Asymmetric Conjugate Addition of Alkylzirconocenes to Cyclopent-4-ene-1,3-dione Monoacetals

Article abstract of DOI:10.1055/s-0034-1379928

Copper-catalyzed asymmetric conjugate additions are powerful reactions that allow the formation of single-enantiomer building blocks in a few steps. However, highly enantioselective conjugate addition to five-membered-ring substrates is more challenging a

Full text of DOI:10.1055/s-0034-1379928

SYNTHESIS
0
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1
1
4
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0
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2217–2222
2217
special topic
E. Rideau et al.
Special Topic
Synthesis
Asymmetric Conjugate Addition of Alkylzirconocenes to Cyclo-
pent-4-ene-1,3-dione Monoacetals
Emeline Rideau
Florian Mäsing
O
O
R2
R2
Stephen P. Fletcher*
O
O
O
O
Cp2ZrHCl, CH2Cl2
O
O
P
N
CuOTf, ligand, Et2O
TMSCl, 0 °C
Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK,
stephen.fletcher@chem.ox.ac.uk
R1
R1 R1
R1 = Me, Ph
R1
up to 95% ee
up to 69% yield
ligand
Received: 27.03.2015
Accepted after revision: 06.05.2015
Published online: 01.07.2015
n = 0), only a 23% yield and 75% ee were obtained, and the
results were only slightly improved on performing the reac-
tion at 0 °C.
DOI: 10.1055/s-0034-1379928; Art ID: ss-2015-c0203-st
a. previous work using alkylzirconocenes
Abstract Copper-catalyzed asymmetric conjugate additions are pow-
erful reactions that allow the formation of single-enantiomer building
blocks in a few steps. However, highly enantioselective conjugate addi-
tion to five-membered-ring substrates is more challenging and is often
neglected. Here, we report catalytic asymmetric 1,4-addition of alkyl-
zirconocenes, formed in situ from readily available alkenes, to cyclo-
pent-4-ene-1,3-dione monoacetals. Good to high enantioselectivities
are observed and the procedure tolerates various functional groups.
O
O
ClCp2Zr
R2
CuOTf, A
Et2O, TMSCl
n
R2
n
R1 R1
R1 R1
2
1
R1 = H, Me, Ph
Key words addition reactions, copper, asymmetric catalysis, organo-
metallic reagents, acetals
R
2 = H, alkyl, aryl
n = 1 good yield, high ee
n = 0 r.t.: 23%, 75% ee
0 °C: 29%, 85% ee
The asymmetric conjugate addition of organometallic
nucleophiles is a useful reaction for forming new C–C bonds
enantioselectively.1 Many methods have been developed,
and these are finding use in a variety of applications.1 How-
ever, cyclopent-2-en-1-one is a notoriously difficult sub-
strate, and methods for its use in asymmetric addition are
underdeveloped. Typically, methods that permit successful
additions to cyclohex-2-en-1-one or cyclohept-2-en-1-one
fail to give acceptable yields and enantioselectivities with
cyclopent-2-en-1-one.2 This observation has been attribut-
ed to the high reactivity and relative flatness of cyclopent-
2-en-1-ones.1e,3 Nevertheless, the asymmetric conjugate
addition of cyclopent-2-en-1-ones is desirable and is a key
step in several syntheses of natural products or biologically
active molecules.4
b. Feringa et al. using dialkylzincs
O
O
O
i) Et2Zn, Cu(OTf)2, A
– 45 °C, toluene
R2CHO
R2
O
O
ii) PCC
O
O
R1
R1
R1
R1
3
4
R1 = Ph, R2 = 4-BrC6H4 69%, 96% ee
not tandem: 40%, 90% ee
Scheme 1 Previous work
We have previously developed methods that use alkyl-
zirconium reagents as nucleophiles in asymmetric conju-
gate additions and allylic alkylation reactions.5 Asymmetric
conjugate additions to six-membered rings 1 (n = 1) give
good yields and high enantioselectivities (Scheme 1, a).5a,b
However, cyclopent-2-en-1-ones 1 (n = 0) are problematic
substrates and give both lower yields and enantiomeric ex-
cesses. In the formation of ketone 2 (R1 = H; R2 = CH2CH2Ph;
Feringa and co-workers reported asymmetric conjugate
additions of dialkylzinc reagents to cyclopent-4-ene-1,3-di-
one monoacetals 3 (Scheme 1, b).4d,6 A moderate yields and
high enantiomeric excess of 4 (R1 = Ph; R2 = 4-BrC6H4) were
obtained at –45 °C, but the yield was significantly improved
(to 69%) when the enolate that formed was trapped in situ
with an aldehyde. This trapping procedure prevents nucleo-
philic attack by the intermediate enolate on the unreacted
enone starting material 3, which would otherwise lower
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2217–2222

