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

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Cite This: J. Org. Chem. XXXX, XXX, XXX −XXX

Structure Determination of a Chloroenyne from Laurencia majuscula

Using Computational Methods and Total Synthesis

Erin D. Shepherd,^†Bryony S. Dyson,^†William E. Hak,^†Quynh Nhu N. Nguyen,^†Miseon Lee,^‡

Mi Jung Kim,^‡Te-ik Sohn,^‡Deukjoon Kim,*^,‡Jonathan W. Burton,*^,†and Robert S. Paton*^,†,§

^†Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansﬁeld Road, Oxford OX1 3TA, United

Kingdom

^‡The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea

^§Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States

S

* Supporting Information

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.

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.⁷Although elegant synthetic

approaches have been developed to access multiple diaster-

eomers of a target molecule,⁸the 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, CP3¹⁰and DP4,¹¹

use prior knowledge of the underlying empirical error

distribution of computational predictions to assign statistical

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.¹Unequivocal establish-

ment 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.²Nuclear 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,³to conﬁrm or reassign

proposed natural product structures,⁴to characterize the

identity of a side product,⁵and in conformational assignment

of cyclic peptides.⁶However, 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

Received: January 18, 2019

A

DOI: 10.1021/acs.joc.8b02975

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conﬁdence values to a particular structural assignment. This

has led to their widespread adoption in computational natural

product assignments.¹²These metrics emphasize the impor-

tance 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,¹³has 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,³making 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

Chart 1. Proposed Structures of Chloroenyne from L.

majuscula (Relative Conﬁgurations) along with the

Structures of (Z)- and (E)-Notoryne (Absolute

Conﬁgurations)

1

show that comparison of the experimental H 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.

Further bromoetheriﬁcation of (3Z)-deacetyllaurencin 6a

gives the (3Z)-dibromide 8a, prelaurefucin, via 7a. Trans-

annular 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,^16adisplacement of

bromide by water (or a water equivalent)²⁷would 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, laurendecu-

menyne B,^15dand laurefurenynes A and B,^16awhich begins

from a diﬀerent diastereomer of the laurediols (4b)²⁵and

proceeds via the natural product bromofucin 8b.²⁸Here,

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)²⁷gives 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.²⁵The (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).²⁹Based 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.³⁰We then used quantum chemistry

to predict the most likely stereostructure for 2, based on

Recently, we assigned the full structures of two 2,2′-bifuranyl

natural products using the powerful combination of bio-

synthetic postulates, DFT calculations of NMR chemical shifts,

and total synthesis. We used this combined approach to fully

elucidate the structure of elatenyne¹⁵and to reassign the

stereostructure of laurefurenynes A and B.¹⁶Previously, we

demonstrated that the gross structure of a chloroenyne isolated

from Laurencia majuscula, originally assigned as a pyrano[3,2-

b]pyran (1)¹⁷on the basis of extensive NMR experiments and

comparison with the NMR data of the dactomelynes¹⁸and of

the originally assigned pyrano[3,2-b]pyran structure of

elatenyne,¹⁹was actually a 2,2′-bifuranyl 2 (Chart 1).^15a,b

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 postu-

lates coupled with DFT calculations of NMR chemical shifts

and total synthesis.

Clues from Biosynthesis. Algae of the genus Laurencia

produce a vast array of structurally diverse C₁₅halogenated

natural products. Elatenyne,^19,20notoryne (3),²¹laurendecu-

menyne B,^20,22laurefurenynes A and B,²³and the above

chloroenyne from L. majuscula 2¹⁷are 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.^21aA plausible

biosynthesis of notoryne 3a was proposed by Suzuki and by

Fukuzawa and Murai.^21a,24For (3Z)-notoryne (Z)-3a,

(3Z,12E,R,R)-laurediol 4a²⁵is converted into (3Z)-deacetyl-

laurencin 6a via bromonium ion formation and cyclization

(Figure 1a).²⁶

1

computed ¹³C and H chemical shifts for each of the 32

possible diastereomers.³¹

B

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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.

= 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, consider-

ation 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

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.³²Across 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,31cAs 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 theory³⁴with CPCM (Conductor-

like Polarizable Continuum Model) chloroform.³⁵Conformer

relative energies were checked against COSMO−DLPNO−

CCSD(T)/cc-pVTZ single-point energies³⁶for one diaster-

eomer and showed a good level of agreement (R²= 0.90, rmsd

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 Tantillo¹³to derive new,

optimal scaling parameters for mPW1PW91/6-311G(d,p)//

1

wB97XD/6-31G(d) GIAO shielding tensors for ¹³C and H

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

1

We analyzed the Boltzmann-weighted ¹³C and H 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

C

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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.

which are inherently more sensitive to their relative stereo-

chemistry. 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).

Based on the work of Smith and Goodman,¹¹standard

deviations of 2.3 and 0.19 ppm for errors in ¹³C and H

1

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.

chemical shifts are representative of the underlying computa-

tional 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 intu-

ition, 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.^15cThe

ethyl ¹³CH₂also 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 automati-

cally 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 R²measures 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.

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 improve-

ment 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.^1,2bAdditionally, 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 biomimeti-

cally 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.^15dThe retrosynthetic synthetic route to diaster-

eomers 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

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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,⁴¹was converted into alcohol 18 by ozonolysis

with in situ reduction (PPh₃then NaBH₄). Alcohol 18 was

then converted into the corresponding tetrazole sulfone 14 by

Mitsunobu reaction followed by oxidation.⁴⁰Aldehyde 15 was

readily prepared from alcohol (+)-16, which on PMB

protection gave ether 19.^15dCopper-catalyzed ring opening

of epoxide 19 with methylmagnesium bromide⁴¹followed by

silyl protection gave alkene 20. Ozonolysis of alkene 20 and

reductive phosphine workup gave the required aldehyde 15.

Julia−Kocienski^40,42coupling of sulfone tetrazole 14 with

aldehyde 15 proceeded in good yield with >20:1 E/Z-

selectivity to give alkene 13.⁴³Sharpless asymmetric

dihydroxylation⁴⁴of 13 using super-AD-mix β⁴⁵gave 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 Hunig’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.

