Installation of a chiral side chain to a 2-alkylidene-1-cycloalkan-1-ol unit by using allylic substitution

Article abstract of DOI:10.1002/ejoc.201300792

The allylic substitution of optically active exocyclic allylic esters of cyclopentane and cyclohexane with ArMgBr-based copper reagents (Ar = aryl) was examined. ArMgBr/Cu(acac)₂ in a 2:1 ratio was an adequate reagent to produce the anti-S_N2' products efficiently in terms of regioselectivity (95-99a€‰%), chirality transfer (91-99a€‰%), and yield (71-91a€‰%). The Ar groups that were successfully installed include Ph and p-tolyl, those with electron-donating (i.e., p-MeOC₆H₄) and electron-withdrawing groups (i.e., p-FC₆H₄), and those with sterically demanding groups (i.e., o-tolyl, o-MeOC₆H ₄). In an examination of an alkyl reagent, BuMgBr/CuBr·Me ₂S in a 2:1 ratio in the presence of ZnI₂ afforded the product with high regioselectivity (99a€‰%) and in good yield (91a€‰%). The allylic substitution of exocyclic allylic picolinates (n = 1, 2; R = Ph(CH₂)₂, iPr, Ph) with a ArCu(acac)MgBr reagent (Ar = Ph, p-tolyl, p-MeOC₆H₄, p-FC₆H₄, o-tolyl, o-MeOC₆H₄) that was derived from a 2:1 ratio of ArMgBr and Cu(acac)₂ efficiently afforded the anti-S_N2' products in terms of regioselectivity (95-99a€‰%), chirality transfer (91-99a€‰%), and yield (71-91a€‰%). Copyright

Full text of DOI:10.1002/ejoc.201300792

FULL PAPER
DOI: 10.1002/ejoc.201300792
Installation of a Chiral Side Chain to a 2-Alkylidene-1-cycloalkan-1-ol Unit by
Using Allylic Substitution
Chao Feng[a] and Yuichi Kobayashi*[a]
Keywords: Synthetic methods / Allylic compounds / Nucleophilic substitution / Copper / Magnesium / Regioselectivity
The allylic substitution of optically active exocyclic allylic es-
ters of cyclopentane and cyclohexane with ArMgBr-based
copper reagents (Ar = aryl) was examined. ArMgBr/Cu(acac)2
in a 2:1 ratio was an adequate reagent to produce the anti-
SN2Ј products efficiently in terms of regioselectivity (95–
99%), chirality transfer (91–99%), and yield (71–91%). The
Ar groups that were successfully installed include Ph and p-
tolyl, those with electron-donating (i.e., p-MeOC6H4) and
electron-withdrawing groups (i.e., p-FC6H4), and those with
sterically demanding groups (i.e., o-tolyl, o-MeOC6H4). In an
examination of an alkyl reagent, BuMgBr/CuBr·Me2S in a 2:1
ratio in the presence of ZnI2 afforded the product with high
regioselectivity (99%) and in good yield (91%).
Introduction
The allylic substitution of secondary allylic esters with
organocopper reagents that are prepared in situ or gener-
ated under catalytic conditions has recently been actively
investigated with highly activated leaving groups[1] such as
o-(PPh2)C6H4CO2,
o-[P(O)Ph2]C6H4CO2,
C6F5CO2,
(RO)2PO2, and 2-PyCO2 (Py = pyridine). By employing
these leaving groups, alkyl copper reagents as well as less
reactive aryl, alkenyl, heteroaryl, and alkynyl reagents can
take part in substitution reactions that furnish γ products
with high regio- and stereoselectivity.[2,3] The 2-PyCO2 leav-
ing group that we introduced was activated by Mg2+ and/
or Zn2+ to allow for the participation of the above classes
of reagents.[3] Furthermore, ArMgBr-based copper reagents
could be used for the efficient construction of a quaternary
carbon.[4]
Figure 1. Substrate types for the allylic substitution (L = leaving
group).
During the investigation, we learned that acyclic and cy-
clic allylic esters of types I and II as shown in Figure 1 have
been used as test substrates and that exocyclic allylic esters
III that are part cyclic and acyclic have been studied in a
few cases. In brief, the methylation of 2-butylidene-1-cy-
clopentyl alcohol derivatives III [(Z) olefin, n = 1, R = Pr,
L = OCO-tBu, OCONHPh] afforded the desired γ product
regioselectively.[5] However, the scope of the reagents that
includes aromatic compounds is unclear.[6] In contrast, the
CuCl-catalyzed substitution of 2-benzylidene-1-cycloalkyl
acetates III [(E) olefin, n = 1, 2, R = Ph, L = OAc) with
alkyl- and arylMgBr gave α products with 65–100%
Scheme 1. Goal of the present allylic substitution reaction.
regioselectivity, which depended on the ring size of the sub-
strates and the reagents.[7] With these publications in mind,
we selected picolinates 1 with n = 1, 2 as in III and studied
their allylic substitution with aryl copper reagents as de-
picted in Scheme 1 as well as with an alkyl copper reagent.
The structure of the γ product 2 evokes several biologically
[a] Department of Bioengineering, Tokyo Institute of Technology,
Box B52, Nagatsuta-cho 4259, Midori-ku,
Yokohama 226-8501, Japan
E-mail: ykobayas@bio.titech.ac.jp
Homepage: http://www.kobayashi.bio.titech.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300792.
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Allylic Substitution of Exocyclic Allylic Picolinates
active compounds such as classical steroids, vitamin D
compounds, the OSW-1 series of compounds, ophiobolins,
biyouyanagin A, zingiberene, and the heliannuols (see Fig-
ure 2), which are characterized by chiral side chains. Herein,
we present the results of this investigation, which focuses on
regioselectivity (2 over 3) and chirality transfer (C.T.).[8,9]
Scheme 2. Synthesis of the substrates [DMAP = 4-(dimethyl-
amino)pyridine].
Figure 2. Natural products that possess a chiral carbon on a side
chain.
Results and Discussion
The allylic substrates shown in Figure 3 were synthesized
by methods delineated in Scheme 2. In brief, the aldol reac-
tion of cyclopentanone and 3-phenylpropionaldehyde fol-
lowed by elimination of the hydroxy group with MsCl and
Et3N produced (E)-olefin 5a in a 40% unoptimized yield.
The examination of the 1H NMR spectrum of crude 5a
indicated the absence of the (Z) isomer [olefinic H of 5a,
multiplet, 6.50–6.63 ppm; olefinic H of (Z) isomer, probably
5.6–6.0 ppm[10]]. A Corey–Bakshi–Shibata (CBS) reduc-
tion[11] using (S)-3,3-diphenyl-1-methylpyrrolidino[1,2-c]-
1,3,2-oxazaborole [(S)-MeCBS] was applied to the enone,
and the resulting alcohol (R)-4a was converted into picolin-
ate (R)-1a in 72% yield by employing a DCC-mediated
(DCC = N,NЈ-dicyclohexycarbodiimide) condensation with
Scheme 3. Synthesis of regioisomers (DIEA = N,N-diisopropyl-
ethylamine, rs = regioselectivity).
Figure 3. Substrates for the present study.
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PyCO2H. The enantiomeric purity of (R)-1a, which was (THF) at an initial temperature of –40 or –30 °C that was
prepared twice, was 94 and 97%ee as determined by chiral gradually increased to –10 or 0 °C over 2 h to afford rac-
HPLC analysis. Likewise, picolinate (R)-1b with 86%ee was 2aA as the major product. To calculate the regioselectivity
1
synthesized from cyclohexanone through enone 5b.[12] For of rac-2aA over rac-3aA by H NMR spectroscopy, the al-
a preliminary investigation, racemic picolinates rac-1a and lylation of regioisomeric substrate rac-6a with a 2:1 ratio of
-1b were synthesized in yields of 73–80% from enones 5a PhMgBr/CuBr·Me2S was carried out to produce rac-3aA as
and 5b by reduction with NaBH4 followed by a DCC-as- a 4:1 mixture with its (Z) isomer (see Scheme 3).[13] The
sisted esterification with PyCO2H. Similarly, enone 5c was reaction proceeded regioselectively (Ͼ95:5) with a 1:1 ratio
prepared through an aldol condensation of cyclopentanone of PhMgBr/CuBr·Me2S (1.5 equiv.), but 7% of rac-1a was
with isobutyraldehyde followed by conversion into racemic recovered (data not shown). On the other hand, 3 equiv. of
picolinate rac-1c, which was used to examine the steric in- the reagent completely consumed the substrate to afford
fluence of the bulky side chain on the allylic substitution rac-2aA with 96% regioselectivity (see Table 1, Entry 1).
reaction. To examine influence of an aryl substituent on the The substitution of rac-1a with 1 equiv. of the 2:1 PhMgBr/
regioselectivity of the reaction, rac-1d was prepared.
CuBr·Me2S reagent afforded rac-2aA with a similar regiose-
The allylic substitution of rac-1a was first investigated by lectivity (see Table 1, Entry 2). The completion of the reac-
using phenyl reagents that were derived from PhMgBr and tion within 2 h, even with 1 equiv. of the reagent, suggests
CuBr·Me2S in ratios of 1:1 and 2:1 in tetrahydrofuran the participation of the 1:1 PhMgBr/CuBr·Me2S reagent,
Table 1. Optimization of conditions.
