Regio- and stereoselective SN2′ reaction of an allylic picolinate in the synthesis of LY426965

Article abstract of DOI:10.1016/j.tet.2018.02.045

Allylic substitution of secondary γ,γ-disubstituted allylic picolinates with ArMgBr-based copper reagents was applied to the synthesis of LY426965. Reduction of (R)-6-(PMB-oxy)-3-hexyn-2-ol of 93% ee (PMB = p-MeOC₆H₄CH₂) using Red-Al gave (R,Z)-4-iodo-5-(PMB-oxy)hex-3-en-2-ol, which was later converted to the Me-substituted allylic picolinate by Pd-catalyzed coupling with MeZnI followed by esterification with picolinic acid. Allylic substitution with PhMgBr/Cu(acac)₂ proceeded with high anti S_N2′ selectivity (99%). Ozonolysis, addition of c-Hex-MgBr to the resulting aldehyde, and reductive amination with the piperazine derivative afforded LY426965.

Full text of DOI:10.1016/j.tet.2018.02.045

Accepted Manuscript
Regio- and stereoselective S 2′ reaction of an allylic picolinate in the synthesis of
N
LY426965
Yuichi Kobayashi, Kai Yamaguchi, Masao Morita
PII:
S0040-4020(18)30190-X
10.1016/j.tet.2018.02.045
TET 29316
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 December 2017
Revised Date: 7 February 2018
Accepted Date: 20 February 2018
Please cite this article as: Kobayashi Y, Yamaguchi K, Morita M, Regio- and stereoselective S 2′
N
reaction of an allylic picolinate in the synthesis of LY426965, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.02.045.
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Regio- and stereoselective SN2' reaction of an allylic
picolinate in the synthesis of LY426965
Yuichi Kobayashi,* Kai Yamaguchi, Masao Morita
Department of Bioengineering, Tokyo Institute of Technology

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Regio- and stereoselective SN2' reaction of an allylic picolinate in the synthesis of
LY426965
Yuichi Kobayashi,* Kai Yamaguchi, Masao Morita
Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Allylic substitution of secondary γ,γ-disubstituted allylic picolinates with ArMgBr-based copper
reagents was applied to the synthesis of LY426965. Reduction of (R)-6-(PMB-oxy)-3-hexyn-2-
ol of 93% ee (PMB = p-MeOC6H4CH2) using Red-Al gave (R,Z)-4-iodo-5-(PMB-oxy)hex-3-en-
2-ol, which was later converted to the Me-substituted allylic picolinate by Pd-catalyzed coupling
with MeZnI followed by esterification with picolinic acid. Allylic substitution with
PhMgBr/Cu(acac)2 proceeded with high anti SN2' selectivity (99%). Ozonolysis, addition of c-
Hex-MgBr to the resulting aldehyde, and reductive amination with the piperazine derivative
afforded LY426965.
Available online
Keywords:
Allylic substitution
Picolinate
2009 Elsevier Ltd. All rights reserved
.
Copper
Quaternary carbon
Verapamil
1. Introduction
Scheme 1. Construction of quaternary carbons via allylic
substitution.
Recently, we have reported the allylic substitution of γ,γ-
disubstituted secondary allylic picolinates 1 to afford anti SN2'
products 2 possessing a quaternary C–C bond with high regio-
and stereoselectivity (Scheme 1, Eq. 1).1 The use of aryl reagents,
flexibility in choosing any alkyl substituent as R3, and attainable
high enantiopurity of the products are synthetic advantages of the
substitution. We also developed a stereoselective access to allylic
picolinates 1 from propargylic alcohol 3 via iodoalcohols 4 (Eq.
2) because the stereochemical purity of the olefin moiety is
directly transferred to enantiopurity of allylation products 2.
Feasibility of this strategy has been examined during the
synthesis of mesembrine2 and verapamil3 successfully. To further
demonstrate the synthetic potential of this strategy, LY426965
(6)4 was chosen as the next target (Fig. 1), which is a serotonin
1A receptor antagonist and would clinically be useful for
neuropsychiatric disorders. Up to date, 6 has been synthesized by
several methods,5
Fig. 1. The structure of LY426965.
which feature chiral phosphoramide-catalyzed addition of 3,3′-
disubstituted allylsilane to the chiral
aldehyde,5a,b
sulfonamide/oxazoline/Cr complex-catalyzed addition of 3,3′-
disubstituted allylic chloride to the aldehyde,5d and Rh-catalyzed
allylic substitution of the carbonate derived from the
enantioenriched tertiary allylic alcohol.5c These methods produce
terminal alkenes, whereas our method described herein would be
useful for synthesis of internal alkenes in developing a drug that
is more effective than 6.
2. Results and discussion
Taking account of the method described in Scheme 1 in mind,
we envisaged synthesis of 6 as delineated in Ph–. This method
consists of ozonolysis of the olefin in 9 derived from 7 via allylic
picolinate 8, addition of the cyclohexyl ring (c-Hex) to the
resulting aldehyde, and installation of the piperazine ring.

