Preparation of chiral building blocks for the enantioselective total synthesis of ent-kauranoids by the pig liver esterase-catalyzed asymmetric hydrolysis of a dialkyl malonate-type prochiral diester

Article abstract of DOI:10.1016/j.tetasy.2014.01.019

The preparation of chiral building blocks, suitable for use in the enantioselective total synthesis of kauranoids and ent-kauranoids, is reported herein. The pig liver esterase-catalyzed asymmetric hydrolysis of dimethyl 3,3-dimethyl-2-methylenecyclohexane-1,2-dicarboxylate, a malonate-type prochiral diester, afforded the corresponding half-ester in 96% yield and with 99% enantiomeric excess. The absolute configuration of the half-ester was determined by X-ray crystallographic analysis of its derivative and its enantiodivergent transformations are also described herein.

Full text of DOI:10.1016/j.tetasy.2014.01.019

Tetrahedron: Asymmetry 25 (2014) 718–724
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Preparation of chiral building blocks for the enantioselective total
synthesis of ent-kauranoids by the pig liver esterase-catalyzed
asymmetric hydrolysis of a dialkyl malonate-type prochiral diester
⇑
Yuji Namiki, Tomohiro Fujii, Masahisa Nakada
Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 December 2013
Accepted 10 January 2014
The preparation of chiral building blocks, suitable for use in the enantioselective total synthesis of kaura-
noids and ent-kauranoids, is reported herein. The pig liver esterase-catalyzed asymmetric hydrolysis of
dimethyl 3,3-dimethyl-2-methylenecyclohexane-1,2-dicarboxylate, a malonate-type prochiral diester,
afforded the corresponding half-ester in 96% yield and with 99% enantiomeric excess. The absolute con-
figuration of the half-ester was determined by X-ray crystallographic analysis of its derivative and its
enantiodivergent transformations are also described herein.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
OPP
Isodon is a genus of the Lamiaceae family; it has been tradition-
ally used in Chinese folk medicine. Terpenoids with diverse struc-
tures and interesting biological activities, such as antibacterial,
anti-inflammatory, and antitumor activities, have been isolated
from Isodon. More than 60 Isodon species from China have been
phytochemically investigated while more than 600 new diterpe-
noids, such as abietanes, labdanes, pimaranes, isopimaranes,
gibberellanes, and clerodanes, but mainly ent-kauranoids, have
been isolated and characterized.1
H
OPP
1
H
H+
OPP
GGP
H
In biogenetics, the protonation of a terminal trisubstituted al-
kene of geranylgeranyl pyrophosphate (GGP) leads to a cascade
cyclization to afford two enantiomeric trans-decalin derivatives
(Scheme 1, compounds 1 and ent-1). Furthermore, the divergent
biogenetic conversions of compound 1 afford diterpenes such as
beyeranes, kauranes, and pimaranes, whereas those from com-
pound ent-1 afford the corresponding enantiomers (Fig. 1).2
Certain ent-kauranoids possess the common polycarbocyclic
scaffold, featuring a unique carbocyclic ring system consisting of
a trans-decalin skeleton with a cis-fused bicyclo[3.2.1]octane core
ent-1
Scheme 1. Proposed biogenetic formation of 1 and ent-1 from geranylgeranyl
pyrophosphate (GGP).
Xerophilusin B 2 and macrocalin B 3 (Fig. 2), isolated from
Isodon xerophylus, belong to ent-kauranoids, and their structures
have been established by various spectroscopic and X-ray crystal-
lographic analyses.3–5 Compounds 2 and 3 significantly inhibit the
proliferation of some tumor cell lines such as K562, HL-60, A549,
MKN, HCT, and CA in vitro.6 Compounds 2 and 3 markedly inhibit
the telomerase activity in K562 cells below a concentration of
10ꢀ4–10ꢀ8 mol/L; this effect is exhibited in a dose-dependent
manner.
(Fig. 1). The ABC-ring of the ent-kaurane scaffold has
a
trans–anti–cis tricyclic ring system with three all-carbon quater-
nary centers, two of which are stereogenic and embedded at the
ring junctions.
The unique structure and potent cytotoxic activity of com-
pounds 2 and 3 inspired us to study their synthesis. Compound 3
has the same structure as compound 2 except for an extra hydroxyl
group. Therefore, we decided to pursue the total synthesis of
⇑
Corresponding author. Tel./fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
http://dx.doi.org/10.1016/j.tetasy.2014.01.019
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

Y. Namiki et al. / Tetrahedron: Asymmetry 25 (2014) 718–724
719
enzymes exceptionally catalyze diverse substrates and have been
utilized to prepare many new chiral compounds. Among the many
biocatalysts, lipase and PLE have been widely used in the prepara-
tion of chiral compounds;9,10 baker’s yeast also shows a broad
applicability although it is a single-celled microorganism.11
PLE shows low substrate specificity and has been utilized in the
catalytic asymmetric hydrolysis of prochiral diesters and in the ki-
netic resolution of racemic esters.12 Although many successful
applications of PLE have been reported, further improvements
are possible. In this regard, when a new prochiral diester is de-
signed, it may be possible to prepare the corresponding half-ester
by the PLE-catalyzed asymmetric hydrolysis.
H
H
H
beyeranes
kauranes
pimaranes
scaffolds of terpenes from 1
We envisioned that the structures of 2 and 3 are comprised of a
common chiral unit (the moiety surrounded by the red line in
H
H
H
Scheme 2) with a hidden
r-symmetry. Therefore, lactone ent-4
was expected to be a good intermediate because it possesses
appropriate functionality that can be independently converted into
other functional groups. Lactone ent-4 can be formed by the
stereoselective transformation of compound 5, which can be
retrosynthetically converted into the corresponding prochiral dies-
ter 6. Thus, the PLE-catalyzed asymmetric hydrolysis of 6 may
afford the corresponding chiral half-ester.
ent-beyeranes
ent-kauranes
ent-pimaranes
1
scaffolds of terpenes from ent-
Figure 1. Scaffolds of terpenes from 1 and ent–1.