[a] Reaction temperature was gradually raised to –10 or 0 °C over 2 h for Entries 1–14 and over 3 h for Entries 15 and 16. [b] Determined
1
by H NMR spectroscopic analysis. [c] Isolated yield. [d] n.d.: not determined.
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Allylic Substitution of Exocyclic Allylic Picolinates
which is produced in situ through a reaction with the 2:1 to afford rac-2cA and -2cB regioselectively[14] (see Table 1,
reagent. In fact, the 1:1 reagent produced rac-2aA regiose- Entries 13 and 14).
lectively (see Table 1, Entry 1). The 2:1 reagent in the pres-
ence of ZnI2 resulted in somewhat lower regioselectivity (see
Table 1, Entry 3). The reagent that was derived from a 2:1
ratio of PhMgBr and Cu(acac)2 (acac = acetylacetonate)
furnished rac-2aA with 96% regioselectivity (see Table 1,
Entry 4).
The influence of an aryl group attached to the allylic
moiety on the regioselectivity was examined by using rac-
1d, which upon reaction with the 2:1 PhMgBr/Cu(acac)2
reagent afforded rac-2dA with a regioselectivity of Ͼ99%
(see Table 1, Entry 15; the 1H NMR of regioisomer rac-3dA
is published[7] and was used to calculate the regioselectiv-
ity). Such a high regioselectivity was also attained with the
2:1 p-TolMgBr/Cu(acac)2 reagent (see Table 1, Entry 16).
Throughout the above examination, the 2:1 ArMgBr/Cu-
(acac)2 reagents (Ar = Ph, p-Tol) provided high regioselec-
tivity in all of the reactions. As for the 2:1 ArMgBr/
CuBr·Me2S reagents, the Ph reagent was highly regioselec-
tive, but that with p-Tol was not. With these results in hand,
the allylic substitution of (R)-1a (94 and 97%ee) and (R)-
1b (86%ee) was studied to evaluate the chirality transfer
(C.T.)[8] and determine the stereochemical course of the re-
action. The 2:1 PhMgBr/Cu(acac)2 reagent was first sub-
jected to reaction with the five-membered substrate (R)-1a
to produce (R)-2aA (Ar = Ph) with a C.T. of Ͼ99% and a
regioselectivity of Ͼ99% in 80% isolated yield (see Table 2,
Entry 1). The 2:1 PhMgBr/CuBr·Me2S reagent produced
(R)-2aA with a C.T. of 98% as well (see Table 2, Entry 2).
Similarly, the p-Tol, p-MeOC6H4, and p-FC6H4 reagents
participated in the substitution reaction to afford (R)-2aB,
-2aD, and -2aF efficiently (see Table 2, Entries 3, 5, and 7).
The rac-1a substrate from Table 1, Entries 1–4 was then
treated with p-TolMgBr. The Cu(acac)2-based reagent
showed high regioselectivity (98%)[14] to produce rac-2aB
[B refers to p-tolyl (p-Tol) as the Ar group, see Table 1, En-
try 8], whereas low regioselectivity was observed with the
CuBr·Me2S-based reagents (see Table 1, Entries 5–7).
With the above results in hand, the six-membered ring
substrate rac-1b was submitted to the substitution reactions
with the Ph and p-Tol copper reagents. Regioisomer rac-
3bA with the Ph substituent was independently synthesized
through the reaction shown in Scheme 3 to determine the
diagnostic absorbance in its 1H NMR spectrum to estimate
the regioselectivity of the reaction. As summarized in
Table 1, Entries 11 and 12, the Cu(acac)2-derived Ph and p-
Tol reagents afforded rac-2bA and -2bB, respectively, with
high regioselectivity (99% and 96%).[14] Similar regioselec-
tivity results were obtained in the phenylation reactions that
used 1:1 and 2:1 ratios of PhMgBr/CuBr·Me2S (see Table 1,
Entries 9 and 10).
Next, the influence of steric factors on the regioselectiv- The steric congestion from the Me and MeO groups in the
ity was examined by employing the iPr-substituted substrate o-Tol and o-MeOC6H4 reagents, respectively, resulted in a
rac-1c, which was treated with the Cu(acac)2-derived Ph slight decrease to the C.T. and regioselectivity, but the selec-
and p-Tol reagents. The reactions proceeded without delay tivity was still at an acceptable level (see Table 2, Entries 4
Table 2. Allylic substitution with optically active picolinates (R)-1a and -1b.
[a] (R)-1a (94 or 97%ee), (R)-1b (86%ee). [b] Enantiomeric excess value for calculation of C.T. was determined by chiral HPLC analysis.
[c] Isolated combined yield of 2 and 3. [d] Absolute configuration was determined as described in the text.
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and 6). Comparable results were also observed with the six-
membered substrate (R)-1b (see Table 2, Entries 8–10).
Scheme 4 shows the transformation[15] of (R)-2aA and
-2bA into known alcohol 8, and the specific rotations of 8
were compared with the literature value[16] to establish not
only the R configuration of 2aA and 2bA but also the anti-
SN2Ј pathway of the allylic substitution. The configurations
of the other products were determined by analogy.
Scheme 5. Allylation of (R)-1a with butyl copper reagent (rs = re-
gioselectivity; the 1H NMR spectrum of rac-3aG was used as a
reference to calculate the regioselectivity of (R)-2aG).
ordinates to the double bond as the latter cation activates
the PyCO2 leaving group through chelation to facilitate the
subsequent elimination of the PyCO2 group and produce
the anti-SN2Ј product with high γ selectivity.
Conclusions
We have developed a method to construct a cycloalkenyl-
substituted carbon unit through an allylic substitution that
employs 2:1 ArMgBr/Cu(acac)2 reagents and proceeds with
excellent regioselectivity and C.T.[19] Reagents with steri-
cally demanding groups as well as those with electron-do-
nating and electron-withdrawing groups were successfully
used in the reaction. Overall, the present results provide the
transformation as depicted in Scheme 7. The total synthesis
of biologically active compounds by employing this trans-
formation will be reported in the near future.
Scheme 4. Transformation of (R)-2aA and -2bA into the known
alcohol (S)-8.
Next, we turned our attention to a butyl copper reagent
as a typical example of alkyl copper reagents. Surprisingly,
the 2:1 BuMgBr/CuBr·Me2S reagent was less regioselective
(rs of 74%, see Scheme 5). As observed in the previous ex-
periment, the regioselectivity of (R)-2aG was greatly im-
proved at 99% by the addition of ZnI2. The activation of
the 2-PyCO2 group through chelation was stronger to Zn2+
than to Mg2+, which might be a reason for the high regiose-
lectivity. In contrast, the 2:1 BuMgBr/Cu(acac)2 reagent
was regioselective to produce (R)-2aG, but the product was
contaminated with unidentified compound(s).[17]
A possible pathway based on a recent mechanism for all-
ylic substitution[2b,2c,18] is illustrated in Scheme 6. The reac-
tion of ArMgBr and Cu(acac)2 in a 2:1 ratio produces the
[ArCu(acac)]– species and (MgBr)+. This Ar–Cu species co- Scheme 7. Overall transformation.
Scheme 6. Plausible mechanism.
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Allylic Substitution of Exocyclic Allylic Picolinates
H), 5.53–5.62 (m, 1 H), 7.15–7.22 (m, 3 H), 7.25–7.32 (m, H) ppm.
13C NMR (100 MHz, CDCl3): δ = 22.0 (–), 27.0 (–), 31.3 (–), 35.6
(–), 35.7 (–), 75.7 (+), 123.3 (+), 125.9 (+), 128.4 (+), 128.5 (+),
142.1 (–), 146.8 (–) ppm. HRMS (EI): calcd. for C14H18O [M]+
202.1358; found 202.1356.
Experimental Section
1
General Methods: The H (300 or 400 MHz) and 13C NMR (75 or
100 MHz) spectroscopic data were recorded in CDCl3 using SiMe4
(δ = 0 ppm) and the centerline of the triplet (δ = 77.1 ppm), respec-
tively, as internal standards. Signal patterns are indicated as br. s
(broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), and
m (multiplet). Coupling constants (J) are given in Hertz (Hz).
Chemical shifts of carbons are accompanied by minus (for C and
CH2) and plus (for CH and CH3) signs of the attached proton test
(APT) experiments. The solvents that were distilled prior to use are
THF (from Na/benzophenone), Et2O (from Na/benzophenone),
and CH2Cl2 (from CaH2). After the reactions were completed, the
organic extracts were concentrated by using an evaporator, and
then the residues were purified by chromatography on silica gel
(Kanto, spherical silica gel 60N). Cu(acac)2 was purchased from
TCI, Japan and used without purification, whereas CuBr·Me2S was
prepared as described previously.[3e]
(R,E)-2-(3-Phenylpropylidene)cyclopentyl Picolinate [(R)-1a]: To an
ice-cold solution of (R)-4a (80.1 mg, 0.396 mmol) in CH2Cl2
(5 mL) were added DCC (109 mg, 0.528 mmol), DMAP (49.0 mg,
0.401 mmol), and picolinic acid (59.0 mg, 0.479 mmol). The mix-
ture was stirred at room temp. for 2 h and then diluted with Et2O.