2
Tetrahedron
PMB ether 10 derived from commercially available 3-butyn-
Scheme 3. Synthesis of the picolinate 7.
ACCEPTED MANUSCRIPT
a RuCl(p-cymene)[(R,R)-TsDPEN]. b With [2-Cl-1-MeC5H4N]+ I–.
1-ol, PMB-OC(=NH)CCl3, and CSA (cat.) in 81% yield was
To find a suitable reagent for the methyl coupling of 12
without the protection of the hydroxy group, methylation of a
model iodoalcohol 15 was examined first. The methylation of the
corresponding bromide with Me4CoLi2 in the literature gave a
55:45 mixture of 16 and the Z-isomer.8 Therefore, the
conveniently preparable MeZnI with a Pd/dppf catalyst was
selected instead, considering similar Pd-catalyzed couplings with
MeZnBr9 and with Me2Zn.10 The reaction proceeded cleanly to
afford 16 in 98% yield with 2% drop in chemical purity over
protonated byproduct 17 (Scheme 4). Methylation of 12 under
the conditions established above gave allylic alcohol 14 with
96% purity over 13. Condensation with PyCO2H using the
Mukaiyama reagent followed by chromatographic purification
afforded allylic picolinate 8 as a sole product in 89% yield with
93% ee as determined by chiral HPLC analysis.
Scheme 2. Synthetic plan of LY426965 (6).
converted to ketone 11 in 75% yield according to the literature
procedure6 with a modification that less hygroscopic ZnI2 was
used instead of ZnCl2 (Scheme 3). Asymmetric hydrogen transfer
reaction7 of the ketone by using RuCl(p-cymene)[(R,R)-
TsDPEN] in i-PrOH gave alcohol 7 in 74% yield with 93% ee as
determined by chiral HPLC analysis. The absolute configuration
was tentatively determined as expected from the reagent and was
proven by comparing specific rotations of the compounds (21,
23, and 6) with those reported in the literature. Subsequently,
Red-Al reduction of
7 followed by iodination afforded
iodoalcohol 12 in 71% yield with 99% product selectivity over
protonated byproduct 13 as determined by 1H NMR
spectroscopy.
Scheme 4. Preliminary results of Pd-catalyzed coupling
reaction.
The allylic substitution of 8 with the Ph copper reagent (2
equiv),11,12 derived from PhMgBr and Cu(acac)2 in the 2:1 ratio,
proceeded smoothly and gave 9 in 82% yield with 99%
1
regioselectivity (rs) as determined by H NMR: δ 5.45 (dq, J =
15.6, 6.2 Hz, 1 H) for 9 and 5.35 (d, J = 8.8 Hz, 1 H) for
regioisomer 18 (Scheme 5). This isomer was synthesized as a 1:1
mixture with 9 using PhMgBr/Cu(acac)2 in a 3:1 ratio on the
basis of the previous result.1a The PMB protective group in 9 was
removed with DDQ to afford alcohol 19, which was 92% ee by
HPLC analysis, indicating 99% chirality transfer (CT) for the
allylic
substitution
of
picolinate
8
(93%
ee).
Scheme 5. Synthesis of LY426965 (6).
Ozonolysis of 19 followed by Me2S work-up afforded lactol
20 in 64% yield from 9. Addition of c-Hex-MgBr to the lactol in
refluxing THF produced a mixture of diastereomers 21 and 22,
which were separated by chromatography on silica gel for

3
4.3. 6-[(4-Methoxybenzyl)oxy]hex-3-yn-2-one (11)
determination of the structures. The major isomer obtained in
ACCEPTED MANUSCRIPT
1
52% yield was identified as 21 by H NMR spectroscopy and
[α]D analysis with the literature data5a,b and, thus, the minor
isomer isolated in 27% yield was assigned as 22. The isomers
were mixed again and subjected to Swern oxidation to give keto
aldehyde 23 in 72% yield. According to the literature
procedure,5a,b the piperazine derivative 24 was attached to 23 in
To a solution of acetylene 10 (3.41 g, 17.9 mmol) in THF (80
mL) was added n-BuLi (1.55 M in hexane, 11.6 mL, 17.9 mmol)
dropwise at –78 C. The cooling bath was replaced by an ice-
water bath. The solution was stirred at 0 °C for 30 min and
cooled again to –78 oC. A solution of ZnI2 (6.86 g, 21.5 mmol) in
THF (15 mL) was added dropwise. After the addition, the
o
1
83% yield by reductive amination. The H and 13C NMR spectra
o
of 6 thus synthesized were consistent with those reported.5c The
total yield was 6.1% in 11 steps from 10. In addition, consistent
specific rotations of 21, 23, and 6 with those reported in the
literatures indicate that the allylic substitution of 8 proceeded
with anti SN2' to construct the quaternary carbon indicated in 9.