2218
E. Rideau et al.
Special Topic
Synthesis
the yield of the reaction, and it allows the formation of
three stereogenic centers in one step. Because a mixture of
isomers was obtained at the center bearing the hydroxy
group, pyridinium chlorochromate was used to oxidize the
aldol product to give the diketone 4.
bis(copper(I) trifluoromethanesulfonate) benzene complex
in air.5a Our self-prepared bis(acetonitrile)copper(I) trifluo-
romethanesulfonate complex as well as copper(I) triflate
generated by metathesis of commercial copper(I) chloride
and silver triflate were tested. The use of bis(acetoni-
We had previously observed that asymmetric conjugate
addition to sterically bulky derivatives of cyclohex-2-en-1-
one gave higher isolated yields than additions to cyclohex-
2-en-1-one itself5a and, inspired by the work described
above,4d,6 we decided to examine Feringa’s cyclopent-4-
ene-1,3-dione monoacetals with our method. The presence
of the acetal alters the steric properties of the cyclopenten-
one and provides extensive opportunities for further deri-
vatization of the products for applications in synthesis.
First, we examined the in situ hydrometalation and
asymmetric conjugate addition of but-3-en-1-ylbenzene
(5) to enone 3a (Table 1). Subtle variations in the amine
moiety of the phosphoramidite ligand proved important.
Structural isomers A and B gave similar results (80% and
84% ee, respectively; Table 1, entries 1 and 2a). On the other
hand, C and D, which are close relatives of A and B, gave
poorer enantioselectivities (54% and 68% ee, respectively;
entries 3 and 4). At this stage, lowering the temperature
lowered the resulting ee (78% ee; entry 2b).
Table 1 Initial Screeninga
O
O
O
5
Cp2ZrHCl, CH2Cl2
O
O
O
CuX, L*, solvent, TMSCl
3a
6a
O
O
P
N
P N
O
O
A
B
When we explored various counterions to the copper
(Table 1, entries 5–7), it became clear that the initial triflate
salt [from (CuOTf)2·PhH] gave the highest enantiomeric ex-
cess and yield. Increasing the catalyst loading to 20% im-
proved the enantioselectivity to 87% ee. As a solvent, dieth-
yl ether gave the best results. Other solvents (entries 9–12)
were detrimental to yields, although good enantiomeric ex-
cesses were obtained in dichloromethane, methyl tert-butyl
ether, or toluene (81%, 85%, and 94% ee, respectively). The
role of trimethylsilyl chloride is unclear, but it increases the
enantioselectivity in these reactions (compare entries 8a to
8b and 10a to 10b), especially in diethyl ether (87% versus
33% ee), but it did not affect the yield.
These studies allowed us to achieve a good enantiose-
lectivity (87% ee), but the yield was poor. We therefore
went on to examine more subtle differences in the system
that might lead to improved yields (Table 2). Conducting the
reaction on cyclopent-4-ene-1,3-dione monoacetal 3b (Ta-
ble 2, entry 2) improved the ee to 90%, but gave a similar
yield (43%). Increasing the amount of zirconocene nucleo-
phile used (entries 3 and 4) improved the yield moderately
(46%), and the ee remained unchanged. At this stage, a
slight excess of ligand over copper (entry 3b) lowered both
the ee and yield.