The resulting mixture was filtered through a pad of Celite. The
filtrate was concentrated to afford a residual oil, which was purified
by chromatography on silica gel (hexane/EtOAc) to furnish (R)-1a
1
(120 mg, 99%). H NMR (400 MHz, CDCl3): δ = 1.66–1.77 (m, 1
H), 1.84–2.07 (m, 3 H), 2.10–2.22 (m, 1 H), 2.29–2.42 (m, 3 H),
2.61–2.76 (m, 2 H), 5.74–5.82 (m, 2 H), 7.13–7.20 (m, 3 H), 7.20–
7.27 (m, 2 H), 7.46 (ddd, J = 8, 5, 1 Hz, 1 H), 7.83 (dt, J = 2, 8 Hz,
1 H), 8.08 (dt, J = 8, 1 Hz, 1 H), 8.78 (dm, J = 5 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 22.8 (–), 27.3 (–), 31.7 (–), 33.1
(–), 35.4 (–), 79.1 (+), 125.1 (+), 125.8 (+), 126.7 (+), 127.1 (+),
128.3 (+), 128.6 (+), 136.9 (+), 141.3 (–), 142.0 (–), 148.7 (–), 150.1
(+), 165.1 (–) ppm. HRMS (EI): calcd. for C20H21NO2 [M]+
307.1572; found 307.1578. The enantiomeric purity (97%ee) was
determined by chiral HPLC analysis (Chiralcel OD-H; hexane/
iPrOH, 98:2; 0.5 mL/min; 25 °C): tR = 40.8 (R isomer) and
46.0 min (S isomer). The reaction was repeated to obtain (R)-1a
with 94%ee.
Synthesis of Picolinates (R)-1a and rac-1a
(E)-2-(3-Phenylpropylidene)cyclopentanone (5a): To an ice-cold
solution of diisopropylamine (0.80 mL, 5.69 mmol) in THF (8 mL)
was added nBuLi (1.65 m in hexane, 3.0 mL, 4.95 mmol) dropwise.
The solution was stirred for 15 min at 0 °C and then cooled to
–70 °C. Cyclopentanone (0.30 mL, 3.47 mmol) was added to the
solution. After 30 min of stirring at –70 to –50 °C, 3-phenyl-
propionaldehyde (0.30 mL, 2.28 mmol) was added dropwise at
–70 °C. After 30 min of stirring at –70 °C, the solution was poured
into a mixture of EtOAc and saturated NH4Cl with vigorous stir-
ring. The layers were separated, and the aqueous layer was ex-
tracted with EtOAc (2ϫ). The combined extracts were washed with
brine, dried with MgSO4, and concentrated to give a residue that
was passed through a short column of silica gel (hexane/EtOAc) to
afford the aldol, which was used for the next reaction without fur-
ther purification. To an ice-cold solution of the alcohol, Et3N
(0.45 mL, 3.26 mmol), and DMAP (29.0 mg, 0.237 mmol) in
CH2Cl2 (10 mL) was added MsCl (0.17 mL, 2.18 mmol) dropwise.
The solution was warmed to room temp. over 2 h and then diluted
with saturated NaHCO3 with vigorous stirring. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(2ϫ). The extracts were washed with brine, dried with MgSO4, and
concentrated to afford a residue, which was purified by chromatog-
raphy on silica gel (hexane/EtOAc) to furnish 5a (182 mg, 40% over
(E)-2-(3-Phenylpropylidene)cyclopentyl Picolinate (rac-1a): To an
ice-cold solution of 5a (70.4 mg, 0.352 mmol) and CeCl3·7H2O
(135 mg, 0.362 mmol) in MeOH (4 mL) was added NaBH4
(13.0 mg, 0.344 mmol). After stirring at room temp. for 1 h, the
solution was diluted with HCl (1 n solution) and Et2O with vigor-
ous stirring. The organic layer was separated, and the aqueous layer
was extracted with Et2O (3ϫ). The combined extracts were dried
with MgSO4 and concentrated to afford a residue, which was puri-
fied by chromatography on silica gel (hexane/EtOAc) to furnish
1
alcohol rac-4a (55.4 mg, 80%). The H NMR spectrum was iden-
tical with that of (R)-4a. According to the procedure for synthesis
of (R)-1a, rac-4a (55.0 mg, 0.272 mmol) was subjected to esterifica-
tion with picolinic acid (42.0 mg, 0.341 mmol), DCC (74.0 mg,
0.359 mmol), and DMAP (34.0 mg, 0.278 mmol) in CH2Cl2 (2 mL)
at room temp. for 2 h to furnish rac-1a (73.1 mg, 87%). The 1H
and 13C NMR spectra were identical with those of (R)-1a.
two steps). IR (neat): ν = 1723, 1651, 1454, 747, 699 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 1.87 (quintet, J = 8 Hz, 2 H), 2.30
(t, J = 8 Hz, 2 H), 2.40–2.53 (m, 4 H), 2.77 (t, J = 8 Hz, 2 H),
6.50–6.63 (m, 1 H), 7.16–7.38 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.8 (–), 26.8 (–), 31.7 (–), 34.6 (–) 38.7 (–), 126.2 (+),
128.47 (+), 128.50 (+), 134.7 (+), 138.0 (–), 141.2 (–), 207.2
(–) ppm. HRMS (EI): calcd. for C14H16O [M]+ 200.1201; found
200.1202.
Synthesis of Picolinates (R)-1b and rac-1b
(E)-2-(3-Phenylpropylidene)cyclohexanone (5b): According to the
procedure for the synthesis of 5a, cyclohexanone (2.30 mL,
22.3 mmol) was converted into the aldol as a mixture of dia-
stereomers through the reaction with 3-phenylpropionaldehyde
(2.00 mL, 15.2 mmol), diisopropylamine (6.30 mL, 44.8 mmol),
and nBuLi (1.62 m in hexane, 23.0 mL, 37.3 mmol) in THF
(50 mL). The aldol was subjected to a reaction with MsCl
(1.90 mL, 24.5 mmol), Et3N (5.10 mL, 36.6 mmol), and DMAP
(1.50 g, 12.3 mmol) in CH2Cl2 (40 mL) at 0 °C to room temp. for
2 h to furnish 5b (1.73 g, 53% over two steps). 1H NMR (300 MHz,
CDCl3): δ = 1.59–1.72 (m, 2 H), 1.75–1.87 (m, 2 H), 2.30–2.48 (m,
6 H), 2.70–2.79 (m, 2 H), 6.63 (tt, J = 8, 2 Hz, 1 H), 7.12–7.32 (m,
5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.4 (–), 23.6 (–),
26.7 (–), 29.8 (–), 34.7 (–), 40.3 (–), 126.2 (+), 128.5 (+), 137.0 (–),
(R,E)-2-(3-Phenylpropylidene)cyclopentanol [(R)-4a]: To a solution
of (S)-methyl oxazaborolidine (1.0 m in toluene, 0.11 mL,
0.11 mmol) and N,N-diethylaniline–borane (0.11 mL, 0.619 mmol)
at –20 °C in THF (3 mL) was added a solution of enone 5a
(110.4 mg, 0.551 mmol) in THF (3 mL) over 60 min. After stirring
at –20 °C for 1 h, the reaction was quenched carefully by the ad-
dition of cold MeOH (3 mL, –20 °C). After additional stirring for
1 h at room temp., the solution was concentrated to afford a resi-
due, which was passed through a pad of silica gel (hexane/EtOAc)
to furnish alcohol (R)-4a (80.1 mg, 72%). IR (neat): ν = 3348, 1496,
˜
1453, 1080, 748, 699 cm–1. H NMR (400 MHz, CDCl3): δ = 1.45 138.0 (+), 141.3 (–), 201.3 (–) ppm. HRMS (EI): calcd. for C15H18O
1
(br. s, 1 H), 1.53–1.66 (m, 2 H), 1.74–1.90 (m, 2 H), 2.04–2.16 (m,
1 H), 2.22–2.38 (m, 3 H), 2.69 (t, J = 7.5 Hz, 2 H), 4.34 (br. s, 1
[M]+ 214.1358; found 214.1363. The 1H and 13C NMR spectra were
consistent with those reported.[12]
Eur. J. Org. Chem. 2013, 6666–6676
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6671

C. Feng, Y. Kobayashi
FULL PAPER
(R,E)-2-(3-Phenylpropylidene)cyclohexanol [(R)-4b]: According to
the procedure for the synthesis of (R)-4a, a solution of enone 5b
(202 mg, 0.942 mmol) in THF (9 mL) was added over 50 min to a
solution of (S)-methyl oxazaborolidine (1.0 m in toluene, 0.20 mL,
0.200 mmol) and N,N-diethylaniline–borane (0.18 mL, 1.01 mmol)
in THF (5 mL) at –20 °C. The solution was stirred at –20 °C for
30 min to afford alcohol (R)-4b (162 mg, 79%). 1H NMR
22.2 mmol). The mixture was stirred at room temp. for 1 h and
then diluted with HCl (aqueous 1 n solution) and Et2O with vigor-
ous stirring. The organic layer was separated, and the aqueous layer
was extracted with Et2O (2ϫ). The combined extracts were dried
with MgSO4 and concentrated to afford an oil, which was purified
by chromatography on silica gel (hexane/EtOAc) to furnish 5c
1
(715 mg, 47% over three steps). H NMR (400 MHz, CDCl3): δ =
(300 MHz, CDCl3): δ = 1.23–1.62 (m, 5 H), 1.68–1.96 (m, 3 H), 1.04 (d, J = 6 Hz, 6 H), 1.94 (tt, J = 8, 8 Hz, 2 H), 2.33 (t, J =
2.26–2.40 (m, 3 H), 2.66 (t, J = 8 Hz, 2 H), 4.00–4.08 (m, 1 H),
5.39 (dt, J = 1, 7 Hz, 1 H), 7.12–7.20 (m, 3 H), 7.22–7.29 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.0 (–), 26.1 (–), 27.2
8 Hz, 2 H), 2.41–2.55 (m, 1 H), 2.60 (dt, J = 2.5, 7 Hz, 2 H), 6.38
(dt, J = 10, 2.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
19.9 (–), 21.8 (+), 26.6 (–), 29.2 (+), 38.6 (–), 135.0 (–), 142.6 (+),
(–), 28.9 (–), 36.2 (–), 36.3 (–), 73.8 (+), 120.1 (+), 125.8 (+), 128.2 207.9 (–) ppm.
