Stereoselective anti -S N 2′-Substitutions of Secondary Alkylcopper-Zinc Reagents with Allylic Epoxides: Total Synthesis of (3 S,6 R,7 S)-Zingiberenol

Article abstract of DOI:10.1055/s-0039-1690766

Chiral secondary mixed alkylcopper-zinc reagents were prepared from the corresponding alkyl iodides and reacted with allylic epoxides via an anti -S _N 2′-substitution and retention of configuration of the chiral alkylorganometallic, leading to

Full text of DOI:10.1055/s-0039-1690766

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
paper
A
en
J. Skotnitzki et al.
Paper
Synthesis
Stereoselective anti-SN2′-Substitutions of Secondary Alkylcopper-
Zinc Reagents with Allylic Epoxides: Total Synthesis of (3S,6R,7S)-
Zingiberenol
Juri Skotnitzki
Alexander Kremsmair
Bilal Kicin
anti
R2
H
R4
H
O
1. tBuLi (inv. add.)
–100 °C, 10 s
R3
R4
H
Me
R2
Me
Me
ZnCl2
+
R1
OH
R1 Cu
R1
I
SN2'-substitution
–10 °C, 12 h
Rakan Saeb
Vincent Ruf
0
0
0
0-0
0
0
3-0
9
0
7-9
1
4
1
2. CuBr·P(OEt)3
–100 °C, 1 min stable in THF
R3
Paul Knochel*
0
0
0
0-0
0
0
1-7
9
1
3-
4
3
3
2
Me
Me
(3S,6R,7S)-zingiberenol
H
7
Ludwig-Maximilians-Universität, Department Chemie
und Biochemie, Butenandtstr. 5–13, 81377 München,
Germany
(S)
Me
(R)
6
9.7% yield over 8 steps;
dr(C3,C6) = 99:1; dr(C6,C7) = 81:19
OH
3
(S) Me
paul.knochel@cup.uni-muenchen.de
Received: 31.10.2019
Accepted after revision: 26.11.2019
Published online: 06.12.2019
alkenes of type 5 with absolute control of two adjacent ste-
reocenters (see Scheme 1). Furthermore, this methodology
was used in the enantioselective total synthesis of several
natural products, for example, the ant pheromones (+)-lasi-
ol and (+)-faranal.5
DOI: 10.1055/s-0039-1690766; Art ID: ss-2019-t0608-op
Abstract Chiral secondary mixed alkylcopper-zinc reagents were pre-
pared from the corresponding alkyl iodides and reacted with allylic ep-
oxides via an anti-SN2′-substitution and retention of configuration of
the chiral alkylorganometallic, leading to chiral allylic alcohols. This
method was used in a total synthesis of the natural product (3S,6R,7S)-
zingiberenol in 8 steps and 9.7% overall yield [dr (3S,6R) = 99:1; dr
(6R,7S) = 81:19] starting from commercially available 3-methyl-2-cyclo-
hexenone.
anti
R2
H
R4
R3
H
Me
4
OP(O)(OEt)2
R4
R1
previous work
R3
5
R2
Me
Me
Me
ZnCl2
SN2'
R1
I
R1 Li
R1 Cu
Key words lithium, stereoselective, copper, allylic epoxides, natural
products
2
3
1
R4
Me
H
OH
this work
R1
anti
R3
7
R2
R3
R2
H
R4
H
O
Metal-catalyzed SN2- and SN2′-substitutions of allylic
substrates are common methods for the preparation of chi-
ral molecules.1,2 Thereby the chirality depends on the use of
chiral ligands1 or the use of chiral allylic substrates, which
react according to an anti-SN2′-substitution.2 In addition,
the control of regioselectivity of allylic substitutions is of
high importance for organic synthesis and was intensively
investigated.3
Recently, we have reported that chiral secondary alkyl-
copper reagents undergo highly selective SN2- and SN2′-
substitution reactions with allylic halides and phosphates
depending on the nature of the organometallic reagent.4
Thus, secondary alkylcopper reagents of type 1 were pre-
pared via a retentive I/Li-exchange reaction of secondary al-
kyl iodides 2 with tBuLi followed by a transmetalation with
CuBr·P(OEt)3 (see Scheme 1).5 Compared to the correspond-
ing alkyllithium reagents 3, these organocopper reagents
have a significantly higher configurational stability (up to
–50 °C for several hours) in THF making them suitable for
SN2-substitutions with allylic bromides.4 The addition of
ZnCl2 and the use of chiral allylic phosphates 4 switches the
regioselectivity towards SN2′-substitutions, leading to
6
Scheme 1 Stereoselective preparation of chiral alkylcopper reagents 1
and subsequent anti-SN2′-substitutions with allylic electrophiles 4 and 6
Herein, we report the stereoselective reaction of sec-
ondary alkylcopper-zinc reagents with allylic epoxides 6
leading to chiral allylic alcohols of type 7 (Scheme 1), which
represent a common motif in organic synthesis and natural
products. An example for a chiral cyclic allylic alcohol is the
natural product zingiberenol (8) (see Figure 1).6 Only two of
8 possible stereoisomers exist in nature, (3S,6R,7S)- and
(3S,6S,7S)-zingiberenol. Retrosynthetic analysis showed
that (3S,6R,7S)-zingiberenol (8) can be prepared via an anti-
SN2′-substitution reaction of the chiral allylic epoxide 9 and
the copper reagent 10 (prepared from the corresponding al-
kyl iodide 11, see Figure 1). Starting from zingiberenol, sev-
eral other natural products can be prepared using literature
known transformations. Reaction of zingiberenol with AD-
mix- and subsequent epoxidation leads to the pheromone
of the brown marmorated stink bug, murgantiol (12).7
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Skotnitzki et al.
Paper
Synthesis
Further dehydration using sulfuric acid leads to the -ses-
quiphellandrene (13) and the monocyclic sesquiterpene
zingiberene (14).6a
In preliminary experiments, the regioselectivity of SN2′-
substitution reactions of various allylic epoxides with chiral
alkylcopper reagents was examined. Therefore, the diaste-
reomerically enriched alkyl iodide syn-2a (dr = 98:2) was
treated with tBuLi (2.2 equiv) at –100 °C in pentane/diethyl
ether affording the corresponding alkyllithium reagent syn-
3a. Subsequent treatment with CuBr·P(OEt)3 (1.5 equiv) led
to the organocopper reagent syn-1a (see Table 1). This al-
kylcopper reagent is configurationally stable in THF and
thus, a solvent switch was performed at –50 °C.5 The addi-
tion of ZnCl2 (1.5 equiv, –30 °C, 10 min) and subsequent
treatment with the allylic epoxide 6a (3.0 equiv, –30 °C to
–10 °C, 12 h) furnished the allylic alcohol syn-7a in 46%
yield with retention of configuration (dr = 94:6; E/Z =
86:14; Table 1, entry 1). Interestingly, the ratio of SN2′-sub-
stitution (-position) to SN2-substitution (-position) was
higher than 95:5. In the same way, the corresponding anti-
allylic alcohol (anti-7a) was prepared with retention of
configuration and high SN2′-selectivity (54% yield; dr =
9:91; : = 95:5; E/Z = 88:12; entry 2).
