Catalytic asymmetric synthesis of dihydrofurans and cyclopentenols with tertiary stereocenters

Article abstract of DOI:10.1002/ejoc.201301476

A new asymmetric synthesis of dihydrofurans and cyclopentenols has been developed and is based on the copper-catalyzed 1,2-addition of Grignard reagents to enones in combination with Sonogashira coupling/cyclization or ring-closing metathesis. By this approach, dihydrofurans with an oxygen-containing tertiary stereocenter and chiral tertiary cyclopentenols are efficiently prepared. The absolute stereochemistry of the products has been established. The copper-catalyzed 1,2-addition of Grignard reagents to enones, combined with Sonogashira coupling/cyclization or ring-closing metathesis, provides a new asymmetric synthesis of dihydrofurans and cyclopentenols. Two different kinds of dihydrofurans are obtained with medium-to-high enantioselectivities. Copyright

Full text of DOI:10.1002/ejoc.201301476

Job/Unit: O31476
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FULL PAPER
DOI: 10.1002/ejoc.201301476
Catalytic Asymmetric Synthesis of Dihydrofurans and Cyclopentenols with
Tertiary Stereocenters
Zhongtao Wu,[a] Ashoka V. R. Madduri,[a] Syuzanna R. Harutyunyan,*[a] and
Adriaan J. Minnaard*[a]
Keywords: Synthetic methods / Nucleophilic addition / Cyclization / Alcohols / Oxygen heterocycles
A new asymmetric synthesis of dihydrofurans and cyclo-
pentenols has been developed and is based on the copper-
catalyzed 1,2-addition of Grignard reagents to enones in
combination with Sonogashira coupling/cyclization or ring-
closing metathesis. By this approach, dihydrofurans with an
oxygen-containing tertiary stereocenter and chiral tertiary
cyclopentenols are efficiently prepared. The absolute stereo-
chemistry of the products has been established.
For cyclic ether formation by the alternative approach,
that is, the alkylation of a chiral tertiary alcohol followed
Introduction
Functionalized chiral five-membered cyclic ethers, for ex- by a ring-closing reaction, the literature is particularly
ample, dihydro- and tetrahydrofuran derivatives, are scarce. This is easily explained by the limited examples of
ubiquitous structural units in natural products.[1] Also, effective methods for the enantioselective synthesis of the
owing to their wide-spread applications,[2] for example, as latter.
probe molecules for chemical reactions,[3] in complex phar-
Recently, we reported the use of a copper/Josiphos-type
maceuticals, and in commodity chemicals,[2,4] the synthesis catalyst system to accomplish the enantioselective 1,2-ad-
of compounds containing chiral (dihydro)furans has been dition of Grignard reagents to α,β-unsaturated ketones
intensively studied.[3,5]
(Scheme 1).[12] This leads to chiral enantioenriched tertiary
The asymmetric synthesis of five-membered ring ethers allylic alcohols, although currently β-branched Grignard
in which the oxygen atom is connected to a secondary or reagents are required for high enantioselectivity.[13] We real-
tertiary stereocenter is of particular importance. Ring clos- ized that with the subsequent alkylation of the oxygen atom
ing by face-selective attack of an oxygen nucleophile to an to provide the corresponding ethers, together with suitable
alkene is most commonly used. In this process, the alkene ring-closing reactions, this strategy will provide a useful
is activated either by a Lewis acid by protonation,[6] allylic method for the synthesis of chiral five-membered cyclic
substitution,[7] or conjugate addition[8] or alternatively by ethers. As the tertiary stereocenter formed is clearly not
ring-opening of the corresponding epoxide[9] or halonium prone to racemization and not involved in the ring-closing
ion.[10] Alternatively, asymmetric ring-closing olefin metath- reaction, the latter process should not lead to erosion of ee.
esis has been applied.[11]
As an additional task, we planned to unambiguously estab-
Scheme 1. Asymmetric Cu-catalyzed 1,2-addition of Grignard reagents.
[a] Stratingh Institute for Chemistry, University of Groningen,
Nijenborgh 7, 9747 AG, Groningen, The Netherlands
E-mail: a.j.minnaard@rug.nl
lish the absolute configuration of the tertiary alcohols and
ethers formed in this way, as reliable data on these com-
pounds are practically absent.
On the basis of the product of the enantioselective 1,2-
Grignard addition reaction, several approaches for ring clo-
s.harutyunyan@rug.nl
http://www.rug.nl/staff/departments/11680
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301476.
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Z. Wu, A. V. R. Madduri, S. R. Harutyunyan, A. J. Minnaard
FULL PAPER
sure were selected (Scheme 2). When the X substituent is performed on gram-scale without deterioration in yield or
bromide, we have already shown that a Sonogashira reac- ee except for 2d, for which a longer reaction time led to a
tion readily leads to the corresponding enyne.[12c] Base-in- slightly lower ee.
duced intramolecular hydroalkoxylations by literature pro-
cedures[14] then lead directly to substituted dihydrofurans
Table 1. Asymmetric 1,2-addition to α-bromo enones 1.
(route A).
Scheme 2. Strategies for the formation of chiral cyclic ethers.
[a] The absolute configuration of 2 is R, vide infra.
Upon allylation of the hydroxy group in the addition
product, formally 1,6-dienes are formed. These should be
With the products 2 in hand, the Sonogashira reactions,
very suitable substrates for ring-closing olefin metathesis to
as part of route A, were performed with 5 mol-%
form chiral dihydrofurans with a double bond at the 3,4-
Pd(PPh3)2Cl2 and 10 mol-% CuI as the catalysts in Et3N.
position (route B). In turn, these out-of-conjugation alkenes
The corresponding enynes 3a–3d were isolated in high
can be further functionalized to provide highly substituted
tetrahydrofurans.
yields (Table 2).[18] The subsequent treatment with tBuOK
in dimethyl sulfoxide (DMSO) for 1 h at 60 °C afforded the
The use of butenylmagnesium bromide in the asymmetric
desired cyclized products 4a–4d in good yields.[14a] 3-
addition reaction also gives direct access to 1,6-dienes
Benzylidene-2,3-dihydrofurans are strongly fluorescent
(route C). Although the enantioselectivity of the addition
compounds.[19]
reaction in this particular case is less satisfactory (the reac-
The synthesis of the 2,5-dihydrofurans 7 by route B also
started from the chiral tertiary alcohols 2. The allylation of
the tertiary alcohols 2 was extremely sluggish, as was the
subsequent metathesis step, so the debromination of 2 was
tion requires branched Grignard reagents to reach excellent
ee values), we wanted to pursue this approach, as subse-
quent ring closure by olefin metathesis leads to chiral allylic
cyclopentenols. Formally, these originate from the addition
performed first. The debromination with tBuLi in dry Et2O
of a carbon nucleophile to cyclopentenone,[15] but this reac-
at –78 °C for 0.5 h,[20] followed by aqueous workup, yielded
tion in an enantioselective fashion is not known. Alterna-
the desired products 5a–5c in good isolated yields (Table 3).