(+), 128.5 (+), 141.7 (–), 142.0 (–) ppm. HRMS (EI): calcd. for
(E)-2-(2-Methylpropylidene)cyclopentanol (rac-4c): According to
C15H20O [M]+ 216.1514; found 216.1518.
the procedure for the synthesis of rac-4a, the reduction of enone
5c (89.6 mg, 0.648 mmol) with NaBH4 (25.0 mg, 0.661 mmol) and
CeCl3·7H2O (250 mg, 0.671 mmol) in MeOH (7 mL) gave alcohol
rac-4c (70.2 mg, 77%). 1H NMR (400 MHz, CDCl3): δ = 0.966 (d,
J = 7 Hz, 3 H), 0.971 (d, J = 7 Hz, 3 H), 1.54–1.73 (m, 2 H), 1.75–
1.91 (m, 2 H), 2.14–2.26 (m, 1 H), 2.30–2.46 (m, 2 H), 4.33–4.41
(m, 1 H), 5.36 (dm, J = 9 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.2 (–), 22.6 (+), 22.8 (+), 26.7 (–), 28.9 (+), 35.6
(–), 75.8 (+), 131.8 (+), 143.6 (–) ppm.
(R,E)-2-(3-Phenylpropylidene)cyclohexyl Picolinate [(R)-1b]: Ac-
cording to the procedure for the synthesis of (R)-1a, a solution of
(R)-4b (162 mg, 0.749 mmol), picolinic acid (115.6 mg,
0.939 mmol), DCC (214 mg, 1.04 mmol), and DMAP (91.7 mg,
0.751 mmol) in CH2Cl2 (8 mL) was stirred at room temp. for 2 h
1
to furnish (R)-1b (231 mg, 96%). H NMR (400 MHz, CDCl3): δ
= 1.28–1.42 (m, 1 H), 1.44–1.64 (m, 2 H), 1.76–1.98 (m, 3 H), 2.09–
2.19 (m, 1 H), 2.22–2.40 (m, 3 H), 2.65 (t, J = 8 Hz, 2 H), 5.49–
5.56 (m, 2 H), 7.10–7.18 (m, 3 H), 7.18–7.26 (m, 2 H), 7.46 (ddd,
J = 8, 5, 1 Hz, 1 H), 7.82 (dt, J = 1, 8 Hz, 1 H), 8.09 (d, J = 8 Hz,
1 H), 8.79 (dm, J = 5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 22.6 (–), 26.0 (–), 26.7 (–), 28.9 (–), 33.0 (–), 35.9 (–), 77.3 (+),
123.6 (+), 125.0 (+), 125.7 (+), 126.6 (+), 128.2 (+), 128.6 (+),
136.67 (–), 136.86 (+), 141.8 (–), 148.7 (–), 150.0 (+), 164.1 (–) ppm.
HRMS (EI): calcd. for C21H23NO2 [M]+ 321.1729; found 321.1729.
The enantiomeric purity (86%ee) was determined by chiral HPLC
analysis (Chiralcel OD-H; hexane/iPrOH, 98:2; 0.8 mL/min;
25 °C): tR = 29.0 (R isomer) and 32.7 min (S isomer).
(E)-2-(2-Methylpropylidene)cyclopentyl Picolinate (rac-1c): Accord-
ing to the procedure for the synthesis of rac-1a, the condensation
of rac-4c (180 mg, 1.28 mmol) with picolinic acid (198.6 mg,
1.61 mmol) in CH2Cl2 (12 mL) was carried out with DCC
(348.4 mg, 1.69 mmol) and DMAP (155.5 mg, 1.27 mmol) at room
temp. for 1 h to furnish picolinate rac-1c (291 mg, 92%). IR (neat):
1
ν = 1714, 1304, 1245, 1127 cm–1. H NMR (300 MHz, CDCl ): δ
˜
3
= 0.95 (d, J = 7 Hz, 3 H), 0.96 (d, J = 7 Hz, 3 H), 1.69–1.85 (m, 1
H), 1.85–2.11 (m, 3 H), 2.21–2.54 (m, 3 H), 5.54 (dm, J = 9.5 Hz,
1 H), 5.76 (tm, J = 4 Hz, 1 H), 7.43 (ddd, J = 8, 5, 1 Hz, 1 H),
7.80 (dt, J = 2, 8 Hz, 1 H), 8.07 (dm, J = 8 Hz, 1 H), 8.75 (dm, J
= 5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.5 (+),
22.6 (+), 22.9 (–), 27.1 (–), 29.2 (+), 33.1 (–), 79.3 (+), 125.1 (+),
126.6 (+), 135.4 (+), 136.9 (+), 138.1 (–), 148.8 (–), 150.0 (+), 165.0
(–) ppm. HRMS (EI): calcd. for C15H19NO2 [M]+ 245.1416; found
245.1420.
(E)-2-(3-Phenylpropylidene)cyclohexanol (rac-4b): According to the
procedure for the synthesis of rac-4a, the reduction of 5b (183 mg,
0.855 mmol) with NaBH4 (32.4 mg, 0.856 mmol) was carried out
in the presence of CeCl3·7H2O (330 mg, 0.885 mmol) in MeOH
(9 mL) at room temp. for 1 h to furnish racemic alcohol rac-4b
1
(135 mg, 73%). The H and 13C NMR spectra were identical with
those of (R)-4b.
Synthesis of Picolinate rac-1d
(E)-2-(3-Phenylpropylidene)cyclohexyl Picolinate (rac-1b): Accord-
ing to the procedure for the synthesis of rac-1a, the condensation
of rac-4b (135 mg, 0.624 mmol) with picolinic acid (99.5 mg,
0.808 mmol) was carried out with DCC (175 mg, 0.848 mmol) and
DMAP (73.5 mg, 0.602 mmol) in CH2Cl2 (7 mL) at room temp. for
2 h to furnish rac-1b (163 mg, 81%). The 1H and 13C NMR spectra
were identical with those of (R)-1b.