Me
Me
H
7(S)
I
(S)
6
(R)
(S)
3
(S)
HO
Me
Me
(R)
O
Me
Me
Me
Me
(3S,6R,7S)-zingiberenol (8)
9
11
Me
H
(R)
Me
7
Me
H
H
7
6
6
(S)
Me
HO
O
Me
Me
Me
Me
Me
Me
(3R,6S,7R,10S)-
murgantiol (12)
(6R,7S)-zingiberene (14)
(6R,7S)-β-sesquiphellandrene (13)
Figure 1 Retrosynthetic analysis of (3S,6R,7S)-zingiberenol (8). Struc-
tures of murgantiol (12), -sesquiphellandrene (13), and zingiberene (14)
Table 1 Optimization Reactions for the Opening of Allylic Substrates 6
1) tBuLi (inv. add.)
Et2O/pentane
–100 °C, 10 s
4)
ZnCl2
R3
Me
Me
Me
–30 °C, 10 min
R1
I
α
γ
R1
OH
R1 Cu
1
2) CuBr · P(OEt)3
–100 °C, 1 min
5)
X
R2
2
R2
3) solvent switch to
7a–c
R3
dr = 98:2
stable in THF
at –50 °C
THF at –50 °C
α:γ = up to 95:5
6a–d (X = O, NTs)
–30 °C to −10 °C, 12 h
Retention
Entry
1
Alkylcopper
Electrophile
Product of type 7
Me Me
Ph
Me Me
γ
α
O
OH
Ph
Cu
syn-7a, 46%, dr = 94:6,
α:γ = 95:5, E/Z = 86:14
6a
syn-1a
Me Me
Me Me
γ
α
α
O
O
Ph
OH
2
3
Ph
Ph
Cu
anti-7a, 54%, dr = 9:91,
α:γ = 95:5, E/Z = 88:12
6a
anti-1a
γ
Me
Ph
OH
Me
Cu
Ph
Ph
7b, 43%, α:γ = 80:20,
E/Z = 99:1
1b
1b
6b
Me
H
γ
α
α
Me
Cu
Ph
O
4
5
Ph
Ph
OH
H
6c
7c, 51%, α:γ = 95:5
Me
γ
Me
Cu
Ph
N
Ts
NTs
7d, trace, α:γ = n.a.
1b
6d
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

C
J. Skotnitzki et al.
Paper
Synthesis
Switching to the cyclic allylic epoxide 6c increased the
regioselectivity significantly (7c, 51% yield, : = 95:5; see
Table 1, entry 4). We assume that the SN2′-substitution of 6c
proceeds in an anti-SN2′-fashion leading to 7c as shown in
Table 1 (hydroxyl group and hydrogen atom have a syn-
orientation). Furthermore, the cyclic allylic aziridine 6d
was prepared according to literature from cyclohexadiene.8
However, all attempts to open this allylic aziridine were un-
successful. These preliminary experiments showed, that the
anti-SN2′-substitution of allylic epoxides is regioselective
(: = 95:5) and proceeds with retention of configuration of
the secondary alkylcopper reagent.
anti
H
anti
Me
H
Me
Cu
rotation
H
R2
H
H
H
H
R2
H
+
R1
+
Cu
R1
1
6B
O
1
6A
O
Zn-mediated
anti-SN2'
substitution
Zn-mediated
anti-SN2'
substitution
Me
Me
R2
R1
R1
OH
H
R2
OH
Z-product
E-product
(favored if R2 = bulky group)
Scheme 2 SN2′-substitution reaction via two different conformers 6A
or 6B leading to the E- or the Z-product
Having these results in hand, the enantioselective syn-
thesis of the chiral epoxide 19 was performed (see Scheme
3). Thus, the commercially available 3-methylcyclohex-2-
en-1-one (15) was converted to the iodo derivative 16 (81%
yield) using a pyridinium dichromate (PDC)-mediated
To further investigate the stereo- and regioselectivity,
the anti-SN2′-substitution was performed with higher sub-
stituted allylic substrates 6b–d. Thus, 2-phenyl-3-vinylox-
irane (6b) was prepared and reaction with the chiral sec-
ondary alkylcopper reagent 1b led to the racemic allylic al-
cohol 7b in moderate yield (43%) and SN2′-selectivity (: =
80:20), but with excellent E/Z ratio (99:1; Table 1, entry 3).
The observed E/Z-ratios by using 6a or 6b as electrophiles
are rationalized in Scheme 2. The anti-substitution via con-
former 6A affords the E-product, whereas the substitution
of conformer 6B results in the Z-product. Depending on the
1,3-allylic strain, one conformer is more favored. If the resi-
due R2 of the allylic epoxide is bulky, such as the phenyl
group of electrophile 6b, the substitution proceeds via con-
former 6A due to steric reasons. Thus, the reaction of alkyl-
copper anti-1a with 6a led to a mixture of E- and Z-prod-
ucts (E/Z = 88:12, see Table 1), whereas the reaction of 1b
with 6b led exclusively to the E-product (E/Z = 99:1).
1) (R)-diphenylprolinol
B(OMe)3
OH
O
O
I
I
I2, PDC
THF, 1 h, rt
DCM
16 h, rt
2) borane N,N-diethylaniline
Me
Me
Me
THF, 1 h, rt
15
16
17
81% yield
88% yield, 98% ee
OH
OH
tBuLi
Et2O
30 min, –78 °C
mCPBA
17
O
DCM,
0 °C, 15 min
Me
Me
18
19
95% yield,
98% ee
80% yield,
98% ee
Scheme 3 Enantioselective synthesis of the precursor 19
Table 2 Enantioselective Elimination of the Alcohol Leading to the Chiral Allylic Epoxide 9
Route C
I
R
OH
route A
route B
route D
(S)
O
O
O
O
Me
Me
Me
Me
20
(S)-21
9,
98% ee
19,
98% ee
Route
Entry
Reagents and conditions
Product; yield (%)
A
1
2
3
1
2
3
1
2
1
2
3
MsCl (4.5 equiv), NEt3 (6.0 equiv), DCM, –10 °C
TsCl (4.5 equiv), NEt3 (2.2 equiv), DCM, –10 °C
20a, R = OMs; 80
20b, R = OTs; 49
20a to 20c, R = SePh; 42
20a to 21; 62
20b to 21; 48
20c direct to 9; trace
21; trace
(PhSe)2 (4.0 equiv), NaHBH4 (4.0 equiv), AcOH (1.8 equiv), DMF, rt, 24 h
NaI (10 equiv), NaHCO3 (20 equiv), THF, 65 °C
NaI (10 equiv), NaHCO3 (20 equiv), THF, 65 °C
H2O2 (2.0 equiv), DCM, 0 °C to rt
B
C
I2 (1.6 equiv), PPh3 (1.6 equiv), NMI (1.6 equiv), DCM, –10 °C, 1 h
CI4 (1.1 equiv), PPh3 (1.1 equiv), NMI (1.1 equiv), DCM, 0 °C, 1 h
DBU (5.0 equiv), THF, 60 °C, 12 h
21; trace
D
9; 60
NaOEt (1.5 equiv), EtOH, 60 °C, 12 h
9; trace
TBD (5.0 equiv), THF, 60 °C, 12 h
9; trace
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

