Total synthesis and structure confirmation of elatenyne: Success of computational methods for NMR prediction with highly flexible diastereomers

Article abstract of DOI:10.1021/ja304554e

Elatenyne is a small dibrominated natural product first isolated from Laurencia elata. The structure of elatenyne was originally assigned as a pyrano[3,2-b]pyran on the basis of NMR methods. Total synthesis of the originally proposed pyrano[3,2-b]pyran structure of elatenyne led to the gross structure of the natural product being reassigned as a 2,2′-bifuranyl. The full stereostructure of this highly flexible small molecule was subsequently predicted by Boltzmann-weighted DFT calculations of ¹³C NMR chemical shifts for all 32 potential diastereomers, with the predicted structure being in accord with the proposed biogenesis outlined below. Herein we report two complementary total syntheses of elatenyne, which confirm the computer-predicted stereostructure. Additionally, the total syntheses of (E)-elatenyne and a related 2,2′-bifuranyl, laurendecumenyne B, are reported. This work has not only allowed the full structure determination of all of these natural products but also provides excellent supporting evidence for their proposed biogenesis. The total synthesis of elatenyne demonstrates that DFT calculations of ¹³C NMR chemical shifts coupled with biosynthetic postulates, comprise a very useful method for distinguishing among large numbers of highly flexible, closely related molecules.

Full text of DOI:10.1021/ja304554e

Article
pubs.acs.org/JACS
Total Synthesis and Structure Confirmation of Elatenyne: Success of
Computational Methods for NMR Prediction with Highly Flexible
Diastereomers
Bryony S. Dyson,† Jonathan W. Burton,*,† Te-ik Sohn,‡ Byungsook Kim,‡ Hoon Bae,‡
and Deukjoon Kim*,‡
†Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
‡The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
S
* Supporting Information
ABSTRACT: Elatenyne is a small dibrominated natural
product first isolated from Laurencia elata. The structure of
elatenyne was originally assigned as a pyrano[3,2-b]pyran on
the basis of NMR methods. Total synthesis of the originally
proposed pyrano[3,2-b]pyran structure of elatenyne led to the
gross structure of the natural product being reassigned as a
2,2′-bifuranyl. The full stereostructure of this highly flexible
small molecule was subsequently predicted by Boltzmann-
weighted DFT calculations of 13C NMR chemical shifts for all
32 potential diastereomers, with the predicted structure being in accord with the proposed biogenesis outlined below. Herein we
report two complementary total syntheses of elatenyne, which confirm the computer-predicted stereostructure. Additionally, the
total syntheses of (E)-elatenyne and a related 2,2′-bifuranyl, laurendecumenyne B, are reported. This work has not only allowed
the full structure determination of all of these natural products but also provides excellent supporting evidence for their proposed
biogenesis. The total synthesis of elatenyne demonstrates that DFT calculations of 13C NMR chemical shifts coupled with
biosynthetic postulates, comprise a very useful method for distinguishing among large numbers of highly flexible, closely related
molecules.
the basis of total synthesis and a 13C NMR chemical shift/
structure correlation, we reassigned the gross structure of the
INTRODUCTION
The use of DFT calculations to predict the spectroscopic
properties of organic molecules has emerged as a powerful
additional tool for structure determination. In particular, the
use of ab initio methods to calculate NMR chemical shifts has
proven beneficial in both gross structural assignment as well as
■
natural product from a pyrano[3,2-b]-pyran to a 2,2′-bifuranyl
2.10,11 Elatenyne contains six stereocenters, and hence the
stereostructure of the natural product is one of 32 possible
diastereomers. In collaboration with Dr. Jonathan Goodman
(University of Cambridge, UK) we predicted the stereo-
stereochemical assignment. The technique, which was
structure of elatenyne by comparison of the 13C NMR chemical
shifts of the natural product with the Boltzmann-weighted
GIAO 13C NMR chemical shifts calculated using DFT
methods.12 Several structural features made elatenyne challeng-
ing to study computationally: (i) two highly flexible THF rings,
(ii) an inter-ring torsion, (iii) side-chain torsions, (iv) the
presence of bromine atoms, and (v) the presence of sp-
hybridized carbon atoms. Nevertheless, analysis of the
computational data by comparison of the average difference
in the chemical shift across a number of carbon atoms between
the computed data and the natural product data (mean average
error, MAE)1,12 gave four promising candidates for the
stereostructure of elatenyne (diastereomers 2a−d) with
structure 2a being the most likely structure of the natural
product. What was particularly encouraging about the computer
pioneered by Bifulco1,2 and co-workers, has played a key role
in the structure assignment or reassignment of a number of
natural products or natural product fragments.3−5 Moreover,
Goodman and Smith4 have developed a statistical method, the
DP4 probability, to aid structure assignment from a range of
candidate structures.5 The majority of these DFT studies for
the prediction of 13C NMR chemical shifts have been
conducted with relatively rigid molecules, although increasingly
these techniques are being successfully used with flexible
molecules.1a,2,6 Herein, we report two complementary total
syntheses of the highly flexible 2,2′-bifuranyl natural product
elatenyne, which demonstrate the success of DFT calculations
of GIAO 13C NMR chemical shifts, and biosynthetic postulates,
to predict the correct stereostructure of a highly flexible natural
product from a set of 32 possible diastereomers.
