the natural product. Key to the success of this work is to analyze the computational data to provide the greatest distinction between each diastereomer, by identifying chemical shifts that are most sensitive to changes in relative stereochemistry. The success of the computational methods in the structure determination of stereochemically rich, flexible organic molecules will allow all involved in structure determination to use these methods with confidence.

Introduction

Elucidating the structures of natural products that are available only in very small quantities is often exceptionally difficult, highlighted by the high number of structure revisions reported every year in the chemical literature.¹ Unequivocal establishment of molecular structure may be possible using single-crystal X-ray diffraction; however, for molecules that will not crystallize or that form poorly diffracting crystals, alternative methods must be used.² Nuclear magnetic resonance (NMR) spectroscopy remains one of the primary means of molecular structure determination. Comparison of computationally predicted NMR chemical shifts, coupling constants, and internuclear distances have also emerged as a powerful and reliable way to assess the likelihood of a putative structure being correct. NMR computations have thus been used to establish relative stereochemistry,³ to confirm or reassign proposed natural product structures,⁴ to characterize the identity of a side product,⁵ and in conformational assignment of cyclic peptides.⁶ However, this approach can become particularly challenging for molecules containing multiple stereogenic centers and with a high degree of conformational flexibility. In such cases, weighted ensemble averages must be considered in comparison against experimentally observed NMR parameters. In the case of complex structures such as baulamycin, hundreds and thousands of conformations may be relevant at room temperature.⁷ Although elegant synthetic approaches have been developed to access multiple diastereomers of a target molecule,⁸ the ability to predict the most plausible relative and absolute configuration of flexible natural product structures is desirable. Flexible, halogenated natural products epitomize this challenge and have been variously misassigned.⁹

Comparison of experimental NMR parameters, such as chemical shifts, against calculated values can reveal obvious discrepancies and raise doubts about a proposed structure.^4a Furthermore, several measures have been used to quantify the “best match” from several putative structures with respect to an experimental spectrum. In particular, statistical parameters developed in the Goodman group, namely, CP3¹⁰ and DP4,¹¹ use prior knowledge of the underlying empirical error distribution of computational predictions to assign statistical confidence values to a particular structural assignment. This has led to their widespread adoption in computational natural product assignments.¹² These metrics emphasize the importance of ensuring a narrow underlying prediction error as this allows greater significance to be attached to the differences between incorrect structures and experiment. More confident assignments can be made as a result. Empirical linear scaling, aided greatly through contributions from the Tantillo group and the CHESHIRE repository,¹³ has contributed to this as have modified DP4 models and the use of different internal standards against which chemical shifts are referenced.¹⁴ However, molecules with many accessible conformers can give rise to larger prediction errors,³ making the use of these now standard tools more precarious. Herein, we report the full structure determination of a 2,2′-bifuranyl chloroenyne natural product isolated from Laurencia majuscula (2) using the powerful combination of biosynthetic postulates, density functional theory (DFT) calculations of NMR chemical shifts, and total synthesis. In addition, we report the synthesis of all four biosynthetically relevant diastereomers of 2 (2a–d) and show that comparison of the experimental ¹H and ¹³C NMR data for any of these four diastereomers with the computed ¹H and ¹³C NMR data for all 32 diastereomers of the natural product allows each specific biomimetic diastereomer to be identified. Finally, we report the structure confirmation of (Z)-notoryne as (Z)-3a using the above combined approach of quantum chemical calculations coupled with two distinct total syntheses.

Recently, we assigned the full structures of two 2,2′-bifuranyl natural products using the powerful combination of biosynthetic postulates, DFT calculations of NMR chemical shifts, and total synthesis. We used this combined approach to fully elucidate the structure of elatenyne¹⁵ and to reassign the stereostructure of laurefurenynes A and B.¹⁶ Previously, we demonstrated that the gross structure of a chloroenyne isolated from Laurencia majuscula, originally assigned as a pyrano[3,2-b]pyran (1)¹⁷ on the basis of extensive NMR experiments and comparison with the NMR data of the dactomelynes¹⁸ and of the originally assigned pyrano[3,2-b]pyran structure of elatenyne,¹⁹ was actually a 2,2′-bifuranyl 2 (Chart 1).^15a,15b The 2,2′-bifuranyl 2 contains six stereocenters, with the full structure of the natural product being one of 32 possible diastereomers. We aimed to solve the complete stereostructure of this natural product using the combined approach which we had previously found successful, namely, biosynthetic postulates coupled with DFT calculations of NMR chemical shifts and total synthesis.

Chart 1. Proposed Structures of Chloroenyne from L. majuscula (Relative Configurations) along with the Structures of (Z)- and (E)-Notoryne (Absolute Configurations).

Clues from Biosynthesis

Algae of the genus Laurencia produce a vast array of structurally diverse C₁₅ halogenated natural products. Elatenyne,^19,20 notoryne (3),²¹ laurendecumenyne B,^20,22 laurefurenynes A and B,²³ and the above chloroenyne from L. majuscula2(17) are currently the only 2,2′-bifuranyl natural products that have been isolated from Laurencia spp. Notoryne 3 was the first of these 2,2′-bifuranyls to be isolated, and its structure was determined through extensive chemical degradation and by comparison with chemical degradation products of laurencin.^21a A plausible biosynthesis of notoryne 3a was proposed by Suzuki and by Fukuzawa and Murai.^21a,24 For (3Z)-notoryne (Z)-3a, (3Z,12E,R,R)-laurediol 4a(25) is converted into (3Z)-deacetyllaurencin 6a via bromonium ion formation and cyclization (Figure 1a).²⁶

Figure 1.

(a) Plausible biosynthesis of notoryne 3a as proposed by Suzuki and by Fukuzawa and Murai along with the proposed biosynthesis of diastereomer 2a of the chloroenyne from L. majuscula. (b) Proposed biosynthesis of diastereomer 2b of the chloroenyne from L. majuscula via the natural products bromofucin 8b and laurendecumeyne B 3b. (c) Proposed stereostructures 2c and 2d of the chloroenyne from L. majuscula derived from the (12Z)-laurediols 4c and 4d.

Further bromoetherification of (3Z)-deacetyllaurencin 6a gives the (3Z)-dibromide 8a, prelaurefucin, via 7a. Transannular displacement of bromide gives (3Z)-tricyclic oxonium ion 9a, which on opening at C-7 with chloride gives (3Z)-notoryne (3Z)-3a. As we previously proposed for the biosynthesis of laurefurenynes A and B,^16a displacement of bromide by water (or a water equivalent)²⁷ would give rise to 2a as a potential stereostructure for the chloroenyne from L. majuscula. Based on this proposed biosynthesis of notoryne 3a, we recently proposed a biosynthesis of elatenyne, laurendecumenyne B,^15d and laurefurenynes A and B,^16a which begins from a different diastereomer of the laurediols (4b)²⁵ and proceeds via the natural product bromofucin 8b.²⁸ Here, laurediol 4b undergoes bromoetherification to give a diastereomer of deacetyllaurencin 6b, which undergoes further bromoetherification to give bromofucin 8b (Figure 1b). Transannular displacement of bromide gives the oxonium ion 9b, which on C-7 opening with chloride gives the notoryne diastereomer 3b, (3Z)-laurendecumenyne B. Displacement of bromide by water (or a water equivalent)²⁷ gives diastereomer 2b of the chloroenyne from L. majuscula. The laurediols exist naturally as unequal mixtures of (R,R), (S,S), (3E), (3Z), (12E), and (12Z)-diastereomers.²⁵ The (3E) and (12Z)-laurediols 4c and 4d are therefore also plausible starting points for the biosynthesis of the chloroenyne 2, leading to stereostructures 2c and 2d (Figure 1c).²⁹ Based on our biosynthetic analysis, the structure of the chloroenyne from L. majuscula is plausibly, therefore, one of the four diastereomers 2a, 2b, 2c, or 2d, each of which could be produced from the above biogenetic schemes.³⁰ We then used quantum chemistry to predict the most likely stereostructure for 2, based on computed ¹³C and ¹H chemical shifts for each of the 32 possible diastereomers.³¹

Results and Discussion

Computational Prediction

The specific challenges associated with the computational structural assignment of chloroenyne 2 (and related molecules) influenced the computational methods employed. First, each diastereomer is highly flexible. A Monte Carlo conformational search with the Merck Molecular Force Field (MMFF) was used to obtain the low-energy conformations within 10 kJ/mol of the lowest-energy structure of each diastereomer.³² Across all of the diastereomers, there are 1277 conformers in this energy range that contribute to the predicted Boltzmann-weighted chemical shifts! Furthermore, the level of theory used for geometry optimization influences both the estimated populations and the computed chemical shifts of each conformation. Although MMFF geometries have been used in structure prediction,^31c,33 DFT optimization allows for more confident structural assignment as there is a narrower distribution of errors with respect to experimental chemical shifts.^16a,31c As an illustration, for 82 molecules with 709 experimentally assigned ¹³C chemical shifts, we verified that DFT optimizations led to a 2 ppm reduction in root-mean-square deviation (rmsd) compared to MMFF geometries, even though both sets of calculations used the same level of theory for shielding tensor calculation and empirical scaling (Figure S1). In this work, we optimized all structures with dispersion-corrected DFT, at the wB97XD/6-31G(d) level of theory³⁴ with CPCM (Conductor-like Polarizable Continuum Model) chloroform.³⁵ Conformer relative energies were checked against COSMO–DLPNO–CCSD(T)/cc-pVTZ single-point energies³⁶ for one diastereomer and showed a good level of agreement (R² = 0.90, rmsd = 3.1 kJ/mol) against this high accuracy method (Figure S2). Manual data processing is prohibitively difficult for so many conformations; a Python program was developed to automate all analysis given a collection of output files and a text file with experimental chemical shifts. Conformational Boltzmann weighting, empirical scaling, symmetry averaging, consideration of alternative assignments, and calculation of rmsd/MAD and DP4 for all structures are fully automated (Supporting Information shows example usage). We note that the DP4 workflow has now been automated (pyDP4) by Ermanis and Goodman.¹²

Halogenated natural products pose a further challenge due to the so-called heavy-atom light-atom (HALA) effect.³⁷ Relativistic spin–orbit contributions shift carbon atoms bonded to Cl, Br, or I to lower parts per million. In this work, we used the CHESHIRE database test set of molecules developed by Rablen, Bally, and Tantillo¹³ to derive new, optimal scaling parameters for mPW1PW91/6-311G(d,p)//wB97XD/6-31G(d) GIAO shielding tensors for ¹³C and ¹H nuclei (Figure S3). Several chlorine-containing compounds appear in this data set, from which we found an additive correction of 7.6 ppm applied to the shielding tensors of C–Cl atoms results in an rmsd no worse than if these atoms are excluded entirely. Such a correction (which is level of theory dependent) has also been used by Rzepa and Braddock.³⁸

We analyzed the Boltzmann-weighted ¹³C and ¹H chemical shifts for all 32 diastereomers at every position except the hydroxyl proton. The variability in computed shifts across the entire set of diastereomers (Figure 2) shows the extent to which each nucleus acts as a reporter for stereochemical changes. Larger standard deviations are obtained for positions which are inherently more sensitive to their relative stereochemistry. Stereostructure assignment can be made more confidently when these values are large in relation to the inherent accuracy of the computed chemical shifts versus experiment (i.e., by ensuring a higher signal-to-noise ratio).

Figure 2.

Standard deviations of computed ¹³C and ¹H chemical shifts at each position over all 32 diastereomers of 2. These values, illustrated by circle size, show the sensitivity of each shift to stereochemical changes. Values in black were excluded from experimental comparison.

Based on the work of Smith and Goodman,¹¹ standard deviations of 2.3 and 0.19 ppm for errors in ¹³C and ¹H chemical shifts are representative of the underlying computational accuracy, although because previous calculations used MM geometries, these values are likely to be pessimistic for the DFT optimizations used here. For chloroenyne 2, a handful of nuclei have low variability and are thus very poor reporters of stereochemical information. Consistent with chemical intuition, these are exocyclic positions remote from stereocenters. These nuclei were excluded from further analysis as they contribute minimally to stereochemical assignment. The inclusion of the halogenated carbon atom is important as this is the best stereochemical reporter from all of the ¹³C shifts. This is important because halogenated carbons have been omitted previously from structural prediction due to the aforementioned challenges associated with the HALA.^15c The ethyl ¹³CH₂ also provides one of the more diagnostic values. There are several protons which show a standard deviation larger than 0.19 ppm. This is consistent with the idea that structural differences in ¹H chemical shifts are more diagnostic than ¹³C in relation to the underlying theoretical accuracy.³⁹ We compared predicted chemical shifts for each diastereomer against those of the natural product. The ¹³C spectrum was fully assigned, whereas for three pairs of protons, the best possible (lowest rmsd) assignment was generated automatically for each structure. The rmsd values and DP4 metrics were generated using 10 ¹³C and 14 ¹H chemical shifts (Figure 3). If one assumes that the underlying error distribution of n chemical shifts is Gaussian (in its original formulation, the DP4 metric assumes a t-distribution, although a Gaussian distribution was also proposed), the sum of squared errors obeys a χ²-distribution with n degrees of freedom. The rmsd values can therefore be interpreted in a probabilistic fashion as is done for DP4: for example, incorrect structures can be rejected at the p = 0.05 significance level, where the rmsd falls above a critical value (Figure 3). Importantly, the statistical significance of differences between rmsd values is intrinsically linked to the number of chemical shifts being compared. Although rmsd, MAE, and R² measures have been used previously to compare the relative likelihood of structures being correct, the statistical confidence of these measures has not received much attention. Here, in addition to DP4 values, we show the 95% confidence intervals for rmsd values, above which structures are deemed to be unlikely candidates.

Figure 3.

Comparison of computed ¹³C and ¹H chemical shifts for 32 diastereomers of 2 against the natural product. The smallest rmsd values and largest DP4 probabilities point to biosynthetically predicted compound 2b.

We found that one of the four biogenetically plausible structures (2b) was the best match for ¹³C and ¹H experimental data, giving the smallest rmsd and largest DP4* values. The convergence of all four metrics, combined with biosynthetic arguments, overwhelmingly suggests the identity of the chloroenyne from L. majuscula as 2b. In using the original t-distribution parameters (σ, υ) derived for MMFF-optimized geometries, we are being deliberately conservative: we expect a narrower error distribution using DFT optimizations that would penalize the less likely structures more severely. DP4 relies on individually scaling each structure against experiment, which can lead to a fortuitous improvement of incorrect structures, particularly for a small number of nuclei. Indeed, we found better predictive performance without individually scaling the ¹³C shifts (indicated as DP4*).

All of our biosynthetic and computational analysis provided compelling evidence that the correct structure for the chloroenyne from L. majuscula was represented by 2b; however, proof of this could only come through total synthesis.^1,2b Additionally, we decided to synthesize all four biosynthetically relevant diastereomers of the chloroenyne from L. majuscula, which would allow us to obtain NMR data for each diastereomer. With these data in hand, we could further test the computational methods; would it be possible computationally to correctly identify each of the four biosynthetically predicted diastereomers (2a–d) from the computed data of the 32 possible diastereomers of the chloroenyne from L. majuscula?

Synthesis

The proposed synthesis of the four biomimetically plausible diastereomers of the chloroenyne form L. majuscula (2a–d) presented us with the opportunity to modify and improve our modular route to 2,2′-bifuranyl natural products.^15d The retrosynthetic synthetic route to diastereomers 2a and 2c is shown in Figure 4. Enynes 2a and 2c were to be readily derived from the 2,2′-bifuranyl 10, which itself was to be derived from 11 and subsequently from diol 12 following a route analogous to that described in our recent synthesis of elatenyne.^15d Diol 12 was to be derived from alkene 13, which was to be constructed by Julia–Kocienski olefination of aldehyde 15 with sulfone 14.⁴⁰ The two coupling partners 14 and 15 were to be derived from protection of the known enantiomeric epoxy alkenes (+)-16 and (−)-16. In the forward direction (Scheme 1), the known benzyl-protected epoxy alkene 17, prepared according to the method of Crimmins,⁴¹ was converted into alcohol 18 by ozonolysis with in situ reduction (PPh₃ then NaBH₄). Alcohol 18 was then converted into the corresponding tetrazole sulfone 14 by Mitsunobu reaction followed by oxidation.⁴⁰ Aldehyde 15 was readily prepared from alcohol (+)-16, which on PMB protection gave ether 19.^15d Copper-catalyzed ring opening of epoxide 19 with methylmagnesium bromide⁴¹ followed by silyl protection gave alkene 20. Ozonolysis of alkene 20 and reductive phosphine workup gave the required aldehyde 15. Julia–Kocienski^40,42 coupling of sulfone tetrazole 14 with aldehyde 15 proceeded in good yield with >20:1 E/Z-selectivity to give alkene 13.⁴³ Sharpless asymmetric dihydroxylation⁴⁴ of 13 using super-AD-mix β⁴⁵ gave the corresponding diols in 91% yield as a 6:1 mixture of syn-diastereomers; diol 12 could be isolated in pure form in 64% yield. Under acid catalysis, diol 12 underwent cyclization to give THF 21. Formation of the second THF ring was achieved using a three-step procedure. Exposure of diol 21 to mesyl chloride and Hünig’s base gave dimesylate 23 which, without purification, was treated with (±)-10-camphorsulfonic acid to remove the silyl-protecting group. Exposure of the resulting alcohol to potassium tert-butoxide gave 2,2′-bifuranyl 24 in 52% yield over three steps.

Figure 4.

Retrosynthetic analysis of diastereomers 2a and 2c.

Scheme 1. Synthesis of Chloride 28.

Reagents and conditions: (a) O₃/O₂, CH₂Cl₂, MeOH, −78 °C, then PPh₃, 30 min, then NaBH₄, −78 °C to rt, 2 h, 92%; (b) DIAD, PPh₃, THF, 0 °C, then 18, then 1-phenyl-1H-tetrazole-5-thiol, rt, 16 h, 88%; (c) 3-chloroperbenzoic acid, CH₂Cl₂, rt, 72 h, 60%; (d) NaH, PMBBr, Bu₄NI, THF, −78 °C to rt, 16 h; (e) MeMgBr, CuI, THF, −20 °C, 1 h, 88% (two steps); (f) TBSCl, imidazole, DMF, 60 °C, 16 h, 99%; (g) O₃/O₂, CH₂Cl₂, −78 °C, then PPh₃, −78 °C to rt, 16 h, 98%; (h) 14, DME, NaHMDS, −78 °C, 15 min, then add 15 in DME, −78 °C, 1 h, then warm to rt, 2 h, 80%; (i) K₂OsO₄(OH)₄, K₃Fe(CN)₆, (DHQD)₂PHAL, K₂CO₃, MeSO₂NH₂, tBuOH, water, rt, 24 h, 64% pure 12 (6:1 mixture of syn-diol diastereomers 91% total); (j) (±)-10-camphorsulfonic acid, CH₂Cl₂, 0 °C, 2 h, 86%; (k) MsCl, i-Pr₂NEt, CH₂Cl₂, 0 °C, 1 h; (l) (±)-10-camphorsulfonic acid, CH₂Cl₂, MeOH, rt, 24 h; (m) t-BuOK, tBuOH, 35 °C, 52% (three steps); (n) Bu₄NI, toluene, 110 °C, 16 h, 80%; (o) CH₂=CHMgBr, benzene, THF, 40 °C, 3 h, 57%; (p) Li, 4,4′-di-tert-butyl-1,1′-biphenyl, THF, −78 °C, 77%; (q) CCl₄, PPh₃, CH₂Cl₂, rt, 3 h, 78%.

