Umpolung Pd-Catalyzed α-arylation reactions in natural product synthesis: Syntheses of (+)-xestodecalactone A, (-)-curvularin, (+)-12-oxocurvularin and (-)-citreofuran

Article abstract of DOI:10.1002/ejoc.201500287

The syntheses (total and formal) of four phenylacetic acid lactone (PAL) natural products have been accomplished by utilizing a unified strategy of an umpolung Pd-catalyzed α-arylation of complex α-bromo esters and boronic acids under mild reaction conditions. As part of the synthetic approaches to these natural products, it was observed that the mild coupling reaction conditions readily tolerated terminal alkenes, other labile ester functionalities, an α,β-unsaturated ester moiety, and a protected allylic alcohol, while chemoselectively engaging the α-bromo ester. The completion of (+)-xestodecalactone A and (-)-curvularin coupled with the formal syntheses of (+)-12-oxocurvularin and (-)-citreofuran highlight the umpolung Pd-catalyzed α-arylation strategy as a key convergent tactic in complex natural product synthesis.

Full text of DOI:10.1002/ejoc.201500287

FULL PAPER
DOI: 10.1002/ejoc.201500287
Umpolung Pd-Catalyzed α-Arylation Reactions in Natural Product Synthesis:
Syntheses of (+)-Xestodecalactone A, (–)-Curvularin, (+)-12-Oxocurvularin and
(–)-Citreofuran
Dripta De Joarder[a] and Michael P. Jennings*[a]
Keywords: α-Arylation / Curvularin / Xestodecalactone A / Umpolung / Natural products
The syntheses (total and formal) of four phenylacetic acid
lactone (PAL) natural products have been accomplished by
utilizing a unified strategy of an umpolung Pd-catalyzed α-
arylation of complex α-bromo esters and boronic acids under
mild reaction conditions. As part of the synthetic approaches
other labile ester functionalities, an α,β-unsaturated ester
moiety, and a protected allylic alcohol, while chemoselec-
tively engaging the α-bromo ester. The completion of (+)-xes-
todecalactone A and (–)-curvularin coupled with the formal
syntheses of (+)-12-oxocurvularin and (–)-citreofuran high-
to these natural products, it was observed that the mild cou- light the umpolung Pd-catalyzed α-arylation strategy as a
pling reaction conditions readily tolerated terminal alkenes,
key convergent tactic in complex natural product synthesis.
Introduction
Marine as well as terrestrial sources persistently provide
the synthetic organic community with a variety of structur-
ally intriguing and biologically relevant natural products.[1]
As disclosed by Bringmann, Proksch, and co-workers in
2002, the xestodecalactones were isolated from the fungus
Penicillium cf. montanense secured from the marine sponge
Xestospongia exigua.[2] As shown in Figure 1, xestodeca-
lactone A (1) is comprised of a 10-membered macrolactone
core with a sole chiral center coupled with a fused 1,3-di-
hydroxybenzene ring. In addition, other structurally similar
macrolactone natural products (phenylacetic acid lactones,
PALs) have been isolated from a variety of fungi sources.
For example, curvularin (2), 12-oxocurvularin (3), and
citreofuran (4) all possess a 12-membered macrolactone
structure fused to a 1,3-dihydroxybenzene ring as also de-
lineated in Figure 1. As disclosed by Musgrave in 1956, cur-
vularin (2) was isolated from the fungus Curvularia.[3] Simi-
larly, 12-oxocurvularin (3) and citreofuran (4) were both
isolated in 1989 from a hybrid strain ME 0005 derived from
Penicillium citreoviride B. IF0 6200 and 4692 as reported by
Yamamura.[4] It is notable that natural products containing
such structural motifs (1–4) and other PALs have signifi-
cant biological profiles ranging from cAMP-PDE and
TGF-β inhibitors to anti-inflammatory properties, thus
making them extremely attractive as synthetic targets.[5–14]
Figure 1. Structures of 10- and 12-membered 1,3-dihydroxybenzene
PAL natural products 1–4.
The Pd-catalyzed α-arylation of the ester moiety holds
significant opportunities for the construction of medicinally
valuable compounds, most notably macrocyclic PALs. As
shown in Figure 1, natural products 1–4 collectively contain
an α-aryl ester linkage, which could be highly amenable to
construction by a Pd-catalyzed carbonyl arylation process.
With respect to the Pd-catalyzed α-arylation of esters there
are two modes of reactivity that have been explored. The
first centers on utilizing a preformed or in-situ generated
enolate (or silyl ketene acetal) in conjunction with an elec-
trophilic aryl halide or triflate as the coupling partner.[15,16]
The umpolung approach employs an enolate precursor, typ-
ically an α-halo ester, which serves as the electrophilic coun-
terpart combined with a nucleophilic aryl group (i.e.
boronic ester/or acid) as described in generic form in Fig-
ure 2.[17] Initially, the Pd0 complex undergoes oxidative ad-
dition with an α-halo ester to afford the PdII enolate, which
[a] Department of Chemistry, The University of Alabama
250 Hackberry Lane, Tuscaloosa, AL 35487-0336, USA
E-mail: jenningm@ua.edu
http://chemistry.ua.edu/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500287.
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typically exists in the carbon tautomeric form due to the Schemes 1, 2, and 3. With respect to the synthesis of (+)-1
low oxophilicity of Pd. An ensuing transmetallation of the by the α-arylation of α-brom oester 9, treatment of homo-
boronic acid (or ester) in the presence of a mild base would allylic alcohol 5[18] with excess tert-butyl acrylate (5 equiv.)
furnish the aryl–PdII enolate intermediate, and subsequent in the presence of Grubbs’ catalyst 6[19] furnished the α,β-
reductive elimination of the enolate complex would ulti- unsaturated ester 7 in 60% yield with an (E)/(Z) ratio of
mately provide the newly formed α-aryl ester product while Ͼ 20:1 as deduced by 1H NMR spectroscopy as highlighted
regenerating the Pd0 catalyst. While both tactics eventually in Scheme 1. While the dr of the cross-metathesis is excel-
lead to identical α-arylated ester products, the former reac- lent for this example (5 Ǟ 7), the stereochemistry of the
tion conditions require the usage of a strong base such as corresponding olefin product was insignificant as it was re-
LDA or LiHMDS, which can limit the reaction scope due duced in the next step. Along this line, hydrogenation of the
to functional-group incompatibilities and/or unwanted side olefin moiety of 7 was accomplished with H2 and Pd/C in
products.[15]
Scheme 1. Completion of the aliphatic portion 9 of (+)-xestodeca-
lactone A.
Figure 2. General Pd-catalyzed mechanism for α-arylation of an α-
bromo ester and boronic acid.
Conversely, the latter approach (Figure 2) utilizes typi-
cally milder conditions, which should greatly enhance its
usage in complex molecule synthesis based on multiple
functional-group compatibilities.[17] Surprisingly, there have
been very few examples of Pd-catalyzed α-arylation reac-
Scheme 2. Synthesis of the aliphatic portion 13 of (–)-curvularin
from alcohol 5.
tions with complex α-bromo esters and nucleophilic cou-
pling partners such as boronic esters or acids. It was our
initial goal to expand the umpolung approach to α-aryl-
ation by employing more complex α-bromo ester coupling
partners within the context of natural product synthesis.
Based on this unified strategy, our results on the successful
syntheses (two total and two formal) of the four PAL natu-
ral products 1–4 are presented herein.
Results and Discussion
With the current synthetic strategy of Pd-catalyzed α-
arylation reactions with complex α-bromo esters and
boronic acids in mind, we commenced our investigation by
constructing the required carbon frameworks of the ali-
phatic coupling segments 9, 13, 15, and 18 as shown in Scheme 3. Synthesis of α-bromo esters 15 and 18 from alcohol 14.
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Umpolung Pd-Catalyzed α-Arylation in Natural Product Synthesis
EtOAc at –20 °C in nearly quantitative yield (98%) to af- partners. Using the optimized catalyst/ligand system as de-
ford hydroxy ester 8. If the hydrogenation of 7 was per- scribed by Gooßen as an initial guide [3 mol-% Pd(OAc)2,
formed in either EtOAc or other solvents (i.e. CH2Cl2, 9 mol-% P(o-tolyl)3, 5 equiv. K3PO4], we observed modest
THF, and EtOH) at room temp., significant cyclization of to good yields (60–80%) for the coupling products 21–26
ester 8 occurred, and the corresponding lactone was iso- from a series of α-bromo esters with protected (Bn and Me)
lated as the major product. An ensuing esterification (3,5-dihydroxyphenyl)boronic acids.[17a,22] It is worth noting
(bromoacetyl bromide and pyridine) of the free hydroxy that the coupling reaction conditions required a strict O2-
group resident in 8 afforded α-bromo ester 9 in a modest free environment to allow for a meaningful yield (Ͼ 20%).
57% yield.
The major byproduct isolated was the biaryl product de-
Analogous to the proposed completion of (+)-1, rived from the presumed reduction of PdII to Pd0 with
Scheme 2 delineates the synthesis of the α-bromo ester cou-
pling partner 13 required for the construction of (–)-2.
Hence, treatment of homoallylic alcohol ent-5 with excess
acrolein (10 equiv.) in the presence of catalyst 6 afforded the
Table 1. Umpolung Pd-catalyzed α-arylation of functionalized α-
bromo esters and boronic acids.[a,b]
α,β-unsaturated aldehyde 10 in 88% yield with an (E)/(Z)
1
ratio of Ն 20:1 as determined by H NMR spectroscopy.
An ensuing olefination of the aldehyde moiety resident
in 10 with 3 equiv. of the stabilized phosphorane tert-butyl
ester provided the diene product 11 in 94% yield, thus com-
pleting the requisite aliphatic carbon chain resident in (–)-
2. While the diastereomeric ratios of both the cross-me-
tathesis and olefination reactions are excellent [Ն 20:1, (E)/
(Z)], the stereochemistry of the corresponding diene in
product 11 was inconsequential. The resultant hydrogen-
ation of the diene moiety resident in 11 was accomplished
with H2 and Pd/C in EtOAc at room temp. for 12 h in 90%
yield to afford the saturated hydroxy ester 12. A subsequent
esterification with 2 equiv. of bromoacetyl bromide and
pyridine of the free hydroxy group resident in 12 furnished
α-bromo ester 13 in a modest 65% yield.
