Asymmetric Kulinkovich Hydroxycyclopropanation of Alkenes Mediated by Titanium(IV) TADDOLate Complexes

Article abstract of DOI:10.1055/s-0037-1611709

Asymmetric Kulinkovich cyclopropanation of carboxylic esters with prochiral alkenes is reported. The process is mediated by titanium(IV) (4 R,5 R)-TADDOLate complexes and affords correspondingly (Z)- or (E)-cyclopropanols with up to 84-87% ee in the event of intra- or intermolecular olefin ligand exchange in intermediate titanacyclopropane [titanium(II)-alkene] species. Configuration of the olefin double bond is preserved in the cyclopropane products, pointing out on total retention of configuration at Ti-C bond in the cyclopropane forming step. The results have been interpreted in the framework of ate complex mechanism, suggesting formation of pentacoordinated titanium ate species as a prerequisite of high enantiocontrol.

Full text of DOI:10.1055/s-0037-1611709

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–N
feature
A
en
M. Iskryk et al.
Feature
Synthesis
Asymmetric Kulinkovich Hydroxycyclopropanation of Alkenes
Mediated by Titanium(IV) TADDOLate Complexes
Marharyta Iskryka,b
Maryia Barysevicha,b
Maksim Ošekaa
Jasper Adamsonc
Dzmitry Kananovich*a
R2 R2
R2 R2
OTIPS
OH
n
n
1. (TADDOL)TiX2
2. R1CO2CH(CF3)2,
i-AmMgBr or BuMgBr
0
0
0
0-0
0
0
2-2
6
6
4-4
4
9
1
R2 R2
OH
R2 R2
OH
R1
HO
a Tallinn University of Technology, School of Science, Department of Chemistry
and Biotechnology, Akadeemia tee 15, 12618 Tallinn, Estonia
dzmitry.kananovich@taltech.ee
b Laboratory of Steroids, Institute of Bioorganic Chemistry, National Academy of
Sciences of Belarus, Kuprevich 5/2, 220141 Minsk, Belarus
c National Institute of Chemical Physics and Biophysics, Akadeemia tee 23,
12618 Tallinn, Estonia
n
n
R
2 = H, Me; n = 1–3
X = Me, Oi-Pr
R1
OH
(E)
up to 84% ee
(Z)
up to 87% ee
Dedicated to Prof. Oleg Kulinkovich on the occasion of his 70th birthday
Received: 15.11.2018
Accepted after revision: 18.12.2018
Published online: 05.02.2019
2-substituted cyclopropanol fragment as an essential part
of its macrocylic core.8 Evidently, both the use as synthetic
intermediates and synthesis of cyclopropane-containing
bioactive and natural products requires easy access to di-
versely functionalized chiral cyclopropanol building blocks.
DOI: 10.1055/s-0037-1611709; Art ID: ss-2018-z0768-fa
Abstract Asymmetric Kulinkovich cyclopropanation of carboxylic
esters with prochiral alkenes is reported. The process is mediated by
titanium(IV) (4R,5R)-TADDOLate complexes and affords corresponding-
ly (Z)- or (E)-cyclopropanols with up to 84–87% ee in the event of intra-
or intermolecular olefin ligand exchange in intermediate titanacyclo-
propane [titanium(II)-alkene] species. Configuration of the olefin dou-
ble bond is preserved in the cyclopropane products, pointing out on
total retention of configuration at Ti–C bond in the cyclopropane form-
ing step. The results have been interpreted in the framework of ate
complex mechanism, suggesting formation of pentacoordinated titani-
um ate species as a prerequisite of high enantiocontrol.
R2
R1
R2
R1
E+
a)
E
OH
OH
O
HOOC
NH2
OH
allo-coronamic acid
HNR'2
Zn(CN)2, Na2CO3
Key words titanium, Kulinkovich reaction, cyclopropanation, esters,
cyclopropanols, asymmetric synthesis, reaction mechanisms
R
NR'2
R
OH
1,4-dioxane, 110 °C
b)
O
O
O
H
OH
S
N
O
O
Cyclopropanols have occupied a niche in organic syn-
thesis as readily available and versatile synthetic intermedi-
ates.1 The strained three-carbon ring of cyclopropanols can
be easily cleaved under mild conditions with a variety of
electrophilic or radical species, producing valuable carbonyl
compounds.2 In the case of 1,2-disubstituted cyclopropa-
nols, reactions with a number of electrophilic reagents can
occur selectively at the least substituted C1–C3 bond with-
out affecting the stereocenter at C2. This property is widely
used for preparation of α-methyl branched ketones
(Scheme 1a).3 The cyclopropane ring can also be retained in
some transformations, for example, en route to cyclopro-
pylamines.4 Essentially, enantiomeric purity of a chiral
cyclopropane precursor is preserved in products. Moreover,
besides occurrence in some natural products, for example,
phorbol5 and recently discovered toblerols,6 the cyclopro-
panol unit has growing importance as a structural motif in
medicinal chemistry (Scheme 1b).7,8 As an example, grazo-
previr, approved for treatment of HCV infection, contains a
OH
H
N
H
H
N
O
HN
H
OH
MeO
N
N
O
O
O
HO
OH
grazoprevir
phorbol
O
OH
O
OH
toblerol A
Scheme 1 a) Cyclopropanols as synthetic intermediates en route to
α-branched ketones and cyclopropylamines; b) examples of natural and
bioactive compounds with incorporated cyclopropanol unit
Currently, enantiopure 2-substituted cyclopropanols
are usually prepared from readily available chiral precur-
sors, mainly cyclopropyl boronates.9 However, asymmetric
synthesis of more complex hydroxy-substituted cyclopro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

B
M. Iskryk et al.
Feature
Synthesis
Biographical Sketches
Marharyta Iskryk was born in
Minsk, Belarus in 1993. She was
graduated from the Belarusian
State University in 2016. For her
Master studies, in 2016 she joined
Dr. Alaksiej Hurski’s group at the
Institute of Bioorganic Chemistry of
National Academy of Science of Be-
larus, where her task was synthesis
of long-term metabolites of anabol-
ic steroids. From 2017, Marharyta
continues as a Ph.D. student in the
same laboratory. In 2018, she
worked in Tallinn University of
Technology as a visiting Ph.D. stu-
dent.
Maryia Barysevich was born in
Minsk, Belarus in 1994. She re-
ceived her B.Sc. degree in chemis-
try from the Belarusian State
University in 2016. She completed
her M.Sc. studies in organic chem-
istry at the Institute of Bioorganic
Chemistry of National Academy of
Science of Belarus in 2017 under
the supervision of Dr. Alaksiej Hur-
ski where she worked on C–H acti-
vation strategies in application to
synthesis and modification of ste-
roids. Recently she commenced her
Ph.D. studies in the same laborato-
ry. As a part of her doctoral studies,
in 2018 she visited Tallinn Universi-
ty of Technology with support of
Dora Plus program.
Maksim Ošeka was born in
Tallinn, Estonia in 1988. As an un-
dergraduate student, he joined the
research group of Prof. Tõnis
Kanger at Tallinn University of
Technology in 2009, where he
focused on the development of
asymmetric organocatalytic reac-
tions and continued as a Master
and then as a Ph.D. student. As part
of his master’s studies, Maksim
undertook an Erasmus placement
at Oslo University, Norway, working
with Prof. Lise-Lotte Gundersen. As
a visiting Ph.D. student, Maksim
worked in the group of Prof. Paolo
Melchiorre (ICIQ, Spain) and partic-
ipated in the development of photo-
chemically driven enantioselective
transformations. Maksim obtained
his Ph.D. degree in 2017 and cur-
rently continues as
a research
scientist at Tallinn University of
Technology.
Jasper Adamson was born in
Tallinn, Estonia in 1985. He re-
ceived his B.Sc. and M.Sc. degrees
from the University of Cambridge,
UK, where he undertook a final year
project with Prof. David Spring to
study fluoride-free cross-coupling
reactions. He then continued with
a D.Phil. at the University of Oxford
working with Prof. Andrew
Goodwin to study crystallographic
properties of layered materials,
graduating in 2015. Jasper subse-
fellowship at the National Institute
of Chemical Physics and Biophysics
in Estonia and has since then start-
ed his own research group focusing
on aromatic macrocycles and their
molecular recognition properties.
quently undertook
a
research
Dzmitry Kananovich was born in
Borisov, Belarus in 1982. In 2008,
he completed his Ph.D. under the
guidance of Prof. Oleg Kulinkovich
at the Belarusian State University
(Minsk, Belarus) and continued his
work as a research fellow at the
Laboratory of Organoelement
Synthesis at the same university. In
2011, he moved to Tallinn University
of Technology (Estonia) for a post-
doctoral stay in the group of Prof.
Margus Lopp. In 2015, he was ap-
pointed as a senior researcher at
the Chair of Green Chemistry at the
same university and soon after
started his independent carrier. His
research interests are currently
focused on organometallic chemis-
try, transition-metal catalysis,
chemistry of strained carbo- and
heterocyclic compounds as well as
on the development of new enantio-
selective transformations.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