During optimization studies, the monomesylate 22 was isolated and characterized. Mosher ester formation using 22 allowed the sense of the Sharpless asymmetric dihydroxylation reaction to be confirmed.⁴⁶ As with the synthesis of elatenyne,^15d forcing conditions (Bu₄NI, toluene, reflux) were required to convert the mesylate 24 into the corresponding iodide 25. Iodide 25 underwent displacement with vinylmagnesium bromide in a mixed benzene/THF solvent system to give the allyl-substituted 2,2′-bifuranyl 11 in 57% yield.⁴⁷ Deprotection of the benzyl group in 11 in the presence of the PMB group was achieved by titrating LiDBB⁴⁸ into a THF solution of 11 to minimize formation of diol 27. Attempted chlorination of alcohol 26 using triphenylphosphine with carbon tetrachloride as both reagent and solvent led to very little conversion of 26 into chloride 28.⁴⁹ Appel reported a large solvent effect on the chlorination of alcohols using tertiary phosphines and carbon tetrachloride with the use of dichloromethane and acetonitrile, resulting in significant rate enhancements.⁴⁹ Conducting the chlorination of alcohol 26 using dichloromethane as solvent gave chloride 28 in 78% yield. Conversion of chloride 28 into the biosynthetically plausible diastereomers 2a and 2c required introduction of the (E)-enyne (Scheme 2). Previously the Oxford group have used a Wittig reaction with the ylide derived from (3-trimethylsilyl-2-propynyl)triphenylphosphonium bromide^15a,15b,15d for the stereoselective synthesis of (E)-enynes from aldehydes; however, the diastereocontrol in these reactions was never above 9:1 E/Z. We therefore elected to use the recently developed methodology for (E)-enyne synthesis from alkenes reported by the Seoul group, which gives very high E-selectivity.^15d,16a,50 Cross-metathesis of alkene 28 with crotonaldehyde and Grubbs’ second generation catalyst 29 gave the corresponding α,β-unsaturated aldehyde 30, which was immediately exposed to lithiated trimethylsilyl diazomethane (Colvin–Ohira homologation) to give enyne 31. Removal of the para-methoxy benzyl group⁵¹ from 31 gave 2c, the first of the enyne targets. Mitsunobu inversion⁵² of the secondary alcohol in 2c followed by ester methanolysis gave 2a, the second of the biomimetically plausible diastereomers.

Scheme 2. Synthesis of Diastereomers 2a and 2c.

Reagents and conditions: (a) crotonaldehyde, catalyst 29, CH₂Cl₂, 40 °C, 1 h then Me₂SO, rt, 16 h, 88%; (b) (trimethylsilyl)diazomethane, n-BuLi, THF, add 30, −78 °C to rt, 1 h 70%; (c) BCl₃·SMe₂, CH₂Cl₂, rt, 5 min, 84%; (d) DIAD, PPh₃, THF, 0 °C, then 2c, then 4-nitrobenzoic acid, rt; (e) K₂CO₃, MeOH, rt, 20 min, 25% two steps).

The synthesis of the final two biosynthetically plausible diastereomers of the chloroenyne from L. majuscula (enynes 2b and 2d) began from the known 2,2′-bifuranyl 32, an intermediate in our recent synthesis of elatenyne (Scheme 3).^15d Selective removal of the para-bromobenzyl group in the presence of the more electron-rich para-methoxy benzyl group was achieved using LiDBB⁴⁸ in the presence of a proton donor,⁵³ which gave the requisite alcohol 34 in 66% yield along with 18% of the benzyl ether 33.⁵⁴ Chlorination of 34 as before⁴⁹ provided chloride 35 in 96% yield, which was readily deprotected under Lewis acidic conditions to give alcohol 36.⁵¹ Mitsunobu inversion of 36(52) to give 37, followed by enyne introduction, as before,^15d,50 gave the third biomimetic diastereomer 2b. A further Mitsunobu reaction gave the fourth and final biomimetic diastereomer 2d.⁵⁵

Scheme 3. Synthesis of Diastereomers 2b and 2d.

Reagents and conditions: (a) Li, 4,4′-di-tert-butyl-1,1′-biphenyl, bis(2-methoxyethyl)amine, THF, −78 °C, 18% of 33, 66% of 34; (b) CCl₄, PPh₃, CH₂Cl₂, rt, 3 h, 96%; (c) BCl₃·SMe₂, CH₂Cl₂, rt, 5 min; 94%; (d) DIAD, PPh₃, THF, 0 °C, then 36, then 4-nitrobenzoic acid, rt; (e) K₂CO₃, MeOH, rt, 30 min, 79% (two steps); (f) crotonaldehyde, catalyst 29, CH₂Cl₂, 40 °C, 90 min; (g) (trimethylsilyl)diazomethane, n-BuLi, THF, add 37, −78 to 0 °C; (h) Bu₄NF, THF, 0 °C, 5 min, 39% (three steps); (i) DIAD, PPh₃, THF, 0 °C, then 2b, then 4-nitrobenzoic acid, rt; (j) K₂CO₃, MeOH, rt, 30 min.

Analysis

Having completed the total synthesis of all four of the biosynthetically relevant diastereomers of the chloroenyne from L. majuscula (2a–d), we were delighted to find that the ¹H and ¹³C NMR data for diastereomer 2b were in excellent agreement with that reported for the natural product.¹⁷ Our synthesis of the chloroenyne from L. majuscula2b proceeds in 16 steps (longest linear sequence) from (+)-16. The optical rotation for our synthetic 2b was in good agreement in terms of both sign and magnitude with that recorded for the natural product,¹⁷ demonstrating that the absolute configuration of the chloroenyne from L. majuscula is as represented by 2b. The chloroenyne from L. majuscula2b thus sits on the same proposed biosynthetic pathway as elatenyne,^15d laurendecumenyne B,^15d and laurefurenynes A and B,¹⁶ proceeding from (3E/Z)-laurediols 4b via the bromofucins 8b.

The identification of the full stereostructure of the chloroenyne from L. majuscula as 2b on the basis of DFT methods demonstrates the power and utility of these methods to aid in the structure determination of stereochemically rich organic molecules. The synthesis of the remaining three biosynthetically relevant diastereomers 2a, 2c, and 2d provided us with the opportunity to further test the computational methods. We had acquired ¹H and ¹³C NMR data for the chloroenynes 2a, 2c, and 2d, which allowed us to determine whether it would be possible, computationally and correctly, to identify each of these diastereomers from the computed data of the 32 possible diastereomers of the chloroenyne from L. majuscula. We found the correct stereostructures identified among structures with the smallest rmsd values: the two structures with the lowest rmsd values contain the correct structure in all but one case (¹H of 2d), where it is in the lowest four (Figure 5). ¹H DP4 values were more diagnostic, with the correct structure predicted with 60–98% confidence (compared to 40–55% for ¹³C). The product of the DP4/DP4* values for both nuclei provide an unequivocal and, importantly, correct stereostructure prediction for all four diastereomers studied, including the natural product.

Figure 5.

Comparison of computed ¹³C and ¹H chemical shifts for 32 diastereomers of 2 against experimental spectra for 2a, 2c, and 2d.

Notoryne

Notoryne (Z)-3a is the first halogenated 2,2′-bifuranly natural product isolated from Laurencia spp.⁵⁶ The structure of (Z)-notoryne (Z)-3a was originally assigned by careful chemical degradation and comparison with chemical degradation products from laurefucin and laurencin, whose structures and absolute configurations were securely established through single-crystal X-ray analysis.²¹ As noted above, a biosynthesis of notoryne 3 was first proposed by Suzuki and by Fukuzawa and Murai (Figure 1a).^21,24 Previously, the Oxford group had prepared the 2,2′-bifuranyl 28 (Scheme 1), with the necessary stereochemical arrangement for ready conversion into notoryne (Z)-3a. Additionally, the Seoul group had demonstrated a number of biomimetic syntheses of halogenated natural products from Laurencia spp., including the synthesis of the 2,2′-bifuranyl natural products (Z)- and (E)-elatenyne^15d and laurendecumenyne B.^15d In their synthesis of laurefucin,^50a the Seoul group had prepared the bromooxocene 39, which on treatment with N-phenylselenophthalimide (N-PSP) under aqueous acidic conditions gave rise to the [5.2.1]dioxabicyclic bromide 44 in quantitative yield (Scheme 4); the bromide was readily converted into the natural product laurefucin 45. The formation of the [5.2.1]dioxabicyclic bromide 44 most likely follows the mechanism indicated. Here, seleniranium ion formation occurs from the oxocene 39, giving 40, which undergoes ether formation to yield the selenide 41. Activation of the selenide group in 41 by reaction with further N-PSP gives prelaurefucin surrogate 42. Transannular C–O bond formation then occurs, giving the key oxonium ion 43. Attack at C-10 by water with loss of a proton leads to the laurefucin precursor 44 that was readily transformed into the natural product 45. Opening of the oxonium ion 43 at C-7 by chloride with inversion of configuration would yield the notoryne precursor 46 with the correct absolute configuration for synthesis of the natural product (Z)-3a. Given the previous preparation of the 2,2′-bifuranyl 28 and the oxocene 39, we reasoned that synthesis of the natural product notoryne could be readily achieved by two independent routes (Scheme 5). The Oxford group began their synthesis from the previously prepared chloroalcohol 28, which was readily converted into chloroalcohol 10 through deprotection, Mitsunobu inversion, and saponification. Bromination of alcohol 10 using the Hooz procedure⁵⁷ gave bromide 47. The Seoul team prepared the same bromide beginning with their previously prepared oxocene 39. After extensive experimentation, the Seoul team found that exposure of the oxocene alcohol 39 to phenylselenyl chloride in the presence of activated silica gel followed by treatment of the crude mixture with water in acetonitrile gave the 2,2′-bifuranyl chloride 46 along with alcohol 44.⁵⁸ It is of note that in the absence of silica gel, the [5.2.1]-bicyclic chloride 49 was formed.^50a In both the Oxford and Seoul syntheses, the chlorine-bearing carbon atoms could be identified using ¹³C NMR chlorine-induced isotopic shift.⁵⁹ The Seoul group converted the benzyl-protected alcohol 46 into the corresponding alkene 47 using standard procedures. Comparison of the ¹³C NMR chemical shifts of the 2,2′-bifuranyls 47 synthesized in Oxford and Seoul, with the corresponding chemical shifts for notoryne, indicated that the synthesized material had the same stereostructure as that of the natural product (Scheme 5). Completion of the synthesis of the natural products was accomplished by two independent routes. In Oxford, the terminal alkene in 47 was subject to ozonolysis followed by reductive workup to give the corresponding aldehyde (uncharacterized) that was subject to a Yamamoto–Petersen reaction⁶⁰ to give the (Z)-enyne 48 with high diastereoselectivity. Removal of the terminal silyl group was readily achieved on brief exposure of 48 to fluoride to give notoryne (Z)-3a. In Seoul, the (Z)-enyne was introduced directly from the terminal alkene 47 via a relay cross-metathesis using enyne 50 and catalyst 51,^15d,50b,61 which gave the desired enyne 52 as a 3:1 mixture of Z/E-enynes in 82% combined yield.

Scheme 4. Key Step in the Seoul Synthesis of Laurefucin, along with the Proposed Route to Notoryne.

Scheme 5. Oxford and Seoul Syntheses of Notoryne.

Reagents and conditions: (a) BCl₃·SMe₂, CH₂Cl₂, rt, 5 min, 95%; (b) DIAD, PPh₃, THF, 0 °C, then 4-nitrobenzoic acid, rt, 74%; (c) K₂CO₃, MeOH, rt, 20 min, 91%; (d) CBr₄, PPh₃, toluene, 80 °C, 75 min, 75%; (e) O₃, CH₂Cl₂, −78 °C then PPh₃, −78 °C to rt, 15 h; (f) TMSC≡CCH2TBS, tBuLi, THF, −78 °C, 1 h, then Ti(OiPr)₄, 10 min, then add 47, −78 °C, 30 min, rt, 30 min, 32% (two steps); (g) TBAF, THF, −20 °C, 5 min, quant.; (h) PhSeCl, n-hexane; (i) PhSeCl (3 equiv), activated silica gel, n-hexane, rt, 72 h; (j) CH₃CN/H₂O (9:1), rt, 24 h, 80% of 46, 20% of 44; (k) H₂, Pd(OH)₂/C, EtOH, 1 h, 95%; (l) o-nitrophenylselenocyanide, (Oct)₃P, THF, rt, 10 min, then H₂O₂, 0 °C to rt, 24 h, 85%; (m) 50, catalyst 51, benzene, 70 °C, 1.5 h, then additional 50 and 51, 82% 3:1 Z/E; (n) TBAF, THF, 0 °C, 1 h, 95%; (o) crotonaldehyde, catalyst 29, CH₂Cl₂, 40 °C, 1.5 h then Me₂SO, rt, 12 h; (p) (trimethylsilyl)diazomethane, LDA, THF, −78 to 0 °C, 2 h, 88% (two steps). Note: The difference in the¹³C NMR chemical shifts between the synthetic compounds47prepared by the Oxford and Seoul groups and natural notoryne (Z)-3aare shown adjacent to the relevant carbon atoms in structures47.

Fluoride treatment of 52 gave notoryne (Z)-3a. The Oxford and Seoul ¹H and ¹³C NMR data were in excellent agreement with each other and with the data reported by Suzuki.^21a,62 Additionally, the optical rotations of the synthetic materials confirm that the absolute configuration of the natural product is as represented by (Z)-3a as originally assigned by Suzuki. Additionally, the Seoul team synthesized (E)-notoryne (E)-3a^21b from alkene 47. Cross-metathesis of alkene in 47 using crotonaldehyde and the Grubbs–Hoveyda catalyst 29 gave the corresponding α,β-unsaturated aldehyde as a single E-isomer,^15d,50 which on Colvin–Ohira homologation gave (E)-notoryne (E)-3a in 88% overall yield from alkene 47.^21b

Having synthesized notoryne by two independent routes, we elected to further test the computational methods for prediction/confirmation of structure of these halogenated 2,2′-natural products. As with the previous 2,2′-bifuranyls from Laurencia spp. we have studied, notoryne (Z)-3a contains six stereocenters, resulting in 32 diastereomeric notorynes. We decided to challenge the computational method to see if it could predict the correct structure of notoryne from the pool of 32 diastereomeric notorynes.

Upon computing the Boltzmann-weighted chemical shifts for all 32 diastereomers, we found maximum variance to stereochemical changes occurs for carbon atoms directly attached to halogen atoms and the attached protons (Figure 6). As with earlier studies, the exocyclic positions offer little for predictive power and were excluded from further analysis. The stereostructure for notoryne, (Z)-3a, is clearly favored in the analysis of ¹³C predictions, whereas from ¹H chemical shifts, it ranks in the top two structures. Again, the cumulative ¹H/¹³C DP4 metric gives (Z)-3a as the single most likely stereostructure. The total synthesis and structure confirmation of notoryne (Z)-3a further demonstrates the utility of computational methods to not only predict but also confirm the structures of stereochemically rich, functionalized, and flexible organic molecules and natural products.

Figure 6.

Comparison of computed ¹³C and ¹H chemical shifts for 32 diastereomers against experimental spectra of notoryne. Data for (Z)-3a are shown as blue circles in rmsd and blue area in DP4*.

Conclusions

We have demonstrated that computational methods are able to predict the structure of a highly flexible chloroenyne natural product from L. majuscula containing six stereocenters from the 32 possible diastereomeric structures of the natural product. Moreover, we have synthesized three further “biomimetic” diastereomers of the natural product. Using the NMR data of these diastereomers, we have shown that the same computational methods can identify each diastereomer out of the set of 32 possible diastereomers. Key to these computational methods was to use the computed NMR chemical shift data only for those atoms that are good reporters of stereochemical information across all 32 diastereomers, that is, those atoms that show a large standard deviation in computed NMR chemical shift among the diastereomers. Furthermore, we applied both computational methods and synthesis to confirm the structure of notoryne, a further halogenated 2,2′-bifuranyl natural product isolated from Laurencia spp.

Experimental Section

General Procedures

Proton (¹H), carbon (¹³C), and fluorine (¹⁹F) NMR spectra were recorded on a Bruker AV 500 (500/125 MHz), Bruker AV 400 (400/100 MHz), or Bruker DPX 300 (300/75 MHz) spectrometer. Proton and carbon chemical shifts (δ) are quoted in parts per million and referenced to tetramethylsilane with residual protonated solvent as internal standard. Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double doublet), and so on. Coupling constants (J) are given in hertz and are rounded to the nearest 0.1 Hz. H and H′ refer to diastereotopic protons attached to the same carbon and imply no particular stereochemistry. All assignments are confimed by ¹H–¹H COSY and ¹H–¹³C HSQC experiments. Low-resolution mass spectra were recorded on a Fisons Platform spectrometer (ES). High-resolution mass spectra were recorded by the mass spectrometry staff at the Chemistry Research Laboratory, University of Oxford, using a Bruker Daltronics microTOF spectrometer (ES) or a Micromass GCT (FI). The m/z values are reported in Daltons with their percentage abundances and, where known, the relevant fragment ions in parentheses. High-resolution values are calculated to four decimal places from the molecular formula, with all found values being within a tolerance of 5 ppm. Infrared spectra were recorded on a Bruker Tensor 27 Fourier transform spectrometer, as a thin film on diamond ATR. Absorption maxima (ν_max) are quoted in wavenumbers (cm^–1). Optical rotations were measured using a PerkinElmer 241 polarimeter in a cell of 1 dm path length (l). TLC was performed on Merck DC-Alufolien 60F254 0.2 mm precoated plates and visualized using an acidic vanillin or basic potassium permanganate dip. Retention factors (R_f) are reported with the solvent system used in parentheses. Flash column chromatography was performed on Merck 60 silica (particle size 40–63 μm, pore diameter 60 Å), and the solvent system used is recorded in parentheses.

All nonaqueous reactions were carried out in oven-dried glassware under an inert atmosphere of nitrogen and employing standard techniques for handling air-sensitive materials. Solvents and commercially available reagents were dried and purified before use, as appropriate. In particular, DCM and THF were distilled from CaH₂ and stored over 3 Å molecular sieves. “Petrol” refers to the fraction of light petroleum ether boiling in the range of 40–60 °C unless otherwise stated. All water used experimentally was distilled, and the term “brine” refers to a saturated solution of sodium chloride in water.