O
O
O
O
P
N
P N
D
C
Entry Catalyst
Amount Ligand Solvent
(mol%)
Yieldb
(%)
eec
(%)
1
(CuOTf)2·PhH
(CuOTf)2·PhH
10
10
A
B
Et2O
Et2O
41
80
2a
31
–
84
78
2bd
3
4
5
6
7
(CuOTf)2·PhH
(CuOTf)2·PhH
CuNTf2 (Ag)
CuClO4 (Ag)
Cu(OTf)2
10
10
10
10
20
20
C
D
B
B
B
B
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
–
–
54
68
65
73
60
7
28
25
8a
(CuOTf)2·PhH
~40
~40
87
33
8be
9
(CuOTf)2·PhH
(CuOTf)2·PhH
20
20
B
B
CH2Cl2
MTBE
~20
81
10a
~20
~20
85
70
10be
11
(CuOTf)2·PhH
(CuOTf)2·PhH
20
20
B
B
THF
–
–
Interestingly, the use of a pre-prepared copper complex5c
gave better results. A procedure involving mixing the cop-
per and ligand in situ gave a lower yield (34%), while the ee
was almost unchanged (85% ee; Table 2, entry 3c). This
finding raised questions on the effect of isolating the cop-
per complex and the difficulties associated with handling
12
toluene
traces
94
a Reaction conditions: but-3-en-1-ylbenzene (2.5 equiv), Cp2ZrHCl (2.0
equiv), CH2Cl2 (0.2 mL), 8,8-dimethyl-6,10-dioxaspiro[4.5]dec-3-en-2-one
(1.0 equiv), CuL* complex, TMSCl (5.0 equiv), solvent (2.0 mL), r.t.,
b Isolated yield.
c Determined by chiral HPLC.
d The reaction was performed at 0 °C.
e The reaction was performed without TMSCl. For detailed information on
the procedures, see the Supporting Information.
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2219
E. Rideau et al.
Special Topic
Synthesis
the solvent, lowered the yield (27% and 29%, respectively,
entries 7b and 7c) without affecting the ee. We found that
the use of a slight excess of ligand over copper (1.1:1) im-
proved the yield to ~48% (entry 7) but further additional li-
gand did not lead to any improvement (entries 7–9). The
yields and ee obtained from cyclopent-4-en-1,3-dione
monoacetal 3b (entry 10a) were similar to those obtained
with monoacetal 3a. Finally, we examined the effect of the
concentration. Increasing the concentration lowered the
yield (37%, entry 10b), whereas diluting the mixture im-
proved the enantioselectivity to 90% ee (entry 10c). At this
concentration, lowering the temperature to 0 °C improved
the results (61% yield, 92% ee).
Table 2 Improving the Yielda
O
O
O
5
O
O
O
Cp2ZrHCl, CH2Cl2
CuOTf, B, Et2O,TMSCl
R
R
R
R
3a R = Me
3b R = Ph
6a R = Me
7a R = Ph
Entry
R
Cu
(CuOTf)2·PhHd
Zr
(equiv)
B
Yieldb eec
(%) (%)
(equiv)
We next examined the addition of various alkylzircono-
cene species to Feringa’s cyclopentenone derivative 3b at
both room temperature and 0 °C (Figure 1). Nonfunctional-
ized and functionalized alkenes both gave moderate to
1
2
Me
Ph
2.0
2.0
3.0
0.20
0.20
~40
43
87
(CuOTf)2·PhHd
(CuOTf)2·PhHd
90
3a
Me
0.20
0.22
0.20
46
42
34
87
83
85
3b
3ce
O
4
5
Ph
(CuOTf)2·PhHd
Cu(MeCN)2OTfd
3.0
3.0
3.0
0.20
0.22
0.20
–
90
73
O
Me
Me
53
O
O
6a
6b
6c
CuOTff
41
27
29
88
86
86
CuOTff,g
CuOTff,h
O
O
7
8
9
Me
Me
Me
Ph
CuOTff
CuOTff
CuOTff
CuOTff
3.0
3.0
3.0
3.0
0.22
0.30
0.40
0.22
48
49
47
86
86
86
7a
7b
54%, 90% ee
61%, 92% eea
20%, 95% ee
36%, 95% eea
10ai
50
37
54
61
87
87
90
92
10bj
10ck
10dk,l
O
O
a Reaction conditions: but-3-en-1-ylbenzene (5; 2.5 or 3.5 equiv),
O
O
O
O
Cp2ZrHCl, CH2Cl2 (0.2 mL), cyclopent-4-en-1,3-dione monoacetal 3 (1.0
equiv), Cu (20 mol%), ligand B, TMSCl (5.0 equiv), Et2O (2.2 mL), r.t.
b Isolated yield.
c Determined by chiral HPLC.
d Reaction performed using a preprepared CuL* complex.
e Reaction performed using CuL* prepared in situ.
f Reaction performed using CuL* prepared in situ from CuCl (20 mol%),
AgOTf (20 mol%), and B, and filtered.