Similar to Schemes 1 and 2, we required the construc-
tion, in part, of the aliphatic portion of both natural prod-
ucts 3 and 4 prior to the convergent Pd-catalyzed α-aryl-
ation reaction. As delineated in Scheme 3, we streamlined
the synthetic sequence by utilizing the α-bromo ester as a
bifunctional moiety, first as an initial protecting group and
then subsequently as the Pd–enolate precursor. Thus, esteri-
fication of the free hydroxy group resident in 14[20] with
bromoacetyl bromide in the presence of pyridine readily
furnished α-bromo ester 15 in nearly quantitative yield
(98%). With 15 in hand, we envisioned directly investigating
15, as well as homologating the aliphatic carbon chain prior
to the Pd-catalyzed α-arylation reaction en route to 3 and
4. Consequently, ozonolysis of the terminal olefin of 15 fol-
lowed by a reductive workup with Me2S afforded aldehyde
16 in a modest 55% yield.
An ensuing chemoselective addition of vinylmagnesium
bromide to the corresponding aldehyde moiety of 16 pro-
vided allylic alcohol 17 in 50% yield as a ca. 1:1 mixture of
diastereomers. Fortunately, the stereochemistry of the sec-
ondary allylic alcohol was inconsequential due to a pending
oxidation to the ketone in later steps, vide infra. Protection
of the free hydroxy group resident in 17 as a TBS ether was
readily accomplished with TBSOTf and 2,6-lutidine and
furnished α-bromo ester 18 in 67% yield.
As shown in Table 1, we investigated a series of α-bromo
esters (9, 13, 15, 18–20[21]) as electrophilic PdII enolate pre-
[a] Quoted yields are of purified products. [b] Reactions were per-
cursors combined with electron-rich boronic acid coupling formed at room temp.
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2 equiv. of boronic acid in the presence of O2. It is also the completion of (–)-curvularin (2) as shown in Scheme 5.
notable that the described reactions did not require heating While the synthetic operations leading to the completion of
and freely proceeded at room temperature. The coupling 2 closely parallel that of 1, the 12-membered fused macro-
reaction conditions readily tolerated terminal alkenes (15 cyclic lactone ring of 2 was one significant structural differ-
and 19), other ester functionalities (9, 13, and 20), an α,β- ence with respect to 1 (10-membered lactone). Accordingly,
unsaturated ester moiety (20), and a protected allylic hydrolysis of the tert-butyl ester resident in 24 with
alcohol (18) while chemoselectively engaging the α-bromo TMSOTf and 2,6-lutidine delivered acid 29 in 77% yield
ester ultimately providing the corresponding products in and set the stage for the intramolecular Friedel–Crafts ring
good yields (60–80%).
closure. The acylation reaction of 29 under identical condi-
With the umpolung Pd-catalyzed α-arylation protocol of tions (TFA/TFAA = 2:1, room temp., 0.01 m) as noted in
complex α-bromo esters coupled with electron-rich boronic Scheme 4, provided the corresponding macrocycle 30 and
acids firmly in hand, attention was focused on the chemose- final reductive bis(hydrogenolysis) of the phenolic benzyl
lective hydrolysis of the tert-butyl ester resident in 23 fol- ether protecting groups with H2 and Pd/C in a solution of
lowed by final ring closure of the corresponding acid en THF/MeOH = 1:1 furnished (–)-curvularin (2) in a 21%
route to (+)-xestodecalactone A (1).[6a] As shown in yield over two steps from 29. For comparison, the 12-mem-
Scheme 4, hydrolysis of the tert-butyl ester resident in 23 bered ring formation (29 Ǟ 2) proceeded in a higher yield
with TMSOTf and 2,6-lutidine provided acid 27 in 83% (21% vs. 13%) than that of the 10-membered analogue (27
yield and set the stage for the intramolecular Friedel–Crafts Ǟ 1; Scheme 4). The spectroscopic data (1H NMR,
ring closure.[23]
500 MHz; 13C NMR, 125 MHz), optical rotation {[α]2D3
=
–7.31 (c = 0.52, EtOH)}, and HRMS data of synthetic 2
are in agreement with those of the natural sample and in
accord with the prior synthetic ventures.[10] The overall
yield of the curvularin synthesis was 5.5% over eight steps
from homoallylic alcohol ent-11.
Scheme 4. Synthesis of (+)-xesotdecalactone A (1).
The intramolecular acylation reaction of 27 under sim-
ilar conditions (TFA/TFAA = 2:1, room temp., 0.01 m) to
that of the Bringmann report provided macrocycle 28 with
a yield of 38%.[6a] Final reductive bis(hydrogenolysis) of the
phenolic benzyl ether protecting groups of macrocycle 28
with H2 and Pd/C as a solution in MeOH afforded (+)-
xestodecalactone A (1) in a modest 35% yield. The spectro-
scopic data (1H NMR, 500 MHz; 13C NMR, 125 MHz),
optical rotation {[α]D23 = +46.8 (c = 0.02, MeOH)}, and
Scheme 5. Completion of (–)-curvularin (2).
With the umpolung Pd-catalyzed α-arylation synthesis of
HRMS data of synthetic 1 are in close agreement with ester 26 firmly in hand, attention was focused on the final
those of the natural sample and in accord with both the completion of the aliphatic portion of both natural prod-
Bringmann and Danishefksy reports.[6] It was surprising ucts 3 and 4 as shown in Scheme 6. Unfortunately, an at-
1
that the H and 13C NMR spectra of (+)-xestodecalactone tempted streamlined synthesis of the entire aliphatic por-
had not been disclosed previously in the literature (only tab- tion of 3 and 4 prior to the Pd-catalyzed arylation did not
ulated data appears in both the Bringmann and Danish- provide the α-bromo ester coupling partner due to a series
efksy papers) making the direct spectral comparison unvi- of functional-group incompatibilities (i.e. necessary protect-
able.[6] The overall yield of this more convergent approach ing-group shuffles and chemoselective hydrogenation of an
to 1 was 2.8% from homoallylic alcohol 11 compared to alkene in the presence of the α-bromo ester). Thus, ester
0.22% as we had previously reported.[24]
26 served as a realistic platform to launch the final carbon
With the completion of 1, attention was focused on the homologation and required adjustment of oxidation states
final ring closure of the corresponding carboxylic acid for of specific carbon atoms resident in the macrocycles of 3
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Umpolung Pd-Catalyzed α-Arylation in Natural Product Synthesis
and 4. Hence, subsequent dihydroxylation of the olefin moi- and Pd/C provided the saturated oxo ester 34 in 68% yield.
ety resident in 26 was accomplished with OsO4/NMO fol- Final chemoselective hydrolysis (conditions similar to those
lowed by an in-situ diol cleavage with PhI(OAc)2 to furnish as described in Schemes 4 and 5) of the tert-butyl ester in
aldehyde 31 in 82% overall yield.[25] A two-carbon homolo- 34 with TMSOTf and 2,6-lutidine furnished acid 35 in 79%
gation of the aldehyde moiety of 31 by utilizing an ole- yield much to our delight. The completion of 35 constitutes
fination protocol with an α-tert-butyl ester stabilized phos- a formal synthesis of 12-oxocurvularin (3) and ultimately
phorane afforded the α,β-unsaturated diester 32 in 62% citreofuran (4) by intercepting the previously reported inter-
yield with an (E)/(Z) ratio of ca. 10:1.
mediate as described by Yamamura and Lai.[4,11]
Conclusions
The syntheses (total and formal) of the four PAL natural
products 1–4 have been accomplished by exploiting a uni-
fied tactic of an umpolung Pd-catalyzed α-arylation of com-
plex α-bromo esters and boronic acids under mild reaction
conditions. As part of the synthetic approaches to PALs 1–
4, it was observed that the mild coupling reaction condi-
tions readily tolerated terminal alkenes, other labile ester
functionalities, an α,β-unsaturated ester moiety, and a pro-
tected allylic alcohol while chemoselectively engaging the α-
bromo ester. This straightforward and convergent approach
by means of the mild α-arylation reaction conditions be-
tween α-bromo esters and boronic acids should allow for
the synthesis of other PAL natural products and structur-
ally related analogues.
Experimental Section
General Procedure: All of the reactions were performed under ar-
gon in flame-dried glassware. All starting materials and solvents
were commercially available and were used without further purifi-
cation. Deuterated chloroform (CDCl3) was stored over molecular
sieves (4 Å). The NMR spectra were recorded on 360 or 500 MHz
spectrometers. 1H and 13C NMR spectra were obtained by using
either CDCl3, CD3OD, or (CD3)2CO as the solvent with chloro-
form (CHCl3: δ = 7.26 ppm), methanol (MeOH: δ = 3.31 ppm), or
[D5]acetone [CD3(CO)CHD2: δ = 2.05 ppm] as the internal stan-
dard. High-resolution mass spectra were recorded on an EBE sec-
tor instrument by using electron ionization (EI) at 70 eV. Column
chromatography was performed by using 60–200 μm silica gel. An-
alytical thin layer chromatography was performed on silica-coated
glass plates with F-254 indicator. Visualization was accomplished
by UV light (254 nm), KMnO4, or ceric sulfate/phosphomolybdic
acid stain.
tert-Butyl (R,E)-5-Hydroxyhex-2-enoate (7): To
round-bottomed flask with a solution of 5 (4.00 g, 46.4 mmol,
a flame-dried
Scheme 6. Formal syntheses of 12-oxocurvularin (3) and citreo-
furan (4).
1.00 equiv.) in anhydrous CH2Cl2 (232 mL) under Ar at room temp.