Elatenyne is a C15 dibrominated marine natural product
isolated by Hall and Reiss in 1983 from Laurencia elata and
assigned the pyrano-[3,2-b]-pyran structure 1 (Chart 1).7−9 On
Received: May 10, 2012
Published: July 3, 2012
© 2012 American Chemical Society
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would give (E)-elatenyne 3. The above transannular bio-
synthetic rearrangements find precedent in the work of
Suzuki,14b Fukuzawa,21 and, more recently, Braddock22 and
our own work.23,24 The natural products (3Z)-25 and (3E)-
chlorofucin 1126 are most likely biosynthesized by an analogous
route from laurediol 5 by opening of the tricyclic oxonium ion
10 at C-10 with chloride. The absolute configuration of (3E)-
chlorofucin (E)-11 has previously been assigned by X-ray
crystallography26a that, by analogy, would give elatenyne the
absolute configuration shown in Scheme 1. However, the
Chart 1. Proposed Structures of Elatenyne and Other
Natural Products from L. spp. (relative configurations)
Scheme 1. Proposed Biosynthesis
prediction was that the most likely stereostructure was in
keeping with that predicted from a plausible biosynthetic
pathway (vide infra). In this article, we report both a ‘modular’
and a ‘biomimetic’ total synthesis of the most likely structure of
elatenyne, which confirms the relative configuration of natural
elatenyne as 2a. Most importantly however, this work
demonstrates that DFT calculations of GIAO 13C NMR
chemical shifts coupled with biosynthetic postulates are an
excellent method for distinguishing among a large number of
highly flexible diastereomers. Additionally, we report the total
synthesis and hence full stereostructure, of a second
dibrominated enyne from L. majuscula,13 which, on the basis
of this work, corresponds to (E)-elatenyne 3, and laurendecu-
menyne B 4,9a,b a bromo−chloro enyne from L. decumbens,
which is assigned the same relative configuration as that of
elatenyne 2a.
Proposed Biosynthesis and Absolute Configuration.
The biosynthesis of C15 halogenated natural products from L.
spp. has been widely studied.14 Murai has demonstrated that a
number of C15 halogenated natural products can be derived
from laurediol (e.g., 5)15 via bromoperoxidase-mediated
bromonium ion-induced cyclizations. Based on the above
precedent14 and analogous to the proposed biosynthesis of the
natural product notoryne,14b a biosynthesis for elatenyne may
be outlined as follows. (3Z, 12E)-Laurediol 5, would be
converted into the corresponding bromonium ion 6 by the
action of bromide and a bromoperoxidase16 which would
undergo cyclization to give 7, a diastereomer of deacetyl
laurencin.17 Bromoperoxidase-mediated endo-cyclic bromonium
ion formation, giving 8, followed by etherification would deliver
the natural product (Z)-bromofucin (Z)-9.18 Transannular
displacement of bromide would give the tricyclic oxonium ion
(Z)-10 which would be opened by bromide at C-7 to give the
specific elatenyne diastereomer 2a.19 Similarly, the tricyclic
oxonium ion (E)-10 derived from (E)-bromofucin (E)-920
absolute configuration of the natural product (3Z)-chlorofucin
(Z)-11 has not been unequivocally determined, and the
isolation chemists noted that there is the possibility of its
being enantiomeric with (3E)-chlorofucin (E)-11.25 Consider-
ing the fact that the laurediols exist naturally as unequal
mixtures of (3E/Z, 12E/Z, RR/SS) stereoisomers15 and that
the absolute configuration of the bromofucins 9 and (3Z)-
chlorofucin (Z)-11 have not been unequivocally determined,27
it was deemed prudent for the Oxford and Seoul groups to
pursue the total synthesis of opposite enantiomers of elatenyne.
STRATEGY AND RETROSYNTHESIS
■
The computational analysis had predicted the most likely
structure for elatenyne as 2a12 that also corresponded to one of
the diastereomers predicted on the basis of biosynthetic
arguments. We were confident, therefore, that 2a was indeed
the structure of elatenyne; however, we deemed it prudent to
design a modular synthesis of elatenyne, which could, with
minimum modification, allow the synthesis of any of the 32
diastereomers of the natural product. At the same time we
pursued a biomimetic synthesis of diastereomer 2a. Given the
inherent difficultly in unambiguously assigning the relative
configuration of flexible, polysubstituted 5-membered rings, we
elected to introduce the stereocenters of elatenyne using
stereochemically unambiguous reactions, namely the Sharpless
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Figure 1. Retrosynthetic analysis of both enantiomers of elatenyne 2a showing both modular and biomimetic routes.
asymmetric epoxidation (SAE)28 and Sharpless asymmetric
dihydroxylation (SAD),29 and to manipulate the installed
stereocenters using stereochemically unequivocal reactions
(e.g., SN2-reactions). Use of either enantiomer/pseudo-
enantiomer of ligand in the SAE and SAD reactions, followed
by further manipulation of stereocenters would allow us to
introduce the necessary diversity into the synthesis such that we
could, in principle, synthesize any of the 32 diastereomers of
elatenyne.