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.⁴⁶As with the synthesis of

elatenyne,^15dforcing conditions (Bu₄NI, toluene, reﬂux) were

synthesis of elatenyne.^15dDiol 12 was to be derived from

alkene 13, which was to be constructed by Julia−Kocienski

oleﬁnation of aldehyde 15 with sulfone 14.⁴⁰The two coupling

partners 14 and 15 were to be derived from protection of the

a

Scheme 1. Synthesis of Chloride 28

a

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%.

E

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a

required to convert the mesylate 24 into the corresponding

iodide 25. Iodide 25 underwent displacement with vinyl-

magnesium 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 LiDBB⁴⁸into 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 28.⁴⁹Appel 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.⁴⁹Conducting 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

Scheme 3. Synthesis of Diastereomers 2b and 2d

a

Scheme 2. Synthesis of Diastereomers 2a and 2c

a

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.

presence of the more electron-rich para-methoxy benzyl group

was achieved using LiDBB⁴⁸in the presence of a proton

donor,⁵³which gave the requisite alcohol 34 in 66% yield

along with 18% of the benzyl ether 33.⁵⁴Chlorination of 34 as

before⁴⁹provided chloride 35 in 96% yield, which was readily

deprotected under Lewis acidic conditions to give alcohol

36.⁵¹Mitsunobu inversion of 36⁵²to give 37, followed by

enyne introduction, as before,^15d,50gave the third biomimetic

diastereomer 2b. A further Mitsunobu reaction gave the fourth

and ﬁnal biomimetic diastereomer 2d.⁵⁵

a

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).

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.¹⁷Our

synthesis of the chloroenyne from L. majuscula 2b 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,¹⁷demonstrating that the absolute conﬁguration of the

chloroenyne from L. majuscula is as represented by 2b. The

chloroenyne from L. majuscula 2b thus sits on the same

proposed biosynthetic pathway as elatenyne,^15dlaurendecu-

menyne B,^15dand laurefurenynes A and B,¹⁶proceeding 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

a Wittig reaction with the ylide derived from (3-trimethylsilyl-

2-propynyl)triphenylphosphonium bromide^15a,b,dfor the ster-

eoselective 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 homo-

logation) to give enyne 31. Removal of the para-methoxy

benzyl group⁵¹from 31 gave 2c, the ﬁrst of the enyne targets.

Mitsunobu inversion⁵²of the secondary alcohol in 2c followed

by ester methanolysis gave 2a, the second of the biomimeti-

cally plausible diastereomers.

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).^15dSelective removal of the para-bromobenzyl group in the

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1

Figure 5. Comparison of computed ¹³C and H chemical shifts for 32 diastereomers of 2 against experimental spectra for 2a, 2c, and 2d.

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

1

methods. We had acquired H 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

structures and absolute conﬁgurations were securely estab-

lished through single-crystal X-ray analysis.²¹As noted above, a

biosynthesis of notoryne 3 was ﬁrst proposed by Suzuki and by

Fukuzawa and Murai (Figure 1a).^21,24Previously, 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 halo-

genated natural products from Laurencia spp., including the

synthesis of the 2,2′-bifuranyl natural products (Z)- and (E)-

elatenyne^15dand laurendecumenyne B.^15dIn their synthesis of

laurefucin,^50athe 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

1

lowest four (Figure 5). H 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.

Notoryne. Notoryne (Z)-3a is the ﬁrst halogenated 2,2′-

bifuranly natural product isolated from Laurencia spp.⁵⁶The

structure of (Z)-notoryne (Z)-3a was originally assigned by

careful chemical degradation and comparison with chemical

degradation products from laurefucin and laurencin, whose

G

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a

Scheme 5. Oxford and Seoul Syntheses of Notoryne

a

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 the ¹³C NMR chemical shifts between the synthetic compounds 47 prepared by the Oxford and Seoul groups and natural notoryne (Z)-3a are shown

adjacent to the relevant carbon atoms in structures 47.

selenide 41. Activation of the selenide group in 41 by reaction

with further N-PSP gives prelaurefucin surrogate 42. Trans-

annular 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. Bromi-

nation of alcohol 10 using the Hooz procedure⁵⁷gave 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 44.⁵⁸It is of note that in the

absence of silica gel, the [5.2.1]-bicyclic chloride 49 was

formed.^50aIn both the Oxford and Seoul syntheses, the

chlorine-bearing carbon atoms could be identiﬁed using ¹³C

NMR chlorine-induced isotopic shift.⁵⁹The Seoul group

converted the benzyl-protected alcohol 46 into the corre-

sponding 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 reaction⁶⁰to 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,61which

gave the desired enyne 52 as a 3:1 mixture of Z/E-enynes in

82% combined yield.

Fluoride treatment of 52 gave notoryne (Z)-3a. The Oxford

1

and Seoul H 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^21bfrom alkene 47. Cross-metathesis of alkene in 47 using

crotonaldehyde and the Grubbs−Hoveyda catalyst 29 gave the

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corresponding α,β-unsaturated aldehyde as a single E-

isomer,^15d,50which 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

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

1

by H−¹H COSY and H−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. O₂was sparged through the

solution for 5 min followed by O₃/O₂until a faint blue hue appeared.

Then the reaction was sparged with O₂for 5 min and PPh₃was added

(11.6 g, 44 mmol) and the reaction stirred at −78 °C for 30 min. To

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*.

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

1

ranks in the top two structures. Again, the cumulative H/¹³C

DP4 metric gives (Z)-3a as the single most likely stereo-

structure. The total synthesis and structure conﬁrmation of

notoryne (Z)-3a further demonstrates the utility of computa-

tional methods to not only predict but also conﬁrm the

structures of stereochemically rich, functionalized, and ﬂexible

organic molecules and natural products.

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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_f0.40 (1:1 petrol/diethyl

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]²_D⁵+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-Methoxybenzyl-

oxy)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 chromatog-

raphy (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_f0.62 (20:1

petrol/diethyl ether); ν_max/cm⁻¹(thin ﬁlm) 3076m, 2957s, 2931s,

1

ether); ν_max/cm⁻¹(thin ﬁlm) 3434s br, 2875m; H 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]²_D⁵+32.0 (c = 1.0 in

CHCl₃).

1

2857s, 1641m; H NMR (400 MHz CDCl₃) δ 7.28 (d, J = 8.6 Hz,

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,

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]²_D⁵−11.9 (c = 1.0 in CHCl₃).