It is worth noting that cross-metathesis of terminal al- was added tert-butyl acrylate (33.6 mL, 232 mmol, 5.00 equiv.)
dropwise. To the resulting solution was added Grubbs’ second-gen-
eration catalyst 6 (1.97 g, 0.241 mmol, 0.05 equiv.). The solution
was stirred at room temp. for 12 h. The solution was then concen-
trated under reduced pressure, and the resulting residue was puri-
fied by flash column chromatography (20% EtOAc/hexanes) to af-
ford 7 as a brown viscous oil (1.05 g, 60%). TLC: Rf = 0.3 (20%
EtOAc/hexanes). [α]2D2 = –7.5 (c = 0.08, CH2Cl2). 1H NMR
(360 MHz, CDCl3): δ = 6.80 (m, 1 H), 5.77 (m, 1 H), 3.90 (m, 1
H), 2.42 (br. s, 1 H), 2.28 (m, 2 H), 1.43 (s, 9 H), 1.17 (d, J =
6.13 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 165.7, 143.7,
kene 26 was not successful with excess tert-butyl acrylate or
acrylic acid in the presence of catalyst 6 to directly afford
32 or the corresponding acid. With the complete carbon
skeleton in place, attention was turned to the completion of
acid 35. Thus, TBAF-mediated desilylation of the TBS
ether resident in diester 33 afforded the free hydroxy group,
which was subsequently oxidized to the corresponding
ketone with Dess–Martin periodinane to provide α,β-unsat-
urated oxo diester 33 in 51% over two steps from 32.[26] An
ensuing hydrogenation of the olefin moiety of 33 with H2 125.4, 80.2, 66.5, 41.6, 28.0, 23.0 ppm. IR (CH Cl ): ν = 3403,
˜
2
2
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2973, 2927, 2251, 1711, 1646, 1456, 1396, 1365, 1327, 1167, 1076,
1034, 981, 928, 848, 738 cm–1. HRMS (EI): calcd. for C6H9O3 [M –
C4H9] 129.0552; found 129.0548.
0.3 (30% EtOAc/hexanes). [α]2D0 = +16.0 (c = 0.012, CH2Cl2). 1H
NMR (360 MHz, CDCl3): δ = 7.11 (dd, J = 15.4, 10.7 Hz, 1 H),
6.10 (m, 2 H), 5.69 (d, J = 15.4 Hz, 1 H), 3.85 (m, 1 H), 2.27 (m,
2 H), 1.43 (s, 9 H), 1.15 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 166.4, 143.3, 139.0, 130.8, 121.9, 80.0, 66.9,
tert-Butyl (R)-5-Hydroxyhexanoate (8): To a solution of 7 (4.33 g,
23.2 mmol, 1.00 equiv.) in EtOAc (465 mL) at –20 °C was added
Pd/C (220 mg). The mixture was then subjected to H2 (1 atm) and
stirred at –20 °C overnight. The catalyst was filtered off through
Celite, and the filtrate was concentrated to leave a crude residue,
which was purified by flash column chromatography (15% EtOAc/
hexanes) to afford 8 as a light yellow oil (4.26 g, 98%). TLC: Rf =
0.4 (20% EtOAc/hexanes). [α]2D2 = –4.2 (c = 0.012, CH2Cl2). 1H
NMR (360 MHz, CDCl3): δ = 3.74 (m, 1 H), 2.18 (m, 4 H), 1.60
(m, 2 H), 1.39 (s, 6 H), 1.13 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 173.1, 80.0, 67.2, 38.4, 35.2, 27.9, 23.3,
42.5, 28.0, 22.9 ppm. IR (CH Cl ): ν = 3410, 2974, 2928, 1698,
˜
2
2
1641, 1614, 1455, 1363, 1147, 1001, 940 851, 739 cm–1. HRMS (EI):
calcd. for C12H20O3 [M+] 212.1412; found 212.1412.
tert-Butyl (S)-7-Hydroxyoctanoate (12): To a solution of 11 (3.48 g,
16.4 mmol, 1.00 equiv.) in EtOAc (325 mL) at room temp. was
added Pd/C (522 mg). The mixture was then subjected to H2
(1 atm) and stirred at room temp. overnight. The catalyst was fil-
tered off through Celite, and the filtrate was concentrated to leave
a crude residue. The residue was purified by flash column
chromatography (30% EtOAc/hexanes) to afford 12 as a light yel-
low oil (3.23 g, 90%). TLC: Rf = 0.4 (30% EtOAc/hexanes). [α]2D0
= +1.90 (c = 0.028, CH2Cl2). 1H NMR (360 MHz, CDCl3): δ =
3.72 (m, 1 H), 2.15 (t, J = 7.5 Hz, 2 H), 1.95 (s, 1 H), 1.53 (m, 2
H), 1.38 (s, 9 H) 1.34 (m, 2 H), 1.27 (m, 4 H), 1.12 (d, J = 6.1 Hz,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 173.1,79.8, 67.7, 39.0,
21.0 ppm. IR (CH Cl ): ν = 2942, 2839, 1725, 1597, 1461, 1431,
˜
2
2
1293, 1207, 1159, 1062 cm–1. HRMS (EI): calcd. for C23H30O4Si
[M – C4H9] 341.1209; found 341.1208.
tert-Butyl (R)-5-(2-Bromoacetoxy)hexanoate (9): To a flame-dried
round-bottomed flask with a solution of secondary alcohol 8
(4.26 g, 22.6 mmol, 1.00 equiv.) in anhydrous CH2Cl2 (75.0 mL)
under Ar at 0 °C was added pyridine (3.60 mL, 45.3 mmol,
2.00 equiv.) followed by bromoacetyl bromide (4.00 mL,
45.3 mmol, 2.00 equiv.) dropwise. The reaction mixture was
warmed to room temp. Upon completion, as monitored by TLC,
the reaction was quenched by the addition of a saturated aqueous
NH4Cl solution (500 mL). The aqueous phase was extracted with
CH2Cl2 (3ϫ 100 mL), and the organic extracts were washed with
a saturated CuSO4 solution to remove excess pyridine. The crude
material was concentrated under vacuum and purified by gradient
column chromatography (3% to 5% EtOAc/hexanes) to afford 9 as
colorless oil (4.00 g, 57%). TLC: Rf = 0.6 (10% EtOAc/hexanes).
35.4, 28.9, 27.9, 25.3, 24.9, 23.3 ppm. IR (CH Cl ): ν = 3415, 2968,
˜
2
2
2931, 2863, 1727, 1455, 1368, 1256, 1155, 1050 cm–1. HRMS (EI):
calcd. for C10H19O2 [M – C2H5O] 171.1385; found 171.1379.
tert-Butyl (S)-7-(2-Bromoacetoxy)octanoate (13): To a flame-dried
round-bottomed flask with a solution of secondary alcohol 12
(1.00 g, 46.2 mmol, 1.00 equiv.) in anhydrous CH2Cl2 (15 mL) un-
der Ar at 0 °C was added pyridine (0.750 mL, 92.4 mmol,
2.00 equiv.) followed by bromoacetyl bromide (0.800 mL,
92.4 mmol, 2.0 equiv.) dropwise. The reaction mixture was warmed
to room temp. Upon completion, as monitored by TLC, the reac-
tion was quenched by a saturated aqueous NH4Cl solution
(300 mL). The aqueous phase was extracted with CH2Cl2 (3ϫ
100 mL), and the organic extracts were washed with saturated
CuSO4 solution to remove excess pyridine. The crude material was
concentrated under vacuum and purified by gradient column
chromatography (1% to 3% EtOAc/hexanes) to afford 13 as color-
[α]2D2 = –4.7 (c = 0.16, CH2Cl2). H NMR (350 MHz, CDCl3): δ =
1
4.90 (m, 1 H), 3.75 (m, 2 H), 2.17 (m, 2 H), 1.56 (m, 4 H), 1.38 (s,
9 H), 1.19 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 172.1, 166.4, 79.8, 72.5, 34.7, 27.8, 25.9, 20.5, 19.3 ppm. IR
(CH Cl ): ν = 2977, 2935, 1730, 1464, 1365, 1281, 1156, 962,
˜
2
2
840 cm–1. HRMS (EI) calcd. for C8H12O3Br [M
– C4H9O]
less oil (1.04 g, 65%). TLC: Rf = 0.3 (5% EtOAc/hexanes). [α]2D0
=
234.9970; found 234.9969.
+4.46 (c = 0.0089, CH2Cl2). 1H NMR (360 MHz, CDCl3): δ = 4.91
(m, 1 H), 3.76 (d, J = 1.9 Hz, 2 H), 2.16 (t, J = 7.6 Hz, 2 H), 1.54
(m, 4 H), 1.40 (s, 9 H), 1.24 (m, 4 H), 1.20 (d, J = 6.3 Hz, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 172.9, 166.7, 79.8, 73.1,
(S,E)-5-Hydroxyhex-2-enal (10): To a flame-dried round-bottomed
flask with a solution of ent-5 (3.0 g, 34.8 mmol, 1.00 equiv.) in an-
hydrous CH2Cl2 (350 mL) under Ar at room temp. was added acro-
lein (23.1 mL, 348 mmol, 10.0 equiv.). To the resulting solution was
added Grubbs’ second-generation catalyst 6 (1.40 g, 1.74 mmol,
0.0500 equiv.). The solution was stirred at room temp. for 12 h. The
reaction mixture was then concentrated under reduced pressure and
purified by gradient column chromatography (20% to 50% EtOAc/
hexanes) to afford 10 as a brown viscous oil (3.52 g, 88%). TLC:
Rf = 0.2 (50% EtOAc/hexanes). [α]2D2 = +16.7 (c = 0.008, CH2Cl2).
1H NMR (360 MHz, CDCl3): δ = 9.38 (d, J = 7.9 Hz, 1 H), 6.85
(m, 1 H), 6.06 (ddt, J = 15.7, 7.9, 1.4 Hz, 1 H), 3.92 (m, 1 h), 3.11
(s, 1 H), 2.40 (m, 2 H), 1.14 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 194.1, 155.3, 134.3, 66.1, 41.8, 23.1 ppm.