HO
O
O
R
O
O
O
HO
O
O
O
OH
OH
H
H
O
OH
O
OH
O
OH
H
2
3
macrocalin B
xerophilusin B
OH
R = H: xerophilsin B 2
R = OH: macrocalin B 3
ent-4
Figure 2. Structures of xerophilsin B 2 and macrocalin B 3.
compounds 2 and 3 via a divergent approach; that is, by employing
the same starting material or intermediate for both syntheses. It is
important to synthesize a bioactive compound in an enantiopure
form because of the close relationship between the chirality and
the corresponding bioactivity. In general, chiral compounds, suit-
able for use in the enantioselective total synthesis of complex mol-
ecules, are limited; therefore, when unsuitable chiral compounds
are used as starting materials, many steps are inevitably required
to complete the total synthesis.
CO2H
CO2Me
CO2Me
CO2Me
5
6
Scheme 2. Retrosynthetic analysis of xerophilsin B 2 and macrocalin B 3.
Thus, the preparation of a new enantiopure compound that is
suitable for use in a planned total synthesis should reduce the
number of steps in the total synthesis, thereby improving the effi-
ciency. For this purpose, we have prepared new chiral building
blocks and demonstrated their utility for the enantioselective total
synthesis of certain natural products. Herein we report the
preparation of new chiral building blocks via the pig liver esterase
(PLE)-catalyzed asymmetric hydrolysis of dimethyl 3,3-dimethyl-
2-methylenecyclohexane-1,2-dicarboxylate, which are suitable
for use in the enantioselective total synthesis of compounds 2
and 3, and other bioactive terpenes.
The yield and enantioselectivity of the PLE-catalyzed reaction
are difficult to predict. However, we have previously observed that
the PLE-catalyzed asymmetric hydrolysis of malonate-type dies-
ters proceeds in quantitative yield and with excellent enantioselec-
tivity.13 Therefore, we decided to examine the PLE-catalyzed
asymmetric hydrolysis of the prochiral diester 6, which can be ob-
tained by the intramolecular cyclization of compound 13
(Scheme 3). Consequently, the preparation of 13 was first
examined.
The preparation of compound 13 commenced with the ethylene
acetal formation of the known aldehyde 7, which was prepared by
the Claisen rearrangement of the allyl alkenyl ether generated by
the acid-catalyzed reaction of 2-methylpropyl aldehyde and allyl
alcohol under dehydrative conditions.14 Aldehyde 7 was converted
into ethylene acetal 8. Next, the hydroboration and subsequent
work-up with hydrogen peroxide under basic conditions afforded
alcohol 9, which was then converted into iodide 10 under standard
reaction conditions. Next, the ethylene acetal of compound 10 was
removed to afford aldehyde 11, followed by reaction with an
Ohira–Bestmann reagent to afford compound 12. The subsequent
reaction with dimethyl malonate and sodium hydride afforded
compound 13.
2. Results and discussion
Chiral compounds have been prepared by diverse methods, for
example, (i) from chiral pools such as amino acids, sugars, and
terpenes; (ii) asymmetric synthesis from prochiral compounds;
and (iii) resolution of racemic compounds.7 Among these methods,
biocatalytic transformations are advantageous because of the mild
reaction conditions that do not require anhydrous or toxic re-
agents, organic solvents, or an inert atmosphere. They also meet
the requirements of environmentally benign processes because
they do not produce toxic effluents or by-products.8 Enzyme-cata-
lyzed transformations are easy to scale-up; therefore, they have
also been utilized in industrial-scale syntheses. An enzyme usually
catalyzes the reaction of a specific substrate; however, certain
Next, the 6-exo-dig cyclization of compound 13 was examined
(Scheme 4). The Tamura protocol15 was employed for the

720
Y. Namiki et al. / Tetrahedron: Asymmetry 25 (2014) 718–724
suitable for X-ray crystallographic analysis.16 The crystal structure
of compound 14b (Fig. 3) indicated the absolute configuration of
the half-ester 5 as shown in Scheme 5.
O
(CH2OH)2, PPTS (cat)
benzene, Dean-Stark
CHO
O
reflux, 55%
7
8
OH
O
I2, PPh3, imidazole
BH3, THF, 0 °C
then, NaOH, H2O2
H2O, 0 °C
CH2Cl2, 0 °C to rt
85%
O
9
I
COCH3
N2
I
P(O)(OMe)2
O
pTsOH (cat)
CHO
acetone, H2O
50 °C, 80%
O
K2CO3, MeOH
rt, 68%
10
11
I
CO2Me
CO2Me
CH2(CO2Me)2
NaH, THF
0 to 50 °C
85%
Figure 3. X-ray crystallographic structure of 14b.
13
12
Scheme 3. Preparation of 13.
In order to utilize compound 5 for the total synthesis of the
kauranoids, its functionalities were transformed in further conver-
sions (Scheme 6). Compound 5 was successfully converted into the
corresponding alcohol 15 by the formation of the corresponding
acid chloride and subsequent reduction with sodium borohydride.
In order to generate the stereogenic center adjacent to the
quaternary stereogenic center in compound 15, the stereoselective
transformation of the alkene in compound 15 was examined. After
several experiments, the hydroboration of compound 15 with bor-
ane–dimethyl sulfide complex followed by treatment with an
aqueous hydrogen peroxide solution under basic conditions
afforded lactone 4 as the sole product. This high stereoselectivity
is attributed to the directing effect of the hydroxyl group.
CO2Me
CO2Me
CO2Me
CO2Me
1) SnCl4 (2.0 equiv)
Et3N (1.0 equiv)
CH2Cl2, rt
2) 11M H2SO4
THF, rt, 87%
13
6
CO2H
CO2Me
PLE, KPB 8, 30 °C, 6 h
97%, 99% ee
5
Scheme 4. Preparation and the PLE-catalyzed asymmetric hydrolysis of 6.
OH
CO2H
1) (COCl)2, DMF (cat)
CH2Cl2, -78 °C, 9 h
CO2Me
CO2Me
cyclization of compound 13 to efficiently afford prochiral diester 6.
The PLE-catalyzed asymmetric hydrolysis of prochiral diester 6 un-
der standard reaction conditions13 smoothly afforded half-ester 5
in 96% yield. No decarboxylation was observed during the reaction
or work-up.