C
M. Iskryk et al.
Feature
Synthesis
panes is challenging,10 and their occurrence in pharmaceu-
tically relevant molecules is rare.7e Among the methods ex-
isting, Kulinkovich cyclopropanation of carboxylic esters11
and its extensions,12 including olefin ligand exchange vari-
ant,13 stands as a highly desired approach to access hetero-
atom-substituted cyclopropane compounds because of its
generality and broad scope. Furthermore, Kulinkovich reac-
tion is often highly diastereoselective,11 allowing substrate-
controlled preparation of chiral cyclopropanols from enan-
tiomerically pure starting materials.3a,14 However, elabora-
tion of a practical procedure for the asymmetric Kulinkov-
ich reaction controlled by a chiral titanium alkoxide catalyst
has turned out to be a challenging task. The first encourag-
ing result was reported in 1994 by the Corey group (Scheme
2, I),15 who demonstrated that (1S,2R)-cyclopropanol 1a can
be prepared with 70–78% ee by using titanium spiro-
TADDOLate 2. However, the succeeding activity in the field
has not yielded any superior results in the course of the
next twenty years.16,17 Thus, enantioselectivity up to 65% ee
was reported for cyclopropanation of isopropyl 4-chloro-
butanoate with n-BuMgBr in the presence titanium(IV)
(4R,5R)-TADDOLate catalyst 3 (Scheme 2, II),16b while the
use of Ti(TADDOL)2, BINOL, and (S)-1,3-butanediol as chiral
ligands was not as successful.16a
rather than tetracoordinated titanium compounds as reac-
tive intermediates. The revision of the original mechanism
allowed to explain several unique features of Kulinkovich
reaction,19 including its high cis-diastereocontol.20 More-
over, further advancement in the development of asymmet-
ric cyclopropanation with titanium(IV) (4R,5R)-TADDOLate
3 was made possible due to ingenious insight that penta-
coordinated ate complexes mediate the process, which was
also confirmed by the direct NMR observation.21 Experi-
mental data were consistently interpreted in the frame-
work of ate complex mechanism, suggesting formation of
titanacyclopropane [or titanium(II)-alkene] species A as the
key reactive intermediates. It was also found in the same
work that enantiomeric purity of the cyclopropanol prod-
uct strongly depended on the nature of the leaving alkoxide
group in the carboxylic ester, with the highest enantioselec-
tivity (up to 84% ee) achieved for hexafluoroisopropyl
esters 4. To rationalize these observations, it was supposed
that the ester alkoxide group could have an effect on the
rate of the cyclopropane ring-closing step, which can pro-
ceed either with retention or (partially) with inversion of
the configuration at the stereogenic carbanion center
(Scheme 2, III). The latter process could be enhanced in the
case of a poor leaving alkoxide group, thus decreasing enan-
tiomeric purity of the product.
In part, the disappointing early results could be con-
nected with insufficient understanding of the reaction
mechanism and nature of intermediate species. To address
this issue, Kulinkovich proposed18,19 titanium ate complexes
Following previous works16b,21 on titanium(IV) TADDOL-
ate-controlled asymmetric cyclopropanation of esters with
alkylmagnesium halides, we report here the expansion of
I) Corey 1994
III) Kulinkovich 2014
1. Ti(OR*)4 (0.3–1 equiv)
PhCH2CH2MgBr (2.2 equiv)
Et2O
1. (TADDOL)Ti(Oi-Pr)2 (2 equiv)
R2CH2CH2MgBr (4 equiv)
Et2O
Ph
R2
2. H3O+
O
O
2. H2O
OEt
OH
65–72%
R1
OCH(CF3)2
R1
OH
45–87%
(1S,2R)-1a
70–78% ee
4
(1S,2S)-1
66–84% ee
Ar
Ar
Ar
Ar
Ar
Ar
Ar
CF3
O
O
O
Ph
R2
O
O
R2
O
O
Ph
O
R1CO2R
Ti(OR*)4
=
Ar =
Ti
2
O
H
L3Ti
A
H
O
Ti
O
CF3
O
Ph
Ar
Oi-Pr
BrMg+
Ph
II) Kulinkovich 2013
R2
R2
1. (TADDOL)Ti(Oi-Pr)2 (0.2–1 equiv)
OMgBr
BrMgOi-Pr
EtCH2CH2MgBr (2.2–3 equiv)
Et2O
2. H3O+
L3Ti
OR
R1
R1
L3Ti
Et
Cl
O
Oi-Pr
O
OR
Cl
OH
55%
Oi-Pr
Ti–C
Ti–C
3
3
retention
inversion
(1S,2S)-1b
Ph
Ph
R2
R2
R1
65% ee
O
O
O
(TADDOL)Ti(Oi-Pr)2
=
Ti(Oi-Pr)2
OH
HO
R1
O
(1S,2S)-1
major
(1R,2R)-1
minor
Ph
Ph
3
Scheme 2 Milestones in asymmetric cyclopropanation of carboxylic esters with titanacyclopropane reagents
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

D
M. Iskryk et al.
Feature
Synthesis
I)
Ti
BrMg+
Ph
R'
Ti(TADDOL)2
Ph
2 R'CH2CH2MgBr
O
R'
O
O
O
H
O
O
4
H
L*Ti
Ti
toluene
O
Ph
6
O
BrMgO
R'
Ph
5
L* = TADDOL
A
R'
R'
BrMg+
L*Ti
1. PhCH2CH2COOR
2. H2O
BrMg+
L*Ti
BrMg+
L*Ti
Ph
or
OH
O
OH
(Z)-1c
O
O
R'
Et
C
B'
B
(52–86% ee)
II)
BrMg+
TIPSO
BrMg+
1. ester 4a
2. H2O
OTIPS
HO
Oi-Pr
Oi-Pr
2 n-BuMgBr
OX
10
(TADDOL)Ti
L*Ti
L*Ti
Ph
Oi-Pr
Oi-Pr
3
i-PrOMgBr,
butane
1-butene
E
(E)-1d (X = TIPS)
(E)-1c (X = H)
(80% ee)
D
TBAF
1. ester 4a
2. H2O
3. TBAF
OTIPS
2 n-BuMgBr
OTIPS
10
(E)-1c
L*Ti
(TADDOL)TiCl2
L*Ti
(66% ee)
Et
MgBrCl,
butane
11
1-butene
F
G
Scheme 3 Enantioselective cyclopropanation of 3-phenylpropionates with titanium(IV) but-3-en-1-oxide 6 and its synthetic equivalents via (I) intra-
and (II) intermolecular olefin ligand exchange to the corresponding titanacyclopropane intermediates
the same methodology on enantioselective synthesis of
cyclopropanols via an olefin ligand exchange method.
Furthermore, disubstituted and deuterium-labeled
olefins as precursors of reactive titanacyclopropane species
provide a convenient opportunity to obtain experimental
evidence if the inversion of configuration at Ti–C bond
during the ring-closing step is responsible for the observed
dependence of enantioselectivity on the nature of carboxyl-
ic ester substrate.
Taking into account the advantage of homoallylic alco-
hols to provide high Z-diastereocontrol due to the directing
effect of a hydroxyl group,14,22 at the initial stage we investi-
gated asymmetric cyclopropanation of 3-phenylpropio-
nates with alkoxide complex of homoallylic alcohol 5
(Scheme 3, I). The latter was conveniently generated by
mixing of equimolecular amounts of Ti(TADDOL)2 and the
corresponding titanium tetraalkoxide 6. Assuming forma-
tion of pentacoordinated titanium ate complexes as inter-
mediate species,21 generation of bicyclic titanacyclopro-
pane complex C could be expected as a consequence of dou-
ble alkylation of 5 with a Grignard reagent, via initial
elimination of an alkane from ate complex A and subse-
quent intramolecular olefin ligand exchange in complex B.
Intermediacy of pentacoordinated ate complexes is strongly
supported by NMR data [see Supporting Information (SI),
Section II]. Thus, stable dimethyltitanium analogue23 of A
can be generated by the reaction of (TADDOL)Ti(Oi-Pr)2 (3)
with 2 equivalents of MeMgBr. Due to chelate control of the
oxygen tether,14,22 reaction of C with a carboxylic ester
would eventually produce Z-1,2-disubstituted cyclopropa-
nol (Z)-1c in enantioselective fashion.
Indeed, cyclopropanol 1c was obtained exclusively as Z-
diastereomer in 66% yield and with good enantioselectivity
(74% ee) when hexafluoroisopropyl 3-phenylpropionate
(4a) was treated with n-BuMgBr in the presence of titanium
alkoxide 5 (Table 1, entry 1). On the other hand, alternative
method for preparation of (Z)-1c via intramolecular cyclo-
propanation22a,b of homoallylic ester 7 (entry 2) resulted in
lower diastereoselectivity and poor enantiocontrol for Z-
diastereomer of 1c (only 20% ee).
As in the case of enantioselective cyclopropanation with
alkylmagnesium bromides,21 enantiomeric purity of (Z)-1c
strongly depended on the nature of the leaving alkoxide
group in the ester precursor. Thus, ethyl 3-phenylpropio-
nate (8) afforded (Z)-1c with noticeably lower enantioselec-
tivity than the corresponding hexafluoroisopropyl ester 4a
(52 vs. 74% ee, Table 1, entries 3 and 1), and the best result
(86% ee) was achieved for cyclopropanation of nonafluoro-
tert-butyl ester 9 (entry 4). It is worth noting that attempts
to improve ee by performing the same reaction at 0 °C re-
sulted in the formation of 5-phenethylnonane-1,5-diol
(~30%) as the main product and only a trace amount (>5%)
of cyclopropane (Z)-1c, along with 50% recovery of ester 9,
as established by 1H NMR analysis of the crude reaction
mixture (entry 5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

E
M. Iskryk et al.
Feature
Synthesis
Table 1 Enantioselective Cyclopropanation of 3-Phenylpropionates
with Titanium(IV) But-3-en-1-oxide 6 and Its Synthetic Equivalents
Mediated by Titanium TADDOLates
Besides titanium-tethered 3-butenoxide, we were
pleased to find that good yields and enantioselectivity
could also be attained in an intermolecular olefin ligand ex-
change process (Scheme 3, II). Thus, cyclopropanation of
ester 4a with TIPS-protected homoallylic alcohol 10 in the
presence of titanium TADDOLate 3 (Table 1, entry 11) af-
forded cyclopropanol 1d predominantly as E-isomer20 with
80% ee [as determined after deprotection into diol (E)-1c].
Use of dichlorotitanium TADDOLate 11 in the same process
was less efficient, producing cyclopropanol (E)-1d in low
20% yield and, more importantly, with noticeably lower 66%
ee (entry 12). In line with previous results,21 we believe that
additional steric interaction of incoming olefin moiety with
isopropoxide ligand in ate complex intermediates D and E
(missed in non-ate F and G, Scheme 3, II), could be responsi-
ble for higher enantioselectivity attained in the case of iso-
propoxide complex 3.
As an alternative to the generation of TADDOLate 5 from
the preformed titanium alkoxide 6, a more convenient one-
pot procedure for the installation of alkenoxide ligand with
neat homoallylic alcohol has also been developed (Table 2).
In this approach, easily available dichlorotitanium TADDOL-
ate24 11 was treated with methyllithium to produce di-
methyltitanium compound 12 (see SI for NMR data). Addi-
tion of homoallylic alcohol (1 equiv) resulted in fast genera-
tion of methyltitanium alkoxide 13, which could serve as an
immediate precursor of the same titanacyclopropane ate
complex C (Scheme 3, I). As shown in Table 2, the alterna-
tive procedure affords (Z)-1c with similar (or slightly bet-
ter) enantiomeric purity as the generic procedure based on
alkoxide 5, albeit the latter provides generally better yields.
Entry
Ester
Grignard reagent Yield (%)a
drb(Z/E)
ee (%)c
1
2d
3
4a
7
n-BuMgBr
n-BuMgBr
n-BuMgBr
n-BuMgBr
n-BuMgBr
EtMgBr
66
65
45
40
>5f
40
75
70
71
77
57h
20h
100:0
87:13
100:0
100:0
–
74
20e
52
86
–
8
4
9
5
9
6
4a
4a
4a
4a
4a
4a
4a
100:0
100:0
100:0
100:0
100:0
>2:98
>5:95
70
74
74
54
62
80
66
7
i-AmMgBr
n-PrMgBr
i-PrMgBr
8
9
10
11d,g
12g,i
c-C5H11MgBr
n-BuMgBr
n-BuMgBr
CF3
CF3
Ph
OR
O
O
(4a),
O
CF3 (9)
OR =
CF3
CF3
O
(7), OEt (8)
a Yield of isolated product, unless indicated otherwise.
b Ratio of Z/E-1c determined by 1H NMR analysis of the crude reaction
mixture.
c Determined by HPLC analysis.
d With (TADDOL)Ti(Oi-Pr)2 (3).
e Minor isomer (E)-1c was obtained with 66% ee.
f The reaction was performed at 0 °C.
g TIPS-protected alcohol 10 was used.
h Yield of (E)-1d by 1H NMR spectroscopy. Isolated as (E)-1c (41%) after
removal of TIPS group.
i (TADDOL)TiCl2 (11) was used.
Table 2 Generation of Methyltitanium Complex 13 and Its Use for
Cyclopropanation of 3-Phenylpropionates 4a and 9
Influence of a Grignard reagent was tested next (Table 1,
entries 6–10). In addition to the already-tested n-BuMgBr
(entry 1), primary alkylmagnesium bromides (EtMgBr, n-PrMgBr,
i-AmMgBr) produced (Z)-1c with nearly the same enanti-
oselectivity (70–74% ee, entries 6–8), while enantiocontrol
was noticeably lower for secondary alkyl Grignard reagents
(i-PrMgBr and c-C5H11MgBr, entries 9 and 10). The differ-
ence between i-PrMgBr and n-PrMgBr is notable, since both
should provide the same titanacyclopropane [titanium(II)
η2-propene] species prior to the ligand exchange. A similar
trend, however, was observed earlier21 and could be ac-
counted by the formation of diastereomeric complexes B
and B′ (Scheme 3, I) from the primary and secondary alkyl-
magnesium halides correspondingly. On the other hand, the
relatively high level of enantioselectivity observed with Et-
MgBr (70% ee, entry 6), along with lower ee produced by
cyclopentylmagnesium bromide (62% ee, enrtry 10), might
point to an alternative explanation (see discussion below),
since both Grignard reagents must transform into symmet-
rical titanium(II)-alkene complexes in these cases.
TiCl4
2 MeLi
– LiCl
(TADDOL)TiMe2
(TADDOL)TiCl2
Ti(TADDOL)2
toluene
12
11
1. Ph(CH2)2COOR
R'MgBr (2 equiv)
2. H2O
HO
Me
(1 equiv)
(TADDOL)
Ti
(Z)-1c
12
OR =
OCH(CF3)2 (4a);
OC(CF3)3 (9)
O
– CH4
13
Entry
Ester
Grignard reagent
Yield (%)a
ee (%)b
1
4a
9
n-BuMgBr
n-BuMgBr
i-AmMgBr
i-AmMgBr
51
36
54
68
80
84
74
80
2
3
4a
4a
4c
a Yield of isolated (Z)-1c.
b Determined by HPLC analysis.
c 2 equiv of homoallylic alcohol were added to generate alkoxide 5 in situ.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

