Catalytic asymmetric claisen rearrangement of gosteli-type allyl vinyl ethers: Total synthesis of (-)-9,10-dihydroecklonialactone B

Article abstract of DOI:10.1021/jo5001466

The enantioselective synthesis of (-)-9,10-dihydroecklonialactone B is described. The catalytic asymmetric Claisen rearrangement of a Gosteli-type allyl vinyl ether was utilized to afford an acyclic α-keto ester building block endowed with functionality a

Full text of DOI:10.1021/jo5001466

Article
pubs.acs.org/joc
Catalytic Asymmetric Claisen Rearrangement of Gosteli-Type Allyl
Vinyl Ethers: Total Synthesis of (−)-9,10-Dihydroecklonialactone B
Julia Becker, Lena Butt, Valeska von Kiedrowski, Elisabeth Mischler, Florian Quentin,
and Martin Hiersemann*
Fakultat Chemie und Chemische Biologie, Technische Universitat Dortmund, 44227 Dortmund, Germany
̈
̈
S
* Supporting Information
ABSTRACT: The enantioselective synthesis of (−)-9,10-
dihydroecklonialactone B is described. The catalytic asymmetric
Claisen rearrangement of a Gosteli-type allyl vinyl ether was
utilized to afford an acyclic α-keto ester building block endowed
with functionality amenable to the preparation of the carbocyclic
target molecule by suitable postrearrangement transformations:
A highly diastereoselective Corey−Bakshi−Shibata reduction of
a β-chiral α-keto ester and a reductive homologation of an α-
hydroxy ester. A transprotection tactic by a chemoselective
intramolecular 6-exo-trig iodoetherification enabled regioselec-
tive ring-closing alkene metatheses to afford the 5- as well as the
14-membered ring, however, with mixed success in terms of E/Z
selectivity.
secured by crystallography, whereas the absolute configuration
was deduced from the chiroptical properties of the levorotatory
natural product.13 The structure of (−)-2 was initially deduced
from the similarities of the spectroscopic properties of (−)-1
and (−)-2.12 Semisynthesis of the saturated 9,10-dihydro
ecklonialactone B (+)-3 from either (−)-1 or (−)-2 by
hydrogenation corroborated the assignment.12
INTRODUCTION
■
The [3,3]-sigmatropic rearrangement of allyl vinyl ethers is
generally known as the Claisen rearrangement.1,2 The catalysis
of the Claisen rearrangement requires matching combinations
of electrophilic catalysts and specifically substituted allyl vinyl
ethers.3,4 Sufficient σ- or π-electrophilicity of the catalyst has to
be carefully balanced against transition-state-structure chair/
boat dichotomy, substrate decomposition by C/O bond
heterolysis, and product inhibition of the catalyst. Hence, the
known catalysts suffer from a rather narrow substrate
specificity.4 Furthermore, only a very limited number of chiral
catalyst/allyl vinyl ether combinations that enable truly catalytic
asymmetric Claisen rearrangements (CAC) are known, and the
application of the CAC in target-oriented synthesis is still in a
stage of infancy.4
During the past decade, it has been demonstrated that the
Claisen rearrangement of Gosteli-type allyl vinyl ethers, the
Gosteli−Claisen rearrangement,5 can be catalyzed by chiral
copper(II) bis(oxazoline) Lewis acids or guanidinium dual
hydrogen-bond-donating organocatalysts.6−8 The Cu(box)-
catalyzed catalytic asymmetric Gosteli−Claisen rearrangement
(CAGC) delivers branched and functionalized δ,ε-unsaturated
α-keto esters in a synthetically useful selectivity.9,10 Intending
to demonstrate the utility of acyclic α-keto esters in the
synthesis of carbocyclic target molecules as well, we considered
the total synthesis of carbocyclic oxylipins as a rewarding
challenge.11
The first total synthesis of (−)-1 or (−)-2 was reported by
Furstner in 2010 and features a ring-closing alkyne metathesis
̈
and a subsequent hydrogenation for the construction of the Z-
configured 9,10-double bond.14 Following an initial report on
the synthesis of a cyclopentanoid building block in 2007,15 we
achieved the first total synthesis of (+)-3 via (−)-2 in 2013.16
Our route embarked from the enantiomerically pure building
block (+)-6 which is accessible from the Gosteli-type allyl vinyl
ether (E,Z)-5 by [Cu{(S,S)-t-Bu-box}(tfe)2](SbF6)217 ((S,S)-4)
catalyzed Claisen rearrangement (Figure 2). A ring-closing
alkene metathesis was used for the formation of the
cyclopentanoid segment; the 14-membered lactone was
synthesized from the corresponding hydroxy acid.
Our laboratory was intrigued by the possibility of using
(Z,Z)-5, on hand from the synthetic campaign that made
available (E,Z)-5, to access syn-6 and to explore opportunities
to harvest the pseudodiastereotopic relationship between the
vinyl and the benzyloxymethyl group (Figure 2). If successful,
the diastereomeric rearrangement product syn-6 could be
The oxylipins ecklonialactone A (1) and B (2) have been
isolated from the brown algae Ecklonia stolonifera by Kurata et
al. (Figure 1).12 The relative configuration of (−)-1 was
Received: January 21, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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Figure 1. Ecklonialactones from the brown algae Ecklonia stolonifera and the semisynthetic saturated derivative 9,10-dihydroecklonialactone B.
Figure 2. Assembling enantiomeric target molecules from diastereomeric building blocks.
converted to the enantiomeric target molecule (−)-3; in this
Synthesis of the Gosteli-Type Allyl Vinyl Ether 5. The
synthesis of the Gosteli-type allyl vinyl ether (Z,Z)-5
commenced from commercial (Z)-butene-1,4-diol as outlined
in Scheme 1. Two successive Williamson etherifications and a
subsequent Fischer esterification delivered the ester 10. Aldol
reaction between the lithium enolate of 10 and (4-
phenylselenyl)butanal 11,15 a synthetic equivalent for 3-
butenal18 for which, in our hands, double-bond isomerization
was unavoidable, delivered the β-hydroxy ester 12 in a roughly
2:1 ratio of diastereomers. No attempts were made to assign
the relative configuration of the diastereomeric β-hydroxy esters
12. Synthesis of the aldehyde 11 was accomplished by reductive
ring-opening of tetrahydrofuran19 followed by Parikh−Doering
oxidation.20
paper, we describe in detail the results from this endeavor.
RESULTS AND DISCUSSION
■
In retrospective, our synthetic planning toward (−)-9,10-
dihydroecklonialactone B ((−)-3) was guided by the possibility
of a differentiation of the double bonds of 12,13-desepoxy-
ecklonialactone B (7) by a regio- and diastereoselective
epoxidation of the 12,13-double bond (Figure 3).16 Further-
Mesylation of 12 followed by treatment of the crude
mesylate with DBU at ambient temperature delivered the
Gosteli-type allyl vinyl ether 13 as a mixture of vinyl ether
double-bond isomers (Z/E = 3:2). Separation of the double-
bond isomers was achieved by preparative HPLC. Oxidation of
the separated selenides (E,Z)- and (Z,Z)-13 triggered
elimination21 to afford the Gosteli-type allyl vinyl ethers
(E,Z)- and (Z,Z)-5.
The uncatalyzed Gosteli−Claisen rearrangement of (E,Z)-5
was briefly studied on preparative scale delivering the racemic
α-keto ester anti-6 in good yield and diastereoselectivity. The
Claisen rearrangement was performed at 80 °C in 1,2-
dichloroethane for several days to ensure complete conversion
of the starting material. The relative configuration of anti-6 was
initially assigned assuming a chairlike transition-state structure.
NOE analysis of a synthetic derivative provided evidence for
the feasibility of the assignment.15
Our laboratory is interested in rate effects on pericyclic
reactions in general and the Claisen rearrangement in
particular.22 Having gained access to the Gosteli-type allyl
vinyl ethers 5 and 13, we elected to pursue a kinetic study.
Thus, temperature-dependent kinetics of the uncatalyzed
Figure 3. Synthesis of (−)-3 in retrospective.
more, we intended to make use of 9-decenoic acid, which is
commercially available, for the assemblage of the C1−C9
segment of 7. The approach toward 7 then required three
distinct stages. First, a robust scalable synthesis of the
functionalized Gosteli-type allyl vinyl ether 5, containing a
skipped dienoate, was in demand. Second, 5 needed to be
converted into the elaborated chiral building block 8. Third,
following the protection of the 13,13′-double bond in 8 against
an untimely participation on a metathesis event, successive ring-
closing olefin metatheses (RCM) were envisioned for
formation of desepoxyecklonialactone (7).
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Scheme 1. Synthesis of the Gosteli-Type Allyl Vinyl Ether 5 by Aldol Condensation
Scheme 2. Synthesis of the Gosteli-Type Allyl Vinyl Ether 5 by Horner−Wadsworth−Emmons Olefination
Gosteli−Claisen rearrangement of (Z,Z)-5 and (Z,Z)-13 were
measured, and Eyring analyses of the obtained data provided
activation parameters for the rearrangement of the two allyl
vinyl ethers. From the Eyring plot, we determined for (Z,Z)-5
in 1,2-dichloroethane at 80 °C a ΔG⧧ = 28.7 kcal/mol. This
value compares well with free energies of activation previously
determined by our laboratory for structurally related Gosteli-
type allyl vinyl ethers.22 The Gosteli-type allyl vinyl ethers 13
(PhSeCH2CH2CH2) and 5 (H2CCHCH2) are distinguished
by the nature of the substituent at the terminal carbon atom of
the vinyl ether double bond. The question surfaced whether the
two substituents would exert a significant substituent-rate effect
on the uncatalyzed rearrangement. Judging from the com-
parable steric and electronic bias of the two substituents, we
expected, if any, a rather small substituent rate effect. Indeed,
(Z,Z)-13 in 1,2-dichloroethane at 80 °C was found to be only
slightly less reactive (ΔG⧧ = 29.2 kcal/mol) than (Z,Z)-5 (ΔG⧧
= 28.7 kcal/mol). From the Eyring plot we found that in
comparison to 1,2-dichloroethane, the solvent 2,2,2-trifluoro-
ethanol (Z,Z)-5 at 80 °C has a small barrier-lowering bias (ΔG⧧
= 28.2 kcal/mol) which is also measurable for (Z,Z)-13 in
trifluoroethanol at 80 °C (ΔG⧧ = 28.4 kcal/mol). Notably, our
Eyring analyses indicate a negative ΔS⧧ in all cases (between
−21 and −30 cal/K mol) as would be expected for a concerted
rearrangement.23
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Scheme 3. Successive Catalytic Asymmetric Transformations Are Key to the Synthesis of the Triene 8
Turning back to synthesis, we investigated an alternative to
the aldol condensation route to the allyl vinyl ether 5 with the
aim of improving our control over the vinyl ether double-bond
configuration. From previous experience, we expected that an
E-selective olefination route using a functionalized trimethyl
phosphonoacetate would be a viable alternative (Scheme 2).9
To access the required phosphonate 16, the diazo phosphonate
1524 and the allylic alcohol 9 were subjected to a Rh(II)-
catalyzed O−H insertion.25 As anticipated, subsequent
Horner−Wadsworth−Emmons olefination between the result-
ing phosphonate 16 and the aldehyde 11 delivered 5 with an E/
Z = 5:1 selectivity.26,27 However, despite being more E-
selective, the olefination route is less attractive for our
laboratory because of the cost of the catalyst for the O−H-
insertion reaction and, in our hands, its limited scalability.