1

88%): R_f0.5 (5:1 petrol/acetone); ν_max/cm⁻¹(thin ﬁlm) 2870; H

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]²_D⁵+26.0 (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 O₂for 2 min.

O₃/O₂was then bubbled through the stirred solution until a faint blue

color appeared, and excess ozone was then sparged out with O₂for 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 chromatog-

raphy (16:1 → 8:1 petrol/diethyl ether) yielded the title compound

as a colorless oil (3.60 g, 9.8 mmol, 98%): R_f0.63 (10:1 petrol/ethyl

1

acetate); ν_max/cm⁻¹(thin ﬁlm) 2931s, 2858s, 1725s; H 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]²_D⁵−15.6 (c = 1.0 in

CHCl₃).

(((3R,4S,9R,E)-9-(Benzyloxy)-4-((4-methoxybenzyl)oxy)-9-((S)-ox-

iran-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).

5-(((R)-3-(Benzyloxy)-3-((S)-oxiran-2-yl)propyl)sulfonyl)-1-phe-

nyl-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_f0.52 (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),

J

DOI: 10.1021/acs.joc.8b02975

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

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

Na]⁺calcd for C₃₂H₅₀O₇SiNa 597.3218; found 597.3221; [α]²_D⁰−4.0

(c = 1.0 in CHCl₃).

(1R,3S,4R)-1-((2R,4R,5R)-4-(Benzyloxy)-5-(hydroxymethyl)tetra-

hydrofuran-2-yl)-4-((tert-butyldimethylsilyl)oxy)-3-((4-methoxy-

benzyl)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]²_D⁰−13.0 (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

1

m, 1613w; H 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]²_D⁰−17.2 (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). Al-

kene 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

1

total, 0.66 mmol 91% 6:1 3R,4R:3S,4S diastereomers from H NMR

analysis of the crude, from which 268 mg, 0.47 mmol, 64% could be

obtained in pure form): R_f0.38 (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 +

(427 mg, 0.82 mmol, 52%): R_f0.56 (2:1 petrol/ethyl acetate); ν_max

/

cm⁻¹(thin ﬁlm) 2935m, 1356s, 1175s; H 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

1

K

DOI: 10.1021/acs.joc.8b02975

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

(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]²_D⁰+4.0 (c =

1.0 in CHCl₃).

((2R,3R,5R)-3-(Benzyloxy)-5-((1R,3S,4R)-4-((tert-butyldimethyl-

silyl)oxy)-1-hydroxy-3-((4-methoxybenzyl)oxy)hexyl)tetrahydro-

furan-2-yl)methylmethanesulfonate (22). The title compound was

isolated as a side product in the synthesis of 24: R_f0.63 (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]²_D⁰−55.6 (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_f₁0.47 (10:1 petrol/ethyl acetate); ν_max/cm⁻¹(thin ﬁlm)

2961m; H 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]²_D⁰−16.5 (c = 1.0 in CHCl₃).

(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_f0.45

1

(10:1 petrol/ethyl acetate); ν_max/cm⁻¹(thin ﬁlm) 2933m; H 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]²_D⁰−6.4 (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_f0.34 (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]²_D⁰+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),

(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

L

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The Journal of Organic Chemistry

Featured Article

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]²_D⁰+5.9 (c = 0.2 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_f0.78 (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, CHORCH-

OR), 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]²_D⁰

+34.2 (c = 1.0 in CHCl₃).

(2R,2′S,4S,4′S,5R,5′R)-5-Allyl-4-chloro-5′-ethyl-4′-((4-methoxy-

benzyl)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_f0.89 (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]²_D⁰

+55.9 (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_f0.60 (3:1 petrol/ethyl acetate); ν_max/cm⁻¹(thin ﬁlm)

(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_f₁0.25 (5:1 petrol/ethyl acetate); ν_max/cm⁻¹(thin ﬁlm)

2934m, 1691s; H 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, CHORCH-

OR), 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]²_D⁰+22.8 (c = 1.0 in

CHCl₃).

1

3420br, 3294m (CH), 2964m; H 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]²_D⁰

+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

M

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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_f0.62 (3:1 petrol/ethyl

(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_f0.89 (6:1 petrol/ethyl

1

acetate); ν_max/cm⁻¹(thin ﬁlm) 2916m, 2930m, 2876m; H 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]²_D⁰

+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_f0.34 (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]²_D⁰−38.6 (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_f0.43 (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,

1

acetate); ν_max/cm⁻¹(thin ﬁlm) 3455m, 3291m, 2969m; H 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]²_D⁰

+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]²_D⁰+38.1 (c = 1.0 in CHCl₃).

N

DOI: 10.1021/acs.joc.8b02975

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

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]²_D⁰

−12.4 (c = 1.0 in CHCl₃).

column chromatography (5:1 petrol/ethyl acetate) gave the title

compound as a colorless oil (5 mg, 18 μmol, 39%): R_f0.40 (5:1:

petrol/ethyl acetate); ν_max/cm⁻¹(thin ﬁlm) 3461br (OH), 3296m

1

(CH), 2968m, 1442m, 1066s; H 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]²_D⁰−51.9 (c = 0.45

in CHCl₃), lit. [α]²_D²−67.8 (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]²_D⁰−31.3 (c = 0.16 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-ethyl-

octahydro-[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_f0.32 (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 (EtCH-

OR), 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]²_D⁰

−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

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_f0.56 (3:1 petrol/ethyl acetate); ν_max/cm⁻¹

1

(thin ﬁlm) 3432br (OH), 2964s, 1642w,1438w, 1074s, 921m; H

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

O

DOI: 10.1021/acs.joc.8b02975

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

= 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]²_D⁰+60.4 (c = 1.0 in CHCl₃).

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₃H₂₁O₃ClNa

283.1071; found 283.1071; [α]²_D⁰+6.8 (c = 1.0 in CHCl₃).

(2R,2′S,4S,4′S,5R,5′R)-5-Allyl-4′-bromo-4-chloro-5′-ethyloctahy-

dro-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_f0.82 (5:1

petrol/ethyl acetate); ν_max/cm⁻¹(thin ﬁlm) 2964m, 1456m, 1262m,

1

1067s; H 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]²_D⁰+29.5 (c =

1.0 in CHCl₃).