solution was stirred at 0 °C for 20 min, cooled to –78 C, and
added AcCl (2.53 mL, 35.5 mmol) dropwise. The solution was
allowed to warm to rt over 3 h and diluted with saturated
NaHCO3. The resulting mixture was extracted with EtOAc three
times. The combined extracts were washed with aqueous
Na2S2O3, dried over MgSO4, and concentrated to give a residue,
which was purified by chromatography on silica gel
(hexane/EtOAc) to afford ketone 11 (3.14 g, 75%): liquid; Rf
0.48 (hexane/EtOAc 2:1); IR (neat) 2214, 1675, 1514, 1249 cm–1;
1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3 H), 2.65 (t, J = 6.8 Hz, 2
H), 3.60 (t, J = 6.8 Hz, 2 H), 3.81 (s, 3 H), 4.49 (s, 2 H), 6.89 (d,
J = 8.2 Hz, 2 H), 7.27 (d, J = 8.2 Hz, 2 H); 13C–APT NMR (100
MHz, CDCl3) δ 20.4 (–), 32.7 (+), 55.3 (+), 66.8 (–), 72.8 (–),
81.9 (–), 90.6 (–), 113.9 (+), 129.4 (+), 129.8 (–), 159.3 (–),
184.7 (–); HRMS (FAB+) calcd for C14H16O3 [M+]; 232.1099,
found 232.1096.
3. Conclusion
The target compound 6 was synthesized stereoselectively by a
strategy consisting of the construction of γ,γ-disubstituted
secondary allylic picolinates and subsequent allylic substitution
(Scheme 2). The Pd-catalyzed coupling reaction of iodoallylic
alcohol 6 with MeZnI proceeded without the protection of the
hydroxy group, and allylic substitution took place
stereoselectively with high CT of 99%. It should be noted that the
present method allows the synthesis of analogues with
substituent(s) other than Ph, c-Hex, and/or the peperazine groups
for finding a more powerful antagonist than 6.
4.4. (R)-6-[(4-Methoxybenzyl)oxy]hex-3-yn-2-ol (7)
A mixture of RuCl(p-cymene)[(R,R)-TsDPEN] (281 mg,
0.442 mmol) and crashed KOH (ca. 28 mg, 0.50 mmol) in
CH2Cl2 (3.5 mL) was stirred at rt for 40 min. The mixture was
brought to pH 7 (pH-paper) by washing with H2O (3 mL each, 6
times). The CH2Cl2 solution was transferred to another flask with
CH2Cl2. The solution was dried over CaH2, decanted, and
concentrated to afford a purple solid, to which i-PrOH (80 mL)
and ketone 11 (1.77 g, 7.64 mmol) were added. The mixture was
stirred at rt overnight and concentrated to afford a residue, which
was purified by chromatography on silica gel (hexane/EtOAc) to
afford alcohol 7 (1.33 g, 74%): liquid; Rf 0.32 (hexane/EtOAc
2:1); 93% ee determined by HPLC (Chiralcel OD-H; hexane/i-
PrOH = 98.2:1.8, 0.5 mL/min, 35 ºC; tR (min) = 81.3 (major),
4. Experimental
4.1. General
1
The H (300 or 400 MHz) and 13C NMR (75 or 100 MHz)
spectroscopic data were recorded in CDCl3 using Me4Si (δ = 0
ppm) and the centerline of the triplet (δ = 77.1 ppm),
respectively, 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. High-resolution mass
spectroscopy (HRMS) was performed with a double-focusing
mass spectrometer with an ionization mode of positive FAB or EI
as indicated for each compound. The solvents that were distilled
prior to use are THF (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).
24
95.1 (minor)); [α]D +13 (c 1.05, CHCl3); IR (neat) 3409, 1613,
1
1514, 1249 cm–1; H NMR (400 MHz, CDCl3) δ 1.40 (d, J = 6.4
Hz, 3 H), 2.49 (dt, J = 2.0, 7.2 Hz, 2 H), 2.57 (d, J = 4.0 Hz, 1
H), 3.53 (t, J = 7.0 Hz, 2 H), 3.79 (s, 3 H), 4.44–4.52 (m, 1 H),
4.47 (s, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.4 Hz, 2 H);
13C–APT NMR (100 MHz, CDCl3) δ 20.0 (–), 24.5 (+), 55.3 (+),
58.3 (+), 68.0 (–), 72.5 (–), 81.1 (–), 83.5 (–), 113.8 (+), 129.4
(+), 130.0 (–), 159.2 (–); HRMS (FAB+) calcd for C14H18O3 [M+];
234.1256, found 234.1261.