Catalytic Asymmetric Synthesis of the Triene 8. With a
robust and scalable synthesis of the Gosteli-type allyl vinyl ether
(Z,Z)-5 developed, we turned our attention to the stereo-
selective synthesis of the triene 8 (Scheme 3). (S,S)-4 catalyzed
Claisen rearrangement of (Z,Z)-5 afforded the α-keto ester 6 in
high yield and synthetically useful diastereo- and enantiose-
lectivity.28 Catalysis performed on a preparative scale in 1,2-
dichloroethane at room temperature required a liberal loading
of (S,S)-4 (0.1 equiv) to ensure complete conversion. The
copper(II) bis(oxazoline) precatalyst (S,S)-4 was found to be
particularly effective for the CAGC enabling an even faster
turnover than the related bis(aqua) complex [Cu{(S,S)-t-Bu-
Figure 4. Schematized catalytic cycle for the catalytic asymmetric
Gosteli−Claisen rearrangement. Formal charges on Cu(II) and
counterions are omitted for clarity.
catalyst decreases the rearrangement barrier by a peak-affinity
transition-state (ts) complexation. In comparison to the
uncatalyzed rearrangement, an increased “looseness” of the
Cu(box)-complexed transition-state structure is predicted by
calculation.30 The C2 dissymmetric t-Bu-BOX ligand is
responsible for the enantioface differentiation with respect to
the vinyl ether double bond.31 A direct substrate (20)/product
(21) exchange at the catalyst without the assistance of auxiliary
ligands is assumed.32
Our next objective was to investigate the diastereoselective
reduction of the α-keto ester 6. In order to exploit the
anticipated intrinsic substrate-induced diastereoselectivity in
favor of the desired diastereomer of 17,33 we initially selected
29
box}(H2O)2](SbF6)2 originally reported by Evans. The
bis(trifluoroethanol) complex (S,S)-4 can be synthesized as a
stock solution from the commercial t-Bu-BOX ligand and
shows a characteristic UV−vis spectrum.17 The proposed
catalytic cycle is depicted in Figure 4 for the generic Gosteli-
type allyl vinyl ether (Z,Z)-20.4 Substrates containing a (Z)-
configured allylic ether double bond are required to alleviate
the propensity for a chair/boat dichotomy. The σ-electrophilic
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Scheme 4. Successive Ring-Closure by Alkene Metathesis
K-Selectride as a bulky reducing agent.6 In the event, and as
expected, the reduction (THF, below −90 °C) proceeded
highly diastereoselectively (dr >95:5) in favor of (2S)-17.
However, and despite being a spot-to-spot reaction judging
from TLC, the yield of the K-Selectride reduction never
exceeded 80% in a reliable and scalable fashion. Fortunately,
our laboratory had previously observed encouraging results
applying the Corey−Bakshi−Shibata protocol for the diastereo-
selective reduction of β-chiral α-keto esters from the Gosteli−
Claisen rearrangement.34,35 Accordingly, application of the (R)-
MeCBS catalyst afforded the (2S)-configured α-hydroxy ester
17 as a single diastereomer (NMR) in high yield on gram
scale.36 Notably, application of the (S)-MeCBS catalyst also
delivered (2S)-17 albeit in slightly lower yield (dr >95:5, 81%).
This result illustrates the dominance of the substrate-induced
2Re-diastereoface-differentiation for (3S,4R)-6.
With the key stereotriad in place, we turned our attention to
the reductive homologation of the α-hydroxy ester 17 to afford
the secondary alcohol 19 with retention of configuration. Thus,
exposing 17 to LAH afforded the diol 18 in high yield on a
gram scale. We then opted for a telescoped transformation
consisting of oxirane formation by SNi and position-selective
oxirane ring-opening by a methyl nucleophile. Formation of the
epoxide from 18 was conducted using an excess of NaH and
stoichiometric amounts of N-tosylimidazole (TsIm).37 Sub-
sequent addition of superstoichiometric amounts of CuI (2
equiv) and MeMgBr (10 equiv) afforded the secondary alcohol
19 in a just acceptable yield.38 Attempts to lower the copper
load or to improve the yield by varying the copper source
(CuBr·SMe2, CuCN) were ineffective.
avoid the cumbersome separation of unconsumed acid and the
ester 8.
Synthesis of (−)-Dihydroecklonialactone B (3). With
the desired acyclic triene 8 in hand, we proceeded to investigate
the formation of the 14-membered lactone by ring-closing
alkene metathesis (RCM) with a particular interest in the
expectable E/Z selectivity.40 At first glance, we presumed, but
never established experimentally, an unselective initiation of the
RCM at the C13/C13′ and C9/C9′ terminal monosubstituted
double bonds of 8. Hence, we shied away from subjecting 8 to
the conditions of the RCM and, instead, opted for a tactic
which combines the mandatory cleavage of the benzyl ether
protecting group with a protection of the C13/C13′ double
bond by iodoetherification. The thus envisioned trans-
protection could be complicated by regioselectivity and
chemoselectivity (iodo lactonization) issues. However, we
were hopeful that the desired 6-exo-trig iodoetherification
would prevail over the 4-exo-, 5-endo-, 7-endo-trig alternatives.41
The participation of the C9/C9′ double bond in a macro-
cyclization event was considered improbable.42 To our delight,
subjecting the benzyl ether 8 to an excess of iodine and
NaHCO3 in dry MeCN43 at low temperature indeed delivered
the desired product 22 of a 6-exo-trig iodoetherification as a
mixture of diastereomers (dr = 77:23);44 no attempt was made
to separate the diastereomers or to assign the configuration of
the labile compound.
Having masked the C13/C13′ double bond by iodo
etherification, we proceeded to realize the envisioned lactone
formation by RCM. Unfortunately, in our hands, this endeavor
turned out to be much more challenging than desired because
intermediate compounds proved to be labile and/or difficult to
purify. After screening commercial catalyst and conditions for
the ring-closing event, in our hands the Grela catalyst45 (0.05
equiv) in the presence of 1,4-benzoquinone46 (0.1 equiv) at
elevated temperature was best performing and delivered the
corresponding labile bicyclic lactone. In order to avoid
extensive decomposition, particularly in solution, this bicyclic
To conclude the assemblage of the triene 8 a seemingly
straightforward esterification between the alcohol 19 and the
commercially available 9-decenoic acid was required. Applica-
tion of the protocol according to Steglich39 indeed yielded the
desired ester 8 along with the unconsumed alcohol 19, which
could be separated and reused. Using an excess of the alcohol
19 to enforce complete conversion of the acid was a tribute to
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lactone was immediately subjected to Zn-mediated β-
elimination to deliver the lactone 23 in a low yield (41%)
and, unfortunately, as an inseparable mixture of double bond
isomers (Z/E = 2:1).47
droecklonialactone B (3). Thus, we have demonstrated that
the catalytic asymmetric Claisen rearrangement of Gosteli-type
allyl vinyl ethers delivers acyclic α-keto ester building blocks
endowed with functionality amenable to the preparation of
carbocyclic natural products by suitable postrearrangement
transformations.
Nevertheless, having closed the lactone, reinstated the C13/
C13′ double bond, and exposed the C12 hydroxyl group, we
proceeded to introduce the C12/C12′ double bond in
preparation for the final RCM event (Scheme 4). Hence, the
alcohol 23 was oxidized with IBX48 and subjected to a Wittig
methylenation which delivered the diene 24 as a mixture of
double bond isomers. Diene 24 was then subjected to a RCM
employing “Grubbs I”49 at slightly elevated temperature to
deliver the 12,13-desepoxy ecklonialactone B (7) as a mixture
of C9/C10 double-bond isomers. The mixture of C9/C10
double bond isomers was inconsequential at this stage as the
double bond would need to be hydrogenated for the
completion of the synthesis of (−)-3. However, we were thus
denied access to a pure sample of (+)-ecklonialactone B (2),
the enantiomer of the actual natural product. The regio- and
diastereoselective epoxidation of the C12/C13 double bond
was accomplished by employing our previously discovered two-
step procedure.16 Thus, subjecting 7 to NBS (1 equiv) in
aqueous acetone delivered a bromohydrin which upon
treatment with Ag2O at elevated temperature underwent an
SNi to deliver (+)-2 still as a mixture of C9/C10 double-bond
isomers and contaminated with an inseparable impurity.
EXPERIMENTAL SECTION
■
Materials and Methods. Unless otherwise stated, commercially
available reagents were used as purchased. Solvents (tetrahydrofuran,
dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylfor-
mamide, and toluene) were dried deploying a commercially available
solvent purification system. Diisopropylamine and triethylamine were
dried (CaH2, rt, 12 h; distillation) and stored over activated 4 Å
molecular sieves. DMSO was used as purchased (99.5% purity).
CDCl3 was stored under argon over activated 4 Å molecular sieves.
Moisture-sensitive reactions were performed in flame-dried septum-
sealed glassware under an atmosphere of argon. Reagents were
transferred by means of syringe. Analytical TLC was performed using
precoated silica gel foils (4 cm height). Visualization was achieved
using 254 nm ultraviolet irradiation followed by staining (Kagi−
̈
Miescher reagent: p-anisaldehyde 2.53% v/v, acetic acid 0.96% v/v,
ethanol 93.06% v/v, concd H2SO4 3.45% v/v; KMnO4 reagent:
KMnO4 (3 g), K2CO3 (20 g), NaOH (0.25 g in 5 mL H2O), H2O
(300 mL).51 Chromatographic purification was performed on silica gel
(particle size 0.040−0.063 mm) using mixtures of cyclohexane and
ethyl acetate, heptane and ethyl acetate, or n-pentane and diethyl
1
ether. H NMR spectra were recorded at 400 or 500 MHz. Chemical
1
shifts (δ) are reported in ppm relative to chloroform (7.26 ppm).52
Signal splitting patterns are reported as they appear and are labeled
accordingly: s = singlet, d = doublet, t = triplet, q = quartet, quintet =
quint, m = multiplet or overlap of nonequivalent signals. 13C NMR
spectra were recorded at 101 or 126 MHz. Chemical shifts are
reported in ppm relative to CDCl3 (77.16 ppm); the total number of
reported 13C atom signals may fall short of the expected number
because of coincidental chemical shifts, even for constitutopic or
diastereotopic carbon atoms. HSQC and/or HMBC experiments were
used to confirm the NMR signal assignments. Unless stated otherwise,
IR spectra were recorded as a thin film on a KBr disk. Infrared
absorptions are reported in reciprocal wavelength ν (cm−1) and are
adjusted down- or upward to 0 or 5 cm−1. Relative intensities are
indicated as they appear using the following abbreviations: s = strong,
m = middle, w = weak, br = broad. Molecular formula assignment was
confirmed by combustion elemental analysis and copies of reports are
given in the Supporting Information. High-resolution mass spectra
were recorded on a commercial spectrometer by electrospray
ionization (ESI) using an Orbitrap mass analyzer. Optical rotations
were measured deploying a commercial polarimeter operating on the
sodium D line (589 nm) and using a 1 mL cuvette and are reported as:
Interestingly, H NMR data suggest the formation of single
constitutional isomer of the intermediate bromohydrin;
however, no attempts were made to unambiguously assign its
structure. To complete the synthesis of (−)-dihydroecklonia-
lactone B (3), hydrogenation of the remaining C9/C10 double
bond was required. Thus, subjecting (+)-2 to a hydrogen
atmosphere in the presence of Adams’ catalyst50 delivered
(−)-3 having proton and carbon NMR spectra in very good
accordance with those reported for (+)-3 by Kurata12 and by
our laboratory.16 However, our synthetic (−)-3 was contami-
nated by an NMR-visible inseparable minor impurity, which
judging from our experience,16 is not the (12S,13R)-configured
diastereomer of (−)-3. Under these circumstances, the
measured specific rotation for (−)-3 [[α]23 −16.5 (c 0.58,
D
CHCl3)] compared well to those reported for (+)-3 [[α]23
D
+14.5 (c 0.55, CHCl3)] by Kurata12 and by our laboratory16
[[α]25 +12.6 (c 1.0, CHCl3)].