ocene 22 would be prepared from the amide 23 which, in turn,
would be available by ring-closing-metathesis of the diene
24.32b,c Diastereoselective alkylation of the amide 25, using
methodology developed by the Seoul group,33b would deliver
the diene 24, with the amide itself, being prepared from the
known allylic alcohol 26.34
Synthesis of the Dibromide 12 - Modular Route. The
“modular” route to elatenyne 2a began with the known SAE
(kinetic resolution) of 1,5-hexadien-3-ol 1935 which we
prepared in 100 g batches by Barbier coupling of allyl bromide
and acrolein according to the procedure of Barfield (Scheme
2).36 The epoxy alcohol 27 was converted into the PMB-
protected epoxide,37 and the epoxide opened at the terminal
position with methylmagnesium bromide in the presence of a
copper(I) catalyst35c to give the C-10−C-15 fragment of
elatenyne 28 on protection with triethylsilyl chloride. For the
second cross metathesis partner corresponding to 17, we
required a protecting group that could be removed in the
presence of a terminal olefin. We elected to use the 4-
bromobenzyl protecting group rather than the more usual
benzyl protecting group, as it would give us added flexibility on
deprotection if required.38 Moreover, the 4-bromobenzyl group
had the added advantage of giving the majority of our
intermediates a clear isotope signature in the mass spectrum,
thus greatly simplifying reaction analysis. Cross metathesis32a of
28 with 29 required careful optimization. Ultimately we found
that treatment of 4 equiv of 29 and 1 equiv of 28 with the
second-generation Grubbs−Hoveyda catalyst 30 (10 mol %)39
and 1,4-benzoquinone (25 mol %)40 in DCM at reflux gave the
alkene 31 as a 3:1 mixture of geometrical isomers in 60%
yield;41 the (E)-isomer of 31 could be separated in pure form
by chromatography on silver nitrate-impregnated silica gel
(45% yield from 28).42 The alkene 31 underwent clean, albeit
slow, SAD28 with super AD-mix-α employed by Nicolaou and
co-workers in their synthesis of zaragozic acid,43 which gave the
corresponding diols in 88% yield as a 4:1 mixture of syn-
diastereomers; diol 32 could be isolated in pure form in 71%
yield.44 Cyclization of the C-9 hydroxy group onto the epoxide
under acidic conditions required careful optimization so that
loss of the C-13 silyl protecting group was minimized. In the
In concert with this modular approach, we devised a route to
elatenyne which would serve not only to secure the structure of
the natural product but also to give additional weight to the
biosynthesis of halogenated 2,2′-bifuranyls isolated from L. spp.
Retrosynthetic analyses of both enantiomers of elatenyne 2a/
ent-2a are shown in Figure 1. Thus, the enyne was to be readily
installed from the terminal olefin 12/ent-12 as previously
demonstrated in related systems.10,30 In the “modular” route,
the dibromide 12 was to be prepared from the diol 13 by
bromination with inversion of configuration, with the diol, in
turn, being available from the 2,2′-bifuranyl 14 following C-12
inversion of configuration.31 The 2,2′-bifuranyl would then be
synthesized from the alkene epoxide 16 by an SAD reaction29
with concomitant THF formation giving 15, followed by C-13
alkoxy to C-10 cyclization. The key alkene 16 was to be
prepared by cross-metathesis32 of substrates 17 and 18 both of
which would be available from 1,5-hexadien-3-ol 19 by an SAE
reaction. The modularity of the route arises from the use of
either enantiomer/pseudo-enantiomer of ligand in both the SAE
and SAD reactions coupled with the formation of the 2,2′-
bifuranyl and the installation of the bromine atoms with either
overall inversion or retention of configuration. With the
“biomimetic” route, the common intermediate dibromide ent-
12 was to be available from the protected alcohol 20. The key
“biomimetic” step involves formation of the tricyclic oxonium
ion 21 from the bromooxocene 22 followed by regioselective
opening of 21 with bromide to give the 2,2′-bifuranyl 20 with
all of the stereocenters of elatenyne installed. The brominated
oxocene 22 was to be prepared using methodology previously
developed within the Seoul group, and utilized in the total
synthesis of numerous natural products.23,33 The bromoox-
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a
a
Scheme 2. Synthesis of the 2,2′-Bifuranyl 34
Scheme 3. Nitrile Introduction
a
Reagents and conditions: (a) TBAI, toluene, reflux, 16 h, 83%; (b)
nBu4NCN, MeCN, reflux, 4 h, 36, 71%, 37, 21%.
corresponding iodide 38 in 83% yield. Exposure of the iodide
to tetrabutylammonium cyanide in acetonitrile at reflux gave
the desired nitrile 3645 in 71% yield along with the enol ether
37 (21%). Although we had secured a route to the desired
nitrile 36, the enol ether 37 was also formed in significant
quantities under the basic reaction conditions.45,46 We
therefore sought an alternative method of enyne introduction.