F
M. Iskryk et al.
Feature
Synthesis
RO
BrMg+
R1
D
Ph
D
R1
OR
OMgBr
MgBr+
Ph
O
D
Y
L*Ti
O
O
L*Ti
O
BuMgBr
R1CO2R
YMgBr
O
Me
H
O
H
O
L*Ti
Ti
Ph
L* = TADDOL
1 = PhCH2CH2
Y = alkoxide, Bu
O
+ O
BrMg
Ph
R
D
13-d
D
D'
C-d
ROMgBr
ROMgBr
1. (TADDOL)TiMe2
2. Ph(CH2)2COOR,
BuMgBr (2 equiv)
D
D
R1
R1
Y
L*Ti
O
HO
Ph
I)
D
OH
O
L*Ti
O
D
O
OH
1c–d
single diastereomer
Mg
Br
14-d
E
E'
RO
yield
e.r.
retention
inversion
YMgBr
OCH(CF3)2
OEt
46%
35%
88:12
70:30
R1
D
O
MgBr+
L*Ti
O
O
Y
O
L*Ti
Y
Et
MgBr+
R1
same conditions
HO
D
Ph
II)
F
F'
OH
OH
Et
H2O
H2O
1e
15
single diastereomer
D
D
RO
yield
e.r.
R1
R1
OH
OCH(CF3)2
OEt
OH
50%
41%
88:12
82:18
HO
OH
1c–d
1c–d'
Scheme 4 Stereochemistry of the asymmetric cyclopropanation of ethyl and hexafluoropropyl 3-phenylpropionates with homoallylic alcohols 14-d
and 15
Armed with expedient procedures for the asymmetric
cyclopropanation of 3-phenylpropionate esters with unsat-
urated alcohols as the next step, we aimed to apply deuter-
ated homoallylic alcohol 14-d (Scheme 4, I) as a stereo-
chemical probe to reveal if partial inversion of configura-
tion occurs during the cyclopropane ring closure.
Casey and Strotman first demonstrated with such an
elegant experiment that total retention of configuration at
C–Ti bond takes place in Kulinkovich cyclopopropanol syn-
thesis, while cyclopropanation of amides proceeds with
complete inversion of configuration via a W-shaped transi-
tion state.25 Following this seminal work, Cha further re-
vealed that both retention and inversion of configuration at
the Ti–C bond occurred in intermolecular coupling between
a homoallylic alcohol and a nitrile.26
In the event of asymmetric cyclopropanation with
alkoxide 13-d, the formation of diastereomeric cyclopropa-
nols 1c-d and 1c-d′ could be expected as a result of reten-
tion or inversion of configuration at Ti–C bond respectively
(Scheme 4). It is remarkable that both diastereomers 1c-d
and 1c-d′ must behave as a pair of enantiomers during
HPLC analysis with a chiral column, since isotopic substitu-
tion cannot strongly affect retention times. If the measured
apparent e.r. values correlate to dr (determined by 1H NMR
analysis) for the products obtained from different 3-
phenylpropionate esters (e.g., 4a and 8) it would indicate
that partial inversion of configuration indeed takes place
during the ring-closing step and spoils enantiomeric purity
of the product.
However, cyclopropanol 1c-d was obtained as a single
diastereomer from both ethyl and hexafluoropropyl esters
(Scheme 4, I). Stereochemical assignment of 1c-d based on
NOESY experiment and the value of a coupling constant
between two cyclopropane protons (Jcis = 9.3 Hz) confirms
retention of olefin configuration, which corresponds to
retention of configuration at Ti–C bond in the cyclopropane
forming step.
On the other hand, cyclopropanol 1c-d was produced
with different ratio of enantiomers from two tested ester
substrates, with higher e.r. in the case of hexafluoroiso-
propyl ester 4a. This result clearly indicates that inversion
of configuration at Ti–C bond during cyclopropane ring
closure cannot be responsible for erosion of enantioselec-
tivity observed in the case of ethyl ester 8.
As further evidence, similar set of experiments were
performed with E-disubstituted olefin 15 (Scheme 4, II).14b
Again, the corresponding cyclopropane product 1e was ob-
tained as a single diastereomer with preserved configura-
tion of the olefin double bond, though ratio of enantiomers
was different in the event of cyclopropanation of ethyl and
hexafluoroisopropyl 3-phenylpropionates.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

G
M. Iskryk et al.
Feature
Synthesis
Although these results cannot fully exclude the possibil-
ity of inversion of configuration at the stereogenic carbon
during cyclopropanol synthesis,14b obviously a different
mechanism must be responsible for the observed effect of
carboxylic ester substrate on the reaction enantioselectivity.
At the very least, ester could affect stereochemical outcome
of the stereogenic titanacyclopropane-forming step by be-
ing included into intermediate species via coordination to
metal atoms (Mg and/or Ti).19 This is not surprising, taking
into account that complexation of some carboxylic esters
(e.g., ethyl ester 8, see SI) with alkyltitanium ate species can
Scope and limitations for the developed methods of
enantioselective hydroxycyclopropanation of prochiral ole-
fins were briefly evaluated. First of all, titanium 3-butenox-
ide 5 was used to perform the synthesis of (Z)-2-(2-hydro-
xyethyl)cyclopropanols 1f–i using a number of other hexa-
fluoroisopropyl esters 4b–e besides 3-phenylpropionate 4a
(Scheme 5, Procedure A). Good yields (63–69%) of the corre-
sponding Z-cyclopropane products 1f, 1h, 1i with respect-
able level of enantioselectivity (70% ee) were attained for
primary alkyl-substituted ester substrates. Among them,
cyclopropanol 1i with a trisubstituted double bond was
prepared flawlessly. In contrast, phenylcyclopropanol 1g
was obtained with noticeably higher 84% ee but in low 35%
yield. The reaction was accompanied by enhanced forma-
tion of tertiary alcohol by-product 16, suggesting unfavor-
able steric repulsion between phenyl group from the sub-
strate and phenyl groups of TADDOL ligand to hamper the
ring-closing step in the corresponding β-titanoketone inter-
mediate.
1
be indeed observed by H NMR spectroscopy.21 Although
the reasons for such a negative influence must be further
investigated to clarify its origin, as a further hint we found
that less Lewis basic hexafluoroisopropyl ester 4a coordi-
nates to the model methyl titanium ate complex rather
weakly (see SI) and therefore, cannot strongly disrupt the
structure of organometallic intermediates as more basic
ethyl ester 8 presumably does. Such observation also stays
in line with generally high enantioselectivities observed in
reactions of hexafluoroisopropyl esters and negative effect
of basic solvents and additives on the reaction enantio-
selectivity.16b,21
Secondly, effect of a linker length between the double
bond and the hydroxyl group of ω-alkenol substrate on the
reaction outcome was tested, following tethering procedure
with in situ generated dimethyltitanium TADDOLate 12
(Scheme 5, Procedure B).
Procedure B:
Procedure C:
Procedure A:
1) R1CO2CH(CF3)2, alkoxide 5 (1 equiv),
i-AmMgBr (3 equiv)
2) H2O
1) (TADDOL)TiMe2, alkenol (1 equiv)
2) ester 4a, n-BuMgBr or i-AmMgBr
(3 equiv)
1) (TADDOL)Ti(Oi-Pr)2, alkene (1 equiv)
ester 4a, n-BuMgBr (3 equiv)
2) H2O; 3) TBAF in THF (optional)
3) H2O
Procedure A
Ph
Ph
OH
OH
OH
OH
OH
(Z)-1f (63%), 70% ee
OH
OH
OH
(Z)-1g (35%), 84% ee
(Z)-1h (69%), 70% ee
(Z)-1i (68%) 70% ee
Procedure B
Procedure C
Alkenol
Product
Alkene
Product
HO
HO
OH
Ph
OH
OH
OTIPS
17
Ph
(E)-1j (40%), 84% ee
OH
21
22
(Z)-1j (35%), 87% ee
45:55 dra
OTIPS
OH
Ph
(E)-1k (41%), 81% ee
HO
OH
OH
Ph
(E)-1k (70%), 28% ee
18
OTIPS
HO
OTIPS
Ph
(E)-1m (38%), 80% ee
23
24
OH
Ph
OH
OTBS
HO
OH
OH
19
(Z)-1l (20%), 58% ee
Ph
85:15 drb
(E)-1n (40%), 74% ee
by-products:
i-Am
Ph
OH
Ph
OH
HO
Ph
Et
OH
O
(E)-1o
20
16
Scheme 5 Asymmetric cyclopropanation of hexafluoroisopropyl esters 4a–e with olefins: scope and limitations. Yields of isolated products are given.
a (E)-1j was obtained with 20% ee. b (E)-1l was obtained with 12% ee.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