D
CONCLUSION
■
[α]T (concentration in g/100 mL, solvent). Kinetic measurements
We have outlined herein the total synthesis of (−)-9,10-
dihydroecklonialactone B (3). This endeavor was accomplished
in three stages. First, a robust scalable synthesis of the
functionalized Gosteli-type allyl vinyl ethers (E,Z)- and (Z,Z)-5
was established using either a Z-selective aldol condensation or
an E-selective olefination route; the separation of the vinyl
ether double-bond isomers was accomplished by automated
preparative HPLC. Second, key to the conversion of (Z,Z)-5
into the elaborated chiral building block 8 was a sequence of
two successive catalytic asymmetric transformations: a highly
diastereo- and enantioselective Gosteli−Claisen rearrangement
and a highly diastereoselective Corey−Bakshi−Shibata reduc-
tion. Third, an interesting transprotection tactic enabled
successive ring-closing olefin metatheses (RCM) to provide
the bicyclic core of the target molecule. Although we were
unable to achieve the ring-closing metathesis to form the 14-
membered macrolacatone with complete Z-selectivity, subse-
quent hydrogenation provided access to (−)-9,10-dihy-
D
for each substrate at each temperature were performed in double-
parallel experiments. A sealable glass pressure tube was charged with a
homogeneous solution of the corresponding allyl vinyl ether (60 mg)
in the respective solvent (5 mL). The tube was sealed with a Teflon
screw cap and placed in a preheated oil bath at the indicated
temperature (60−85 °C). At the specified time, an aliquot (0.7 mL)
was sampled and immediately chilled to 0 °C. The solvent was
removed under reduced pressure at room temperature. The
percentage of conversion was determined by integration of
representative 1H NMR (CDCl3) signals. In order to probe for
deviations in the mass balance of the uncatalyzed rearrangement, two
experiments were performed in the presence of an internal standard.
[Cu{(S,S)-t-Bu-box}(tfe)2](SbF6)2 (S,S)-4. The synthesis of (S,S)-4
was accomplished from (S,S)-t-Bu-bis(oxazoline); this ligand was
prepared from (S)-tert-leucine following the procedures reported by
Evans.53−55 [Cu[(S,S)-t-Bu-box]Cl2]·(CH2Cl)2. To a solution of 2,2′-
isopropylidene bis[(4S)-4-tert-butyl-2-oxazoline] (294.43 g/mol, 4.0 g,
13.59 mmol, 1 equiv) in (CH2Cl)2 (50 mL) at room temperature was
added dried (0.1 mbar, 70 °C, 1 h) CuCl2 (99.999%, 134.45 g/mol,
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1.83 g, 13.59 mmol, 1 equiv). The mixture was stirred for 3 h in the
dark. The resulting light green solution was filtered through a plug of
cotton, and the filtrate was concentrated at reduced pressure and dried
in vacuo. The title compound (7.09 g, 13.43 mmol, 99%) was isolated
as a light green solid. C19H34Cl4CuN2O2, 527.84 g/mol. [Cu{(S,S)-t-
Bu-box}(tfe)2](SbF6)2 (S,S)-4. To the light green solution of the
[Cu[(S,S)-t-Bu-box]Cl2]·(CH2Cl)2 complex (527.84 g/mol, 1372 mg,
2.6 mmol, 1 equiv) in (CH2Cl)2 (26 mL) at 0 °C under the exclusion
of light was added AgSbF6 (343.62 g/mol, 1787 mg, 5.2 mmol, 2
equiv). The reaction mixture was stirred for 2 h at 0 °C in the dark.
The resulting dark green solution was filtered through a syringe filter
(PTFE, 0.45 μm) in order to remove the precipitated AgCl. To the
filtrate was added CF3CH2OH (100.04 g/mol, 1.39 g/mL, 0.74 mL,
10.32 mmol, 4 equiv), and the resulting green stock solution (0.1 M)
of the title compound was used for the catalytic asymmetric Gosteli−
Claisen rearrangement.
extracted with CH2Cl2 (3×). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. Chromatographic
purification of the residue (cyclohexane/ethyl acetate 10/1 to 5/1 to
1/1) afforded the alcohol 9 (29.107 g, 163.3 mmol, 84% from benzyl
bromide) as pale yellow oil: Rf 0.48 (cyclohexane/ethyl acetate 1/1);
1H NMR (CDCl3, 400 MHz) δ 1.86 (br s, 1H), 4.10 (d, J = 6.0 Hz,
2H), 4.18 (d, J = 6.5 Hz, 2H), 4.53 (s, 2H), 5.72−5.78 (m, 1H), 5.80−
5.86 (m, 1H), 7.29−7.39 (m, 5H); 13C NMR (CDCl3, 101 MHz) δ
58.9, 65.8, 72.6, 128.0, 128.5, 128.1, 128.6, 132.5, 130.0; C11H14O2,
178.23 g/mol.
Synthesis of α-Allyloxy Acetate 10. Williamson Etherification.
To a stirred solution of bromoacetic acid (138.94 g/mol, 6.343 g,
45.65 mmol, 1.1 equiv) in THF (75 mL) at −78 °C was added sodium
hydride (24.0 g/mol, 60% m/m dispersion in mineral oil, 4.98 g, 124.5
mmol, 3 equiv). After being stirred at −78 °C for 0.5 h, a solution of
the alcohol 9 (178.23 g/mol, 7.355 g, 41.27 mmol, 1 equiv) in THF
(20 mL) was added at −78 °C, and the resulting mixture was allowed
to warm to ambient temperature overnight. The reaction mixture was
diluted with aqueous KOH (1 M, 60 mL), and the layers were
separated. The aqueous phase was acidified by the addition of
concentrated HCl (pH < 4) and extracted with CH2Cl2 (3×). The
combined organic layers were dried (MgSO4) and concentrated. After
removing all volatiles in vacuo, the crude product was used without
further purification. Fischer Esterification. To a solution of the crude
acid in MeOH (41 mL) at 0 °C was added concentrated (98% v/v)
sulfuric acid (98.08 g/mol, 1.84 g/mL, 0.66 mL, 12.45 mmol, 0.3
equiv). After being stirred at reflux for 5 h, the reaction mixture was
diluted with H2O and brine at room temperature. The phases were
separated, and the aqueous phase was extracted with CH2Cl2 (3×).
The combined organic layers were dried (MgSO4) and concentrated.
Purification of the residue by chromatography (cyclohexane/ethyl
acetate 10/1 to 5/1) afforded the ester 10 (8.4 g, 33.56 mmol, 81%) as
a colorless oil: Rf 0.47 (cyclohexane/ethyl acetate 2/1); 1H NMR
(CDCl3, 400 MHz) δ 3.75 (s, 3H), 4.07 (s, 2H), 4.09 (d, J = 5.9 Hz,
2H), 4.15 (d, J = 6.2 Hz, 2H), 4.51 (s, 2H), 5.72−5.78 (m, 1H), 5.80−
5.86 (m, 1H), 7.27−7.37 (m, 5H); 13C NMR (CDCl3, 101 MHz) δ
51.9, 65.7, 66.9, 67.2, 72.4, 127.7, 127.8, 128.4, 130.5, 138.1, 170.7; IR
ν 3030 (w), 2855 (w), 1755 (s), 1455 (m), 1440 (m), 1280 (w), 1210
(s), 1135 (s), 1075 (m), 1005 (w), 945 (w), 740 (m), 700 (m), 580
(w); C14H18O4; 250.29 g/mol.
Reductive Selenation: Phenyl Selenide 14.56 The synthesis of
the title compound was performed in parallel using three commercially
available glass pressure tubes with Teflon screw cap. To three solutions
of diphenyl diselenide (C12H10Se2, 312.13 g/mol, 3 × 3.121 g, 3 × 9.99
mmol, 3 × 1 equiv) in THF (3 × 20 mL) at 0 °C was added LAH
(37.95 g/mol, 3 × 228 mg, 3 × 6.0 mmol, 3 × 0.6 equiv). The pressure
tubes were sealed, and the reaction mixtures were subsequently heated
to 120 °C in an oil bath for 6 h. The reaction mixtures were cooled to
ambient temperature and combined. The combined reaction mixtures
were diluted with H2O and aqueous HCl (1 M). The phases were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × ).
The combined organic phases were dried (MgSO4) and concentrated.
Purification of the residue by chromatography (cyclohexane/ethyl
acetate 20/1 to 5/1) afforded the phenyl selenide 14 (13.469 g, 58.77
1
mmol, 99%): Rf 0.31 (cyclohexane/ethyl acetate 2/1); H NMR (400
MHz, CDCl3) δ 1.35 (br s, 1H), 1.69−1.76 (m, 2H), 1.80−1.87 (m,
2H), 2.99 (t, J = 7.3 Hz, 2H), 3.69 (t, J = 6.5 Hz, 2H), 7.27−7.33 (m,
3H), 7.51−7.55 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 26.6
(CH2), 27.8 (CH2), 32.9 (CH2), 62.5 (CH2), 126.9 (CH), 129.2
(CH), 130.4 (C), 132.7 (CH); IR ν 3350 (br s), 2930 (s), 2865 (m),
1580 (m), 1480 (s), 1440 (m), 1385 (w), 1070 (m), 1025 (m), 735
(s), 690 (m), 670 (w). Anal. Calcd for C10H14OSe: C, 52.4; H, 6.1.
Found: C, 52.4; H, 6.2; 229.18 g/mol.