35.4, 35.3, 28.7, 28.0, 26.1, 24.8, 19.6 ppm. IR (CH Cl ): ν = 3437,
˜
2
2
2978, 2936, 2862, 1725, 1459, 1421, 1367, 1278, 1159, 1108, 959,
847 cm–1. HRMS (EI): calcd. for C10H16O3Br [M – C4H9O]
263.0283; found 263.0284.
(R)-Hex-5-en-2-yl 2-Bromoacetate (15): To a flame-dried round-
bottomed flask with a solution of secondary alcohol 14 (7.00 g,
69.9 mmol, 1.00 equiv.) in anhydrous CH2Cl2 (233 mL) under Ar
at 0 °C was added pyridine (12.0 mL, 139.9 mmol, 2.00 equiv.) fol-
lowed by bromoacetyl bromide (13.0 mL, 139.9 mmol, 2.00 equiv.)
dropwise. The reaction mixture was warmed to room temp. Upon
completion as monitored by TLC, the reaction was quenched by a
saturated aqueous NH4Cl solution (1000 mL). The aqueous phase
was extracted with CH2Cl2 (3ϫ 200 mL), and the organic extracts
were washed with a saturated CuSO4 solution to remove excess
IR (CH Cl ): ν = 3398, 2970, 2928, 2835, 2743, 1949, 1683, 1637,
˜
2
2
1405, 1375, 1305, 1147, 1112, 978, 936 cm–1. HRMS (EI): calcd.
for C6H10O3 [M+] 114.0681; found 114.0686.
tert-Butyl (S,2E,4E)-7-Hydroxyocta-2,4-dienoate (11): To a solution pyridine. The crude material was concentrated under vacuum and
of 10 (2.01 g, 17.5 mmol, 1.00 equiv.) in CH2Cl2 (350 mL) was
added (tert-butoxycarbonylmethylene)triphenylphosphorane
purified by flash column chromatography (3% EtOAc/hexanes) to
afford 15 as light yellow oil (15.0 g, 98%). TLC: Rf = 0.5 (10%
(19.8 g, 52.6 mmol, 3.00 equiv.). The mixture was stirred at room EtOAc/hexanes). [α]2D3 = –12.1 (c = 0.049, CH2Cl2). 1H NMR
temp. overnight. The solution was concentrated, and the residue
was purified by flash column chromatography (25% EtOAc/hex-
(360 MHz, CDCl3): δ = 5.77 (ddt, J = 17.0, 10.4, 6.6 Hz, 1 H), 4.97
(m, 3 H), 3.78 (m, 2 H),2.09 (m, 2 H), 1.66 (m, 2 H), 1.24 (d, J =
anes) to afford 11 as a light yellow oil (3.48 g, 94%). TLC: Rf = 6.3 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.7, 137.3,
3308
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3303–3313

Umpolung Pd-Catalyzed α-Arylation in Natural Product Synthesis
115.1, 72.7, 34.7, 29.4, 26.1, 19.6 ppm. IR (CH Cl ): ν = 3080, 1.00 equiv.) in anhydrous CH2Cl2 (136 mL) under Ar at 0 °C. To
˜
2
2
2977, 2939, 1734, 1639, 1449, 1418, 1376, 1281, 1171, 1118, 993,
962, 916, 738 cm–1. HRMS (EI): calcd. for C5H7O2Br [M – C3H6]
177.9629; found 177.9624.
this solution was added pyridine (6.55 mL, 81.2 mmol, 2.00 equiv.),
followed by bromoacetyl bromide (7.07 mL, 81.2 mmol,
2.00 equiv.). The reaction mixture was warmed to room temp.
Upon completion, as determined by TLC analysis, the reaction was
quenched with a saturated aqueous NH4Cl solution (250 mL). The
aqueous phase was extracted with CH2Cl2 (3ϫ 100 mL), and the
organic extracts were washed with saturated CuSO4 solution to re-
move excess pyridine. The crude material was concentrated under
vacuum and purified by flash column chromatography (1% EtOAc/
hexanes) to afford 19 as colorless oil (4.61 g, 55%). TLC: Rf = 0.2
(R)-5-Oxopentan-2-yl 2-Bromoacetate (16):
A solution of 15
(6.60 g, 29.9 mmol, 1.00 equiv.) dissolved in CH2Cl2 (600 mL) was
cooled to –78 °C, and O3 was bubbled through the solution until
the starting material was consumed as indicated by TLC analysis
(1.5 h). The solution was then purged with O2, and the reaction
was quenched by addition of Me2S (44.0 mL, 596.0 mmol,
20.0 equiv.) and stirred overnight. The resulting mixture was con-
centrated in vacuo to yield the crude aldehyde as light yellow oil.
Purification by flash column chromatography (20% EtOAc/hex-
anes) afforded 16 as light yellow oil (3.7 g, 55%). TLC: Rf = 0.2
(20% EtOAc/hexanes). [α]2D3 = –8.23 (c = 0.084, CH2Cl2). 1H NMR
(360 MHz, CDCl3): δ = 9.69 (s, 1 H), 4.90 (m, 1 H), 2.47 (m, 2 H),
1.86 (m, 2 H), 1.21 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 200.8, 166.5, 72.1, 39.4, 27.6, 25.9, 19.4 ppm. IR
1
(20% EtOAc/hexanes). [α]2D3 = +0.11 (c = 0.38, CHCl3). H NMR
(360 MHz, CDCl3): δ = 5.66 (m, 1 H), 4.96 (m, 3 H), 3.72 (s, 2 H),
2.25 (m, 2 H), 1.17 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 166.3, 132.8, 117.8, 71.9, 39.7, 25.9, 18.9 ppm. IR
(CH Cl ): ν = 2982, 2937, 2256, 1735, 1644, 1283, 1175, 1110, 910,
˜
2
2
730 cm–1. HRMS (EI): calcd. for C4H6O2Br [M – C3H5] 164.9551;
found 164.9548.
(CH Cl ): ν = 2981, 2939, 2829, 2730, 2258, 1734, 1418, 1380, 1281,
˜
2
2
tert-Butyl (R,E)-5-(2-Bromoacetoxy)hex-2-enoate (20): To a solu-
tion of 19 (1.00 g, 4.83 mmol, 1.00 equiv.) in anhydrous CH2Cl2
(25.0 mL) was added tert-butyl acrylate (1.50 mL, 103 mmol,
2.00 equiv.) and Grubbs’ second-generation catalyst 6 (0.205 g,
0.241 mmol, 0.0500 equiv.) at room temp. The reaction mixture was
stirred under reflux for 12 h, and the solvent was removed in vacuo
to afford the crude product. Column chromatography on silica gel
(5% EtOAc/hexanes) afforded 20 (1.05 g, 70%) as brown viscous
oil. TLC: Rf = 0.2 (20% EtOAc/hexanes). [α]2D0 = +1.7 (c = 0.007,
CH2Cl2). 1H NMR (360 MHz, CDCl3): δ = 6.74 (m, 1 H), 5.77 (dt,
J = 15.7, 1.4 Hz, 1 H), 5.01 (m, 1 H), 3.76 (s, 2 H), 2.43 (m, 1 H),
2.19 (m, 1 H), 1.43 (s, 9 H), 1.24 (d, J = 6.4 Hz, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 166.5, 165.3, 141.3, 126.3, 80.3, 71.4,
1167, 1122, 1091, 1038, 993, 958, 909, 734, 650 cm–1. HRMS (EI):
calcd. for C7H10O3Br [M – H] 220.9813; found 220.9811.
(2R)-5-Hydroxyhept-6-en-2-yl 2-Bromoacetate (17): To a stirred
solution of 16 (3.03 g, 13.4 mmol, 1.00 equiv.) in Et2O (135 mL)
under Ar at –78 °C was added vinylmagnesium bromide (1.0 m in
THF, 20.1 mL, 1.50 equiv.) dropwise. The reaction mixture was
stirred at that temperature for 8 h before being quenched with satu-
rated aqueous NaHCO3 solution (300 mL). The mixture was sepa-
rated and the aqueous layer extracted with Et2O (3ϫ 100 mL). The
combined organic layers were dried with Na2SO4, filtered, and the
solvent was removed under reduced pressure to afford the crude
product, which was purified by flash column chromatography (17%
EtOAc/hexanes) to afford 17 as a yellow oil (1.68 g, 50%). TLC:
40.9, 37.8, 28.0, 25.9, 19.3 ppm. IR (CH Cl ): ν = 2978, 2936, 2254,
˜
2
2
1
Rf = 0.3 (30% EtOAc/hexanes). H NMR (360 MHz, CDCl3): δ =
1737, 1710, 1660, 1455, 1390, 1367, 1282, 1162, 1058, 982, 913, 847,
731, 647 cm–1. HRMS (EI): calcd. for C8H10O3Br [M – C4H9O]
232.9813; found 232.9816.
5.85 (ddd, J = 16.6, 10.4, 6.1 Hz, 1 H), 5.17 (m, 2 H), 4.98 (m, 1
H), 4.11 (m, 1 H), 3.80 (m, 2 H), 1.62 (m, 6 H), 1.26 (d, J = 6.3 Hz,
3 H) ppm; dr = 1:0.7. 13C NMR (125 MHz, CDCl3): δ = 166.9,
140.7, 115.07, 115.03, 114.96, 114.95, 73.2, 73.0, 72.8, 72.6, 72.3,
71.9, 71.7, 39.7, 36.0, 32.5, 32.4, 32.3, 31.7, 31.5, 31.4, 31.3, 27.9,
(R)-Pent-4-en-2-yl 2-(3,5-Dimethoxyphenyl)acetate (21): A flame-
dried round-bottomed flask with
a solution of 19 (1.80 g,
8.69 mmol, 1 equiv.) in THF (44 mL) and water (0.3 mL) was
strictly deoxygenated by using the freeze-pump-thaw procedure.