Given that the iodide 38 was more prone to nucleophilic
substitution than the mesylate 34, we attempted to displace the
iodide directly with a vinyl anion from which the enyne could
be installed by both Wittig−Peterson olefination reactions from
the corresponding aldehyde,10 or using metathesis based
reactions directly from the alkene.30 In the event, exposure of
the iodide 38 to excess vinylmagnesium bromide in benzene/
THF at 40 °C gave the terminal alkene 39 in 58% yield along
with 26% recovered starting material (Scheme 4).47 It was now
a
Reagents and conditions: (a) L-(+)-Dicyclohexyl tartrate (DCT),
Ti(OiPr)4, tBuOOH, 4 Å molecular sieves, CH2Cl2, −20 °C, 42 h,
38%; (b) NaH, PMBBr, TBAI, THF, −78 °C to rt, 16 h; (c) MeMgBr,
CuI, THF, −23 °C, 1 h, 90% for two steps; (d) TESCl, imidazole,
DMAP, CH2Cl2, rt, 16 h, 97%; (e) p-bromobenzyl bromide (PBBBr),
NaH, TBAI, THF −78 °C to rt, 17 h, 95%; (f) Grubbs−Hoveyda II
30, 1,4-benzoquinone, CH2Cl2, reflux, 45%; (g) K2OsO4(OH)4,
K3Fe(CN)6, (DHQ)2PHAL, K2CO3, MeSO2NH2, tBuOH, water, 0
°C, 96 h, 71%; (h) CSA, CH2Cl2, 0 °C, 3 h, 72% (87% brsm); (i)
MsCl, Et3N, CH2Cl2, 0 °C, 10 min.; (j) TBAF, THF, rt, 16 h, 34, 66%
(for two steps), and 35, 26%; (k) KHMDS, THF, rt, 20 min, 84%.
a
Scheme 4. Synthesis of the Dibromide 12
event, exposure of the diol epoxide 32 to ( )-10-
camphorsulfonic acid at 0 °C in DCM gave the THF 33 in
72% yield along with 15% recovered starting material. The diol
33 was readily converted into the corresponding bis-mesylate,
which on treatment with TBAF gave a mixture of the 2,2′-
bifuranyl 34 and bis-mesylate 35; the bis-mesylate 35 could be
coaxed into cyclizing to give 34 on treatment with potassium
bis(trimethylsilyl)amide.
A stereocontrolled route to the 2,2′-bifuranyl 34 having been
secured, all that remained was to introduce the bromine atoms
and the (Z)-enyne. Our initial strategy for enyne introduction
involved installation of a nitrile, which would serve as a
surrogate aldehyde from which the enyne could be introduced
by Wittig−Peterson olefination strategies.10 Surprisingly, under
a range of conditions, the mesylate 34 was unreactive toward
substitution by cyanide anion. Heating the mesylate 34 with
tetrabutylammonium cyanide in acetonitrile at reflux gave trace
amounts of a product with molecular mass corresponding to 36
(Scheme 3); however, we were unable to obtain further
supporting evidence that substitution by cyanide anion had
indeed occurred. Surprised by the recalcitrant nature of the
mesylate 34 toward substitution by cyanide, we investigated the
substitution with the more nucleophilic iodide anion. Conven-
tional Finkelstein reaction conditions (sodium iodide, acetone,
reflux) gave the desired iodide 38 in 25% yield. Ultimately, it
was found that exposure of the mesylate 34 to excess
tetrabutylammonium iodide in toluene at reflux gave the
a
Reagents and conditions: (a) CH2CHMgBr, benzene, THF, 40 °C,
4 h 58% (84% brsm); (b) BCl3·SMe2, CH2Cl2, rt, 10 min, quant.; (c)
DIAD, Ph3P, p-nitrobenzoic acid, THF, 0 °C, 2 h, 85%; (d) K2CO3,
MeOH, 0 °C to RT, 2 h, 94%; (e) BCl3, CH2Cl2, rt, 30 min, quant.; (f)
CBr4, Ph3P, toluene, 80 °C, 75 min, 70%.
necessary to invert the configuration at C-12, as we deemed
attempted introduction of the bromide directly from the
corresponding alcohol with retention of configuration was
unlikely to prove successful.48 The PMB group was readily
removed in the presence of the less electron-rich PBB group on
exposure of 39 to boron trichloride-dimethyl sulfide complex.49
Mitsunobu reaction50 followed by ester removal gave the
inverted secondary alcohol 41 in 80% overall yield from the
2,2′-bifuranyl 40. The PBB group was now removed on
exposure of the alcohol to the stronger Lewis acid, boron
trichloride,51 which gave the diol 13 in quantitative yield.