((Z)-5-((2R,2′S,4S,4′S,5R,5′R)-4′-Bromo-4-chloro-5′-ethyloctahy-

dro-[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.

(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′-bifur-

an]-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_f0.45(8:1 petrol/acetone); ν_max/cm⁻¹(thin

1

ﬁlm) 2967w, 1725s, 1529s, 1348w, 1274s, 1103m; H 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]²_D⁰−4.0 (c = 1.0 in

CHCl₃).

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)

(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,

1

1055s, 1013m, 924s; H 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);

1

from crude H 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,

P

DOI: 10.1021/acs.joc.8b02975

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

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]²_D⁵+37.5 (c =

0.16 in CHCl₃).

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_f0.67 (n-hexane/ethyl acetate, 4/1); [α]²_D⁵= +37.5 (c

1

0.805, CHCl₃); H 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.

(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

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 bistetrahy-

drofuran 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_f0.33 (n-hexane/ethyl

title compound as a colorless oil (1.7 mg, 4.8 μmol, quant.): ν_max

/

1

cm⁻¹(thin ﬁlm) 3294, 1728, 1460, 1289, 1071, 966; H 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 C₁₅H₂₀⁷⁹Br³⁵ClNaO₂369.0227;

found 369.0231, calcd for C₁₅H₂₀^79/81Br^37/35ClNaO₂371.0206; found

371.0203; [α]²_D⁵+19.2 (c = 0.125 in CHCl₃) {lit.^21a[α]_D= +40.3 (c

1.03 CHCl₃)}.

acetate, 2/1); [α]²_D⁵= +48.4 (c 1.01, CHCl₃); H NMR (500 MHz,

1

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 C₁₃H₂₃⁷⁹Br³⁵ClO₃341.0514; found 341.0514.

(2R,2′S,4S,4′S,5R,5′R)-5-Allyl-4′-bromo-4-chloro-5′-ethyloctahy-

dro-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_f0.61 (n-hexane/ethyl acetate, 1/1); [α]²_D⁵= +66.8 (c

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 CHCl₃as 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.

1

0.395, CHCl₃); H 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′-ethyloctahy-

dro-[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

(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

Q

DOI: 10.1021/acs.joc.8b02975

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

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_f0.40 (n-

hexane/ethyl acetate, 10/1) (for TIPS-(Z)-enyne 52) [α]²_D⁵= +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.

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_f0.69 (n-hexane/ethyl acetate, 4/1); [α]²_D⁵= +47.6 (c

1

0.225, CHCl₃); H 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 CDCl₃peak 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.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.8b02975.

■

S

(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_f0.68 (n-hexane/ethyl acetate, 1/1); [α]²_D⁵=

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)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: deukjoon@snu.ac.kr.

*E-mail: jonathan.burton@chem.ox.ac.uk.

*E-mail: robert.paton@colostate.edu.

■

+40.6 (c 0.16 CHCl₃) {lit.^21a[α]_D= +40.3 (c 1.03 CHCl₃)}; H

1

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,

ORCID

Deukjoon Kim: 0000-0003-4079-8734

Robert S. Paton: 0000-0002-0104-4166

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

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 C₁₀H₁₅⁷⁹Br³⁵ClO₂280.9938; 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_f0.37 (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

Financial support was provided by the EPSRC (UK).

Q.N.N.N. acknowledges funding from the European Union’s

Horizon 2020 research and innovation programme under the

Marie Skłodowska-Curie Grant Agreement No. 752491. We

used the Dirac cluster at Oxford (EP/L015722/1); the

RMACC Summit supercomputer, which is supported by the

National Science foundation (ACI-1532235 and ACI-

1532236), the University of Colorado Boulder and Colorado

State University; the Extreme Science and Engineering

Discovery Environment (XSEDE) through allocation TG-

̈

CHE180056. We are grateful to Prof. Gabrielle Konig for

providing NMR spectra of the chloroenyne from L. majuscula

(2b).

DEDICATION

■

This paper is dedicated to the memory of Erin D. Shepherda

brilliant chemist and an amazing individual.

REFERENCES

■

(1) (a) Nicolaou, K. C.; Snyder, S. A. Chasing molecules that were

never there: Misassigned natural products and the role of chemical

synthesis in modern structure elucidation. Angew. Chem., Int. Ed.

2005, 44, 1012−1044. (b) Nicolaou, K. C.; Snyder, S. A. Chasing

molecules that were never there: Misassigned natural products and

R

DOI: 10.1021/acs.joc.8b02975

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

the role of chemical synthesis in modern structure elucidation (vol 44,

pg 1012, 2005). Angew. Chem., Int. Ed. 2005, 44, 2050.

Biomol. Chem. 2016, 14, 3943−3949. (b) Ermanis, K.; Parkes, K. E.

B.; Agback, T.; Goodman, J. M. Doubling the power of DP4 for

computational structure elucidation. Org. Biomol. Chem. 2017, 15,

8998−9007.

(2) (a) Liu, Y.; Saurí, J.; Mevers, E.; Peczuh, M. W.; Hiemstra, H.;

Clardy, J.; Martin, G. E.; Williamson, R. T. Unequivocal

determination of complex molecular structures using anisotropic

NMR measurements. Science 2017, 356, No. eaam5349. (b) Fujita’s

crystalline sponge method that allows the X-ray structure of

noncrystalline small molecules to be obtained has been applied to

structure determination of noncrystalline natural products: Lee, S.;

Hoshino, M.; Fujita, M.; Urban, S. Cycloelatanene A and B: absolute

configuration determination and structural revision by the crystalline

sponge method. Chem. Sci. 2017, 8, 1547−1550. (c) Very recently,

the electron cryo-microscopy (cryoEM) method of microcrystal

diffraction (MicroED) that allows the structure determination of

small organic molecules, including natural products, from simple

powders has been reported: Jones, C. G.; Martynowycz, M. W.;

Hattne, J.; Fulton, T. J.; Stoltz, B. M.; Rodriguez, J. A.; Nelson, H. M.;

Gonen, T. The CryoEM Method MicroED as a Powerful Tool for

Small Molecule Structure Determination. ACS Cent. Sci. 2018, 4,

1587−1592.

(13) CHESHIRE, CHEmical SHift REpository with Coupling

Constants Added Too; http://cheshirenmr.info.