The alkylation of the hydroxy groups in 5 was surprisingly
difficult, and substituents other than allyl could not be in-
tively, 1-methyl-2-cyclopentenol has been prepared from
linalool by ring-closing metathesis.[16]
troduced. However, under optimized conditions, namely,
the use of 1.5 equiv. allyl bromide, 1.5 equiv. NaH, and
3.0 equiv. hexamethylphosphoramide (HMPA) in dry tetra-
Results and Discussion
The study commenced with the preparation of the en- hydrofuran (THF) at reflux,[21] 6a–6c were prepared in
antioenriched tertiary allylic alcohols by the catalytic asym- high-to-excellent yield. Remarkably, 2d refused to react un-
metric addition of Grignard reagents to the corresponding der all conditions, presumably because of steric hindrance.
enones. These α-bromo enones 1, in turn, are readily ob-
Compounds 6a–c were subsequently transformed into
tained by aldol condensation of benzaldehyde and the ap- the corresponding 2,5-dihydrofurans 7a–7c by treatment
propriate ketone, followed by dibromination/HBr elimi- with 5 mol-% Hoveyda–Grubbs second-generation catalyst
nation.[17]
in dichloromethane (Table 3).[22] The reactions was fully se-
Upon treatment of the α-bromo enones 1a and 1b with lective to complete conversion, and the high yields are prob-
isobutylmagnesium bromide in the presence of CuBr·SMe2 ably only reduced because of the volatility of the products.
(5 mol-%) and (S,RFe)-L (6 mol-%) in methyl tert-butyl
For the synthesis of cyclopentenols according to route C,
ether (MTBE) at –78 °C, the desired chiral tertiary alcohols butenylmagnesium bromide was added to 1a and its α-
2a and 2b were obtained in good yields and good-to-excel- methyl (instead of α-bromo) analogue 1c (Scheme 3).[12]
lent enantioselectivities (Table 1).[12] In addition, 1a was The enantioselectivities were modest, as expected. The sub-
used in the addition of (2-ethyl)butylmagnesium bromide sequent debromination of 2e by the procedure described
and cyclohexylmethylmagnesium bromide to form the cor- earlier gave 5e in 83% isolated yield. The subsequent ring-
responding alcohols. As expected, the reactions could be closing metathesis resulted in 1-methyl-2-cyclopentenol (8a)
2
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Synthesis of Dihydrofurans and Cyclopentenols
Table 2. Synthesis of 3-benzylidene-2,3-dihydrofurans 4.
Scheme 3. Synthesis of 2-cyclopenten-1-ols 8.
To determine the absolute configuration of this class of
tertiary alcohols and ethers, we decided to prepare the cor-
responding α-hydroxy acids 9a and 9b from 2a, 2b, and 2g
(Table 4). This would lead to known well-described com-
pounds, and this approach might serve as an alternative
route to chiral enantioenriched α,α-disubstituted acids,
which are important building blocks in natural product syn-
thesis and normally prepared from chiral pool precursors.
Hydroxy acid 9a and 9b were obtained from 2a and 2b in
good yield by ozonolysis in acetone. The sign of their op-
tical rotation, in comparison with the literature data,
1
[a] E/Z = 5:1, determined by H NMR spectroscopy.
Table 3. Synthesis of 2,5-dihydrofurans 7.
Table 4. Synthesis of α-hydroxy acids 9.
in 40% yield; the moderate yield is solely caused by its ex-
treme volatility. The ring-closing metathesis of its congener
2f gave 8b in high yield.
[a] Reaction (ii) is only for the synthesis of 9b from 2g.
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Z. Wu, A. V. R. Madduri, S. R. Harutyunyan, A. J. Minnaard
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1a–1c: The starting materials were prepared by following literature
showed unambiguously that the (S,RFe) enantiomer of li-
gand L produces the opposite stereochemistry for R1 = Me
than for R1 = Ph, though both products are assigned the R
configuration owing to the application of the Cahn–Ingold–
Prelog (CIP) rules. For 2g, the ozonolysis was followed by
a bromoform reaction, which provided 9b in low yield. For
this substrate, it follows that the (S,RFe) enantiomer of L
provides the same stereochemistry as for 2b (in both cases
R1 is Ph), although the product is designated S by the CIP
rules.[23]
procedures.[17]
General Procedure for the Copper-Catalyzed 1,2-Addition of Grig-
nard Reagents: A Schlenk tube equipped with a septum and stirring
bar was charged with CuBr·SMe2 (11.3 mg, 0.055 mmol, 5 mol-%)
and ligand (S,RFe)-L (39.2 mg, 0.066 mmol, 6 mol-%). Under nitro-
gen, dry tBuOMe (8 mL) was added, and the solution was stirred
at room temperature for 15 min. Then, the corresponding enone
(1.10 mmol, in 5 mL tBuOMe) was added, and the resulting solu-
tion was cooled to –78 °C. The corresponding Grignard reagent
(1.32 mmol, 1.2 equiv. in Et2O) was diluted with tBuOMe (2 mL)
and added to the reaction mixture over 3 h. The mixture was left
to stir overnight at –78 °C. The reaction was quenched by the ad-
dition of MeOH and saturated aqueous NH4Cl, and the mixture
was warmed to room temperature and diluted with Et2O. The lay-
ers were then separated, and the aqueous layer was extracted with
Et2O. The combined organic phases were dried with anhydrous
Na2SO4, filtered, and the solvents were evaporated in vacuo. The
residue was purified by column chromatography on silica gel (pent-
ane/Et2O 20:1) to afford alcohol 2.
Conclusions
We have developed a new approach for the enantioselec-
tive synthesis of chiral dihydrofurans with a tertiary oxy-
gen-containing stereocenter and of tertiary cyclopentenols.
By the catalytic asymmetric 1,2-addition of Grignard rea-
gents, combined with a Sonogashira coupling/cyclization
approach or an alkylation followed by ring-closing metathe-
sis, different kinds of dihydrofurans were prepared ef-
ficiently. With their absolute stereochemistry established,
the obtained compounds are versatile building blocks both
for natural product synthesis and pharmaceuticals.
(R)-(Z)-2-Bromo-3,5-dimethyl-1-phenyl-1-hexen-3-ol (2a): Light yel-
low oil (265 mg, 85%). 86%ee determined by HPLC (Chiral AS-
H column, heptane/iPrOH 90:10, 40 °C, 210 nm). Retention time:
tmajor = 23.6 and tminor = 22.5 min. [α]2D0 = +10.0 (c = 1.04, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.56–7.54 (m, 2 H), 7.39–7.35
(m, 2 H), 7.32–7.28 (m, 1 H), 7.24 (s, 1 H), 2.01 (br s, 1 H), 1.89
(dd, J = 14.0, 5.6 Hz, 1 H), 1.84–1.78 (m, 1 H), 1.65 (dd, J = 14.0,
6.0 Hz, 1 H), 1.58 (s, 3 H), 1.00 (2ϫd, J = 6.4 Hz, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 136.2, 134.7, 129.0, 128.1, 127.7,
126.3, 77.6, 49.1, 28.8, 24.5, 24.2 ppm.