7c
7d
Cl
36%, 84% ee
63%, 89% eea
41%, 87% ee
56%, 91% eea
g As above, without filtration.
h Reaction performed by using CH2Cl2 to prepare CuL*, with subsequent fil-
tration, solvent removal, and addition of Et2O.
i Reaction performed in Et2O (2 mL).
O
O
j Reaction performed in Et2O (1 mL).
k Reaction performed in Et2O (3 mL).
O
O
l Reaction performed at 0 °C. For more information on the procedures see
the Supporting Information.
O
O
trile)copper(I) triflate with an excess of ligand (entry 5) im-
proved the yield (53%), but at the expense of enantioselec-
tivity, which fell to 73% ee. The use of copper(I) triflate
prepared from silver triflate gave the same results as
bis(copper(I) trifluoromethanesulfonate) benzene complex,
but the former system was operationally more convenient
and gave more-reproducible results, so further experiments
were carried out by using this procedure. When copper(I)
triflate was synthesized in this way, the silver chloride was
removed by filtration. We considered that this procedure
might also remove some of the catalyst complex. However,
not removing the silver chloride by filtration or changing
Si
OCH2Ph
7e
7f
10%, 60% ee
39%, 92% eea
65%, 84% ee
69%, 89% eea
Figure 1 Scope of nucleophiles. Reagents and conditions: alkene (3.5
equiv), Cp2ZrHCl (3.0 equiv), cyclopentenone 3b (1.0 equiv), CuCl (20
mol%), ligand B (22 mol%), AgOTf (20 mol%), TMSCl (5.0 equiv), Et2O
(3.0 mL), r.t. Isolated yield and ee values determined by chiral HPLC are
reported.
a Reaction performed at 0 °C. For more information on the procedures,
see the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2217–2222

2220
E. Rideau et al.
Special Topic
Synthesis
good yields and high enantiomeric excesses, especially at
0 °C, showing that the reaction is quite tolerant to changes
in the alkene coupling partner. The use of electron-rich sty-
rene or allyl(trimethyl)silane in asymmetric hydrometala-
tion and 1,4-addition procedures is often challenging, but
here they gave high enantioselectivities (95% ee and 92% ee,
respectively) and moderate yields (36% and 39%, respective-
ly) at 0 °C.
We have demonstrated that, despite some problems,
highly functionalized enantioenriched cyclopentanone de-
rivatives can be successfully prepared by asymmetric con-
jugate addition reactions of alkylzirconocene species. Good
yields and high levels of enantioselectivity are observed.
Further experiments are ongoing.
(10 × 4 mm), were used as specified. Solvents used were of HPLC
grade (Fisher Scientific, Sigma Alrich or Rathburn). All eluent systems
were isocratic.
6,10-Dioxaspiro[4.5]decan-2-ones 6 and 7; General Procedure
In a flame-dried flask under an argon atmosphere, Cp2ZrHCl (3.0
equiv) was added to a solution of the appropriate alkene (3.5 equiv) in
CH2Cl2 (0.5 mL), and the mixture was vigorously stirred until a clear
yellow solution was obtained (20–40 min). Simultaneously, in anoth-
er flask under an inert atmosphere, CuCl (0.20 equiv) and ligand (R)-B
(0.22 equiv) were covered with Et2O (2.2 mL), and the mixture was
stirred for 1 h at r.t. AgOTf (0.20 equiv) was added to the freshly pre-
pared Cu/ligand-containing solution and the mixture was stirred for
an additional 1 h. The resulting catalyst mixture was taken up by sy-
ringe and injected through a filter into the flask containing the freshly
prepared alkylzirconocene species, and this flask was then cooled to
0 °C. After 10 min, the solid cyclopent-4-ene-1,3-dione monoacetal 3
(1.0 equiv) was added in one portion by quickly tipping the solid into
the black solution. TMSCl (5.0 equiv) was then added dropwise, and
the mixture was stirred overnight then allowed to warm slowly to r.t.