(14) (a) Grimblat, N.; Zanardi, M. M.; Sarotti, A. M. Beyond DP4:

an Improved Probability for the Stereochemical Assignment of

Isomeric Compounds using Quantum Chemical Calculations of NMR

Shifts. J. Org. Chem. 2015, 80, 12526−12534. (b) Sarotti, A. M.;

Pellegrinet, S. C. A multi-standard approach for GIAO (13)C NMR

calculations. J. Org. Chem. 2009, 74, 7254−7260. (c) Andrews, K. G.;

Spivey, A. C. Improving the accuracy of computed (13)C NMR shift

predictions by specific environment error correction: fragment

referencing. J. Org. Chem. 2013, 78, 11302−11317.

(15) (a) Sheldrake, H. M.; Jamieson, C.; Burton, J. W. The changing

faces of halogenated marine natural products: Total synthesis of the

reported structures of elatenyne and an enyne from Laurencia

majuscula. Angew. Chem., Int. Ed. 2006, 45, 7199−7202. (b) Sheldrake,

H. M.; Jamieson, C.; Pascu, S. I.; Burton, J. W. Synthesis of the

originally proposed structures of elatenyne and an enyne from

Laurencia majuscula. Org. Biomol. Chem. 2009, 7, 238−252. (c) Smith,

S. G.; Paton, R. S.; Burton, J. W.; Goodman, J. M. Stereostructure

assignment of flexible five-membered rings by GIAO (13)C NMR

calculations: Prediction of the stereochemistry of elatenyne. J. Org.

Chem. 2008, 73, 4053−4062. (d) Dyson, B. S.; Burton, J. W.; Sohn, T.

I.; Kim, B.; Bae, H.; Kim, D. Total synthesis and structure

confirmation of elatenyne: success of computational methods for

NMR prediction with highly flexible diastereomers. J. Am. Chem. Soc.

2012, 134, 11781−11790. (e) In 2016, the absolute configuration of

elatenyne was confirmed by X-ray crystallography using Fujita’s

crystalline sponge method: Urban, S.; Brkljaca, R.; Hoshino, M.; Lee,

S.; Fujita, M. Determination of the Absolute Configuration of the

Pseudo-Symmetric Natural Product Elatenyne by the Crystalline

Sponge Method. Angew. Chem., Int. Ed. 2016, 55, 2678−2682.

(16) (a) Shepherd, D. J.; Broadwith, P. A.; Dyson, B. S.; Paton, R. S.;

Burton, J. W. Structure Reassignment of Laurefurenynes A and B by

Computation and Total Synthesis. Chem. - Eur. J. 2013, 19, 12644−

12648. (b) For a strategically different synthesis of laurefurenyne A,

see: Holmes, M. T.; Britton, R. Total synthesis and structural revision

of laurefurenynes A and B. Chem. - Eur. J. 2013, 19, 12649−12652.

(17) Wright, A. D.; Konig, G. M.; Denys, R.; Sticher, O. Seven New

Metabolites From The Marine Red Alga Laurencia Majuscula. J. Nat.

Prod. 1993, 56, 394−401.

(3) Bifulco, G.; Dambruoso, P.; Gomez-Paloma, L.; Riccio, R.

Determination of relative configuration in organic compounds by

NMR spectroscopy and computational methods. Chem. Rev. 2007,

107, 3744−3779.

(4) (a) Rychnovsky, S. D. Predicting NMR spectra by computational

methods: Structure revision of hexacyclinol. Org. Lett. 2006, 8, 2895−

2898. (b) Lodewyk, M. W.; Soldi, C.; Jones, P. B.; Olmstead, M. M.;

Rita, J.; Shaw, J. T.; Tantillo, D. J. The correct structure of aquatolide-

experimental validation of a theoretically-predicted structural revision.

J. Am. Chem. Soc. 2012, 134, 18550−18553. (c) Tantillo, D. J.

Walking in the woods with quantum chemistry–applications of

quantum chemical calculations in natural products research. Nat.

Prod. Rep. 2013, 30, 1079−1086. (d) Navarro-Vazquez, A. State of the

art and perspectives in the application of quantum chemical

1

prediction of H and ¹³C chemical shifts and scalar couplings for

structural elucidation of organic compounds. Magn. Reson. Chem.

2017, 55, 29−32.

(5) (a) Michels, T. D.; Dowling, M. S.; Vanderwal, C. D. A synthesis

of echinopine B. Angew. Chem., Int. Ed. 2012, 51, 7572−7576. (b) Shi,

H.; Michaelides, I. N.; Darses, B.; Jakubec, P.; Nguyen, Q. N. N.;

Paton, R. S.; Dixon, D. J. Total Synthesis of (−)-Himalensine A. J.

Am. Chem. Soc. 2017, 139, 17755−17758.

(6) Nguyen, Q. N. N.; Schwochert, J.; Tantillo, D. J.; Lokey, R. S.

Using (1)H and (13)C NMR chemical shifts to determine cyclic

peptide conformations: a combined molecular dynamics and quantum

mechanics approach. Phys. Chem. Chem. Phys. 2018, 20, 14003−

14012.

(7) Wu, J.; Lorenzo, P.; Zhong, S.; Ali, M.; Butts, C. P.; Myers, E. L.;

Aggarwal, V. K. Synergy of synthesis, computation and NMR reveals

correct baulamycin structures. Nature 2017, 547, 436−440.

(8) Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K.

Iterative assembly line synthesis of polypropionates with full

stereocontrol. Nat. Chem. 2017, 9, 896−902.

(9) (a) Sohn, T. I.; Kim, D.; Paton, R. S. Substrate-Controlled

Asymmetric Total Syntheses of Microcladallenes A, B, and C Based

on the Proposed Structures. Chem. - Eur. J. 2015, 21, 15988−15997.

(b) Jeong, D.; Sohn, T. I.; Kim, J. Y.; Kim, G.; Kim, D.; Paton, R. S.

Construction of 6,10-syn- and -anti-2,5-dioxabicyclo[2.2.1]heptane

skeletons via oxonium ion formation/fragmentation: prediction of

structure of (E)-ocellenyne by NMR calculation. Org. Lett. 2017, 19,

6252−6255.

(10) Smith, S. G.; Goodman, J. M. Assigning the Stereochemistry of

Pairs of Diastereoisomers Using GIAO NMR Shift Calculation. J. Org.