(R)-3-(Benzyloxy)-3-((S)-oxiran-2-yl)propan-1-ol (18)

Alkene 17 (3 g, 14.7 mmol) was dissolved in DCM/MeOH (1:1, 200 mL) and the stirred solution cooled to −78 °C. O₂ was sparged through the solution for 5 min followed by O₃/O₂ until a faint blue hue appeared. Then the reaction was sparged with O₂ for 5 min and PPh₃ was added (11.6 g, 44 mmol) and the reaction stirred at −78 °C for 30 min. To the reaction mix was added NaBH₄ (1.6 g, 44 mmol), and the reaction was allowed to warm to rt over 2 h. The reaction was quenched with H₂O (100 mL) and then diluted with DCM (100 mL). The aqueous phase was separated and extracted with DCM (3 × 50 mL). The combined organic phases were dried (MgSO₄), filtered, and concentrated in vacuo. The crude mixture was dry-loaded onto silica and purified by rapid flash column chromatography (2:1→ 1:1 petrol bp 30–40 °C/diethyl ether 1% NEt₃) to give the title compound as a colorless oil (2.81 g, 13.5 mmol, 92%): R_f 0.40 (1:1 petrol/diethyl ether); ν_max/cm^–1 (thin film) 3434s br, 2875m; ¹H NMR (400 MHz C₆D₆) δ 7.06–7.23 (m, 5H, ArH), 4.46 (d, J = 11.6 Hz, 1H, CHH′Ar), 4.23 (d, J = 11.6 Hz, 1H, CHH′Ar), 3.48–3.73 (m, 2H, CH₂OH), 3.24 (dt, J = 6.8, 5.6 Hz, 1H, CHOBn), 2.61 (ddd, J = 5.6, 3.8, 2.8 Hz, 1H, CHOCH₂), 2.35 (dd, J = 5.3, 2.6 Hz, 1H, CHOCHH′), 2.29 (dd, J = 5.4, 3.8 Hz, 1H, CHOCHH′), 1.75–1.60 (m, 3H, COH, CH₂CH₂OH); ¹³C{¹H} NMR (100 MHz, C₆D₆) δ 139.0 (Ar), 128.2 (Ar), 128.0 (Ar), 127.8 (Ar), 76.9 (CHOBn), 72.4 (CH₂Ar), 59.5 (CH₂OH), 53.1 (CHOCH₂) 45.3 (CHOCH₂), 35.6 (CH₂CH₂OH); HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₂H₁₆O₃Na 231.0992; found 231.0992; [α]_D²⁵ +32.0 (c = 1.0 in CHCl₃).

5-(((R)-3-(Benzyloxy)-3-((S)-oxiran-2-yl)propyl)thio)-1-phenyl-1H-tetrazole

PPh₃ (4.23 g, 16.1 mmol) was dissolved in dry THF (50 mL) and cooled to 0 °C, and DIAD (3.2 mL, 16.1 mmol) was added dropwise to the solution and stirred at 0 °C for 15 min. Alcohol 18 (2.8 g, 13.4 mmol) was dissolved in dry THF (25 mL) and added dropwise to the reaction mixture followed by a wash with dry THF (5 mL), and the reaction was stirred at 0 °C for 15 min. 1-Phenyl-1H-tetrazole-5-thiol (3.12 g, 17.5 mmol) was added in one portion, and the reaction mixture was warmed to rt and stirred for 16 h. The reaction mixture was concentrated in vacuo and dry-loaded on silica. Purification by flash column chromatography (5:1 petrol/acetone) yielded the title compound as a colorless oil (4.37 g, 11.8 mmol, 88%): R_f 0.5 (5:1 petrol/acetone); ν_max/cm^–1 (thin film) 2870; ¹H NMR (400 MHz CDCl₃) δ 7.54–7.58 (m, 5H, ArH), 7.27–7.35 (m, 5H, ArH), 4.70 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.50 (d, J = 11.4 Hz, 1H, CHH′Ar), 3.56 (ddd, J = 13.3, 7.9, 5.4 Hz, 1H, CHOBn), 3.43–3.51 (m, 2H, CH₂SAr), 2.98 (ddd, J = 5.2, CH₂CH₂OH4.0, 2.8 Hz, 1H, CHOCH₂), 2.81 (dd, J = 5.0, 4.0 Hz, 1H, CHOCHH′), 2.75 (dd, J = 5.0, 2.8 Hz, 1H, CHOCHH′), 2.25 (dtd, J = 14.4, 7.6, 3.8 Hz, 1H, CHH′CH₂SAr), 2.13 (dddd, J = 14.4, 8.8, 7.6, 3.3 Hz, 1H, CHH′CH₂SAr); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.2 (Ar), 138.0 (Ar) 133.7 (Ar), 130.1 (Ar), 128.5 (Ar), 127.9 (Ar), 127.6 (Ar) 123.8 (Ar), 76.1 (CHOBn), 72.5 (CH₂Ar), 53.0 (CHOCH₂), 45.6 (CHOCH₂), 32.12 (CH₂CH₂SAr), 29.3 (CH₂SAr); MS (ESI-TOF) m/z 391 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₉H₂₀N₄O₂SNa 391.1199; found 391.1201; [α]_D²⁵ +26.0 (c = 1.0 in CHCl₃).

5-(((R)-3-(Benzyloxy)-3-((S)-oxiran-2-yl)propyl)sulfonyl)-1-phenyl-1H-tetrazole (14)

5-(((R)-3-(Benzyloxy)-3-((S)-oxiran-2-yl)propyl)thio)-1-phenyl-1H-tetrazole (4.3 g, 11.8 mmol) was dissolved in DCM (200 mL), and to the stirring solution was added mCPBA (7.2 g, 41.6 mmol), and the mixture was stirred at rt for 3 days. The reaction mixture was quenched with saturated aqueous Na₂S₂O₃ (1 mL) and then with saturated aqueous NaHCO₃ (200 mL). The aqueous layer was separated and extracted with DCM (3 × 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification via flash column chromatography (DCM) gave the title compound as white needles (2.85 g, 7.1 mmol, 60%): R_f 0.52 (5:1 petrol/acetone); mp 90–92 °C; ν_max/cm^–1 (thin film) 2918s, 1342s, 1150s; ¹H NMR (400 MHz CDCl₃) δ 7.56–7.70 (m, 5H, ArH), 7.29–7.38 (m, 5H, ArH), 4.69 (d, J = 11.6 Hz, 1H, CHH′Ar), 4.52 (d, J = 11.6 Hz, 1H, CHH′Ar), 3.93 (ddd, J = 14.9, 10.2, 5.3 Hz, 1H, CHH′SAr), 3.81 (ddd, J = 14.9, 10.3, 5.6 Hz, 1H, CHH′SAr), 3.47 (ddd, J = 8.3, 5.6, 4.3 Hz, 1H, CHOBn), 2.96 (ddd, J = 5.6, 3.8, 2.5 Hz, 1H, CHOCH₂), 2.82 (dd, J = 5.0, 3.8 Hz, 1H, CHOCHH′), 2.72 (dd, J = 5.0, 2.5 Hz, 1H, CHOCHH′), 2.37 (dddd, J = 14.4, 9.9, 5.6, 4.3 Hz, 1H, CHH′CH₂SAr) 2.24 (dddd, J = 14.4, 10.3, 8.3, 5.3 Hz, 1H, CHH′CH₂SAr); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.3 (Ar) 137.5 (Ar), 133.0 (Ar), 131.5 (Ar), 129.7 (Ar), 128.6 (Ar), 128.1 (Ar), 127.9 (Ar), 125.1 (Ar), 75.6 (CH₂Ar), 72.4 (CHOBn), 52.6 (CH₂SAr), 52.3 (CHOCH₂), 45.7(CHOCH₂), 25.5 (CH₂CH₂SAr); MS (ESI-TOF) m/z 423 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₉H₂₀N₄O₄SNa 423.1097; found 423.1089; [α]_D²⁵ +14.5 (c = 1.0 in CHCl₃).

tert-Butyl-(((3R,4S)-4-((4-methoxybenzyl)oxy)hept-6-en-3-yl)oxy)dimethylsilane (20)

The known alcohol (3R,4S)-4-(4-methoxybenzyloxy)hept-6-en-3-ol was readily prepared from the epoxy alcohol (+)-16 via the p-methoxybenzyl ether 19 according to our previously reported route.^15d (3R,4S)-4-(4-Methoxybenzyloxy)hept-6-en-3-ol thus prepared (3.3 g, 13.2 mmol) was dissolved in dry DMF (100 mL), then imidazole (1.97 g, 29.6 mmol) and TBSCl (2.98 g, 19.8 mmol) were added. The reaction mixture was heated to 60 °C for 16 h. The reaction was cooled to rt and then quenched with water (50 mL). The aqueous layer was separated and extracted with diethyl ether (3 × 75 mL). The combined organic layers were washed with water (3 × 50 mL) and brine (50 mL), dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (20:1 petrol bp 30–40 °C/diethyl ether) gave the title compound as a colorless oil (4.81 g, 13.0 mmol, 99%): R_f 0.62 (20:1 petrol/diethyl ether); ν_max/cm^–1 (thin film) 3076m, 2957s, 2931s, 2857s, 1641m; ¹H NMR (400 MHz CDCl₃) δ 7.28 (d, J = 8.6 Hz, 2H, ArH), 6.87 (d, J = 8.6 Hz, 2H, ArH), 5.90 (ddt, J = 17.0, 10.0, 7.0 Hz, 1H, CH=CH₂), 5.10 (dq, J = 17.0, 1.7 Hz, 1H, CH= CHH), 5.05 (ddt, J = 10.0, 2.3, 1.1 Hz, 1H, CH= CHH) 4.59 (d, J = 11.3 Hz, 1H, CHH′Ar), 4.49 (d, J = 11.3 Hz, 1H, CHH′Ar), 3.81 (s, 3H, OMe), 3.69 (dt, J = 6.6, 4.3 Hz, 1H, CHOTBS), 3.41 (td, J = 6.0, 4.3 Hz, 1H, CHOPMB), 2.33 (dd J = 7.0, 6.0 Hz, 2H, CH₂CH = CH₂), 1.43–1.71 (m, 2H, CH₃CH₂), 0.92 (s, 9H, CMe₃), 0.90 (t, J = 7.5 Hz, 3H, CH₃CH₂), 0.07 (s, 3H, SiCH₃), 0.06 (s, 3H, SiCH₃); ¹³C{¹H} NMR (100 MHz CDCl₃) δ 159.0 (Ar), 136.0 (CH=CH₂), 131.1 (Ar), 129.3 (Ar), 116.4 (CH=CH₂), 113.6 (Ar), 81.4 (CHOPMB), 74.9 (CHOTBS), 72.0 (CH₂Ar), 55.3 (OMe), 35.6 (CH₂CH=CH₂), 26.0, (CMe₃), 25.5 (CH₃CH₂), 18.2 (SiC), 9.7 ((CH₃)₃C), −4.3 (SiCH₃), −4.5 (SiCH₃); MS (ESI-TOF) m/z 387 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₁H₃₆O₃SiNa 387.2326; found 387.2326; [α]_D²⁵ −11.9 (c = 1.0 in CHCl₃).

(3S,4R)-4-((tert-Butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)hexanal (15)

Alkene 20 (3.68 g, 10 mmol) was dissolved in DCM (300 mL), cooled to −78 °C, and sparged with O₂ for 2 min. O₃/O₂ was then bubbled through the stirred solution until a faint blue color appeared, and excess ozone was then sparged out with O₂ for 5 min before adding PPh₃ (7.9 g, 30 mmol). The reaction mixture was allowed to warm to rt over 16 h before being concentrated in vacuo and dry-loaded onto silica. Purification via rapid column chromatography (16:1 → 8:1 petrol/diethyl ether) yielded the title compound as a colorless oil (3.60 g, 9.8 mmol, 98%): R_f 0.63 (10:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2931s, 2858s, 1725s; ¹H NMR (400 MHz CDCl₃) δ 9.80 (t, J = 2.0 Hz, 1H, CHO), 7.24–7.30 (m, 2H,ArH), 6.86–6.92 (m, 2H, ArH), 4.57 (d, J = 11.2 Hz, 1H, CHH′Ar), 4.45 (d, J = 11.2 Hz, 1H, CHH′Ar), 3.87 (dt, J = 7.4, 3.6 Hz, 1H, CHOPMB), 3.80 (s, 3H, OMe), 3.78 (dt, J = 7.0, 3.6 Hz, 1H, CHOTBS), 2.69 (ddd, J = 16.7, 7.0, 2.0 Hz, 1H, CHH′CHO), 2.56 (ddd, J = 16.7, 7.0, 2.0 Hz, 1H, CHH′CHO), 1.37–1.62 (m, 2H, CH₃CH₂), 0.91 (t, J = 7.3 Hz, 3H, CH₃CH₂), 0.90 (s, 9H, CMe₃), 0.08 (s, 3H, SiCH₃), 0.07 (s, 3H, SiCH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 202.0 (C=O), 159.2 (Ar), 130.2 (Ar), 129.4 (Ar), 113.8 (Ar), 76.8 (CHOPMB), 74.5 (CHOTBS), 71.6 (CH₂Ar) 55.3 (OMe), 44.4 (CH₂CO), 26.6 (CH₃CH₂), 25.9 (C(CH₃)₃), 18.2 (CH₃CH₂), 9.8 (C(CH₃)₃), −4.2 (SiCH₃), −4.6 (SiCH₃); MS (ESI-TOF) m/z 389 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + N]⁺ calcd for C₂₀H₃₄O₄SiNa 389.2119; found 389.2117; [α]_D²⁵ −15.6 (c = 1.0 in CHCl₃).

(((3R,4S,9R,E)-9-(Benzyloxy)-4-((4-methoxybenzyl)oxy)-9-((S)-oxiran-2-yl)non-6-en-3-yl)oxy)(tert-butyl)dimethylsilane (13)

To a stirred solution of sulfone 14 (1.95 g, 4.88 mmol), in dry DME (60 mL) cooled to −78 °C, was added NaHDMS (3.42 mL, 2 M in THF, 6.83 mmol) dropwise. The reaction was stirred for 15 min, and a solution of aldehyde 15 (3.57g, 9.75 mmol) in DME (20 mL) was added dropwise over 15 min followed by a wash of DME (10 mL). The reaction mixture was stirred at −78 °C for 1 h. The reaction was then warmed to rt and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (30 mL) and then diluted with H₂O (20 mL) and EtOAc (50 mL). The aqueous layer was separated and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (20:1 → 15:1 → 10:1 petrol/ethyl acetate) gave the title compound as a colorless oil (2.1 g, 3.9 mmol, 80%) and recovered aldehyde (1.2 g, 3.2 mmol): R_f 0.49 (10:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2930s, 2856 m, 1613w; ¹H NMR (400 MHz CDCl₃) δ 7.24–7.36 (m, 7H, ArH), 6.84–6.88 (m, 2H, ArH), 5.54–5.67 (m, 2H, CH=CH), 4.63 (d, J = 11.8 Hz, 1H, CHH′Ar), 4.58, (d, J = 11.2 Hz, 1H, CHH′Ar), 4.53 (d, J = 11.8 Hz, 1H, CHH′Ar), 4.46 (d, J = 11.2 Hz, 1H, CHH′Ar), 3.80 (s, 3H, OMe), 3.68 (dt, J = 6.5, 4.3 Hz, 1H, CHOTBS), 3.37 (td, J = 5.9, 4.3 Hz, 1H, CHOPMB), 3.31 (dt, J = 6.7, 5.2 Hz, 1H, CHOBn), 2.97 (ddd, J = 5.2, 4.0, 2.8 Hz, 1H, CHOCH₂), 2.77 (dd, J = 5.3, 4.0 Hz, 1H, CHOCHH′), 2.73 (dd, J = 5.3, 2.8 Hz, 1H, CHOCHH′), 2.33–2.47 (m, 2H, CHOBnCH₂), 2.29 (m, 2H, CHOPMBCH₂), 1.58–1.69 (m, 1H, CH₃CHH), 1.45–1.55 (m, 1H, CH₃CHH), 0.92 (s, 9H, CMe₃) 0.91 (t, J = 8.4 Hz, 3H, CH₃CH₂), 0.06 (s, 3H, SiCH₃), 0.06 (s, 3H, SiCH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.0 (Ar), 138.5 (Ar), 131.1 (Ar), 130.4 (CH=CH), 129.3 (Ar), 128.3 (Ar), 127.6 (Ar) 127.2 (Ar) 127.2 (CH=CH) 113.6 (Ar), 81.7 (CHOPMB) 78.0 (CHOBn), 75.0 (CHOTBS), 72.2 (CH₂Ar), 72.0 (CH₂Ar), 55.3 (OMe), 53.2 (CHOCH₂), 45.6 (CHOCH₂), 36.1 (CHOBnCH₂), 34.1 (CHOPMBCH₂), 26.0 (CMe₃) 25.5 (CH₃CH₂), 18.2 (CMe₃), 9.8 (CH₃CH₂), −4.2 (SiCH₃), −4.5 (SiCH₃); MS (ESI-TOF) m/z 563 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₃₂H₄₈O₅SiNa 563.3163; found 563.3174; [α]_D²⁰ −17.2 (c = 1.0 in CHCl₃).

(1R,3R,4R,6S,7R)-1-(Benzyloxy)-7-((tert-butyldimethylsilyl)oxy)-6-((4-methoxybenzyl)oxy)-1-((S)-oxiran-2-yl)nonane-3,4-diol (12)

Alkene 13 (400 mg, 0.74 mmol), methanesulfonamide (211 mg, 2.22 mmol), (DHQD₂)PHAL (55.6 mg, 0.074 mmol), K₃Fe(CN)₆ (730 mg, 0.28 mmol), and K₂CO₃ (307 mg, 2.22 mmol) were dissolved in ^tBuOH/H₂O (8 mL:8 mL). K₂OsO₄(OH)₂ (2.73 mg, 7.4 μmol) was added and the reaction stirred for 24 h. Sodium sulfite (279 mg, 2.22 mmol) was added, and the reaction was stirred at rt for 30 min. H₂O (10 mL) was added, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic phases were then washed with aqueous NaOH (10 mL, 0.1 M), and the aqueous layer was back extracted with EtOAc (15 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (3:1 petrol/ethyl acetate) gave the title compound as a partially separable mixture of colorless oils (377 mg total, 0.66 mmol 91% 6:1 3R,4R:3S,4S diastereomers from ¹H NMR analysis of the crude, from which 268 mg, 0.47 mmol, 64% could be obtained in pure form): R_f 0.38 (3:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3471m, 2930s, 2859s; ¹H NMR (400 MHz C₆D₆) δ 7.15–7.47 (m, 7H, ArH), 6.85–6.91 (m, 2H, ArH), 4.72 (d, J = 11.5 Hz, 1H, CHH′Ar), 4.67 (d, J = 10.9 Hz, 1H, CHH′Ar), 4.54 (d, J = 11.5 Hz, 1H, CHH′Ar), 4.39 (d, J = 10.9 Hz, 1H, CHH′Ar), 4.26 (1H, br, OH), 4.06 (1H, br, CHOH), 3.82–3.87 (m, 2H, CHOH, CHOBn), 3.76 (ddd, J = 1.9, 4.9, 7.7 Hz, 1H, CHOTBS), 3.62 (ddd, J = 1.9, 3.0, 8.5 Hz, 1H, CHOPMB), 3.38 (s, 3H, OMe), 2.86 (ddd, J = 2.7, 3.8, 6.3 Hz, 1H, CHOCH₂), 2.81 (br s, 1H, OH), 2.56 (dd, J = 2.7, 5.5 Hz, 1H, CHOCHH′), 2.45, (dd, J = 3.8, 5.5 Hz, 1H, CHOCHH′), 2.02–2.16 (m, 2H, 2 × CHH′CHOH), 1.91 (ddd, J = 14.2, 9.5, 3.0 Hz, 1H, CHOPMBCHH′), 1.78 (ddd, J = 15.8, 3.5, 2.5 Hz, 1H, CHOBnCHH′), 1.64 (dq, J = 14.0, 7.6 Hz, 1H, CH₃CHH′), 1.42 (dqd, J = 14.0, 7.5, 4.9 Hz, 1H, CH₃CHH′), 1.11 (s, 9H, CMe₃), 0.97 (t, J = 7.5 Hz, 3H, CH₃CH₂), 0.25 (s, 3H, SiCH₃), 0.19 (s, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, C₆D₆) δ 159.9 (Ar), 139.4 (Ar), 130.4 (Ar), 130.0 (Ar), 128.5 (Ar), 127.6 (Ar), 128.5 (Ar), 114.2 (Ar), 82.3 (CHOBn), 76.0 (CHOPMB), 75.9 (CHOTBS), 73.2 (CHOH), 73.0 (CH₂Ar), 72.0 (CHOH), 71.0 (CH₂Ar), 54.7 (OMe), 53.6 (CHOCH₂), 45.2 (CHOCH₂), 37.3 (CHOPMBCH₂), 33.1 (CHOBnCH₂), 26.5 (CH₃CH₂), 26.2 (CMe₃), 18.5 (CMe₃), 10.9 (CH₃CH₂), −3.9 (SiMe), −4.6 (SiMe); HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₃₂H₅₀O₇SiNa 597.3218; found 597.3221; [α]_D²⁰ −4.0 (c = 1.0 in CHCl₃).