2) NaBH4, K2CO3
18-crown-6 (cat)
CH2Cl2, H2O, 0 °C
1 h, 81% (2 steps)
15
5
Half-ester 5 was converted into the corresponding anilide 14a
to determine the enantiomeric excess (ee) by HPLC analysis using
a chiral column (Scheme 5); the half-ester was found to be formed
with 99% ee. Next, half-ester 5 was converted into 4-bromo-2-m
ethyl anilide 14b. The recrystallization of 14b afforded a crystal
HO
O
1) BH3·SMe2 (1.0 equiv)
THF, 0 °C to rt, 12 h
O
2) H2O2, 2M NaOH. rt
2 h, 73%
4
Scheme 6. Transformation of 5 into 4.
CO2NHR
CO2Me
CO2H
CO2Me
1) (COCl)2, DMF (cat)
CH2Cl2, –78 °C, 9 h
2) RNH2, CH2Cl2
0 °C to rt, 12 h
Next, we examined an enantiodivergent approach from 5 to
ent-4. The chemoselective reduction of the methyl ester 5 using
LiBH4 and iPrOH17 in THF to prepare 16 was attempted (Scheme 7);
however, the reaction only afforded the compound derived from
decarboxylation and reduction. Consequently, compound 5 was
converted into the corresponding tert-butyl ester 17 via reaction
14a
14b
(R = Ph)
5
88% (2 steps)
(R = 4-Br-2-MePh)
85% (2 steps)
Scheme 5. Preparation of 14a and 14b from 5.

Y. Namiki et al. / Tetrahedron: Asymmetry 25 (2014) 718–724
721
with the reported reagent18 (Scheme 8), and then the selective
hydrolysis of the methyl ester in compound 17 was examined. In
general, hydrolysis of methyl esters at an all-carbon quaternary
stereogenic center proceeds sluggishly under basic conditions;
moreover, in this case, a bulky tert-butyl ester group was one of
the substituents at the all-carbon quaternary center. Therefore,
the hydrolysis of compound 17 required special conditions.
Indeed, the reaction of compound 17 under the usual basic con-
ditions failed with the starting material being quantitatively recov-
ered. After an extensive survey of reaction conditions, the
hydrolysis of compound 17 with ‘anhydrous KOH’19 efficiently
afforded compound 18 in 95% yield. No decarboxylation was ob-
served during the hydrolysis.
1,2-dicarboxylate, a prochiral diester, afforded the corresponding
half-ester in 96% yield and with 99% ee. The absolute configuration
of the half-ester was successfully established by X-ray
crystallographic analysis. The transformations of the half-ester into
(3aS,7aR)-7a-hydroxymethyl-4,4-dimethylhexahydroisobenzofura
n-1(3H)-one and its enantiomeric synthetic intermediate were suc-
cessfully established. The chiral building blocks prepared herein will
be useful for the enantioselective total synthesis of ent-kauranoids
and other natural products.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on JEOL AL-400 spec-
trometers. 1H and 13C chemical shifts are reported in ppm down-
field from tetramethylsilane (TMS, d scale) with the solvent
resonances as the internal standards. The following abbreviations
are used to explain the multiplicities: s, singlet; d, doublet; t, trip-
let; q, quartet; m, multiplet; band, several overlapping signals; br,
broad. IR spectra were recorded on a JASCO FT/IR-8300. Optical
rotations were measured using a 2 mL cell with a 1 dm path length
on a JASCO DIP-1000. Chiral HPLC analysis was performed on a
JASCO PU-980 and UV-970. Mass spectra and elemental analyses
were provided at the Materials Characterization Central Labora-
tory, Waseda University. All reactions were monitored by thin-
layer chromatography carried out on 0.25 mm E. Merck silica gel
plates (60F-254) using UV light as visualizing agent and phospho-
molybdic acid and heat as developing agents. E. Merck silica gel
(60, particle size 0.040–0.063 mm) was used for flash chromatog-
raphy. Preparative thin-layer chromatography (PTLC) separations
were carried out on self-made 0.3 mm E. Merck silica gel plates
(60F-254). Pig liver esterase was purchased from Sigma–Aldrich,
and all other reagents were purchased from Aldrich, TCI, or Kanto
Chemical Co. Ltd.
CO2H
CO2Me
CO2H
LiBH4, iPrOH
THF, 0 °C
OH
5
16
Scheme 7. Attempted chemoselective reduction of 5 to prepare 16.
CO2tBu
CO2Me
CO2H
CO2Me
iPrNC(OtBu)NiPr
CH2Cl2, rt, 90%
17
5
CO2tBu
CO2H
1) ClCO2Me, Et3N
CH2Cl2, 0 °C
tBuOK/H2O = 4/1
Et2O, rt, 95%
2) NaBH4
60% (2 steps)
18
4.2. Preparation of 6
CO2tBu
OH
CO2Me
Di-ester 6 was prepared from known 9.20
1) TFA, CH2Cl2, 0 °C
OH
2) conc. H2SO4, MeOH
72% (2 steps)
4.2.1. 2-(5-Iodo-2-methylpentan-2-yl)-1,3-dioxolane 10
To a stirred solution of imidazole (3.91 g, 57.4 mmol, 2.0 equiv)
and PPh3 (9.03 g, 34.4 mmol, 1.2 equiv) in CH2Cl2 (140 mL) was
added I2 (8.01 g, 31.6 mmol, 1.1 equiv), and the reaction mixture
was stirred at room temperature for 5 min. Then, to the reaction
mixture was added 915 (5.00 g, 28.7 mmol) in CH2Cl2 (8 mL) at
0 °C and the resulting mixture was stirred at 0 °C for 2 h. After
the disappearance of the starting material, to the reaction mixture
was added H2O (140 mL), the aqueous layer was extracted with
CH2Cl2 (50 mL ꢁ 2), and the combined organic layer was washed
with brine (50 mL ꢁ 1), dried over Na2SO4, and evaporated. The
residue was purified by flash chromatography (hexane/ethyl ace-
tate = 40:1) to afford product 10 (6.93 g, 24.4 mmol, 85%) as a col-
orless oil: Rf = 0.72 (hexane/ethyl acetate = 4:1); 1H NMR
(400 MHz, CDCl3) d 4.53 (1H, s), 3.93 (1H, m), 3.86 (1H, m), 3.16
(2H, t, J = 7.2 Hz), 1.91–1.36 (2H, m), 1.43–1.36 (2H, m), 0.90 (6H,
s); 13C NMR (400 MHz, CDCl3) d 109.7, 65.2, 38.6, 36.8, 28.4, 21.6,
7.7; IR (neat) mmax 2957, 2874, 1474, 1397, 1360, 1294, 1210,
ent-15
19
Scheme 8. Transformation of 5 to ent-15.