Chem. 2009, 74, 4597−4607.

(11) Smith, S. G.; Goodman, J. M. Assigning Stereochemistry to

Single Diastereoisomers by GIAO NMR Calculation: The DP4

Probability. J. Am. Chem. Soc. 2010, 132, 12946−12959.

(12) (a) Ermanis, K.; Parkes, K. E.; Agback, T.; Goodman, J. M.

Expanding DP4: application to drug compounds and automation. Org.

(18) Gopichand, Y.; Schmitz, F. J.; Shelley, J.; Rahman, A.; Van der

Helm, D. Marine natural products: halogenated acetylenic ethers from

the sea hare Aplysia dactylomela. J. Org. Chem. 1981, 46, 5192−5197.

(19) Hall, J. G.; Reiss, J. A. Elatenyne − a Pyrano[3,2-b]pyranyl

Vinyl Acetylene from the Red Alga Laurencia elata. Aust. J. Chem.

1986, 39, 1401−1409.

(20) For the total synthesis of (E)- and (Z)-elatenyne and of

laurendecumenyne B, see ref 15d.

(21) (a) Kikuchi, H.; Suzuki, T.; Kurosawa, E.; Suzuki, M. The

Structure Of Notoryne, A Halogenated C15 Nonterpenoid With A

Novel Carbon Skeleton From The Red Alga Laurencia Nipponica

Yamada. Bull. Chem. Soc. Jpn. 1991, 64, 1763−1775. (b) 3(E)-

Notoryne has also been reported as a natural product: Fukuzawa, A.;

Aye, M.; Nakamura, M.; Tanura, M.; Murai, A. Structure elucidation

of laureoxanyne, a new nonisoprenoid C-15-enyne, using lactoperox-

idase. Tetrahedron Lett. 1990, 31, 4895−4898.

(22) (a) Ji, N. Y.; Li, X. M.; Li, K.; Wang, B. G. Laurendecumallenes

A-B and laurendecumenynes A-B, halogenated nonterpenoid C-15-

Acetogenins from the marine red alga Laurencia decumbens. J. Nat.

Prod. 2007, 70, 1499−1502. (b) Ji, N. Y.; Li, X. M.; Li, K.; Wang, B.

G. Laurendecumallenes A-B and Laurendecumenynes A-B, Halo-

genated Nonterpenoid C(15)-Acetogenins from the Marine Red Alga

Laurencia decumbens. (vol 70, pg 1499, 2007). J. Nat. Prod. 2010, 73,

1192.

S

DOI: 10.1021/acs.joc.8b02975

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

(23) Abdel-Mageed, W. M.; Ebel, R.; Valeriote, F. A.; Jaspars, M.

Laurefurenynes A−F, new Cyclic Ether Acetogenins from a Marine

Red Alga, Laurencia sp. Tetrahedron 2010, 66, 2855−2862.

(24) Murai, A. Biosynthesis of Cyclic Bromoethers from Red Algae.

In Comprehensive Natural Products Chemistry; Barton, D. H. R., Meth-

Cohn, O., Nakinishi, K., Eds.; Elsevier: Oxford, 1999; Vol. 1, pp 303−

324.

G.; Guida, W. C.; Still, W. C. An internal-coordinate Monte Carlo

method for searching conformational space. J. Am. Chem. Soc. 1989,

̈

111, 4379−4386 as implemented in Macromodel (Schrodinger, LLC,

New York, NY, 2018 .

(33) Jackson, K.; Jaffar, S. K.; Paton, R. S. Computational organic

chemistry. Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 2013, 109,

235−255.

(25) (a) Kurosawa, E.; Irie, T.; Fukuzawa, A. trans-Laurediol and cis-

laurediol, unsaturated glycols from Laurencia Nipponica yamada.

Tetrahedron Lett. 1972, 13, 2121−2124. (b) Fukuzawa, A.; Honma,

T.; Takasugi, Y.; Murai, A. Biogenetic intermediates, (3E and

3Z,12Z)-laurediols and (3E and 3Z)-12,13-dihydrolaurediols, isolated

from Laurencia Nipponica. Phytochemistry 1993, 32, 1435−1438.

(26) For reviews of halogenating enzymes, see: (a) Butler, A.;

Carter-Franklin, J. N. The role of vanadium bromoperoxidase in the

biosynthesis of halogenated marine natural products. Nat. Prod. Rep.

2004, 21, 180−188. (b) Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.;

Garneau-Tsodikova, S.; Walsh, C. T. Nature’s inventory of

halogenation catalysts: Oxidative strategies predominate. Chem. Rev.

2006, 106, 3364−3378.

(34) (a) Chai, J. D.; Head-Gordon, M. Long-range corrected hybrid

density functionals with damped atom-atom dispersion corrections.

Phys. Chem. Chem. Phys. 2008, 10, 6615−6620. (b) Frisch, M. J.; et al.

Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009.

(35) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies,

structures, and electronic properties of molecules in solution with the

C-PCM solvation model. J. Comput. Chem. 2003, 24, 669−681.

(36) (a) Riplinger, C.; Sandhoefer, B.; Hansen, A.; Neese, F. Natural

triple excitations in local coupled cluster calculations with pair natural

orbitals. J. Chem. Phys. 2013, 139, 134101−13413. (b) We used Orca

4.0: Neese, F. Software Update: The ORCA Program System, Version

4.0. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2018, 8, No. e1327.

̈

(37) (a) Pyykko, P.; Gorling, A.; Rosch, N. A transparent

interpretation of the relativistic contribution to the N.M.R. ‘heavy

atom chemical shift’. Mol. Phys. 1987, 61, 195−205. (b) Kutateladze,

A. G.; Reddy, D. S. High-Throughput in Silico Structure Validation

and Revision of Halogenated Natural Products Is Enabled by

Parametric Corrections to DFT-Computed (13)C NMR Chemical

Shifts and Spin-Spin Coupling Constants. J. Org. Chem. 2017, 82,

3368−3381.

(27) Braddock, D. C. A hypothesis concerning the biosynthesis of

the obtusallene family of marine natural products via electrophilic

bromination. Org. Lett. 2006, 8, 6055−6058.

(28) (a) McPhail, K. L.; Davies-Coleman, M. T. (3Z)-bromofucin

from a South African sea hare. Nat. Prod. Res. 2005, 19, 449−452.