D
J. Skotnitzki et al.
Paper
Synthesis
iodination.9 The bulky iodo substituent allowed an enantio-
selective CBS-reduction of 16, furnishing the chiral alcohol
17 in 88% yield and 98% ee.9 Removal of the iodine via I/Li-
exchange and subsequent protonolysis afforded the chiral
allylic alcohol 18 in almost quantitative yield (95% yield)
and 98% ee. Stereoselective directed epoxidation of 18 using
mCPBA afforded the chiral epoxyalcohol 19 in 80% yield
(98% ee).10
The elimination of the hydroxyl containing epoxide 19
to the desired allylic epoxide 9 proved to be rather challeng-
ing (see Table 2). Direct elimination using the Burgess reac-
tion11 or elimination via the corresponding phenylsele-
nide12 was unsuccessful. Thus, we envisioned a synthetic
route, in which the hydroxyl group is converted into a good
leaving group R (route A) followed by SN2-substitution to
the iodide 21 (routes B and C) and subsequent elimination
leading to the allylic epoxide 9 (route D). After intensive
screening of various leaving groups, the preparation of the
mesylate 20a (80% yield, R = OMs) followed by a Finkelstein
reaction led to the desired iodide 21 (62% yield) with inver-
sion of configuration (S/R = 80:20).13 Subsequent elimina-
tion reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) as base furnished the desired epoxide 9 in 60% yield
and with excellent enantiomeric excess (98% ee).14
the C7-stereocenter.15 All attempts to improve the stereose-
lectivity during the reaction by variation of conditions or
additives, like BF3·OEt2 were unsuccessful.16 However, the
substitution of allylic epoxide 9 proceeded in a highly anti-
SN2′-fashion leading to the syn-orientation of the hydroxyl
group and the proton (3S,6R) of zingiberenol (dr = 99:1; see
Scheme 5). This emphasizes the previous assumption that
opening of allylic epoxides proceeds via an anti-SN2′-substi-
tution reaction.
In summary, we have shown that secondary alkylcopper-
zinc reagents react regioselectively with allylic epoxides
leading to chiral allylic alcohols (: >95:5). This method
was used in the total synthesis of the naturally occurring
(3S,6R,7S)-zingiberenol (8 steps; 9.7% overall yield) starting
from commercially available chemicals. Further mechanis-
tical and computational studies are currently under investi-
gation in our laboratories.
All reactions were carried out under argon atmosphere in flame-
dried glassware. Syringes which were used to transfer anhydrous sol-
vents or reagents were purged with argon prior to use. Yields refer to
isolated yields of compounds estimated to be >95% pure as deter-
mined by 1H NMR (25 °C) and capillary GC analysis. Column chro-
matographic purification was performed by using silica gel (0.040–
0.063 mm, 230–400 mesh ASTM) from Merck. NMR spectra were re-
corded on Varian Mercury 200, Bruker AXR 300, Varian VXR 400 S,
and Bruker AMX 600 instruments. Chemical shifts are reported as 
Next, the optically enriched iodide 11 was prepared
(Scheme 4). Insertion of magnesium into commercially
available 1-chloro-3-methyl-2-butene led to 22. Subse-
quent copper-catalyzed epoxide opening of (R)-23 led to
chiral alcohol 24 in 85% yield. After inversion of the config-
uration via an Appel reaction, the enantiomerically pure io-
dide 11 was obtained in 73% yield.5b
values in ppm relative to the deuterated solvent peak: CDCl3 (H
=
7.26; C = 77.16). High-resolution mass spectra by electron impact
ionization (EI) and low-resolution mass spectra were recorded on a
Finnigan MAT 95Q instrument. EI was conducted with an electron en-
ergy of 70 eV. For the combination of gas chromatography with mass
Finally, the secondary alkyl iodide 11 was converted to
the corresponding alkylcopper reagent (S)-10 under the
above mentioned conditions (see Scheme 5). Subsequent
zinc-mediated anti-SN2′-substitution with allylic epoxide 9
led to (3S,6R,7S)-zingiberenol (8) in 61% yield [dr (C3,C6) =
99:1; and dr (C6,C7) = 81:19] with moderate selectivity at
spectroscopic detection,
a GC/MS from Hewlett-Packard HP
6890/MSD 5973 was used. IR spectra were recorded from 4500 cm–1
to 650 cm–1 on a PerkinElmer Spectrum BX-59343 instrument. For
detection, a Smiths Detection Dura SamplIR II Diamond ATR sensor
was used. The absorption bands were reported in wavenumbers (cm–1).
GC-spectra were recorded on Hewlett-Packard 6890 or 5890 Series II
O
(R)
Me
(R)-23
Me
Me
Me
OH
Me
Me
PPh3, I2, NMI
Me
MgCl
Me
Me
I
(S)
DCM, –10 °C, 1 h
CuI (10% mol)
(R)
–50 °C to rt, 12 h
22
24, 85% yield
11, 73% yield,
98% ee
Scheme 4 Enantioselective synthesis of the iodide 11
dr = 81:19
Me
7
H
dr = 99:1
(iv)
ZnCl2
Me
Me
Me
Me
(i–iii)
6
3
HO
Me
Me
I
Me
Cu
(S)
(R)
(S)
(S)
O
11
(S)-10
Me
Me
Me (3S,6R,7S)-zingiberenol (8), 61% yield,
9
dr(C3,C6) = 99:1, dr(C6,C7) = 81:19
98% ee
Scheme 5 Synthesis of zingiberenol. Reagents and conditions: i) tBuLi (2.2 equiv), inverse addition, pentane/Et2O (3:2), –100 °C, 1 min; (ii) CuBr·P(OEt)3
(1.5 equiv), pentane/Et2O, –100 °C, 1 min; (iii) solvent switch to THF at –50 °C; (iv) ZnCl2 (1.5 equiv), –30 °C, 10 min; then 9 (3.0 equiv), –30 °C to
–10 °C, 12 h.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

E
J. Skotnitzki et al.
Paper
Synthesis
instruments (Hewlett Packard, 5% phenylmethylpolysiloxane; length:
10 m, diameter: 0.25 mm; film thickness: 0.25 m). All reagents not
listed in the Supporting Information were obtained from commercial
suppliers.
1H NMR (CDCl3, 400 MHz):  = 7.32–7.26 (m, 2 H), 7.21–7.14 (m, 3 H),
5.69–5.48 (m, 2 H), 4.18–3.99 (m, 2 H), 2.85–2.67 (m, 1 H), 2.04–1.93
(m, 1 H), 1.90–1.79 (m, 1 H), 1.72–1.60 (m, 1 H), 1.37–1.27 (m, 2 H),
1.22 (d, J = 6.9 Hz, 3 H), 0.86 (d, J = 6.0 Hz, 3 H).
13C NMR (CDCl3, 100 MHz):  = 147.5, 131.8, 130.4, 128.5, 127.2,
126.0, 64.0, 45.3, 40.2, 37.5, 30.5, 23.6, 19.4.
CuBr·P(OEt)3
A dry and argon-flushed 100 mL Schlenk flask was charged with a
magnetic stirring bar, freshly distilled P(OEt)3 (4.98 g, 30 mmol,
5.14 mL) and toluene (30 mL). CuBr (4.30 g, 30 mmol) was added por-
tionwise and the mixture was stirred for 1 h at rt. The light green
solution was stirred 30 min at 80 °C. The cooled solution was filtered
to obtain a clear solution of CuBr·P(OEt)3. To the solution was added
i-hexane (20 mL) and the solvent was removed under high vacuum.
This step was repeated three times affording the purified complex
without traces of toluene.
MS (EI, 70 eV): m/z (%) = 157 (6), 145 (100), 131 (10), 118 (47), 106
(34), 105 (47), 91 (62), 79 (19), 77 (21), 55 (6), 41 (13).