Exposure of the diol to standard Hooz bromination conditions
(CBr4, PPh3) cleanly gave the desired dibromide 12 in 70%
yield.52
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Synthesis of the Dibromide ent-12 - Biomimetic
Route. The proposed “biomimetic” synthesis of elatenyne
ent-2a required the preparation of an α,α′-trans-disubstituted
oxocene 22 which was to undergo electrophile-mediated
rearrangement to give the desired dibrominated 2,2′-bifuranyl
corresponding to 20. The oxocene 22 was to be prepared from
23, which, in turn would be synthesized by a ring closing
metathesis of the bis-terminal alkene 24 followed by
bromination with inversion of configuration. The bis-terminal
alkene 24 was to be prepared by an α,α′-anti-selective alkylation
of the dianion derived from the amide 25. Both of these steps
have been developed and used by us in the synthesis of a large
number of natural products, and we were confident that this
robust methodology would provide an efficient route to the
desired oxocene.23,33b−d The amide 24 was to be prepared from
the known secondary allylic alcohol 26 by a diastereoselective
allylation of the dianion derived from the amide 25. Thus,
known allylic alcohol 2634 was alkylated with 2-chloro-N,N-
dimethylacetamide to give the amide 42 in 93% yield (Scheme
5). Cleavage of the alkene 42 by a Lemieux−Johnson oxidation
The stereocontrol of this selective alkylation presumably arises
by alkylation of the (Z)-enolate via pretransition state assembly
45 with the electrophile approaching from the least hindered
side in the H,H-eclipsed conformation. After extensive
experimentation it was found that the desired bromide 46
could be formed by the displacement of the corresponding
chloromesylate 44 by bromide (vide infra).53 Formation of the
oxocene 23 occurred efficiently on treatment of the bromide 46
with Grubbs’ first-generation catalyst at ambient temperature
(94%).32b The structure of the bromoamide 23 was confirmed
by X-ray crystallographic analysis.
Our extensive experience54−57 in the field suggested
bromination of α,α′-trans-12,13-syn-oxocene alcohol 47 with
inversion of configuration might be problematic. Thus, the
alcohol 24 underwent efficient ring-closing-metathesis on
exposure to Grubbs’ second-generation catalyst 48 to give the
oxocene 47 in 84% yield.32b,c As anticipated, attempted Hooz
bromination52 of 47 gave the desired bromide 23 along with
the diene 49 as a 1:1 mixture (by 500 MHz, 1H NMR) in 54%
combined yield.56 Therefore, in order to overcome the obstacle
of this seemingly straightforward transformation, the synthesis
of the bromide 46 from the alcohol 24 prior to formation of the
oxocene ring was initially attempted under modified Hooz
conditions.33d,e,37 However, under these conditions the alcohol
was converted into the desired bromide 46 along with a second
component tentatively assigned to the bromide 50 as a 1:1.4
a
Scheme 5. Synthesis of the Bromoamide 23
1
mixture (by 500 MHz H NMR) in 80% yield (Scheme 6).
a
Scheme 6. Bromination Studies
a
Reagents and conditions: (a) ClCH2CONMe2, NaH, THF, 0 °C to
a
Reagents and conditions: (a) cat. 48, CH2Cl2, 40 °C, 2 h, then
rt, 3 h, 93%; (b) OsO4, NMO, acetone, rt, 18 h, then NaIO4, acetone/
H2O (3:1), rt, 3 h; (c) allyltributyltin, MgBr2·Et2O, CH2Cl2, −78 °C
to rt, 15 h, 92% for 2 steps, syn/anti = 18:1; (d) LiHMDS, CH2
CHCH2Br, THF, −78 °C to −40 °C, 2 h, 85%, anti/syn = 9.3:1; (e)
ClSO2CH2Cl, 2,6-lutidine, CH2Cl2, 0 °C, 1.5 h; (f) LiBr, Et2O/THF
(10:1), rt, 6 h, 72% for 2 steps; (g) (Cy3P)2Cl2RuCHPh, CH2Cl2,
40 °C, 2 h, then DMSO, rt, 12 h, 94%.
DMSO, rt, 12 h, 84%; (b) CBr4, Oct3P, BnEt3NBr, toluene, 70 °C, 9 h,
54%, 23:49 = 1:1; (c) CBr4, Oct3P, 1-methyl-1-cyclohexene, toluene,
70 °C, 2 h, 80%, 46:50 = 1:1.4,
These unsatisfactory results led us to develop an efficient two-
step procedure. Ultimately, we found that activation of the
alcohol 24 as the chloromesylate 44 followed by displacement
of the sulfonate ester with bromide with inversion of
configuration gave the bromoamide 46 (Scheme 5).53 This
two-step procedure was practically straightforward to conduct,
and we were able to prepare gram quantities of the
diastereomerically pure bromide 46 with relative ease.
gave the aldehyde 43. Chemoselective chelation controlled
nucleophilic addition of allyltributylstannane to the aldehyde in
the presence of the α-alkoxy amide, yielded the hydroxy amide
25 as an 18:1 mixture of diastereomers (92% from 42) setting
the stage for the pivotal dianion alkylation.
Treatment of the hydroxy amide 25 with LiHMDS followed
by allyl bromide produced the desired α,α′-anti-isomer 24 in
85% yield with 9.3:1 anti/syn stereoselectivity, in accord with
our previous work on the synthesis of (+)-microcladallene B.33b
Having secured an efficient synthesis of the medium-ring
amide 23, we next proceeded to address the synthesis of the
crucial oxocene corresponding to 22 which would allow the key
electrophile-induced biomimetic rearrangement to be inves-
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tigated. Application of our direct ketone synthesis protocol to
the amide 23 with 3-benzyloxypropylmagnesium bromide
followed by Felkin-Anh L-Selectride reduction of the resultant
ketone 52, provided the requisite alcohol 53 as a single
stereoisomer in 93% overall yield (Scheme 7).23a,33b−e,58 Upon
properties and equal and opposite optical rotations (see
Supporting Information).