(b) Coll, J. C.; Wright, A. D. Tropical Marine-Algae. IV. Novel

Metabolites from the Red Alga Laurencia implicata (Rhodophyta,

Rhodophyceae, Ceramiales, Rhodomelaceae). Aust. J. Chem. 1989, 42,

1685−1693. (c) For a recent biomimetic synthesis of the bromo- and

chlorofucins, see: Kim, B.; Sohn, T. I.; Kim, D.; Paton, R. S.

Asymmetric Total Syntheses and Structure Confirmation of

Chlorofucins and Bromofucins. Chem. - Eur. J. 2018, 24, 2634−2642.

(29) The conﬁgurations of the natural products obtusenyne,

laurepinnacin, and isolaurepinnacin are consistent with them being

biosynthetically derived from a 12(Z)-laurediol derivative: (a) King,

(38) Braddock, D. C.; Rzepa, H. S. Structural reassignment of

obtusallenes V, VI, and VII by GIAO-based density functional

prediction. J. Nat. Prod. 2008, 71, 728−730.

(39) (a) Marell, D. J.; Emond, S. J.; Kulshrestha, A.; Hoye, T. R.

Analysis of seven-membered lactones by computational NMR

methods: proton NMR chemical shift data are more discriminating

than carbon. J. Org. Chem. 2014, 79, 752−758. (b) Chini, M. G.;

Riccio, R.; Bifulco, G. Computational NMR Methods in the

Stereochemical Analysis of Organic Compounds: Are Proton or

Carbon NMR Chemical Shift Data More Discriminating? Eur. J. Org.

Chem. 2015, 2015, 1320−1324.

̈

T. J.; Imre, S.; Oztunc, A.; Thomson, R. H. Obtusenyne, a new

acetylenic nine-membrered cyclic ether from Laurenica obtusa.

Tetrahedron Lett. 1979, 20, 1453−1454. (b) Howard, B. M.;

Schulte, G. R.; Fenical, W.; Solheim, B.; Clardy, J. Three new vinyl

acetylenes from the marine red alga Laurencia. Tetrahedron 1980, 36,

1747−1751. (c) Fukuzawa, A.; Masamune, T. Laurepinnacin and

isolaurepinnacin, new acetylenic cyclic ethers from the marine red alga

Laurencia pinnata Yamada. Tetrahedron Lett. 1981, 22, 4081−4084.

(30) For alternative biosynthetic postulates, see: (a) Snyder, S. A.;

Treitler, D. S.; Brucks, A. P.; Sattler, W. A general strategy for the

stereocontrolled preparation of diverse 8- and 9-membered laurencia-

type bromoethers. J. Am. Chem. Soc. 2011, 133, 15898−15901.

(b) Bonney, K. J.; Braddock, D. C. A unifying stereochemical analysis

for the formation of halogenated C15-acetogenin medium-ring ethers

from Laurencia species via intramolecular bromonium ion assisted

epoxide ring-opening and experimental corroboration with a model

epoxide. J. Org. Chem. 2012, 77, 9574−9584.

(31) (a) Lodewyk, M. W.; Siebert, M. R.; Tantillo, D. J.

Computational prediction of ¹H and ¹³C chemical shifts: a useful

tool for natural product, mechanistic, and synthetic organic chemistry.

Chem. Rev. 2012, 112, 1839−1862. (b) Nguyen, Q. N.; Tantillo, D. J.

The many roles of quantum chemical predictions in synthetic organic

chemistry. Chem. - Asian J. 2014, 9, 674−680. (c) Willoughby, P. H.;

Jansma, M. J.; Hoye, T. R. A guide to small-molecule structure

assignment through computation of ((1)H and (13)C) NMR

chemical shifts. Nat. Protoc. 2014, 9, 643−660. (d) Jackson, K. E.;

Paton, R. S. A Guide to Small-Molecule Structure Assignment

through Computation of (¹H and ¹³C) NMR Chemical Shifts. In

Applied Theoretical Organic Chemistry; Tantillo, D. J., Ed.; World

Scientific, 2018; Vol. 1, pp 165−189.

(40) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. A

Stereoselective Synthesis of trans-1,2-Disubstituted Alkenes Based on

the Condensation of Aldehydes with Metallated 1-Phenyl-1H-

tetrazol-5-yl Sulfones. Synlett 1998, 1998, 26−28.

(41) Crimmins, M. T.; Powell, M. T. Enantioselective total synthesis

of (+)-obtusenyne. J. Am. Chem. Soc. 2003, 125, 7592−7595.

(42) For a review of the mechanisms of the Julia−Kocienski

reaction, see: Aïssa, C. Mechanistic Manifold and New Developments

of the Julia-Kocienski Reaction. Eur. J. Org. Chem. 2009, 2009, 1831−

1844.

(43) The geometry of the double bond was assigned as (E) on the

basis of the ¹³C NMR chemical shifts of the allylic carbon atoms (δ =

36.1, 34.1 ppm), see: Crews, P.; Rodríguez, J.; Jaspars, M. Organic

Structure Analysis, 2nd ed.; Oxford University Press: New York, 2010;

pp 59−60, and by comparison with closely related compounds refs

15d and 16a.

(44) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.

A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z.

M. The osmium-catalyzed asymmetric dihydroxylation: a new ligand

class and a process improvement. J. Org. Chem. 1992, 57, 2768−2771.

(b) Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Catalytic

Asymmetric Dihydroxylation. Chem. Rev. 1994, 94, 2483−2547.

(45) Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; La Greca, S.; Tsuri,

T.; Yue, E. W.; Yang, Z. Synthesis of the First Fully Functionalized

Core of the Zaragozic Acids/Squalestatins. Angew. Chem., Int. Ed.

Engl. 1994, 33, 2187−2190.

(46) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. High-field

FT NMR application of Mosher’s method. The absolute config-

urations of marine terpenoids. J. Am. Chem. Soc. 1991, 113, 4092−

4096.

(32) (a) Halgren, T. A. Merck molecular force field. I. Basis, form,

scope, parameterization, and performance of MMFF94. J. Comput.