(1R,3S,4R)-1-((2R,4R,5R)-4-(Benzyloxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)hexan-1-ol (21)

To a solution of diol 12 (1.3 g, 2.3 mmol) in DCM (18 mL) at 0 °C was added a solution of camphorsulfonic acid (10.6 mg, 0.05 mmol) in DCM (1.1 mL). The reaction was stirred for 2 h at 0 °C, and the cold reaction mixture was immediately purified by flash column chromatography (1:1 petrol/ethyl acetate) to give the title compound as a colorless oil (1.12 g, 2.0 mmol, 86%): R_f (5:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3419br, 2930s, 2858s; ¹H NMR (400 MHz CDCl₃) δ 7.24–7.39 (m, 7H, ArH), 6.85–6.89 (m, 2H, ArH), 4.70 (d, J = 11.0 Hz, 1H, CHH′Ar), 4.62 (d, J = 11.9 Hz, 1H, CHH′Ar), 4.42 (d, J = 11.9 Hz, 1H, CHH′Ar), 4.41 (d, J = 11.0 Hz, CHH′Ar), 4.25 (q, J = 6.2 Hz, 1H, CHOBn), 3.95 (dt, J = 6.1, 4.5 Hz, 1H, CHORCHOH), 3.81–3.88 (m, 4H, CHOH, CHORCH₂OH), 3.80 (s, 3H, OMe), 3.75 (ddd, J = 7.1, 5.0, 2.0 Hz, 1H, CHOTBS), 3.64 (ddd, J = 8.1, 3.8, 2.0 Hz, 1H, CHOPMB), 2.80 (br, 1H, OH), 2.14 (ddd, J = 13.4, 7.0, 6.2 Hz, 1H, CHH′CHOBn), 2.00 (ddd, J = 13.4, 8.0, 6.2 Hz, 1H, CHH′CHOBn), 1.80 (dt, J= 14.8, 8.1 Hz, 1H, CHH′CHOPMB), 1.70 (dt, J = 14.8, 3.8 Hz, 1H, CHH′OPMB), 1.51–1.63 (m, 1H, CH₃CHH′), 1.40–1.50 (m, CH₃CHH′), 0.92 (t, J = 7.5 Hz, 3H, CH₃CH₂), 0.91 (s, 9H, CMe₃), 0.09 (s, 3H, SiCH₃), 0.08 (s, 3H, SiCH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.2 (Ar), 137.6 (Ar), 130.4 (Ar), 129.6 (Ar), 128.5 (Ar), 127.9 (Ar), 127.6 (Ar), 113.8 (Ar), 81.1(CHOPMB), 80.3 (CHORCHOH), 80.2 (CHORCH₂OH), 79.6 (CHOBn), 75.6 (CHOTBS), 71.6 (CHOH), 71.6 (CH₂Ar), 71.4 (CH₂Ar), 62.3 (CH₂OH), 55.3 (OMe), 33.4 (CH₂CHOBn), 33.0 (CH₂CHOPMB), 26.0 (CMe₃, CH₃CH₂), 18.2 (CMe₃), 10.6 (CH₃CH₂), −4.1 (SiCH₃), −4.7 (SiCH₃); HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₃₂H₅₀O₇SiNa 597.3218; found 597.3240; [α]_D²⁰ −13.0 (c = 1 in CHCl₃).

((2R,2′S,4R,4′S,5R,5′R)-4-(Benzyloxy)-5′-ethyl-4′-((4-methoxybenzyl)oxy)octahydro-[2,2′-bifuran]-5-yl)methylmethanesulfonate (24)

To a stirred solution of diol 21 (900 mg, 1.57 mmol) in DCM (30 mL) at 0 °C were added ethyldiisopropylamine (2.72 mL, 15.6 mmol) and MsCl (1 mL, 12.5 mmol) and stirred for 1 h before being quenched with saturated aqueous NH₄Cl (30 mL) and diluted with H₂O (30 mL) and DCM (30 mL). The aqueous layer was separated and extracted with DCM (3 × 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo to give a crude oil (23). The crude oil was dissolved in DCM/MeOH (1:1, 30 mL); then CSA (363 mg, 1.57 mmol) was added, and the reaction was stirred for 24 h before being quenched by the addition of saturated aqueous NaHCO₃ (40 mL). The aqueous layer was separated and extracted with DCM (3 × 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo to give a crude oil. The crude oil was then dissolved in ^tBuOH (20 mL) and warmed to 35 °C; ^tBuOK (527 mg, 4.71 mmol) was added and the reaction stirred for 1 h. The reaction was quenched with saturated aqueous NH₄Cl (30 mL). The aqueous layer was separated and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. Purification via flash column chromatography (2:1 petrol/ethyl acetate) gave the title compound as a colorless oil (427 mg, 0.82 mmol, 52%): R_f 0.56 (2:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2935m, 1356s, 1175s; ¹H NMR (400 MHz CDCl₃) δ 7.22–7.38 (m, 7H, ArH), 6.88 (d, J = 8.6 Hz, 2H, ArH), 4.61 (d, J = 11.8 Hz, 1H, CHH′Ar), 4.36 (d, J = 11.9 Hz, 1H, CHH′Ar), 4.32–4.52 (m, 5H, 2 × CHH′Ar, CHORCH₂OMs), 4.12–422 (m, 2H, CHOBn, CHOPMB), 4.00–4.09 (m, 2H, CHORCHOR), 3.85–3.92 (m, 1H, EtCHOR), 3.81 (s, 3H, OMe), 3.00 (s, 3H, SMe), 2.21–2.30 (m, 2H, 2 × CHH′CHOR), 2.16 (dt, J = 13.1, 4.4 Hz, 1H, CHH′CHOBn), 2.00 (dt, J = 12.6, 4.4 Hz, 1H, CHOPMBCHH′), 1.48 (qn, J = 7.6 Hz, 2H, CH₃CH₂), 0.93 (t, J = 7.6 Hz, 3H, CH₃CH₂); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.2 (Ar), 137.5 (Ar), 130.2 (Ar), 129.3 (Ar), 128.5 (Ar), 127.9 (Ar), 127.8 (Ar), 113.8 (Ar), 84.9 (EtCHOR), 82.4 (CHOPMB), 80.9 (CHOBn), 79.8 (CHORCHOR), 79.3 (CHORCHOR), 78.7 (CH₂OMs), 77.3 (CHORCH₂OMs), 71.1 (CH₂Ar), 69.8 (CH₂Ar), 55.3 (OMe), 37.8 (SCH₃), 34.6 (CH₂), 34.1 (CH₂), 26.7 (CH₃CH₂), 10.1 (CH₃); MS (ESI-TOF) m/z 543 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₇H₃₆O₈SNa 543.2023; found 543.2022; [α]_D²⁰ +4.0 (c = 1.0 in CHCl₃).

((2R,3R,5R)-3-(Benzyloxy)-5-((1R,3S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-hydroxy-3-((4-methoxybenzyl)oxy)hexyl)tetrahydrofuran-2-yl)methylmethanesulfonate (22)

The title compound was isolated as a side product in the synthesis of 24: R_f 0.63 (2:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3540br, 2931m, 1356s, 1174s; ¹H NMR (400 MHz CDCl₃) δ 7.25–7.37 (m, 7H, ArH), 6.88 (d, J = 8.1 Hz, 2H, ArH), 4.69 (d, J = 11.0 Hz, 1H, CHH′Ar), 4.57 (d, J = 11.7 Hz, 1H, CHH′Ar), 4.43–4.46 (m, 2H, CH₂OMs), 4.41 (d, J = 11.1 Hz, 1H, CHH′Ar), 4.36 (d, J = 11.7 Hz, 1H, CHH′Ar), 4.19 (q, J = 5.3 Hz, 1H, CHORCH₂OMs), 4.12 (q, J = 5.3 Hz, 1H, CHOBn), 3.91 (q, J = 5.0 Hz, 1H, CHOHCHOR), 3.80 (s, 4H, OMe, OH), 3.75 (ddd, J = 7.3, 4.9, 2.0 Hz, 1H, CHOTBS), 3.62 (td, J = 6.0, 2.0 Hz, 1H, CHOPMB), 2.99 (s, 3H, SMe), 2.07–2.18 (m, 1H, CHHCHOBn), 1.98 (ddd, J = 13.1, 7.6, 4.4 Hz, 1H, CHHCHOBn), 1.71–1.75 (m, 2H, CH₂CHOPMB), 1.50–1.61 (m, 1H, CH₃CHH), 1.49–1.39 (m, 1H, CH₃CHH), 0.92 (t, J = 7.6 Hz, 3H, CH₃CH₂), 0.91 (s, 9H, CMe₃), 0.09 (s, 3H, SiCH₃), 0.08 (s, 3H, SiCH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.2 (Ar), 137.4 (Ar), 130.4 (Ar), 129.6 (Ar) 128.5 (Ar), 128.0 (Ar), 127.7 (Ar), 113.8 (Ar), 80.9 (CHORCHOH), 80.8 (CHOPMB), 80.6 (CHOBn), 78.7 (CHORCH₂OMs), 78.4 (CH₂OMs), 75.5 (CHOTBS), 71.4 (CH₂Ar), 71.0 (CHOH), 69.4 (CH₂Ar), 55.3 (OMe), 37.5 (CH₂CHOBn), 32.6 (CH₂CHOPMB), 26.1 (CH₃CH₂), 26.0 (CMe₃), 18.2 (CMe₃), 10.9 (CH₃CH₂), −4.1 (SiMe), −4.7 (SiMe); MS (ESI-TOF)m/z 675 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₃₃H₅₂O₉SiSNa 675.2994; found 675.2990; [α]_D²⁰ −55.6 (c = 1.0 in CHCl₃).

(2R,2′S,4R,4′S,5S,5′R)-4-(Benzyloxy)-5′-ethyl-5-(iodomethyl)-4′-((4-methoxybenzyl)oxy)octahydro-2,2′-bifuran (25)

TBAI (3 g, 8.2 mmol) and mesylate 24 (420 mg, 0.82 mmol) were dissolved in dry toluene (6 mL) and heated to 110 °C for 16 h with vigorous stirring. The reaction mixture was cooled to rt, and then filtered through a sinter washing with diethyl ether (100 mL). The filtrate was concentrated in vacuo and purified by flash column chromatography (8:1 petrol/ethyl acetate) to give the title compound as a colorless oil (360 mg, 0.65 mmol, 80%) and recovered SM (40 mg, 0.08 mmol, 9%): R_f 0.47 (10:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2961m; ¹H NMR (400 MHz CDCl₃) δ 7.23–7.39 (m, 7H, ArH), 6.86–6.90 (m, 2H, ArH), 4.63 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.49 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.43 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.38 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.17 (td, J = 4.6, 2.8 Hz, 2H, CHORCHOR), 4.08–4.15 (m, 2H, CHOBnCHOR), 3.99 (td, J = 7.3, 5.0 Hz, 1H, CHORCHOR), 3.88 (td, J = 6.6, 3.7 Hz, 1H, CHOPMB), 3.81 (s, 3H, OMe), 3.79 (dt, J = 6.4, 3.5 Hz, 1H), 3.41 (dd, J = 9.4, 8.3 Hz, 1H, CHH′I), 3.28 (dt, J = 9.3, 5.8 Hz, 1H, CHH′I), 2.18–2.33 (m, 3H, CH₂CHOBn, CHH′CHOPMB), 2.03 (ddd, J = 13.2, 7.3, 3.0 Hz, 1H, CHH′CHOPMB), 1.52–1.42 (m, 2H, CH₃CH₂), 0.93 (t, J = 7.0 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.2 (Ar), 138.0 (Ar), 130.2 (Ar), 129.3 (Ar), 128.3 (Ar), 127.9 (Ar), 127.7 (Ar), 113.8 (Ar), 84.8 (EtCHOR), 83.0 (CHOBn), 82.5 (CHOPMB), 81.3 (CHORCH₂I), 80.1 (CHORCHOR), 78.6 (CHORCHOR), 71.3 (CH₂Ar), 70.8 (CH₂Ar), 55.3 (OMe), 34.6 (CH₂CHOBn), 34.1 (CH₂CHOPMB), 26.7 (CH₃CH₂), 10.1 (CH₃), 2.2 (CH₂I); MS (ESI-TOF) m/z 575 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₆H₃₃O₅INa 575.1265; found 575.1283; [α]_D²⁰ −16.5 (c = 1.0 in CHCl₃).

(2R,2′S,4R,4′S,5R,5′R)-5-Allyl-4-(benzyloxy)-5′-ethyl-4′-((4-methoxybenzyl)oxy)octahydro-2,2′-bifuran (11)

Iodide 25 (360 mg, 0.65 mmol) was dried by being azeotroped with dry benzene three times and then dissolved in dry benzene (13 mL) and warmed to 40 °C. Vinylmagnesium bromide (13 mL, 1 M in THF, 13 mmol) was added and the reaction stirred for 3 h. The reaction mixture was cooled to 0 °C and then quenched with dropwise addition of saturated aqueous NH₄Cl (20 mL) and diluted with H₂O (10 mL) and EtOAc (10 mL). The aqueous layer was separated and extracted (3 × 30 mL EtOAc). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (50:1 → 25:1 DCM/ethyl acetate) gave the title compound as a colorless oil (166 mg, 0.37 mmol, 57%): R_f 0.45 (10:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2933m; ¹H NMR (400 MHz CDCl₃) δ 7.23–7.39 (m, 7H, ArH), 6.86–6.90 (m, 2H, ArH), 5.86 (ddt, J = 17.0, 10.2, 7.7 Hz, 1H, CH=CH₂), 5.12 (dq, J = 17.0, 2.0 Hz, 1H, CH=CHH′), 5.04 (ddt, J = 10.2, 2.0, 1.2 Hz, 1H, CH=CHH′), 4.62 (d, J = 11.9 Hz, 1H, CHH′Ar), 4.49 (d, J = 11.9 Hz, 1H, CHH′Ar), 4.38 (d, J = 11.9 Hz, 2H, CHH′Ar), 3.93–4.03 (m, 2H, CHOBn, CHORCHOR), 3.88 (td, J = 6.5, 3.9 Hz, 1H, EtCHOR), 3.81 (s, 3H, OMe), 3.76–3.80 (m, 3H, CHOPMB, CHORCHOR, CHOBnCHOR), 2.42–2.57 (m, 2H, CH₂CH=CH₂), 2.18–2.34 (m, 2H, 2 × CHH′CHOR), 2.11 (ddd, J = 13.7, 4.9, 2.3 Hz, 1H, CHH′CHOPMB), 2.06 (dt, J = 13.4, 5.2 Hz, 1H, CHH′CHOBn), 1.45–1/52(m, 2H, CH₃CH₂), 0.93 (t, J = 7.5 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.2 (Ar) 138.4 (Ar), 135.4 (CH=CH₂), 130.3 (Ar), 129.3 (Ar), 128.3 (Ar), 127.6 (Ar), 127.5 (Ar), 116.6 (CH=CH₂), 113.8 (Ar), 84.6 (EtCHOR), 82.5, 82.3, 80.4 (CHOPMB, CHORCHOR, CHORCHOPMB), 80.0, 78.8 (CHORCHOR, CHOBn), 70.8 (CH₂Ar), 70.7 (CH₂Ar), 55.3 (OMe), 34.8 (CH₂CHOPMB), 34.6 (CH₂COBn), 33.9 (CH₂CH=CH₂), 26.7 (CH₃CH₂), 10.1 (CH₃); MS (ESI-TOF) m/z 475 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₈H₃₆O₅Na 475.2455; found 475.2440; [α]_D²⁰ −6.4 (c = 1.0 in CHCl₃).

(2R,2′S,4R,4′S,5R,5′R)-5-Allyl-5′-ethyl-4′-((4-methoxybenzyl)oxy)octahydro-[2,2′-bifuran]-4-ol (26)

To a stirring solution of ether 11 (150 mg, 0.33 mmol) in THF (12 mL) at −78 °C was added dropwise LiDBB (2 mL of a solution of LIDBB prepared by sonicating DBB (1.0 g, 3.7 mmol) and lithium (26 mg, 3.7 mmol) in THF (4 mL) for 2 h). Reaction progress was monitored by TLC every 0.4 mL of LiDBB solution. When no starting material was detected, the reaction was quenched with saturated aqueous NH₄Cl (10 mL), diluted with EtOAc (10 mL), and warmed to rt. The aqueous layer was separated and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (5:1 petrol/ethyl acetate) gave the title compound as a colorless oil (92 mg, 2.5 mmol, 77%): R_f 0.34 (5:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3413br, 2934; ¹H NMR (400 MHz CDCl₃) δ 7.23–7.28 (m, 2H, ArH), 6.87–6.91 (m, 2H, ArH), 5.88 (ddt, J = 17.4, 10.2, 7.0 Hz, 1H, CH=CH₂), 5.16 (dq, J = 17.4, 1.5 Hz, 1H, CH=CHH′), 5.07 (ddt, J = 10.2, 2.1, 1.5 Hz, 1H, CH=CHH′), 4.46 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.43 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.23 (ddd, J = 9.4, 7.1, 1.8 Hz, 1H, CHORCHOR), 4.16–4.08 (m, 2H, CHORCHOR, OH), 4.00 (br s, 1H, CHOH), 3.91 (dt, J = 7.7, 5.2 Hz, 1H, EtCHOR), 3.79–3.83 (m, 4H, OMe, CHOPMB), 3.66 (td, J = 7.0, 2.4 Hz, 1H, CHORCHOH), 2.54–2.37 (m, 2H, CH₂CH=CH₂), 2.30 (dt, J = 12.7, 6.9 Hz, 1H, CHH′CHOPMB) 2.21 (ddd, 1H, J = 14.0, 10.0, 5.2 Hz, CHH′CHOH), 2.14 (td, J = 14.0, 3.9 Hz, CHH′CHOH), 1.59–1.51 (3H, m, CHH′CHOPMB, CH₃CH₂), 0.96 (t, J = 7.5 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.3 (Ar), 135.2 (CH=CH₂), 129.9 (Ar), 129.2 (Ar), 116.7 (CH=CH₂), 133.9 (Ar), 85.0 (EtCHOR), 83.8 (CHORCHOH), 81.8 (CHOPMB), 79.7 (CHORCHOR), 78.5 (CHORCHOR), 71.5 (CH₂Ar), 70.9 (CHOH), 55.3 (OMe), 34.9 (CH₂CHOPMB), 34.2 (CH₂CHOH), 33.6 (CH₂CH=CH₂), 26.4 (CH₃CH₂), 10.3 (CH₃); MS (ESI-TOF) m/z 385 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₁H₃₀O₅Na 385.1985; found 385.1987; [α]_D²⁰ +18.9 (c = 1.0 in CHCl₃).