The round-bottomed flask was then transferred inside a glove box,
and (3,5-dimethoxyphenyl)boronic acid (1.2 g, 10.42 mmol,
1.2 equiv.), Pd(OAc)2 (0.06 g, 0.26 mmol, 0.03 equiv.), P(o-Tol)3
(0.238 g, 0.78 mmol, 0.09 equiv.) and K3PO4 (9.2 g, 43.45 mmol,
5 equiv.) were added sequentially. The solution was stirred inside
the glove box for 24 h. The reaction slurry was poured into water
(300 mL) and extracted with CH2Cl2 (3ϫ 100 mL). The combined
organic layers were dried with anhydrous MgSO4, filtered, and vol-
atiles were removed in vacuo. The residue was purified by gradient
column chromatography (1% to 3% EtOAc/hexanes) to afford 21
as yellow oil (0.32 g, 60%). TLC: Rf = 0.3 (10% EtOAc/hexanes).
26.1, 25.9, 19.9, 19.7, 16.2 ppm. IR (CH Cl ): ν = 3155, 2981, 2255,
˜
2
2
1726, 1285, 905, 738, 650 cm–1. HRMS (EI): calcd. for C6H11O2Br
[M – C3H4O] 193.9942; found 193.9945.
(2R)-5-[(tert-Butyldimethylsilyl)oxy]hept-6-en-2-yl 2-Bromoacetate
(18): To a stirred solution of 17 (2.48 g, 9.87 mmol, 1.00 equiv.) in
anhydrous CH2Cl2 (100 mL) under Ar at 0 °C was added 2,6-luti-
dine (2.87 mL, 24.7 mmol, 2.50 equiv.) and tert-butyldimethylsilyl
trifluoromethanesulfonate (3.40 mL, 14.8 mmol, 1.5 equiv.) se-
quentially. The mixture was warmed to room temp. and stirred
overnight. The mixture was then diluted with water (300 mL), and
the aqueous layer was extracted with EtOAc (3ϫ 100 mL). The
combined organic layers were washed with water (3ϫ 20 mL), then
dried with MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (1%
EtOAc/hexanes) to afford 18 as a yellow oil (2.4 g, 67%). TLC: Rf
= 0.5 (5% EtOAc/hexanes). 1H NMR (360 MHz, CDCl3): δ = 5.76
(m, 1 H), 4.95 (m, 1 H), 3.79 (m, 2 H), 1.56 (m, 4 H), 1.24 (d, J =
6.3 Hz, 3 H), 0.88 (s, 9 H), 0.04 (m, 6 H) ppm; dr = 1:0.6. 13C
NMR (125 MHz, CDCl3): δ = 166.8, 141.1, 114.0, 73.4, 73.2, 73.0,
33.4, 33.3, 31.1, 30.9, 26.2, 25.8, 19.7, –4.4, –4.8 ppm. IR (CH2Cl2):
1
[α]2D4 = +6.10 (c = 0.0052, CH2Cl2). H NMR (360 MHz, CDCl3):
δ = 6.43 (d, J = 2.2 Hz, 2 H), 6.36 (t, J = 2.2 Hz, 1 H), 5.71 (m, 1
H), 5.02 (m, 3 H), 3.77 (s, 6 H), 3.51 (s, 2 H), 2.30 (m, 2 H), 1.21
(d, J = 6.3 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.7,
160.7, 136.2, 133.4, 117.6, 107.2, 99.1, 70.5, 55.2, 41.8, 40.1,
19.3 ppm. IR (CH Cl ): ν = 3425, 2947, 1729, 1598, 1463, 1205,
˜
2
2
1159, 1066 cm–1. HRMS (EI): calcd. for C15H20O4 [M+] 264.1362;
found 264.1359.
ν = 2951, 2927, 2859, 1730, 1460, 1281, 1099, 1027, 836, 772,
˜
745 cm–1. HRMS (EI): calcd. for C11H20O3BrSi [M – C4H9]
307.0365; found 307.0363.
tert-Butyl (R,E)-5-[2-(3,5-Dimethyloxyphenyl)acetoxy]hex-2-enoate
(22): A flame-dried round-bottomed flask with a solution of 20
(R)-Pent-4-en-2-yl 2-Bromoacetate (19): In a flame-dried round- (0.500 g, 1.63 mmol, 1.00 equiv.) in THF (8.20 mL) and H2O
bottomed flask was placed a solution of 5 (3.50 g, 40.6 mmol, (0.05 mL) was degassed by using the freeze-pump-thaw technique
Eur. J. Org. Chem. 2015, 3303–3313
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3309

D. De Joarder, M. P. Jennings
FULL PAPER
(3ϫ). The round-bottomed flask was transferred to a glove box,
and (3,5-dimethoxyphenyl)boronic acid (0.350 g, 1.96 mmol,
1.20 equiv.), Pd(OAc)2 (0.0110 g, 0.0489 mmol, 0.0300 equiv.), P(o-
Tol)3 (0.1 g, 0.147 mmol, 0.0900 equiv.) and K3PO4 (1.72 g,
8.15 mmol, 5.00 equiv.) were added sequentially. The reaction mix-
ture was stirred inside the glove box for 24 h. The reaction slurry
was poured into water (150 mL) and extracted with CH2Cl2 (3ϫ
50 mL). The combined organic layers were dried with anhydrous
MgSO4, filtered, and the volatiles were removed in vacuo. The resi-
due was purified by gradient column chromatography (2% to 5%
EtOAc/hexanes) to afford 22 as brown oil (0.32 g, 78%). TLC: Rf
= 0.2 (10% EtOAc/hexanes). [α]2D4 = +3.0 (c = 0.0135, CH2Cl2). 1H
NMR (360 MHz, CDCl3): δ = 6.72 (m, 1 H), 6.37 (d, J = 2.2 Hz,
2 H), 6.30 (t, J = 2.2 Hz, 1 H), 5.72 (td, J = 15.6, 1.4 Hz, 1 H),
4.96 (m, 1 H), 3.71 (s, 6 H), 3.47 (s, 2 H), 2.36 (m, 2 H), 1.42 (s, 9
H), 1.18 (d, J = 6.30 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 170.6, 160.8, 141.1, 136.0, 125.9, 123.4, 107.2, 99.2, 80.2, 69.7,
173.0, 159.9, 136.8, 136.4, 128.5, 127.9, 127.5, 108.5, 100.8, 71.4,
70.0, 41.9, 35.6, 35.4, 28.8, 28.1, 25.1, 24.9, 19.8 ppm. IR (CH2Cl2):
˜
ν = 3437, 2088, 1725, 1641, 1452, 1151 cm–1. HRMS (EI): calcd.
for C30H33O6 [M – C4H9] 489.2277; found 489.2289.
(R)-Hex-5-en-2-yl 2-(3,5-Dimethoxyphenyl)acetate (25): A flame-
dried round-bottomed flask containing a solution of 15 (8.00 g,
36.2 mmol, 1.00 equiv.) in THF (180 mL) and water (1.50 mL) was
degassed by using the freeze-pump-thaw procedure. The round-bot-
tomed flask was then placed into a glove box, and (3,5-dimeth-
oxyphenyl)boronic acid (7.80 g, 43.4 mmol, 1.20 equiv.), Pd(OAc)2
(0.240 g, 1.08 mmol, 0.0300 equiv.), P(o-Tol)3 (0.990 g, 3.25 mmol,
0.0900 equiv.) and K3PO4 (38.4 g, 181 mmol, 5.00 equiv.) were
added sequentially. The solution was stirred inside the glove box
for 24 h. The reaction slurry was poured into H2O (1000 mL) and
extracted with CH2Cl2 (3ϫ 100 mL). The combined organic layers
were dried with MgSO4, filtered, and the volatiles were removed in
vacuo. The residue was purified by gradient column chromatog-
raphy (2% to 5% EtOAc/hexanes) to afford 25 as yellow oil (8.11 g,
80%). TLC: Rf = 0.4 (10% EtOAc/hexanes). [α]2D3 = –5.7 (c = 0.06,
55.2, 41.7, 38.1, 34.2, 27.8, 19.4 ppm. IR (CH Cl ): ν = 2975, 2937,
˜
2
2
2839, 1733, 1712, 1597, 1464, 1428, 1363, 1325, 1293, 1248, 1207,
1062, 979, 846 cm–1. HRMS (EI): calcd. for C20H28O6 [M+]
364.1886; found 364.1884.
1
CH2Cl2). H NMR (360 MHz, CDCl3): δ = 6.44 (d, J = 2.5 Hz, 2
H), 6.36 (m, 1 H), 5.75 (m, 1 H), 4.93 (m, 3 H), 3.76 (s, 6 H), 3.51
(s, 2 H), 2.02 (m, 2 H), 1.63 (m, 2 H), 1.21 (d, J = 6.3 Hz, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 170.8, 160.7, 137.6, 136.3,
114.8, 107.1, 99.1, 70.8, 55.1, 41.9, 34.9, 29.5, 19.8 ppm. IR
tert-Butyl
(R)-5-{2-[3,5-Bis(benzyloxy)phenyl]acetoxy}hexanoate
(23): A flame-dried round-bottomed flask with a solution of 20
(1.40 g, 4.52 mmol, 1.00 equiv.) in THF (23.0 mL) and water
(0.160 mL) was degassed by using the freeze-pump-thaw procedure.
The round-bottomed flask was transferred inside a glove box, and
[3,5-bis(benzyloxy)phenyl]boronic acid (1.81 g, 5.42 mmol,
1.20 equiv.), Pd(OAc)2 (0.0300 g, 0.130 mmol, 0.0300 equiv.), P(o-
Tol)3 (0.123 g, 0.400 mmol, 0.0900 equiv.) and K3PO4 (4.79 g,
22.6 mmol, 5.00 equiv.) were added sequentially. The solution was
stirred inside the glove box for 24 h. Upon completion, the reaction
mixture was poured into water (300 mL) and extracted with
CH2Cl2 (3ϫ 100 mL). The combined organic layers were dried
with MgSO4, filtered, and the volatiles were removed in vacuo. The
residue was purified by gradient column chromatography (2% to
4% EtOAc/hexanes) to afford 23 as yellow oil (1.81 g, 77%). TLC:
Rf = 0.3 (10% EtOAc/hexanes). [α]2D2 = +0.03 (c = 0.20, CH2Cl2).