Experimental Section
General: 1H (400 MHz) and 13C NMR (100 MHz) spectra were re-
corded with CDCl3 as solvent. Chemical shifts were determined
1
(R)-(Z)-2-Bromo-5-methyl-1,3-diphenyl-1-hexen-3-ol (2b): Light yel-
low oil (239 mg, 63%). 98%ee determined by HPLC (Chiral OD-
H column, heptane/iPrOH 99:1, 40 °C, 230 nm). Retention time:
tmajor = 21.9 and tminor = 20.8 min. [α]2D0 = –7.8 (c = 0.49, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 7.6 Hz, 2 H), 7.56
(d, J = 7.6 Hz, 2 H), 7.43–7.32 (m, 7 H), 2.60 (s, 1 H), 2.23 (dd, J
= 14.4, 5.6 Hz, 1 H), 2.14–2.09 (m, 1 H), 1.91–1.84 (m, 1 H), 1.08
(d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.4, 135.9, 134.9, 129.2, 128.3, 128.2,
128.0, 127.5, 126.0, 81.0, 48.0, 24.7, 24.5 ppm. HRMS (APCI):
calcd. for C19H20Br [M – OH]+ 327.0743; found 327.0740.
relative to the residual solvent peaks (CHCl3, δ = 7.26 ppm for H
NMR, δ = 77.0 ppm for 13C NMR). The following abbreviations
are used to indicate signal multiplicity: s, singlet; d, doublet; t, trip-
let; m, multiplet; br, broad. Enantiomeric excesses were determined
by chiral HPLC in comparison with racemic products. Racemic
products were obtained by the same procedure as used for the
enantioselective 1,2-addition but with the ligand and CuBr·SMe2
(5 mol-%) omitted and only the Grignard reagent (1.2 equiv.) at
0 °C in Et2O used. Regioselectivities were determined by 1H NMR
spectroscopy. Optical rotations were measured with a 10 cm cell (c
given in g/100 mL) at 20 °C. Thin-layer chromatography (TLC) was
performed on TLC silica gel. Flash chromatography was performed
on silica gel. Mass spectra were obtained from a high-resolution
[ESI+ or atmospheric-pressure chemical ionization (APCI+)] mass
spectrometer. All starting materials, copper salt, ligand (S,RFe)-L,
and iBuMgBr (2 m in Et2O) were purchased and used without fur-
ther purification. All Grignard reagents were prepared from the
corresponding alkyl bromides and Mg activated with I2 in Et2O.
(R)-(Z)-2-Bromo-5-ethyl-3-methyl-1-phenyl-1-hepten-3-ol
(2c):
Light yellow oil (281 mg, 82%). 94%ee determined by HPLC (Chi-
ral AS-H column, heptane/iPrOH 90:10, 40 °C, 210 nm). Retention
time: tmajor = 16.0 and tminor = 17.6 min. [α]2D0 = +14.1 (c = 1.05,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 7.2 Hz, 2
H), 7.39–7.35 (m, 2 H), 7.32–7.28 (m, 1 H), 7.22 (s, 1 H), 1.98 (br
s, 1 H), 1.87–1.83 (m, 1 H), 1.69–1.64 (m, 1 H), 1.59 (s, 3 H),
1.46–1.35 (m, 5 H), 0.90–0.86 (m, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 136.3, 135.0, 129.0, 128.1, 127.6, 126.3, 77.6, 43.8,
36.4, 28.6, 26.5, 10.8 ppm. HRMS (ESI): calcd. for C16H22Br [M –
OH]+ 293.0905; found 293.0879.
For the stereochemistry of α-bromo enones 1, to our surprise, we
could not find a rigorous proof of the stereochemistry of the so-
obtained bromo enones in literature, although these compounds
have been reported several times. In this study, the stereochemistry
is determined unambiguously a posteriori; upon catalytic asymmet-
ric 1,2 addition with the bromo enones as substrate, the products
are identical to those obtained in the uncatalyzed addition with
the same Grignard reagent used to prepare the racemic reference
material, so isomerization during the Grignard addition can be ex-
cluded. After debromination of the resulting tertiary alcohols with
(R)-(Z)-3-Bromo-1-cyclohexyl-2-methyl-4-phenyl-3-buten-2-ol (2d):
Light yellow oil (249 mg, 70%). 75%ee determined by HPLC (Chi-
ral AD-H column, heptane/iPrOH 98:2, 40 °C, 250 nm). Retention
time: tmajor = 25.1 and tminor = 23.9 min. [α]2D0 = +12.2 (c = 0.64,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.2 Hz, 2
1
tBuLi (vide infra), H NMR spectroscopy clearly shows the pres-
H), 7.41–7.38 (m, 2 H), 7.34–7.30 (m, 1 H), 7.27 (s, 1 H), 2.18 (s,
1 H), 1.91–1.83 (m, 3 H), 1.74–1.65 (m, 4 H), 1.61 (s, 3 H), 1.56–
1.49 (m, 1 H), 1.35–1.17 (m, 3 H), 1.13–1.03 (m, 2 H) ppm. 13C
ence of an E carbon–carbon double bond. This determines that the
stereochemistry of the starting bromo enones is as shown.
4
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Synthesis of Dihydrofurans and Cyclopentenols
NMR (100 MHz, CDCl3): δ = 136.4, 134.9, 129.1, 128.1, 127.7,
(R)-3-[(E)-Benzylidene]-6-methyl-1,4-diphenyl-1-heptyn-4-ol
(3b):
126.3, 77.7, 48.0, 34.9, 34.7, 33.9, 28.8, 26.5, 26.3 ppm. HRMS Light brown oil (147 mg, 80%). [α]2D0 = +28.0 (c = 1.18, CHCl3).
(ESI): calcd. for C17H22Br [M – OH]+ 305.0899; found 305.0901.
1H NMR (400 MHz, CDCl3): δ = 7.82–7.80 (m, 2 H), 7.55–7.52
(m, 2 H), 7.28–7.12 (m, 11 H), 7.05 (s, 1 H), 2.31 (dd, J = 14.4,
5.6 Hz, 1 H), 2.20 (br s, 1 H), 2.04 (dd, J = 14.4, 5.6 Hz, 1 H),
1.86–1.79 (m, 1 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.8 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.9, 136.4, 132.9,
131.3, 129.0, 128.50, 128.46, 128.43, 128.22, 128.21, 128.1, 127.1,
125.9, 123.3, 98.1, 88.2, 79.5, 48.5, 24.9, 24.8, 24.5 ppm. HRMS
(ESI): calcd. for C27H25 [M – OH]+ 349.1951; found 349.1948.