4.5. (R,Z)-4-Iodo-6-[(4-methoxybenzyl)oxy]hex-3-en-2-ol (12)
4.2. 1-[(But-3-yn-1-yloxy)methyl]-4-methoxybenzene (10)
To an ice-cold solution of alcohol 7 (93% ee, 1.33 g, 5.69
mmol) in THF (60 mL) was added Red-Al (60 wt% in toluene,
1.036 g/mL, 2.78 mL, 8.55 mmol). The solution was heated
under reflux for 2 h and cooled to rt. A solution of NIS (2.11 g,
9.38 mmol) in THF (8 mL) was added. The reaction was
continued at rt for 2.5 h and quenched by carefully adding 1 N
HCl. The resulting mixture was extracted with EtOAc three
times. The combined extracts were washed with aqueous
Na2S2O3, dried over MgSO4, and concentrated. The residue was
purified by chromatography on silica gel (hexane/EtOAc) to
To an ice-cold solution of PMBOC(NH)CCl3 (11.85 g, 41.9
mmol) in CH2Cl2 (100 mL) was added but-3-yn-1-ol (1.47 g,
20.97 mmol) and CSA (731 mg, 3.15 mmol). The solution was
stirred at rt overnight and diluted with hexane (200 mL). The
resulting mixture was filtered through a pad of Celite and the
filtrate was concentrated. The residue was diluted with hexane
(100 mL) and filtered again. The filtrate was concentrated to give
a residue, which was purified by chromatography on silica gel
(hexane/EtOAc) to afford alcohol 10 (3.23 g, 81%): liquid; Rf
1
0.62 (hexane/EtOAc 2:1); H NMR (400 MHz, CDCl3) δ 1.99 (t,
1
afford iodoalcohol 12 (1.47 g, 71%): 12/13 = 99:1 by H NMR
J = 2.4 Hz, 1 H), 2.49 (dt, J = 2.8, 7.2 Hz, 2 H), 3.57 (t, J = 7.2
Hz, 2 H), 3.81 (s, 3 H), 4.49 (s, 2 H), 6.88 (d, J = 8.8 Hz, 2 H),
7.27 (d, J = 8.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 19.9 (–
), 55.3 (+), 67.8 (–), 69.4 (–), 72.6 (–), 81.4 (–), 113.8 (+), 129.3
analysis (see the 1H NMR spectrum of 12); liquid; Rf 0.38
23
(hexane/EtOAc 2:1); [α]D +2 (c 1.14, CHCl3); IR (neat) 3404,
1612, 1513, 1249, 1100 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.26
(d, J = 6.4 Hz, 3 H), 2.48 (br s, 1 H), 2.73 (t, J = 6.4 Hz, 2 H),
3.55 (dt, J = 9.6, 6.4 Hz, 1 H), 3.61 (dt, J = 9.6, 6.4 Hz, 1 H),
1
(+), 130.1 (–), 159.3 (–). The H and 13C NMR spectra were
consistent with those in the literature.13

4
Tetrahedron
ACCEPTED MANUSCRIPT
3.79 (s, 3 H), 4.44 (s, 2 H), 4.39–4.48 (m, 1 H), 5.70 (d, J = 7.2
1713, 1513, 1247, 1036 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.46
Hz, 1 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.25 (d, J = 8.6 Hz, 2 H);
13C–APT NMR (100 MHz, CDCl3) δ 21.9 (+), 45.1 (–), 55.3 (+),
68.3 (–), 72.68 (–), 72.74 (+), 103.6 (–), 113.8 (+), 129.4 (+),
130.1 (–), 140.5 (+), 159.2 (–); HRMS (FAB+) calcd for
(d, J = 6.4 Hz, 3 H), 1.79 (d, J = 1.2 Hz, 3 H), 2.27–2.40 (m, 2
H), 3.54 (t, J = 6.8 Hz, 2 H), 3.79 (s, 3 H), 4.43 (s, 2 H), 5.42 (dq,
J = 9.0, 1.2 Hz, 1 H), 5.95 (dq, J = 9.0, 6.4 Hz, 1 H), 6.85 (dm, J
= 8.8 Hz, 2 H), 7.24 (dm, J = 8.8 Hz, 2 H), 7.46 (ddd, J = 7.6,
4.6, 1.2 Hz, 1 H), 7.82 (dt, J = 1.8, 7.6 Hz, 1 H), 8.11 (dm, J =
7.6 Hz, 1 H), 8.77 (dm, J = 4.6 Hz, 1 H); 13C–APT NMR (100
MHz, CDCl3) δ 17.0 (+), 20.9 (+), 39.4 (–), 55.3 (+), 68.3 (–),
69.8 (+), 72.5 (–), 113.7 (+), 125.1 (+), 125.8 (+), 126.6 (+),
129.2 (+), 130.5 (–), 136.9 (+), 137.4 (–), 148.6 (–), 149.9 (+),
159.1 (–), 164.6 (–); HRMS (FAB+) calcd for C21H26NO4
[(M+H)+] 356.1862, found 356.1863.