(2R,2′S,4R,4′S,5R,5′R)-5-Allyl-5′-ethyloctahydro-[2,2′-bifuran]-4,4′-diol (27)

Isolated as a side product during the synthesis of 26: R_f 0.40 (ethyl acetate); ν_max/cm^–1 (thin film) 3394br, 2935m; ¹H NMR (500 MHz CDCl₃) δ 5.87 (ddt, J = 17.0, 10.0, 7.0 Hz, 1H, CH=CH₂), 5.18 (dq, J = 17.0, 1.6 Hz, 1H, CH=CHH′), 5.09 (ddt, J = 10.0, 2.1 1.6 Hz, 1H, CH=CHH′), 4.26 (ddd, J = 8.6, 7.3, 1.8 Hz, 1H, CHORCHOR), 4.12–4.17 (m, 2H, CHORCHOR, CH₂CHOH), 4.07 (dt, J = 6.3, 4.3 Hz, 1H, CHOHCH₂), 3.82 (ddd, J = 9.2, 6.3, 4.3 Hz, 1H, EtCHOR), 3.73 (td, J = 6.9, 2.7 Hz, 1H, CHOHCHOR), 2.49 (tq, J = 6.9, 1.6 Hz, 2H, CH₂CH=CH₂), 2.25–2.33 (m, 2H, 2 × CHOHCHH′), 1.88 (dd, J = 14.0, 4.5 Hz, 1H, CHOHCHH′), 1.80 (ddd, J = 13.3, 7.3, 4.5 Hz, 1H, CHH′CHOH), 1.42–1.55 (m, 2H, CH₃CH₂), 0.98 (t, J = 7.4 Hz, 3H, CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 134.6 (CH=CH₂), 117.1 (CH=CH₂), 88.3 (EtCHOR), 83.4 (CHORCH₂CH=CH₂), 79.4 (CHORCHOR), 78.6 (CHORCHOR), 75.0 (CHOHCH₂), 71.3 (CH₂CHOH) 35.6 (CH₂), 35.4 (CH₂), 33.3 (CH₂CH=CH₂), 26.1 (CH₃CH₂), 10.2 (CH₃); MS (ESI-TOF) m/z 265 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₂₂O₄Na 265.1410; found 265.1413; [α]_D²⁰ +5.9 (c = 0.2 in CHCl₃).

(2R,2′S,4S,4′S,5R,5′R)-5-Allyl-4-chloro-5′-ethyl-4′-((4-methoxybenzyl)oxy)octahydro-2,2′-bifuran (28)

To a stirred solution of alcohol 26 (86 mg, 0.24 mmol) and PPh₃ (186 mg, 0.70 mmol) in DCM (6 mL) was added CCl₄ (1.5 mL). The reaction mixture was stirred for 3 h, and the yellow reaction mixture was loaded straight onto the column. Purification by flash column chromatography (DCM → 5:1 petrol/ethyl acetate) gave the title compound as a colorless oil (70 mg, 0.18 mmol, 78%); R_f 0.89 (5:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2933m; ¹H NMR (400 MHz CDCl₃) δ 7.26 (d, J = 8.3 Hz, 2H, ArH), 6.89 (d, J = 8.3 Hz, 2H, ArH), 5.85 (ddt, J = 17.2, 10.1, 6.8 Hz, 1H, CH=CH₂), 5.25–4.77 (m, 2H, CH=CH₂), 4.49 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.40 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.22 (q, J = 6.6 Hz, 1H, CHORCHOR), 4.00–4.06 (m, 2H, CHORCHCl), 3.94 (q, J = 6.6 Hz, 1H, CHORCHOR), 3.85–3.90(m, 1H, EtCHOR), 3.81 (OMe), 3.78–3.82 (m, 1H, CHOPMB), 2.19–2.43 (m, 5H, CH₂CHOBn, CHH′CHOPMB, CH₂CH=CH₂), 1.93 (dt, J = 12.3, 6.6 Hz, 1H, CHH′CHOPMB), 1.49 (qn, J = 7.6 Hz, 2H, CH₃CH₂), 0.93 (t, J = 7.6 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.2 (Ar), 133.6 (CH=CH₂), 130.2 (Ar), 129.2 (Ar), 117.8 (Ar), 113.8 (CH=CH₂), 113.7 (Ar), 86.2 (CHORCHCl), 84.8 (EtCHOR), 82.2 (CHOPMB), 80.1 (CHORCHOR), 79.3 (CHORCHOR), 71.0 (CH₂Ar), 59.2 (CHCl), 55.3 (OMe), 38.1 (CH₂CH=CH₂), 37.9 (CH₂CHCl), 34.6 (CH₂CHOPMB), 26.6 (CH₃CH₂), 10.1 (CH₃); MS (ESI-TOF) m/z 403 [³⁵M + Na]⁺, 405 [³⁷M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₁H₂₉O₄³⁵ClNa 403.1647; found 403.1635; [α]_D²⁰ +55.9 (c = 1.0 in CHCl₃).

(E)-4-((2R,2′S,4S,4′S,5R,5′R)-4-Chloro-5′-ethyl-4′-((4-methoxybenzyl)oxy)octahydro-[2,2′-bifuran]-5-yl)but-2-enal (30)

To a stirred solution of alkene 28 (62 mg, 0.16 mmol) in dry degassed DCM (4.5 mL) were added crotonaldehyde (134 μL, 114 mg, 1.6 mmol) and Grubbs’ second generation catalyst (14 mg, 16 μmol). The reaction mixture was stirred for 1.5 h at 40 °C and then cooled to rt and quenched with the addition of DMSO (0.1 mL) and stirred for 16 h. The mixture was concentrated in vacuo and purification by flash column chromatography (5:1 petrol ethyl acetate) gave the title compound as a colorless oil (58 mg, 14 mmol, 88%): R_f 0.25 (5:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2934m, 1691s; ¹H NMR (400 MHz CDCl₃) δ 9.52 (d, J = 7.8 Hz, 1H, CHO), 7.25 (d, J = 12.4 Hz, 2H, ArH), 6.86–6.93 (m, 3H, ArH, CH₂CH=CH), 6.21 (ddt, J = 15.7, 7.8, 1.3 Hz, 1H, CHCHO), 4.47 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.41 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.24 (td, J = 6.9, 5.4 Hz, 1H, CHORCHOR), 4.05 (ddd, J = 7.2, 5.8, 4.5 Hz, 1H, CHORCHCl), 4.01–3.96 (m, 2H, CHCl, CHORCHOR), 3.88 (td, J = 6.7, 4.0 Hz, 1H, EtCHOR), 3.79–3.83 (m, 1H, CHOPMB), 3.81 (s, 3H, OMe), 2.72 (dddd, J = 14.3, 8.1, 5.8, 1.3 Hz, 1H, CHH′CH=CH), 2.58 (dt, J = 14.3, 5.8 Hz, 1H, CHH′CH=CH), 2.46 (dt, J = 13.9, 6.0 Hz, 1H, CHH′CHCl), 2.30–2.19 (m, 2H, CHH′CHCl, CHH′CHOH), 1.83 (ddd, J = 13.1, 6.0, 4.6 Hz, 1H, CHH′CHOPMB), 1.48 (qn, J = 7.6 Hz, 2H, CH₃CH₂), 0.93 (t, J = 7.6 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 193.8 (CHO), 159.3 (Ar), 153.1 (CH=CHCHO), 135.1 (CH=CHCHO), 130.0 (Ar), 129.2 (Ar), 113.8 (Ar), 85.0 (CHORCHCl), 84.7 (EtCHOR), 82.1 (CHOPMB), 80.4 (CHORCHOR), 78.9 (CHORCHOR), 71.1 (CH₂Ar), 58.8 (CHCl), 55.3 (OMe), 37.3 (CH₂CHCl), 36.3 (CH₂CH=CH), 34.4 (CH₂CHOPMB), 26.5 (CH₃CH₂), 10.2 (CH₃); MS (ESI-TOF) m/z 431 [³⁵M + Na]⁺, 433 [³⁵M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₂H₂₉O₅³⁵ClNa 431.1596; found 431.1585; [α]_D²⁰ +22.8 (c = 1.0 in CHCl₃).

(2R,2′S,4S,4′S,5R,5′R)-4-Chloro-5′-ethyl-4′-((4-methoxybenzyl)oxy)-5-((E)-pent-2-en-4-yn-1-yl)octahydro-2,2′-bifuran (31)

To a solution of (diazomethyl)trimethylsilane (50 μL, 2 M in ether, 0.1 mmol) in THF at −78 °C was added BuLi (62 μL, 1.6 M in hexanes, 0.1 mmol) dropwise. The reaction mixture was stirred for 30 min before being transferred rapidly to a solution of enal 30 (4.2 mg, 10 μmol) in THF (0.5 mL) at −78 °C. The reaction was stirred at −78 °C for 1 h before warming to 0 °C for a further 1 h. The reaction was quenched with acetic acid (0.1 mL) and then saturated aqueous NaHCO₃ (10 mL). The aqueous layer was separated and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (16:1 petrol/ethyl acetate) gave the title compound as a colorless oil (2.9 mg, 7 μmol, 70%): R_f 0.78 (8:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2930; ¹H NMR (400 MHz CDCl₃) δ 7.26 (d, J = 8.8 Hz, 2H, ArH), 6.89 (d, J = 8.8 Hz, 2H, ArH), 6.27 (dt, J = 15.7, 7.0 Hz, 1H, CH₂CH=CH), 5.58 (dq, J = 15.7, 2.0 Hz, 1H, CH₂CH=CH), 4.49 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.41 (d, J = 11.4 Hz, 1H, CHH′Ar), 4.21 (q, J = 6.8 Hz, 1H, CHORCHOR), 3.92–4.01 (m, 3H, CHORCHCl, CHORCHOR), 3.88 (td, J = 7.3, 4.0 Hz, 1H, EtCHOR), 3.81 (s, 3H, OMe), 3.78–3.82 (m, 1H, CHOPMB), 2.83 (d, J = 2.0 Hz, 1H, CCH), 2.47 (dddd, J = 13.4, 6.8, 4.8 Hz, 1.5, 1H, CHH′CHCl), 2.33–2.40 (m, 2H, CH₂CH=CH), 2.19–2.30 (m, 2H, 2 × CHH′CHX), 1.90 (ddd, J = 13.2, 6.6, 5.0 Hz, 1H, CHH′CHOPMB), 1.48 (qn, J = 7.3 Hz, 2H, CH₃CH₂), 0.93 (t, J = 7.3 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 159.2 (Ar), 141.0 (CH₂CH=CH), 130.1 (Ar), 129.3 (Ar), 113.8 (Ar), 111.6 (CH₂CH=CH), 85.5 (CHORCHCl), 84.9 (EtCHOR), 82.2 (CHOPMB), 82.0 (CCH), 80.2 (CHORCHOR), 79.1 (CHORCHOR), 77.2 (CCH), 71.1 (CH₂Ar), 58.9 (CHCl), 55.3 (OMe), 37.9 (CH₂CHCl), 36.7 (CH₂CH=CH), 34.5 (CH₂CHOPMB), 26.6 (CH₃CH₂), 10.2 (CH₃); MS (ESI-TOF) m/z 427 [³⁵M + Na]⁺, 429 [³⁵M + Na] ⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₃H₂₉O₄³⁵ClNa 427.1647; found 427.1634; [α]_D²⁰ +34.2 (c = 1.0 in CHCl₃).

(2S,2′R,4S,4′S,5R,5′R)-4′-Chloro-5-ethyl-5′-((E)-pent-2-en-4-yn-1-yl)octahydro-[2,2′-bifuran]-4-ol (2c)

To a stirred solution of ether 31 (21 mg, 50 μmol) in DCM (5 mL) was added BCl₃.DMS (120 μL, 2 M in DCM, 0.24 mmol). The reaction was stirred for 5 min and then quenched with saturated aqueous NaHCO₃ (5 mL). The mixture was then extracted with DCM (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (3:1) petrol/ethyl acetate) gave the title compound as a colorless oil (12 mg, 42 μmol, 84%); R_f 0.60 (3:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3420br, 3294m (CH), 2964m; ¹H NMR (400 MHz CDCl₃) δ 6.22 (dt, J = 15.4, 7.4 Hz, 1H, CH₂CH=CH), 5.59 (dq, J = 15.4, 2.0 Hz, 1H, CH₂CH=CH), 4.39 (ddd, J = 9.1, 6.8, 4.0 Hz, 1H, CHORCHOR), 4.16 (dt, J = 9.1, 3.5 Hz, 1H, CHORCHOR), 4.07 (dt, J = 6.8, 5.4, Hz, 1H, CHClCHOR), 4.03 (dt, J = 6.1, 2.0 Hz, 1H, CHCl), 3.97 (ddd, J = 7.8, 5.4, 4.3 Hz, 1H, CHOH), 3.86 (td, J = 6.9, 1.8 Hz, 1H, EtCHOR), 3.13 (br, 1H, OH), 2.84 (d, J = 2.0 Hz, 1H, CCH), 2.51 (dddd, J = 14.4, 7.4, 5.3, 2.0 Hz, 1H, CHH′CH=CH), 2.41 (dddd J = 14.4, 7.4, 5.3, 2.0 Hz, 1H, CHH′CH=CH), 2.30 (ddd, J = 13.9, 9.1, 6.1 Hz, 1H, CHH′CHOH), 2.19 (ddd, J = 13.9, 6.8, 4.0 Hz, 1H, CHH′CHCl), 2.08 (ddd, J = 13.9, 8.9, 7.8 Hz, 1H, CHH′CHCl), 1.76 (ddd, J = 13.9, 4.2, 2.0 Hz, CHH′CHOH), 1.39 (2H, qn, J = 7.6 Hz, CH₃CH₂), 0.95 (3H, t, J = 7.6 Hz, 1H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 140.1 (CH₂CH=CH), 112.3 (CH₂CH=CH), 88.9 (EtCHOR), 86.0 (CHORCHCl), 81.7 (CCH), 79.8 (CHORCHOR), 78.2 (CHORCHOR), 77.2 (CCH), 74.8 (CHOH), 58.3 (CHCl), 38.2 (CH₂CHCl), 36.6 (CH₂CH=CH), 34.3 (CH₂CHOH), 26.0 (CH₃CH₂), 10.2 (CH₃); MS (ESI-TOF) m/z 307 [³⁵M + Na]⁺, 309 [³⁵M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₅H₂₁O₃³⁵ClNa 307.1071; found 307.1070; [α]_D²⁰ +53.4 (c = 1.0 in CHCl₃).

(2S,2′R,4R,4′S,5R,5′R)-4′-Chloro-5-ethyl-5′-((E)-pent-2-en-4-yn-1-yl)octahydro-[2,2′-bifuran]-4-ol (2a)

Alcohol 2c (2 mg, 7 μmol) and PPh₃ (20.2 mg, 77 μmol) were dissolved in THF (0.3 mL) and cooled to 0 °C. DIAD (15.6 μL, 77 μmol), was added dropwise and the reaction stirred for 30 min before the addition of 4-nitrobenzoic acid (13 mg, 77 μmol). The reaction was then warmed to rt and stirred for 2 h before being concentrated in vacuo. Purification by short silica plug (DCM) gave the intermediate ester mixed with DIADH₂. The mixture was then dissolved in MeOH (0.2 mL), and cooled to 0 °C and K₂CO₃ (5.5 mg, 40 μmol) was added. The reaction was stirred for 30 min, then diluted with H₂O (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were then dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography gave the title compound as a colorless oil (0.5 mg, 2 μmol, 25%): R_f 0.62 (3:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3455m, 3291m, 2969m; ¹H NMR (500 MHz CDCl₃) δ 6.25 (dt, J = 15.8, 7.3 Hz, 1H, CH₂CH=CH), 5.58 (dq, J = 15.8, 2.2 Hz, 1H, CH₂CH=CH), 4.30 (br m, 1H, CHOH), 4.15–4.23 (m, 2H, CHORCHOR), 3.98–4.03 (m, 2H, CHORCHCl), 3.73 (td, J = 7.0, 2.8 Hz, 1H, EtCHOR), 2.83 (d, J = 2.2 Hz, 1H, CCH), 2.47 (dddd, J = 12.3, 7.3, 5.0, 2.2 Hz, 1H, CHH′CH=CH), 2.37 (dddd, J = 12.3, 7.3, 6.3, 2.2 Hz, 1H, CHH′CH=CH), 2.28–2.17 (m, 2H, CH₂CHCl), 2.10 (dd, J = 13.6, 6.3 Hz, 1H, CHH′CHOH), 1.94 (ddd, J = 13.6, 9.1, 4.6 Hz, 1H, CHH′CHOH), 1.70 (dq, J = 13.6, 7.6 Hz, 1H, CH₃CHH′), 1.61 (dq, J = 13.6, 7.6 Hz, 1H, CH₃CHH′), 0.99 (t, J = 7.6 Hz, 3H, CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 140.8 (CH₂CH=CH), 117.8 (CH₂CH=CH), 85.7 (CHORCHCl), 84.7 (EtCHOR), 81.9 (CCH), 80.3 (CHORCHOR), 78.3 (CHORCHOR), 77.2 (CCH), 72.6 (CHOH), 58.8 (CHCl), 37.9 (CH₂CHOH), 37.9 (CH₂CHCl), 36.7 (CH₂CH=CH), 22.0 (CH₃CH₂), 10.5 (CH₃); MS (ESI-TOF) m/z 307 [³⁵M + Na] ⁺, 309 [³⁵M + Na] ⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₅H₂₁O₃³⁵ClNa 307.1071; found 307.1070; [α]_D²⁰ +66.0 (c = 0.05 in CHCl₃).