COMPLETION OF THE SYNTHESIS
■
Having secured efficient syntheses of the allyl-substituted
dibromo 2,2′-bifuranyls 12 and ent-12, all that remained for the
completion of the synthesis of elatenyne, was the installation of
the (Z)-enyne. The Oxford group has previous experience with
the use of the Yamamoto−Peterson reaction10 for the
installation of the (Z)-enyne, whereas the Seoul group had
developed a metathesis strategy for (Z)-enyne introduction.30
Accordingly, ozonolysis of the alkene in 12 followed by a
reductive workup delivered the aldehyde 60. Yamamoto−
Peterson reaction60 using the aldehyde 60 gave the
corresponding (Z)-enyne as the major product in 83% yield
(>30:1, Z:E, Scheme 8). Removal of the acetylene protecting
a
Scheme 7. Biomimetic Route to the 2,2′-Bifuranyl ent-12
a
Scheme 8. Completion of the Synthesis
a
Reagents and conditions: (a) O3/O2, CH2Cl2, −78 °C, 2 min, then
a
Ph3P, −78 °C to rt, 15 h, 85%; (b) TMSCCCH2TBS, tBuLi, THF,
−78 °C 1 h, then Ti(OiPr)4, 10 min, then 60, −78 °C, 30 min, rt, 30
min, 83%, Z:E > 30:1; (c) TBAF, THF, −20 °C, 5 min, 80%; (d)
enyne 61, Grubbs−Hoveyda II 30, benzene, 70 °C, 6 h, 78%, Z:E =
4.6:1; (e) TBAF, THF, 0 °C, 30 min, 98%.
Reagents and conditions: (a) BnO(CH2)3MgBr, THF, rt, 1 h, 94%;
(b) L-Selectride, THF, −78 °C, 1 h, 99%; (c) PhSeBr, SiO2, K2CO3,
CH2Cl2, rt, 20 h, 70%; (d) NBS, CH2Cl2, rt, 2 h, 91%; (e) CH3CN
(0.005 M), 80 °C, 10 h, 93%; (f) H2, Pd(OH)2, THF, 10 min, rt, 95%;
(g) o-nitrophenylselenocyanide, (Oct)3P, THF, rt, 30 min, then 30%
H2O2, rt, 12 h, 97%.
group gave elatenyne 2a in 80% yield. Alternatively, (Z)-
selective cross metathesis of enyne 61 with the alkene ent-12, in
the presence of the Grubbs−Hoveyda second-generation
catalyst39 30 gave the (Z)-enyne 62 as the major product in
a combined yield of 78% (4.6:1, Z:E).30 Removal of the
acetylene protecting group gave elatenyne ent-2a in 98% yield.
The original 1H NMR spectrum of elatenyne (200 MHz,
C6D6)61 and that of the synthetic molecules 2a and ent-2a (200
MHz, C6D6) were in excellent agreement, in addition the 13C
NMR (125 MHz, C6D6) spectra were in excellent agreement
with the listed resonances in the original isolation paper [13C
NMR (50 MHz, C6D6)] and confirm that the stereostructure of
elatenyne is as represented by 2a/ent-2a. Unfortunately, we
were unable to assign the absolute configuration of elatenyne as
the optical rotations measured on the sodium ‘D’ line of both
the Oxford and Seoul samples were close to zero and differed
significantly from that reported for the natural product.7,61 The
optical rotations of the synthetic materials recorded with a
mercury lamp at 365 nm were equal and opposite in sign.62
exposure to PhSeBr and activated silica gel in the presence of
potassium carbonate, the oxocene 53 gave the dibrominated
2,2′-bifuranyl 58 in 70% yield. This complex biomimetic
rearrangement is likely initiated by selenonium ion formation
(54) followed by seleno ether formation giving 55.23
Subsequent activation of the phenylselenyl group in 55 by
PhSeBr followed by displacement of the nucleofuge by
transannular attack of the oxocane oxygen would give the
dioxatricyclic oxonium ion 57. Regioselective opening of the
oxonium ion 57 by bromide with inversion of configuration
gives the dibrominated 2,2′-bifuranyl 58. This transformation
could be indirectly achieved by initial treatment of the oxocene
53 with NBS, resulting in the formation of the dioxabicyclic
dibromide 59 which on heating at 80 °C gave the dibrominated
2,2′-bifuranyl 58 in 85% overall yield. The 2,2′-bifuranyl 58 was
readily converted into the allyl-substituted 2,2′-bifuranyl ent-12
using Grieco’s method as a key step.59 The allyl-substituted
2,2′-bifuranyls 12 and ent-12 had identical spectroscopic
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In 2007, Wang and co-workers reported the isolation of an
inseparable 1:1 mixture of dihalogenated C15 natural products
from L. decumbens which were ultimately assigned as 2,2′-
bifuranyls,9a,b structurally related to notoryne14b and the
reassigned gross structure of elatenyne.10 The 13C NMR
spectra of this mixture of natural products matched closely to
the 13C NMR spectrum of elatenyne, although the 1H NMR in
derived from the oxonium ion 10 by attack of chloride anion
with inversion of configuration at C-7.