Compound 18 was successfully converted into alcohol 19 by
reduction of the mixed acid anhydride, which was formed by
the reaction of compound 18 with methyl chloroformate. The
mixed acid anhydride was relatively stable and observed as a
single spot on the TLC plate, probably because of the diminished
reactivity of the mixed acid anhydride caused by the steric
hindrance arising from the all-carbon quaternary center and
the tert-butyl ester. Treatment of compound 19 with trifluoro-
acetic acid and subsequent conversion into the methyl ester
ent-15 was successfully carried out under conventional reaction
conditions as shown in Scheme 8. Transformation of ent-15 into
ent-4 can be carried out according to the procedure in Scheme 6.
Therefore, the formal preparation of ent-4, which is a synthetic
intermediate for the total synthesis of ent-kauranoids, was
achieved.
1161, 1106, 1037, 1003, 950 cmꢀ1
.
4.2.2. 5-Iodo-2,2-dimethylpentanal 11
To a stirred solution of 10 (6.72 g, 23.7 mmol) in acetone/H2O
(1:1 volume, 120 mL) was added p-toluenesulfonic acid (1.80 g,
9.46 mmol, 0.4 equiv), and the reaction mixture was stirred at
50 °C for 10 h. After the disappearance of the starting material,
to the reaction mixture was added saturated aqueous NaHCO3
3. Conclusion
In conclusion, we found that the PLE-catalyzed asymmetric
hydrolysis of dimethyl 3,3-dimethyl-2-methylenecyclohexane-

722
Y. Namiki et al. / Tetrahedron: Asymmetry 25 (2014) 718–724
solution (100 mL). The aqueous layer was extracted with Et2O
(50 mL ꢁ 2), and the combined organic layer was washed with
brine (50 mL ꢁ 1), dried over Na2SO4, and evaporated. The residue
4.3. PLE-catalyzed asymmetric hydrolysis of 6
To a stirred solution of 6 (0.0174 g, 0.0724 mmol) in potassium
phosphate buffer (KPB, pH 8.0, 1.5 mL) was added PLE (165 units),
and the reaction mixture was stirred at 30 °C for 6 h. To the reac-
tion mixture was added 2 M HCl to make the pH of the solution
equal to pH 1. The aqueous layer was extracted with ethyl acetate
(5 mL ꢁ 2), and the combined organic layer was washed with brine
(5 mL ꢁ 1), dried over Na2SO4, and evaporated. The residue was
purified by flash chromatography (hexane/ethyl acetate = 3/1) to
afford product 5 (0.016 g, 0.0707 mmol, 97%) as a white solid.
Rf = 0.3 (hexane/ethyl acetate = 2:1); 1H NMR (400 MHz, CDCl3) d
5.29 (1H, s), 4.93 (1H, s), 3.76 (3H, s), 2.31 (1H, ddd, J = 13.3, 6.0,
6.0 Hz), 2.18 (1H, ddd, J = 13.3, 6.4, 6.4 Hz), 1.72–1.63 (2H, m),
1.48–1.40 (2H, m), 1.11 (3H, s), 1.05 (3H, s); 13C NMR (400 MHz,
CDCl3) d 177.6, 171.7, 150.4, 113.8, 62.0, 52.7, 39.8, 36.7, 32.8,
29.9, 29.4, 18.5; IR (neat) mmax 2950, 1731, 1702, 1633, 1435,
was
purified
by
flash
chromatography
(hexane/ethyl
acetate = 40:1) to afford product 11 (4.55 g, 19.0 mmol, 80%) as a
colorless oil: Rf = 0.69 (benzene); 1H NMR (400 MHz, CDCl3) d
9.46 (1H, s), 3.16 (2H, t, J = 6.8 Hz), 1.80–1.70 (2H, m), 1.61–1.52
(2H, m), 1.07 (6H, s); 13C NMR (400 MHz, CDCl3) d 205.6, 45.4,
37.8, 28.4, 21.6, 21.4, 6.5; IR (neat) mmax 2960, 2700, 2153, 1985,
1725, 1469, 1397, 1207, 1109, 1008, 947 cmꢀ1
; HRMS-ESI
[M+Na]+ calculated for C7H13IO: 241.0084, found: 241.0084.
4.2.3. Dimethyl 2-(4,4-dimethylhex-5-ynyl)malonate 13
To a stirred solution of 11 (1.67 g, 6.96 mmol) in methanol
(140 mL) were added potassium carbonate (1.92 g, 13.9 mmol,
2.0 equiv) and Ohira–Bestmann reagent (1.45 g, 8.37 mmol, 1.2
equiv), and the reaction mixture was stirred at room temperature
for 12 h. After the disappearance of the starting material, to the
reaction mixture was added saturated aqueous NH4Cl solution
(140 mL). The aqueous layer was extracted with Et2O
(50 mL ꢁ 2), and the combined organic layer was washed with
brine (50 mL ꢁ 1), dried over Na2SO4, and evaporated. The residue
was purified by short flash chromatography (hexane/ethyl ace-
tate = 50:1) to afford product 12 (1.12 g, 4.74 mmol, 68%) as a col-
orless oil, which was immediately used for the next reaction:
Rf = 0.8 (hexane/ethyl acetate=10:1). To a stirred solution of NaH
(0.145 g, 6.04 mmol, 1.3 equiv) in THF (40 mL) was added dimethyl
malonate (0.69 mL, 6.04 mmol, 1.3 equiv) at 0 °C, and the reaction
mixture was stirred at 0 °C for 5 min. To the reaction mixture was
added 12 (1.10 g, 4.65 mmol) in THF (20 mL), after which the reac-
tion mixture was stirred at 50 °C for 4 h. After the disappearance of
the starting material, to the reaction mixture was added saturated
aqueous NH4Cl solution (40 mL). The aqueous layer was extracted
with Et2O (20 mL ꢁ 2), and the combined organic layer was
washed with brine (20 mL ꢁ 1), dried over Na2SO4, and evaporated.