HRMS (EI): m/z calcd for C15H22O: 218.1671; found: 218.1673.
anti-(E)-5-Methyl-7-phenyloct-2-en-1-ol (anti-7a)
The allylic alcohol anti-7a was prepared according to GP1 from the al-
kyl iodide anti-2a (0.1 mmol, 27 mg) and 3,4-epoxy-1-butene (6a; 0.3
mmol, 0.024 mL). The crude product was purified by flash column
chromatography on silica gel with n-pentane/Et2O (4:1) to afford
anti-7a as a colorless oil; yield: 11.8 mg (0.054 mmol, 54%).
ZnCl2
IR (diamond-ATR, neat): 3344 (m), 3026 (m), 2957 (s), 2912 (s), 2870
(m), 2141 (vw), 2009 (vw), 1603 (w), 1493 (m), 1452 (m), 1377 (m),
1084 (m), 1024 (m), 970 (s), 908 (m), 762 (s), 733 (m), 671 cm–1 (vs).
1H NMR (CDCl3, 400 MHz):  = 7.32–7.26 (m, 2 H), 7.21–7.11 (m, 3 H),
5.69–5.52 (m, 2 H), 4.13–4.02 (m, 2 H), 2.80 (q, J = 7.0 Hz, 1 H), 2.14–
2.02 (m, 1 H), 1.94–1.81 (m, 1 H), 1.54–1.38 (m, 3 H), 1.21 (d, J = 6.9
Hz, 3 H), 0.85 (d, J = 6.4 Hz, 3 H).
A 1 L Schlenk flask, equipped with a magnetic stirring bar, was
charged with ZnCl2 (68.2 g, 500 mmol). The mixture was heated un-
der vacuum at 140 °C for 5 h. After cooling the mixture to 25 °C, an-
hyd THF (500 mL) was added and stirring was continued until the salt
was dissolved, providing a 1.0 M solution.
I/Li-Exchange Reaction Using tBuLi and Subsequent SN2′-Substitu-
tion Reaction of Secondary Alkylcopper Reagents 3 with Allylic
Electrophiles 6a–d; General Procedure 1 (GP1)
13C NMR (CDCl3, 100 MHz):  = 148.2, 131.8, 130.5, 128.5, 127.1,
126.0, 64.0, 45.7, 39.6, 37.3, 30.7, 22.2, 19.8.
3,4-Epoxy-1-butene (6a) and 3,4-epoxy-1-cyclohexene (6c) are com-
mercially available (Sigma Aldrich). The alkyl iodides 2a5c and 2b5b as
well as the electrophiles 2-phenyl-3-vinyloxirane (6b)2g and 7-tosyl-
7-azabicyclo[4.1.0]hept-2-ene (6d)8 were prepared according to liter-
ature.
MS (EI, 70 eV): m/z (%) = 218 (1), 185 (2), 145 (32), 106 (11), 105
(100), 91 (14), 77 (6), 41 (4).
HRMS (EI): m/z calcd for C15H22O: 218.1671; found: 218.1666.
(E)-5-Methyl-1,7-diphenylhept-2-en-1-ol (7b)
A dry and argon-flushed Schlenk tube was cooled to –100 °C and
charged with a solution of tBuLi (0.22 mmol, 2.2 equiv) together with
a mixture of Et2O (1.00 mL) and n-pentane (1.50 mL). A solution of al-
kyl iodide 2 (0.10 mmol, 1.0 equiv) in Et2O (0.40 mL) was added drop-
wise over 1 min. After stirring for 10 s, a solution of CuBr·P(OEt)3
(0.05 mL, 3 M in Et2O, 0.15 mmol, 1.5 equiv) was added and the reac-
tion mixture was stirred for 1 min at –100 °C to observe the color
change from yellow to green. The Schlenk tube was transferred to a
cooling bath (–50 °C) and the solvent was pumped away under high
vacuum (10 min). Precooled THF (2 mL) was added and after 10 s,
ZnCl2 (0.15 mmol, 0.15 mL, 1.0 M in THF, 1.5 equiv) was added drop-
wise. The mixture was warmed to –30 °C and stirred for 10 min. The
allylic epoxide 6 (0.3 mmol, dissolved in 0.60 mL THF) was added and
the mixture was warmed to –10 °C. After 12 h, the mixture was
quenched with aq NH3 solution and extracted with Et2O (3 × 10 mL).
The combined organic phases were dried (MgSO4) and the solvents
were evaporated. The obtained crude product was purified by flash
column chromatography on silica gel to afford products of type 7.
The allylic alcohol 7b was prepared according to GP1 from the alkyl
iodide 2b (0.1 mmol, 26 mg) and 2-phenyl-3-vinyloxirane (6b; 0.3
mmol, 44 mg). The crude product was purified by flash column chro-
matography on silica gel with n-pentane/Et2O (4:1) to afford 7b as a
colorless oil and a mixture of two diastereoisomers, which could not
be separated; yield: 12.1 mg (0.043 mmol, 43%).
Analytic data refer to the two diastereoisomers of the -substitution
product.
IR (diamond-ATR, neat): 3354 (w), 3061 (w), 3026 (w), 2953 (w),
2921 (w), 2869 (w), 2361 (vw), 1667 (vw), 1603 (w), 1493 (m), 1453
(m), 1377 (w), 1243 (w), 1192 (w), 1068 (w), 1029 (m), 969 (m), 915
(w), 842 (w), 745 (m), 723 (m), 697 cm–1 (vs).
1H NMR (CDCl3, 400 MHz):  = 7.40–7.31 (m, 8 H), 7.31–7.25 (m, 6 H),
7.21–7.09 (m, 6 H), 5.80–5.60 (m, 4 H), 5.20–5.16 (m, 2 H), 2.70–2.60
(m, 2 H), 2.60–2.49 (m, 2 H), 2.20–2.04 (m, 2 H), 2.02–1.90 (m, 2 H),
1.85 (s, 1 H), 1.85 (s, 1 H), 1.74–1.51 (m, 4 H), 1.51–1.40 (m, 2 H),
0.99–0.91 (m, 6 H).
13C NMR (CDCl3, 100 MHz):  = 143.5, 143.0, 133.9, 131.0, 131.0,
128.7, 128.6, 128.5, 128.4, 127.7, 127.7, 126.3, 126.3, 125.8, 75.3, 75.3,
39.6, 39.6, 38.5, 38.5, 33.5, 33.5, 32.7, 32.7, 19.7, 19.6.
syn-(E)-5-Methyl-7-phenyloct-2-en-1-ol (syn-7a)
The allylic alcohol syn-7a was prepared according to GP1 from the al-
kyl iodide syn-2a (0.1 mmol, 27 mg) and 3,4-epoxy-1-butene (6a; 0.3
mmol, 0.024 mL). The crude product was purified by flash column
chromatography on silica gel with n-pentane/Et2O (4:1) to afford syn-
7a as a colorless oil; yield: 10 mg (0.046 mmol, 46%).
MS (EI, 70 eV): m/z (%) = 280 (8), 262 (25), 173 (12), 171 (12), 158
(29), 157 (22), 133 (26), 129 (19), 120 (25), 117 (114), 115 (17), 105
(33), 92 (11), 91 (100), 77 (22).
HRMS (EI): m/z calcd for C20H24O: 280.1827; found: 280.1817.