C14H19O3I [M+]; 362.0379, found 362.0372. The H spectrum of
1
13, obtained from this experiment and several attempts of the
iodinations, was identical with that reported14 and that prepared
by Red-Al reduction of rac-7 independently. Thus, Red-Al (3.6
M in toluene, 0.41 mL, 1.48 mmol) was added to a solution of
rac-7 (57 mg, 0.24 mmol) in toluene (5 mL). The solution was
heated to 100 °C for 20 min, cooled to 0 °C, and added saturated
NH4Cl. The resulting mixture was extracted with EtOAc three
times. The combined extracts were dried over MgSO4 and
4.8. (R,E)-1-Methoxy-4-[{(3-methyl-3-phenylhex-4-en-1-
yl)oxy}methyl]benzene (9)
concentrated to give
a residue, which was purified by
chromatography on silica gel (hexane/EtOAc) to afford rac-13
(32 mg, 55%): liquid; Rf 0.34 (toluene/EtOAc 4:1); H NMR
To an ice-cold suspension of Cu(acac)2 (881 mg, 3.37 mmol)
in THF (14 mL) was added a solution of PhMgBr (0.98 M in
THF, 7.0 mL, 6.86 mmol) dropwise. The mixture was stirred at 0
°C for 1 h, cooled to –40 °C, and added a solution of picolinate 8
(93% ee, 497 mg, 1.40 mmol) in THF (2 mL). The resulting
mixture was allowed to warm to –20 °C over 2 h, stirred at –20
ºC overnight, and diluted with saturated NH4Cl and ammonium
hydroxide solution. The resulting mixture was extracted with
hexane three times. The combined extracts were dried over
MgSO4 and concentrated. The residue was purified by
chromatography on silica gel (hexane/EtOAc) to afford 9 (355
1
(400 MHz, CDCl3) δ 1.24 (d, J = 6.4 Hz, 3 H), 1.70–1.89 (br s, 1
H), 2.32 (q, J = 6.4 Hz, 2 H), 3.47 (t, J = 6.4 Hz, 2 H), 3.80 (s, 3
H), 4.25 (quint., J = 6.4 Hz, 1 H), 4.44 (s, 2 H), 5.59 (dt, J = 15.4,
6.0 Hz, 1 H), 5.64 (dt, J = 15.4, 6.0 Hz, 1 H), 6.87 (d, J = 8.8 Hz,
2 H), 7.25 (d, J = 8.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ
23.3, 32.5, 55.2, 68.8, 69.3, 72.5, 113.8, 127.1, 129.3, 130.4,
136.1, 159.2.
4.6. (R,E)-6-[(4-Methoxybenzyl)oxy]-4-methylhex-3-en-2-ol (14)
1
1
mg, 82%): 9/18 = 99:1 by H NMR analysis (see the H NMR
spectrum of 9); liquid; Rf 0.63 (hexane/EtOAc 2:1); [α]D119 +1.9 (c
1.02, CHCl3); IR (neat) 1613, 1513, 1248, 1094 cm–1; H NMR
(400 MHz, CDCl3) δ 1.36 (s, 3 H), 1.71 (dd, J = 6.2, 1.4 Hz, 3
H), 2.07 (ddd, J = 13.6, 9.2, 5.8 Hz, 1 H), 2.15 (ddd, J = 13.6,
9.2, 5.8 Hz, 1 H), 3.35 (dt, J = 5.8, 9.2 Hz, 1 H), 3.39 (dt, J = 5.6,
9.2 Hz, 1 H), 5.45 (dq, J = 15.6, 6.2 Hz, 1 H), 5.62 (dq, J = 15.6,
1.4 Hz, 1 H), 6.85 (d, J = 8.8 Hz, 2 H), 7.14–7.24 (m, 3 H), 7.25–
7.33 (m, 4 H); 13C–APT NMR (100 MHz, CDCl3) δ 18.2 (+),
26.1 (+), 40.7 (–), 42.5 (–), 55.3 (+), 67.5 (–), 72.6 (–), 113.8 (+),
122.2 (+), 125.8 (+), 126.5 (+), 128.1 (+), 129.2 (+), 130.7 (–),
139.6 (+), 147.9 (–), 159.1 (–); HRMS (EI+) calcd for C21H26O2
[M+] 310.1933, found 310.1935.
To an ice-cold solution of ZnI2 (4.59 g, 14.4 mmol) in THF
(35 mL) was added MeLi (1.16 M in Et2O, 12.2 mL, 14.2 mmol).
The mixture was stirred at rt for 1 h and added a solution of
iodoalcohol 12 (12/13 = 99:1, 1.46 g, 4.03 mmol) in THF (5 mL).