Parikh−Doering Oxidation:20 Aldehyde 11.15 To a suspension
of O3S·pyridine (C5H5NO3S, 159.16 g/mol, 17.1 g, 107.3 mmol, 2
equiv) and pyridine (C5H5N, 79.1 g/mol, 0.982 g/mL, 8.64 mL, 107.3
mmol, 2 equiv) in DMSO (53 mL) at 0 °C was added a chilled
solution (0 °C) of the alcohol 14 (229.18 g/mol, 12.292 g, 53.63
mmol, 1 equiv) and Et3N (101.19 g/mol, 0.73 g/mL, 29.7 mL, 214.52
mmol, 4 equiv) in CH2Cl2 (214 mL). After being stirred for 6 h at
room temperature, the reaction mixture was diluted with H2O. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (3×). The combined organic phases were dried (MgSO4) and
concentrated. Purification of the residue by chromatography (cyclo-
hexane/ethyl acetate 50/1 to 10/1) delivered the aldehyde 11 (10.907
Ester Enolate Aldol Addition: β-Hydroxy Ester 12. LDA was
prepared in situ from diisopropylamine (101.19 g/mol, 0.72 g/mL,
3.65 mL, 26.0 mmol, 1.3 equiv) and n-BuLi (10 mL, 24.0 mmol, 1.2
equiv, 2.4 M in n-hexanes) in THF (60 mL) at 0 °C. To this THF
solution of LDA (1.2 equiv) at −78 °C was added the ester 10 (250.29
g/mol, 5.0 g, 20.0 mmol, 1 equiv) in THF (60 mL). The reaction
mixture was stirred for 15 min at −78 °C. A solution of the aldehyde
11 (227.16 g/mol 5.446 g, 24.0 mmol, 1.2 equiv) in THF (20 mL) was
then added. After being stirred for 35 min at −78 °C, the reaction
mixture was diluted by the addition of saturated aqueous NH4Cl
solution and the mixture was allowed to warm to room temperature.
The phases were separated, and the aqueous phase was extracted with
CH2Cl2 (3×). The combined organic layers were dried (MgSO4) and
concentrated. Purification of the residue by chromatography (cyclo-
hexane/ethyl acetate 50/1 to 5/1) provided the β-hydroxy ester 12 as
a mixture of diastereomers (7.483 g, 15.67 mmol, 78%, dr ∼2:1). The
diastereomeric ratio was difficult to quantify because of overlapping
NMR signals. Characterization data are reported for the mixture of
1
g, 48.01 mmol, 90%): Rf 0.45 (cyclohexane/ethyl acetate 5/1); H
NMR (CDCl3, 400 MHz) δ 2.05 (t, J = 7.0 Hz, 2H), 2.64 (t, J = 7.0
Hz, 2H), 2.98 (t, J = 7.0 Hz, 2H), 7.29−7.33 (m, 3H), 7.52−7.54 (m,
2H), 9.80 (s, 1H); 13C NMR (CDCl3, 101 MHz) δ 22.6, 27.2, 43.6,
127.2, 129.3, 129.7, 132.9, 201.6; IR ν 3425 (m), 3070 (m), 2940 (m),
2825 (w), 1715 (s), 1580 (m), 1480 (m), 1435 (m), 1390 (w), 1070
(w), 1020 (w), 735 (s), 690 (s), 670 (w). Anal. Calcd for C10H12OSe:
C, 52.9; H, 5.3. Found: C, 52.9; H, 5.7; 227.16 g/mol.
1
Protecting Group Transformation: Benzyl Ether 9.57 To a
stirred solution of cis-2-butene-1,4-diol (C4H8O2, 88.11 g/mol, 50.0 g,
567.5 mmol, 2.93 equiv) in THF (200 mL) was added sodium hydride
(24.0 g/mol, 60% m/m dispersion in mineral oil, 7.8 g, 195 mmol,
1.01 equiv) at 0 °C. After being stirred for 30 min at room
temperature, benzyl bromide (used as purchased, C7H7Br, 171.03 g/
mol, 1.44 g/mL, 23.0 mL, 193.7 mmol, 1 equiv) was added, and the
resulting mixture was stirred at reflux for 1 h. The reaction mixture was
diluted at room temperature by the addition of saturated aqueous
NH4Cl solution at 0 °C. Water was added until the white solid was
dissolved. The layers were separated, and the aqueous phase was
syn/anti diastereomers: Rf 0.37 (cyclohexane/ethyl acetate 2/1); H
NMR (CDCl3, 400 MHz) δ 1.60−1.68 (m, 2H), 1.75−1.85 (m, 1H),
1.90−1.97 (m, 1H), 2.27−2.31 (m, 1H), 2.92−2.97 (m, 2H), 3.76 (s,
3H), 3.79−3.90 (m, 1H), 3.92−3.93 (m, 1H), 4.03−4.10 (m, 3H),
4.25−4.30 (m, 1H), 4.53 (s, 2H), 5.71−5.80 (m, 1H), 5.81−5.88 (m,
1H), 7.26−7.39 (m, 8H), 7.49−7.52 (m, 2H); 13C NMR (CDCl3, 101
MHz) δ 26.3, 26.5, 27.7, 32.4, 33.3, 52.2, 52.3, 65.8, 66.6, 66.7, 71.8,
72.0, 72.6, 80.9, 81.4, 126.9, 127.9, 128.4, 128.5, 128.6, 129.2, 130.4,
130.6, 130.7, 132.7, 138.1, 171.1, 171.5; IR ν 3470 (br m), 2950 (m),
2925 (m), 2860 (m), 1745 (s), 1480 (m), 1440 (m), 1265 (w), 1205
(m), 1075 (s), 1025 (m), 910 (s), 735 (s), 700 (m), 650 (w). Anal.
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Article
Calcd for C24H30O5Se: C, 60.4; H, 6.3. Found: C, 60.5; H, 6.4; 477.45
g/mol.
(d, J = 4.2 Hz, 3H), 3.84 (d, J = 4.0 Hz, 3H), 4.07 (d, J = 6.2 Hz, 2H),
4.18 (dd, J1 = 12.2 Hz, J2 = 7.0 Hz, 1H), 4.30 (dd, J1 = 12.5 Hz, J2 =
6.0 Hz, 1H), 4.40 (d, J = 18.9 Hz, 1H), 4.50 (s, 2H), 5.71−5.76 (m,
1H), 5.84−5.89 (m, 1H), 7.28−7.36 (m, 5H); 13C NMR (CDCl3, 101
MHz) δ 52.8, 54.2, 65.6, 67.8, 67.9, 72.5, 74.1, 75.7, 127.3, 127.4,
127.7, 128.4, 131.6, 137.9, 167.7; IR ν 3030 (w), 2955 (m), 2855 (m),
1750 (s), 1455 (m), 1265 (s), 1035 (s), 915 (s), 735 (s), 700 (m);
HRMS (ESI) calcd for C16H24O7P ([M + H]+) 359.1254, found
359.1260; calcd for C16H23NaO7P ([M + Na]+) 381.1074, found
381.1076; C16H23O7P, 358.32 g/mol.
Synthesis of Gosteli-Type Allyl Vinyl Ethers by Horner−
Wadsworth−Emmons Reaction: Allyl Vinyl Ether (E,Z)-13 and
(Z,Z)-13. LDA was prepared in situ from diisopropylamine (101.19 g/
mol, 0.72 g/mL, 2.4 mL, 17.2 mmol, 1.3 equiv) and n-BuLi (7.2 mL,
15.8 mmol, 1.2 equiv, 2.2 M in n-hexanes) in THF (53 mL) at 0 °C.
To this THF solution of LDA (1.1 equiv) at −78 °C was added the
phosphonate 16 (358.32 g/mol, 4.73 g, 13.2 mmol, 1 equiv) in THF
(53 mL), and the mixture was stirred for 20 min at −78 °C. A solution
of the aldehyde 11 (227.16 g/mol, 3.0 g, 13.2 mmol, 1 equiv) in THF
was slowly added at −78 °C. The cooling bath was immediately
removed, the reaction mixture was allowed to stir at ambient
temperature for 100 min, and saturated aqueous NH4Cl solution
was added. The layers were separated, and the organic phase was
extracted with CH2Cl2 (3 × 50 mL). The combined organic phases
were dried (MgSO4) and concentrated. The residue was purified by
chromatography (cyclohexane/ethyl acetate 50/1 to 10/1) to deliver
the Gosteli-type allyl vinyl ether 13 (5 g, 10.9 mmol, 81%) as a mixture
of double bond isomers {(E,Z):(Z,Z) = 5:1}. The double-bond
isomers were separated as described above.
Selenide Oxidation and Elimination: Gosteli-Type Allyl Vinyl
Ether (E,Z)-5. To a solution of the selenide (E,Z)-13 (459.44 g/mol,
3.997 g, 8.70 mmol, 1 equiv) in THF (87 mL) at 0 °C were added
NaHCO3 (84.01 g/mol, 7.309 g, 87.0 mmol, 10 equiv) and H2O2
(34.02 g/mol, 1.5 mL of a 30% m/v H2O, 1.11 g/mL, 495 mg, 14.55
mmol, 1.7 equiv). The reaction mixture was stirred at room
temperature for 3 days. H2O was subsequently added, and the layers
were separated. The aqueous phase was extracted with ethyl acetate
(3×), and the combined organic phases were dried (MgSO4). The
solvents were removed, and the residue was purified by chromatog-
raphy (cyclohexane/ethyl acetate 100/1 to 20/1) to afford (E,Z)-5
(2.291 g, 7.58 mmol, 87%): Rf 0.49 (cyclohexane/ethyl acetate 5/1);
1H NMR (CDCl3, 400 MHz) δ 3.21 (m, 2H), 3.79 (s, 3H), 4.11 (d, J
Gosteli-Type Allyl Vinyl Ether (E,Z)-13 and (Z,Z)-13.