H
M. Iskryk et al.
Feature
Synthesis
In contrast to exclusively Z-diastereoselective hydro-
cyclopropanation of homoallylic alcohol, nearly an equi-
molecular mixture of the corresponding E- and Z-cyclopro-
panols 1j was obtained from pent-4-en-1-ol (17), while the
use of hex-5-en-1-ol (18) resulted in exclusive formation of
the corresponding (E)-cyclopropanol 1k in 70% yield. More
remarkable is the significant difference in enantiomeric
purity for the obtained E- and Z-diastereomers: although
(Z)-1j was formed with high 87% ee, enantiomeric purity of
both (E)-1j, 1k was poor and did not exceed 30% ee. Tertiary
homoallylic alcohol 19 was examined next (Scheme 5).
Cyclopropanol 1l was formed as predominantly Z-diaste-
reoisomer, suggesting chelation control; however, both en-
antio- and diastereoselectivities were diminished in com-
parison with the analogous transformation of 3-buten-1-ol
(Scheme 3, Tables 1 and 2). Again, minor E-diastereomer of
1l was obtained with considerably lower enantioselectivity
(12% ee) than its Z counterpart (58% ee). Increased steric
hindrance of alkenol substrate also resulted in low yield
(20%) of 1l; ketone 20 was isolated as the main by-product
(35% yield).
HO
OH
Ph
H
H
(1S,2S)-1c, 84% ee
Mg(OMe)2
Ph
OX
hexane
90%
Ph
O
OH
(R)-25, 40–60% ee
OH
(X = H)
(1R,2S)-1c, 80% ee
MTPACl,
pyridine
(R)-26, X = (S)-MTPA
(S)-26, X = (S)-MTPA
(R)-26, Δδ = 0 (major)
(S)-26
(S)-26, Δδ = 0.14 (minor)
In contrast to rather unsatisfactory results obtained
with unprotected alkenols 17–19, to our delight silyl-pro-
tected derivatives 21–24 were highly suitable substrates in
cyclopropanation reaction mediated by titanium iso-
propoxide 3 (Scheme 5, Procedure C). The corresponding E-
cyclopropanols 1j–n can be conveniently isolated and
TADDOL ligand can be nearly fully recovered (95–97% yield)
by silica gel column chromatography after an optional silyl
deprotection step (to facilitate chromatographic separation
of more polar diols from TADDOL). Although yields of the
target products 1j–n (~50% by NMR) were moderate due to
accompanying direct reaction of titanacyclopropane D
(Scheme 3) with ester 4a leading to 2-ethylcyclopropanol
(E)-1o,27 cyclopropane products 1j–n were obtained with
respectable enantioselectivities (74–84% ee) and exclusive-
ly as E-diastereomers, regardless the length of the alkyl
chain and substitution at the protected carbinol moiety of
the alkene.
Finally, we aimed to assign the absolute configuration of
the cyclopropanol products obtained in both intra- and inter-
molecular ligand exchange processes. The easiest way to
implement this task in our hands was to perform regio-
selective C1–C3 ring cleavage of both E- and Z-cyclopro-
panes 1c with magnesium methoxide3a to produce the cor-
responding α-methyl-branched hydroxy ketone 25 (Scheme
6). Absolute configuration of the latter can be straightfor-
wardly assigned by NMR analysis of the corresponding
Mosher’s esters, displaying a different pattern of signals for
diastereotopic oxymethylene protons in the case of R- and
S-enantiomers, respectively.28
+MgBr
+MgBr
O
Ti
O
O
Ti
O
H
O
O
(S)
preferred
(R)
Scheme 6 Assignment of the absolute configuration for the major
enantiomer of (Z)- and (E)-1c by 1H NMR analysis of Mosher esters
derived from hydroxy ketone 25. Stereochemical model accounting for
the preference of S-titanacyclopropane in the event of intramolecular
ligand exchange.
chiral center caused by Mg(OMe)2 reagent over the course
of the 40 minute reaction. More importantly, overlapping
signals of oxymethylene protons (Δδ = 0) in the H NMR
1
spectrum for the major diastereomer of (S)-MTPA ester 26
unequivocally indicate a predominant R-configuration of
the chiral center,28 which in turn leads to (1R,2S)-configura-
tion of the cyclopropanol precursor and eventually evi-
dences S-configuration of the reactive titanacyclopropane
species C (as depicted in Scheme 3).
Analogously, the same ketone 25 was obtained from (E)-
1c with a bit higher 60% ee due to shorter reaction time (20
min). Again, 1H NMR analysis of the corresponding S-
Mosher’s ester confirms the formation of R-ketone 25 as
the main enantiomer, which indicates a predominant S-
configuration of the stereocenter in metallacycle
(Scheme 3).
E
Treatment of (Z)-1c (80% ee) with Mg(OMe)2 in hexane
led to ketone 25 in high 90% yield, but with low enantio-
meric purity (ca. 40% ee) due to partial epimerization of the
Preference of S-configuration was noted before for the
titanacyclopropane reagent produced from (4R,5R)-
TADDOLate 3 and n-pentylmagnesium bromide16b and
agrees with the formation of less hindered metallacycle
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

I
M. Iskryk et al.
Feature
Synthesis
having the most distant position of an alkyl substituent
from the pseudo axial phenyl groups of (4R,5R)-TADDOL
ligand.21 The same stereochemical model is also suitable for
intermolecular ligand exchange (D → E, Scheme 3, II), since
the same steric interactions of the chiral ligand with the in-
coming alkene should be expected. Adaptation of the same
model for intramolecular ligand exchange with titanium-
tethered alkenols is also consistent with preferential forma-
tion of bicyclic (S)-titanacyclopropane ate complex, since
destabilizing steric repulsion between the methylene units
and nearby pseudo axial phenyl group should be expected
for R-stereoisomer (Scheme 6). The destabilizing effect of
the linker should be greater in the case of pent-4-en-1-ol
(17), which agrees with a bit higher enantioselectivity (87%
ee).
Configuration of the olefin precursor is preserved in the
cyclopropane product, thus confirming total retention of
configuration at Ti–C bond in the cyclopropane forming
step and implying other mechanisms responsible for dimin-
ished enantiocontrol observed for non-fluorinated carbox-
ylic ester substrates. Generation of non-ate species from
sterically encumbered pentacoordinated titanium TADDOL-
ate complexes might contribute to derogation of stereose-
lectivity. The reported findings might be helpful in further
development of miscellaneous enantioselective transforma-
tions mediated by chiral titanacyclopropane reagents, with
a potentially broad spectrum of applications in organic syn-
thesis.
A notable feature of the cyclopropanation reaction with
unprotected alkenols 17 and 19 (Scheme 5) is drastically
high difference in enantiomeric purity of E- and Z-cyclopro-
panol products obtained in the same reaction, pointing out
on their origin from the distinct organometallic precursors.
Although Z-isomers are likely formed from the correspond-
ing bicyclic titanacylopropane ate complexes, the pathways
leading to E-diastereomers in the same transformations are
currently obscure. At least one of the possible processes
leading to erosion of enantioselectivity could be degrada-
tion of pentacoordinated ate complex intermediates into
the more reactive but less sterically hindered non-ate
species. In support, NMR monitoring demonstrates that
sterically encumbered dimethyltitanium ate complex A
(Equation 1) is prone to easy dissociation with release of
bulky magnesium tert-butoxide and dimethyltitanium
compound 12 (see SI for details), thus indicating feasibility
of this scenario at least for tert-alkenol 19. It seems likely
that similar decomposition of dialkyltitanium ate complex-
es bearing bulky secondary alkyl groups could also play role
in slight decrease of enantioselectivity observed in the case
of cyclopentyl and isopropylmagnesium bromides (Table 1,
entries 9 and 10).
Ti(Oi-Pr)4 was purchased from Sigma-Aldrich, purified by distillation
and stored in a Schlenk tube under argon. (R,R)-TADDOL ligand was
purchased from TCI. Other reagents were used as purchased from
commercial suppliers, or prepared as described (see SI). All manipula-
tions with air- and moisture-sensitive compounds were carried out
under argon using Schlenk techniques. Solvents used for the reactions
were dried and stored over 4Å molecular sieves. Other solvents were
purified and dried by conventional methods, or used as obtained
from commercial sources. Concentration of commercial MeLi (Sigma-
Aldrich, 1.6 M in Et2O) was checked using Gilman double titration.29
Silica gel 63–200 μm was used for preparative flash chromatography
on a Biotage Isolera Prime instrument. Silica gel 60 F254 plates were
used for TLC. 1H NMR (400 MHz) and 13C NMR (100.6 MHz) spectra
were recorded on a Bruker Avance III spectrometer. Chemical shifts
were given in δ value with CHCl3 (δ = 7.26) and CDCl3 (δ = 77.16) as
internal standards for 1H NMR and 13C NMR spectra, respectively.
HPLC determination of ee was performed with an Agilent Technolo-
gies 1200 series chromatograph by using appropriate chiral columns
(see below). Specific rotations were measured using an Anton Paar
MCP 500 polarimeter. HRMS data were obtained on an Agilent
HPLC/Q-TOF G6540A Mass Spectrometer using APCI or AJESI methods
in positive ion detection modes.
Preparation of starting materials and titanium complexes are detailed
in the Supporting Information.
Grignard Reagents
Grignard reagents were prepared according to conventional proce-
dure, from Mg turnings (0.146 g, 6 mmol) and the corresponding
alkyl bromides (6 mmol) in Et2O (1.5 mL) and toluene (ca. 4.5 mL) to
produce ~1 М solutions. Concentration was checked prior to use by
the Knochel method.30
Ph
Ph
Ph
Ph
O
O
Me
Ti
O
O
H
O
Me
Me
H
O
H
O
H
O
Me
Ti
– t-BuOMgBr
Ph
Ph
Ot-Bu
BrMg+
Ph
Ph
12
A
Asymmetric Cyclopropanation of Carboxylic Esters with Homo-
allylic Alcohol via Titanium Alkoxide 5; General Procedure A
Equation 1 Dissociation of dimethyltitanium ate complex A
A 25 mL Schlenk tube was charged with Ti(TADDOL)2 (254 mg, 0.26
mmol), closed with a septum cap, and evacuated-backfilled with
argon three times. Neat titanium(IV) alkoxide 6 (83 mg, 0.25 mmol)
was added via a syringe. The tube was evacuated-backfilled with
argon again, and then toluene (4 mL) was added to give a transparent
solution containing titanium alkoxide 5 (see SI for NMR data). Then,
the respective carboxylic ester (0.5 mmol) was added followed by
slow (40 min) dropwise addition of a Grignard reagent (n-BuMgBr or
i-AmMgBr, 1.5 mmol) using a syringe pump. After completion of the
addition, the resulting brown solution was stirred for an additional 30
In conclusion, we have successfully expanded the scope
of the asymmetric Kulinkovich reaction to enantioselective
hydroxycyclopropanation of prochiral olefins and alkenols,
furnishing the corresponding E- or Z-cyclopropanols with
up to 84–87% ee via intermediate formation of reactive
titanacyclopropane intermediates with preferential S-con-
figuration of the chiral center in the metallacycle.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