The residue was purified by flash chromatography (hexane/ethyl
acetate = 20:1) to afford the product 13 (0.951 g, 3.96 mmol, 85%)
as a colorless oil: Rf = 0.6 (hexane/ethyl acetate = 2:1); 1H NMR
(400 MHz, CDCl3) d 3.75 (6H, s), 3.40 (2H, t, J = 7.6 Hz), 2.07 (1H,
s), 1.95 (2H, m), 1.52–1.34 (4H, m), 1.19 (6H, s); 13C NMR
(400 MHz, CDCl3) d 169.9, 91.5, 68.0, 52.4, 51.6, 42.5, 30.8, 29.1,
29.0, 23.1; IR (neat) mmax 3303, 2955, 1733, 1436, 1355, 1260,
1238, 1198, 1154, 1051, 1015, 912 cmꢀ1; HRMS-ESI [M+Na]+ calcu-
lated for C13H20O4Na: 263.1253, found: 263.1254.
1383, 1364, 1244, 1204, 1165, 1141, 1111, 1061, 1019, 989 cmꢀ1
;
HRMS-ESI [M+Na]+ calculated for C12H18O4Na: 249.1097, found:
249.1097; ½a 2D3
¼ ꢀ18:6 (c 0.80, CHCl3), mp 72.4 °C.
ꢂ
4.3.1. (S)-Methyl 3,3-dimethyl-2-methylene-1-(phenylcarbamoyl)
cyclohexanecarboxylate 14a
To a stirred solution of 5 (0.0255 g, 0.113 mmol) in CH2Cl2
(1.1 mL) were added (COCl)2 (0.019 mL, 0.225 mmol, 2.0 equiv)
and DMF (1 drop) at ꢀ78 °C, and the reaction mixture was stirred
at ꢀ78 °C for 9 h. The reaction mixture was dried under reduced
pressure, and to the residue were added CH2Cl2 (1.1 mL) and ani-
line (0.021 mL, 0.225 mmol, 2.0 equiv), and the reaction mixture
was stirred at room temperature for 8 h. Next, to the reaction mix-
ture was added saturated aqueous NH4Cl solution (5.0 mL). The
aqueous layer was extracted with Et2O (10 mL ꢁ 2), and the com-
bined organic layer was washed with 2 M HCl (10 mL ꢁ 1), satu-
rated aqueous NaHCO3 solution (10 mL ꢁ 1), brine (10 mL ꢁ 1),
dried over Na2SO4, and evaporated. The residue was purified by
PTLC (hexane/ethyl acetate = 4:1 ꢁ 2) to afford product 14a
(0.030 g, 0.0996 mmol, 88%) as a white solid: Rf = 0.7 (hexane/ethyl
acetate = 2:1); 1H NMR (400 MHz, CDCl3) d 7.94 (1H, br), 7.50 (2H,
d, J = 7.7 Hz), 7.33 (2H, dd, J = 7.7, 7.7 Hz), 7.11 (2H, d, J = 7.7 Hz),
5.42 (1H, s), 5.07 (1H, s), 3.76 (3H, s), 2.63 (1H, ddd, J = 13.6, 4.5,
4.5 Hz), 2.09 (1H, ddd, J = 13.6, 5.0, 5.0 Hz), 1.82–1.62 (2H, m),
1.51–1.46 (2H, m), 1.18 (3H, s), 1.10 (3H, s); 13C NMR (400 MHz,
CDCl3) d 173.0, 167.2, 154.7, 137.5, 129.0, 124.4, 119.7, 113.8,
63.3, 52.9, 40.0, 37.4, 31.9, 31.5, 30.6, 29.8, 29.7, 18.5; IR (neat) mmax
3397, 2950, 2917, 2849, 2150, 2027, 1728, 1691, 1598, 1527, 1500,
1463, 1440, 1382, 1364, 1313, 1242, 1177, 1143, 1111, 1079, 1061,
1029, 960 cmꢀ1; HRMS-ESI [M+Na]+ calculated for C18H23O3NNa:
4.2.4. Dimethyl 3,3-dimethyl-2-methylenecyclohexane-1,1-di-
carboxylate 6
To a stirred solution of 13 (0.105 g, 0.435 mmol) in CH2Cl2
(4.4 mL) were added triethylamine (0.061 mL, 0.435 mmol, 1.0
equiv) and SnCl4 (0.1 mL, 0.871 mmol, 2.0 equiv), and the reaction
mixture was stirred at room temperature for 14 h. To the reaction
mixture were added THF (5.0 mL) and 5.5 M H2SO4 (2.5 mL), after
which the reaction mixture was stirred at room temperature for
1 h. Next, the aqueous layer was extracted with Et2O (10 mL ꢁ 2),
and the combined organic layer was washed with brine
(10 mL ꢁ 1), dried over Na2SO4, and evaporated. The residue was
purified by flash chromatography (hexane/ethyl acetate = 25:1)
to afford product 6 (0.091 g, 0.379 mmol, 87%) as a colorless oil:
Rf = 0.7 (hexane/ethyl acetate = 2:1); 1H NMR (400 MHz, CDCl3) d
5.24 (1H, s), 4.79 (1H, s), 3.75 (6H, s), 2.22 (2H, t, J = 5.9 Hz), 1.65
(2H, tt, J = 5.9, 5.4 Hz), 1.44 (2H, t, J = 5.4 Hz), 1.05 (6H, s); 13C
NMR (400 MHz, CDCl3) d 172.2, 151.0, 113.5, 62.2, 52.6, 40.1,
36.8, 33.2, 29.7, 18.7; IR (neat) mmax 2950, 1726, 1634, 1433,
1383, 1363, 1245, 1225, 1206, 1140, 1113, 1062, 1032, 1019,
324.1569, found: 324.1570; ½a D22
¼ þ77:7 (c 0.39, CHCl3), mp
ꢂ
57.4 °C. HPLC: chiralpak OD-3 (hexane/2-PrOH = 9:1, 0.5 mL/
min); tR 12.1, 15.1 min, 99% ee. The peaks were confirmed by HPLC
of the racemic sample.