(R)-(Z)-2-Bromo-3-methyl-1-phenyl-1,6-heptadien-3-ol (2e): Light
yellow oil (191 mg, 62%). 52%ee determined by HPLC (Chiral
AD-H column, heptane/iPrOH 98:2, 40 °C, 260 nm). Retention
time: tmajor = 15.9 and tminor = 14.1 min. [α]2D0 = +4.8 (c = 0.58,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 7.9 Hz, 2
H), 7.45–7.27 (m, 3 H), 7.21 (s, 1 H), 5.88 (m, 1 H), 5.19–4.83 (m,
2 H), 2.21–2.10 (m, 3 H), 2.10–1.98 (m, 1 H), 1.82 (m, 1 H), 1.57
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.4, 136.1,
133.7, 129.0, 128.1, 127.8, 126.8, 115.1, 77.3, 39.7, 28.4, 27.9 ppm.
HRMS (ESI): calcd. for C14H16Br [M – OH]+ 263.0436; found
263.0431.
(R)-3-[(E)-Benzylidene]-6-ethyl-4-methyl-1-phenyl-1-octyn-4-ol
(3c):[12c] Light brown oil (152 mg, 92%). [α]2D0 = +51.6 (c = 1.80,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.02–7.84 (m, 2 H),
7.59–7.26 (m, 8 H), 7.07 (s, 1 H), 2.06–1.88 (m, 2 H), 1.78 (s, 1 H),
1.60 (s, 3 H), 1.54–1.28 (m, 5 H), 0.88 (t, J = 7.2 Hz, 3 H), 0.72 (t,
J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.6,
131.8, 131.3, 129.2, 128.9, 128.44, 128.37, 128.2, 128.1, 127.9,
123.4, 97.4, 88.2, 76.5, 44.7, 36.3, 29.3, 26.9, 10.8 ppm. HRMS
(ESI): calcd. for C24H27 [M – OH]+ 315.2113; found 315.2107.
(S)-(E)-2-Methyl-1,3-diphenyl-1,6-heptadien-3-ol (2f): Light yellow
oil (199 mg, 65%). 44%ee determined by HPLC (Chiral AD-H col-
umn, heptane/iPrOH 98:2, 40 °C, 250 nm). Retention time: tmajor
=
30.6 and tminor = 27.8 min. [α]2D0 = –19.4 (c = 0.95, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 7.6 Hz, 2 H), 7.38–7.22
(m, 8 H), 6.91 (s, 1 H), 5.97–5.87 (m, 1 H), 5.07 (d, J = 17.2 Hz, 1
H), 5.00 (d, J = 10.4 Hz, 1 H), 2.31–2.10 (m, 4 H), 1.97 (s, 1 H),
1.67 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.1, 141.7,
138.9, 138.1, 129.1, 128.2, 128.1, 127.1, 126.4, 125.9, 124.8, 114.8,
79.6, 38.0, 28.2, 15.1 ppm. HRMS (APCI): calcd. for C20H21 [M –
OH]+ 261.1638; found 261.1639.
(R)-3-[(E)-Benzylidene]-1-cyclohexyl-2-methyl-5-phenyl-4-pentyn-2-
ol (3d): Light brown oil (145 mg, 84%). [α]2D0 = +37.6 (c = 1.20,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.84–7.82 (m, 2 H),
7.40–7.38 (m, 2 H), 7.32–7.25 (m, 5 H), 7.23–7.22 (m, 1 H), 6.98
(s, 1 H), 1.88–1.83 (m, 1 H), 1.75 (d, J = 12.4 Hz, 2 H), 1.67 (s, 1
H), 1.62–1.56 (m, 3 H), 1.53 (d, J = 1.2 Hz, 1 H), 1.49 (s, 3 H),
1.18–1.08 (m, 3 H), 1.07–0.92 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 136.6, 131.7, 131.3, 129.2, 128.8, 128.43, 128.37, 128.2,
127.9, 123.4, 97.4, 88.1, 76.5, 48.9, 35.2, 34.8, 33.8, 29.5, 26.4, 26.3
ppm. HRMS (ESI): calcd. for C25H27 [M – OH]+ 327.2107; found
327.2107.
(S)-(E)-2,5-Dimethyl-1,3-diphenyl-1-hexen-3-ol (2g): Light yellow
oil (188 mg, 61%). 37%ee determined by HPLC (Chiral OD-H col-
umn, heptane/iPrOH 98:2, 40 °C, 250 nm). Retention time: tmajor
=
14.1 and tminor = 14.5 min. [α]2D0 = –16.3 (c = 0.32, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.43–7.38 (m, 2 H), 7.25–7.08 (m, 8
H), 6.81 (s, 1 H), 2.03 (dd, J = 14.4, 5.6 Hz, 1 H), 1.93 (dd, J =
14.4, 5.6 Hz, 1 H), 1.75–1.70 (m, 2 H), 1.55 (d, J = 0.8 Hz, 3 H),
0.91 (d, J = 6.8 Hz, 3 H), 0.80 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 145.9, 142.4, 138.3, 129.1, 128.16, 128.11,
126.9, 126.3, 125.9, 124.4, 80.1, 47.2, 24.84, 24.83, 24.2, 15.4 ppm.
HRMS (ESI): calcd. for C20H23 [M – OH]+ 263.1794; found
263.1800.
General Procedure for the Cyclization of the Enyne:[14a,19] To a solu-
tion of 3 (0.25 mmol) in DMSO (4.0 mL) was added tBuOK
(31 mg, 0.275 mmol, 1.1 equiv.), and the resulting mixture was
stirred at 60 °C for 1 h. The mixture was poured into water (50 mL)
and extracted with Et2O. The combined organic phases were dried
with Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (pentane) to af-
ford 4.
General Procedure for the Pd-Catalyzed Synthesis of Enynes:[18] To
a solution of 2 (0.50 mmol) in Et3N (5 mL) was added Pd(PPh3)2-
Cl2 (17.5 mg, 0.025 mmol, 5 mol-%), CuI (9.5 mg, 0.050 mmol,
10 mol-%), phenylacetylene (0.082 mL, 0.75 mmol, 1.5 equiv.), and
H2O (0.045 mL, 2.5 mmol, 5 equiv.), and the resulting mixture was
stirred at 80 °C. The solvent was evaporated under reduced pres-
sure after the starting material had been consumed, and the residue
was diluted with Et2O and washed with saturated aqueous NH4Cl.
The organic layer was separated, and the aqueous layer was ex-
tracted with Et2O. The combined organic layers were dried with
Na2SO4, concentrated in vacuo, and the residue was purified by
column chromatography on silica gel (pentane/Et2O 12:1) to afford
enyne 3.
(R)-3-[(E)-Benzylidene]-2-isobutyl-2-methyl-5-phenyl-2,3-dihydro-
furan (4a): Yellow oil (61 mg, 80%). [α]2D0 = +27.6 (c = 2.05,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.63 (dd, J = 8.4,
1.6 Hz, 2 H), 7.32–7.24 (m, 7 H), 7.10–7.05 (m, 1 H), 6.55 (s, 1 H),
5.62 (s, 1 H), 1.81–1.71 (m, 2 H), 1.62–1.57 (m, 1 H), 1.41 (s, 3 H),
0.86 (dd, J = 11.2, 6.4 Hz, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 163.0, 150.5, 139.1, 130.8, 129.3, 128.49, 128.45, 127.5,
125.7, 125.5, 111.6, 98.7, 91.9, 50.1, 28.2, 24.6, 24.5, 24.3 ppm.