J
M. Iskryk et al.
Feature
Synthesis
min, quenched with H2O (0.5 mL) under vigorous stirring, and left
overnight. The precipitate formed was removed by filtration through
a layer of Celite and washed with EtOAc. The solvent was removed un-
der reduced pressure, and the residue was subjected to flash silica gel
column chromatography using PE/EtOAc gradient (from 10% to 80% of
EtOAc) as an eluent, collecting recovered TADDOL ligand (230–235
mg, 95–97% yield) and the corresponding cyclopropanol product.
using PE/EtOAc gradient as an eluent, collecting the recovered
TADDOL ligand (230–235 mg, 95–97% yield) and the corresponding
cyclopropanol product.
(1R,2S)-2-(2-Hydroxyethyl)-1-phenethylcyclopropan-1-ol [(Z)-1c]
(Table 1, entry 7)
Yield: 77 mg (75%), following General Procedure A with i-AmMgBr;
74% ee; colorless oil; Rf = 0.20 (hexane/EtOAc 1:1); [α]D20 +6.9 (c 0.40,
CHCl3).
Asymmetric Cyclopropanation of Carboxylic Esters with
Unsaturated Alcohols via Dimethyltitanium TADDOLate 12;
General Procedure B
HPLC: Phenomenex Lux 3μ Amylose-2; hexane/i-PrOH (90:10), flow
rate = 1.0 mL/min, λ = 210 nm, 25 °C; tR = 7.5 min (minor), tR = 8.9 min
(major).
Ti(TADDOL)2 (245 mg, 0.25 mmol) was placed in a 25 mL Schlenk
tube, evacuated-backfilled with argon three times and dissolved in
toluene (3 mL). TiCl4 (0.25 mL, 0.25 mmol, 1 M solution in toluene)
was added carefully via a syringe in a dropwise manner while stir-
ring. At the end of the addition, the almost-colorless solution sharply
attained a pale-yellow color, indicating the equivalence point. The
obtained solution of dichlorotitanium TADDOLate 11 was cooled to
–15 °C with a salt/ice bath and then MeLi (1 mmol, 0.63 mL, 1.6M in
Et2O) was added dropwise to afford a yellow solution of dimethyltita-
nium TADDOLate 12 (see SI for NMR data) and insoluble LiCl. A solu-
tion of unsaturated alcohol (0.5 mmol) in toluene (0.5 mL) was then
added, causing rapid evolution of methane. The yellow reaction mix-
ture was warmed to r.t. Then, the respective carboxylic ester (0.5
mmol) was added followed by slow (40 min) dropwise addition of a
Grignard reagent (n-BuMgBr or i-AmMgBr, 1.5 mmol) using a syringe
pump. After completion of the addition, the resulting brown solution
was stirred for an additional 30 min, quenched with H2O (0.5 mL) un-
der vigorous stirring and left overnight. The precipitate formed was
removed by filtration through a layer of Celite and washed with EtO-
Ac. The solvent was removed under reduced pressure, and the residue
was subjected to flash silica gel column chromatography using
PE/EtOAc gradient (from 10% to 80% of EtOAc) as an eluent, collecting
recovered TADDOL ligand (230–235 mg, 95–97% yield) and the corre-
sponding cyclopropanol product.
IR (KBr): 3346, 3063, 2937, 1497, 1454, 1026 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.33–7.25 (m, 2 H), 7.24–7.14 (m, 3 H),
3.80 (dt, J = 9.9, 4.0 Hz, 1 H), 3.62 (ddd, J = 10.8, 9.9, 2.8 Hz, 1 H), 2.95–
2.78 (m, 2 H), 2.80 (br s, 2 H), 2.01 (dtd, J = 15.0, 4.0, 2.8 Hz, 1 H), 1.93
(ddd, J = 14.0, 10.1, 6.1 Hz, 1 H), 1.73 (dddd, J = 14.0, 10.3, 6.3, 1.2 Hz,
1 H), 1.55 (dddd, J = 15.0, 10.8, 9.7, 4.0 Hz, 1 H), 0.77–0.62 (m, 2 H),
0.44 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 142.6, 128.6, 128.5, 125.8, 63.0, 57.6,
41.9, 32.3, 31.3, 22.9, 19.8.
HRMS (ESI): m/z [M + H]+ calcd for C13H19O2: 207.1380; found:
207.1371.
5-Phenethylnonane-1,5-diol
Isolated as a by-product; yield: 12 mg (9%); colorless oil; Rf = 0.14
(hexane/EtOAc 1:1).
1H NMR (CDCl3, 400 MHz): δ = 7.34–7.24 (m, 2 H), 7.24–7.11 (m, 3 H),
3.66 (t, J = 6.4 Hz, 2 H), 2.63 (m, 2 H), 1.75 (m, 2 H), 1.62–1.48 (m, 8 H),
1.43 (m, 2 H), 1.36–1.27 (m, 4 H), 0.92 (t, J = 6.8 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 142.7, 128.5, 128.4, 125.9, 74.5, 62.8,
41.4, 39.0, 38.9, 33.2, 30.1, 25.9, 23.4, 19.8, 14.3.
HRMS (ESI): m/z [M + H]+ calcd for C17H29O2: 265.2162; found:
265.2158.
Asymmetric Cyclopropanation of Carboxylic Esters with Silyl-Pro-
tected Alkenols Using Titanium TADDOLate 3; General Procedure C
(1R,2S,3R)-2-(2-Hydroxyethyl)-1-phenethylcyclopropan-3-d-1-ol
(1c-d)
A 25 mL Schlenk tube was charged with Ti(TADDOL)2 (254 mg, 0.26
mmol), closed with a septum cap, and evacuated-backfilled with ar-
gon three times. Neat Ti(Oi-Pr)4 (71 mg, 0.25 mmol) was added via a
syringe. The tube was evacuated-backfilled with argon again, and
then toluene (4 mL) was added to give a transparent solution contain-
ing titanium alkoxide 3 (see SI for NMR data). Then, the respective
carboxylic ester (0.5 mmol) and alkene (0.5 mmol) were added fol-
lowed by slow (40 min) dropwise addition of a Grignard reagent (n-
BuMgBr, 1.5 mmol) using a syringe pump. After completion of the ad-
dition, the resulting brown solution was stirred for an additional 30
min, quenched with H2O (0.5 mL) under vigorous stirring, and left
overnight. The precipitate was removed by filtration through a layer
of Celite and washed with EtOAc. The solvent was removed under re-
duced pressure. Cyclopropanol product was isolated by flash silica gel
column chromatography using gradient flow of PE/EtOAc, or (option-
ally) subjected to silyl deprotection prior the isolation as described
below: The reaction mixture was dissolved in THF (5 mL), cooled in an
ice bath, and a solution of TBAF (0.8 mL, 0.8 mmol, 1 M in THF) was
added. The mixture was stirred at r.t. until completion of the reaction
(ca. 4 h, TLC control), then diluted with H2O (10 mL), extracted with
EtOAc (3 × 5 mL) and dried (Na2SO4). After evaporation of the solvent,
the residue was subjected to flash silica gel column chromatography
Yield: 47 mg (46%), following General Procedure B with n-BuMgBr;
76% ee; colorless oil.
1H NMR (CDCl3, 400 MHz): δ = 7.32–7.25 (m, 3 H), 7.24– 7.14 (m, 3 H),
3.80 (dt, J = 9.9, 4.0 Hz, 1 H), 3.62 (ddd, J = 10.8, 9.9, 2.8 Hz, 1 H), 2.95–
2.78 (m, 2 H), 2.01 (dtd, J = 15.0, 4.0, 2.8 Hz, 1 H), 1.93 (ddd, J = 14.0,
10.1, 6.1 Hz, 1 H), 1.73 (ddd, J = 14.0, 10.3, 6.3 Hz, 1 H), 1.55 (dddd, J =
15.0, 10.8, 9.7, 4.0 Hz, 1 H), 0.69 (td, J = 9.3, 4.4 Hz, 1 H), 0.63 (d, J = 9.3
Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 142.6, 128.6, 128.5, 125.8, 63.0, 57.5,
41.8, 32.3, 31.2, 22.8, 19.5 (t, JCD = 24.2 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C13H18DO2: 208.1442; found:
208.1429.
(1R,2S,3S)-2-Ethyl-3-(2-hydroxyethyl)-1-phenethylcyclopropan-1-
ol (1e)
Yield: 58 mg (50%), following General Procedure B with n-BuMgBr;
20
76% ee; colorless oil; Rf = 0.31 (hexane/EtOAc 1:1); [α]D –0.26
(c 0.37, CH2Cl2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