Mesylation. To a solution of the alcohol 12 (477.45 g/mol 27.8 g,
58.23 mmol, 1 equiv) in CH2Cl2 (175 mL) were successively added
Et3N (101.19 g/mol, 0.726 g/mL, 10.55 mL, 75.69 mmol, 1.3 equiv)
and methanesulfonyl chloride (114.55 g/mol, 1.478 g/mL, 5.4 mL,
69.67 mmol, 1.2 equiv) at 0 °C. After being stirred for 1.5 h at room
temperature, the reaction mixture was diluted by the addition of
saturated aqueous NaHCO3 solution. The layers were separated, and
the aqueous phase was extracted with CH2Cl2 (3×). The combined
organic phases were dried (MgSO4) and concentrated. Volatiles were
removed in vacuo, and the crude product was used without further
purification. Elimination. To a solution of the crude mesylate in THF
(175 mL) at 0 °C was added DBU (C9H16N2, 152.24 g/mol, 1.02 g/
mL, 26.3 mL, 176.21 mmol, 3 equiv). The reaction mixture was
allowed to warm to room temperature and stirred for 16 h at ambient
temperature. H2O was then added, and the layers were separated. The
aqueous layer was extracted with ethyl acetate (3×). The combined
organic phases were dried (MgSO4) and concentrated. Purification by
chromatography (cyclohexane/ethyl acetate 50/1 to 10/1) afforded
the allyl vinyl ether 13 (20.4 g, 44.40 mmol, 76%) as mixture of
double-bond isomers (E,Z):(Z,Z) = 40:60; the ratio was determined
1
by integration of the H NMR signals at 2.34 ppm {(Z,Z)-13} and
2.56 ppm {(E,Z)-13}, 3.74 ppm {(Z,Z)-13} and 3.78 ppm (E,Z)-13},
4.31 ppm {(E,Z)-13} and 4.41 ppm {(Z,Z)-13}, 5.17 {(E,Z)-13} and
6.23 {(Z,Z)-13}. The double-bond isomers were separated by
preparative HPLC: Nucleosil 50-5, 32 × 250 mm, heptane/ethyl
acetate 8/1, 25 mL/min, (Z,Z)-13 at 19 min (10.17 g, 22.13 mmol,
38%), (E,Z)-13 at 22 min (6.55 g, 14.26 mmol, 25%); Rf 0.39
(cyclohexane/ethyl acetate 5/1). (Z,Z)-13: 1H NMR (CDCl3, 400
MHz) δ 1.76−1.83 (m, 2H), 2.34 (q, J = 7.5 Hz, 2H), 2.90 (t, J = 7.4
Hz, 2H), 3.74 (s, 3H), 4.09 (d, J = 4.5 Hz, 2H), 4.41 (d, J = 4.8 Hz,
2H), 4.50 (s, 2H), 5.79−5.81 (m, 2H), 6.23 (t, J = 7.6 Hz, 1H), 7.23−
7.37 (m, 8H), 7.47−7.49 (m, 2H); 13C NMR (CDCl3, 101 MHz) δ
26.0, 27.4, 29.2, 52.1, 65.8, 67.8, 72.5, 127.0, 127.8, 127.9, 128.3, 128.5,
128.6, 129.2, 130.1, 130.5, 132.8, 138.2, 145.0, 164.3; IR ν 2950 (w),
2860 (w), 1725 (s), 1650 (w), 1440 (w), 1455 (w), 1325 (w), 1270
(m), 1280 (m), 1215 (m), 1095 (s), 1030 (m), 1000 (m), 915 (w),
780 (w), 740 (w), 700 (w). Anal. Calcd for C24H28O4Se: C, 62.7; H,
6.1. Found: C, 63.0; H, 6.4. (E,Z)-13: 1H NMR (CDCl3, 400 MHz) δ
1.81 (quint, J = 7.4 Hz, 2H), 2.56 (dt, J1 = 7.6 Hz, J2 = 7.6 Hz, 2H),
2.91 (t, J = 7.4 Hz, 2H), 3.78 (s, 3H), 4.09 (d, J = 4.5 Hz, 2H), 4.30 (d,
J = 4.5 Hz, 2H), 4.51 (s, 2H), 5.17 (t, J = 7.8 Hz, 1H), 5.80 (dt, J1 = J2
= 4.6 Hz, 2H), 7.22−7.34 (m, 8H), 7.49 (dd, J1 = 7.5 Hz, J2 = 1.5 Hz,
2H); 13C NMR (CDCl3, 101 MHz) δ 27.1, 27.3, 30.7, 52.1, 64.9, 65.9,
72.5, 116.0, 126.8, 127.9, 128.6, 129.1, 129.9, 130.5, 132.6, 138.1,
144.8, 164.0; IR ν 2950 (m), 2860 (m), 1725 (s), 1635 (m), 1480 (w),
1455 (m), 1440 (s), 1095 (m), 1075 (m), 1025 (w), 910 (s), 735 (s),
695(m). Anal. Calcd for C24H28O4Se: C, 62.7; H, 6.1. Found: C, 62.4;
H, 6.0; 459.44 g/mol.
= 4.0 Hz, 2H), 4.35 (d, J = 4.5 Hz, 2H), 4.52 (s, 2H), 5.00−5.09 (m,
2H), 5.23 (t, J = 7.8 Hz, 1H), 5.77−5.89 (m, 3H), 7.27−7.37 (m, 5H);
13C NMR (CDCl3, 101 MHz) δ 31.1, 52.1, 64.9, 66.0, 72.5, 114.2,
115.3, 127.8, 127.9, 128.6, 130.0, 136.7, 138.1, 144.8, 164.0; IR ν 2950
(w), 2860 (w), 1730 (s), 1640 (m), 1455 (w), 1435 (m), 1370 (m),
1290 (w), 1225 (s), 1155 (s), 1115 (m), 1075 (m), 990 (w), 915 (w),
735 (m), 700 (m). Anal. Calcd for C18H22O4: C, 71.5; H, 7.3. Found:
C, 71.7; H, 7.3; 302.37 g/mol.
Selenide Oxidation and Elimination: Gosteli-Type Allyl Vinyl
Ether (Z,Z)-5. To a solution of the selenide (Z,Z)-13 (459.44 g/mol,
5.867 g, 12.79 mmol, 1 equiv) in THF (64 mL) were added NaHCO3
(84.01 g/mol, 10.745 g, 127.90 mmol, 10 equiv) and H2O2 (34.02 g/
mol, 2.2 mL of a 30% m/v H2O, 1.11 g/mL, 733 mg, 21.53 mmol, 1.7
equiv). The reaction mixture was stirred at room temperature for 3
days. Water was added, the layers were separated, and the aqueous
phase was extracted with ethyl acetate (3×). The combined organic
layers were dried (MgSO4) and concentrated. Purification of the
residue by chromatography (cyclohexane/ethyl acetate 100/1 to 20/1)
afforded (Z,Z)-5 (3.243 g, 10.78 mmol, 84%): Rf 0.52 (cyclohexane/
ethyl acetate 5/1); 1H NMR (CDCl3, 400 MHz) δ 2.96−3.00 (ddt, J1
= 7.7 Hz, J2 = 6.2 Hz, J3 = 1.6 Hz, 2H), 3.75 (s, 3H), 4.10 (m, 2H),
4.44 (d, J = 5.0 Hz, 2H), 4.50 (s, 2H), 5.02−5.10 (m, 2H), 5.74 (m,
3H), 6.30 (t, J = 7.5 Hz, 1H), 7.27−7.37 (m, 5H); 13C NMR (CDCl3,
101 MHz) δ 30.0, 52.1, 65.8, 67.8, 72.5, 116.2, 126.9, 127.8, 127.9,
128.3, 128.5, 130.5, 134.9, 138.2, 144.9, 164.3; IR ν 3030 (m), 2950
(m), 2860 (m), 1730 (s), 1650 (s), 1435 (m), 1455 (m), 1370 (m),
1325 (m), 1280 (m), 1210 (m), 1095 (m), 1025 (m), 915 (m), 780
Phosphonate 16. To each of the three solutions of the alcohol 9
(178.23 g/mol, 3 × 341 mg, 3 × 1.91 mmol, 3 × 1 equiv) and
Rh2(OAc)4 (441.99 g/mol, 3 × 33.8 mg, 3 × 0.0765 mmol, 3 × 0.04
equiv) in 1,2-dichloroethane (3 × 20 mL) under reflux was slowly
added a solution of methyl 2-diazo-2-(dimethoxyphosphoryl)acetate
15 (C5H9N2O5P, 208.11 g/mol, 3 × 477 mg, 3 × 2.29 mmol, 3 × 1.2
equiv) in 1,2-dichloroethane (3 × 20 mL) over a period of 110 min.
The three reaction mixtures were then cooled to ambient temperature
and combined, and the solvent was removed at reduced pressure. The
residue was filtered through a short plug of silica (cyclohexane/ethyl
acetate 1/1), and the eluent was concentrated at reduced pressure.
The residue was dissolved in CH2Cl2 (10 mL), and the solution was
successively washed with water (2 × 30 mL) and saturated aqueous
NH4Cl (4 × 30 mL). The combined aqueous phases were extracted
with CH2Cl2 (2 × 30 mL). The combined organic phases were then
dried (MgSO4) and concentrated. The residue was purified by
chromatography (cyclohexane/ethyl acetate 1/1 to 0/1) to deliver the
phosphonate 16 (1.6 g, 4.47 mmol, 78%) as a pale grayish oil: Rf =
0.35 (ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 3.8 (s, 3H), 3.82
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Article
(m), 740 (m), 700 (m). Anal. Calcd for C18H22O4: C, 71.5; H, 7.3.
Found: C, 71.3; H, 7.4; 302.37 g/mol.
concentrated under reduced pressure. Purification of the residue by
chromatography (cyclohexane/ethyl acetate 5/1 to 2/1) afforded the
diol 18 (1.64 g, 5.93 mmol, 97%): Rf 0.41 (cyclohexane/ethyl acetate
Catalytic Asymmetric Gosteli−Claisen Rearrangement: α-
Keto Ester (+)-(3S,4R)-6. To a solution of (Z,Z)-5 (302.37 g/mol,
2.30 g, 7.61 mmol, 1 equiv) in (CH2Cl)2 (40 mL) was added
[Cu{(S,S)-t-Bu-box}(tfe)2](SbF6)2 (S,S)-4 (7.6 mL, 0.1 M in 1,2-
dichloroethane, 0.76 mmol, 0.1 equiv). The reaction mixture was
stirred for 18 h at ambient temperature. The solvent was removed
under reduced pressure, and the residue was purified by chromatog-
raphy (cyclohexane/ethyl acetate 100/1 to 50/1) to afford (3S,4R)-6
(2.197 g, 7.27 mmol, 96%, dr >95/5, 98% ee). Only one diastereomer
was detectable by NMR. The enantiomeric excess was determined by
HPLC: Chiracel IA, 4.6 × 250 mm, n-heptane/ethyl acetate, 99.5/0.5,
1 mL/min, (3S,4R)-6 22.5 min, (3R,4S)-6 19.5 min; Rf 0.34
1
1/1); H NMR (400 MHz, CDCl3) δ 1.80 (qd, J1 = 6.7 Hz, J2 = 2.3
Hz, 1H), 2.02−2.13 (m, 2H), 2.14−2.18(m, 1H), 2.73−2.77 (m, 1H),
3.49−3.59 (m, 3H), 3.61−3.66 (m, 2H), 4.08 (d, J = 5.7 Hz, 1H),
4.53−4.59 (m, 2H), 5.02−5.13 (m, 4H), 5.67−5.76 (m, 1H), 5.78−
5.87 (m, 1H), 7.29−7.39 (m, 5H); 13C NMR (101 MHz, CDCl3) δ
32.2, 43.0, 44.0, 65.8, 71.4, 72.2, 73.7, 116.8, 116.9, 128.1, 128.2, 128.7,
137.2, 137.3, 137.6; IR ν 3435 (s), 2920 (m), 2870 (m), 1640 (m),
1455 (w), 1095 (m), 1030 (w), 915 (w), 735 (m), 700 (m). Anal.
Calcd for C17H24O3: C, 73.9; H, 8.8. Found: C, 73.8; H, 9.1. [α]20
D
+31.9 (c 1.64, CHCl3); 276.37 g/mol.
Reductive Homologation of α-Hydroxy Esters: Alcohol 19.