(2S,2′R,4S,4′S,5S,5′R)-5-Allyl-5′-ethyl-4′-((4-methoxybenzyl)oxy)octahydro-[2,2′-bifuran]-4-ol (34)

To a solution of (2S,2′R,4S,4′S,5S,5′R)-5-allyl-4-((4-bromobenzyl)oxy)-5′-ethyl-4′-((4-methoxybenzyl)oxy)octahydro-2,2′-bifuran 32 (50 mg, 94 μL) and bis(methoxyethyl)amine (44 μL, 39 mg, 0.3 mmol) in THF (4 mL) at −78 °C was titrated a solution of LiDBB (ca. 1 mL of a solution prepared by sonicating DBB (0.75 g, 2.8 mmol), lithium (20 mg, 2.8 mmol) in THF (3 mL) for 2 h). The reaction progress was monitored by TLC. When no more starting material was detected, the reaction was quenched by the addition of saturated aqueous NH₄Cl and diluted with EtOAc and then allowed to warm to rt. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (5:1 petrol/ethyl acetate) gave the title compound as a colorless oil (23 mg, 62 μmol, 66%) and benzyl-protected intermediate 33 (8 mg, 17 μmol, 18%). Data for 34: ν_max/cm^–1 (thin film) 3437br, 2960m, 2934m; R_f 0.38 (5:1 petrol/ethyl acetate); ¹H NMR (500 MHz C₆D₆) δ 7.15 (d, J = 8.6 Hz, 2H, ArH), 6.81 (d, J = 8.6 Hz, 2H, ArH), 6.07(ddt, J = 17.0, 10.0, 7.0 Hz, 1H, CH=CH₂), 5.20 (dq, J = 17.0, 2.0 Hz, 1H, CH=CHH′), 5.08 (ddt, J = 10.0, 2.0 Hz, 1H, CH=CHH′), 4.46 (ddd, J = 10.8, 5.7, 2.0 Hz, 1H, CHORCHOR), 4.19 (d, J = 11.6 Hz, 1H, CHH′Ar), 4.14 (d, J = 11.6 Hz, 1H, CHH′Ar), 3.89–3.93 (m, 3H, EtCHOR, CHORCHOR, CHOH), 3.76 (d, J = 10.7 Hz, 1H, OH), 3.55 (td, J = 7.0, 2.8 Hz, 1H, CHORCHOH), 3.40–3.44 (m, 1H, CHOPMB), 3.31 (s, 3H, OMe), 2.67–2.78 (m, 2H, CH₂CH=CH₂), 1.78 (ddd, J = 13.6, 10.2, 5.3 Hz, 1H, CHH′CHOH), 1.70 (dd, J = 13.6, 2.8 Hz, 1H, CHH′CHOH), 1.65 (ddd, J = 13.2, 5.5, 2.0 Hz, 1H, CHH′CHOPMB), 1.44 (dq, J = 14.6, 7.3 Hz, 1H, CH₃CHH′), 1.26–1.33 (m, 1H, CH₃CHH′), 1.12 (ddd J = 13.2, 10.3, 6.5 Hz, 1H, CHH′CHOMPB), 0.83 (t, J = 7.4 Hz, 3H, CH₃); ¹³C{1H} NMR (125 MHz C₆D₆) δ 159.8 (Ar), 136.0 (CH=CH₂), 130.7 (Ar), 129.3 (Ar), 127.5 (Ar), 116.6 (CH=CH₂) 114.1 (Ar), 86.3 (EtCHOR), 84.0 (CHORCHCl), 82.2 (CHOPMB), 79.9 (CHORCHOR), 78.9 (CHORCHOR), 71.4 (CHOH), 70.8 (CHOH), 54.8 (OMe), 34.9 (CH₂CHOH), 34.8 (CH₂CHOPMB), 34.5 (CH₂CH=CH₂), 27.4 (CH₃CH₂), 10.4 (CH₃); MS (ESI-TOF) m/z 385 [M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₁H₃₀O₅Na 385.1985; found 385.1985; [α]_D²⁰ +38.1 (c = 1.0 in CHCl₃).

(2S,2′R,4R,4′S,5S,5′R)-5-Allyl-4-chloro-5′-ethyl-4′-((4-methoxybenzyl)oxy)octahydro-2,2′-bifuran (35)

Alcohol 34 (24 mg, 66 μmol) was dissolved in DCM/CCl₄ (2.4 mL/0.6 mL) and PPh₃ (72.5 mg, 396 μmol) was added and the reaction stirred for 2.5 h. Direct purification of the reaction mixture via flash column chromatography (DCM → 5:1 petrol/ethyl) gave the title compound as a colorless oil (24 mg, 64 μmol, 96%): R_f 0.89 (6:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2916m, 2930m, 2876m; ¹H NMR (500 MHz C₆D₆) 7.19 (d, J = 8.5 Hz, 2H, ArH), 6.81 (d, J = 8.5 Hz, 2H, ArH), 5.78 (ddt, J = 16.5, 10.0, 7.0 Hz, 1H, CH=CH₂), 4.96–5.01 (m, 1H, CH=CH₂), 4.27 (d, J = 11.5 Hz, 1H, CHH′Ar), 4.21 (d, J = 11.5 Hz, 1H, CHH′Ar), 4.00–4.13 (m, 3H, CHORCHOR, CHClCHOR), 3.96 (ddd, J = 7.0, 6.0, 3.0 Hz, 1H, EtCHOR), 3.77 (dt, J = 7.0, 5.0 Hz, 1H, CHCl), 3.55 (ddd, J = 6.5, 3.0, 2.5 Hz, 1H, CHOPMB), 3.30 (s, 3H, OMe), 2.06–2.17 (m, 4H, CH₂CH=CH₂, CH₂CHCl), 2.04 (ddd, J = 13.4, 6.0, 2.5 Hz, 1H, CHH′CHOPMB), 1.57 (ddd, J = 13.4, 9.0, 6.5 Hz, 1H, CHH′CHOPMB), 1.32–1.48 (m, 2H, CH₃CH₂), 0.90 (t, J = 7.5 Hz, 3H, CH₃CH₂); ¹³C{¹H} NMR (125 MHz C₆D₆) δ 159.8 (Ar), 134.1 (CH=CH₂), 130.9 (Ar), 129.4 (Ar), 127.5 (Ar), 117.4 (CH=CH₂), 114.1 (Ar), 86.7 (CHORCHCl), 85.9 (EtCHOR), 82.8 (CHOPMB), 80.8 (CHORCHOR), 80.4 (CHORCHOR), 70.9 (CH₂Ar), 59.8 (CHCl), 54.8 (OMe), 38.9 (CH₂CHCl), 38.3 (CH₂CH=CH₂), 35.7 (CH₂CHOPMB), 27.8 (CH₃CH₂), 10.5 (CH₃); MS (ESI-TOF) m/z 403 [³⁵M + Na]⁺, 405 [³⁷M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₁H₂₉O₄³⁵ClNa 403.1647; found 403.1638; [α]_D²⁰ +8.1 (c = 1.0 in CHCl₃).

(2R,2′S,4S,4′R,5R,5′S)-5′-Allyl-4′-chloro-5-ethyloctahydro-[2,2′-bifuran]-4-ol (36)

Chloride 35 (24 mg, 66 μmol) was dissolved in DCM (6 mL) and BCl₃·DMS (165 μL, 2 M in DCM, 0.33 mmol) was added dropwise. The reaction was stirred for 5 min and then quenched by the addition of saturated aqueous NaHCO₃ (4 mL). The mixture was then extracted with DCM (3 × 10 mL). The combined organic layers were then dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification via flash column chromatography (4:1 petrol/ethyl acetate) gave the title compound as a colorless oil (16 mg, 62 μmol, 94%): R_f 0.34 (5:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3423br (OH), 2965m, 1437w, 1067s; ¹H NMR (400 MHz CDCl₃) δ 5.83 (ddt, J = 17.0, 9.9, 7.0 Hz, 1H, CH=CH₂), 5.13 (d, J = 17.0 Hz, 1H, CH=CHH′), 5.11 (d, J = 9.9 Hz, 1H, CH=CHH′), 4.06–4.15 (m, 3H, CHOH, CHORCHOR), 4.00–4.06 (m, 2H, CHClCHOR), 3.68 (td, J = 6.6, 2.8 Hz, 1H, EtCHOR), 2.30–2.40 (m, 2H, CH₂CH=CH₂), 2.17–2.29 (m, 2H, CH₂CHCl), 1.85–1.98 (m, 2H, CH₂CHOH), 1.74 (br s, 1H, OH), 1.44–1.57 (m, 2H, CH₃CH₂), 0.96 (t, J = 7.4 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 133.5 (CH=CH₂), 117.9 (CH=CH₂), 88.2 (EtCHOR), 86.4 (CHORCHCl), 80.0 (CHORCHOR), 79.2 (CHORCHOR), 75.7 (CHOH), 59.2 (CHCl), 38.0 (CH₂CH=CH₂), 38.0 (CH₂CHCl), 37.6 (CH₂CHOH), 27.1 (CH₃CH₂), 10.2 (CH₃); MS (ESI-TOF) m/z 283 [³⁵M + Na]⁺, 285 [³⁷M + Na]⁺; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₂₁O₃³⁵ClNa 283.1071; found 283.1073; [α]_D²⁰ −38.6 (c = 1.0 in CHCl₃).

(2R,2′S,4R,4′R,5R,5′S)-5′-Allyl-4′-chloro-5-ethyloctahydro-[2,2′-bifuran]-4-yl 4-nitrobenzoate

Alcohol 36 (15.5 mg, 60 μmol) and PPh₃ (156 mg, 600 μmol) were dissolved in THF (0.8 mL) and cooled to 0 °C. DIAD (120 μL, 600 μmol) was added dropwise, and the reaction was stirred for 30 min before the addition of 4-nitrobenzoic acid (99.6 mg, 600 μmol). The reaction was then warmed to rt and stirred for 2 h before being concentrated in vacuo. Purification via flash column chromatography (DCM) gave the title compound as a colorless oil (20 mg, 49 μmol, 81%): R_f 0.43 (8:1 petrol/acetone); ν_max/cm^–1 (thin film) 2972w, 1724s (CO), 1528s, 1350m; ¹H NMR (400 MHz CDCl₃) δ 8.31 (d, J = 9.1 Hz, 2H, ArH), 8.20 (d, J = 9.1 Hz, 2H, ArH), 5.77 (ddt, J = 17.0, 10.0, 7.1 Hz, 1H, CH=CH₂), 5.54 (ddd, J = 6.5, 3.6, 1.6 Hz, 1H, CHOPNB), 5.07 (dd, J = 17.0, 1.2 Hz, 1H, CH=CHH′), 5.05 (dd, J = 10.0, 1.2 Hz, 1H, CH=CHH′), 4.24 (dt, J = 7.5, 6.1 Hz, 1H, CHORCHOR), 4.01–4.11 (m, 2H, CHClCHOR), 3.97 (dt, J = 8.3, 6.0 Hz, 1H, CHORCHOR), 3.81 dd, J = 7.4, 6.1, 3.5 Hz, 1H, EtCHOR), 2.57 (ddd, J = 14.9, 8.5, 6.5 Hz, 1H, CHH′CHOPNB), 2.22–2.38 (m, 4H, CH₂CH=CH₂, CH₂CHCl), 2.02 (ddd, J = 14.8, 6.0, 1.7 Hz, 1H, CHH′CHOPNB), 1.63–1.85 (m, 2H, CH₃CH₂), 0.99 (t, J = 7.4 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 164.0 (C=O), 150.7 (Ar), 135.4 (Ar), 133.3 (CH=CH₂), 130.7 (Ar), 123.7 (Ar), 118.0 (CH=CH₂), 86.4 (CHORCHCl), 83.7 (EtCHOR), 79.6 (CHORCHOR), 79.0 (CHORCHOR), 75.9 (CHOPNB), 59.1 (CHCl), 38.2 (CH₂CH=CH₂), 37.9 (CH₂CHCl), 35.9 (CH₂CHOPNB), 22.2 (CH₃CH₂), 10.6 (CH₃); MS (ESI-TOF) m/z 432 [³⁵M + Na⁺], 434 [³⁷M + Na⁺]; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₀H₂₄NO₆³⁵ClNa 432.1184; found 432.1184; [α]_D²⁰ −12.4 (c = 1.0 in CHCl₃).

(2R,2′S,4R,4′R,5R,5′S)-5′-Allyl-4′-chloro-5-ethyloctahydro-[2,2′-bifuran]-4-ol (37)

(2R,2′S,4R,4′R,5R,5′S)-5′-allyl-4′-chloro-5-ethyloctahydro-[2,2′-bifuran]-4-yl 4-nitrobenzoate (20 mg, 49 μmol) was dissolved in MeOH (2 mL) and cooled to 0 °C, and K₂CO₃ (40 mg, 290 μmol) was added. The reaction was stirred for 30 min and then diluted with H₂O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were then dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (4:1 petrol/ethyl acetate) gave the title compound as a colorless oil (13 mg 48 μmol, 98%): R_f 0.32 (5:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3461br (OH), 2968m, 1430m, 1050s; ¹H NMR (400 MHz CDCl₃) δ 5.82 (ddt, J = 17.0, 10.0, 6.8 Hz, 1H, CH=CH₂), 5.17 (dd, J = 17.0, 1.5 Hz, 1H, CH=CHH′), 5.15 (dd, J = 10.0, 1.5 Hz, 1H, CH=CHH′), 4.44 (ddd, J = 9.1, 6.8, 2.6 Hz, 1H, CHORCHOR), 4.16 (dt, J = 9.8, 2.6 Hz, 1H, CHORCHOR), 4.11–4.14 (m, 1H, CHORCHCl), 3.99–4.04 (m, 2H, CHOH, CHCl), 3.54 (tdfz, J = 6.9, 2.5 Hz, 1H, EtCHOR), 3.24 (br s, 1H, OH), 2.33–2.47 (m, 2H, CH₂CH=CH₂), 2.25 (ddd, J = 14.0, 9.8, 5.5 Hz, 1H, CHH′CHOH), 2.15 (ddd, J = 13.8, 6.8, 3.7 Hz, 1H, CHH′CHCl), 2.00 (ddd, J = 13.8, 9.6, 7.8 Hz, 1H, CHH′CHCl), 1.81 (dd, J = 14.0, 3.3 Hz, 1H, CHH′CHOH), 1.65–1.74 (m, 2H, CH₃CH₂), 0.97 (t, J = 7.6 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 132.7 (CH=CH₂), 118.6 (CH=CH₂), 86.6 (CHORCHCl), 85.7 (EtCHOR), 79.0 (CHORCHOR), 77.9 (CHORCHOR), 70.9 (CHOH), 58.4 (CHCl), 38.2 (CH₂CHCl), 37.6 (CH₂CH=CH₂), 34.7 (CH₂CHOH), 21.8 (CH₃CH₂), 10.5 (CH₃); MS (ESI-TOF) m/z 283 [³⁵M + Na⁺], 285 [³⁷M + Na⁺]; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₂₁O₃³⁵ClNa 283.1071; found 283.1072; [α]_D²⁰ −40.2 (c = 1.0 in CHCl₃).

(2R,2′S,4R,4′R,5R,5′S)-4′-Chloro-5-ethyl-5′-((E)-pent-2-en-4-yn-1-yl)octahydro-[2,2′-bifuran]-4-ol, L. majuscula Enyne (2b)

To a stirred solution of alkene 37 (12 mg, 46 μmol) (62 mg, 0.16 mmol) in dry degassed DCM (1.4 mL) were added crotonaldehyde (38 μL, 0.46 mmol) and Grubbs’ second generation catalyst (3.9 mg, 4.6 μmol). The reaction mixture was stirred for 1.5 h at 40 °C and then cooled to rt and quenched with the addition of DMSO (30 μL) and stirred for 16 h. The mixture was concentrated in vacuo and purified by flash column chromatography (5:1 petrol ethyl acetate) to give the intermediate enal (38) (12.6 mg), which was used immediately in the next reaction: MS (ESI-TOF) m/z 311 [³⁵M + Na⁺], 313 [³⁷M + Na⁺]; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₄H₂₁O₄³⁵ClNa 311.1021; found 311.1026.

To a solution of (diazomethyl)trimethylsilane (230 μL, 2 M in ether, 0.46 mmol) in THF (1 mL) at −78 °C was added BuLi (288 μL, 1.6 M in hexanes, 0.46 mmol) dropwise. The reaction mixture was stirred for 30 min before a solution of the intermediate enal 38 was added as a solution in THF (0.5 + 0.5 mL) at −78 °C. The reaction was stirred at −78 °C for 1 h before being warmed to 0 °C for a further 1 h. The reaction was quenched with acetic acid (0.1 mL) and then saturated aqueous NaHCO₃ (10 mL). The aqueous layer was separated and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (20:1 petrol/ethyl acetate) gave the OTMS-protected version title compound (m/z 379 M + Na⁺, 100), which was then dissolved in THF (1 mL) and cooled to 0 °C, and TBAF (0.13 mL, 1 M in THF, 0.13 mmol) was added and the reaction stirred for 5 min. The reaction was quenched with saturated aqueous NH₄Cl (1 mL). The aqueous layer was separated and extracted with EtOAc (3 × 8 mL). Purification by flash column chromatography (5:1 petrol/ethyl acetate) gave the title compound as a colorless oil (5 mg, 18 μmol, 39%): R_f 0.40 (5:1: petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3461br (OH), 3296m (CH), 2968m, 1442m, 1066s; ¹H NMR (500 MHz CDCl₃) δ 6.22 (dt, J = 15.9, 7.4 Hz, 1H, CH₂CH=CH), 5.59 (dddd, J = 15.9, 2.2, 1.6, 1.5 Hz, 1H, CH₂CH=CH), 4.41 (ddd, J = 9.1, 6.8, 2.6 Hz, 1H, CHORCHOR), 4.11 (ddd, J = 9.8, 3.3, 2.6 Hz, 1H, CHORCHOR), 4.08 (ddd, J = 6.5, 5.6, 5.4 Hz, 1H, CHORCHCl), 4.05 (br m, 1H, CHOH) 3.96 (ddd, J = 7.8, 5.4, 4.2 Hz, 1H, CHCl), 3.54 (dt, J = 6.9, 2.5 Hz, 1H, EtCHOR), 3.00 (br s, 1H, OH), 2.83 (d, J = 2.2 Hz, 1H), 2.40–2.53 (m, 2H, CH₂CH=CH), 2.25 (ddd, 1H, J = 14.0, 9.8, 5.5 Hz, CHH′CHOH), 2.18 (ddd, J = 13.8, 6.8, 4.2 Hz, 1H, CHH′CHCl), 2.05 (ddd, J = 13.8, 9.1, 7.8 Hz, 1H, CHH′CHCl), 1.78 (dd, J = 14.0, 3.3 Hz, 1H, CHH′CHOH), 1.70 (qn, J = 7.5 Hz, 2H, CH₃CH₂), 0.98 (t, J = 7.5 Hz, 1H, CH₃); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 139.9 (CH₂CH=CH), 112.4 (CH=CH₂), 86.0 (CHORCHCl), 85.7 (EtCHOR), 81.7 (CCH), 79.2 (CHORCHOR), 77.9 (CHORCHOR), 77.2 (CCH), 71.0 (CHOH), 58.2 (CHCl), 38.1 (CH₂CHCl), 36.5 (CH₂CH=CH₂), 35.1(CH₂CHOH), 21.7 (CH₃CH₂), 10.5 (CH₃); MS (ESI-TOF) m/z 307 [³⁵M + Na⁺], 309 [³⁷M + Na⁺]; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₅H₂₁³⁵ClO₃Na 307.1071; found 307.1066; [α]_D²⁰ −51.9 (c = 0.45 in CHCl₃), lit. [α]_D −67.8 (c = 0.09 in CHCl₃).