1H NMR (360 MHz, CDCl3): δ = 7.39 (m, 10 H), 6.56 (m, 3 H),
5.03 (s, 4 H), 4.92 (m, 1 H), 3.53 (s, 2 H), 2.21 (m, 2 H), 1.58 (m,
4 H), 1.44 (s, 9 H), 1.22 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 170.8, 159.9, 128.4, 127.4, 127.8, 108.4,
100.8, 80.0, 71.0, 69.9, 41.8, 35.0, 28.0, 20.8, 19.7 ppm. IR
(CH Cl ): ν = 2939, 2840, 2255, 1726, 1601, 1464, 1433, 1293, 1205,
˜
2
2
1156, 1065, 909, 833, 730, 650 cm–1. HRMS (EI): calcd. for
C16H22O4 [M+] 278.1518; found 278.1516.
(2R)-5-[(tert-Butyldimethylsilyl)oxy]hept-6-en-2-yl 2-(3,5-Dimeth-
oxyphenyl)acetate (26): To a flame-dried round-bottomed flask
with a solution of 18 (0.850 g, 2.34 mmol, 1.00 equiv.) in anhydrous
THF (12.0 mL) under argon was added water (0.100 mL), and the
solution was degassed. The round-bottomed flask was then placed
into a glove box, and (3,5-dimethoxyphenyl)boronic acid (0.500 g,
2.80 mmol, 1.20 equiv.), Pd(OAc)2 (0.0150 g, 0.0700 mmol,
0.0300 equiv.), P(o-Tol)3 (0.0640 g, 0.210 mmol, 0.0900 equiv.) and
K3PO4 (2.48 g, 11.7 mmol, 5.00 equiv.) were added sequentially.
The solution was stirred inside the glove box for 24 h. The reaction
slurry was poured into water (100 mL) and extracted with CH2Cl2
(3ϫ 30 mL). The combined organic layers were dried with MgSO4,
filtered, and the volatiles were removed in vacuo. The residue was
purified by flash column chromatography (3% EtOAc/hexanes) to
afford 26 as yellow oil (0.52 g, 53%). TLC: Rf = 0.5 (10% EtOAc/
hexanes). 1H NMR (360 MHz, CDCl3): δ = 6.43 (m, 2 H), 6.35 (m,
1 H), 5.73 (m, 1 H), 5.11 (m, 1 H), 5.01 (m, 1 H), 4.91 (m, 1 H),
4.06 (m, 1 H), 3.76 (s, 6 H), 3.51 (s, 2 H), 1.51 (m, 4 H), 1.20 (d, J
= 6.3 Hz, 3 H), 0.88 (m, 9 H), 0.02 (m, 6 H) ppm; dr = 1:0.9. 13C
NMR (125 MHz, CDCl3): δ = 170.8, 160.7, 141.3, 136.3, 113.8,
107.1, 99.2, 73.3, 73.0, 71.5, 71.3, 55.2, 41.9, 33.5, 33.3, 31.3, 31.1,
(CH Cl ): ν = 3425, 2080, 1639, 1172 cm–1. HRMS (EI): calcd. for
˜
2
2
C32H38O6 [M+] 518.2668; found 518.2673.
tert-Butyl
(S)-7-{2-[3,5-Bis(benzyloxy)phenyl]acetoxy}octoanoate
(24): A flame-dried round-bottomed flask with a solution of 13
(0.950 g, 2.81 mmol, 1.00 equiv.) in THF (15.0 mL) and water
(0.100 mL) was degassed by using the freeze-pump-thaw technique.
The round-bottomed flask was transferred into a glove box, and
[3,5-bis(benzyloxy)phenyl]boronic acid (1.12 g, 3.37 mmol,
1.20 equiv.), Pd(OAc)2 (0.0190 g, 0.0840 mmol, 0.0300 equiv.), P(o-
Tol)3 (0.0770 g, 0.250 mmol, 0.0900 equiv.) and K3PO4 (2.98 g,
14.1 mmol, 5.00 equiv.) were added sequentially. The solution was
stirred inside the glove box for 24 h. The reaction slurry was poured
into H2O (400 mL) and extracted with CH2Cl2 (3ϫ 100 mL). The
combined organic layers were dried with MgSO4, filtered, and the
volatiles were removed in vacuo. The residue was purified by flash
column chromatography (5% EtOAc/hexanes) to afford 24 as yel-
low oil (1.05 g, 70%). TLC: Rf = 0.4 (10% EtOAc/hexanes). [α]2D0
= +2.66 (c = 0.012, CH2Cl2). 1H NMR (360 MHz, CDCl3): δ =
7.37 (m, 10 H), 6.54 (m, 3 H), 5.02 (s, 4 H), 4.89 (m, 1 H), 3.51 (s,
2 H), 2.17 (m, 2 H), 1.57 (m, 5 H), 1.43 (s, 9 H), 1.27 (m, 4 H),
25.8, 19.9, 18.1, –4.4, –4.9 ppm. IR (CH Cl ): ν = 2954, 2931, 2855,
˜
2
2
2255, 1723, 1597, 1464, 1426, 1293, 1255, 1205, 1156, 1065, 909,
833, 734, 647 cm–1. HRMS (EI): calcd. for C19H29O5Si [M – C4H9]
365.1784; found 365.1784.
(R)-5-{2-[3,5-Bis(benzyloxy)phenyl]acetoxy}hexanoic Acid (27): To a
solution of 23 (1.56 g, 30.0 mmol, 1.00 equiv.) in anhydrous CH2Cl2
under argon at 0 °C were added 2,6-lutidine (0.731 mL, 2.86 mmol,
2.10 equiv.) and TMSOTf (1.22 mL, 3.07 mmol, 2.26 equiv.) se-
quentially. The mixture was warmed to room temp. and stirred un-
til consumption of the starting material as determined by TLC.
H2O (300 mL) was added to the mixture, and the aqueous phase
was acidified and extracted with CH2Cl2 (3ϫ 100 mL). The com-
bined organic phases were dried with anhydrous MgSO4, filtered,
1.18 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = and concentrated in vacuo. The crude product was purified by flash
3310 Eur. J. Org. Chem. 2015, 3303–3313
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Umpolung Pd-Catalyzed α-Arylation in Natural Product Synthesis
column chromatography (20% EtOAc/hexanes) to afford 27 as yel-
low viscous oil (0.37 g, 83%). TLC: Rf = 0.2 (30% EtOAc/hexanes).
1 H), 3.51 (s, 2 H), 2.29 (t, J = 7.5 Hz, 2 H), 1.45 (m, 8 H), 1.18
(d, J = 6.1 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.9,
159.9, 136.8, 136.2, 128.5, 127.9, 127.5, 108.5, 100.8, 71.4, 70.0,
1
[α]2D2 = +0.22 (c = 0.0087, CH2Cl2). H NMR (360 MHz, CDCl3):
δ = 7.66 (m, 10 H), 6.55 (m, 3 H), 5.03 (s, 4 H), 4.93 (m, 1 H), 3.54
42.0, 35.6, 33.5, 28.7, 24.9, 24.4, 19.9 ppm. IR (CH Cl ): ν = 2936,
˜
2 2
(s, 2 H), 2.32 (m, 2 H), 1.60 (m, 4 H), 1.22 (d, J = 6.3 Hz, 3 H) 2862, 1725, 1706, 1590, 1452, 1448, 1378, 1290, 1159, 1054, 735,
ppm. 13C NMR (125 MHz, CDCl3): δ = 170.9, 159.9, 136.8, 136.2,
128.4, 127.8, 127.4, 108.4, 100.8, 70.9, 69.9, 41.8, 34.9, 33.4, 20.3,
693 cm–1. HRMS (EI): calcd. for C30H34O6 [M+] 490.2355; found
490.2376.
19.7 ppm. IR (CH Cl ): ν = 2977, 2935, 2871, 2251, 1711, 1597,
˜
2
2
(–)-Curvularin (2): The acid 29 (0.391 g, 0.611 mmol, 1.00 equiv.)
was dissolved in a mixture of TFA (53.0 mL) and TFAA (27.0 mL),
and the solution was stirred at room temp. for 6 h. The volatile
components were removed in vacuo. The residue was dissolved in
CH2Cl2 and washed with a saturated aqueous NHCO3 solution.
The organic layer was dried with MgSO4, filtered, and the volatiles
were removed in vacuo to leave a crude material that was used
without purification. The crude product (30) (0.127 g, 0.260 mmol,
1.00 equiv.) was dissolved in MeOH/THF (1:1) (45.0 mL). At room
temp. was added Pd/C (25.0 mg). The mixture was then subjected
to H2 (1 atm) and stirred at room temp. for 6 h. The catalyst was
filtered off through Celite, and the filtrate was concentrated to leave
a crude residue. The residue was purified by flash chromatography
(50% EtOAc/hexanes) to afford 2 as a white solid (0.0500 g, 21%
from 29). TLC: Rf = 0.6 (50% EtOAc/hexanes). [α]2D2 = –7.30 (c =
1453, 1376, 1293, 1160, 1053, 909, 829, 738, 696, 650 cm–1. HRMS
(EI): calcd. for C28H30O6 [M+] 462.2042; found 462.2047.
(R)-9,11-Bis(benzyloxy)-4-methyl-4,5,6,7-tetrahydro-1H-benzo[d]-
oxecine-2,8-dione (28): To a flame-dried round-bottomed flask with
a solution of acid 27 (0.620 g, 1.34 mmol, 1.00 equiv.) in anhydrous
TFA (89.0 mL) under argon was added TFAA (45.0 mL). The reac-
tion mixture was stirred at room temp. for 5 h. The volatile compo-
nents were removed in vacuo. The residue was dissolved in CH2Cl2
and washed with saturated aqueous NHCO3 solution. The organic
layer was dried with MgSO4, filtered, and volatiles were removed
in vacuo. The crude material was purified by gradient column
chromatography (5% to 11% EtOAc/hexanes) to afford 28 as yel-
low oil (0.230 g, 38%). TLC: Rf = 0.5 (20% EtOAc/hexanes).