HRMS (APCI): calcd. for C22H25O [M + H]+ 305.1900; found
305.1905.
4b: Yellow oil (75 mg, 82%, Z/E = 5:1). [α]2D0 = +41.1 (c = 0.94,
CHCl3). HRMS (ESI): calcd. for C27H27O [M + H]+ 367.2056;
found 367.2055. The NMR data of (E)-4b and (Z)-4b are given
(R)-3-[(E)-Benzylidene]-4,6-dimethyl-1-phenyl-1-heptyn-4-ol
(3a): separately as the two groups of signals are clearly identified in the
Light brown oil (134 mg, 88%). [α]2D0 = +24.2 (c = 0.48, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.0 Hz, 2 H), 7.51–
7.49 (m, 2 H), 7.42–7.37 (m, 5 H), 7.32–7.29 (m, 1 H), 7.10 (s, 1
H), 1.99 (dd, J = 14.0, 5.6 Hz, 1 H), 1.92–1.86 (m, 1 H), 1.81 (br
s, 1 H), 1.74–1.69 (m, 1 H), 1.60 (s, 3 H), 1.04–1.00 (m, 6 H) ppm.
NMR spectrum of 4b, although no separation was performed. (R)-
3-[(E)-Benzylidene]-2-isobutyl-1,5-diphenyl-2,3-dihydrofuran [(E)-
4b]: H NMR (400 MHz, CDCl3): δ = 7.86 (dd, J = 7.2, 1.2 Hz, 2
1
H), 7.59–7.57 (m, 2 H), 7.49–7.37 (m, 10 H), 7.22–7.18 (m, 1 H),
6.73 (s, 1 H), 6.00 (s, 1 H), 2.39–2.34 (m, 1 H), 2.18–2.12 (m, 1 H),
13C NMR (100 MHz, CDCl3): δ = 136.5, 131.8, 131.3, 128.9, 128.5, 2.02–1.96 (m, 1 H), 1.08–1.06 (m, 3 H), 1.02 (dd, J = 6.8, 1.6 Hz,
128.4, 128.2, 128.0, 126.3, 123.4, 97.5, 88.1, 76.5, 50.1, 29.6, 24.6,
24.52, 24.50 ppm. HRMS (ESI): calcd. for C22H23 [M – OH]+
287.1794; found 287.1795.
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.2, 149.5, 144.3,
138.7, 130.4, 129.5, 128.6, 128.5, 128.4, 127.8, 127.3, 125.8, 125.5,
124.8, 114.3, 98.9, 94.1, 49.4, 29.8, 24.9, 24.6 ppm.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O31476
/KAP1
Date: 20-11-13 19:29:59
Pages: 9
Z. Wu, A. V. R. Madduri, S. R. Harutyunyan, A. J. Minnaard
FULL PAPER
(R)-3-[(Z)-Benzylidene]-2-isobutyl-1,5-diphenyl-2,3-dihydrofuran
[(Z)-4b]: H NMR (400 MHz, CDCl3): δ = 7.70–7.68 (m, 0.40 H),
7.63–7.61 (m, 0.40 H), 7.49–7.37 (m, 0.20 H), 7.33–7.29 (m, 1.00
H), 7.25–7.22 (m, 1 H), 6.60 (d, J = 16.0 Hz, 1 H), 6.30 (d, J =
16.0 Hz, 1 H), 1.61–1.58 (m, 3 H), 1.42 (s, 3 H), 1.42–1.34 (m, 5
H), 0.89–0.83 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
1
H), 7.12–7.11 (m, 0.60 H), 6.95–6.93 (m, 0.40 H), 6.61 (s, 0.20 H), 137.3, 137.2, 128.6, 127.3, 126.5, 126.4, 73.8, 46.3, 36.3, 29.0, 27.0,
6.27 (s, 0.20 H), 2.39–2.34 (m, 0.40 H), 2.02–1.96 (m, 0.20 H), 1.08–
26.9, 10.8 ppm. HRMS (ESI): calcd. for C16H23 [M – OH]+
1.02 (m, 1.20 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.0, 215.1794; found 215.1793.
148.9, 143.6, 137.1, 130.5, 129.1, 128.5, 128.0, 127.8, 126.4, 125.9,
125.6, 117.2, 105.9, 93.5, 42.9, 29.4, 25.0, 24.9 ppm.
(R)-(E)-3-Methyl-1-phenyl-1,6-heptadien-3-ol (5e): Light yellow oil
(92 mg, 83%). [α]2D0 = +9.1 (c = 1.95, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.22 (m, 5 H), 6.60 (d, J = 16.0 Hz, 1 H), 6.28
(d, J = 16.0 Hz, 1 H), 5.91–5.81 (m, 1 H), 5.05 (d, J = 17.6 Hz, 1
H), 4.97 (d, J = 10.4 Hz, 1 H), 2.20–2.14 (m, 2 H), 1.76–1.72 (m,
3 H), 1.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.8,
136.9, 136.4, 128.6, 127.4, 127.3, 126.4, 114.6, 73.3, 41.7, 28.6, 28.4
ppm. HRMS (ESI): calcd. for C14H17 [M – OH]+ 185.1325; found
185.1322.
(R)-3-[(E)-Benzylidene]-2-(2-ethylbutyl)-2-methyl-5-phenyl-2,3-dihy-
drofuran (4c):[12c] Yellow oil (76 mg, 91%). [α]2D0 = +37.7 (c = 0.90,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.82–7.65 (m, 2 H), 7.37
(m, 7 H), 7.17 (t, J = 7.1 Hz, 1 H), 6.64 (s, 1 H), 5.73 (s, 1 H), 1.76
(m, 2 H), 1.50 (s, 3 H), 1.42–1.24 (m, 5 H), 0.80 (t, J = 7.1 Hz, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.0, 150.5, 139.1,
130.7, 129.3, 128.5, 128.4, 127.5, 125.7, 125.4, 111.6, 98.7, 92.0,
44.5, 36.4, 28.1, 26.8, 26.5, 10.9 ppm.
General Procedure for the Allylation of the α,β-Unsaturated Tertiary
Alcohols:[21] To a solution of 5 (0.35 mmol) in dry THF (5.0 mL)
was added NaH (21.0 mg, 0.53 mmol, 1.5 equiv., 60% oil disper-
sion) under nitrogen, and the resulting mixture was stirred under
reflux for 2 h. Then, HMPA (0.18 mL, 1.05 mmol, 3.0 equiv.) was
added to the mixture followed by allyl bromide (0.046 mL,
0.53 mmol, 1.5 equiv.). After the addition, the mixture was stirred
under reflux for another 2 h. The reaction mixture was cooled to
room temperature, quenched with 2 m aqueous HCl, and extracted
with Et2O. The combined organic phases were washed with satu-
rated NaHCO3 and brine, dried with Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy on silica gel (pentane/Et2O 100:1) to afford diene 6.