To a suspension of sodium hydride (24.00 g/mol, 280 mg of a 60%
m/m dispersion in mineral oil, 168 mg, 7.0 mmol, 1.5 equiv) in THF
(48 mL) at 0 °C was added the diol 18 (276.37 g/mol, 1.302 g, 4.71
mmol, 1 equiv) in THF (5 mL). The suspension was stirred for 30
min at room temperature. 1-(p-Toluenesulfonyl)imidazole (TsIm,
C10H10N2O2S, 222.26 g/mol, 1.15 g, 5.17 mmol, 1.1 equiv) was added,
and the reaction mixture was stirred for 1 h at room temperature. CuI
(190.45 g/mol, 1.79 g, 9.40 mmol, 2 equiv) was added. The reaction
mixture was chilled to −46 °C, and MeMgBr (47 mL, 47.04 mmol, 10
equiv, 1 M in THF) was added dropwise. The solution was allowed to
warm to −4 °C and stirred for an additional 2 h at this temperature.
The reaction mixture was then diluted by the addition of saturated
aqueous NH4Cl solution. The aqueous phase was extracted with
CH2Cl2 (4×). The combined organic phases were dried (MgSO4) and
concentrated. Purification of the residue by chromatography (cyclo-
hexane/ethyl acetate 50/1 to 20/1) delivered the alcohol 19 (0.948 g,
1
(cyclohexane/ethyl acetate 10/1); H NMR (CDCl3, 400 MHz) δ
2.21−2.27 (m, 1H), 2.40−2.46 (m, 1H), 2.72−2.77 (m, 1H), 3.45 (dd,
J1 = 9.2 Hz, J2 = 5.4 Hz, 1H), 3.57 (dd, J1 = 9.2 Hz, J2 = 4.2 Hz, 1H),
3.65 (s, 3H), 3.71 (dd, J1 = 8.7, J2 = 5.4 Hz, 1H), 4.37−4.43 (m, 2H),
4.98−5.15 (m, 4H), 5.66−5.75 (m, 1H), 5.85−5.92 (m, 1H), 7.25−
7.28 (m, 2H), 7.31−7.34 (m, 3H); 13C NMR (CDCl3, 101 MHz) δ
33.4, 46.9, 47.2, 52.8, 72.0, 73.0, 117.5, 118.0, 127.5, 127.7, 128.4,
135.2, 135.7, 137.8, 161.8, 195.1; IR ν 3080 (m), 3030 (m), 2950 (m),
2860 (m), 1730 (s), 1640 (s), 1495 (w), 1450 (m), 1435 (m), 1360
(m), 1275 (s), 1225 (m), 1105 (m), 1030 (w), 995 (m), 920 (m), 740
(m), 700 (m). Anal. Calcd for C18H22O4: C, 71.5; H, 7.3. Found: C,
20
71.4; H, 7.3; [α]D +23.3 (c 1.03, CHCl3); 302.37 g/mol.
Gosteli−Claisen Rearrangement: α-Keto Ester ( )-(3R,4R)-6.
A solution of (E,Z)-5 (302.37 g/mol, 0.1 g, 0.33 mmol) in 1,2-
dichloroethane (5 mL) was stirred at 80 °C for 140 h. The solvent was
removed in vacuo, and the residue was purified by chromatography
(hexanes/ethyl acetate 100/1 to 50/1) to deliver the title compound
(93 mg, 0.31 mmol, 93%). 1H NMR (CDCl3, 400 MHz) δ 2.30−2.37
(m, 3H), 2.77−2.88 (m, 1H), 3.33 (m, 1H), 3.37−3.46 (m, 1H), 3.55
(s, 3H), 4.30 (m, 2H), 4.88−4.99 (m, 2H), 5.10−5.20 (m, 2H), 5.43−
5.59 (m, 1H), 5.59−5.70 (m, 1H), 7.16−7.34 (m, 5H); 13C NMR
(CDCl3, 101 MHz) δ 34.7, 48.2, 48.3, 52.5, 72.6, 117.2, 118.9, 127.5,
128.2, 134.7, 135.4, 137.3, 161.2, 194.8.
1
3.45 mmol, 73%): Rf 0.48 (cyclohexane/ethyl acetate 5/1); H NMR
(400 MHz, CDCl3) δ 0.94 (t, J = 7.4 Hz, 3H), 1.48−1.55 (m, 2H),
1.68−1.73 (m, 1H), 2.03−2.09 (m, 1H), 2.16−2.24 (m, 1H), 2.75−
2.78 (m, 1H), 3.41−3.55 (m, 4H), 4.51−4.58 (m, 2H), 4.99−5.12 (m,
4H), 5.72−5.84 (m, 2H), 7.28−7.38 (m, 5H); 13C NMR (101 MHz,
CDCl3) δ 10.7, 28.5, 31.7, 42.4, 46.3, 70.8, 73.0, 73.6, 115.9, 116.3,
128.0, 128.6, 137.5, 138.0, 139.0; IR ν 3440 (s), 3075 (w), 2960 (w),
2930 (w), 2875 (w), 1640 (m), 1455 (w), 1095 (m), 1075 (w), 910
(w), 735 (m), 670 (w). Anal. Calcd for C18H26O2: C, 78.8; H, 9.6.
Found: C, 78.6; H, 9.4. [α]20D = +39.6 (c 1.06, CHCl3); 274.40 g/mol.
Alternative Procedure. To a suspension of sodium hydride (24.00 g/
mol, 181 mg of a 60% m/m dispersion in mineral oil, 109 mg, 4.54
mmol, 2.5 equiv) in THF (18 mL) at 0 °C was added the diol 18
(276.37 g/mol, 500 mg, 1.81 mmol, 1 equiv) in THF (1.8 mL). The
suspension was stirred for 30 min at room temperature. TsIm (222.26
g/mol, 442 mg, 1.95 mmol, 1.1 equiv) was added, and the reaction
mixture was stirred for 1 h at room temperature. CuBr·SMe2
(C2H6BrCuS, 205.58 g/mol, 744 mg, 3.62 mmol, 2 equiv) was
added. The reaction mixture was chilled to −46 °C, and MeMgBr (1
M in THF, 18.1 mL, 18.1 mmol, 10 equiv) was added dropwise. The
solution was allowed to warm to −4 °C and stirred for an additional 2
h at this temperature. The reaction mixture was then diluted with
saturated aqueous NH4Cl solution. The aqueous phase was extracted
with CH2Cl2 (4×), and the combined organic phases were dried
(MgSO4). After evaporation of the solvents, purification by
chromatography (cyclohexane/ethyl acetate 50/1 to 20/1) delivered
the alcohol 19 (277.40 g/mol, 376 mg, 1.36 mmol, 75%).
Steglich Esterification: Ester 8. To a solution of 9-decenoic acid
(170.25 g/mol, ≥90% purity, used as purchased, 527 mg, 3.36 mmol,
0.81 equiv) in 1,2-dichloroethane (3 mL) at 0 °C was added a solution
of DCC (206.33 g/mol, 633 mg, 3.07 mmol, 0.73 equiv) in 1,2-
dichloroethane (4 mL). DMAP (122.17 g/mol, 17 mg, 0.14 mmol,
0.03 equiv) and alcohol 19 (274.40 g/mol, 1.148 g, 4.18 mmol, 1.0
equiv) were successively added at ambient temperature. After being
stirred for 16 h, the reaction mixture was filtered through a plug of
Celite on silica gel. The plug was rinsed with CH2Cl2. The solvents
were evaporated, and subsequent purification of the residue by
chromatography (cyclohexane/ethyl acetate 200/1) afforded the ester
8 (1.033 g, 2.42 mmol, 58% from 19) along with recovered 19 (274.40
g/mol, 358 mg, 1.29 mmol, 31%): Rf 0.53 (cyclohexane/ethyl acetate
Diastereoselective Reduction: α-Hydroxy Ester 17. To a
solution of the α-ketoester 6 (302.37 g/mol, 1.977 g, 6.54 mmol, 1
equiv) in THF (65 mL) at −82 °C was added (R)-(+)-2-methyl-CBS-
oxazaborolidine (C18H20BNO, 277.17 g/mol, 1 M in CH2Cl2, 0.78
mL, 0.78 mmol, 0.12 equiv). After 20 min of stirring, borane dimethyl
sulfide complex (75.97 g/mol, 0.801 g/mL, 0.37 mL, 3.90 mmol, 0.6
equiv) was added, and the reaction mixture was allowed to warm to
−75 °C over a period 35 min. The reaction mixture was diluted with
MeOH (65 mL), warmed to ambient temperature, and further diluted
by the addition of saturated aqueous NH4Cl solution. The phases were
separated, the aqueous layer was extracted with CH2Cl2 (3×), and the
combined organic phases were dried (MgSO4) and concentrated.
Purification of the residue by chromatography (cyclohexane/ethyl
acetate 50/1 to 10/1) provided the α-hydroxy ester 17 (1.867 g, 6.13
mmol, 94%, dr >95:5) as a clear oil: Rf 0.35 (cyclohexane/ethyl acetate
1
5/1); H NMR (400 MHz, CDCl3) δ 2.15−2.22 (m, 3H), 2.51−2.54
(m, 1H), 3.42−3.51 (m, 2H), 3.74 (s, 3H), 4.17 (d, J = 8.4 Hz, 1H),
4.26 (dd, J1 = 8.4 Hz, J2 = 2.9 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.59
(d, J = 12.1 Hz, 1H), 5.01−5.12 (m, 4H), 5.68−5.83(m, 2H), 7.27−
7.39 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 31.1, 43.5, 44.4, 52.1,
70.0, 71.6, 73.5, 116.6, 117.5, 128.0, 128.6, 136.5, 137.4, 138.2, 175.5;
IR ν 3445 (s), 1730 (s), 1640 (s), 1455 (w), 1220 (w), 1095 (m), 915
(w), 735 (w), 700 (m). Anal. Calcd for C18H24O4: C, 71.0; H, 8.0.
Found: C, 70.9; H, 7.8; [α]20D +45.6 (c 1.065, CHCl3); 304.38 g/mol.