(2R,2′S,4S,4′R,5R,5′S)-4′-chloro-5-ethyl-5′-((E)-pent-2-en-4-yn-1-yl)octahydro-[2,2′-bifuran]-4-ol (2d)

Alcohol 2b (2 mg, 7 μmol) and PPh₃ (20.2 mg, 77 μmol) were dissolved in THF (0.3 mL) and cooled to 0 °C. DIAD (15.6 μL, 77 μmol) was added dropwise, and the reaction was stirred for 30 min before the addition of 4-nitrobenzoic acid (13 mg, 77 μmol). The reaction was then warmed to rt and stirred for 2 h before being concentrated in vacuo. Purification by short silica plug (DCM) gave the intermediate ester mixed with DIADH₂. The mixture was then dissolved in MeOH (0.2 mL) and cooled to 0 °C, and K₂CO₃ (5.5 mg, 40 μmol) was added. The reaction was stirred for 30 min, diluted with H₂O (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were then dried (MgSO₄), filtered, and concentrated in vacuo. Purification by column chromatography (3:1 petrol/ethyl acetate) gave the title compound as a colorless oil (1.8 mg, 7 μmol, 90%): R_f 0.62 (3:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3444br (OH), 3291m (CH), 2966m, 1442m, 1066s; ¹H NMR (500 MHz CDCl₃) δ 6.25 (dt, J = 16.2, 7.4 Hz, 1H, CH₂CH=CH), 5.57 (d t, J = 16.2, 1.8 Hz, 1H, CH=CH), 4.08–4.15 (m, 3H, CHORCHOR, CHOH), 3.97–4.02 (m, 2H, CHClCHOR), 3.70 (td, J = 6.7, 3.1 Hz, 1H, CHEt), 2.83 (d, J = 1.8 Hz, 1H, CCH), 2.43–2.49 (m, 2H, CHH′CH=CH), 2.34–2.40 (m, 1H, CHH′CH=CH), 2.26–2.32 (m, 1H, CHH′CHCl), 2.19 (ddd, J = 13.4, 6.4, 4.7 Hz, 1H, CHH′CHCl), 1.95 (ddd, J = 13.3, 5.9, 2.7 Hz, 1H, CHOHCHH′), 1.86 (ddd, J = 13.2, 8.8, 6.2 Hz, 1H, CHOHCHH′), 1.46–1.56 (m, 2H, CH₂Me), 0.97 (t, J = 7.4 Hz, 3H, Me); ¹³C{¹H} NMR (125 MHz CDCl₃) δ 140.9 (CH₂CH=CH), 111.7 (CH=CH), 88.2 (CHEt), 85.7 (CHClCHOR), 81.9 (CCH), 79.9, (CHORCHOR), 79.1 (CHORCHOR), 76.6 (CCH), 75.7 (CHOH), 58.9 (CHCl), 37.8 (CH₂CHCl), 37.6 (CHOHCH₂), 36.8 (CH₂CH=CH), 27.0 (CH₂Me), 10.2 (Me); HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₅H₂₁ClO₃Na 307.1071; found 307.1070; [α]_D²⁰ −31.3 (c = 0.16 in CHCl₃).

Notoryne: Oxford Route

(2S,2′R,4S,4′S,5R,5′R)-5′-Allyl-4′-chloro-5-ethyloctahydro-[2,2′-bifuran]-4-ol

To a stirred solution of ether 28 (35 mg, 0.09 mmol) in DCM (9 mL) was added BCl₃·SMe₂ (0.23 mL, 2 M in DCM, 0.45 mmol), and the reaction was stirred for 5 min. The reaction was quenched with saturated aqueous NaHCO₃ (6 mL) and the stirred vigorously for 10 min. The aqueous layer was separated and extracted with DCM (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (3:1 petrol/ethyl acetate) gave the title compound as a colorless oil (22 mg, 86 μmol, 95%): R_f 0.56 (3:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 3432br (OH), 2964s, 1642w,1438w, 1074s, 921m; ¹H NMR (500 MHz CDCl₃) δ 5.82 (ddt, J = 17.2, 10.1, 6.8 Hz, 1H, CH=CH₂), 5.17 (dd, J = 17.2, 1.6 Hz, 1H, CH=CHH′), 5.14 (dd, J = 10.1, 1.6 Hz, 1H, CH=CHH′), 4.42 (ddd, J = 9.3, 6.4, 2.6 Hz, 1H, CHORCHOR), 4.19 (dt, J = 9.3, 3.1 Hz, 1H, CHORCHOR), 4.12 (dt, J = 6.6, 5.3 Hz, 1H, CHORCHCl), 3.99–4.04 (m, 2H, CHCl, CHOH), 3.88 (td, J = 7.4, 1.0 Hz, 1H, EtCHOR), 3.43 (br s, 1H, OH), 2.41–2.47 (m, 1H, CHHCH=CH₂), 2.33–2.39 (m, 1H, CHHCH=CH₂), 2.28 (ddd, J = 13.9, 6.4, 3.8 Hz, 1H, CHH′CHOH), 2.18 (ddd, J = 13.9, 6.4, 2.6 Hz, 1H, CHH′CHCl), 2.04 (ddd, J = 13.9, 9.3, 8.0 Hz, 1H, CHH′CHCl), 1.78 (ddd, J = 13.9, 3.4, 1.6 Hz, 1H, CHH′CHOH), 1.38 (qn, J = 7.4 Hz, 2H, CH₃CH₂), 0.95 (t, J = 7.4 Hz, 3H, CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 132.8 (CH=CH₂), 118.5 (CH=CH₂), 89.1 (EtCHOR), 86.7 (CHORCHCl), 79.7 (CHORCHOR), 78.2 (CHORCHOR), 74.8 (CHOH), 58.5 (CHCl), 38.3 (CH₂CHCl), 37.6 (CH₂CH=CH₂), 33.8 (CH₂CHOH), 26.1 (CH₃CH₂), 10.2 (CH₃); MS (ESI-TOF) m/z 283 [³⁵M + Na⁺], 285 [³⁷M + Na⁺]; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₂₁NO₃³⁵ClNa 283.1071; found 283.1072; [α]_D²⁰ +60.4 (c = 1.0 in CHCl₃).

(2S,2′R,4R,4′S,5R,5′R)-5′-Allyl-4′-chloro-5-ethyloctahydro-[2,2′-bifuran]-4-yl 4-nitrobenzoate

To a stirred solution of (2S,2′R,4S,4′S,5R,5′R)-5′-allyl-4′-chloro-5-ethyloctahydro-[2,2′-bifuran]-4-ol (16 mg, 62 μmol) and PPh₃ (78 mg, 0.3 mmol) in THF (0.9 mL) at 0 °C was added DIAD (60 μL, 60 μg, 0.3 mmol). The reaction mixture was stirred for 30 min at 0 °C, during which time a white precipitate formed. 4-Nitrobenzoic acid (50 mg, 0.3 mmol) was added in one batch, and the reaction was stirred for 1 h. The reaction was then concentrated in vacuo and purified by flash column chromatography (DCM) to give the title compound as a colorless oil (19 mg, 46 μmol, 74%): R_f 0.45(8:1 petrol/acetone); ν_max/cm^–1 (thin film) 2967w, 1725s, 1529s, 1348w, 1274s, 1103m; ¹H NMR (400 MHz CDCl₃) δ 8.30 (dd, J = 7.0, 1.9 Hz, 2H, ArH), 8.22 (dd, J = 7.0, 1.9 Hz, 2H, ArH), 5.83 (ddt, J = 17.0, 10.0, 6.7 Hz, 1H, CH=CH₂), 5.63 (t, J = 3.4 Hz, 1H, CHOPNB), 5.13 (dd, J = 17.0, 0.9 Hz, 1H, CH=CHH′), 5.12 (dd, J = 10.0, 0.9 Hz, 1H, CH=CHH′), 4.22–4.30 (m, 2H, CHORCHOR), 4.05–4.09 (m, 2H, CHClCHOR), 4.02 (td, J = 7.1, 3.4 Hz, 1H, EtCHOR), 2.32–2.39 (m, 2H, CH₂CH=CH₂), 2.20–2.28 (m, 4H, CH₂CHOPNB, CH₂CHCl), 1.57–1.80 (m, 2H, CH₃CH₂), 0.97 (t, J = 7.5 Hz, 3H, CH₃); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 164.0 (C=O), 150.7 (Ar), 135.3 (Ar), 133.3 (CH=CH₂), 130.8 (Ar), 123.6 (Ar), 118.0 (CH=CH₂), 86.5 (CHORCHCl), 83.4 (EtCHOR), 80.0, 78.8 (CHORCHOR), 76.6 (CHOPNB), 59.0 (CHCl), 38.1 (CH₂), 37.9 (CH₂CH=CH₂), 35.6 (CH₂), 22.6 (CH₃CH₂), 10.5 (CH₃); MS (ESI-TOF) m/z 432 [³⁵M + Na⁺], 434 [³⁷M + Na⁺]; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₂₀H₂₄NO₆³⁵ClNa 432.1184; found 432.1185; [α]_D²⁰ −4.0 (c = 1.0 in CHCl₃).

(2S,2′R,4R,4′S,5R,5′R)-5′-Allyl-4′-chloro-5-ethyloctahydro-[2,2′-bifuran]-4-ol (10)

To a stirred solution of (2S,2′R,4R,4′S,5R,5′R)-5′-allyl-4′-chloro-5-ethyloctahydro-[2,2′-bifuran]-4-yl 4-nitrobenzoate (19 mg, 46 μmol) in MeOH (1 mL) was added K₂CO₃ (39 mg, 132 mmol), and the reaction was stirred for 30 min. The mixture was diluted with H₂O (3 mL) and the aqueous layer extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (3:1 petrol/ethyl acetate) gave the title compound as a colorless oil (11 mg, 42 μmol, 91%): R_f (0.54 3:1 petrol/ethyl acetate); v_max/cm^–1 (thin film) 3247br (OH), 2932s, 1642w, 1434w, 1055s, 1013m, 924s; ¹H NMR (500 MHz CDCl₃) δ 5.83 (ddt, J = 17.1, 10.3, 7.0 Hz, 1H, CH=CH₂), 5.14 (dd, J = 17.1, 1.5 Hz, 1H, CH=CHH′), 5.11 (dd, J = 10.3, 1.5 Hz, 1H, CH=CHH′), 4.28–4.31 (m, 1H, CHOH), 4.16–4.22 (m, 2H, CHORCHOR), 4.02–4.07 (m, 2H, CHClCHOR), 3.73 (td, J = 7.3, 2.8 Hz, 1H, EtCHOR), 2.28–2.42 (m, 2H, CH₂CH=CH₂), 2.16–2.24 (m, 2H, CH₂CHCl), 2.10 (ddd, J = 13.0, 5.6, 1.0 Hz, 1H, CHH′CHOH), 1.97 (ddd, J = 13.0, 8.7, 4.7 Hz, 1H, CHH′CHOH), 1.57–1.74 (m, 2H, CH₃CH₂), 1.45 (d, J = 5.3 Hz, 1H, OH), 0.99 (t, J = 7.5 Hz, 3H, CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 133.4 (CH=CH₂), 117.9 (CH=CH₂), 86.4 (CHORCHCl), 84.6 (EtCHOR), 80.3 (CHORCHOR), 78.4 (CHORCHOR), 72.7 (CHOH), 59.1 (CHCl), 38.1 (CH₂CHCl), 37.9 (CH₂CH=CH₂, CH₂CHOH), 22.0 (CH₃CH₂), 10.4 (CH₃); HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₂₁O₃ClNa 283.1071; found 283.1071; [α]_D²⁰ +6.8 (c = 1.0 in CHCl₃).

(2R,2′S,4S,4′S,5R,5′R)-5-Allyl-4′-bromo-4-chloro-5′-ethyloctahydro-2,2′-bifuran (47-Oxford)

To a stirred solution of alcohol 10 (14 mg, 57 μmol) in toluene (2.4 mL) were added PPh₃ (78 mg, 0.3 mmol) and CBr₄ ((99 mg, 0.3 mmol), which was then purified by sublimation, dissolved in DCM, filtered through deactivated alumina, and dried in a desiccator over KOH for 16 h), and the mixture was heated to 80 °C for 75 min. The reaction mixture was cooled to rt and then diluted with DCM (1 mL) and loaded directly onto a column. Purification by flash column chromatography (DCM) gave the title compound as a colorless oil (14 mg, 43 μmol, 75%): R_f 0.82 (5:1 petrol/ethyl acetate); ν_max/cm^–1 (thin film) 2964m, 1456m, 1262m, 1067s; ¹H NMR (500 MHz CDCl₃) δ 5.83 (ddt, J = 17.0, 10.1, 6.9 Hz, 1H, CH=CH₂), 5.15 (dd, J = 17.0, 1.6 Hz, 1H, CH=CHH′), 5.12 (dd, J = 10.1, 1.6 Hz, 1H, CH=CHH′), 4.24 (dt, J = 7.2, 5.5 Hz, 1H, CHORCHOR), 4.03–4.07 (m, 2H, CHCl, CHORCHCl), 3.97 (ddd, J = 8,2, 6.9, 5.5 Hz, 1H, CHORCHOR), 3.91 (td, J = 7.5, 4.0 Hz, 1H, EtCHOR), 3.86 (td, J = 8.7, 7.3 Hz, 1H, CHBr), 2.66 (dt, J = 13.1, 6.9 Hz, 1H, CHH′CHBr), 2.31–2.40 (m, 2H, CH₂CH=CH₂), 2.24–2.26 (m, 2H, CH₂CHCl), 2.18 (dt, J = 13.6, 8.0 Hz, 1H, CHH′CHBr), 1.76 (dqd, J = 13.8, 7.5, 3.8 Hz, 1H, CH₃CHH′), 1.50 (dqn, J = 13.8, 7.5 Hz, 1H, CH₃CHH′), 1.01 (t, J = 7.5 Hz, 3H, CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 133.3 (CH=CH₂), 118.0 (CH=CH₂), 87.1 (EtCHOR), 86.4 (CHORCHCl), 79.9 (CHORCHOR), 78.9 (CHORCHOR), 58.9 (CHCl), 47.3 (CHBr), 39.3 (CH₂CHCl), 38.0 (CH₂CHBr), 37.8 (CH₂CH=CH₂), 25.4 (CH₃CH₂), 10.0 (CH₃); MS (ESI-TOF) m/z 345 [M + Na⁺], 347[M + Na⁺]; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₂₀O₂³⁵Cl⁷⁹BrNa 345.0227; found 345.0235; [α]_D²⁰ +29.5 (c = 1.0 in CHCl₃).

((Z)-5-((2R,2′S,4S,4′S,5R,5′R)-4′-Bromo-4-chloro-5′-ethyloctahydro-[2,2′-bifuran]-5-yl)pent-3-en-1-yn-1-yl)trimethylsilane (48)

A mixture of ozone and oxygen was gently bubbled through a stirred solution of 47-Oxford (5 mg, 15 μmol) in DCM (3 mL) at −78 °C until the solution became pale blue (approximately 2 min). The excess ozone was purged from the solution by bubbling oxygen through for a further 5 min. Triphenylphosphine (20 mg, 75 μmol) was added, and the reaction mixture was allowed to warm to rt over 15 h. The reaction mixture was dry-loaded onto silica and rapidly purified by flash column chromatography (5:1 petrol bp 30–40 °C/diethyl ether) to give the corresponding aldehyde as a colorless oil (4.4 mg, 13.6 μmol, 91%) that was used in the subsequent transformation without characterization.

To a solution of 3-(tert-butyldimethylsilyl)-1-trimethylsilanyl-propyne (135 mg, 0.63 mmol) in dry THF (1 mL) at −78 °C was added dropwise tert-butyllithium (0.37 mL, 1.7 M in pentane, 0.63 mmol), and this solution was stirred at −78 °C for 1 h. A solution of titanium(IV) isopropoxide (0.19 mL, 180 mg, 0.63 mmol) in dry THF (0.5 mL) was added dropwise to the reaction mixture; the resulting solution was stirred for 10 min, and then 1.94 mL was removed and discarded. To the remaining 0.12 mL (36 μmol) was added dropwise a solution of the aldehyde prepared above in dry THF (0.5 mL + 0.5 mL rinse). The reaction mixture was stirred at −78 °C for 30 min, and then the cooling bath was removed and the reaction mixture stirred at rt for 30 min. The reaction mixture was then poured into a separating funnel containing 0.1 M aqueous HCl (2 mL), and the aqueous layer was extracted with diethyl ether (3 × 5 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash column chromatography (50:1 petrol bp 30–40 °C/diethyl ether) gave the title compound as a colorless oil (2 mg, 4.8 μmol, 32% from 47-Oxford, >30:1 (Z):(E) from crude ¹H NMR analysis and characterized as such a mixture): ν_max/cm^–1 (thin film) 2963; ¹H NMR (500 MHz, CDCl₃) δ 6.02 (dt, J = 10.9, 7.5 Hz, 1HCH₂CH=CH), 5.63 (dt, J = 10.9, 1.3 Hz, 1H, CH₂CH=CH), 4.25 (td, J = 7.3, 5.6 Hz, 1H, CHClCH₂CHO), 4.13–4.08 (m, 2H, CHCH₂CH=CH, CHCl), 3.97 (ddd, J = 8.3, 6.7, 5.5 Hz, 1H, CHBrCH₂CHO), 3.91 (td, J = 7.5, 4.0 Hz, 1H, CHEt), 3.86 (dt, J = 8.7, 7.3 Hz, 1H, CHBr), 2.66 (dt, J = 13.2, 6.7 Hz, 1H, CHBrCHH), 2.69–2.63 (m, 1H, CHHCH=CH), 2.61–2.55 (m, 1H, CHHCH=CH), 2.29–2.22 (m, 2H, CHClCH₂), 2.18 (dt, J = 13.2, 8.3 Hz, 1H, CHBrCHH), 1.75 (dqd, J = 13.9, 7.4, 4.0 Hz, 1H, CHHCH₃), 1.49 (dqn, J = 14.0, 7.4 Hz, 1H, CHHCH₃), 1.00 (t, J = 7.4 Hz, 3H, CH₂CH₃), 0.20 (s, 9H, Si(CH₃)₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 139.3 (CH₂CH=CH), 112.4 (CH₂CH=CH), 101.6 (C≡C), 100.0 (C≡C), 87.3 (CHEt), 86.5 (CHCH₂CH=CH), 80.3 (CHClCH₂CH), 79.1 (CHBrCH₂CH), 59.4 (CHCl), 47.5 (CHBr), 39.5 (CHBrCH₂), 38.3 (CHClCH₂), 34.6 (CH₂CH=CH), 25.6 (CH₂CH₃), 10.2 (CH₂CH₃), 0.11 (Si(CH₃)₃); [α]_D²⁵ +37.5 (c = 0.16 in CHCl₃).