(E)-2-Benzylidenecyclohexanol (rac-4d): According to the procedure
for the synthesis of rac-4a, the reduction of commercially available
enone 5d (160.5 mg, 0.862 mmol) with NaBH4 (33.1 mg,
0.875 mmol) and CeCl3·7H2O (323 mg, 0.876 mmol) in MeOH
(9 mL) gave alcohol rac-4d (144.1 mg, 89%). IR (neat): ν = 3347,
˜
1445, 1076, 738, 699 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.36–
1.68 (m, 4 H), 1.76–1.91 (m, 1 H), 1.92–2.03 (m, 1 H), 2.03–2.14
(m, 1 H), 2.24 (br. s, 1 H), 2.71 (dt, J = 13.5, 5 Hz), 4.17–4.24 (m,
1 H), 6.51 (s, 1 H), 7.14–7.23 (m, 3 H), 7.25–7.33 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 23.2 (–), 27.0 (–), 27.4 (–), 36.6
(–), 73.7 (+), 120.8 (+), 126.2 (+), 128.1 (+), 128.9 (+), 137.7 (–),
Synthesis of Picolinate rac-1c
(E)-2-(2-Methylpropylidene)cyclopentanone (5c): According to the
procedure for the synthesis of 5a, cyclopentanone (1.48 mL,
16.7 mmol) was converted into the aldol as a mixture of dia-
stereomers through the reaction with isobutyraldehyde (1.02 mL,
11.1 mmol), diisopropylamine (4.66 mL, 33.2 mmol), and nBuLi
(1.60 m in hexane, 17.2 mL, 27.5 mmol) in THF (36 mL). To an ice-
cold solution of the aldol and Et3N (4.64 mL, 33.3 mmol) in
1
144.4 (–) ppm. The H and 13C NMR spectra were identical with
those reported.[20]
(E)-2-Benzylidenecyclohexyl Picolinate (rac-1d): According to the
procedure for the synthesis of rac-1a, the condensation of rac-4d
CH2Cl2 (30 mL) was added MsCl (1.72 mL, 22.2 mmol) dropwise. (144.1 mg, 0.765 mmol) with picolinic acid (122.6 mg, 0.996 mmol)
The solution was stirred between 0 °C and room temp. for 2 h and
then poured into saturated NaHCO3 with vigorous stirring. The
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (2ϫ). The combined extracts were washed with brine,
dried with MgSO4, and concentrated to afford the corresponding
mesylate. To an ice-cold solution of the mesylate in THF (40 mL)
was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.31 mL,
in CH2Cl2 (4 mL) was carried out with DCC (205.7 mg,
0.997 mmol) and DMAP (94.0 mg, 0.769 mmol) at room temp. for
2 h to furnish picolinate rac-1d (202.3 mg, 90%). IR (neat): ν =
˜
1738, 1715, 1583, 1301, 1243, 1133 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.54–1.75 (m, 3 H), 1.85–2.12 (m, 3 H), 2.40 (dt, J =
14, 6 Hz, 1 H), 2.67 (dt, J = 14, 6 Hz, 1 H), 5.71 (t, J = 5.5 Hz, 1
H), 6.60 (s, 1 H), 7.46 (ddd, J = 7.5, 4.5, 1 Hz, 1 H), 7.84 (dt, J =
6672
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6666–6676

Allylic Substitution of Exocyclic Allylic Picolinates
2, 7.5 Hz, 1 H), 8.16 (d, J = 7.5 Hz, 1 H), 8.79 (d, J = 4.5 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.0 (–), 27.1 (–), 27.2
(–), 33.4 (–), 77.0 (+), 123.7 (+), 125.1 (+), 126.5 (+), 126.7 (+),
128.1 (+), 129.0 (+), 136.9 (+), 137.2 (–), 139.1 (–), 148.7 (–), 150.1
(+), 164.1 (–) ppm. HRMS (EI): calcd. for C19H19NO2 [M]+
293.1416; found 293.1423.
determined by chiral HPLC analysis (Chiralcel OJ-H; hexane/
iPrOH; 92:8; 0.3 mL/min; 25 °C): tR = 16.5 (R isomer) and
17.8 min (S isomer).
(R)-1-[1-(Cyclopent-1-en-1-yl)-3-phenylpropyl]-4-methoxybenzene
[(R)-2aD]: (see Table 2, Entry 5). Colorless oil (91% yield). [α]2D7
=
+27 (c = 0.47, CHCl ). IR (neat): ν = 1609, 1507, 1246, 1176,
˜
3
1039 cm–1. H NMR (300 MHz, CDCl3): δ = 1.69–1.85 (m, 2 H),
1
General Procedure for Allylation To Afford (R)-[1-(Cyclopent-1-en-
1-yl)propane-1,3-diyl]dibenzene [(R)-2aA]
1.93–2.23 (m, 4 H), 2.24–2.38 (m, 2 H), 2.50 (t, J = 8 Hz, 2 H),
3.26 (t, J = 7 Hz, 1 H), 3.79 (s, 3 H), 5.47 (s, 1 H), 6.82 (d, J =
8 Hz, 2 H), 7.03–7.19 (m, 5 H), 7.20–7.26 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.2 (–), 32.3 (–), 33.6 (–), 34.0 (–), 35.8
(–), 46.2 (+), 55.2 (+), 113.6 (+), 123.5 (+), 125.6 (+), 128.2 (+),
128.4 (+), 128.8 (+), 135.9 (–), 142.6 (–), 147.6 (–), 157.9 (–) ppm.
HRMS (EI): calcd. for C21H24O [M]+ 292.1827; found 292.1825.
The enantiomeric purity (91%ee) was determined by chiral HPLC
analysis (Chiralcel OD-H; hexane/iPrOH, 99.8:0.2; 0.4 mL/min;
25 °C): tR = 24.7 (S isomer) and 26.6 min (R isomer).
Allylation with Cu(acac)2: (see Table 2, Entry 1). To an ice-cold sus-
pension of Cu(acac)2 (281.3 mg, 1.07 mmol) in THF (7 mL) was
added PhMgBr (1.05 m in THF, 2.00 mL, 2.10 mmol) slowly. The
mixture was stirred at 0 °C for 60 min and then cooled to –40 °C.
A solution of picolinate (R)-1a (220.0 mg, 0.716 mmol, 94%ee) in
THF (3 mL) was added. The resulting mixture was warmed to
–5 °C over 2 h to afford (R)-2aA (149.5 mg, 80%). The enantio-
meric purity (95%ee) was determined by chiral HPLC analysis.
Allylation with CuBr·Me2S: (see Table 2, Entry 2). To an ice-cold
suspension of CuBr·Me2S (20.4 mg, 0.0992 mmol) in THF (1 mL)
was added PhMgBr (0.91 m in THF, 0.23 mL, 0.21 mmol) slowly.
The mixture was stirred at 0 °C for 30 min and then cooled to
–40 °C. A solution of picolinate (R)-1a (30.3 mg, 0.0986 mmol,
97%ee) in THF (1 mL) was added. The resulting mixture was
(R)-1-[1-(Cyclopent-1-en-1-yl)-3-phenylpropyl]-2-methoxybenzene
[(R)-2aE]: (see Table 2, Entry 6). Colorless oil (82% yield). [α]2D0
=
+12 (c = 0.26, CHCl ). IR (neat): ν = 1599, 1492, 1241, 1031, 751,
˜
3
699 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.71–1.87 (m, 2 H),
1.94–2.05 (m, 1 H), 2.09–2.20 (m, 3 H), 2.32 (tt, J = 7, 2.5 Hz, 2
H), 2.49 (ddd, J = 14, 10, 6 Hz, 1 H), 2.58 (ddd, J = 14, 10, 6 Hz,
1 H), 3.80 (s, 3 H), 3.92 (t, J = 7 Hz, 1 H), 5.50 (s, 1 H), 6.87 (d,
J = 8 Hz, 1 H), 6.92 (dt, J = 1, 8 Hz, 1 H), 7.12–7.20 (m, 5 H),
7.22–7.28 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.3
(–), 32.5 (–), 34.20 (–), 34.22 (–), 35.9 (–), 38.6 (+), 55.6 (+), 110.7
(+), 120.6 (+), 123.8 (+), 125.6 (+), 126.9 (+), 127.8 (+), 128.2 (+),
128.4 (+), 132.4 (–), 143.0 (–), 147.0 (–), 157.4 (–) ppm. HRMS
(EI): calcd. for C21H24O [M]+ 292.1827; found 292.1828. The enan-
tiomeric purity (85%ee) was determined by chiral HPLC analysis
(Chiralcel OD-H; hexane/iPrOH, 99.9:0.1; 1.0 mL/min; 25 °C):
tR = 9.5 (S isomer) and 10.3 min (R isomer).
warmed to –10 °C over 1 h to give (R)-2aA (23.0 mg, 89%). [α]2D1
=
+27 (c = 0.12, CHCl ). IR (neat): ν = 3025, 1602, 1494, 1452,
˜
3
699 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.76–1.84 (m, 2 H),
2.00–2.25 (m, 4 H), 2.27–2.39 (m, 2 H), 2.43–2.62 (m, 2 H), 3.32
(t, J = 7 Hz, 1 H), 5.52 (s, 1 H), 7.10–7.23 (m, 6 H), 7.23–7.35 (m,
4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.3 (–), 32.4 (–),
33.7 (–), 34.1 (–), 35.8 (–), 47.2 (+), 123.9 (+), 125.8 (+), 126.2 (+),
128.0 (+), 128.4 (+), 128.5 (+), 142.6 (–), 143.9 (–), 147.3 (–) ppm.
HRMS (EI): calcd. for C20H22 [M]+ 262.1722; found 262.1725. The
enantiomeric purity (94%ee) was determined by chiral HPLC
analysis (Chiralcel OJ-H; hexane/iPrOH, 99.6:0.4; 0.3 mL/min;
25 °C): tR = 34.4 (S isomer) and 39.4 min (R isomer).
(R)-1-[1-(cyclopent-1-en-1-yl)-3-phenylpropyl]-4-fluorobenzene [(R)-
2aF]: (see Table 2, Entry 7). Colorless oil (86% yield). [α]2D1 = +22
Allylation Products
(c = 0.36, CHCl ). IR (neat): ν = 1602, 1508, 1498, 1223, 1156 cm–1.