IR (diamond-ATR, neat): 3344 (m), 3026 (m), 2957 (s), 2916 (s), 2869
(m), 2142 (vw), 2010 (vw), 1603 (w), 1493 (m), 1452 (m), 1378 (m),
1084 (m), 1003 (m), 971 (s), 762 (s), 671 cm–1 (vs).
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Synthesis
4-Phenylbutan-2-ylcyclohex-2-en-1-ol (7c)
duced pressure and the obtained crude product was diluted with
Et2O. The organic phase was washed with 7% aq Na2CO3, 10% aq
KHSO4, and brine. The organic phase was dried (Na2SO4) and concen-
trated under reduced pressure. The crude product was purified by
flash column chromatography on silica gel with n-pentane/Et2O (3:1)
to afford 17 as a white solid; yield: 3.86 g (16.2 mmol, 88%); 98% ee;
mp 39–40 °C; []D20 +54.1 (c 4.9, CHCl3).
The allylic alcohol 7c was prepared according to GP1 from the alkyl
iodide 2b (0.1 mmol, 26 mg) and 3,4-epoxy-1-cyclohexene (6c; 0.3
mmol, 0.020 mL). The crude product was purified by flash column
chromatography on silica gel with n-pentane/Et2O (4:1) to afford 7c
as a colorless oil and a mixture of diastereoisomers, which could not
be separated; yield: 11.7 mg (0.051 mmol, 51%).
IR (diamond-ATR, neat): 3249 (m), 2937 (m), 2916 (m), 2907 (m),
2859 (m), 2820 (w), 1639 (m), 1420 (m), 1290 (m), 1165 (m), 1076
(m), 1065 (m), 1033 (m), 1019 (m), 999 (m), 959 (vs), 898 (m), 880
(s), 783 (s), 730 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 4.37–4.20 (m, 1 H), 2.27–2.02 (m, 3 H),
1.88 (s, 3 H), 1.87–1.74 (m, 2 H), 1.71–1.60 (m, 1 H).
Analytic data refer to the diastereoisomers of the -substitution prod-
uct.
IR (diamond-ATR, neat): 3340 (m), 3025 (m), 2930 (s), 2860 (s), 1603
(w), 1496 (m), 1453 (m), 1379 (m), 1055 (s), 1040 (s), 747 (s), 735 (s),
698 cm–1 (vs).
1H NMR (CDCl3, 400 MHz):  = 7.31–7.27 (m, 4 H), 7.21–7.15 (m, 6 H),
5.74–5.67 (m, 2 H), 5.61 (tq, J = 10.0, 1.8 Hz, 2 H), 4.28–4.16 (m, 2 H),
2.75–2.61 (m, 2 H), 2.61–2.43 (m, 2 H), 2.25–2.00 (m, 4 H), 1.78–1.62
(m, 4 H), 1.58–1.32 (m, 10 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.87 (d, J = 6.7
Hz, 3 H).
13C NMR (CDCl3, 100 MHz):  = 143.1, 104.2, 74.0, 33.4, 31.9, 29.6,
18.6.
MS (EI, 70 eV): m/z (%) = 238 (13), 210 (10), 111 (100), 93 (19), 91
(15), 77 (7).
13C NMR (CDCl3, 100 MHz):  = 142.9, 133.8, 132.7, 131.9, 131.6,
128.5, 128.5, 125.8, 67.8, 40.9, 40.3, 36.7, 36.6, 36.1, 35.6, 34.1, 34.0,
33.02, 32.9, 24.1, 22.4, 16.5, 15.8.
HRMS (EI): m/z calcd for C7H11IO: 237.9855; found: 237.9845.
(R)-3-Methylcyclohex-2-en-1-ol (18)
MS (EI, 70 eV): m/z (%) = 212 (7), 183 (8), 131 (15), 117 (10), 108 (13),
104 (14), 93 (11), 91 (100), 79 (27).
A dry and argon-flushed round-bottomed flask was charged with a
solution of 17 (2.38 g, 10.0 mmol, 1.0 equiv) in Et2O (92 mL). After
cooling to –78 °C, tBuLi (23.9 mL, 45.0 mL, 4.5 equiv) was added drop-
wise. The mixture was stirred for 30 min and then quenched with sat.
aq NaHCO3 (30 mL). The solution was poured into sat. aq NaHCO3
(200 mL) and extracted with Et2O (3 ×). The combined organic phases
were dried (Na2SO4) and concentrated under reduced pressure. The
crude product was purified by flash column chromatography on silica
gel with n-pentane/Et2O (2:1) to afford 18 as a white solid; yield:
HRMS (EI): m/z calcd for C16H22O: 230.1671; found: 230.1656.
Preparation of the Allylic Epoxide 9
2-Iodo-3-methylcyclohex-2-en-1-one (16)
According to literature,9 PDC (3.38 g, 9 mmol, 0.3 equiv) and I2 (12.9 g,
51.0 mmol, 1.7 equiv) were added in one portion to a solution of 3-
methyl-2-cyclohexenone (15; 3.40 mL, 30 mmol, 1.0 equiv) in DCM
(250 mL). The reaction mixture was covered with aluminum foil and
stirred at rt overnight. The mixture was filtered and the filtrate was
extracted with n-pentane. The combined organic phases were
washed with aq 2 M HCl, aq NaHCO3, sat. aq Na2S2O3, and brine, dried
(MgSO4), and concentrated. The crude product was purified by flash
column chromatography on silica gel with n-pentane/Et2O (7:3) to af-
ford 16 as a slightly yellow oil; yield: 5.72 g (24.3 mmol, 81%).
20
1.06 g (9.5 mmol, 95%); 98% ee; mp 34–36 °C; []D +86.3 (c 1.4,
CHCl3).
IR (diamond-ATR, neat): 3320 (br), 2930 (s), 2910 (m), 2859 (m), 2358
(vw), 2333 (vw), 1671 (w), 1447 (m), 1436 (m), 1376 (m), 1343 (m),
1277 (m), 1164 (m), 1074 (m), 1059 (s), 1032 (s), 1013 (m), 992 (s),
956 (vs), 905 (m), 814 (m), 706 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 5.51–5.44 (m, 1 H), 4.22–4.11(m, 1 H),
2.01–1.82 (m, 2 H), 1.81–1.70 (m, 2 H), 1.70–1.66 (m, 3 H), 1.63–1.51
(m, 2 H), 1.40–1.34 (m, 1 H).
IR (diamond-ATR, neat): 2938 (w), 2883 (w), 2866 (w), 1672 (vs),
1589 (s), 1423 (m), 1369 (m), 1261 (s), 1190 (m), 1167 (s), 1131 (m),
968 (s), 908 (m), 781 cm–1 (vs).
13C NMR (CDCl3, 100 MHz):  = 138.9, 124.4, 66.0, 31.8, 30.2, 23.8,
19.1.
1H NMR (CDCl3, 400 MHz):  = 2.63–2.47 (m, 4 H), 2.28–2.20 (m, 3 H),
MS (EI, 70 eV): m/z (%) = 98 (11), 97 (100), 83 (16), 79 (23).
HRMS (EI): m/z calcd for C7H11O [M – H+]: 111.0810; found: 111.0803.
2.03–1.94 (m, 2 H).
13C NMR (CDCl3, 100 MHz):  = 192.3, 166.8, 107.0, 36.4, 34.3, 32.0,
22.2.