K
M. Iskryk et al.
Feature
Synthesis
HPLC: Daicel Chiralcel OJ-H; hexane/i-PrOH (95:5), flow rate =
1.0 mL/min, λ = 210 nm, 25 °C; tR = 12.1 min (minor), tR = 14.2 min
(major).
HPLC: Phenomenex Lux 3μ Amylose-2; hexane/i-PrOH (97:3), flow
rate = 1.0 mL/min, λ = 210 nm, 25 °C; tR = 29.1 min (major), tR = 34.1
min (minor).
IR (KBr): 3332, 3027, 2957, 1496, 1454, 1030 cm–1
.
IR (KBr): 3333, 2937, 1496, 1449, 1293, 1240, 1055, 1026 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.32–7.14 (m, 5 H), 3.78 (dt, J = 9.9, 4.2
Hz, 1 H), 3.60 (ddd, J = 10.6, 9.9, 3.0 Hz, 1 H), 2.91 (ddd, J = 13.7, 11.3,
5.2 Hz, 1 H), 2.81 (ddd, J = 13.7, 11.0, 5.7 Hz, 1 H), 2.06–1.94 (m, 2 H),
1.72 (ddd, J = 14.1, 11.3, 5.7 Hz, 1 H), 1.56 (dddd, J = 14.9, 10.6, 9.8, 4.2
Hz, 1 H), 1.45 (m, 1 H), 1.23–1.08 (m, 1 H), 0.97 (t, J = 7.3 Hz, 3 H), 0.68
(dt, J = 8.1, 6.3 Hz, 1 H), 0.33 (ddd, J = 9.8, 6.3, 4.8 Hz, 1 H). Signals
from 2 OH groups are too broad and undetectable.
13C NMR (CDCl3, 100 MHz): δ = 142.9, 128.5, 128.5, 125.9, 63.1, 60.7,
37.7, 34.3, 32.5, 31.3, 28.8, 22.7, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C15H23O2: 235.1693; found:
1H NMR (CDCl3, 400 MHz): δ = 7.33–7.24 (m, 4 H), 7.22–7.14 (m, 1 H),
4.38 (br s, 1 H, OH), 3.81 (dt, J = 9.9, 3.8 Hz, 1 H), 3.69–3.58 (m, 1 H),
2.52 (br s, 1 H, OH), 2.13 (ddd, J = 14.9, 7.1, 3.3 Hz, 1 H), 1.79–1.66 (m,
1 H), 1.26 (dd, J = 9.4, 5.4 Hz, 1 H), 1.21–1.11 (m, 1 H), 0.94 (dd, J = 6.6,
5.4 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 146.0, 128.3, 126.1, 124.2, 62.6, 57.9,
31.3, 27.8, 23.5.
HRMS (ESI): m/z [M + Na]+ calcd for C11H14O2Na: 201.0886; found:
201.0887.
235.1689.
8-Methyl-5-phenylnonane-1,5-diol (16)
Isolated as a by-product; yield: 37 mg (30%), colorless oil; Rf = 0.20
(hexane/EtOAc 1:1).
(1S,2S)-2-(2-Hydroxyethyl)-1-phenethylcyclopropan-1-ol [(E)-1c]
Yield: 42 mg (41%), following General Procedure C with n-BuMgBr;
80% ee; colorless oil; Rf = 0.16 (hexane/EtOAc 1:1); [α]D20 +3.7 (c 0.27,
CH2Cl2).
1H NMR (CDCl3, 400 MHz): δ = 7.40–7.29 (m, 4 H), 7.25–7.18 (m, 1 H),
3.57 (t, J = 6.5 Hz, 2 H), 1.92–1.73 (m, 4 H), 1.71 (br s, 2 H, 2 × OH),
1.56–1.28 (m, 4 H), 1.22–1.06 (m, 2 H), 0.92 (dddd, J = 13.0, 11.7, 6.9,
4.7 Hz, 1 H), 0.83 (d, J = 6.6 Hz, 3 H), 0.81 (d, J = 6.6 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 146.4, 128.2, 126.4, 125.3, 77.1, 62.8,
42.8, 40.9, 33.0, 32.4, 28.5, 22.8, 22.6, 19.8.
HPLC: Phenomenex Lux 3μ Amylose-2; hexane/i-PrOH (94:6), flow
rate = 1.0 mL/min, λ = 210 nm, 25 °C; tR = 12.8 min (major), tR = 15.5
min (minor).
IR (KBr): 3332, 3026, 2930, 1496, 1454, 1047 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C16H26O2Na: 273.1830; found:
1H NMR (CDCl3, 400 MHz): δ = 7.33–7.27 (m, 2 H), 7.25–7.15 (m, 3 H),
3.69 (m, 2 H), 2.89 (m, 2 H), 1.98 (dddd, J = 14.3, 10.3, 5.9, 1.4 Hz, 1 H),
1.88 (br s, 2 H, 2 × OH), 79 (ddd, J = 14.3, 10.5, 5.9 Hz, 1 H), 1.70 (m, 1
H), 1.36 (ddt, J = 14.4, 8.3, 6.4 Hz, 1 H), 1.10 (ddt, J = 10.1, 8.3, 6.5 Hz, 1
H), 0.91 (ddd, J = 10.1, 5.4, 1.4 Hz, 1 H), 0.17 (dd, J = 6.5, 5.4 Hz, 1 H).
273.1825.
(1R,2S)-1-Butyl-2-(2-hydroxyethyl)cyclopropan-1-ol [(Z)-1h]
Yield: 55 mg (69%), following General Procedure A with i-AmMgBr;
70% ee; colorless oil; Rf = 0.30 (hexane/EtOAc 2:1); [α]D –10.0 (c
20
13C NMR (CDCl3, 100 MHz): δ = 142.4, 128.6, 128.6, 126.1, 62.9, 58.4,
0.69, CH2Cl2).
36.7, 32.6, 32.6, 22.7, 19.4.
HRMS (ESI): m/z [M + H]+ calcd for C13H19O2: 207.1380; found:
Due to bad separation of peaks in HPLC, ratio of enantiomers was de-
termined by 1H NMR using the Mosher method.
207.1371.
IR (KBr): 3346, 2930, 1251, 1031 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 3.79 (dt, J = 10.0, 4.1 Hz, 1 H), 3.66 (td,
J = 10.0, 3.0 Hz, 1 H), 3.28 (br s, 1 H, OH), 2.46 (br s, 1 H, OH), 2.07–
1.94 (m, 1 H), 1.65–1.28 (m, 7 H), 0.90 (t, J = 7.3 Hz, 3 H), 0.72–0.59
(m, 2 H), 0.46–0.35 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 63.0, 57.8, 39.5, 31.4, 28.0, 22.9, 22.6,
19.7, 14.3.
(1S,2S)-1-Benzyl-2-(2-hydroxyethyl)cyclopropan-1-ol [(Z)-1f]
Yield: 60 mg (63%), following General Procedure A with i-AmMgBr;
70% ee; colorless oil; Rf = 0.34 (hexane/EtOAc 2:1); [α]D –11.0 (c
20
0.31, CH2Cl2).
HPLC: Phenomenex Lux 3μ Amylose-2; hexane/i-PrOH (96:4), flow
rate = 1.0 mL/min, λ = 210 nm, 25 °C; tR = 17.7 min (minor), tR = 20.8
min (major).
HRMS (ESI): m/z [M + H]+ calcd for C9H19O2: 159.1385; found:
159.1385.
IR (KBr): 3335, 3028, 2918, 1496, 1454, 1023 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.36–7.21 (m, 5 H), 3.70–3.60 (m, 1 H),
3.46 (dt, J = 10.6, 2.9 Hz, 1 H), 3.23 (br s, 1 H, OH), 3.07 (d, J = 13.8 Hz,
1 H), 2.60 (d, J = 13.8 Hz, 1 H), 1.94 (dq, J = 15.3, 3.4 Hz, 1 H), 1.56–1.43
(m, 1 H), 1.29 (br s, 1 H, OH), 0.88–0.81 (m, 2 H), 0.58–0.50 (m, 1 H).
(1R,2S)-2-(2-Hydroxyethyl)-1-(4-methylpent-3-en-1-yl)cyclo-
propan-1-ol [(Z)-1i]
Yield: 63 mg (68%), following General Procedure A with i-AmMgBr;
70% ee; colorless oil; Rf = 0.30 (hexane/EtOAc 2:1); [α]D20 –3.7 (c 0.45,
CH2Cl2).
13C NMR (CDCl3, 100 MHz): δ = 139.4, 129.6, 128.5, 126.7, 63.0, 58.2,
45.5, 30.9, 22.0, 19.7.
HRMS (ESI): m/z [M + Na]+ calcd for C12H16O2Na: 215.1043; found:
215.1043.
HPLC: Phenomenex Lux 3μ Amylose-2; hexane/i-PrOH (96:4), flow
rate = 1.0 mL/min, λ = 210 nm, 25 °C; tR = 9.3 min (minor), tR = 10.7
min (major).
IR (KBr): 3383, 2926, 1448, 1378, 1260, 1026 cm–1
.
(1R,2S)-2-(2-Hydroxyethyl)-1-phenylcyclopropan-1-ol [(Z)-1g]22b
1H NMR (CDCl3, 400 MHz): δ = 5.19 (m, 1 H), 3.80 (dt, J = 10.2, 4.2 Hz,
1 H), 3.67 (td, J = 10.2, 3.1 Hz, 1 H), 3.19 (br s, 1 H, OH), 2.29–2.14 (m,
2 H), 2.09–1.91 (m, 1 H), 1.70–1.51 (m, 3 H), 1.69 (q, J = 1.4 Hz, 3 H),
1.64 (s, 3 H), 1.50–1.40 (m, 1 H), 0.82–0.57 (m, 2 H), 0.40 (m, 1 H).
Yield: 31 mg (35%), following General Procedure A with i-AmMgBr;
84% ee; colorless oil; Rf = 0.30 (hexane/EtOAc 1:1); [α]D20 +36.4 (c 0.20,
CH2Cl2).
13C NMR (CDCl3, 100 MHz): δ = 132.1, 124.8, 63.1, 57.9, 39.8, 31.3,
25.9, 24.7, 22.8, 19.5, 17.8.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

L
M. Iskryk et al.
Feature
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C11H21O2: 185.1536; found:
185.1528.
(1R,2S)-2-(2-Hydroxy-2-methylpropyl)-1-phenethylcyclopropan-
1-ol [(Z)-1l]
Yield: 23 mg (20%), following General Procedure B with n-BuMgBr;
58% ee; colorless oil; Rf = 0.35 (hexane/EtOAc 2:1); [α]D20 +4.3 (c 0.30,
CH2Cl2).
(1R,2S)-2-(3-Hydroxypropyl)-1-phenethylcyclopropan-1-ol [(Z)-
1j]
Yield: 38 mg (35%), following General Procedure B with i-AmMgBr;
87% ee; colorless oil; Rf = 0.29 (hexane/EtOAc 1:1); [α]D20 +28.1 (c 0.78,
CH2Cl2).
HPLC: Phenomenex Lux 3μ Amylose-2; hexane/i-PrOH (95:5), flow
rate = 1.0 mL/min, λ = 210 nm, 25 °C; tR = 7.5 min (minor), tR = 10.5
min (major).
IR (KBr): 3333, 2969, 1496, 1454, 1365, 1160, 1072 cm–1
.
HPLC: Chiralpak OD-H; hexane/i-PrOH (95:5), flow rate = 1.0 mL/min,
λ = 210 nm, 25 °C; tR = 18.9 min (minor), tR = 31.7 min (major).
1H NMR (CDCl3, 400 MHz): δ = 7.33–7.22 (m, 2 H), 7.22–7.12 (m, 3 H),
4.23 (br s, 1 H, OH), 2.86 (t, J = 8.3 Hz, 2 H), 2.45 (br s, 1 H, OH), 1.95–
1.73 (m, 3 H), 1.51 (dd, J = 14.7, 10.5 Hz, 1 H), 1.28 (s, 3 H), 1.25 (s, 3
H), 0.79 (dddd, J = 10.5, 9.3, 6.0, 4.5 Hz, 1 H), 0.65 (dd, J = 9.3, 5.1 Hz, 1
H), 0.43 (ddd, J = 6.0, 5.1, 1.0 Hz, 1 H).
IR (KBr): 3333, 3026, 2932, 1496, 1455, 1058 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.32–7.24 (m, 2 H), 7.23–7.14 (m, 3 H),
3.80–3.66 (m, 2 H), 2.92–2.79 (m, 2 H), 2.78 (br s, 1 H, OH), 2.22 (br s,
1 H, OH), 2.00–1.90 (m, 1 H), 1.83–1.67 (m, 3 H), 1.62–1.45 (m, 2 H),
0.65–0.62 (m, 2 H), 0.37–0.32 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 142.8, 128.5, 128.4, 125.7, 71.5, 57.5,
13C NMR (CDCl3, 100 MHz): δ = 142.5, 128.5 (2 C), 125.9, 61.5, 58.8,
42.2 (2 C), 32.4, 31.6, 28.0, 20.3, 20.1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H22O2Na: 257.1512; found:
41.9, 32.4, 32.1, 23.9, 23.4, 18.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H21O2: 221.1536; found:
257.1514.
221.1533.
7-Hydroxy-7-methyl-1-phenyloctan-3-one (20)
(1S,2S)-2-(3-Hydroxypropyl)-1-phenethylcyclopropan-1-ol [(E)-1j]
Isolated as a by-product; yield: 38 mg (35%); colorless oil; Rf = 0.26
(hexane/EtOAc 2:1).
IR (KBr): 3397, 2968, 1711, 1496, 1454, 1376, 1092 cm–1
1H NMR (CDCl3, 400 MHz): δ = 7.32–7.14 (m, 5 H), 2.90 (t, J = 7.6 Hz, 2
H), 2.73 (t, J = 7.7 Hz, 2 H), 2.41 (t, J = 7.2 Hz, 2 H), 1.73–1.58 (m, 2 H),
1.43–1.37 (m, 2 H), 1.20 (s, 6 H).
13C NMR (CDCl3, 100 MHz): δ = 210.3, 141.2, 128.6, 128.5, 126.2, 71.0,
44.4, 43.3, 43.2, 29.9, 29.3 (2 C), 18.7.
HRMS (ESI): m/z [M + Na]+ calcd for C15H22O2Na: 257.1512; found:
257.1515.
Yield: 43 mg (40%), following General Procedure B with i-AmMgBr;
20% ee; yield: 43 mg (40%), following General Procedure C with n-
BuMgBr; 84% ee; colorless oil; Rf = 0.19 (hexane/EtOAc 1:1); [α]D
.
20
+4.2 (c 0.31, CH2Cl2, 84% ee).
HPLC: Phenomenex Lux 3μ Amylose-2; hexane/i-PrOH (95:5), flow
rate = 1.0 mL/min, λ = 210 nm, 25 °C; tR = 18.7 min (major), tR = 24.1
min (minor).
IR (KBr): 3333, 3026, 2932, 1496, 1455, 1058 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.35–7.28 (m, 2 H), 7.27–7.18 (m, 3 H),
3.68 (t, J = 6.5 Hz, 2 H), 2.99–2.82 (m, 2 H), 1.98 (dddd, J = 14.1, 10.3,
6.0, 1.4 Hz, 1 H), 1.80 (ddd, J = 14.1, 10.5, 6.0 Hz, 1 H), 1.74–1.47 (m, 5
H), 1.25–1.02 (m, 2 H), 0.87 (ddd, J = 9.8, 5.4, 1.4 Hz, 1 H), 0.11 (dd, J =
6.4, 5.4 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 142.5, 128.6 (2 C), 126.0, 62.8, 59.0,
36.6, 32.8, 32.7, 25.9 (2 C), 19.8.
(1S,2R)-2-{2-Methyl-2-[(triisopropylsilyl)oxy]propyl}-1-phenethyl-
cyclopropan-1-ol [(E)-1m]
Yield: 74 mg (38%), following General Procedure C with n-BuMgBr;
80% ee; colorless oil; Rf = 0.71 (hexane/EtOAc 5:1); [α]D20 +1.3 (c 0.53,
CH2Cl2).
HRMS (ESI): m/z [M + H]+ calcd for C14H21O2: 221.1536; found:
221.1534.
HPLC: Chiralpak OD-H; hexane/i-PrOH (98:2), flow rate = 1.0 mL/min,
λ = 210 nm, 25 °C; tR = 9.4 min (minor), tR = 10.8 min (major).
IR (KBr): 3328, 2943, 2866, 1462, 1223, 1157, 1054, 883 cm–1
.
(1S,2S)-2-(4-Hydroxybutyl)-1-phenethylcyclopropan-1-ol [(E)-1k]
1H NMR (CDCl3, 400 MHz): δ = 7.34–7.27 (m, 2 H), 7.26–7.15 (m, 3 H),
3.09–2.78 (m, 2 H), 1.95 (dddd, J = 14.2, 10.3, 5.7, 1.4 Hz, 1 H), 1.87–
1.69 (m, 3 H), 1.28 (s, 3 H), 1.26 (s, 3 H), 1.24–1.15 (m, 1H), 1.14–0.98
(m, 22 H), 0.94 (ddd, J = 9.8, 5.5, 1.4 Hz, 1 H), 0.23–0.12 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 142.6, 128.6 (2 C), 126.0, 73.9, 58.3,
44.9, 37.1, 32.7, 30.3, 29.7, 22.7, 20.9, 18.6, 13.5.
Yield: 82 mg (70%), following General Procedure B with i-AmMgBr;
28% ee; yield: 48 mg (41%), following General Procedure C with n-
20
BuMgBr; 81% ee; colorless oil; Rf = 0.30 (hexane/EtOAc 1:1); [α]D
+3.6 (c 0.77, CH2Cl2, 81% ee).
HPLC: Phenomenex Lux 3μ Amylose-2; hexane/i-PrOH (95:5), flow
rate = 1.0 mL/min, λ = 210 nm, 25 °C; tR = 20.3 min (major), tR = 23.3
min (minor).
HRMS (ESI): m/z [M + Na – H2O]+ calcd for C24H40OSiNa: 395.2741;
found: 395.2764.
IR (KBr): 3331, 3026, 2932, 1496, 1455, 1229, 1058 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.34–7.25 (m, 2 H), 7.24–7.16 (m, 3 H),
3.63 (t, J = 6.5 Hz, 2 H), 3.00–2.78 (m, 2 H), 2.03–1.87 (m, 3 H), 1.78
(ddd, J = 14.2, 10.7, 5.8 Hz, 1 H), 1.64–1.53 (m, 2 H), 1.52–1.40 (m, 3
H), 1.16–0.99 (m, 2 H), 0.85 (ddd, J = 9.7, 5.3, 1.3 Hz, 1 H), 0.09 (dd, J =
6.2, 5.3 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 142.5, 128.6 (2 C), 126.0, 63.1, 59.0,
36.6, 32.7 (2 C), 29.4, 26.2, 25.9, 19.8.
(1S,2S)-2-[2-(1-Hydroxycyclopropyl)ethyl]-1-phenethylcyclo-
propan-1-ol [(E)-1n]
Yield: 49 mg (40%), following General Procedure C with n-BuMgBr;
74% ee; colorless oil; Rf = 0.47 (hexane/EtOAc 1:1); [α]D20 –5.9 (c 0.18,
CH2Cl2).
HPLC: Phenomenex Lux 3μ Amylose-2; hexane/i-PrOH (97:3), flow
rate = 1.0 mL/min, λ = 210 nm, 25 °C; tR = 26.4 min (major), tR = 37.9
min (minor).
HRMS (ESI): m/z [M + H]+ calcd for C15H23O2: 235.1693; found:
235.1693.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