(R)-3-[(E)-Benzylidene]-2-cyclohexyl-2-methyl-5-phenyl-2,3-dihydro-
furan (4d): Yellow oil (62 mg, 72%). [α]2D0 = +41.4 (c = 1.07,
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 6.8 Hz, 2
H), 7.32–7.24 (m, 7 H), 7.08 (t, J = 7.2 Hz, 1 H), 6.54 (s, 1 H), 5.62
(s, 1 H), 1.77–1.71 (m, 1 H), 1.68 (d, J = 5.6 Hz, 1 H), 1.65–1.60
(m, 1 H), 1.58–1.49 (m, 4 H), 1.40 (s, 3 H), 1.18–0.88 (m, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 163.0, 150.7, 139.1, 130.8,
129.3, 128.50, 128.45, 127.5, 125.7, 125.5, 111.6, 98.6, 91.9, 48.8,
34.8, 34.7, 33.9, 28.1, 26.44, 26.39 ppm. HRMS (ESI): calcd. for
C25H29O [M + H]+ 345.2213; found 345.2211.
1
General Procedure for the Preparation of α,β-Unsaturated
Alcohols:[20] To a solution of 2 (0.55 mmol) in Et2O (5.0 mL) was
slowly added a solution of tBuLi (1.65 mmol, 3.0 equiv., 1.7 m in
pentane) under nitrogen at –78 °C, and the resulting mixture was
stirred at this temperature for 30 min. The reaction was then
quenched with MeOH and saturated aqueous NH4Cl, and the mix-
ture was warmed to room temperature and diluted with Et2O. The
layers were separated, and the aqueous layer was extracted with
Et2O. The combined organic phase was dried with Na2SO4 and
filtered, and the solvents were evaporated in vacuo. The residue
was purified by column chromatography on silica gel (pentane/
Et2O 20:1) to afford alcohol 5.
(R)-(E)-3-Allyloxy-3,5-dimethyl-1-phenyl-1-hexene (6a): Light yel-
low oil (80 mg, 93%). [α]2D0 = –15.4 (c = 0.50, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.40 (d, J = 7.2 Hz, 2 H), 7.35–7.31 (m, 2
H), 7.26–7.22 (m, 1 H), 6.50 (d, J = 16.4 Hz, 1 H), 6.20 (d, J =
16.4 Hz, 1 H), 5.99–5.89 (m, 1 H), 5.33–5.28 (m, 1 H), 5.14–5.10
(m, 1 H), 3.91 (d, J = 5.2 Hz, 2 H), 1.87–1.80 (m, 1 H), 1.63–1.60
(m, 2 H), 1.41 (s, 3 H), 0.98–0.96 (2ϫd, J = 2.2 Hz, 6 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 137.1, 136.1, 135.5, 129.0, 128.6,
127.4, 126.4, 115.4, 78.0, 63.5, 49.7, 24.7, 24.6, 24.1, 22.9 ppm.
HRMS (ESI): calcd. for C14H19 [M – OAllyl]+ 187.1481; found
187.1480.
(R)-(E)-3,5-Dimethyl-1-phenyl-1-hexen-3-ol (5a): Light yellow oil
(94 mg, 84%). [α]2D0 = +32.4 (c = 0.53, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.40 (d, J = 7.6 Hz, 2 H), 7.35–7.31 (m, 2
H), 7.24 (t, J = 7.2 Hz, 1 H), 6.61 (d, J = 16.0 Hz, 1 H), 6.31 (d, J
= 16.0 Hz, 1 H), 1.84–1.79 (m, 1 H), 1.62 (br s, 1 H), 1.59 (d, J =
6.0 Hz, 2 H), 1.40 (s, 3 H), 1.00–0.96 (m, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 137.3, 137.2, 128.6, 127.3, 126.5, 126.4,
73.7, 51.6, 29.2, 24.63, 24.59, 24.45 ppm. HRMS (ESI): calcd. for
C14H19 [M – OH]+ 187.1481; found 187.1480.
(S)-(E)-3-Allyloxy-5-methyl-1,3-diphenyl-1-hexene (6b): Light yel-
low oil (104 mg, 97%). [α]2D0 = –5.5 (c = 0.66, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.54 (d, J = 7.2 Hz, 2 H), 7.46 (d, J =
7.6 Hz, 2 H), 7.41–7.35 (m, 4 H), 7.32–7.26 (m, 2 H), 6.75 (d, J =
16.4 Hz, 1 H), 6.42 (d, J = 16.4 Hz, 1 H), 6.09–5.97 (m, 1 H), 5.44
(dd, J = 17.2, 1.2 Hz, 1 H), 5.21 (d, J = 10.8 Hz, 1 H), 3.94–3.86
(m, 2 H), 2.13–2.02 (m, 2 H), 1.80–1.72 (m, 1 H), 0.91 (dd, J =
50.0, 6.4 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.9,
137.1, 135.6, 134.2, 129.5, 128.6, 128.1, 127.6, 126.9, 126.5, 115.3,
81.8, 63.9, 46.5, 24.5, 24.4, 23.8 ppm. HRMS (APCI): calcd. for
C19H21 [M – OAllyl]+ 249.1638; found 249.1639.
(S)-(E)-5-Methyl-1,3-diphenyl-1-hexen-3-ol (5b): Light yellow oil
(127 mg, 87%). [α]2D0 = +18.8 (c = 0.49, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.56 (d, J = 7.6 Hz, 2 H), 7.44–7.25 (m, 8
H), 6.70 (d, J = 16.0 Hz, 1 H), 6.60 (d, J = 16.0 Hz, 1 H), 2.06–
2.01 (m, 1 H), 2.01 (br s, 1 H), 1.95 (dd, J = 14.4, 6.0 Hz, 1 H),
1.84–1.78 (m, 1 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 146.3, 137.0, 136.6,
128.6, 128.3, 127.5, 127.4, 126.8, 126.6, 125.5, 77.5, 51.3, 24.6, 24.3
ppm. HRMS (APCI): calcd. for C19H21 [M – OH]+ 249.1638;
found 249.1634.