The mixture was diluted with Et2O (2 mL) and the reaction was
quenched with 1 M aq NH4Cl (3 mL). The mixture was partitioned and
the aqueous phase was extracted with Et2O (3 × 10 mL). The organic
extracts were combined, washed with sat. aq NaHCO3 (30 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure. The resi-
due was purified by flash column chromatography to give the enan-
tioenriched products. Additional details are provided in the Support-
ing Information.
All reactions involving oxygen/moisture sensitive reagents were per-
formed with anhydrous solvents in flame-dried glassware under a
positive pressure of anhydrous argon, using standard Schlenk tech-
niques. Cooling of reaction mixtures to –78 °C was effected using an
acetone/dry ice bath; to 0 °C using an ice/water bath; to other tem-
peratures using a Julabo FT902 immersion cooler. Heating was per-
formed using Drysyn® heating blocks. In the cases where silver salts
were used, the resulting solutions were filtered using syringe filters
PTFE (0.2 μm, 13 mm diameter) from Camlab. Analytical thin-layer
chromatography was performed on glassplates pre-coated with silica
gel (Silica Gel 60 F254; Merck). Plates were visualised using UV light
(λ = 254 nm) and then stained with either aqueous ceric ammonium
molybdate (CAM), aqueous basic potassium permanganate (KMnO4)
or anisaldehyde and developed upon heating. Flash chromatography
was performed using silica gel [Apollo Scientific 60 (40–63 μm), Sig-
ma Aldrich (Davisil®grade 636, pore size 60 Å, 35–60 mesh), Merck
60 Å or VWR (40–63 μm)]. Pressure was applied at the column head
via a flow of nitrogen with the solvent system used in parentheses.
Nuclear magnetic resonance spectra were acquired in deuterated sol-
vents at room temperature on Bruker: AVIIIHD 400 nanobay, AVIIIHD
500, AVII 500, AVII 500 with cryoprobe spectrometers. Chemical
shifts (δ) are reported in ppm from the residual solvent. Coupling
constants (J) are quoted in hertz (Hz) and are recorded to the nearest
0.1 Hz. Resonances are described as singlet (s), doublet (d), triplet (t),
quartet (q), quintet (quint), doublet of doublets (dd), doublet of dou-
blets of doublets (ddd), doublet of triplets (dt), multiplet (m) and
broad (br). Labels Hb and Ha refer to diastereotopic protons attached
to the same carbon and impart no stereochemical information. As-
signments were made with the assistance of gCOSY, DEPT-Q, gHSQC
and gHMBC NMR spectra. Low-resolution (LRMS) and high-resolution
(HRMS) mass spectral analyses were acquired by electrospray ionisa-
tion (ESI), electron impact (EI), field ionisation (FI). Low resolution ESI
were recorded using an Agilent 6120 quadrupol LC/MS. High-resolu-
tion accurate ESI were recorded using a Thermo Exactive 1.1 SP5
Benchtop orbitrap MS and EI/FI on a Waters GTC temperature pro-
grammed solid probe inlet within the department of chemistry, Uni-
versity of Oxford. Infrared spectroscopy (IR) measurements (neat,
thin film) were carried out using a Bruker Tensor 27 FT-IR with inter-
nal calibration in the range of 4000–600 cm–1. Absorption maxima
are reported as wavenumbers (cm–1). Optical rotations were recorded
using a Schmidt Haensch Unipol L 2000 Polarimeter. Chiral HPLC sep-
arations were achieved using an Agilent 1260 Infinity series normal
phase HPLC unit and HP Chemstation software. Chiralpak® columns
(250 × 4.6 mm), fitted with matching Chiralpak® Guard Cartridges
(4S)-8,8-Dimethyl-4-(4-phenylbutyl)-6,10-dioxaspiro[4.5]decan-
2-one (6a)
Prepared by the general procedure from but-3-en-1-ylbenzene and
8,8-dimethyl-6,10-dioxaspiro[4.5]dec-3-en-2-one (3a), and purified
by flash chromatography (silica gel, 5–10% Et2O–pentane) to give a
clear oil; yield: 60.5 mg (48%; 87% ee).