˜
3
1H NMR (400 MHz, CDCl3): δ = 1.73–1.87 (m, 2 H), 1.96–2.25
(m, 4 H), 2.27–2.36 (m, 2 H), 2.50 (t, J = 8 Hz, 2 H), 3.30 (t, J =
8 Hz, 1 H), 5.50 (s, 1 H), 6.98 (tt, J = 8, 2.5 Hz, 2 H), 7.09–7.21
(m, 5 H), 7.23–7.30 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 23.3 (–), 32.4 (–), 33.7 (–), 34.0 (–), 35.9 (–), 46.4 (+), 115.1 (d,
J = 21 Hz, +), 124.1 (+), 125.8 (+), 128.4 (+), 128.5 (+), 129.3 (d,
J = 8 Hz, +), 139.5 (d, J = 3 Hz, –), 142.4 (–), 147.2 (–), 161.4 (d,
J = 242 Hz, –) ppm. HRMS (EI): calcd. for C20H21F [M]+
280.1627; found 280.1621. The enantiomeric purity (90%ee) was
determined by chiral HPLC analysis (Chiralcel OJ-H; hexane/
iPrOH, 99.6:0.4; 1.0 mL/min; 25 °C): tR = 8.7 (S isomer) and
10.8 min (R isomer).
(R)-1-[1-(Cyclopent-1-en-1-yl)-3-phenylpropyl]-4-methylbenzene
[(R)-2aB]: (see Table 2, Entry 3). Colorless oil (80 % yield). IR
1
(neat): ν = 1604, 1512, 1496, 1454, 699 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 1.72–1.84 (m, 2 H), 1.97–2.23 (m, 4 H), 2.33 (s, 3 H),
2.27–2.35 (m, 2 H), 2.51 (t, J = 8 Hz, 2 H), 3.29 (t, J = 8 Hz, 1 H),
5.50 (s, 1 H), 7.05–7.20 (m, 6 H), 7.23–7.29 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.1 (+), 23.3 (–), 32.4 (–), 33.7 (–),
34.1 (–), 35.8 (–), 46.8 (+), 123.7 (+), 125.7 (+), 127.9 (+), 128.3
(+), 128.5 (+), 129.0 (+), 135.6 (–), 140.9 (–), 142.7 (–), 147.5
(–) ppm. HRMS (EI): calcd. for C21H24 [M]+ 276.1878; found
276.1882. The enantiomeric purity (97%ee) was determined by chi-
ral HPLC analysis (Chiralcel OJ-H; hexane/iPrOH, 99.6:0.4;
0.3 mL/min; 25 °C): tR = 25.1 (S isomer) and 31.7 min (R-isomer).
(R)-[1-(Cyclohex-1-en-1-yl)propane-1,3-diyl]dibenzene [(R)-2bA]:
(R)-1-[1-(Cyclopent-1-en-1-yl)-3-phenylpropyl]-2-methylbenzene (see Table 2, Entry 8). Colorless oil (89% yield). [α]2D1 = –3 (c =
[(R)-2aC]: (see Table 2, Entry 4). Colorless oil (87% yield). [α]2D1
=
0.26, CHCl ). IR (neat): ν = 3025, 1602, 1494, 1451, 699 cm–1. H
1
˜
3
–4 (c = 0.47, CHCl ). IR (neat): ν = 1603, 1454, 754, 729, 699 cm–1.
NMR (300 MHz, CDCl3): δ = 1.44–1.62 (m, 4 H), 1.65–1.90 (m, 2
˜
3
1H NMR (400 MHz, CDCl3): δ = 1.72–1.86 (m, 2 H), 1.98–2.07 H), 1.92–2.22 (m, 4 H), 2.42–2.62 (m, 2 H), 3.13 (t, J = 7 Hz, 1
(m, 1 H), 2.07–2.14 (m, 2 H), 2.23 (s, 3 H), 2.15–2.26 (m, 1 H), H), 5.62 (s, 1 H), 7.08–7.32 (m, 10 H) ppm. 13C NMR (75 MHz,
2.28–2.35 (m, 2 H), 2.48–2.63 (m, 2 H), 3.60 (t, J = 7 Hz, 1 H),
5.47 (s, 1 H), 7.06–7.21 (m, 6 H), 7.23–7.29 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 19.6 (+), 23.2 (–), 32.3 (–), 33.6 (–),
34.0 (–), 35.6 (–), 42.1 (+), 124.1 (+), 125.66 (+), 125.71 (+), 126.0
(+), 126.5 (+), 128.3 (+), 128.4 (+), 130.2 (+), 136.2 (–), 141.8 (–),
142.5 (–), 146.5 (–) ppm. HRMS (EI): calcd. for C21H24 [M]+
276.1878; found 276.1871. The enantiomeric purity (90%ee) was
CDCl3): δ = 22.8 (–), 23.2 (–), 25.6 (–), 26.7 (–), 34.3 (–), 34.6 (–),
52.6 (+), 121.6 (+), 125.6 (+), 126.0 (+), 127.9 (+), 128.1 (+), 128.2
(+), 128.4 (+), 139.8 (–), 142.6 (–), 144.2 (–) ppm. HRMS (EI):
calcd. for C21H24 [M]+ 276.1878; found 276.1875. The enantiomeric
purity (86%ee) was determined by chiral HPLC analysis (Chiralcel
OD-H; hexane/iPrOH, 100:0; 0.8 mL/min; 20 °C): tR = 13.2 (S iso-
mer) and 14.1 min (R isomer).
Eur. J. Org. Chem. 2013, 6666–6676
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6673

C. Feng, Y. Kobayashi
FULL PAPER
1-[1-(Cyclohex-1-en-1-yl)-3-phenylpropyl]-4-methylbenzene (rac-
= 1.49–1.68 (m, 4 H), 1.89–1.98 (m, 2 H), 1.99–2.08 (m, 2 H), 4.62
(s, 1 H), 5.16–5.24 (m, 1 H), 7.11–7.22 (m, 6 H), 7.23–7.30 (m, 4
2bB): (see Table 1, Entry 12). Colorless oil (82% yield). IR (neat):
1
ν = 1511, 1496, 1453, 698 cm–1. H NMR (400 MHz, CDCl ): δ = H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.6 (–), 23.3 (–), 25.6
˜
3
1.48–1.56 (m, 4 H), 1.67–1.87 (m, 2 H), 1.94–2.17 (m, 4 H), 2.32
(–), 29.1 (–), 59.0 (+), 125.54 (+), 125.58 (+), 126.1 (+), 128.2 (+),
(s, 3 H), 2.46–2.62 (m, 2 H), 3.10 (t, J = 7.0 Hz, 1 H), 5.62 (s, 1
129.4 (+), 140.0 (–), 143.1 (–) ppm. The 1H NMR spectrum was
H), 7.06–7.30 (m, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = identical with that reported.[21]
21.1 (+), 22.8 (–), 23.1 (–), 25.5 (–), 26.6 (–), 34.2 (–), 34.6 (–), 52.1
1-[Cyclohex-1-en-1-yl(phenyl)methyl]-4-methylbenzene
(see Table 1, Entry 16). Colorless oil (82% yield). IR (neat): ν =
(rac-2dB):
(+), 121.5 (+), 125.7 (+), 127.9 (+), 128.3 (+), 128.5 (+), 128.9 (+),
135.5 (–), 140.1 (–), 141.3 (–), 142.8 (–) ppm. HRMS (EI): calcd.
for C22H26 [M]+ 290.2035; found 290.2035.
˜
1511, 1448, 800, 700 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.51–
1.66 (m, 4 H), 1.88–1.98 (m, 2 H), 1.98–2.08 (m, 2 H), 2.31 (s, 3
H), 4.58 (s, 1 H), 5.17–5.22 (m, 1 H), 7.00–7.11 (m, 4 H), 7.11–7.20
(m, 3 H), 7.23–7.29 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.1 (+), 22.6 (–), 23.3 (–), 25.6 (–), 29.1 (–), 58.6 (+), 125.31
(R)-1-[1-(Cyclohex-1-en-1-yl)-3-phenylpropyl]-4-methoxybenzene
[(R)-2bD]: (see Table 2, Entry 9). Colorless oil (87% yield). [α]2D1
=
–2 (c = 0.498, CHCl ). IR (neat): ν = 1608, 1509, 1246, 1177,
˜
3
1039 cm–1. H NMR (400 MHz, CDCl3): δ = 1.46–1.60 (m, 4 H), (+), 125.35 (+), 126.1 (+), 128.2 (+), 128.9 (+), 129.3 (+), 129.4
1
1.66–1.86 (m, 2 H), 1.92–2.16 (m, 4 H), 2.44–2.59 (m, 2 H), 3.08
(+), 135.6 (–), 140.05 (–), 140.11 (–), 143.3 (–) ppm. HRMS (EI):
(t, J = 8 Hz, 1 H), 3.80 (s, 3 H), 5.61 (s, 1 H), 6.83 (dm, J = calcd. for C20H22 [M]+ 262.1722; found 262.1723.
9 Hz, 2 H), 7.09–7.20 (m, 4 H), 7.23–7.29 (m, 3 H) ppm. 13C NMR
(R)-[3-(Cyclopent-1-en-1-yl)heptyl]benzene
[(R)-2aG]:
(see
(100 MHz, CDCl3): δ = 22.7 (–), 23.1 (–), 25.4 (–), 26.6 (–), 34.2
(–), 34.7 (–), 51.6 (+), 55.3 (+), 113.5 (+), 121.4 (+), 125.7 (+),
128.3 (+), 128.5 (+), 128.8 (+), 136.4 (–), 140.2 (–), 142.8 (–), 157.9
(–) ppm. HRMS (EI): calcd. for C22H26O [M]+ 306.1984; found
306.1981. The enantiomeric purity (80%ee) was determined by chi-
ral HPLC analysis (Chiralcel OD-H; hexane/iPrOH, 99.9:0.1;
1.0 mL/min; 20 °C): tR = 16.7 (S isomer) and 22.5 min (R isomer).