(R)-(E)-3-Allyloxy-5-ethyl-3-methyl-1-phenyl-1-heptene (6c): Light
yellow oil (80 mg, 84%). [α]2D0 = –24.1 (c = 0.49, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.41 (d, J = 7.2 Hz, 2 H), 7.36–7.33 (m, 2
H), 7.27–7.24 (m, 1 H), 6.50 (d, J = 16.4 Hz, 1 H), 6.21 (d, J =
16.4 Hz, 1 H), 5.99–5.92 (m, 1 H), 5.35–5.30 (m, 1 H), 5.14 (dd, J
= 10.4, 1.6 Hz, 1 H), 3.93 (d, J = 5.2 Hz, 2 H), 1.64–1.62 (m, 2 H),
1.42 (s, 3 H), 1.42–1.36 (m, 4 H), 1.29 (s, 1 H), 0.89–0.83 (m, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 137.1, 136.2, 135.4, 129.2,
(R)-(E)-5-Ethyl-3-methyl-1-phenyl-1-hepten-3-ol (5c): Light yellow 128.6, 127.4, 126.4, 115.2, 78.3, 63.6, 45.0, 36.0, 26.9, 26.8, 22.5,
oil (105 mg, 82%). [α]2D0 = +38.7 (c = 0.45, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.39 (d, J = 7.2 Hz, 2 H), 7.35–7.31 (m, 2
10.82, 10.76 ppm. HRMS (ESI): calcd. for C16H23 [M – OAllyl]+
215.1794; found 215.1795.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31476
/KAP1
Date: 20-11-13 19:29:59
Pages: 9
Synthesis of Dihydrofurans and Cyclopentenols
General Procedure for the Ring-Closing Metathesis of the Dienes:[22]
To a solution of diene (0.29 mmol) in dichloromethane (5 mL) was
added Hoveyda–Grubbs second-generation catalyst (9.4 mg,
0.015 mmol, 0.05 equiv.), and the resulting mixture was stirred un-
der nitrogen at room temperature for 2 h. The mixture was then
concentrated in vacuo, and the crude product was purified by
column chromatography (pentane/Et2O 200:1) to afford five-mem-
bered ring 7 or 8.
209.9, 141.7, 128.5, 127.8, 126.1, 82.8, 44.9, 24.6, 24.2, 23.8, 23.7
ppm. HRMS (ESI): calcd. for C13H17O [M – OH]+ 189.1274; found
189.1268.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all compounds.
Acknowledgments
(R)-2-Isobutyl-2-methyl-2,5-dihydrofuran (7a): Colorless oil (35 mg,
85%). [α]2D0 = –7.5 (c = 1.13, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 5.71 (d, J = 6.0 Hz, 1 H), 5.64–5.63 (m, 1 H), 4.58–4.51 (m, 2
H), 1.63–1.55 (m, 1 H), 1.50–1.37 (m, 2 H), 1.19 (s, 3 H), 0.84–0.81
(m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 134.4, 124.9,
90.4, 74.1, 49.4, 34.1, 24.6, 24.4, 24.3 ppm. HRMS (ESI): calcd.
for C9H17O [M + H]+ 141.1274; found 141.1276.
Financial support by the Netherlands Research School on Chemis-
try and Catalysis (NRSC Catalysis program) is acknowledged. The
authors thank M. Smith and T. D. Tiemersma-Wegman for techni-
cal assistance (GC/HPLC and HRMS, respectively).
[1] a) B. M. Fraga, Nat. Prod. Rep. 1992, 9, 217–241; b) A. T. Mer-
ritt, S. V. Ley, Nat. Prod. Rep. 1992, 9, 243–287; c) B. M. Trost,
M. R. Machacek, B. D. Faulk, J. Am. Chem. Soc. 2006, 128,
6745–6754; d) M. M. Faul, B. E. Huff, Chem. Rev. 2000, 100,
2407–2473; e) E. J. Kang, E. Lee, Chem. Rev. 2005, 105, 4348–
4378; f) Y. J. Shang, K. Ju, X. W. He, J. S. Hu, S. Y. Yu, M.
Zhang, K. S. Liao, L. F. Wang, P. Zhang, J. Org. Chem. 2010,
75, 5743–5745.
(S)-2-Isobutyl-2-phenyl-2,5-dihydrofuran (7b): Colorless oil (53 mg,
90%). [α]2D0 = –94.0 (c = 1.08, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.40 (d, J = 7.6 Hz, 2 H), 7.35–7.32 (m, 2 H), 7.26–
7.21 (m, 1 H), 6.04–6.02 (m, 1 H), 5.86 (d, J = 6.0 Hz, 1 H), 4.82–
4.78 (m, 1 H), 4.73–4.69 (m, 1 H), 1.89 (dd, J = 14.4, 5.6 Hz, 1 H),
1.80 (dd, J = 14.4, 6.0 Hz, 1 H), 1.73–1.67 (m, 1 H), 0.94 (d, J =
6.8 Hz, 3 H), 0.88 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 146.5, 133.4, 128.2, 126.4, 125.2, 124.7, 93.8, 74.7,
50.1, 24.6, 24.32, 24.29 ppm. HRMS (APCI): calcd. for C14H19O
[M + H]+ 203.1430; found 203.1427.
[2] C. M. Horiuchi, J. W. Medlin, Langmuir 2010, 26, 13320–
13332.
[3] a) J. R. Monnier, J. W. Medlin, Y. J. Kuo, Appl. Catal. A 2000,
194, 463–474; b) F. Billes, H. Bohlig, M. Ackermann, M. Ku-
dra, J. Mol. Struct. 2004, 672, 1–16.
[4] A. L. Hall, R. G. Fayter Jr., US 4522950, 1985.
[5] a) N. O. Brace, J. Am. Chem. Soc. 1955, 77, 4157–4158; b) F.
Ozawa, A. Kubo, T. Hayashi, J. Am. Chem. Soc. 1991, 113,
1417–1419; c) Y. Yamamoto, R. Takuma, T. Hotta, K. Yama-
shita, J. Org. Chem. 2009, 74, 4324–4328.
(R)-2-(2-Ethylbutyl)-2-methyl-2,5-dihydrofuran (7c): Colorless oil
(40 mg, 82%). [α]2D0 = –5.7 (c = 0.53, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 5.78 (d, J = 6.4 Hz, 1 H), 5.69 (d, J = 6.4 Hz, 1 H),
4.64–4.57 (m, 2 H), 1.57–1.52 (m, 1 H), 1.45 (dd, J = 14.4, 4.8 Hz,
1 H), 1.39–1.25 (m, 5 H), 1.26 (s, 3 H), 0.85–0.79 (m, 6 H) ppm. [6] a) H. C. Shen, Tetrahedron 2008, 64, 3885–3903; b) N. T. Patil,
13C NMR (100 MHz, CDCl3): δ = 134.4, 125.0, 90.5, 74.3, 44.0,
36.7, 27.1, 26.8, 26.7, 10.82, 10.80 ppm. HRMS (ESI): calcd. for
C11H21O [M + H]+ 169.1587; found 169.1583.
Y. Yamamoto, Chem. Rev. 2008, 108, 3395–3442.
[7] B. M. Trost, H. C. Shen, L. Dong, J. P. Surivet, C. Sylvain, J.
Am. Chem. Soc. 2004, 126, 11966–11983.
[8] K. Asano, S. Matsubara, J. Am. Chem. Soc. 2011, 133, 16711–
(R)-1-Methyl-2-cyclopenten-1-ol (8a):[15] Colorless oil (11 mg,
40%)*. [α]2D0 = +16.8 (c = 0.25, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 5.83–5.81 (m, 1 H), 5.70–5.69 (m, 1 H), 2.51–2.45 (m,
1 H), 2.35–2.29 (m, 1 H), 1.98–1.89 (m, 2 H), 1.68 (br s, 1 H), 1.38
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.9, 132.7, 83.4,
39.7, 31.1, 27.4 ppm. HRMS (ESI): calcd. for C6H9 [M – OH]+
81.0699; found 81.0695.