HPLC: Chiralpak IC; hexane–i-PrOH (95:5); 1.0 mL/min, λ = 210 nm;
tR = 11.8 min (major enantiomer), tR = 15.6 min (minor enantiomer);
87% ee.
IR (ATR): 2931, 2858, 1748, 1466, 1396, 1285, 1186, 1118, 1055, 1017,
979, 747, 700 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.23–7.17 (m, 2 H), 7.13–7.08 (m, 3 H),
3.46–3.34 (m, 4 H), 2.89 (d, J = 18.2 Hz, 1 H), 2.62–2.50 (m, 2 H), 2.41
(dd, J = 17.7, 8.0 Hz, 1 H), 2.27–2.19 (m, 2 H), 2.02 (dd, J = 18.2, 10.7
Hz, 1 H), 1.86–1.77 (m, 1 H), 1.66–1.53 (m, 2 H), 1.42–1.23 (m, 3 H),
1.10 (s, 3 H), 0.70 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 213.7, 142.7, 128.5, 128.4, 125.8,
104.3, 73.1, 71.5, 46.1, 44.3, 43.2, 36.0, 31.8, 30.4, 27.9, 27.5, 22.8,
22.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H29O3: 317.21112; found:
317.21117.
[α]25589 = +67.9 (c = 1.0 in CHCl3, 87% ee).
(4S)-8,8-Diphenyl-4-(4-phenylbutyl)-6,10-dioxaspiro[4.5]decan-2-
one (7a)
Prepared by the general procedure from but-3-en-1-ylbenzene and
8,8-diphenyl-6,10-dioxaspiro[4.5]dec-3-en-2-one (3b), and purified
by flash chromatography (silica gel, 10–20% Et2O–pentane) to give a
clear oil; yield: 107.8 mg (61%; 92% ee).
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E. Rideau et al.
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Synthesis
HPLC: Chiralpak IA; hexane–i-PrOH (90:10); 1.0 mL/min, λ = 210 nm;
tR = 7.6 min (major enantiomer), tR = 13.4 min (minor enantiomer);
92% ee.
J = 17.9, 8.0 Hz, 1 H), 2.42 (d, J = 18.2 Hz, 1 H), 2.34–2.25 (m, 1 H), 2.13
(dd, J = 17.9, 10.7 Hz, 1 H), 1.63–1.51 (m, 1 H), 1.35–1.07 (m, 9 H),
0.89 (t, J = 7.5 Hz, 3 H).
IR (ATR): 3026, 2933, 1749, 1400, 1279, 1132, 1044, 751, 699 cm–1
.
13C NMR (126 MHz, CDCl3): δ = 213.4, 143.8, 143.5, 128.8, 128.7,
128.2, 127.1, 126.6, 126.5, 104.9, 70.9, 69.0, 46.0, 45.0, 44.9, 43.4,
31.8, 29.6, 28.0, 27.8, 22.8, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C26H33O3: 393.24242; found:
393.24238.
1H NMR (500 MHz, CDCl3): δ = 7.51 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 7.5
Hz, 2 H), 7.35–7.19 (m, 7 H), 7.18 (d, J = 7.6 Hz, 2 H), 7.11 (d, J = 7.6 Hz,
2 H), 4.67–4.60 (m, 2 H), 4.36 (d, J = 12.0 Hz, 1 H), 4.24 (d, J = 12.0 Hz,
1 H), 3.13 (d, J = 18.0 Hz, 1 H), 2.60–2.48 (m, 3 H), 2.43 (d, J = 18.0 Hz,
1 H), 2.35–2.26 (m, 1 H), 2.15 (dd, J = 18.1, 11.0 Hz, 1 H), 1.70–1.59
(m, 1 H), 1.55 (app. quint, 2 H), 1.36–1.13 (m, 3 H).
[α]25589 = +89.0 (c = 1.4 in CHCl3, 89% ee).