With the relative stereochemistry of elatenyne secured, we
reasoned that preparation of the (Z)- and (E)-chloro and
-bromofucins (10 and 11) would allow their absolute
configuration to be confirmed and allow us to propose the
absolute configuration of elatenyne. We have successfully
synthesized the (Z)- and (E)-chloro and -bromofucins (9 and
11) from the γ,δ-unsaturated oxocene alcohol ent-53 using
haloetherification reactions analogous to the conversion of 53
into 59 depicted in Scheme 7. Comparison of the optical
rotations of the synthetic halofucins with the natural product
data demonstrated that the absolute configurations of the
bromofucins and chlorofucins are represented by structures 9
and 11, respectively, thus confirming the original absolute
configuration assignment of (E)-chlorofucin.26a,66 The likely
absolute configuration of elatenyne is therefore represented by
2a.
1
CDCl3 had significant differences to the H NMR (200 MHz,
CDCl3) resonances listed in the original isolation paper,7,63 and
it therefore appeared that the relative configuration of these
natural products was probably diastereomeric to elatenyne.9b
The 1H and 13C NMR spectra, in CDCl3, of synthetic elatenyne
prepared above matched the 1H and 13C NMR spectra of Wang
and co-workers and, as with Wang’s data, showed some
differences with the listed resonances (200 MHz, CDCl3) for
1
the H NMR spectrum of elatenyne from those in the original
isolation paper.7,64 We concluded that Wang and co-workers
had indeed isolated elatenyne (and the bromo−chloro analogue
of elatenyne, laurendecumenyne B, 4). In order to confirm the
above, the Seoul group synthesized laurendecumenyne B
(Scheme 9). Treatment of the oxocene 53 with PhSeCl gave
the corresponding 2,2′-bifuranyl 63 in 69% yield presumably via
formation of the tricyclic oxonium ion 57 (Scheme 9).
Synthesis of Derivatives. In the original isolation paper,
Hall and Reiss prepared a number of derivatives of elatenyne
including the aldehyde 60, the acetate 66 and the
perhydroderivative 67. As part of the synthesis of elatenyne
2a we had already prepared the aldehyde 60. The 13C NMR
spectrum of the synthetic aldehyde 60 was in excellent
agreement with the listed data reported by Hall and
Reiss.7,61,67 Reduction of the aldehyde with sodium borohy-
dride followed by acetylation gave the acetate 66. The 1H NMR
of the acetate 66 (200 MHz, C6D6) was an excellent match with
a
Scheme 9. Synthesis of Laurendecumenyne B
1
the corresponding H NMR spectrum reported by Hall and
Reiss.61,68 Hydrogenation of a small sample of synthetic
elatenyne 2a gave the perhydroderivative 67 which again
showed excellent agreement of the 13C NMR data between the
data for the synthetic and natural samples.7,67
Chart 2
a
Reagents and conditions: (a) PhSeCl, SiO2, K2CO3, CH2Cl2, rt, 3 d,
69%; (b) H2, Pd(OH)2, THF, 10 min, rt, 94%; (c) o-nitro-
phenylselenocyanide, (Oct)3P, THF, rt, 30 min, then 30% H2O2, rt,
12 h, 92%; (d) enyne 61, Grubbs−Hoveyda II 30, benzene, 70 °C, 6 h,
77%, Z:E 3.8:1; (e) TBAF, THF, 0 °C, 20 min, 95%.
Synthesis of (E)-Elatenyne. In 1989 Erickson and co-
workers reported the isolation and partial structure determi-
nation of a dibrominated 2,2′-bifuranyl from L. majuscula.13
There are striking similarities between the 13C NMR
resonances of elatenyne and the Erickson enyne that led us
to propose that the Erickson enyne and elatenyne might be
double bond isomers.10b The synthesis of the dibrominated
2,2′-bifuranyls 12/ent-12 presented us with an excellent
opportunity to test this proposal. Thus, addition of the ylide
d e r i v e d f r o m ( 3 - t r i m e t h y l s i l y l - 2 - p r o p y n y l ) -
triphenylphosphonium bromide to a cold solution of the
aldehyde 60 gave the (E)-enyne 68 as an 8:1 mixture of (E):
(Z) geometrical isomers (Scheme 10).10 Removal of the
acetylene protecting group gave (E)-elatenyne 3 in 81% yield.
Alternatively, using our previously developed, efficient method-
ology for (E)-enyne synthesis,23a,30a the allyl substituted 2,2′-
bifurnyl ent-12 underwent cross metathesis with crotonalde-
hyde in the presence of the Grubbs−Hoveyda second-
generation catalyst to give exclusively the (E)-α,β-unsaturated
Hydrogenolysis of the benzyl group in 63 followed by Grieco
elimination59 delivered the terminal alkene 64 which was
converted into laurendecumenyne B ent-4 using the metathesis
route analogous to that discussed for the synthesis of 62. The
1H and 13C NMR spectra of synthetic laurendecumenyne B
were an excellent match with the spectra published by
Wang9a,65 and confirm the 2,2′-bifuranyl structure and the
relative configuration of laurendecumenyne B as 4; laurende-
cumenyne B 4 is thus a diastereomer of notoryne.14b
Furthermore, the presence of a chlorine atom at C-7 of
laurendecumenyne 4 coupled with the transformations
described in Schemes 7 and 9, lend weight to the proposed
biosynthesis of these 2,2′-bifuranyl halogenated marine natural
products (Scheme 1).14b Thus, laurendecumenyne B would be
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Article
a
Notes
Scheme 10. Synthesis of (E)-Elatenyne
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the EPSRC (UK) and by the
NRF Grant funded by the MEST, Korea (No. 20120000847).