M
M. Iskryk et al.
Feature
Synthesis
IR (KBr): 3330, 2969, 1452, 1250, 1031 cm–1
.
Supporting Information
1H NMR (CDCl3, 400 MHz): δ = 7.34–7.27 (m, 2 H), 7.25–7.17 (m, 3 H),
2.99–2.81 (m, 2 H), 2.00 (dddd, J = 14.2, 10.3, 6.0, 1.4 Hz, 1 H), 1.89–
1.74 (m, 2 H), 1.73–1.59 (m, 4 H), 1.38–1.21 (m, 1 H), 1.16–1.03 (m, 1
H), 0.86 (ddd, J = 10.0, 5.3, 1.3 Hz, 1 H), 0.78–0.67 (m, 2 H), 0.52–0.38
(m, 2 H), 0.12 (dd, J = 6.5, 5.3 Hz, 1 H).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611709.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References
13C NMR (CDCl3, 100 MHz): δ = 142.5, 128.6 (2 C), 126.0, 59.2, 55.7,
(1) Reviews: (a) Ebner, C.; Carreira, E. M. Chem. Rev. 2017, 117,
11651. (b) Fumagalli, G.; Stanton, S.; Bower, J. F. Chem. Rev.
2017, 117, 9404. (c) Nikolaev, A.; Orellana, A. Synthesis 2016, 48,
1741. (d) Nithiy, M.; Rosa, D.; Orellana, A. Synthesis 2013, 45,
3199 . (e) Haym, I.; Brimble, M. A. Org. Biomol. Chem. 2012, 10,
7649. (f) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.
(g) Kulinkovich, O. Eur. J. Org. Chem. 2004, 4517.
(2) Recent examples: (a) Ma, K.; Yin, X.; Dai, M. Angew. Chem. Int.
Ed. 2018, 57, 15209. (b) Yang, J.; Shen, Y.; Lim, Y. J.; Yoshikai, N.
Chem. Sci. 2018, 9, 6928. (c) Liu, H.; Fu, Z.; Gao, S.; Huang, Y.;
Lin, A.; Yao, H. Adv. Synth. Catal. 2018, 360, 3171. (d) Ye, Z.; Cai,
X.; Li, J.; Dai, M. ACS Catal. 2018, 8, 5907. (e) Che, C.; Qian, Z.;
Wu, M.; Zhao, Y.; Zhu, G. J. Org. Chem. 2018, 83, 5665. (f) Xu, B.;
Wang, D.; Hu, Y.; Shen, Q. Org. Chem. Front. 2018, 5, 1462.
(g) Novikau, I.; Hurski, A. Tetrahedron 2018, 74, 1078. (h) Wu, P.;
Jia, M.; Lin, W.; Ma, S. Org. Lett. 2018, 20, 554. (i) Nikolaev, A.;
Legault, C. Y.; Zhang, M.; Orellana, A. Org. Lett. 2018, 20, 796.
(j) Woźniak, Ł.; Magagnano, G.; Melchiorre, P. Angew. Chem. Int.
Ed. 2018, 57, 1068. (k) Konik, Y. A.; Elek, G. A.; Kaabel, S.;
Järving, I.; Lopp, M.; Kananovich, D. G. Org. Biomol. Chem. 2017,
15, 8334. (l) Deng, Y.; Kauser, N. I.; Islam, S. M.; Mohr, J. T. Eur. J.
Org. Chem. 2017, 5872. (m) Elek, G. Z.; Borovkov, V.; Lopp, M.;
Kananovich, D. G. Org. Lett. 2017, 19, 3544.
38.3, 36.5, 32.7, 26.1 (2 C), 19.9, 13.8 (2 C).
HRMS (ESI): m/z [M + H]+ calcd for C16H23O2: 247.1698; found:
247.1691.
(R)-6-Hydroxy-4-methyl-1-phenylhexan-3-one (25)3a
A 10-fold excess by mass of Mg(OMe)2 (180 mg) was added to a 5%
(w/w) solution of cyclopropanol (E)- or (Z)-1c (18 mg) in hexane
(1 mL). The suspension was stirred at 40 °C [20 min for (E)-1c; 40 min
for (Z)-1c] and quenched with sat. aq NH4Cl (3 mL). The aqueous layer
was separated and extracted with EtOAc. The combined organic lay-
ers were dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel us-
ing hexane/EtOAc as the eluent; yield: 16 mg (90%), 40% ee from (Z)-
1c; 60% ee from (E)-1c; colorless oil; Rf = 0.40 (hexane/EtOAc 2:1);
[α]D20 –4.4 (c 0.29, CH2Cl2, 40% ee).
IR (KBr): 3471, 2925, 1707, 1496, 1455, 1377, 1047 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.32–7.25 (m, 2 H), 7.24–7.14 (m, 3 H),
3.65-3.53 (m, 2 H), 2.94–2.86 (m, 2 H), 2.85–2.75 (m, 2 H), 2.75–2.65
(m, 1 H), 1.95–1.86 (m, 1 H), 1.63–1.52 (m, 1 H), 1.60 (br s, 1 H, OH),
1.09 (d, J = 7.0 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 214.2, 141.3, 128.6, 128.5, 126.2, 60.6,
43.5, 42.9, 35.4, 29.9, 16.6.
(3) (a) Barysevich, M. V.; Kazlova, V. V.; Kukel, A. G.; Liubina, A. I.;
Hurski, A. L.; Zhabinskii, V. N.; Khripach, V. A. Chem. Commun.
2018, 54, 2800. (b) Singh, S.; Simaan, M.; Marek, I. Chem. Eur. J.
2018, 24, 8553. (c) Tumma, N.; Gyanchander, E.; Cha, J. K. J. Org.
Chem. 2017, 82, 4379. (d) Davis, D. C.; Walker, K. L.; Hu, C.; Zare,
R. N.; Waymouth, R. M.; Dai, M. J. Am. Chem. Soc. 2016, 138,
10693. (e) Gyanchander, E.; Ydhyam, S.; Tumma, N.; Belmore,
K.; Cha, J. K. Org. Lett. 2016, 18, 6098. (f) Ydhyam, S.; Cha, J. K.
Org. Lett. 2015, 17, 5820. (g) Murali, R. V. N. S.; Rao, N. N.; Cha, J.
K. Org. Lett. 2015, 17, 3854. (h) Parida, B. B.; Das, P. P.; Niocel,
M.; Cha, J. K. Org. Lett. 2013, 15, 1780. (i) Cheng, K.; Walsh, P. J.
Org. Lett. 2013, 15, 2298. (j) Rosa, D.; Orellana, A. Chem.
Commun. 2013, 49, 5420.
(4) (a) Mills, L. R.; Rousseaux, S. A. L. Synlett 2018, 29, 683. (b) Mills,
L. R.; Arbelaez, L. M. B.; Rousseaux, S. A. L. J. Am. Chem. Soc.
2017, 139, 11357. (c) Racouchot, S.; Ollivier, J.; Salaün, J. Synlett
2000, 1729. (d) Kozyrkov, Y. Y.; Pukin, A.; Kulinkovich, O. G.;
Ollivier, J.; Salaün, J. Tetrahedron Lett. 2000, 41, 6399.
(e) Raiman, M. V.; Il’ina, N. A.; Kulinkovich, O. G. Synlett 1999,
1053.
According to NMR, about 30% of cyclic hemiketal is present.
HRMS (ESI): m/z [M + H]+ calcd for C13H19O2: 207.1380; found:
207.1376.
Funding Information
Funding from the European Union’s Seventh Framework Program for
research, technological development and demonstration Grant No.
621364 (TUTIC-Green) and from Tallinn University of Technology
(Grant No B58) is gratefully acknowledged. M.I. and M.B. are grateful
to Dora Plus program for financial support of a short research stay at
Tallinn University of Technology. J.A. acknowledges support by the
Estonian Ministry of Education and Research through grant IUT23-7
and the EU European Regional Development Fund through grant
TK134. Support from COST Action CA15106 ‘C–H Activation in Organic
Synthesis’ (CHAOS) is gratefully acknowledged.
S
e
v
e
nthFra
m
e
w
orkProgra
m
m
e
(6
2
1
3
6
4)Euro
p
e
a
n
R
e
g
i
o
n
a
lD
e
v
e
l
o
p
m
e
nt
F
u
n
d
(T
K
1
3
4)
(5) Wang, H.-B.; Wang, X.-Y.; Liu, L.-P.; Qin, G.-W.; Kang, T.-G.
Chem. Rev. 2015, 115, 2975.
Acknowledgment
(6) Ueoka, R.; Bortfeld-Miller, M.; Morinaka, B. I.; Vorholt, J. A.; Piel,
J. Angew. Chem. Int. Ed. 2018, 57, 977.
We would like to thank Dr. Ivar Järving (Tallinn University of
Technology, TalTech) for his help with HRMS measurements and Dr.
Alexander-Mati Müürisepp (TalTech) for measuring IR spectra. Dr.
Marina Kudrjašova (TalTech) is acknowledged for her assistance with
NMR investigations. Gábor Zoltán Elek (TalTech) is acknowledged for
the synthesis of compound 24.
(7) (a) Scott, J. D.; DeMong, D. E.; Greshock, T. J.; Basu, K.; Dai, X.;
Harris, J.; Hruza, A.; Li, S. W.; Lin, S.-I.; Liu, H.; Macala, M. K.; Hu,
Z.; Mei, H.; Zhang, H.; Walsh, P.; Poirier, M.; Shi, Z.-C.; Xiao, L.;
Agnihotri, G.; Baptista, M. A. S.; Columbus, J.; Fell, M. J.; Hyde, L.
A.; Kuvelkar, R.; Lin, Y.; Mirescu, C.; Morrow, J. A.; Yin, Z.; Zhang,
X.; Zhou, X.; Chang, R. K.; Embrey, M. W.; Sanders, J. M.; Tiscia,
H. E.; Drolet, R. E.; Kern, J. T.; Sur, S. M.; Renger, J. J.; Bilodeau, M.
T.; Kennedy, M. E.; Parker, E. M.; Stamford, A. W.; Nargund, R.;
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