[α]2D2 = +45.3 (c = 0.0075, CH2Cl2). H NMR (360 MHz, CDCl3):
1
1
δ = 7.38 (m, 10 H), 6.55 (m, 1 H), 6.38 (s, 1 H), 5.04 (s, 4 H), 4.81
0.0052, EtOH). H NMR [360 MHz, (CD3)2CO]: δ = 6.39 (d, J =
(s, 1 H), 4.28 (d, J = 18.6 Hz, 1 H), 3.43 (d, J = 18.0 Hz, 1 H), 2.2 Hz, 1 H), 6.34 (d, J = 2.2 Hz, 1 H), 4.91 (m, 1 H), 3.77 (d, J =
2.83 (m, 2 H), 1.97 (m, 1 H), 1.63 (m, 4 H),1.16 (d, J = 5.7 Hz, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 207.8, 160.2, 136.1,
128.6, 128.6, 128.2, 128.1, 127.5, 127.4, 109.1, 99.1, 70.7, 70.1, 40.4,
15.8 Hz, 1 H), 3.69 (d, J = 15.8 Hz, 1 H), 3.11 (ddd, J = 15.8, 8.5,
2.8 Hz, 1 H), 2.77 (ddd, J1 = 15.4, 9.7, 3.2 Hz, 1 H), 1.74 (m, 1 H),
1.51 (m, 6 H), 1.29 (m, 3 H), 1.11 (d, J = 6.3 Hz, 3 H) ppm. 13C
NMR [125 MHz, (CD3)2CO]: δ = 207.7, 172.0, 161.1, 159.3, 137.9,
122.3, 113.2, 103.6, 73.5, 44.9, 40.7, 33.9, 28.5, 25.5, 24.5,
36.8 ppm. IR (CH Cl ): ν = 3437, 2931, 2874, 2251, 1726, 1681,
˜
2
2
1601, 1578, 1465, 1430, 1373, 1331, 1259, 1236, 1160, 1076, 1042,
909, 734, 696 cm–1. HRMS (EI): calcd. for C28H28O5 [M+]
444.1937; found 444.1943.
21.5 ppm. IR (EtOH): ν = 2868, 2662, 2566, 2352, 2127, 1898,
˜
1611, 1225, 1084, 923 cm–1. HRMS (EI): calcd. for C16H20O5 [M+]
292.1311; found 292.1305.
(+)-Xestodecalactone A (1): To
a solution of 28 (0.100 g,
0.22 mmol, 1.00 equiv.) in MeOH (38.0 mL) was added Pd/C (2R)-5-[(tert-Butyldimethylsilyl)oxy]-6-oxohexan-2-yl
2-(3,5-Di-
(10.0 mg). The mixture was then subjected to H2 (1 atm) and stirred
at room temp. for 6 h. The catalyst was filtered off through Celite,
and the filtrate was concentrated to leave a crude residue. The resi-
due was purified by flash column chromatography (50% EtOAc/
hexanes) to afford 1 as white solid (0.021 g, 35%). TLC: Rf = 0.2
(60% EtOAc/hexanes). [α]2D2 = +46.8 (c = 0.002, MeOH). 1H NMR
(360 MHz, CD3OD): δ = 6.19 (d, J = 1.8 Hz, 1 H), 6.07 (d, J =
methoxyphenyl)acetate (31): To a solution of 26 (3.48 g, 8.23 mmol,
1.00 equiv.) in acetone/H2O (10:1; 0.1 m, 82.3 mL) were added 2,6-
lutidine (1.91 mL, 16.5 mmol, 2.00 equiv.), N-methylmorpholine N-
oxide (1.44 g, 12.4 mmol, 1.50 equiv.) and OsO4 (0.0300 g,
0.160 mmol, 0.0200 equiv.). When the starting material had been
consumed (24 h) as monitored by TLC, [bis(acetoxy)iodo]benzene
(3.97 g, 12.4 mmol, 1.50 equiv.) was added. After stirring for 2 h,
1.8 Hz, 1 H), 4.73 (m, 1 H), 3.98 (d, J = 18.2 Hz, 1 H), 3.42 (d, J the reaction was quenched with saturated aqueous Na2S2O3 solu-
= 18.4 Hz, 1 H), 3.06 (m, 1 H), 2.71 (m, 1 H), 1.85 (m, 3 H), 1.49 tion (400 mL), the mixture extracted with EtOAc (3ϫ 100 mL),
(m, 1 H), 1.13 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (125 MHz, washed with saturated aqueous CuSO4 solution, dried with
CD3OD): δ = 210.5, 170.7, 161.1, 158.1, 134.5, 120.7, 109.7, 107.7,
Na2SO4 and concentrated in vacuo. The crude residue was purified
101.6, 74.1, 39.9, 36.3, 22.3, 19.6 ppm. IR (MeOH): ν = 3369, 2951, by flash column chromatography (5% to 8% EtOAc/hexanes) to
˜
2836, 2502, 2236, 2137, 2076, 1943, 1658, 1460, 1384, 1217, 1118,
973 cm–1. HRMS (EI): calcd. for C14H16O5 [M+] 264.0998; found
264.1003.
afford 31 as yellow oil (2.86 g, 82%). TLC: Rf = 0.3 (10% EtOAc/
hexanes). 1H NMR (360 MHz, CDCl3): δ = 9.52 (dd, J = 3.2,
1.6 Hz, 1 H), 6.42 (m, 2 H), 6.35 (t, J = 2.2 Hz, 1 H), 4.91 (m, 1
H), 3.93 (m, 1 H), 3.76 (s, 6 H) 3.51 (s, 2 H), 1.60 (m, 4 H), 1.21
(d, J = 6.3 Hz, 3 H), 0.90 (s, 9 H), 0.06 (m, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 203.5, 170.8, 160.8, 136.2, 107.2, 99.1, 71.0,
70.7, 55.2, 41.9, 30.9, 30.7, 28.3, 28.0, 25.6, 19.8, 19.8, 18.1 ppm.
(S)-7-{2-[3,5-Bis(benzyloxy)phenyl]acetoxy}octanoic Acid (29): To a
solution of 24 (0.600 g, 11.0 mmol, 1.00 equiv.) in anhydrous
CH2Cl2 under argon at 0 °C were added 2,6-lutidine (0.270 mL,
23.0 mmol, 2.10 equiv.) and TMSOTf (0.451 mL, 24.8 mmol,
2.25 equiv.) sequentially. The mixture was warmed to room temp.
and stirred until consumption of the starting material.
H2O(100 mL) was added to the mixture, and the aqueous phase
IR (CH Cl ): ν = 2951, 2927, 2859, 1734, 1601, 1468, 1430, 1293,
˜
2
2
1255, 1205, 1160, 1068, 836, 776 cm–1. HRMS (EI): calcd. for
C22H36O6Si [M+] 424.2281; found 424.2294.
was acidified and extracted with CH2Cl2 (3ϫ 50 mL). The com- tert-Butyl (7R,E)-4-[(tert-Butyldimethylsilyl)oxy]-7-[2-(3,5-dimeth-
bined organic phases were dried with anhydrous MgSO4, filtered,
and concentrated in vacuo. The crude product was purified by flash
column chromatography (30% EtOAc/hexanes) to afford 29 as a
yellow viscous oil (0.417 g, 77%). TLC: Rf = 0.2 (30% EtOAc/
hexanes). [α]2D0 = +10.4 (c = 0.0027, CH2Cl2). 1H NMR (360 MHz,
oxyphenyl)acetoxy]oct-2-enoate (32): To a flame-dried round-bot-
tomed flask with a solution of 31 (2.85 g, 6.71 mmol, 1.00 equiv.)
in CH2Cl2 (135 mL) under argon, was added (tert-butoxycarbonyl-
methylene)triphenylphosphorane (7.56 g, 20.1 mmol, 3.00 equiv.).
The mixture was stirred at room temp. overnight. The solution was
CDCl3): δ = 7.37 (m, 10 H), 6.54 (m, 3 H), 5.01 (s, 4 H), 4.88 (m, concentrated, and the residue was purified by flash column
Eur. J. Org. Chem. 2015, 3303–3313
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3311

D. De Joarder, M. P. Jennings
FULL PAPER
chromatography (25% EtOAc/hexanes) to afford 32 as a light yel-
(R)-7-[2-(3,5-Dimethoxyphenyl)acetoxy]-4-oxooctanoic Acid (35):
To a solution of 34 (0.130 g, 0.310 mmol, 1.00 equiv.) in anhydrous
low oil (3.48 g, 62%). TLC: Rf = 0.7 (15% EtOAc/hexanes). 1H
NMR (360 MHz, CDCl3): δ = 6.42 (m, 2 H), 6.35 (m, 1 H), 5.83 CH2Cl2 (7.00 mL) under argon at 0 °C were added 2,6-lutidine
(m, 1 H), 4.89 (m, 1 H), 4.25 (m, 1 H), 3.76 (m, 6 H), 3.50 (s, 2
H), 1.48 (m, 11 H), 1.57 (m, 3 H), 1.19 (d, J = 6.3 Hz, 3 H), 0.89
(s, 9 H), 0.02 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
170.9, 165.8, 160.8, 149.0, 136.2, 121.9, 107.2, 99.2, 80.2, 71.3, 71.1,
70.9, 55.2, 41.9, 32.9, 32.7, 31.0, 30.8, 28.1, 25.7, 19.9, 19.8, 18.1,
(0.0780 mL, 0.660 mmol, 2.10 equiv.) and TMSOTf (0.130 mL,
0.710 mmol, 2.25 equiv.) sequentially. The mixture was warmed to
room temp. and stirred until consumption of the starting material
according to TLC analysis. H2O (100 mL) was added to the mix-
ture, and the aqueous phase was acidified and extracted with
CH2Cl2 (3ϫ 50 mL). The combined organic extracts were dried
with anhydrous MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by flash column chromatography (50%
EtOAc/hexanes) to afford 35 as a yellow viscous oil (0.0890 g,
79%). TLC: Rf = 0.3 (60% EtOAc/hexanes). [α]2D2 = –8.5 (c = 0.03,
–4.5, –4.9 ppm. IR (CH Cl ): ν = 3429, 2951, 2901, 2859, 2255,
˜
2
2
1723, 1658, 1601, 1464, 1430, 1369, 1300, 1251, 1205, 1152, 1068,
970, 913, 833, 776, 734 cm–1. HRMS (EI): calcd. for C28H46O7Si
[M+] 522.3013; found 522.3008.