4.3.2. (S)-Methyl 1-(4-bromo-2-methylphenylcarbamoyl)-3,3-di
methyl-2-methylenecyclohexanecarboxylate 14b
To a stirred solution of 5 (0.0226 g, 0.0999 mmol) in CH2Cl2
(1.0 mL) were added (COCl)2 (0.017 mL, 0.200 mmol, 2.0 equiv)
and DMF (1 drop) at ꢀ78 °C, and the reaction mixture was stirred
at ꢀ78 °C for 9 h. The reaction mixture was dried under reduced
pressure, and to the residue were added CH2Cl2 (1.0 mL), triethyl-
amine (0.028 mL, 0.200 mmol, 2.0 equiv), and 4-bromo-2-methyl
aniline (0.0372 mg, 0.200 mmol, 2.0 equiv). The reaction mixture
was stirred at room temperature for 10 h. Then, to the reaction
mixture was added saturated aqueous NH4Cl solution (10 mL),
and the aqueous layer was extracted with Et2O (10 mL ꢁ 2), and
the combined organic layer was washed with 2 M HCl
(10 mL ꢁ 1), saturated aqueous NaHCO3 solution (10 mL ꢁ 1),
991 cmꢀ1
;
HRMS-ESI [M+Na]+ calculated for C13H20O4Na:
263.1254, found: 263.1254.

Y. Namiki et al. / Tetrahedron: Asymmetry 25 (2014) 718–724
723
brine (10 mL ꢁ 1), dried over Na2SO4, and evaporated. The residue
was purified by flash chromatography (hexane/ethyl ace-
tate = 10:1) to afford product 14b (0.0335 g, 0.0849 mmol, 85%)
as a white solid: Rf = 0.8 (hexane/ethyl acetate = 2:1); 1H NMR
(400 MHz, CDCl3) d 7.98 (1H, s), 7.95 (1H, d, J = 8.6 Hz), 7.36–7.29
(2H, m), 5.41 (1H, s), 5.11 (1H, s), 3.77 (3H, s), 2.63 (1H, ddd,
J = 13.6, 4.5, 4.5 Hz), 2.20 (3H, s), 2.09 (1H, ddd, J = 13.6, 5.0,
5.0 Hz), 1.83–1.63 (2H, m), 1.52–1.46 (2H, m), 1.19 (3H, s), 1.10
(3H, s); 13C NMR (400 MHz, CDCl3) d 173.0, 167.0, 155.1, 135.1,
133.0, 129.8, 122.7, 117.2, 113.5, 63.3, 52.9, 39.8, 37.4, 31.2, 30.5,
30.1, 18.4, 17.4; IR (neat) mmax 3411, 2949, 1961, 1739, 1724,
1694, 1625, 1602, 1578, 1518, 1437, 1397, 1364, 1301, 1242,
1185, 1143, 1124, 1060, 1029, 960 cmꢀ1; HRMS-ESI [M+Na]+ calcu-
lated for C19H24O3NBrNa: 416.0830, found: 416.0832;
4.3.5. (S)-1-tert-Butyl 1-methyl 3,3-dimethyl-2-methylenecyclo
hexane-1,1-dicarboxylate 17
To a stirred solution of 5 (0.032 g, 0.141 mmol) in CH2Cl2
(1.4 mL) was added N,N0-diisopropyl-O-tert-butyl isourea (0.0085,
0.424 mmol, 3.0 equiv), and the reaction mixture was stirred at
room temperature for 18 h, then stirred at 50 °C for 3 h. The reac-
tion mixture was evaporated and dried under reduced pressure.
The residue was purified by flash chromatography (hexane/ethyl
acetate = 20:1) to afford product 17 (0.036 g, 0.128 mmol, 90%) as
a white solid: Rf = 0.4 (hexane/ethyl acetate = 10:1); 1H NMR
(400 MHz, CDCl3) d 5.23 (1H, s), 4.85 (1H, s), 3.72 (3H, s), 2.22
(1H, m), 2.13 (1H, m), 1.68–1.58 (2H, m), 1.46 (9H, s), 1.47–1.39
(2H, m), 1.10 (3H, s), 1.03 (3H, s); 13C NMR (400 MHz, CDCl3) d
172.6, 170.5, 151.3, 113.0, 82.0, 62.7, 52.3, 39.9, 36.7, 33.0, 30.2,
29.5, 27.7, 18.7; IR (neat) mmax 2948, 1724, 1633, 1456, 1392,
½
a 2D3
ꢂ
¼ þ100:7 (c 0.60, CHCl3), mp 112.2 °C.
1367, 1300, 1251, 1213, 1161, 1138, 1062, 1022, 991, 952 cmꢀ1
;
4.3.3. (R)-Methyl 1-hydroxymethyl-3,3-dimethyl-2-methylene-
cyclohexanecarboxylate 15
HRMS-ESI [M+Na]+ calculated for C16H26O4Na: 305.1723, found:
305.1723; ½a 1D9
¼ ꢀ6:8 (c 0.65, CHCl3).