Reductive Homologation of α-Hydroxy Esters: Diol 18. To a
solution of the α-hydroxy ester 17 (304.38 g/mol, 1.867 g, 6.13 mmol,
1 equiv) in THF (62 mL) at 0 °C was added LiAlH4 (37.95 g/mol,
697 mg, 18.37 mmol, 3 equiv). After being stirred for 30 min at 0 °C,
the suspension was allowed to warm to ambient temperature and was
stirred for an additional 2.5 h at room temperature. The reaction
mixture was diluted with HCl (1 M) and H2O at 0 °C. The phases
were separated, and the aqueous layer was extracted with CH2Cl2
(6×). The combined organic layers were dried (MgSO4) and
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5/1); 1H NMR (500 MHz, CDCl3) δ 0.78 (t, J = 7.4 Hz, 3H), 1.23 (s,
6H), 1.29−1.34 (m, 2H), 1.46−1.57 (m, 4H), 1.84−1.89 (m, 1H),
1.98 (q, J = 6.9 Hz, 2H), 2.04 (q, J = 6.7 Hz, 2H), 2.13−2.17 (m, 2H),
2.45−2.50 (m, 1H), 3.43 (dd, J1 = 9.1 Hz, J2 = 7.9 Hz, 1H), 3.54 (dd,
J1 = 9.3 Hz, J2 = 4.8 Hz, 1H), 4.41−4.46 (m, 2H), 4.82−4.85 (m, 1H),
4.86−4.88 (m, 1H), 4.91−4.92 (m, 1H), 4.94−4.95 (m, 2H), 5.01−
5.08 (m, 2H), 5.64−5.79 (m, 3H), 7.19−7.22 (m, 2H), 7.25−7.29 (m,
3H); 13C NMR (101 MHz, CDCl3) δ 10.1, 23.9, 25.2, 29.0, 29.1, 29.3,
32.5, 33.9, 34.8, 42.5, 45.0, 71.9, 73.1, 76.1, 114.3, 116.3, 116.8, 127.6,
127.7, 128.4, 137.8, 138.7, 139.3, 173.4; IR ν 3465 (w), 3075 (w),
2970 (m), 2925 (s), 2855 (m), 1730 (s), 1635 (w), 1455 (w), 1370
(w), 1245 (w), 1175 (m), 1105 (s), 910 (s). Anal. Calcd for C28H42O3:
C, 78.8; H, 9.9. Found: C, 78.5; H, 9.8. [α]20D +15.5 (c 1.18, CHCl3);
426.63 g/mol.
(cyclohexane/ethyl acetate 2/1). NMR assignments of selected 1H and
13C signals rests on 1H/1H COSY and 1H/13C HSQC experiments and
are provided for the major compound only. Signals that refer to the
minor diastereomer are labeled accordingly: 1H NMR (400 MHz,
CDCl3) δ 0.83−0.89 (m, 3H), 1.31−1.56 (m, 10H), 1.56−1.65 (m,
2H), 1.67−1.73 (m, 2H), 1.73−1.82 (m, 1H, 15-CH), 1.83−1.90 (m),
2.04−2.14 (m, 1H), 2.16−2.20 (m, 2H), 2.25−2.36 (m, 1H), 2.40−
2.54 (m, 2H), 2.78−2.84 (m, 1H, 11-CH), 3.51 (dd, J1 = 10.2 Hz, J2 =
8.4 Hz, 1H, 12-CH2), 3.62 (dd, J1 = 10.0 Hz, J2 = 9.8 Hz, 1Hminor),
3.69−3.74 (m, 1Hminor), 3.78 (dd, J1 = 10.8 Hz, J2 = 6.8 Hz, 1H, 12-
CH2), 4.99−5.07 (m, 2H, 13′-CH2), 5.08−5.12 (m, 1H, 16-CH),
5.34−5.43 (m, 1Hminor), 5.49−5.55 (m, 1Hminor), 5.61 (dt, J1 = 10.3
Hz, J2 = 8.0 Hz, 1H, 9-CH), 5.71−5.85 (m, 1H, 13-CH); 13C NMR
(126 MHz, CDCl3) δ 9.8, 10.9, 24.1, 24.4, 24.5, 25.2, 25.5, 25.9, 26.2,
26.3, 26.5, 26.8, 27.1, 27.7, 30.6, 32.1, 33.1, 33.2, 37.3, 39.1 (C11),
42.2, 45.1 (C15), 50.1, 63.5 (C12), 65.9, 78.0 (C16), 78.2, 116.1
(C13′), 117.2, 129.8, 131.1 (C9), 132.6 (C10), 134.2, 137.0, 138.1
(C13), 173.9, 174.8 (C1); IR ν 3470 (m), 2930 (s), 2860 (s), 1730
(s), 1640 (m), 1460 (m), 1365 (m), 1225 (s), 1175 (m), 1055 (m),
910 (m), 735 (w). Anal. Calcd for C19H32O3: C, 74.0; H, 10.5. Found:
C, 73.8; H, 10.4; 308.46 g/mol.
Transprotection by Intramolecular Iodo Etherification:
Tetrahydropyran 22. To a solution of the triene 8 (426.63 g/mol,
1.033 g, 2.42 mmol, 1 equiv) in MeCN (25 mL) were successively
added NaHCO3 (84.01 g/mol, 508 mg, 6.05 mmol, 2.5 equiv) and I2
(253.81 g/mol, 1.54 g, 6.07 mmol, 2.5 equiv) at 0 °C. The solution
was allowed to warm to ambient temperature and stirred for 2.5 h. The
reaction mixture was subsequently diluted by the addition of saturated
aqueous Na2S2O3 solution. The layers were separated, and the aqueous
phase was extracted with CH2Cl2 (3×). The combined organic phases
were dried (MgSO4) and concentrated. Purification of the residue by
chromatography (cyclohexane/ethyl acetate 200/1 to 20/1) delivered
the labile tetrahydropyrane 22 (1.096 g, 2.37 mmol, 98%, dr = 77:23)
as a mixture of diastereomers. The dr was determined by integration of
the 1H NMR signals at 5.51−5.60 ppm and 5.75−5.89 ppm. The
relative configuration was not assigned. Characterization data are
reported for the mixture of diastereomers. Isolated signals that are
related to the minor diastereomer are labeled accordingly: Rf 0.70
(cyclohexane/ethyl acetate 5/1); 1H NMR (400 MHz, CDCl3) δ 0.87
(q, J = 7.5 Hz, 3H), 1.15−1.24 (m, 1H), 1.31 (s, 6H), 1.33−1.39 (m,
2H), 1.44−1.56 (m, 1H), 1.58−1.68 (m, 3H), 1.80−1.95 (m, 2H),
2.02 (q, J = 6.6 Hz, 2H), 2.08−2.19 (m, 1H), 2.27−2.33 (m, 2H),
3.18−3.30 (m, 3H), 3.55 (m, 2H), 4.85−4.90 (m, 2Hminor), 4.93 (dd,
J1 =10.2 Hz, J2 = 1.1 Hz, 1H), 4.99 (dd, J1 = 17.1 Hz, J2 = 1.5 Hz, 1H),
Synthesis of the Triene 24. Oxidation. To a solution of the
alcohol 24 (308.46 g/mol, 326 mg, 1.06 mmol, 1 equiv) in CH2Cl2
(10.5 mL) and DMSO (10.5 mL) was added 2-iodoxybenzoic acid
(C7H5IO4, 280.02 g/mol, 592 mg, 2.11 mmol, 2 equiv). After being
stirred for 2.5 h, the reaction mixture was diluted by the addition of
water. The aqueous phase was separated and extracted with CH2Cl2
(3×). The combined organic layers were dried (MgSO4) and
concentrated. The residue was purified by chromatography (cyclo-
hexane/ethyl acetate 100/1 to 50/1) to afford the corresponding
aldehyde (C19H30O3, 306.44 g/mol, 274 mg, 0.894 mmol) as a mixture
of double-bond isomers. Characterization data are reported for the
mixture of isomers; signals that refer to the 9E-configured lactone are
labeled accordingly: Rf 0.59 (cyclohexane/ethyl acetate 5/1); 1H NMR
(400 MHz, CDCl3) δ 0.83−0.91 (m, 3H), 1.25−1.86 (series of m,
12H), 1.97−2.51 (series of m, 6H), 3.02 (dd, J1 = 9.5 Hz, J2 = 2.8 Hz,
1HE), 3.61−3.65 (m, 1H), 4.96−5.12 (m, 3H), 5.19−5.31 (m, 1HE),
5.43−5.49 (m, 1H), 5.56−5.63 (m, 2HE), 5.67−5.81 (m, 2H), 9.56 (d,
J = 2.5 Hz, 1H), 9.75 (s, 1HE), 29 proton signals reported for the
major compound. Methylenation. To a stirred solution of
methyltriphenylphosphonium bromide (357.22 g/mol, 1.596 g, 4.47
mmol, 5 equiv) in THF (15 mL) at 0 °C was added t-BuOK (112.21
g/mol, 2.185 g of a 20% w/w (1.7 M) solution in THF, 437 mg, 3.89
mmol, 4.4 equiv). After being stirred for 20 min at 0 °C, a solution of
the aldehyde just prepared (306.44 g/mol, 274 mg, 0.894 mmol, 1
equiv) in THF (15 mL) at 0 °C was added. After being stirred for 30
min at 0 °C, the reaction mixture was diluted by the addition of
saturated aqueous NH4Cl solution. The aqueous layer was separated
and extracted with CH2Cl2 (3×). The organic extracts were combined,
dried (MgSO4), and concentrated. Purification of the residue by
chromatography (cyclohexane/ethyl acetate 200/1) delivered the
triene 24 (211 mg, 0.69 mmol, 65%) as an inseparable mixture of
double bond isomers. Characterization data are reported for the
mixture of isomers; signals that refer to the 9E-configured lactone are
labeled accordingly: Rf 0.80 (cyclohexane/ethyl acetate 10/1); 1H
NMR (400 MHz, CDCl3) δ 0.83 (t, J = 7.4 Hz, 3H), 1.30−1.43 (m,
7H), 1.48−1.55 (m, 2H), 1.59−1.65 (m, 1H), 1.72−1.79 (m, 2H),
1.82−1.89 (m, 2H), 1.91−1.99 (m, 1H), 2.06−2.12 (m, 1H), 2.18−
2.25 (m, 1H), 2.27−2.36 (m, 2HE), 2.43−2.48 (m, 2H), 2.93−3.00
(m, 1HE), 3.28 (td, J1 = 7.9 Hz, J2 = 4.0 Hz, 1H), 4.95−5.08 (m, 5H),
5.20−5.32 (m, 5HE), 5.46−5.56 (m, 2H), 5.61−5.67 (m, 2HE), 5.74−
5.87 (m, 2H), 5.97−6.05 (m, 2HE); 13C NMR (101 MHz, CDCl3) δ
9.6, 11.1E, 23.8E, 24.5E, 24.6, 24.9, 25.0, 25.7, 25.8, 26.1E, 26.4E, 26.6,
26.7, 27.2E, 27.7E, 30.6E, 32.4, 33.0E, 33.3, 37.0E, 41.2, 45.8E, 46.0,
5.06−5.17 (m, 3H), 5.51−5.60 (m, 2Hminor), 5.75−5.89 (m, 2H); 13
C
NMR (101 MHz, CDCl3) δ 7.8, 9.6, 9.8, 10.7, 21.6, 23.3, 25.2, 27.8,
29.0, 29.1, 29.3, 31.1, 33.9, 34.7, 38.4, 40.7, 42.7, 43.9, 66.2, 72.5, 74.7,
76.1, 76.7, 114.4, 116.9, 118.3, 136.1, 138.3, 139.2, 173.7, 173.8; IR ν
3075 (w), 2925 (m), 2855 (m), 1730 (s), 1640 (s), 1460 (s), 1380 (s),
1245 (s), 1180 (s), 1090 (s), 995 (s), 915 (s); C21H35IO3, 462.41 g/
mol.