(1R,2R,6S)-6-Methyl-7-oxabicyclo[4.1.0]heptan-2-ol (19)
MS (EI, 70 eV): m/z (%) = 236 (100), 208 (68), 81 (10), 79 (8), 53 (48),
41 (10).
A dry and argon-flushed round-bottomed flask was charged with a
solution of 18 (1.12 g, 10.0 mmol, 1.0 equiv) in DCM (70 mL) and
cooled to 0 °C. mCPBA was added dropwise as a solution in DCM
(50 mL). After stirring for 15 min, the reaction mixture was quenched
with a 10% aq Na2CO3 and extracted with DCM (3 × 20 mL). The com-
bined organic phase was washed with brine, dried (Na2SO4), and con-
centrated under reduced pressure. The crude product was purified by
flash column chromatography on silica gel with n-pentane/Et2O (2:1)
to afford 19 as a colorless oil; yield: 1.02 g (8.0 mmol, 80%); 98% ee;
[]D20 +26.9 (c 3.0, CHCl3).
HRMS (EI): m/z calcd for C7H9IO: 235.9698; found: 235.9688.
(R)-2-Iodo-3-methylcyclohex-2-en-1-ol (17)
A dry and argon-flushed round-bottomed flask was charged with a
solution of (R)-diphenylprolinol (232 mg, 0.91 mmol, 0.05 equiv) and
B(OMe)3 (0.095 mL, 0.91 mmol, 0.05 equiv) in THF (18 mL). The mix-
ture was stirred for 1 h at rt. Borane N,N-diethylaniline (3.35 mL,
18.3 mmol, 1.00 equiv) and 2-iodo-3-methylcyclohex-2-en-1-one
(16; 4.31 g, 18.3 mmol, 1.00 equiv; dissolved in 18 mL THF) were add-
ed dropwise. The reaction mixture was stirred for 1 h and then
quenched with MeOH (20 mL). The solvent was removed under re-
IR (diamond-ATR, neat): 3387 (m), 2976 (m), 2937 (m), 2862 (m),
1708 (m), 1423 (m), 1264 (m), 1074 (s), 1063 (s), 1037 (s), 1018 (s),
990 (s), 894 (s), 843 (vs), 766 (s), 669 (s), 654 cm–1 (s).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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J. Skotnitzki et al.
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Synthesis
1H NMR (CDCl3, 400 MHz):  = 4.01 (td, J = 5.5, 3.3 Hz, 1 H), 3.15 (d, J =
3.3 Hz, 1 H), 1.93–1.79 (m, 1 H), 1.68–1.59 (m, 1 H), 1.57–1.43 (m, 3
H), 1.34 (s, 3 H), 1.32–1.23 (m, 1 H).
(1R,6S)-6-Methyl-7-oxabicyclo[4.1.0]hept-2-ene (9)
A dry and argon-flushed pressure tube was charged with a solution of
21 (590 mg, 2.5 mmol, 1.0 equiv) in THF (25 mL). After the addition of
DBU (0.56 mL, 3.75 mmol, 1.5 equiv), the reaction mixture was
stirred for 12 h at 60 °C. The crude reaction mixture was purified by
Kugelrohr distillation (45–55 °C/atmospheric pressure) to afford 9 as
a colorless oil with small impurities of THF; yield: 165 mg (1.5 mmol,
60%); 98% ee; []D20 –8.3 (c 1.0, THF).
13C NMR (CDCl3, 100 MHz):  = 66.5, 62.3, 61.7, 29.3, 28.9, 23.8, 17.6.
MS (EI, 70 eV): m/z (%) = 111 (100), 93 (68), 84 (38), 81 (19), 70 (12),
67 (46), 43 (24).
HRMS (EI): m/z calcd for C7H12O2: 128.0837; found: 128.0830.
IR (diamond-ATR, neat): 3430 (m), 2964 (m), 2931 (s), 2927 (s), 2359
(m), 2328 (m), 1374 (m), 1260 (s), 1123 (s), 1103 (vs), 1091 (vs), 1087
(vs), 1071 (vs), 1058 (vs), 1042 (s), 1038 (s), 1034 (s), 1024 (s), 798 (s),
668 cm–1 (s).
1H NMR (CDCl3, 400 MHz):  = 5.97–5.84 (m, 2 H), 3.04 (dd, J = 3.5, 1.8
Hz, 1 H), 2.21–1.86 (m, 2 H), 1.72–1.53 (m, 2 H), 1.42 (s, 3 H).
(1R,2R,6S)-6-Methyl-7-oxabicyclo[4.1.0]heptan-2-yl Methane-
sulfonate (20a)
A dry and argon-flushed round-bottomed flask was charged with a
solution of 19 (0.64 g, 5.0 mmol, 1.0 equiv) and NEt3 (2.58 mL,
30.0 mmol, 6.0 equiv) in DCM (30 mL). After cooling to –10 °C, MsCl
(1.48 mL, 22.5 mmol, 4.5 equiv) was added dropwise. The reaction
mixture was stirred for 1 h and then diluted with EtOAc (10 mL). The
organic phase was washed with aq 1 M HCl, sat. aq NaHCO3, and
brine. The organic phase was dried (Na2SO4) and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography on silica gel with n-pentane/Et2O (1:2) to afford 20a
as a colorless oil; yield: 0.84 g (4.0 mmol, 80%); 98% ee; []D20 –7.0 (c
1.5, CHCl3).
13C NMR (CDCl3, 100 MHz):  = 132.9, 123.7, 61.2, 54.7, 26.6, 22.3,
22.0.
MS (EI, 70 eV): m/z (%) = 95 (13), 91 (19), 82 (100), 81 (28), 79 (16), 69
(14).
HRMS (EI): m/z calcd for C7H10O: 110.0732; found: 110.0724.
Preparation of the Iodide 11
IR (diamond-ATR, neat): 3519 (w), 2940 (w), 2361 (w), 2332 (w),
1452 (w), 1333 (s), 1170 (vs), 1131 (w), 1057 (m), 1006 (w), 952 (s),
933 (vs), 894 (m), 858 (m), 831 cm–1 (m).
(R)-6-Methylhept-5-en-2-ol (24)
A dry and argon-flushed Schlenk flask was charged with Mg turnings
(0.52 g, 21.0 mmol) and THF (20 mL). After addition of I2 (ca. 5 mg),
the mixture was stirred and warmed until the color of I2 disappeared.
The allylmagnesium chloride 22 (1.94 mL, 20.0 mmol) was added in
such a rate to keep a mild reflux. After the addition, the reaction mix-
ture was stirred for 1 h at rt to obtain the corresponding Grignard re-
agent (67% yield, 0.67 M in THF). To a solution of the Grignard reagent
(15.4 mL, 0.67 M in THF, 10.0 mmol), CuI (186 mg, 1.0 mmol) was
added in one portion at 0 °C and the resulting black suspension was
stirred for 5 min at 0 °C. Then (R)-propylene oxide [(R)-23; 0.70 mL,
10.0 mmol] in THF (10 mL) was added dropwise at 0 °C. The reaction
mixture was warmed to rt and stirred for 12 h. The mixture was
quenched with sat. aq NH4Cl and extracted with Et2O (3 × 20 mL). The
combined organic phases were dried over NaSO4 and the solvents
were evaporated. The crude product was purified by flash column
chromatography on silica gel with n-pentane/Et2O (2:1) to afford 24
as a colorless oil; yield: 1.08 g (8.5 mmol, 85%); 98% ee; []D23 –14.0 (c
0.9, CHCl3).