13C NMR (126 MHz, CDCl3): δ = 213.2, 143.7, 143.4, 142.8, 128.8,
128.7, 128.5, 128.4, 128.2, 127.1, 126.5, 126.5, 125.7, 104.8, 70.9, 68.9,
46.0, 45.0, 44.8, 43.4, 35.8, 31.8, 27.7, 27.5.
HRMS (ESI): m/z [M + Na]+ calcd for C30H32NaO3: 463.22437; found:
463.22410.
(4S)-4-(6-Chlorohexyl)-8,8-diphenyl-6,10-dioxaspiro[4.5]decan-2-
one (7d)
Prepared by the general procedure from 6-chlorohex-1-ene and 8,8-
diphenyl-6,10-dioxaspiro[4.5]dec-3-en-2-one (3b), and purified by
flash chromatography (silica gel, 10–20% Et2O–pentane) to give a
white oil; yield: 96.2 mg (56%; 91% ee).
[α]25589 = +50.4 (c = 1.1 in CHCl3, 92% ee).
HPLC: Chiralpak IA; hexane–i-PrOH (90:10); 1.0 mL/min, λ = 210 nm;
tR = 8.1 min (major enantiomer), tR = 16.5 min (minor enantiomer);
91% ee.
(4S)-8,8-Diphenyl-4-(2-phenylethyl)-6,10-dioxaspiro[4.5]decan-2-
one (7b)
Prepared by the general procedure from styrene and 8,8-diphenyl-
6,10-dioxaspiro[4.5]dec-3-en-2-one (3b), and purified by flash chro-
matography (silica gel, 10–20% Et2O–pentane) to give a white oil;
yield: 64.0 mg (36%; 95% ee).
IR (ATR): 2931, 2859, 1769, 1727, 1275, 1130, 699 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.48 (d, J = 7.3 Hz, 2 H), 7.38–7.21 (m, 6
H), 7.10 (d, J = 7.3 Hz, 2 H), 4.66–4.58 (m, 2 H), 4.35 (d, J = 11.6 Hz, 1
H), 4.22 (d, J = 11.6 Hz, 1 H), 3.52 (t, J = 6.8 Hz, 2 H), 3.12 (d, J = 17.7
Hz, 1 H), 2.51 (dd, J = 17.9, 8.3 Hz, 1 H), 2.42 (d, J = 18.1 Hz, 1 H), 2.33–
2.25 (m, 1 H), 2.14 (dd, J = 17.6, 11.1 Hz, 1 H), 1.78–1.70 (app. quint, 2
H), 1.64–1.53 (m, 1 H), 1.39–1.08 (m, 7 H).
HPLC: Chiralpak IA; hexane–i-PrOH (90:10); 1.0 mL/min, λ = 210 nm;
tR = 7.8 min (major enantiomer), tR = 16.5 min (minor enantiomer);
95% ee.
IR (ATR): 3026, 2924, 1749, 1602, 1496, 1448, 1400, 1279, 1188, 1132,
13C NMR (126 MHz, CDCl3): δ = 213.1, 143.7, 143.3, 128.8, 128.7,
128.2, 127.1, 126.5, 126.4, 104.8, 70.9, 68.9, 46.0, 45.2, 44.9, 44.8,
43.4, 32.7, 29.1, 27.8, 27.6, 26.7.
HRMS (ESI): m/z [M + Na]+ calcd for C26H31ClNaO3: 449.18539; found:
449.18561.
1032, 970, 753, 699 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.51 (d, J = 8.7 Hz, 2 H), 7.42–7.20 (m, 9
H), 7.15 (d, J = 8.4 Hz, 2 H), 7.12 (d, J = 7.6 Hz, 2 H), 4.66 (ddd, J = 12.2,
3.0, 2.7 Hz, 2 H), 4.38 (d, J = 11.9 Hz, 1 H), 4.28 (d, J = 12.2 Hz, 1 H),
3.17 (d, J = 17.9 Hz, 1 H), 2.63–2.50 (m, 3 H), 2.47 (d, J = 18.0 Hz, 1 H),
2.43–2.35 (m, 1 H), 2.22 (dd, J = 17.8, 10.9 Hz, 1 H), 2.07–1.98 (m, 1
H), 1.68–1.58 (m, 1 H).