1
tert-Butyl (R,E)-7-[2-(3,5-Dimethoxyphenyl)acetoxy]-4-oxooct-2-en-
oate (33): To a flame-dried round-bottomed flask with a solution
of 32 (2.00 g, 3.82 mmol, 1.00 equiv.) in anhydrous THF (20 mL)
under argon at 0 °C was added TBAF (1.0 m in THF, 7.60 mL,
2.00 equiv.). The reaction mixture was warmed to room temp. and
stirred until consumption of the starting material according to TLC
analysis. The reaction was quenched with water (200 mL) and the
mixture extracted with EtOAc (3ϫ 100 mL). The combined or-
ganic layers were dried with MgSO4, filtered, and the volatiles were
removed in vacuo to provide the crude alcohol, which was carried
further without purification. A solution of the corresponding
alcohol (0.700 g, 1.71 mmol, 1.00 equiv.) in CH2Cl2 (86.0 mL) at
0 °C was treated with Dess–Martin periodinane (1.45 g, 3.42 mmol,
2.00 equiv.). The reaction mixture was warmed to room temp. and
stirred for 2 h. The reaction was quenched with a saturated aque-
ous NaHCO3 solution (100 mL) and the mixture extracted with
CH2Cl2 (3ϫ 50 mL). The combined organic layers were washed
with a saturated aqueous Na2S2O3, dried with Na2SO4, filtered,
and the solvent was removed under reduced pressure to afford the
crude product. Purification of the crude product by flash column
chromatography (20% EtOAc/hexanes) afforded 33 as yellow oil
(0.54 g, 51% over two steps from 32). TLC: Rf = 0.1 (15% EtOAc/
hexanes). [α]2D2 = –9.6 (c = 0.033, CH2Cl2). 1H NMR (360 MHz,
CDCl3): δ = 6.86 (d, J = 15.9 Hz, 1 H), 6.50 (d, J = 16.1 Hz, 1 H),
6.42 (d, J = 2.3 Hz, 2 H), 6.36 (t, J = 2.3 Hz, 1 H), 4.91 (m, 1 H),
3.76 (s, 6 H), 3.50 (s, 2 H), 2.53 (m, 2 H), 1.86 (m, 2 H), 1.50 (s, 9
H), 1.23 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 198.6, 170.7, 164.4, 160.7, 138.1, 132.6, 107.0, 99.0, 81.7, 70.3,
CH2Cl2). H NMR (360 MHz, CDCl3): δ = 6.42 (d, J = 2.2 Hz, 2
H), 6.36 (t, J = 2.2 Hz, 1 H), 4.89 (m, 1 H), 3.76 (s, 6 H), 3.50 (s,
2 H), 2.59 (m, 4 H), 2.36 (m, 2 H), 1.81 (m, 2 H), 1.21 (d, J =
6.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 207.5, 177.9,
170.9, 160.8, 136.2, 107.2, 99.1, 70.6, 55.2, 41.9, 38.1, 36.6, 29.5,
27.6, 19.9 ppm. IR (CH Cl ): ν = 2939, 2840, 2251, 1719, 1597,
˜
2
2
1460, 1433, 1293, 1205, 1166, 1065, 905, 730,647 cm–1. HRMS (EI):
calcd. for C18H24O7 [M+] 352.1522; found 352.1525.
Acknowledgments
Support for this project was provided in part by the National Sci-
ence Foundation (USA) CAREER program under CHE-0845011.
[1] a) T. S. Bugni, C. M. Ireland, Nat. Prod. Rep. 2004, 21, 143; b)
D. J. Newman, G. M. Cragg, J. Nat. Prod. 2012, 75, 311.
[2] R.-A. Edrada, M. Heubes, G. Brauers, V. Wray, A. Berg, U.
Graefe, M. Wohlfarth, J. Muehlbacher, K. Schaumann, Sudar-
sono, G. Bringmann, P. Proksch, J. Nat. Prod. 2002, 65, 1598.
[3] a) O. C. Musgrave, J. Chem. Soc. 1956, 4301; b) O. C. Mus-
grave, J. Chem. Soc. 1957, 1104; c) A. J. Birch, O. C. Musgrave,
R. W. Richards, H. Smith, J. Chem. Soc. 1959, 3146.
[4] S. Lai, Y. Shizuri, S. Yamamura, K. Kawai, Y. Terada, H. Fu-
rukawa, Tetrahedron Lett. 1989, 30, 2241.
[5] a) K. Kinoshita, T. Sasaki, M. Awata, M. Takada, S. Yagin-
uma, J. Antibiot. 1997, 50, 961; b) J. He, E. M. K. Wijeratne,
B. P. Bashyal, J. Zhan, C. J. Seliga, M. X. Liu, E. E. Pierson,
L. S. Pierson III, H. D. VanEtten, A. L. L. Gunatilaka, J. Nat.
Prod. 2004, 67, 1985.
55.1, 41.8, 36.6, 29.3, 27.8, 19.9 ppm. IR (neat): ν = 2981, 2939,
˜
2840, 2255, 1723, 1601, 1471, 1430, 1365, 1304, 1255, 1156, 1065,
977, 909, 844, 730, 650 cm–1. HRMS (EI): calcd. for C22H30O7 [M+]
406.1992; found 406.2001.
[6] For syntheses of xestodecalactone A, see: a) G. Bringmann, G.
Lang, M. Michel, M. Heubes, Tetrahedron Lett. 2004, 45, 2829;
b) T. Yoshino, F. Ng, S. J. Danishefsky, J. Am. Chem. Soc. 2006,
128, 14185.
[7] For syntheses of both xestodecalactones B and C, see: a) Q.
Liang, J. Zhang, W. Quan, Y. Sun, X. She, X. Pan, J. Org.
Chem. 2007, 72, 2694; b) R. Pal, H. Rahaman, M. K. Gurjar,
Curr. Org. Chem. 2012, 16, 1159.
[8] For syntheses of xestodecalactone C, see: a) J. S. Yadav, N.
Thrimurtulu, K. U. Gayathri, B. V. S. Reddy, A. R. Prasad,
Tetrahedron Lett. 2008, 49, 6617; b) K. Rajesh, V. Suresh, J. J. P.
Selvam, C. Bhujanga Rao, Y. Venkateswarlu, Helv. Chim. Acta
2009, 92, 1866; c) J. S. Yadav, Y. G. Rao, K. Ravindar, B. V. S.
Reddy, A. V. Narsaiah, Synthesis 2009, 3157.
tert-Butyl (R)-7-[2-(3,5-Dimethoxyphenyl)acetoxy]-4-oxooctanoate
(34): To a solution of 33 (0.400 g, 0.908 mmol, 1.00 equiv.) in
MeOH (20.0 mL) at room temp. was added Pd/C (40.0 mg). The
mixture was then subjected to H2 (1 atm) and stirred at room temp.
until consumption of the starting material according to TLC analy-
sis. The catalyst was filtered off through Celite, and the filtrate was
concentrated to leave a crude residue. The residue was purified by
flash column chromatography (30% EtOAc/hexanes) to afford 34
as a light yellow oil (0.270 g, 68%). TLC: Rf = 0.2 (15% EtOAc/
hexanes). [α]2D2 = –5.1 (c = 0.016, CH2Cl2). 1H NMR (360 MHz,
CDCl3): δ = 6.41 (d, J = 2.2 Hz, 2 H), 6.34 (t, J = 2.2 Hz, 1 H),
4.87 (m, 1 H), 3.75 (s, 6 H), 3.48 (s, 2 H), 2.55 (m, 2 H), 2.40 (m,
4 H), 1.80 (m, 2 H), 1.40 (s, 9 H), 1.19 (d, J = 6.3 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 207.8, 171.8, 170.8, 160.7, 136.2,
107.1, 99.1, 80.4, 70.6, 55.2, 41.9, 38.2, 37.0, 29.5, 29.0, 27.9,
[9] J. S. Yadav, N. Thrimurtulu, K. U. Gayathri, B. V. S. Reddy,
A. R. Prasad, Synlett 2009, 790.
[10] For previous total syntheses of curvularin, see: a) H. Gerlach,
Helv. Chim. Acta 1977, 60, 3039; b) F. Bracher, B. Schulte, Nat.
Prod. Lett. 1995, 7, 65; c) F. Bracher, B. Schulte, Liebigs Ann./
Recueil 1997, 1979; d) S. Elzner, D. Schmidt, D. Schollmeyer,
G. Erkel, T. Anke, H. Kleinert, U. Foerstermann, H. Kunz,
ChemMedChem 2008, 3, 924; e) D. K. Mohapatra, H. Raha-
man, R. Pal, M. K. Gurjar, Synlett 2008, 1801; f) P. M. Tad-
ross, S. C. Virgil, B. M. Stoltz, Org. Lett. 2010, 12, 1612.
19.9 ppm. IR (CH Cl ): ν = 2976, 2937, 2842, 2256, 1722, 1601,
˜
2
2
1463, 1430, 1365, 1293, 1251, 1205, 1156, 1064, 916, 845, 733 cm–1.
HRMS (EI): calcd. for C22H32O7 [M+] 408.2158; found 408.2161.
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Umpolung Pd-Catalyzed α-Arylation in Natural Product Synthesis
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Received: March 3, 2015
Published Online: April 14, 2015
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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