The mixture was stirred at rt for 15 min and added a solution of
Pd2(dba)3·CHCl3 (208 mg, 0.201 mmol) and dppf (109 mg, 0.200
mmol) in THF (15 mL). The mixture was stirred at rt for 3 h and
diluted with saturated NH4Cl. The resulting mixture was
extracted with EtOAc three times. The combined extracts were
washed with brine, dried over MgSO4, and concentrated to give a
residue, which was purified by chromatography on silica gel
(hexane/EtOAc) to afford allylic alcohol 14 (710 mg, 70%):
1
14/13 = 96:4 by 1H NMR analysis (see the H NMR spectrum of
24
14); liquid; Rf 0.22 (hexane/EtOAc 2:1); [α]D +12 (c 1.00,
Synthesis of a mixture of 9 and 18: To an ice-cold suspension
of Cu(acac)2 (22 mg, 0.084 mmol) in THF (1 mL) was added a
solution of PhMgBr (0.94 M in THF, 0.28 mL, 0.263 mmol)
dropwise. The mixture was stirred at 0 °C for 1 h, cooled to –40
°C, and added a solution of picolinate 8 (93% ee, 20 mg, 0.056
mmol) in THF (0.5 mL). The resulting mixture was stirred
overnight, and diluted with saturated NH4Cl. The product was
extracted with hexane and purified as described above to afford a
1
CHCl3); IR (neat) 3406, 1613, 1514,1249 cm–1; H NMR (400
MHz, CDCl3) δ 1.23 (d, J = 6.2 Hz, 3 H), 1.50 (br s, 1 H), 1.69
(d, J = 1.2 Hz, 3 H), 2.30 (t, J = 6.8 Hz, 2 H), 3.53 (t, J = 6.8 Hz,
2 H), 3.80 (s, 3 H), 4.44 (s, 2 H), 4.57 (dq, J = 8.4, 6.2 Hz, 1 H),
5.26 (dq, J = 8.4, 1.2 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 2 H), 7.25 (d,
J = 8.4 Hz, 2 H); 13C–APT NMR (100 MHz, CDCl3) δ 16.7 (+),
23.5 (+), 39.3 (–), 55.3 (+), 64.6 (+), 68.4 (–), 72.5 (–) 113.8 (+),
129.3 (+), 130.5 (–), 130.6 (+), 134.6 (–), 159.1 (–); HRMS
(FAB+) calcd for C15H22O3 [M+]; 250.1569, found 250.1569.
1
mixture of 9 and 18 in a 1:1 ratio as determined by H NMR
spectroscopy: liquid; Rf 0.63 (hexane/EtOAc 2:1); selected
1
4.7. (R,E)-6-[(4-Methoxybenzyl)oxy]-4-methylhex-3-en-2-yl
signals of H NMR (300 MHz, CDCl3) δ 1.33 (d, J = 6.9 Hz, 3
picolinate (8)
H), 1.70 (d, J = 1.6 Hz, 3 H), 5.38 (d, J = 9.0 Hz, 1 H).
4.9. (R,E)-3-Methyl-3-phenylhex-4-en-1-ol (19)
To an ice-cold solution of alcohol 14 (710 mg, 2.84 mmol) in
CH2Cl2 (50 mL) were added picolinic acid (1.04 g, 8.45 mmol),
Et3N (2.37 mL, 17.0 mmol), DMAP (351 mg, 2.87 mmol), and 2-
chloro-1-methylpyridinium iodide (2.19 g, 8.57 mmol). The
mixture was heated under reflux for 2 h, cooled to 0 °C, and
diluted with saturated NH4Cl. The resulting mixture was
extracted with CH2Cl2 twice. The combined extracts were dried
over MgSO4 and concentrated to give a residue, which was
purified by chromatography on silica gel (hexane/EtOAc) to
afford 8 (898 mg, 89%): liquid; Rf 0.59 (three-development with
To a solution of the PMB ether 9 (273 mg, 0.879 mmol) in
CH2Cl2 (8 mL) and H2O (0.8 mL) was added DDQ (212 mg,
0.934 mmol). The mixture was stirred at rt overnight and filtered
through a pad of Celite with CH2Cl2 to afford a mixture of
alcohol 19 and 4-(MeO)C6H4CHO. The mixture was separated by
chromatography on silica gel for the next reaction.
20
Characterization of 19: liquid; Rf 0.30 (hexane/EtOAc 2:1); [α]D
–11 (c 1.05, CHCl3); 92% ee (99% CT) by HPLC analysis
(Chiralcel OD-H; hexane/i-PrOH = 98:2, 1.0 mL/min, 35 ºC; tR
(min) = 15.5 (the product), 19.4 (the enantiomer)); IR (neat)
3334, 1599, 1445, 1030 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.30
(br s, 1 H), 1.38 (s, 3 H), 1.73 (dd, J = 6.4, 1.6 Hz, 3 H), 2.02
20
hexane/EtOAc 2:1; cf. 14, Rf 0.65); [α]D –19 (c 1.01, CHCl3);
93% ee by HPLC analysis (Chiralcel OD-H; hexane/i-PrOH =
94:6, 30 ºC; tR (min) = 15.9 (major), 18.2 (minor)); IR (neat)

5
(ddd, J = 13.2, 8.4, 6.4 Hz, 1 H), 2.09 (ddd, J = 13.2, 8.4, 6.0 Hz,
1 H), 3.49–3.67 (m, 1 H), 5.45 (dq, J = 15.6, 6.4 Hz, 1 H), 5.66
(dq, J = 15.6, 1.6 Hz, 1 H), 7.15–7.21 (m, 1 H), 7.27–7.34 (m, 4
H); 13C–APT NMR (100 MHz, CDCl3) δ 18.2 (+), 26.0 (+), 42.4
(–), 44.0 (–), 60.1 (–), 122.5 (+), 126.0 (+), 126.4 (+), 128.2 (+),
139.6 (+), 147.8 (–); HRMS (EI+) calcd for C13H18O [M+]
190.1358, found 190.1358.