N
M. Iskryk et al.
Feature
Synthesis
McCauley, J. A.; Miller, M. W. J. Med. Chem. 2017, 60, 2983.
(b) Delsarte, C.; Etuin, G.; Petit, L. Bioorg. Med. Chem. 2018, 26,
984. (c) Istrate, A.; Katolik, A.; Istrate, A.; Leumann, C. J. Chem.
Eur. J. 2017, 23, 10310. (d) Choi, J.-R.; Cho, D.-G.; Roh, K. Y.;
Hwang, J.-T.; Ahn, S.; Jang, H. S.; Cho, W.-Y.; Kim, K. W.; Cho,
Y.-G.; Kim, J.; Kim, Y.-Z. J. Med. Chem. 2004, 47, 2864. (e) Choi,
J.-R.; Hwang, J.-T.; Cho, D.-G.; Roh, K.-Y.; Kim, C.-H.; Kim, C.-M.;
Han, M.-J.; Kim, J.-M.; Cho, W.-Y.; Kim, G.-W.; Ahn, S.-B. US
Patent US 2006/0111324 A1, 2006.
(13) (a) Kulinkovich, O. G.; Savchenko, A. I.; Sviridov, S. V.; Vasilevski,
D. A. Mendeleev Commun. 1993, 230. (b) Lee, J.; Kim, H.; Cha, J.
K. J. Am. Chem. Soc. 1996, 118, 4198.
(14) (a) Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem. Int.
Ed. 2002, 41, 2160. (b) Astashko, D.; Cha, J. K.; Rao, N. N.; Parida,
B. B. Eur. J. Org. Chem. 2014, 181. (c) Lee, H. G.; Lysenko, I. L.;
Cha, J. K. ARKIVOC 2008, (ix), 133.
(15) Corey, E. J.; Rao, S. A.; Noe, M. C. J. Am. Chem. Soc. 1994, 116,
9345.
(8) (a) Xu, F.; Zhong, Y.-L.; Li, H.; Qi, J.; Desmond, R.; Song, Z. J.;
Park, J.; Wang, T.; Truppo, M.; Humphrey, G. R.; Ruck, R. T. Org.
Lett. 2017, 19, 5880. (b) Harper, S.; McCauley, J. A.; Rudd, M. T.;
Ferrara, M.; DiFilippo, M.; Crescenzi, B.; Koch, U.; Petrocchi, A.;
Holloway, M. K.; Butcher, J. W.; Romano, J. J.; Bush, K. J.; Gilbert,
K. F.; McIntyre, C. J.; Nguyen, K. T.; Nizi, E.; Carroll, S. S.;
Ludmerer, S. W.; Burlein, C.; DiMuzio, J. M.; Graham, D. J.;
McHale, C. M.; Stahlhut, M. W.; Olsen, D. B.; Monteagudo, E.;
Cianetti, S.; Giuliano, C.; Pucci, V.; Trainor, N.; Fandozzi, C. M.;
Rowley, M.; Coleman, P. J.; Vacca, J. P.; Summa, V.; Liverton, N. J.
ACS Med. Chem. Lett. 2012, 3, 332.
(9) Synthesis by oxidation of cyclopropyl boronates: (a) Liskey, C.
W.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 3375. (b) Bassan, E.
M.; Baxter, C. A.; Beutner, G. L.; Emerson, K. M.; Fleitz, F. J.;
Johnson, S.; Keen, S.; Kim, M. M.; Kuethe, J. T.; Leonard, W. R.;
Mullens, P. R.; Muzzio, D. J.; Roberge, C.; Yasuda, N. Org. Process
Res. Dev. 2012, 16, 87. (c) Luithle, J. E. A.; Pietruszka, J. Eur. J. Org.
Chem. 2000, 2557. (d) Luithle, J. E. A.; Pietruszka, J. J. Org. Chem.
2000, 65, 9194. (e) Imai, T.; Mineta, H.; Nishida, S. J. Org. Chem.
1990, 55, 4986. Synthesis from α-chloroaldehydes: (f) Cheng, K.;
Carrol, P. J.; Walsh, P. J. Org. Lett. 2011, 13, 2346. Synthesis by
1,3-cyclization: (g) Díez, D.; García, P.; Marcos, I. S.; Garrido, N.
M.; Basabe, P.; Urones, J. G. Synthesis 2003, 53. (h) Díez, D.;
García, P.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Broughton, H.
B.; Urones, J. G. Org. Lett. 2003, 5, 3687. Enzymatic resolution:
(i) Pietruszka, J.; Rieche, A. C. M.; Wilhelm, T.; Witt, A. Adv.
Synth. Catal. 2003, 345, 1273. (j) Pietruszka, J.; Wilhelm, T.;
Witt, A. Synlett 1999, 1981.
(16) (a) Racouchot, S.; Sylvestre, I.; Ollivier, J.; Kozyrkov, Y. Y.; Pukin,
A.; Kulinkovich, O. G.; Salaün, J. Eur. J. Org. Chem. 2002, 2160.
(b) Konik, Y. A.; Kananovich, D. G.; Kulinkovich, O. G. Tetrahe-
dron 2013, 69, 6673.
(17) For the enantioselective cyclopropanation of amides and
nitriles, see: (a) de Meijere, A.; Chaplinski, V.; Winsel, H.;
Kordes, M.; Strecker, B.; Gazizova, V.; Savchenko, A. I.; Boese, R.;
Schill, F. (née Brackmann) Chem. Eur. J. 2010, 16, 13862.
(b) Caillé, J.; Setzer, P.; Boeda, F.; Pearson-Long, M. S. M.; Bertus,
P. SynOpen 2018, 2, 41.
(18) Kulinkovich, O. G. Pure Appl. Chem. 2000, 72, 1715.
(19) Kulinkovich, O. G.; Kananovich, D. G. Eur. J. Org. Chem. 2007,
2121.
(20) Kananovich, D. G.; Kulinkovich, O. G. Tetrahedron 2008, 64,
1536.
(21) Kulinkovich, O. G.; Kananovich, D. G.; Lopp, M.; Snieckus, V. Adv.
Synth. Catal. 2014, 356, 3615.
(22) (a) Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 6079. (b) Lee,
J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 291.
(c) Savchenko, A. I.; Kulinkovich, O. G. Zh. Org. Khim. 1997, 33,
913; Russ. J. Org. Chem. (Engl. Transl.) 1997, 33, 846. (d) Epstein,
O. L.; Kulinkovich, O. G. Tetrahedron Lett. 2001, 42, 3757.
(23) Dialkyltitanium ate species with β-hydrogens in alkyl groups
(e.g., A shown in Scheme 3) are too unstable at ambient tem-
peratures and not suitable for NMR studies. Instead, stable
dimethyltitanium analogues can be generated and used as
model compounds for testing reliability of mechanistic assump-
tions (see SI, Section II).
(10) Recent review: (a) Dian, L.; Marek, I. Chem. Rev. 2018, 118, 8415.
Notable recent examples: (b) Simaan, M.; Marek, I. Angew.
Chem. Int. Ed. 2018, 57, 1543. (c) Benoit, G.; Charette, A. B. J. Am.
Chem. Soc. 2017, 139, 1364. (d) Simaan, M.; Delaye, P.; Shi, M.;
Marek, I. Angew. Chem. Int. Ed. 2015, 54, 12345.
(24) Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D.
A.; Kühnle, F. N. M. J. Org. Chem. 1995, 60, 1788.
(25) Casey, C. P.; Strotman, N. A. J. Am. Chem. Soc. 2004, 126, 1699.
(26) Astashko, D.; Lee, H. G.; Bobrov, D. N.; Cha, J. K. J. Org. Chem.
2009, 74, 5528.
(11) Reviews: (a) Cha, J. K.; Kulinkovich, O. G. Org. React. 2012, 77, 1.
(b) Wolan, A.; Six, Y. Tetrahedron 2010, 66, 3097. (c) Wolan, A.;
Six, Y. Tetrahedron 2010, 66, 15. (d) Kulinkovich, O.; Isakov, V.;
Kananovich, D. Chem. Rec. 2008, 8, 269. (e) Kulinkovich, O. G.; de
Meijere, A. Chem. Rev. 2000, 100, 2789.
(12) (a) Chaplinski, V.; de Meijere, A. Angew. Chem. Int. Ed. 1996, 35,
413. (b) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 18,
1792.
(27) Optimization of the reaction conditions to improve yields of the
target cyclopropane compounds 1j–n was not performed
(28) Ojika, M.; Qi, J.; Kito, Y.; Sakagami, Y. Tetrahedron: Asymmetry
2007, 18, 1763.
(29) Gilman, H.; Cartledge, F. K. J. Organomet. Chem. 1964, 2, 447.
(30) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N