ꢂ
To a stirred solution of 5 (0.020 g, 0.0884 mmol) in CH2Cl2
(1.0 mL) were added (COCl)2 (0.015 mL, 0.177 mmol, 2.0 equiv)
and DMF (1 drop) at ꢀ78 °C, and the reaction mixture was stirred
at ꢀ78 °C for 9 h. The reaction mixture was dried under reduced
pressure, and the residue in CH2Cl2 (1.0 mL) was added to a mix-
ture of 18-crown-6 (0.0047 mg, 0.0177 mmol, 0.2 equiv), K2CO3
(0.0244 g, 0.177 mmol, 2.0 equiv), and NaBH4 (0.0074 g,
0.194 mmol, 2.2 equiv) in CH2Cl2/H2O (1:1 volume, 2.0 mL). The
reaction mixture was stirred for 1 h at 0 °C. Then, to the reaction
mixture was added H2O (5 mL). The aqueous layer was extracted
with ethyl acetate (5 mL ꢁ 2), and the combined organic layer
was washed with brine (5 mL ꢁ 1), dried over Na2SO4, and evapo-
rated. The residue was purified by flash chromatography (hexane/
ethyl acetate = 5:1) to afford product 15 (0.0152 g, 0.0716 mmol,
81%) as a white solid: Rf = 0.5 (hexane/ethyl acetate = 2:1); 1H
NMR (400 MHz, CDCl3) d 5.15 (1H, s), 4.88 (1H, s), 3.91 (1H, d,
J = 10.9 Hz), 3.72 (1H, d, J = 10.9 Hz), 5.41 (1H, s), 3.69 (3H, s),
2.30 (1H, ddd, J = 13.1, 5.0, 5.0 Hz), 2.19 (1H, br), 1.83 (1H, m),
1.60 (1H, m), 1.53–1.43 (2H, m), 1.35 (1H, m), 1.12 (3H, s), 1.00
(3H, s); 13C NMR (400 MHz, CDCl3) d 176.0, 153.4, 110.3, 68.6,
53.7, 52.2, 40.5, 36.9, 31.2, 31.0, 28.7, 18.6; IR (neat) mmax 3467,
2950, 2846, 1728, 1628, 1434, 1381, 1302, 1269, 1202, 1134,
1055, 1032, 1012, 990 cmꢀ1; HRMS-ESI [M+Na]+ calculated for C12-
4.3.6. (S)-1-tert-Butoxycarbonyl-3,3-dimethyl-2-methylenecy-
clohexane-1-carboxylic acid 18
To a stirred suspension of t-BuOK (0.0668 g, 0.595 mmol, 8.0
equiv) in Et2O (1.5 ml) was added H2O (0.003 ml, 0.149 mmol,
2.0 equiv) at 0 °C, and the reaction mixture was stirred at 0 °C for
5 min. To the resulting mixture was added 17 (0.021 g,
0.0744 mmol) in Et2O. The mixture was stirred at room tempera-
ture for 46 h. Then, to the reaction mixture were added ice cold
water (5.0 mL) and 2 M HCl (2 mL). The aqueous layer was ex-
tracted with ethyl acetate (5 mL ꢁ 2) and the combined organic
layer was washed with brine (5 mL), dried over Na2SO4, and evap-
orated. The residue was purified by flash chromatography (hexane/
ethyl acetate = 4:1) to afford product 18 (0.0189 g, 0.704 mmol,
95%) as a white solid: Rf = 0.4 (hexane/ethyl acetate = 2:1); 1H
NMR (400 MHz, CDCl3) d 5.28 (1H, s), 4.98 (1H, s), 2.24–2.16 (2H,
m), 1.71–1.62 (2H, m), 1.50–1.40 (2H, m), 1.47 (9H, s), 1.10 (6H,
s); 13C NMR (400 MHz, CDCl3) d 177.8, 170.0, 150.9, 113.6, 82.4,
62.6, 39.7, 36.7, 32.7, 30.1, 29.9, 27.7, 18.6; IR (neat) mmax 2968,
2003, 1727, 1702, 1632, 1458, 1393, 1368, 1255, 1163, 1144,
1061, 1020, 953 cmꢀ1; HRMS-ESI [M+Na]+ calculated for C15H24O4-
Na: 291.1566, found: 291.1567; ½a D20
¼ þ7:6 (c 0.75, CHCl3), mp
ꢂ
107.4 °C.
H20O3Na: 235.1305, found: 235.1305; ½a D23
¼ ꢀ61:9 (c 1.5, CHCl3).
ꢂ
4.3.7. (S)-tert-Butyl 1-hydroxymethyl-3,3-dimethyl-2-methyl-
enecyclohexane-1-carboxylate 19
4.3.4. (3aS,7aR)-7a-Hydroxymethyl-4,4-dimethyl-hexahydroiso
benzofuran-1(3H)-one 4
To a stirred solution of 18 (0.0386 g, 0.1438 mmol) in THF
(1.5 mL) were added triethylamine (0.04 ml, 0.288 mmol, 2.0
To a stirred solution of 15 (0.0139 g, 0.0614 mmol) in THF
(1.0 mL) was added BH3SMe2 (0.002 mL, 0.0614 mmol, 1.0 equiv)
at 0 °C, and the reaction mixture was stirred at room temperature
for 10 h. To the reaction mixture were added H2O (2 drops) and
30% H2O2 (0.5 mL), 2 M NaOH (0.5 mL), and the reaction mixture
was stirred at room temperature for 2 h. Then, to the reaction mix-
ture was added saturated aqueous NH4Cl solution (5 mL). The
aqueous layer was extracted with ethyl acetate (5 ml ꢁ 2), washed
with saturated aqueous Na2S2O3 solution (5 mL ꢁ 1), brine
(5 mL ꢁ 1), dried over Na2SO4, and evaporated. The residue was
purified by flash chromatography (hexane/ethyl acetate = 6:1) to
afford product 4 (0.009 g, 0.0455 mmol, 73%) as a colorless oil;
Rf = 0.4 (hexane/ethyl acetate = 2:1); 1H NMR (400 MHz, CDCl3) d
4.27 (1H, dd, J = 9.1, 8.6 Hz), 4.10 (1H, dd, J = 11.3, 9.1 Hz), 3.97
(1H, d, J = 11.3 Hz), 3.76 (1H, d, J = 11.3 Hz), 2.54 (1H, br), 2.40
(1H, m), 1.84 (1H, m), 1.62–1.31 (5H, m), 1.05 (3H, s), 0.90 (3H,
s); 13C NMR (400 MHz, CDCl3) d 182.2, 67.4, 64.3, 46.7, 44.9, 34.7,
30.0, 28.7, 25.2, 17.7; IR (neat) mmax 3445, 2932, 2869, 2028,
1759, 1460, 1390, 1367, 1345, 1224, 1154, 1121, 1046, 1022,
i
equiv) and ClCO2 Pr (0.025 mL, 0.216 mmol, 1.5 equiv) at 0 °C,
and the reaction mixture was stirred at 0 °C for 1 h. After the dis-
appearance of the starting material, to the reaction mixture was
added saturated aqueous NH4Cl solution (5 mL). The aqueous layer
was extracted with Et2O (5 mL ꢁ 2), and the combined organic
layer was washed with brine (5 mL), dried over Na2SO4, and evap-
orated. To the residue were added MeOH (1.0 mL) and NaBH4
(0.0163 g, 0.431 mmol, 3.0 equiv) at 0 °C, and the mixture was stir-
red at 0 °C for 2 h. After the disappearance of the starting material,
to the mixture was added H2O (5 mL). The aqueous layer was ex-
tracted with ethyl acetate (5 mL ꢁ 2), and the combined organic
layer was washed with brine (5 mL), dried over Na2SO4, and evap-
orated. The residue was purified by flash chromatography (hexane/
ethyl acetate = 4:1) to afford product 19 (0.0218 g, 0.0863 mmol,
60%) as a colorless oil: Rf = 0.58 (hexane/ethyl acetate = 2:1); 1H
NMR (400 MHz, CDCl3) d 5.15 (1H, s), 4.91 (1H, s), 3.82 (1H, d,
J = 10.5 Hz), 3.68 (1H, d, J = 10.5 Hz), 2.22–2.14 (2H, m), 1.87–
1.74 (2H, m), 1.63–1.47 (2H, m), 1.44 (9H, s), 1.11 (3H, s), 1.07
(3H, s); 13C NMR (400 MHz, CDCl3) d 174.6, 153.5, 110.3, 81.0,
68.7, 54.1, 40.1, 36.6, 31.0, 30.7, 29.5, 27.8, 18.4; IR (neat) mmax
998 cmꢀ1
;
HRMS-ESI [M+Na]+ calculated for C11H18O3Na:
221.1149, found: 221.1148; ½a D23
¼ ꢀ19:4 (c 0.17, CHCl3).