Scheme 5). Colorless oil (91% yield). IR (neat): ν = 1500, 1455,
˜
1
1260, 1032, 804, 698 cm–1. H NMR (400 MHz, CDCl3): δ = 0.87
(t, J = 7 Hz, 3 H), 1.15–1.40 (m, 6 H), 1.58–1.72 (m, 2 H), 1.85
(quintet, J = 7 Hz, 2 H), 2.12–2.27 (m, 3 H), 2.27–2.36 (m, 2 H),
2.40–2.60 (m, 2 H), 5.36–5.41 (m, 1 H), 7.13–7.19 (m, 3 H), 7.23–
7.30 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2 (+),
22.9 (–), 23.5 (–), 29.8 (–), 31.0 (–), 32.1 (–), 33.5 (–), 34.0 (–), 35.6
(–), 41.0 (+), 125.1 (+), 125.6 (+), 128.3 (+), 128.5 (+), 143.2 (–),
147.1 (–) ppm.
(R)-1-[1-(Cyclohex-1-en-1-yl)-3-phenylpropyl]-2-methoxybenzene
[(R)-2bE]: (see Table 2, Entry 10). Colorless oil (71% yield). [α]2D0
=
+6 (c = 0.36, CHCl ). IR (neat): ν = 1598, 1490, 1460, 1241 cm–1.
˜
3
Determination of Configuration of (R)-2aA
1H NMR (400 MHz, CDCl3): δ = 1.44–1.64 (m, 4 H), 1.76–1.87
(m, 2 H), 1.87–1.99 (m, 1 H), 2.00–2.14 (m, 3 H), 2.47 (ddd, J =
14, 10, 6 Hz, 1 H), 2.59 (ddd, J = 14, 10, 6 Hz, 1 H), 3.71 (t, J =
8 Hz, 1 H), 3.79 (s, 3 H), 5.61 (s, 1 H), 6.82–6.88 (m, 1 H), 6.91 (t,
J = 7 Hz, 1 H), 7.11–7.21 (m, 5 H), 7.22–7.28 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 22.8 (–), 23.2 (–), 25.5 (–), 27.7 (–),
34.3 (–), 35.1 (–), 43.6 (+), 55.6 (+), 110.7 (+), 120.5 (+), 121.3 (+),
125.6 (+), 126.8 (+), 127.6 (+), 128.2 (+), 128.5 (+), 133.0 (+), 139.5
(+), 143.2 (+), 157.7 (+) ppm. HRMS (EI): calcd. for C22H26O
[M]+ 306.1984; found 306.1986. The enantiomeric purity (83%ee)
was determined by chiral HPLC analysis (Chiralcel OD-H; hexane/
iPrOH, 99.9:0.1; 1.0 mL/min; 20 °C): tR = 9.9 (S isomer) and
11.3 min (R isomer).
(S)-Methyl 5-Oxo-6,8-diphenyloctanoate (7): To an ice-cold solu-
tion of (R)-2aA (43.9 mg, 0.167 mmol) in CCl4 (2 mL), MeCN
(2 mL), and H2O (3 mL) were added NaIO4 (150 mg, 0.701 mmol)
and RuCl3·nH2O (ca. 16 mg). The mixture was stirred at room
temp. for 7 h and then diluted with CH2Cl2 (10 mL). The organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (2ϫ). The combined organic layers were dried by MgSO4
and concentrated to afford a residue, which was passed through a
pad of Celite with Et2O to remove the remaining Ru species. The
filtrate was concentrated to afford a crude oil, which was passed
through a short column and then used for the next reaction without
further purification. To an ice-cold solution of the oil in Et2O
(2 mL) was added a solution of CH2N2 in Et2O (2 mL). After 5 min
at 0 °C, the solution was concentrated to afforded a residue, which
was purified by chromatography on silica gel (hexane/EtOAc) to
furnish 7 [9.7 mg, 18% from (R)-2aA]. 1H NMR (400 MHz,
CDCl3): δ = 1.68–1.86 (m, 2 H), 1.94–2.07 (m, 1 H), 2.08–2.26 (m,
2 H), 2.26–2.45 (m, 3 H), 2.49 (tm, J = 7 Hz, 2 H), 3.53–3.61 (m,
1 H), 3.57 (s, 3 H), 7.08–7.13 (m, 2 H), 7.15–7.19 (m, 3 H), 7.22–
7.28 (m, 3 H), 7.28–7.34 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.9 (–), 32.9 (–), 33.4 (–), 40.6 (–), 51.6 (+), 58.2 (+),
126.0 (+), 127.4 (+), 128.44 (+), 128.48 (+), 128.53 (+), 129.1 (+),
138.7 (–), 141.6 (–), 173.6 (–), 209.4 (–) ppm.
[1-(Cyclopent-1-en-1-yl)-2-methylpropyl]benzene (rac-2cA): (see
Table 1, Entry 13). Colorless oil (96% yield). IR (neat): ν = 1493,
˜
1451, 702 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.71 (d, J =
6 Hz, 3 H), 0.96 (d, J = 6 Hz, 3 H), 1.77 (tt, J = 8, 8 Hz, 2 H),
2.06–2.23 (m, 3 H), 2.23–2.35 (m, 2 H), 3.00 (d, J = 10 Hz, 1 H),
5.52 (s, 1 H), 7.13–7.21 (m, 3 H), 7.22–7.29 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.3 (+), 22.0 (+), 23.3 (–), 30.1 (+),
32.2 (–), 32.9 (–), 56.7 (+), 124.5 (+), 125.9 (+), 128.1 (+), 128.4
(+), 143.7 (–), 146.8 (–) ppm. HRMS (EI): calcd. for C15H20 [M]+
200.1565; found 200.1559.
1-[1-(Cyclopent-1-en-1-yl)-2-methylpropyl]-4-methylbenzene
(rac-
(S)-1,3-Diphenylpropan-1-ol (8): To a solution of 7 (15.3 mg,
0.0472 mmol) in CH2Cl2 (5 mL) were added K2CO3 (72.2 mg,
0.522 mmol) and meta-chloroperoxybenzoic acid (mCPBA, 77%
purity, 92.3 mg, 0.412 mmol). The reaction was carried out at room
temp. for 40 h and then quenched by the addition of aqueous
Na2S2O3 and CH2Cl2. The organic layer was separated, and the
aqueous phase was extracted with EtOAc (2ϫ). The combined ex-
tracts were dried with MgSO4 and concentrated. The residue was
passed through a short column of silica gel (hexane/EtOAc) to af-
ford a residue, which was used for the following reaction without
further purification. A mixture of the product and aqueous KOH
(1.8 n, 0.10 mL) in MeOH (1 mL) was stirred at room temp. over-
2cB): (see Table 1, Entry 14). Colorless oil (87% yield). IR (neat):
1
ν = 1512, 1465, 1384, 815 cm–1. H NMR (400 MHz, CDCl ): δ =
˜
3
0.71 (d, J = 6.5 Hz, 3 H), 0.94 (d, J = 6.5 Hz, 3 H), 1.72–1.83 (m,
2 H), 2.07–2.36 (m, 5 H), 2.31 (s, 3 H), 2.97 (d, J = 10 Hz, 1 H),
5.50 (s, 1 H), 7.03–7.12 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.1 (+), 21.3 (+), 22.0 (+), 23.3 (–), 30.1 (+), 32.2
(–), 32.9 (–), 56.3 (+), 124.2 (+), 128.3 (+), 128.8 (+), 135.2 (–),
140.6 (–), 147.0 (–) ppm. HRMS (EI): calcd. for C16H22 [M]+
214.1722; found 214.1722.
(Cyclohex-1-en-1-ylmethylene)dibenzene (rac-2dA): (see Table 1, En-
1
try 15). Colorless oil (89% yield). H NMR (400 MHz, CDCl3): δ
6674
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Eur. J. Org. Chem. 2013, 6666–6676

Allylic Substitution of Exocyclic Allylic Picolinates
b) B. Breit, Y. Schmidt, Chem. Rev. 2008, 108, 2928–2951; c)
S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard,
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7495; d) Y. Kiyotsuka, Y. Katayama, H. P. Acharya, T. Hyodo,
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suka, H. P. Acharya, Y. Katayama, T. Hyodo, Y. Kobayashi,
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night and then diluted with H2O and Et2O. The organic layer was
separated, and the aqueous phase was extracted with Et2O (3ϫ).
The combined extracts were dried with MgSO4 and concentrated.