1H NMR (CDCl3, 400 MHz):  = 5.13–5.01 (m, 1 H), 3.25 (d, J = 2.4 Hz, 1
H), 3.09 (s, 3 H), 1.93–1.79 (m, 1 H), 1.78–1.60 (m, 4 H), 1.36 (s, 3 H),
1.34–1.26 (m, 1 H).
13C NMR (CDCl3, 100 MHz):  = 78.2, 61.5, 59.4, 39.2, 27.8, 25.7, 23.9,
19.1.
MS (EI, 70 eV): m/z (%) = 111 (29), 110 (32), 95 (19), 93 (21), 84 (22),
81 (45), 79 (20), 71 (50), 70 (57), 69 (11), 67 (32), 55 (35), 53 (13), 43
(100), 41 (43).
HRMS (EI): m/z calcd for C8H14O4S: 206.0613; found: 206.0609.
(1S,5S,6S)-5-Iodo-1-methyl-7-oxabicyclo[4.1.0]heptane (21)
A dry and argon-flushed round-bottomed flask was charged with a
solution of 20a (0.84 g, 4.0 mmol, 1.0 equiv), NaHCO3 (6.7 g,
80.0 mmol, 20 equiv), and NaI (6.0 g, 40.0 mmol, 10 equiv) in THF
(10 mL). The mixture was stirred for 10 h at 65 °C, then diluted with
H2O (50 mL), and extracted with Et2O (3 ×). The combined organic
phase was dried (Na2SO4) and concentrated under reduced pressure.
The crude product was purified by flash column chromatography on
silica gel with n-pentane/Et2O (16:1) to afford 21 as a yellow oil;
yield: 590 mg (2.5 mmol, 62%); 98% ee; []D20 +0.3 (c 1.9, CHCl3).
IR (diamond-ATR, neat): 2967 (m), 2917 (m), 2859 (w), 1742 (s), 1728
(m), 1448 (w), 1395 (w), 1374 (s), 1300 (w), 1238 (vs), 1126 (m),
1113 (m), 1071 (m), 1046 (s), 952 (w), 935 cm–1 (w).
1H NMR (CDCl3, 400 MHz):  = 5.18–5.05 (m, 1 H), 3.93–3.72 (m, 1 H),
2.17–1.94 (m, 2 H), 1.69 (s, 3 H), 1.62 (s, 3 H), 1.54–1.39 (m, 2 H), 1.19
(d, J = 6.1 Hz, 3 H).
IR (diamond-ATR, neat): 3503 (br), 2935 (s), 2857 (w), 2538 (w), 1652
(w), 1441 (m), 1413 (w), 1376 (m), 1355 (w), 1295 (w), 1263 (w),
1219 (w), 1199 (w), 1135 (s), 1098 (s), 1050 (vs), 1002 (m), 962 (m),
929 (w), 890 (s), 848 (m), 766 (m), 668 (m), 656 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 4.50 (ddd, J = 8.3, 5.9, 2.6 Hz, 1 H), 3.22
(d, J = 2.7 Hz, 1 H), 2.07–1.89 (m, 3 H), 1.82–1.69 (m, 1 H), 1.62–1.47
(m, 1 H), 1.29 (s, 3 H), 1.27–1.25 (m, 1 H).
13C NMR (CDCl3, 100 MHz):  = 132.3, 124.2, 68.1, 39.3, 25.9, 24.6,
23.6, 17.8.
MS (EI, 70 eV): m/z (%) = 128 (1), 113 (9), 110 (13), 96 (8), 95 (100), 85
(10), 79 (5), 71 (5), 57 (36), 41 (6).
HRMS (EI): m/z calcd for C8H16O: 128.1201; found: 128.1194.
13C NMR (CDCl3, 100 MHz):  = 66.3, 64.1, 32.8, 28.6, 27.8, 24.4, 21.7.
MS (EI, 70 eV): m/z (%) = 127 (67), 111 (93), 93 (100), 91 (60), 81 (17),
79 (16), 77 (23), 67 (67), 55 (9), 43 (46).
(S)-6-Iodo-2-methylhept-2-ene (11)
A dry and argon-flushed Schlenk flask was charged with a solution of
I2 (1.65 g, 6.5 mmol, 1.3 equiv) in DCM (50 mL) and cooled to –10 °C.
PPh3 (1.70 g, 6.5 mmol, 1.3 equiv) was added at –10 °C and the result-
ing yellow suspension was stirred for 1 h at –10 °C. Then N-methyl-
HRMS (EI): m/z calcd for C7H11IO: 237.9855; found: 237.9843.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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Synthesis
imidazole (0.52 mL, 0.53 g, 6.5 mmol, 1.3 equiv) was added. After
10 min of further stirring, the alcohol 24 (0.64 g, 5.0 mmol, 1.0 equiv)
dissolved in DCM (5 mL) was added and the reaction mixture was
stirred for 1 h at –10 °C. The mixture was quenched with freshly pre-
pared sat. aq NaHSO3·Na2S2O5 solution and extracted with DCM
(3 × 50 mL). The combined organic phases were dried (MgSO4) and
the solvents were evaporated at 30 °C. The residue was triturated
three times with a mixture of Et2O/n-pentane (1:4). The precipitate
was filtered off and all organic phases were combined. The solvents
were evaporated at 30 °C. The crude product was purified by flash
column chromatography on silica gel with n-pentane to obtain 11as a
Acknowledgment
We thank Albemarle Germany GmbH for the generous gift of various
lithium reagents. J.S. thanks the FCI-foundation for a fellowship.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690766.
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20
colorless oil; yield: 833 mg (3.5 mmol, 73%); 98% ee; []D +89.0 (c
0.9, CHCl3).
References
IR (diamond-ATR, neat): 2979 (m), 2964 (s), 2914 (s), 2883 (m), 2858
(m), 1443 (s), 1376 (vs), 1231 (m), 1194 (m), 1181 (s), 1142 (s), 1136
(s), 1113 (s), 1080 (m), 843 (m), 824 (m), 805 (m), 744 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 5.14–4.98 (m, 1 H), 4.26–4.02 (m, 1 H),
2.23–1.99 (m, 2 H), 1.93 (d, J = 6.8 Hz, 3 H), 1.92–1.82 (m, 1 H), 1.69 (s,
3 H), 1.65 (s, 3 H), 1.64–1.56 (m, 1 H).
(1) (a) Bertozzi, F.; Crotti, P.; Feringa, B. L.; Macchia, F.; Pineschi, M.
Synthesis 2001, 483. (b) Cullis, C. A.; Mizutani, H.; Murphy, K. E.;
Hoveyda, A. H. Angew. Chem. Int. Ed. 2001, 40, 1456. (c) Trost, B.
M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (d) Campbell, J. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130. (e) van Zijl, A.
W.; Szymanski, W.; Lopez, F.; Minnaard, A. J.; Feringa, B. L.
J. Org. Chem. 2008, 73, 6994. (f) Alexakis, A.; Bä ckvall, J. E.;
Krause, N.; P̀amies, O.; Díeguez, M. Chem. Rev. 2008, 108, 2796.
(g) Goth, S. S.; Guduguntla, S.; Kikuchi, T.; Lutz, M.; Otten, E.;
Fujita, M.; Feringa, B. L. J. Am. Chem. Soc. 2018, 140, 7052.
(h) Cheng, Q.; Tu, C.; Zheng, H.-F.; Qu, J.-P.; Helmchen, G.; You,
S.-L. Chem. Rev. 2019, 119, 1855.