16713.
[9] a) S. Hatakeyama, K. Sakurai, H. Numata, N. Ochi, S. Tak-
ano, J. Am. Chem. Soc. 1988, 110, 5201–5203; b) T. W. Funk,
Org. Lett. 2009, 11, 4998–5001.
[10] S. E. Denmark, M. T. Burk, Org. Lett. 2012, 14, 256–259.
[11] a) D. S. La, J. B. Alexander, D. R. Cefalo, D. D. Graf, A. H.
Hoveyda, R. R. Schrock, J. Am. Chem. Soc. 1998, 120, 9720–
9721; b) T. W. Funk, J. M. Berlin, R. H. Grubbs, J. Am. Chem.
Soc. 2006, 128, 1840–1846.
[12] a) A. V. R. Madduri, S. R. Harutyunyan, A. J. Minnaard, An-
gew. Chem. 2012, 124, 3218; Angew. Chem. Int. Ed. 2012, 51,
3164–3167; b) A. V. R. Madduri, A. J. Minnaard, S. R. Haru-
tyunyan, Chem. Commun. 2012, 48, 1478–1480; c) A. V. R.
Madduri, A. J. Minnaard, S. R. Harutyunyan, Org. Biomol.
Chem. 2012, 10, 2878–2884.
[13] An alternative approach uses the stereospecific conversion of
secondary alcohols into tertiary alcohols, see: A. P. Pulis, V. K.
Aggarwal, J. Am. Chem. Soc. 2012, 134, 7570–7574.
[14] a) S. Takano, Y. Iwabuchi, K. Ogasawara, J. Chem. Soc., Chem.
Commun. 1989, 1371–1372; b) R. Kotikalapudi, K. C. Kum-
ara Swamy, Tetrahedron Lett. 2012, 53, 3831–3834.
[15] I. C. Chiu, H. Kohn, J. Org. Chem. 1983, 48, 2857–2866.
[16] a) D. Bek, H. Balcar, N. Zilkova, A. Zukal, M. Horacek, J.
Cejka, Acs. Catalysis 2011, 1, 709–718; b) H. A. Meylemans,
R. L. Quintana, B. R. Goldsmith, B. G. Harvey, ChemSus-
Chem 2011, 4, 465–469.
*This reaction gave full conversion to the desired product, but the
yield was diminished because of the volatility of the product.
(S)-2-Methyl-1-phenyl-2-cyclopenten-1-ol (8b): Colorless oil (44 mg,
87%). [α]2D0 = +33.2 (c = 0.85, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.32–7.24 (m, 4 H), 7.18–7.15 (m, 1 H), 5.63 (d, J =
1.6 Hz, 1 H), 2.44–2.37 (m, 1 H), 2.33–2.25 (m, 2 H), 2.20–2.12 (m,
1 H), 1.86 (s, 1 H), 1.48–1.47 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 146.0, 144.0, 128.7, 128.1, 126.5, 124.8, 87.9, 43.4,
29.4, 11.9 ppm. HRMS (ESI): calcd. for C12H13 [M – OH]+
157.1012; found 157.1008.
α-Hydroxy Acids 9: Compound 9a–b and S9c were prepared from
2a–b and 2g by following the literature procedure,[24] and S9c af-
forded 9b by following a literature procedure.[23c] The absolute con-
figurations of 9a and 9b were assigned on the basis of specific rota-
tions reported in literatures.[23a,23b]
[17] a) J. C. Banks, D. Van Mele, C. G. Frost, Tetrahedron Lett.
2006, 47, 2863–2866; b) S.-M. Lu, C. Bolm, Angew. Chem.
2008, 120, 9052; Angew. Chem. Int. Ed. 2008, 47, 8920–8923;
c) J. A. Murphy, K. A. Scott, R. S. Sinclair, C. G. Martin, A. R.
Kennedy, N. Lewis, J. Chem. Soc. Perkin Trans. 1 2000, 2395–
2408.
(R)-3-Hydroxy-5-methyl-3-phenyl-2-hexanone (S9c): Colorless oil
(46 mg, 79%). [α]2D0 = –16.9 (c = 0.43, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.42–7.39 (m, 2 H), 7.30–7.26 (m, 2 H), 7.23–7.19 (m,
1 H), 4.46 (s, 1 H), 2.13–2.06 (m, 2 H), 2.04 (s, 3 H), 1.79–1.72 (m,
1 H), 0.90–0.85 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O31476
/KAP1
Date: 20-11-13 19:29:59
Pages: 9
Z. Wu, A. V. R. Madduri, S. R. Harutyunyan, A. J. Minnaard
FULL PAPER
[18] J. Y. Yang, C. Y. Wang, X. Xie, H. F. Li, E. D. Li, Y. Z. Li, Org.
Biomol. Chem. 2011, 9, 1342–1346.
[19] A. Funayama, T. Satoh, M. Miura, J. Am. Chem. Soc. 2005,
127, 15354–15355.
[23]
a) D. Basavaiah, S. Pandiaraju, M. Bakthadoss, K. Muthuku-
maran, Tetrahedron: Asymmetry 1996, 7, 997–1000; b) F. Effen-
berger, B. Horsch, F. Weingart, T. Ziegler, S. Kuhner, Tetrahe-
dron Lett. 1991, 32, 2605–2608; c) G. A. Moniz, J. L. Wood, J.
Am. Chem. Soc. 2001, 123, 5095–5097.
[20] V. G. Nenajdenko, K. I. Smolko, E. S. Balenkova, Tetrahedron:
Asymmetry 2001, 12, 1259–1266.
[24] T. Satoh, K. Onda, K. Yamakawa, J. Org. Chem. 1991, 56,
[21] J. M. Reuter, R. G. Salomon, J. Org. Chem. 1977, 42, 3360–
4129–4134.
3364.
Received: September 29, 2013
Published Online: ᭿
[22] B. C. Maity, V. M. Swamy, A. Sarkar, Tetrahedron Lett. 2001,
42, 4373–4376.
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31476
/KAP1
Date: 20-11-13 19:29:59
Pages: 9
Synthesis of Dihydrofurans and Cyclopentenols
Asymmetric Synthesis
Z. Wu, A. V. R. Madduri,
S. R. Harutyunyan,*
A. J. Minnaard* ................................ 1–9
Catalytic Asymmetric Synthesis of Di-
hydrofurans and Cyclopentenols with Ter-
tiary Stereocenters
The copper-catalyzed 1,2-addition of Grig-
nard reagents to enones, combined with
Sonogashira coupling/cyclization or ring-
closing metathesis, provides a new asym-
metric synthesis of dihydrofurans and
cyclopentenols. Two different kinds of di-
hydrofurans are obtained with medium-to-
high enantioselectivities.
Keywords: Synthetic methods / Nucleo-
philic addition / Cyclization / Alcohols /
Oxygen heterocycles
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