The residue was purified by chromatography on silica gel (hexane/
EtOAc) to furnish 8 (5.2 mg, 52% over two steps). [α]2D3 = –13 (c =
0.17, CHCl3); {cf. [α]2D0 = –27.1 (c = 0.52, CHCl3) for the S enanti-
omer with Ͼ99%ee}.[17] 1H NMR (400 MHz, CDCl3): δ = 1.84
(br. s, 1 H), 1.97–2.20 (m, 2 H), 2.62–2.81 (m, 2 H), 4.70 (dd, J =
8, 5.5 Hz, 1 H), 7.15–7.22 (m, 3 H), 7.25–7.32 (m, 3 H), 7.33–7.37
(m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.2 (–), 40.6 (–
), 74.0 (+), 125.95 (+), 126.01 (+), 127.7 (+), 128.48 (+), 128.52
(+), 128.62 (+), 141.8 (–), 144.6 (–) ppm. The 1H and 13C NMR
spectra were consistent with those reported.[17]
[2]
Determination of the Configuration of (R)-2bA
(S)-Methyl 6-Oxo-7,9-diphenylnonanoate (9): A stream of ozone in
oxygen was slowly bubbled into a solution of (R)-2bA (43.1 mg,
0.156 mmol) in CH2Cl2 (8 mL) at –78 °C until the solution turned
to pale blue (5 min). The excess amount of ozone that remained in
the solution was removed by bubbling argon at –78 °C for 5 min,
and PPh3 (52.0 mg, 0.198 mmol) was added. The solution was
gradually warmed to room temp., stirred overnight, and concen-
trated to afford a residue that was passed through a short column
of silica gel (hexane/EtOAc) to furnish a crude aldehyde, which was
used for the next reaction without further purification. To a solu-
tion of the crude aldehyde in acetone (5 mL) was added Jones rea-
gent (4 m solution, 9 drops) at 0 °C. After 30 min at 0 °C, iPrOH
was added to quench the excess amount of reagent. After concen-
tration, the residue was passed through a short column, and the
filtrate was concentrated to afford a residue, which was used di-
rectly for the next reaction without further purification. To an ice-
cold solution of the residue in Et2O (2 mL) was added a solution
of CH2N2 in Et2O (2 mL). After 5 min, the solution was concen-
trated to afford a residue, which was purified by chromatography
on silica gel (hexane/EtOAc) to furnish ester 9 [21.3 mg, 40% from
(R)-2bA]. 1H NMR (300 MHz, CDCl3): δ = 1.38–1.66 (m, 4 H),
1.94–2.10 (m, 1 H), 2.15–2.25 (m, 2 H), 2.28–2.44 (m, 3 H), 2.45–
2.56 (m, 2 H), 3.54–3.65 (m, 1 H), 3.62 (s, 3 H), 7.06–7.21 (m, 5
H), 7.21–7.36 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
23.2 (–), 24.3 (–), 33.42 (–), 33.45 (–), 33.8 (–), 41.3 (–), 51.6 (+),
58.2 (+), 126.0 (+), 127.4 (+), 128.44 (+), 128.45 (+), 128.52 (+),
129.0 (+), 138.8 (–), 141.6 (–), 173.9 (–), 209.8 (–) ppm.
[3]
[4]
a) C. Feng, Y. Kobayashi, J. Org. Chem. 2013, 78, 3755–3766;
b) Y. Kaneko, Y. Kiyotsuka, H. P. Acharya, Y. Kobayashi,
Chem. Commun. 2010, 46, 5482–5484.
T. B. RajanBabu, W. A. Nugent, D. F. Taber, P. J. Fagan, J. Am.
Chem. Soc. 1988, 110, 7128–7135.
C. C. Tseng, S. D. Paisley, H. L. Goering, J. Org. Chem. 1986,
51, 2884–2891.
M. C. Warner, A. Nagendiran, K. Bogár, J.-E. Bäckvall, Org.
Lett. 2012, 14, 5094–5097.
[5]
[6]
[7]
[8]
[9]
Defined as (% ee of 2)ϫ100/(% ee of 1).
For previous preparations of compounds that correspond to
the γ products, see: a) C. S. Yi, D. W. Lee, Organometallics
2010, 29, 1883–1885; b) J. Almena, F. Foubelo, M. Yus, Tetra-
hedron 1997, 53, 5563–5572.
a) J. K. Crandall, J. P. Arrington, J. Hen, J. Am. Chem. Soc.
1967, 89, 6208–6213; b) S. Nakamura, T. Hayakawa, T. Nishi,
Y. Watanabe, T. Toru, Tetrahedron 2001, 57, 6703–6711; c) K.
Shimoda, N. Kubota, H. Hamada, M. Kaji, T. Hirata, Tetrahe-
dron: Asymmetry 2004, 15, 1677–1679.
[10]
(S)-1,3-Diphenylpropan-1-ol (8): According to the above procedure,
[11]
[12]
E. J. Corey, C. J. Helal, Angew. Chem. 1998, 110, 2092; Angew.
a
mixture of 9 (21.3 mg, 0.0629 mmol), K2CO3 (105 mg,
Chem. Int. Ed. 1998, 37, 1986–2012.
0.760 mmol), and mCPBA (77% purity, 128.3 mg, 0.0.572 mmol)
in CH2Cl2 (6 mL) was stirred at room temp. for 48 h to afford the
ester product, which was subjected to hydrolysis with aqueous
KOH (1.8 n, 0.15 mL) in MeOH (2 mL) at room temp. overnight
to furnish 8 (4.8 mg, 36% from 9). [α]2D3 = –23 (c = 0.25, CHCl3);
{cf. [α]2D0 = –27.1 (c = 0.52, CHCl3) for the S enantiomer with
Ͼ99%ee}.[17]
a) J. R. Falck, A. He, L. M. Reddy, A. Kundu, D. K. Barma,
A. Bandyopadhyay, S. Kamila, R. Akella, R. Bejot, C. Mios-
kowski, Org. Lett. 2006, 8, 4645–4647; b) A. Yanagisawa, R.
Goudu, T. Arai, Org. Lett. 2004, 6, 4281–4283.
The diagnostic olefin protons in the 1H NMR spectrum for
rac-3aA and its Z isomer (4:1) are at δ = 4.93 (tt, J = 7, 2.5 Hz,
0.8 H) and 5.47 (tm, J = 7 Hz, 0.2 H) ppm. The diagnostic
[13]
1
olefin protons in the H NMR spectrum for rac-3bA and its Z
Supporting Information (see footnote on the first page of this arti-
cle): H and 13C NMR spectra of the intermediates, the picolinate
1
isomer (4:1) are at δ = 4.66 (t, J = 7 Hz, 0.8 H) and 5.43 (t, J
= 7 Hz, 0.2 H) ppm. The major absorbance at δ = 4.93 and
4.66 ppm was coincident with the minor signals seen in the
spectra of rac-2aA and -2bA, respectively. On the other hand,
the signals of the olefin protons of rac-3aG and its Z isomer
were overlapped at δ = 5.12–5.32 (m, 1 H) ppm.
substrates, allylation products, and compounds 7–9.
Acknowledgments
[14]
[15]
The olefin and/or allylic signals of rac-3aB, -3bB, -3cA, and -
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, and Culture, Ja-
pan.
1
3cB in the H NMR spectra were assigned by analogy to rac-
3aA and -3bA.
Although the RuCl3-catalyzed oxidation of (R)-2aA with
NaIO4 followed by esterification with CH2N2 suffered from a
low yield of ketone 7 as a result of the difficult separation from
the side product(s), the Baeyer–Villiger oxidation of 7 and sub-
[1] For reviews, see: a) J. F. Teichert, B. L. Feringa, Angew. Chem.
2010, 122, 2538; Angew. Chem. Int. Ed. 2010, 49, 2486–2528;
Eur. J. Org. Chem. 2013, 6666–6676
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6675

C. Feng, Y. Kobayashi
FULL PAPER
sequent hydrolysis gave a sufficient quantity of 8 to determine
the specific rotation. To avoid this problem, an ozonolysis reac-
tion followed by a Jones oxidation was applied to (R)-2bA to
produce ketone 9 in moderate yield. A further transformation
furnished 8 as well.
Z. Cao, Z. Liu, Y. Liu, H. Du, J. Org. Chem. 2011, 76, 6401–
6406.
[19] To compare leaving groups, the substitution of the allylic mes-
ylate and acetate with the PhMgBr/Cu(acac)2 reagent was at-
tempted. However, the mesylation of alcohol rac-4a gave a mix-
ture of products, most likely because of the instability of the
allylic mesylate. On the other hand, the acetate, which was pre-
pared from rac-4a, showed no reactivity toward the 2:1
PhMgBr/Cu(acac)2 reagent under the conditions presented in
Table 1, Entry 4.
[16]
[17] The stereochemistry of the product was speculated. The ee
value and, thus, the C. T. could not be determined by HPLC
analysis, even with six attempted chiral columns.
[18] a) N. Yoshikai, E. Nakamura, Chem. Rev. 2012, 112, 2339–
2372; b) N. Yoshikai, S.-L. Zhang, E. Nakamura, J. Am. Chem.
Soc. 2008, 130, 12862–12863.
[20] A. Martinez-Grau, D. P. Curran, Tetrahedron 1997, 53, 5679–
5698.
[21] E. Wenkert, T. W. Ferreira, Organometallics 1982, 1, 1670–
1673.
Received: May 28, 2013
Published Online: August 27, 2013
6676
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6666–6676