13C NMR (CDCl3, 100 MHz):  = 133.1, 122.7, 43.1, 30.6, 29.1, 28.4,
25.9, 18.1.
MS (EI, 70 eV): m/z (%) = 238 (3), 127 (5), 111 (29), 95 (5), 70 (6), 69
(100), 67 (6), 41 (14).
HRMS (EI): m/z calcd for C8H15I: 238.0218; found: 238.0213.
(2) (a) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.;
Knochel, P. Org. Lett. 2003, 5, 211. (b) Calaza, M. I.; Hupe, E.;
Knochel, P. Org. Lett. 2003, 5, 1059. (c) Breit, B.; Demel, P.;
Studte, C. Angew. Chem. Int. Ed. 2004, 43, 3786. (d) Leuser, H.;
Perrone, S.; Liron, F.; Kneisel, F. F.; Knochel, P. Angew. Chem. Int.
Ed. 2005, 44, 4627. (e) Soorukram, D.; Knochel, P. Angew. Chem.
Int. Ed. 2006, 45, 3686. (f) Perrone, S.; Knochel, P. Org. Lett. 2007,
9, 1041. (g) Welker, M.; Woodward, S.; Alexakis, A. Org. Lett.
2010, 12, 576.
(3) (a) Gini, F.; Del Moro, F.; Macchia, F.; Pineschi, M. Tetrahedron
Lett. 2003, 44, 8559. (b) Pineschi, M.; Del Moro, F.; Crotti, P.; Di
Bussolo, V.; Macchia, F. J. Org. Chem. 2004, 69, 2099. (c) Falciola,
C.; Tissot-Croset, K.; Alexakis, A. Angew. Chem. Int. Ed. 2006, 45,
5995. (d) Perez, M.; Fananas-Mastral, M.; Bos, P. H.; Rudolph, A.
S.; Harutyunyan, R.; Feringa, B. L. Nat. Chem. 2011, 3, 377.
(4) Skotnitzki, J.; Spessert, L.; Knochel, P. Angew. Chem. Int. Ed.
2019, 58, 1509.
All analytical data were in accordance with literature values for the R-
enantiomer.5b
(3S,6R,7S)-Zingiberenol (8)
The natural product 8 was prepared according to GP1 from 11 (98%
ee, 0.20 mmol, 48 mg) and electrophile 9 (0.60 mmol, 66 mg, 98% ee).
The crude product was purified by flash column chromatography on
silica gel with n-pentane/Et2O (3:1) to afford 8 as a colorless oil; yield:
26.7 mg (0.12 mmol, 61%); 98% ee; dr (3S,6R) = 99:1; dr (6R,7S) =
81:19; []D20 –32.9 (c 0.8, CH2Cl2) {Lit.7a []D –37.7 (c 2.0, CH2Cl2)}.
The NMR data refer to the major diastereoisomer (3S,6R,7S)-zingiber-
enol (8).
IR (diamond-ATR, neat): 3381 (br), 2962 (vs), 2928 (vs), 2859 (s),
2363 (w), 2338 (w), 1715 (w), 1669 (w), 1456 (m), 1450 (m), 1376 (s),
1367 (m), 1120 (s), 978 (m), 916 (m), 743 cm–1 (m).
1H NMR (CD2Cl2, 400 MHz):  = 5.59–5.53 (m, 1 H), 5.54–5.45 (m, 1
H), 5.10 (t, J = 7.1 Hz, 1 H), 2.16–2.06 (m, 1 H), 2.04–1.78 (m, 4 H), 1.67
(s, 3 H), 1.60 (s, 3 H), 1.52–1.44 (m, 2 H), 1.42–1.31 (m, 2 H), 1.22 (s, 3
H), 1.20–1.08 (m, 1 H), 0.81 (d, J = 6.8 Hz, 3 H).
(5) (a) Moriya, K.; Schwärzer, K.; Karaghiosoff, K.; Knochel, P. Syn-
thesis 2016, 48, 3141. (b) Morozova, V.; Skotnitzki, J.; Moriya, K.;
Karaghiosoff, K.; Knochel, P. Angew. Chem. Int. Ed. 2018, 57,
5516. (c) Skotnitzki, J.; Morozova, V.; Knochel, P. Org. Lett. 2018,
20, 2365.
13C NMR (CD2Cl2, 100 MHz):  = 135.4, 132.3, 131.7, 125.2, 70.0, 40.7,
(6) (a) Morais de Oliveria, M. W.; Borges, M.; Andrade, C. K. Z.;
Laumann, R. A.; Barrigossi, J. A. F.; Blassioli-Moraes, M. C.
J. Agric. Food Chem. 2013, 61, 7777. (b) Khrimian, A.; Shirali, S.;
Guzman, F. J. Nat. Prod. 2015, 78, 3071. (c) Shirali, S.; Guzman,
F.; Weber, D. C.; Khrimian, A. Tetrahedron Lett. 2017, 58, 2066.
(7) (a) Khrimian, A.; Zhang, A.; Weber, D. C.; Ho, H.-Y.; Aldrich, J. A.;
Vermillion, K. E.; Siegler, M. A.; Shirali, S.; Guzman, F.; Leskey, T.
C. J. Nat. Prod. 2014, 77, 1708. (b) Khrimian, A.; Shirali, S.;
Vermillion, K. E.; Siegler, M. A.; Guzman, F.; Chauhau, K.;
Aldrich, J. A.; Weber, D. C. J. Chem. Ecol. 2014, 40, 1260.
(8) Sureshkumar, D.; Maity, S.; Chandrasekaran, S. J. Org. Chem.
2006, 71, 1653.
38.9, 36.8, 34.7, 28.8, 26.5, 26.0, 22.9, 17.9, 16.0.
MS (EI, 70 eV): m/z (%) = 207 (20), 189 (11), 161 (28), 138 (15), 137
(38), 123 (33), 119 (100), 105 (30), 93 (35), 79 (18), 67 (17).
HRMS (EI): m/z calcd for C15H26O: 222.1984; found: 222.1975.
Funding Information
We thank the Excellence Cluster ‘e-conversion’ for financial support.()
(9) Demay, S.; Harms, K.; Knochel, P. Tetrahedron Lett. 1999, 40,
4981.
(10) Mori, K.; Ogoche, J. I. J. Liebigs Ann. Chem. 1988, 903.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

I
J. Skotnitzki et al.
Paper
Synthesis
(11) Burgess, E. M.; Penton, H. R. J.; Taylor, E. A. J. Am. Chem. Soc.
1970, 92, 5224.
(14) The enantiomeric excess was determined via chiral GC analysis.
For details, see the Supporting Information.
(12) Blay, G.; Cardona, L.; Collado, A. M.; Garcia, B.; Pedro, J. R. J. Org.
Chem. 2006, 71, 4929.
(13) Mori, K.; Hazra, B. G.; Pfeiffer, R. J.; Gupta, A. K.; Lindgren, B. S.
Tetrahedron 1987, 43, 2249.
(15) (a) The stereochemistry was assigned according to literature:
Khrimian, A.; Shirali, S.; Vermillion, K. E.; Siegler, M. A.;
Guzman, F.; Chauhau, K.; Aldrich, J. A.; Weber, D. C. J. Chem. Ecol.
2014, 40, 1260. (b) For details, see the Supporting Information.
(16) For details, see Supporting Information.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I