To a solution of oxalyl chloride (0.136 mL, 1.59 mmol) in
ACCEPTED MANUSCRIPT
CH2Cl2 (4 mL) was added DMSO (0.225 mL, 3.17 mmol) at –70
°C. The solution was stirred at –70 °C for 40 min and the
diastereomeric mixture of alcohols 21 and 22 (104 mg, 0.396
mmol) in CH2Cl2 (3 mL) was added to the solution, which was
then stirred at the same temperature for 1.5 h before addition of
Et3N (0.88 mL, 6.31 mmol). The mixture was warmed to –30 °C
over 2 h and diluted with saturated NH4Cl. The resulting mixture
was extracted with EtOAc three times. The combined extracts
were dried over MgSO4 and concentrated to give a residue, which
was purified by chromatography on silica gel (hexane/EtOAc) to
afford 23 (73 mg, 72%): liquid; Rf 0.60 (hexane/EtOAc 2:1);
[α]D19 +139 (c 1.16, CHCl3); lit.5c [α]D20 +120.7 (c 1.0, CHCl3) for
23 of 92% ee; lit.5a,b [α]D24 +158.58 (c 1.0, CHCl3) for 23 of 94%
ee; 1H NMR (400 MHz, CDCl3) δ 0.86–1.00 (m, 1 H), 1.05–1.22
(m, 3 H), 1.30–1.44 (m, 2 H), 1.50–1.61 (m, 2 H), 1.62–1.73 (m,
2 H), 1.75 (s, 3 H), 2.40 (tt, J = 11.6, 3.2 Hz, 1 H), 2.77 (dd, J =
16.0, 2.2 Hz, 1 H), 2.96 (dd, J = 16.0, 2.2 Hz, 1 H), 7.25–7.33
(m, 3 H), 7.34–7.41 (m, 2 H), 9.59 (t, J = 2.2 Hz, 1 H); 13C–APT
NMR (100 MHz, CDCl3) δ 20.3 (+), 25.47 (–), 25.57 (–), 25.61
(–), 30.6 (–), 30.8 (–), 46.1 (+), 52.1 (–), 54.5 (–), 126.6 (+),
4.10. (1S,2S)- and (1R,2S)-1-Cyclohexyl-2-methyl-2-
phenylbutane-1,4-diols (21 and 22)
Ozonolysis of 19. To a solution of the above alcohol 19 in
CH2Cl2 (8 mL) was gently bubbled a stream of O3/O2 at –78 °C
for 15 min. Argon gas was bubbled to remove excess O3 in the
solution (ca. 10 min) and then Me2S (2 mL, 27 mmol) was added.
The solution was left overnight and concentrated. The residue
was purified by chromatography on silica gel to afford
hemiacetal 20 (101 mg, 64% from the PMB ether 9) as a 6:4
mixture of the diastereomers: liquid; Rf 0.22 (hexane/EtOAc 2:1);
1
IR (CHCl3) 3363, 1445, 1007 cm–1; H NMR (400 MHz, CDCl3)
δ 1.32 and 1.42 (2s, 1.8 H and 1.2 H), 2.04 (ddd, J = 11.4, 7.2,
2.0 Hz, 0.6 H), 2.22 (ddd, J = 12.8, 7.8, 6.4 Hz, 0.4 H), 2.36
(ddd, J = 12.8, 7.8, 6.2 Hz, 0.4 H), 2.64 (dt, J = 11.4, 9.8 Hz, 0.6
H), 2.69–2.86 (m, 1 H), 3.29–3.54 (m, 1 H), 3.88 (dt, J = 6.4, 7.8
Hz, 0.4 H), 4.07–4.20 (m, 1 H), 4.27 (ddd, J = 9.8, 8.4, 2.0 Hz,
0.6 H), 7.19–7.42 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ 22.5,
27.3, 33.1, 37.0, 49.7, 52.0, 65.7, 66.7, 103.2, 103.4, 126.0,
126.38, 126.42, 127.1, 128.5, 144.8, 145.8.