We are grateful to Dr. James Reiss (University of La Trobe,
Australia), for providing NMR spectra of elatenyne and some
derivatives; Dr. Bin-Gui Wang (Chinese Academy of Sciences,
Qingdao, China) for providing NMR spectra of elatenyne and
laurendecumenyne B; and Dr. Sylvia Urban (Royal Melbourne
Institute of Technology (RMIT), Australia), for providing
NMR spectra of elatenyne.
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CONCLUSION
■
In conclusion we have completed the first total syntheses of
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Additionally, we have synthesized laurendecumenyne B ent-4
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AUTHOR INFORMATION
Corresponding Author
jonathan.burton@chem.ox.ac.uk (J.W.B.); deukjoon@snu.ac.kr
(D.K.)
■
̃
́ ́
dez-Barragan, A.;
́
́
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(19) Coupling the different stereoisomers of the laurediols which
occur naturally, with the assumed biosynthetic route depicted in
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Article
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7595. (d) The enantiomeric excess and absolute configuration were
determined and confirmed by Mosher ester analysis see: Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092−4096. Details can be found in the Supporting Information. (e)
Ultimately the preparation of the cross metathesis partners was found
to be most efficient using the SAE kinetic resolution of hex-1,5-dien-3-
ol 19, although we also investigated the synthesis of cross metathesis
partners using a Barbier-type allylation of various glyceraldehyde
acetals with zinc and allyl bromide, according to the procedure of
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(37) The enantiomer has been previously prepared see: Kim, B.;
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see: (a) Murai, A.; Murase, H.; Matsue, H.; Masamune, T. Tetrahedron
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3891−3894. (b) Reference 33e.
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alcohols see: ref 30a.
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alcohols see: ref 37.
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benzoquinone as an additive in the cross metathesis reaction in order
to minimize olefin isomerization of the alkenes 28 and 29; the
isomerized epoxide from 29 was active in the cross metathesis reaction
giving rise to the truncated alkene corresponding to 31 among other
products.
(41) We used the Knight procedure to remove ruthenium residues
see: Knight, D. W.; Morgan, I. R.; Proctor, A. J. Tetrahedron Lett. 2010,
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(44) (a) The absolute configuration of the minor diastereomer from
the SAD reaction of 31 was assigned on a derivative using the method
of Kakisawa, see ref 35d., and the Supporting Information (SI). (b)
SAD of alkene 31 with AD-mix-β gave the corresponding syn-diols as
an approximate 1:3.5 mixture, where as a ‘racemic’ dihydroxylation,
Eames, J.; Mitchell, H. J.; Nelson, A.; O’Brien, P.; Warren, S.; Wyatt, P.
J. Chem. Soc., Perkin Trans. 1 1999, 1095−1103 gave the corresponding
diols as a 1:1.3 mixture indicating little stereocontrol from the
stereocenters present in 31.
(45) The nitrile 36 was isolated as a single diastereomer. The
configuration at C-6 as represented in 36 was assigned by comparison
of the 1H NMR spectrum of 36 with the 1H NMR spectra of
compounds 34, 38, and the p-nitrobenzoate derived from 40 (see SI).
It is possible that the C-6 stereocenter in 36 could be compromised by
a retro-Michael (E1cB), Michael reaction of 36 under the basic
reaction conditions see ref 46.
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(62) The optical rotation of natural elatenyne was reported on the
sodium ’D’ line. See Supporting Information for optical rotation data
for synthetic elatenyne recorded at a number of wavelengths.
(63) Comparing listed proton NMR resonances with actual proton
NMR spectra is not the ideal method for determining whether two
compounds are identical, as it not possible to compare relative peak
heights, line shapes, etc.
(64) Dias and Urban also noted differences in the 1H NMR chemical
shifts in CDCl3 of their isolated sample of elatenyne compared with
the original listed resonances of Hall and Reiss, see ref 9c. The 1H and
13C NMR spectra of our synthetic material (CDCl3 and C6D6) were an
excellent match with the corresponding NMR spectra kindly supplied
by Dr. Urban.
(65) There was also an excellent match between the natural 13C
NMR spectrum of a 1:1 mixture of elatenyne and laurendecumenyne B
reported by Wang and the sum of the 13C NMR spectra of synthetic
elatenyne and laurendecumenyne B.
(66) The full synthesis of the halofucins will be reported in due
course; Kim, B. Ph.D. Thesis, Seoul National University, Seoul, Korea,
2011.
1
(67) The H NMR data were a reasonable match with the listed
resonances reported by Hall and Reiss; see ref 61.
(68) The 13C NMR data were a reasonable match with the listed
resonances reported by Hall and Reiss.
(69) We were unable to determine the absolute configuration of
natural (E)-elatenyne as no optical rotation data were reported in the
original isolation paper. Additionally, we have been unable to obtain
copies of the proton and carbon NMR data of natural (E)-elatenyne.
(46) For an example of epimerization of a β-alkoxy nitrile under basic
conditions see: Ohrui, H.; Jones, G. H.; Moffatt, J. G.; Maddox, M. L.;
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