Alcohol 23. Ring-Closing Metathesis. The RCM was performed
in three parallel reactions. To three solutions of the diene 22 (462.41
g/mol, 3 × 365 mg, 3 × 0.79 mmol, 3 × 1 equiv) in toluene (3 × 158
mL) at ambient temperature were successively added 1,4-benzoqui-
none (108.09 g/mol, 3 × 8 mg, 3 × 0.074 mmol, 3 × 0.1 equiv) and
the Grela metathesis catalyst (C31H37Cl2N3O3, 671.62 g/mol, 3 × 26
mg, 3 × 0.039 mmol, 3 × 0.05 equiv). The reaction mixtures were
refluxed for 2.5 h while a constant stream of argon was maintained.
After being cooled to ambient temperature, the reaction mixtures were
combined and the solvent was removed under reduced pressure.
Purification of the residue by chromatography (cyclohexane/ethyl
acetate 200/1) afforded the labile RCM product (C19H31IO3, 434.35
g/mol, 544 mg, 1.25 mmol) as a mixture of diastereomers, Rf 0.64
(cyclohexane/ethyl acetate 5/1). Reductive Cleavage of the
Tetrahydropyran. To a solution of the purified RCM product (544
mg, 1.25 mmol, 1 equiv) in EtOH (25 mL) were added NH4Cl (53.49
g/mol, 335 mg, 6.26 mmol, 5 equiv) and zinc powder (purity >95%,
particle size <45 μm, 65.39 g/mol, 819 mg, 12.52 mmol, 10 equiv).
After being stirred for 2.5 h at 40 °C, the reaction mixture was filtered
through Celite and the solvent was removed under reduced pressure.
Purification of the residue by chromatography (cyclohexane/ethyl
acetate 50/1 to 20/1 to 10/1) afforded the alcohol 23 (299 mg, 0.97
mmol, 41% from 22) as an (apparent) mixture of double bond
isomers. The E/Z ratio (∼1/2) was determined by integration of the
1H NMR signals at 5.61 ppm and 5.49−5.55 ppm. Characterization
data are reported for the mixture of double-bond isomers, Rf 0.59
E
49.5E, 76.3, 78.7E, 113.6 , 115.8, 116.3, 117.0E, 129.7, 130.5E, 131.7E,
131.8, 137.3E, 137.8, 138.5, 143.5E, 173.8, 174.1E; IR ν 3075 (w), 2930
(s), 2860 (s), 1730 (s), 1640 (m), 1455 (s), 1370 (m), 1220 (s), 1150
(s), 995 (s), 745 (w). Anal. Calcd for C20H32O2: C, 78.9; H, 10.6.
Found: C, 79.1; H, 10.7; 304.47 g/mol.
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(−)-9,10-Dihydroecklonialactone B (3). RCM. To a solution of
the triene 24 (304.47 g/mol, 53 mg, 0.174 mmol, 1 equiv) in toluene
(14 mL) were successively added 1,4-benzoquinone (108.09 g/mol,
0.7 mg, 0.0648 mmol, 0.04 equiv) and Grubbs catalyst, first generation
(C43H72Cl2P2Ru, 822.96 g/mol, 3 mg, 0.00365 mmol, 0.021 equiv).
Under a constant stream of argon, the reaction mixture was stirred for
1.5 h at 35 °C. The solvent was then evaporated at reduced pressure,
and the residue was purified by chromatography (cyclohexane/ethyl
acetate 200/1) to deliver the corresponding bicyclic lactone
(C18H28O2, 276.41 g/mol, 43 mg, 0.156 mmol) as a mixture of
double-bond isomers. Characterization data are reported for the
mixture of isomers; signals that refer to the 9E-configured lactone are
2H), 1.83−1.90 (m, 3H, H-14 and H-15), 2.13 (t, J = 7.9 Hz, 1H, H-
11), 2.35−2.38 (m, 2H), 3.31 (d, J = 2.5 Hz, 1H, H-12), 3.44 (d, J =
2.0 Hz, 1H, H-13), 4.87 (ddd, J1 = 10.2 Hz, J2 = 7.1 Hz, J3 = 2.9 Hz,
1H, H-16); 13C NMR (101 MHz, CDCl3) δ 8.9, 24.40, 24.43, 24.90,
24.93, 25.06, 25.40, 25.88, 26.12, 28.7, 29.1, 33.8, 39.2, 44.4, 57.2, 61.5,
79.2, 174.0; IR ν 2930 (s), 2860 (s), 1730 (s), 1455 (m), 1360 (w),
1260 (m), 1220 (m), 1175 (m), 1045 (m), 1085 (w), 945 (w), 840
(s); HRMS (ESI) calcd for C18H31O3 ([M + H]+) 295.22677, found
295.22734; [α]23 −16.5 (c 0.58, CHCl3); C18H30O3, M = 294.43 g/
D
mol; for comparison, (+)-3: [α]23 = +14.5 (c 0.55, CHCl3).12,16
D
ASSOCIATED CONTENT
■
1
accordingly: Rf 0.73 (cyclohexane/ethyl acetate 5/1); H NMR (400
S
* Supporting Information
MHz, CDCl3) δ 0.87 (t, J = 7.4 Hz, 3H), 1.22−1.50 (m, 8H), 1.53−
1.62 (m, 2H), 1.64−1.69 (m, 2HE), 1.70−1.77 (m, 1H), 1.78−1.84
(m, 1H), 1.94−2.02 (m, 1H), 2.04−2.10 (m, 1H), 2.15−2.23 (m, 1H),
2.25−2.32 (m, 2H), 2.34−2.43 (m, 1H), 2.44−2.52 (m, 1H), 3.15−
3.21 (m, 1HE), 3.49−3.57 (m, 1H), 4.7−4.76 (m, 1HE), 4.84 (ddd, J1
= 8.2 Hz, J2 = 6.7 Hz, J3 = 4.8 Hz, 1H), 4.90−4.97 (m, 1HE), 5.10−
5.15 (m, 1HE), 5.24−5.29 (m, 1H), 5.35−5.39 (m, 1H), 5.42−5.44
(m, 1H), 5.61−5.66 (m, 1H + 1HE), 28 proton signals reported for the
major compound. Bromohydrin. To solution of the RCM product
(43 mg, 0.156 mmol, 1 equiv) in acetone (6.5 mL) and H2O (2.2 mL)
was added NBS (177.99 g/mol, 28 mg, 0.157 mmol, 1 equiv) at 0 °C.
After being stirred at ambient temperature for 1 h, the reaction mixture
was diluted with water. The phases were separated, and the aqueous
layer was extracted with CH2Cl2 (3×). The combined organic layers
were dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by chromatography (cyclohexane/ethyl acetate
50/1 to 20/1) to deliver the bromohydrin (C18H29BrO3, 373.33 g/
mol, 26 mg, 0.070 mmol): Rf 0.53 (cyclohexane/ethyl acetate 2/1); 1H
NMR (400 MHz, CDCl3) δ 0.82−0.90 (m, 3H), 1.20−2.25 (m, 2H),
1.32−1.41 (m, 4H), 1.42−1.48 (m, 2H), 1.52−1.62 (m, 2H), 1.65−
1.75 (m, 3H), 1.88−1.96 (m, 1H), 2.28−2.37 (m, 2H), 2.43−2.55 (m,
2H), 2.62 (ddd, J1 = 14.4 Hz, J2 = 10.4 Hz, J3 = 6.3 Hz, 1H), 3.47 (dd,
J1 = 8.7 Hz, J2 = 4.9 Hz, 1H), 4.15 (d, J = 4.5 Hz, 1H), 4.43 (d, J = 6.3
Hz, 1H), 4.82 (dt, J1 = 6.7 Hz, J2 = 3.4 Hz, 1H), 5.43−5.48 (m, 1H),
5.52−5.59 (m, 1H). (+)-Ecklonialactone B. To a solution of the
bromohydrin (26 mg, 0.07 mmol, 1 equiv) in toluene (3 mL) was
added Ag2O (231.74 g/mol, 16 mg, 0.07 mmol, 1 equiv). The reaction
mixture was heated to 120 °C for 3 h. The reaction mixture was cooled
to ambient temperature and concentrated under reduced pressure.
The residue was purified by chromatography (cyclohexane/ethyl
acetate 200/1 to 100/1) to afford ecklonialactone B (C18H28O3,
292.41 g/mol, 12 mg, 0.041 mmol) as a mixture of Δ9,10-double bond
isomers and contaminated with an inseparable impurity. Character-
ization data are reported for the major compound from the mixture of
isomers: Rf 0.77 (cyclohexane/ethyl acetate 2/1); 1H NMR (400
MHz, CDCl3) δ 0.81 (t, J = 7.3 Hz, 3H), 1.25−1.49 (m, 12H), 1.55−
1.62 (m, 1H), 1.67−1.77 (m, 1H), 1.80−1.95 (m, 2H), 2.05−2.11 (m,
2H), 2.36−2.43 (m, 1H), 3.03 (d, J = 9.5 Hz, 1H), 3.25 (d, J = 2.5 Hz,
1H), 3.50 (d, J = 2.0 Hz, 1H), 4.97 (ddd, J1 = 12.7 Hz, J2 = 7.6 Hz, J3 =
2.7 Hz, 1H), 5.11 (dd, J1 = J2 = 10.2 Hz, 1H), 5.48 (dddd, J1 = 10.4
Hz, J2 = J3 = J4 = 8.0 Hz, 1H). Hydrogenation. To a solution of
synthetic ecklonialactone B as a mixture of Δ9,10-double-bond isomers
and contaminated by the inseparable impurity (12 mg, 0.041 mmol, 1
equiv) in EtOAc (8 mL) was added PtO2 (227.08 g/mol, 6 mg, 0.026
mmol, 0.64 equiv). The vacuum degassed (3×) reaction mixture was
flushed with Ar (2×) and finally with H2 (balloon). The reaction
mixture was then stirred for 3 h at ambient temperature under an
atmosphere of H2 (balloon). The reaction mixture was subsequently
filtered through Celite, and the solvent was removed under reduced
pressure. Purification of the residue by chromatography (cyclohexane/
ethyl acetate 100/1 to 50/1) afforded (−)-9,10-dihydroecklonialac-
tone B [(−)-3] (9 mg, 0.031 mmol, 18%) contaminated with an
NMR-visible but inseparable minor impurity. NMR signal assignment
rests on 1H/1H COSY and 1H/13C HSQC experiments. For copies of
NMR spectra see the Supporting Information: Rf 0.71 (cyclohexane/
ethyl acetate 2/1); 1H NMR (400 MHz, CDCl3) δ 0.81 (t, J = 7.4 Hz,
3H, H-18), 1.23−1.49 (m, 15H), 1.58−1.63 (m, 1H), 1.69−1.82 (m,
1
Copies of H NMR, 13C NMR, and IR spectra. Experimental
details for kinetic measurements. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: martin.hiersemann@tu-dortmund.de.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was made possible by financial support from the
■
Technische Universitat Dortmund. A generous gift of L-tert-
̈
leucine by Evonik Degussa GmbH is gratefully acknowledged.
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