Chem. 1996, 17, 490−519. (b) We used a 10000 step Monte Carlo

multiple minimum (MCMM) search for each diastereomer: Chang,

T

DOI: 10.1021/acs.joc.8b02975

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

(47) (a) Han, J. S.; Lowary, T. L. Total synthesis of buergerinin F

and buergerinin G. J. Org. Chem. 2003, 68, 4116−4119. (b) Takao,

K.; Yasui, H.; Yamamoto, S.; Sasaki, D.; Kawasaki, S.; Watanabe, G.;

Tadano, K. Asymmetric total syntheses of (+)-mycoepoxydiene and

related natural product (−)-1893A: Application of one-pot ring-

opening/cross/ring-closing metathesis to construct their 9-oxabicyclo

4.2.1 nona-2,4-diene skeleton. J. Org. Chem. 2004, 69, 8789−8795.

(c) Some reduced product was also formed where the iodine atom

had been replaced by a hydrogen atom.

(48) (a) Freeman, P. K.; Hutchinson, L. L. Alkyllithium reagents

from alkyl halides and lithium radical anions. J. Org. Chem. 1980, 45,

1924−1930. (b) Ireland, R. E.; Smith, M. G. 3-Acyltetramic Acid

Antibiotics. 2. Synthesis of (+)-Streptolic Acid. J. Am. Chem. Soc.

1988, 110, 854−860.

(49) Appel, R. Tertiary Phosphane/Tetrachloromethane, a Versatile

Reagent for Chlorination, Dehydration, and P-N Linkage. Angew.

Chem., Int. Ed. Engl. 1975, 14, 801−811.

(60) Yamakado, Y.; Ishiguro, M.; Ikeda, N.; Yamamoto, H.

Stereoselective Carbonyl Olefination via Organosilicon Compounds.

J. Am. Chem. Soc. 1981, 103, 5568−5570.

(61) Lee, H.; Kim, K. W.; Park, J.; Kim, H.; Kim, S.; Kim, D.; Hu, X.

Q.; Yang, W. T.; Hong, J. Y. A general strategy for construction of

both 2,6-cis- and 2,6-trans-disubstituted tetrahydropyrans: Substrate-

controlled asymmetric total synthesis of (+)-scanlonenyne. Angew.

Chem., Int. Ed. 2008, 47, 4200−4203.

(62) Some resonances in the ¹³C NMR spectrum of (Z)-notoryne

had originally been misassigned, and the total synthesis of the natural

product allowed complete assignment of the ¹³C NMR spectrum of

the natural product (and see ref 56).

(50) (a) Kim, B.; Lee, M.; Kim, M. J.; Lee, H.; Kim, S.; Kim, D.;

Koh, M.; Park, S. B.; Shin, K. J. Biomimetic asymmetric total synthesis

of (−)-laurefucin via an organoselenium-mediated intramolecular

hydroxyetherification. J. Am. Chem. Soc. 2008, 130, 16807−16811.

(b) Kim, H.; Lee, H.; Lee, D.; Kim, S.; Kim, D. Asymmetric total

syntheses of (+)-3-(Z)-laureatin and (+)-3-(Z)-isolaureatin by ″lone

pair-lone pair interaction-controlled″ isomerization. J. Am. Chem. Soc.

2007, 129, 2269−2274.

(51) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J. G.;

Holmes, A. B. Synthesis of medium ring ethers. 5. The synthesis of

(+)-laurencin. J. Am. Chem. Soc. 1997, 119, 7483−7498.

(52) (a) Mitsunobu, O.; Yamada, M. Preparation of Esters of

Carboxylic and Phosphoric Acid via Quaternary Phosphonium Salts.

Bull. Chem. Soc. Jpn. 1967, 40, 2380−2382. (b) Martin, S. F.; Dodge,

J. A. Efficacious Modification of the Mitsunobu Reaction for the

Inversoins of Sterically Hindered Secondary Alcohols. Tetrahedron

Lett. 1991, 32, 3017−3020. (c) Proctor, A. J.; Beautement, K.;

Clough, J. M.; Knight, D. W.; Li, Y. F. Chromatography-free product

separation in the Mitsunobu reaction. Tetrahedron Lett. 2006, 47,

5151−5154.

(53) Donohoe, T. J.; House, D. Ammonia Free Partial Reduction of

Aromatic Compounds Using Lithium Di-tert-butylbiphenyl (LiDBB).

J. Org. Chem. 2002, 67, 5015−5018.

(54) In the absence of a proton donor, the benzyl ether 33 was

formed as the major product.

(55) (a) DFT calculations had predicted 2b to be the actual

structure of the natural product. We therefore ﬁrst synthesized 2b

before preparing diastereomer 2d. Hence, our synthesis of

diastereomer 2d involves two Mitsunobu reactions. (b) The

Mitsunobu reaction and subsequent methanolysis for the praparation

of 2d from 2b were conducted on very small scale, and hence yields

have not been quoted.

(56) The ﬁrst synthesis of notoryne, the “Seoul” synthesis described

herein, was ﬁrst reported in 2009. See: Lee, M. First Asymmetric

Total Synthesis of (Z)- and (E)-Notorynes. M.S. Thesis, Seoul

National University, Seoul, Korea, 2009. For a very recent total

synthesis of (Z)-notoryne, see: Senapati, S.; Das, S.; Ramana, C. V.

Total Synthesis of Notoryne. J. Org. Chem. 2018, 83, 12863−12868.

(57) Hooz, J.; Gilani, S. S. H. A rapid, mild procedure for the

preparation of alkyl chlorides and bromides. Can. J. Chem. 1968, 46,

86−87.

(58) The spectroscopic data for compound 44 can be found in the

Supporting Information of ref 50a.

(59) (a) Aliev, A. E.; Harris, K. D. M. 37Cl/35Cl isotope effects in

13C NMR spectroscopy of chlorohydrocarbons. Magn. Reson. Chem.

1993, 31, 54−57. (b) For a recent example of the use of ¹³C NMR

chlorine-induced isotopic shift to determine the position fo a chlorine

atom, see: Braddock, D. C.; Bhuva, R.; Millan, D. S.; Perez-Fuertes,

Y.; Roberts, C. A.; Sheppard, R. N.; Solanki, S.; Stokes, E. S. E.;

White, A. J. P. A biosynthetically-inspired synthesis of the

tetrahydrofuran core of obtusallenes II and IV. Org. Lett. 2007, 9,

445−448.

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