(2S,2′R,4S,4′S,5R,5′R)-4-Bromo-4′-chloro-5-ethyl-5′-((Z)-pent-2-en-4-yn-1-yl)octahydro-2,2′-bifuran, (Z)-notoryne ((Z)-3a)

To a stirred solution of 48 (2 mg, 4.8 μmol) in THF (1 mL) at −20 °C was added TBAF (20 μL of a 2.0 M solution in THF, 40 μmol), and stirring was continued for 5 min. The reaction mixture was quenched by the addition of aqueous ammonium chloride (3 mL), and the aqueous phase was extracted with ether (3 × 5 mL). The combined organic extracts were dried (Na₂SO₄). Purification by flash chromatography (30:1 petrol bp 30–40 °C/diethyl ether) gave the title compound as a colorless oil (1.7 mg, 4.8 μmol, quant.): ν_max/cm^–1 (thin film) 3294, 1728, 1460, 1289, 1071, 966; ¹H NMR (500 MHz, CDCl₃) δ 6.08 (dtd, J = 10.9, 7.5, 0.9 Hz, 1H, CH₂CH=CH), 5.60 (ddt, J = 10.9, 2.7, 1.4 Hz, 1H, CH₂CH=CH), 4.25 (td, J = 7.3, 5.6 Hz, 1H, CHClCH₂CHO), 4.11–4.07 (m, 2H, CHCH₂CH=CH, CHCl), 3.98 (ddd, J = 8.3, 6.8, 5.6 Hz, 1H, CHBrCH₂CHO), 3.91 (td, J = 7.5, 3.9 Hz, 1H, CHEt), 3.86 (dt, J = 8.8, 7.3 Hz, 1H, CHBr), 3.12 (dd, J = 2.2, 0.9 Hz, 1H, CCH), 2.66 (dt, J = 13.1, 7.0 Hz, 1H, CHBrCHH), 2.69–2.64 (m, 1H, CHHCH=CH), 2.60 (dddd, J = 14.6, 7.4, 6.0, 1.4 Hz, 1H, CHHCH=CH), 2.29–2.24 (m, 2H, CHClCH₂), 2.17 (dt, J = 13.2, 8.5 Hz, 1H, CHBrCHH), 1.75 (dqd, J = 14.0, 7.5, 3.9 Hz, 1H, CHHCH₃), 1.49 (dqn, J = 14.0, 7.4 Hz, 1H, CHHCH₃), 1.00 (t, J = 7.4 Hz, 3H, CH₂CH₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 139.9 (CH₂CH=CH), 111.1 (CH₂CH=CH), 87.2 (CHEt), 86.1 (CHCH₂CH=CH), 82.3 (HC≡C), 80.1 (CHClCH₂CH), 79.9 (HC≡C), 78.9 (CHBrCH₂CH), 59.3 (CHCl), 47.3 (CHBr), 39.3 (CHBrCH₂), 38.1 (CHClCH₂), 34.4 (CH₂CH=CH), 25.4 (CH₂CH₃), 10.2 (CH₂CH₃); HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₅H₂₀⁷⁹Br³⁵ClNaO₂ 369.0227; found 369.0231, calcd for C₁₅H₂₀^79/81Br^37/35ClNaO₂ 371.0206; found 371.0203; [α]_D²⁵ +19.2 (c = 0.125 in CHCl₃) {lit.^21a [α]_D = +40.3 (c 1.03 CHCl₃)}.

Notoryne: Seoul Route

General Procedures

Proton (¹H) and carbon (¹³C) NMR spectra were obtained on a JEOL JNM-LA300 (300/75 MHz), Bruker AV 400 (400/100 MHz), Bruker AMX 500 (500/125 MHz), Bruker Avance 600 (600/150 MHz), or Bruker Avance 900 (900/225 MHz) spectrometer. Chemical shifts are reported in parts per million units with Me₄Si or CHCl₃ as the internal standard. All reactions were routinely carried out under an inert atmosphere of dry nitrogen or argon. Reactions were checked by thin layer chromatography (Kieselgel 60 F254, Merck). Spots were detected by viewing under a UV light and by colorizing with charring after immersion in a p-anisaldehyde solution or phosphomolybdic acid solution. In an aqueous workup, all organic solutions were dried over anhydrous sodium sulfate and filtered prior to rotary evaporation at water pump pressure. The crude compounds were purified by column chromatography on a silica gel (Kieselgel 60, 70-230 mesh, Merck). Unless otherwise noted, materials were obtained from commercial suppliers and were used without purification. All solvents were purified and dried by standard techniques just before use. THF and Et₂O were freshly distilled from sodium and benzophenone. Methylene chloride, toluene, and benzene were purified by refluxing with CaH₂. Hexanes and ethyl acetate were purified by simple distillation.

(2R,2′S,4S,4′S,5R,5′R)-5-(3-(Benzyloxy)propyl)-4′-bromo-4-chloro-5′-ethyloctahydro-2,2′-bifuran (46)

To a stirred mixture of bromo alcohol 39 (21.9 mg, 0.055 mmol), activated silica gel, and PhSeCl (21.13 mL, 0.005 M) was added anhydrous hexane (4 mL). After being stirred under an argon atmosphere at room temperature for 72 h, the mixture was filtered and concentrated in vacuo. To the resulting mixture was added CH₃CN/H₂O (9:1) solution (3 mL) to convert inseparable chloro ether 49 to hydroxy ether 44. The resulting yellow solution was allowed to stand at room temperature for 24 h. The reaction mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane/ethyl acetate, 15/1) to afford tetrahydrofuran 46 (18.5 mg, 80%) as a colorless oil: R_f 0.67 (n-hexane/ethyl acetate, 4/1); [α]_D²⁵ = +37.5 (c 0.805, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.32 (m, 5H), 4.50 (s, 2 H), 4.21 (ddd, J = 6.5, 6.5, 7.1 Hz, 1H), 4.00–3.78 (m, 5H), 3.54–3.46 (m, 2H), 2.64 (ddd, J = 7.0, 7.0, 13.3 Hz, 1H), 2.28–2.24 (m, 2H), 2.20–2.13 (m, 1H), 1.83–1.67 (m, 4H), 1.65–1.45 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 138.5, 128.4, 127.6, 127.5, 87.12, 87.0, 79.9, 79.1, 72.9, 69.9, 59.9, 47.4, 39.3, 38.4, 30.5, 26.0 25.4 10.0 ; IR (neat) 2925, 2872, 1453, 1295, 1072, 923 cm^–1; HRMS (FAB-TOF) m/z [M + H]⁺ calcd for C₂₀H₂₉O₃⁷⁹Br³⁵Cl 431.0983; found 431.0982.

3-((2R,2′S,4S,4′S,5R,5′R)-4′-Bromo-4-chloro-5′-ethyloctahydro-[2,2′-bifuran]-5-yl)propan-1-ol

To a stirred solution of bistetrahydrofuran 46 (21.9 mg, 0.051 mmol) in THF (21.13 mL, 0.005 M) was added Pd(OH)₂ (4.38 mg, 20 wt % of Pd). The mixture was stirred under hydrogen atmosphere at room temperature for 1 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (n-hexane/ethyl acetate, 2/1) to afford the title alcohol (8.7 mg, 95%) as a colorless oil: R_f 0.33 (n-hexane/ethyl acetate, 2/1); [α]_D²⁵= +48.4 (c 1.01, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 4.26 (ddd, J = 7.0, 7.0, 5.6 Hz, 1 H), 4.01–3.95 (m, 3H), 3.91 (ddd, J = 7.5, 7.5, 4.1 Hz, 1H), 3.90–3.84 (m, 1H), 3.73–3.63 (m, 2H), 2.66 (ddd, J = 6.6, 6.6, 13.6 Hz, 1H), 2.31 (ddd, J = 7.2, 7.2, 13.6 Hz, 1H), 2.23 (dddd, J = 13.6, 6.7, 4.5 Hz, 1H), 2.12 (ddd, J = 8.4, 8.4, 13.6 Hz, 1H), 1.83–1.66 (m, 4H), 1.60–1.46 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 87.3, 87.2, 80,0. 78.7, 62.5, 60.0, 47.2, 39.3, 37.7, 30.3, 29.4, 25.4, 9.97 ; IR (neat) 3408, 2936, 1648, 1295, 1060, 971, 923 cm^–1; HRMS (FAB-TOF) m/z [M + H]⁺ calcd for C₁₃H₂₃⁷⁹Br³⁵ClO₃ 341.0514; found 341.0514.

(2R,2′S,4S,4′S,5R,5′R)-5-Allyl-4′-bromo-4-chloro-5′-ethyloctahydro-2,2′-bifuran (47-Seoul)

To a solution of alcohol 3-((2R,2′S,4S,4′S,5R,5′R)-4′-bromo-4-chloro-5′-ethyloctahydro-[2,2′-bifuran]-5-yl)propan-1-ol (20.2 mg, 0.059 mmol) in dry THF (5.9 mL, 0.05 M) were added o-nitrophenylselenocyanide (66.98 mg, 0.045 mmol) and tri-n-octylphosphine (0.263 mL, tech. 90%, 0.045 mmol) at room temperature under N₂. The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0 °C, and 30% H₂O₂ (0.1 mL) was added. The resulting mixture was stirred at the same temperature for 30 min, allowed to warm to room temperature, and stirred for an additional 24 h. The reaction mixture was neutralized with saturated aqueous NaHCO₃ (1 mL) and diluted with diethyl ether (4 mL). The layers were separated, and the aqueous layer was extracted with Et₂O (2 × 4 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane/ethyl acetate, 25/1) to afford terminal olefin 47-Seoul (16.2 mg, 85%) as a colorless oil: R_f 0.61 (n-hexane/ethyl acetate, 1/1); [α]_D²⁵= +66.8 (c 0.395, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 5.83 (dddd, J = 7.0, 7.0, 10.3, 17.2 Hz, 1H), 5.15–5.10 (m, 2H), 4.26–4.22 (m, 1H), 4.05–3.98 (m, 2H), 3.96 (ddd, J = 6.5, 6.5, 7.4 Hz, 1H), 3.91 (ddd, J = 4.0, 7.5, 7.5 Hz, 1H), 3.89–3.84 (m, 1H), 2.64 (ddd, J = 7.0, 7.0, 13.7 Hz, 1H), 2.39–2.30 (m, 2H), 2.25–2.23 (m, 2H), 2.17 (ddd, J = 8.6, 8.6, 13.4 Hz, 1H), 1.75 (ddddd, J = 4.0, 7.5, 7.5, 7.5, 14.7 Hz, 1H), 1.49 (ddddd, J = 7.4, 7.4, 7.4, 7.4, 14.6 Hz, 1H), 1.00 (t, J = 7.5 Hz, 3H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 133.3, 118.0, 87.1, 86.4, 79.9, 78.9, 59.0, 47.3, 39.3, 38.1, 37.8, 25.4, 10.0; IR (neat) 2966, 2923, 1642, 1294, 1069, 920 cm^–1; HRMS (FAB-TOF) m/z [M + H]⁺ calcd for C₁₃H₂₁O₂ClBrNa 323.0408; found 323.0406.

((Z)-5-((2R,2′S,4S,4′S,5R,5′R)-4′-Bromo-4-chloro-5′-ethyloctahydro-[2,2′-bifuran]-5-yl)pent-3-en-1-yn-1-yl)triisopropylsilane (52)

To a solution of terminal olefin 47-Seoul (13.5 mg, 0.038 mmol) in dry benzene (3.64 mL) were added enyne 50 (52 mg, 0.083 mmol) in benzene (1.0 mL) and Grubbs’ catalyst 51 (15.0 mg, 0.053 mmol) in benzene (0.2 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 1.5 h. Addition of enyne (17.3 mg, 0.062 mmol) in benzene (0.1 mL) and Grubbs’ catalyst (4.2 mg, 0.0067 mmol) in benzene (0.1 mL) was repeated three times every 1.5 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, toluene) to afford enyne as a 3:1 mixture (by ¹H NMR analysis) of TIPS-(Z)- and TIPS-(E)-enynes (17.2 mg, 82%) as a colorless oil: R_f 0.40 (n-hexane/ethyl acetate, 10/1) (for TIPS-(Z)-enyne 52) [α]_D²⁵= +33.4 (c 0.25, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 6.01 (ddd, J = 7.5, 7.5, 10.9 Hz, 1 H), 5.67 (d, J = 10.9 Hz, 1 H), 4.26–4.22 (m, 1H), 4.13–4.08 (m, 2 H), 3.97–3.94 (m, 1H), 3.91 (ddd, J = 4.0, 7.5, 7.5, 1H), 3.86–3.82 (m, 1H), 2.72–2.57 (m, 3H), 2.24–2.22 (m, 2 H), 2.18 (ddd, 8.5, 8.5, 13.2 Hz, 1H), 1.75 (ddddd, J = 4.0, 7.4, 7.4, 7.4, 14.8 Hz, 1 H), 1.50 (ddddd, J = 7.4, 7.4, 7.4, 7.4, 14.8 Hz, 1H), 1.09–1.01 (m, 3H), 1.05 (s, 18H) 1.00 (t, J = 7.4 Hz, 1H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 138.6, 112.5, 103.1, 96.2, 87.1, 86.5, 80.2, 79.0, 59.3, 47.3, 39.3, 38.4, 34.7, 25.4, 18.7, 11.3, 10.0; IR (neat) 2942, 2146, 1260, 1071, 920 cm^–1; HRMS (FAB-TOF) m/z [M + H]⁺ calcd for C₂₄H₄₁⁷⁹Br³⁵ClO₂Si 503.1742; found 503.1768.

(2S,2′R,4S,4′S,5R,5′R)-4-Bromo-4′-chloro-5-ethyl-5′-((Z)-pent-2-en-4-yn-1-yl)octahydro-2,2′-bifuran, (Z)-Notoryne ((Z)-3a)

To a cooled (0 °C) solution of (Z)-TIPS-enyne 52 (5.2 mg, 0.0103 mmol) in THF (0.2 mL) was added dropwise TBAF (0.02 mL, 1.0 M solution in THF, 0.0206 mmol). After the mixture was stirred at the same temperature for 1 h, the reaction was quenched with saturated aqueous NH₄Cl. The resulting mixture was diluted with diethyl ether. The layers were separated, and the aqueous layer was extracted with diethyl ether (2 × 7 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane/ethyl acetate, 4/1) to afford (Z)-notoryne (Z)-3a (3.4 mg, 94%) as a colorless oil: R_f 0.68 (n-hexane/ethyl acetate, 1/1); [α]_D²⁵= +40.6 (c 0.16 CHCl₃) {lit.^21a [α]_D = +40.3 (c 1.03 CHCl₃)}; ¹H NMR (400 MHz, CDCl₃) δ 6.08 (dddd, J = 0.8, 7.5, 7.5, 10.9 Hz, 1H), 5.60 (dddd, J = 1.4, 1.4, 2.6, 10.9 Hz, 1H), 4.25 (ddd, J = 5.6, 7.1, 7.1 Hz, 1H), 4.12–4.06 (m, 2H), 3.97 (ddd, J = 5.6, 6.8, 8.2 Hz, 1H), 3.91 (ddd, J = 4.0, 7.6, 7.6 Hz, 1H), 3.86 (ddd, J = 7.3, 7.3, 8.7 Hz, 1H), 3.12 (d, J = 1.8 Hz, 1H), 2.70–2.55 (m, 3H), 2.32–2.23 (m, 2H), 2.17 (ddd, J = 8.4, 8.4, 13.2 Hz, 1H), 1.75 (ddddd, J = 3.7, 7.5, 7.5, 7.5, 14.3 Hz, 1H), 1.56–1.44 (m, 1H), 1.00 (t, J = 7.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 139.9, 111.1, 87.2, 86.2, 82.3, 80.1, 80.0, 79.0, 59.3, 47.3, 39.4, 38.2, 34.5, 25.5, 10.0; IR (neat) 3293, 2964, 1733, 1712, 1290, 1073, 967, 923 cm^–1; HRMS (EI) m/z [M – C₂H₅]⁺ calcd for C₁₀H₁₅⁷⁹Br³⁵ClO₂ 280.9938; found 280.9935.

(2S,2′R,4S,4′S,5R,5′R)-4-Bromo-4′-chloro-5-ethyl-5′-((E)-pent-2-en-4-yn-1-yl)octahydro-2,2′-bifuran, (E)-Notoryne ((E)-3a)

To a solution of terminal olefin 47-Seoul (7.7 mg, 0.024 mmol) in dry CH₂Cl₂ (0.47 mL, 0.05 M) were added crotonaldehyde (0.015 mL, 0.19 mmol) and Grubbs’ catalyst 29 (2.04 mg, 0.0024 mmol) at room temperature. After the mixture was stirred at 40 °C for 1.5 h, the reaction was quenched with DMSO (0.02 mL). The resulting mixture was stirred at room temperature for 12 h and concentrated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane/ethyl acetate, 6/1) to afford (E)-4-((2R,2′S,4S,4′S,5R,5′R)-4′-bromo-4-chloro-5′-ethyloctahydro-[2,2′-bifuran]-5-yl)but-2-enal (7.3 mg, 87%) as a colorless oil: R_f 0.37 (n-hexane/ethyl acetate, 4/1). To a cooled (−78 °C) solution of LDA (0.42 mL, 0.5 M solution in THF, 0.21 mmol) was added dropwise TMSCH₂N₂ (0.105 mL, 2.0 M solution in Et₂O, 0.021 mmol) under argon atmosphere. After the mixture was stirred at −78 °C for 30 min, (E)-4-((2R,2′S,4S,4′S,5R,5′R)-4′-bromo-4-chloro-5′-ethyloctahydro-[2,2′-bifuran]-5-yl)but-2-enal (7.3 mg, 0.021 mmol) in THF (0.42 mL, 0.05 M) was added dropwise at −78 °C. After the reaction mixture was stirred at −78 °C for 1 h, and then at 0 °C for 1 h, the reaction was quenched with saturated aqueous NH₄Cl. The layers were separated, and the aqueous layer was extracted with diethyl ether (2 × 2 mL). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane/ethyl acetate, 4/1) to afford (E)-notoryne (E)-3a (6.4 mg, 88%) as a colorless oil: R_f 0.69 (n-hexane/ethyl acetate, 4/1); [α]_D²⁵ = +47.6 (c 0.225, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 6.24 (ddd, J = 7.2, 7.2, 16.0 Hz, 1H), 5.57 (dd, J = 1.8, 16.0 Hz, 1H), 4.22 (ddd, J = 5.6, 7.0. 7.0 Hz, 1 H), 4.03–3.94 (m, 3H), 3.93–3.84 (m, 2H), 2.83 (d, J = 2 Hz, 1H), 2.66 (ddd, J = 13.2, 7.0, 7.0 Hz, 1H), 2.46 (dddd, J = 12.9, 6.5, 5.4, 1.6 Hz, 1H), 2.40–2.33 (m, 1H), 2.32–2.20 (m, 2H), 2.14 (dt, J = 13.3, 8.4 Hz, 1H), 1.75 (ddddd, J = 14.1, 7.5, 7.5, 7.5, 3.8 Hz, 1H), 1.55–1.44 (m, 1H), 1.00 (t, J = 7.4 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 140.7, 111.8, 87.3, 85.7, 81.9, 80.0, 78.8, one peak buried under CDCl₃ peak by HSQC, 58.7, 47.3, 39.4, 37.9, 36.6, 25.5, 10.0; IR (neat) 3294, 2963, 1731, 1712, 1295, 1072, 959, 925 cm^–1; HRMS (EI) m/z [M – C₂H₅]⁺ calcd for C₁₀H₁₅⁷⁹Br³⁵ClO₂ 280.9938; found 280.9944.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02975.

• Tables of comparative NMR data (PDF)

• Computational methods, benchmarking, and calculated NMR parameters for all structures (PDF)

• Copies of NMR spectra (PDF)

• Notoryne xyz files (ZIP)

• Chloroenyne xyz files (ZIP)

The authors declare no competing financial interest.

Dedication

This paper is dedicated to the memory of Erin D. Shepherd—a brilliant chemist and an amazing individual.