1
127.7 (+), 129.0 (+), 139.9 (–), 201.7 (+), 213.9 (–). The H and
13C NMR spectra were consistent with those in the literature.5c
4.12. LY426965 (6)
To a solution of aldehyde 23 (56 mg, 0.217 mmol) and amine
24 (42 mg, 0.218 mmol) in (CH2Cl)2 (3 mL) was added
NaBH(OAc)3 (93 mg, 0.439 mmol). The solution was stirred at rt
for 5 h and diluted with saturated NH4Cl. The mixture was
extracted with EtOAc three times, and the combined extracts
were dried over MgSO4 and concentrated. The residue was
purified by chromatography on silica gel (hexane/EtOAc) to give
the LY426965 (6) (79 mg, 83%): liquid; Rf 0.12 (hexane/EtOAc
Reaction with c-Hex-MgBr. To a solution of hemiacetal 20
(99 mg, 0.555 mmol) in THF (2 mL) was added a solution of c-
Hex-MgBr (0.72 M, 6.24 mL, 4.50 mmol). The mixture was
heated under reflux overnight and cooled to 0 °C. The reaction
was quenched by adding 1 N HCl and the resulting mixture was
extracted with EtOAc three times. The combined extracts were
dried over MgSO4 and concentrated to afford a diastereomeric
mixture of alcohols 21 and 22 (116 mg, 79%), which were
separated by chromatography on silica gel (hexane/EtOAc) to
afford 21 (76 mg, 52%) and 22 (40 mg, 27%). Major isomer 21:
2:1); [α]D +32 (c 1.11, CHCl3); lit.5c [α]D +34.3 (c 0.95,
19
20
CHCl3) for 6 of 92% ee; lit.5a,b [α]D +34.28 (c 0.95, CHCl3) for
24
6 of 93% ee; 1H NMR (400 MHz, CDCl3) δ 0.86–1.68 (m, 10 H),
1.57 (s, 3 H), 2.10–2.43 (m, 5 H), 2.65 (br s, 4 H), 3.09 (br s, 4
H), 3.84 (s, 3 H), 6.85 (d, J = 7.6 Hz, 1 H), 6.87–6.96 (m, 2 H),
6.96–7.02 (m, 1 H), 7.22–7.29 (m, 3 H), 7.31–7.38 (m, 2 H); 13C–
APT NMR (100 MHz, CDCl3) δ 20.3 (+), 25.59 (–), 25.65 (–),
25.70 (–), 30.6 (–), 31.0 (–), 33.9 (–), 46.1 (+), 50.4 (–), 53.5 (+),
54.2 (+), 55.0 (+), 55.4 (–), 111.2 (+), 118.3 (+), 121.0 (+), 123.0
(+), 126.9 (+), 127.1 (+), 128.6 (+), 141.15 (–), 141.21 (–), 152.3
(–), 215.3 (–). The 1H and 13C NMR spectra were consistent with
those in the literature.5c
20
solids; mp 46–47; Rf 0.12 (hexane/EtOAc 2:1); [α]D –22 (c
1.15, MeOH); lit.5a,b [α]D24 –21.8 (c 1.05, MeOH) for 94% ee; 1H
NMR (400 MHz, CDCl3) δ 0.96–1.34 (m, 7 H), 1.39 (s, 3 H),
1.47–1.57 (m, 2 H), 1.62–1.70 (m, 2 H), 1.7–2.3 (br s, 2 H), 1.98
(dt, J = 13.6, 6.6 Hz, 1 H), 2.04–2.14 (m, 1 H), 3.49 (dt, J = 11.0,
6.6 Hz, 1 H), 3.60 (dt, J = 11.0, 6.6 Hz, 1 H), 3.70 (d, J = 3.6 Hz,
1 H), 7.18–7.23 (m, 1 H), 7.29–7.36 (m, 4 H); 13C–APT NMR
(100 MHz, CDCl3) δ 18.8 (+), 26.3 (–), 26.8 (–), 28.5 (–), 33.5 (–
), 39.9 (+), 43.8 (–), 45.8 (–), 59.7 (–), 82.2 (+), 126.1 (+), 126.6
(+), 128.4 (+), 145.8 (–). Minor isomer 22: solids; mp 50–51; Rf
Acknowledgments
21
1
0.20 (hexane/EtOAc 2:1); [α]D +14 (c 0.98, MeOH); H NMR
(400 MHz, CDCl3) δ 0.86–1.88 (m, 13 H), 1.38 (s, 3 H), 2.08 (dt,
J = 14.0, 7.6 Hz, 1 H), 2.17 (ddd, J = 14.0, 7.6, 5.6 Hz, 1 H), 3.42
(d, J = 2.0 Hz, 1 H), 3.48 (ddd, J = 10.4, 7.6, 5.6 Hz, 1 H), 3.66
(dt, J = 10.4, 7.6 Hz, 1 H), 7.22 (t, J = 7.2 Hz, 1 H), 7.32 (t, J =
7.2 Hz, 2 H), 7.43 (d, J = 7.2 Hz, 2 H); 13C–APT NMR (100
MHz, CDCl3) δ 20.8 (+), 26.36 (–), 26.41 (–), 27.0 (–), 27.4 (–),
34.2 (–), 39.1 (+), 41.4 (–), 45.5 (–), 59.7 (–), 83.6 (+), 126.4 (+),
127.1 (+), 128.3 (+), 145.0 (–); HRMS (FAB+) calcd for
C17H27O2 [(M+H)+] 263.2011, found 263.2009.
This work was supported by KAKENHI Grant Number
26410111 and the Kobayashi International Scholarship.
Appendix A. Supplementary data
Supplementary data (HPLC chromatograms and NMR
spectra) related to this article can be found at https://xxxxx.
References and notes
The 1H NMR spectrum of the major isomer 21 was consistent
with that in the literature,5a,b while the 13C NMR spectrum was
corrected. In addition, 13C–APT NMR spectrum supported the
structure.
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4.11. (S)-4-Cyclohexyl-3-methyl-4-oxo-3-phenylbutanal (23)

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