ꢂ

724
Y. Namiki et al. / Tetrahedron: Asymmetry 25 (2014) 718–724
Rev. 2008, 108, 2853–2873; (e) Turner, N. J. Chem. Rev. 2011, 111, 4073–4087;
(f) Hall, M.; Bommarius, A. S. Chem. Rev. 2011, 111, 4088–4110; (g) Moyano, A.;
Rios, R. Chem. Rev. 2011, 111, 4703–4832; (h) Wang, J.; Liu, X.; Feng, X. Chem.
Rev. 2011, 111, 6947–6983; (i) Yus, M.; Gonzáez-Gómez, J.; Foubelo, F. Chem.
Rev. 2011, 111, 7774–7854; (j) Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem.,
Int. Ed. 2012, 51, 12662–12686.
3478, 2965, 2931, 1723, 1628, 1458, 1392, 1367, 1247, 1156, 1056,
1031, 1013, 949, 901 cmꢀ1; HRMS-ESI [M+Na]+ calculated for C15-
H26O3Na: 277.1774, found: 277.1774; ½a D20
¼ þ28:8 (c 0.21, CHCl3).
ꢂ
4.3.8. (S)-Methyl 1-hydroxymethyl-3,3-dimethyl-2-methylene-
cyclohexanecarboxylate ent-15
8. Hudlichy, T. Chem. Rev. 2011, 111, 3995–3997.
9. (a) Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S. Chem. Rev. 2011, 111, 4036–
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(d) Bjökling, F.; Boutelje, J.; Gatenbeck, S.; Hult, K.; Norin, T.; Szmulik, P.
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Hult, K.; Norin, T.; Szmulik, P. Bioorg. Chem. 1986, 14, 176–181; (f) Luyten, M.;
Mꢃler, S.; Herzog, B.; Keese, R. Helv. Chim. Acta 1987, 70, 1250–1254; (g) Jeso, B.
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To a stirred solution of 19 (0.0066 g, 0.0259 mmol) in CH2Cl2
(1.0 mL) was added TFA (1.0 mL), and the reaction mixture was
stirred for 3 h at room temperature. After the disappearance of
the starting material, the reaction mixture was concentrated and
dried under reduced pressure. To the residue were added MeOH
(1.0 mL) and conc. H2SO4 (cat.), and the mixture was stirred at
70 °C for 20 h. After disappearance of the starting material, to the
reaction mixture was added saturated aqueous NaHCO3 solution
(5 mL). The aqueous layer was extracted with Et2O (5 mL ꢁ 2),
and the combined organic layer was washed with brine (5 mL),
dried over Na2SO4, and evaporated. The residue was purified by
flash chromatography (hexane/ethyl acetate = 4:1) to afford prod-
uct ent-15 (0.0044 g, 0.0188 mmol, 72%) as a colorless oil: Rf = 0.5
10. Ohno, M.; Otsuka, M. Org. React. 1989, 37, 1–55.
11. (a) Servi, S. Synthesis 1990, 1–25; (b) Cusk, R.; Glänzer, B. I. Chem. Rev. 1991, 91,
49–97; (c) Hoegberg, H.-E.; Berglund, P.; Edlund, H.; Faegerhag, J.;
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Fujieda, S.; Tomita, M.; Fuhshuku, K.; Ohba, S.; Nishiyama, S.; Sugai, T. Adv.
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J. Org. Chem. 2005, 70, 4652–4658.
(hexane/ethyl acetate = 2:1); ½a D20
¼ þ60:0 (c 0.21, CHCl3).
ꢂ
Acknowledgments
12. (a) Domínguez de Maria, P.; García-Burgos, C. A.; Bargeman, G.; van Gemert, R.
W. Synthesis 2007, 1439–1452; (b) Tamm, C. Pure Appl. Chem. 1992, 64, 1187–
1191; (c) Jones, J. B. Aldrichim. Acta 1993, 26, 105–112.
This work was financially supported in part by Waseda Univer-
sity Grant for Special Research Projects, The Grant-in-Aid for Scien-
tific Research on Innovative Areas ‘Organic Synthesis based on
Reaction Integration, Development of New Methods and Creation
of New Substances’ (No. 2105), Grant for Scientific Research (B)
(25293003), and Grants for Excellent Graduate Schools (Practical
Chemical Wisdom), MEXT, Japan.
13. (a) Asakawa, K.; Noguchi, N.; Nakada, M. Heterocycles 2008, 76, 183–190; (b)
Asakawa, K.; Noguchi, N.; Takashima, S.; Nakada, M. Tetrahedron: Asymmetry
2008, 19, 2304–2309; Also see: (c) Jones, J. B. Can. J. Chem. 1993, 71, 1273–
1282; (d) Hallinan, K. O.; Honda, T. Tetrahedron 1995, 51, 12211–12216; (e)
Honda, T.; Ogino, T. Tetrahedron: Asymmetry 1998, 9, 2663–2669.
14. Magnus, P. D.; Nobbs, M. S. Synth. Commun. 1980, 10, 273–278.
15. Kitagawa, O.; Fujiwara, H.; Suzuki, T.; Taguchi, T.; Shiro, M. J. Org. Chem. 2000,
65, 6819–6825.
16. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data centre as
supplementary publication numbers CCDC 974995. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 IEZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
17. Gersch, M.; Gut, F.; Korotkov, V. S.; Lehmann, J.; Böttcher, T.; Rusch, M.;
Hedberg, C.; Waldmann, H.; Klebe, G.; Sieber, S. A. Angew. Chem., Int. Ed. 2013,
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