13C NMR (126 MHz, CDCl3): δ = 213.0, 143.7, 143.4, 142.1, 128.9,
128.7, 128.4, 128.4, 128.3, 127.1, 126.6, 126.5, 125.9, 104.9, 70.9, 68.9,
45.2, 45.0, 44.9, 43.4, 33.9, 29.1.
[α]25589 = +66.5 (c = 0.9 in CHCl3, 91% ee).
(4S)-8,8-Diphenyl-4-[3-(trimethylsilyl)propyl]-6,10-dioxa-
spiro[4.5]decan-2-one (7e)
Prepared by the general procedure from allyl(trimethyl)silane and
8,8-diphenyl-6,10-dioxaspiro[4.5]dec-3-en-2-one (3b), and purified
by flash chromatography (silica gel, 10–20% Et2O–pentane) to give a
clear oil; yield: 65.5 mg (39%; 92% ee).
HRMS (ESI): m/z [M + Na]+ calcd for C28H28NaO3: 435.19307; found:
435.19317.
[α]25589 = +65.6 (c = 1.0 in CHCl3, 95% ee).
HPLC: Chiralpak IA; hexane–i-PrOH (90:10); 1.0 mL/min, λ = 210 nm;
tR = 5.0 min (major enantiomer), tR = 7.3 min (minor enantiomer);
92% ee.
(4S)-4-Hexyl-8,8-diphenyl-6,10-dioxaspiro[4.5]decan-2-one (7c)
Prepared by the general procedure from hex-1-ene and 8,8-diphenyl-
6,10-dioxaspiro[4.5]dec-3-en-2-one (3b), and purified by flash chro-
matography (silica gel, 10–20% Et2O–pentane) to give a yellow oil;
yield: 98.9 mg (63%; 89% ee).
IR (ATR): 2951, 2870, 1749, 1259, 1130, 835, 752, 697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.46 (d, J = 7.6 Hz, 2 H), 7.37–7.21 (m, 6
H), 7.09 (d, J = 7.8 Hz, 2 H), 4.64–4.55 (m, 2 H), 4.34 (d, J = 12.6 Hz, 1
H), 4.21 (d, J = 12.6 Hz, 1 H), 3.08 (d, J = 17.6 Hz, 1 H), 2.52 (dd,
J = 18.1, 8.1 Hz, 1 H), 2.42 (d, J = 18.1 Hz, 1 H), 2.38–2.27 (m, 1 H), 2.14
(dd, J = 17.8, 10.4 Hz, 1 H), 1.63–1.54 (m, 1 H), 1.35–1.20 (m, 2 H),
1.20–1.08 (m, 1 H), 0.48–0.35 (m, 2 H), –0.06 (s, 9 H).
HPLC: Chiralpak IA; hexane–i-PrOH (90:10); 1.0 mL/min, λ = 210 nm;
tR = 5.9 min (major enantiomer), tR = 10.6 min (minor enantiomer);
89% ee.
IR (ATR): 2926, 2856, 2360, 1750, 1496, 1464, 1399, 1280, 1188, 1129,
13C NMR (126 MHz, CDCl3): δ = 231.4, 143.9, 143.5, 128.8, 128.7,
127.1, 126.6, 126.5, 104.9, 70.9, 69.0, 45.6, 44.9, 44.8, 43.3, 31.5, 22.5,
16.8, –1.5.
HRMS (ESI): m/z [M + Na]+ calcd for C26H34NaO3Si: 445.21694; found:
445.21689.
1035, 771, 699, 642 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.47 (d, J = 7.9 Hz, 2 H), 7.37–7.20 (m, 6
H), 7.10 (d, J = 7.2 Hz, 2 H), 4.64–4.57 (m, 2 H), 4.34 (d, J = 12.0 Hz, 1
H), 4.22 (d, J = 12.0 Hz, 1 H), 3.09 (d, J = 17.9 Hz, 1 H), 2.52 (dd,
[α]25589 = +144.3 (c = 1.2 in CHCl3, 92% ee).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2217–2222

2222
E. Rideau et al.
Special Topic
Synthesis
(4S)-4-[4-(Benzyloxy)butyl]-8,8-diphenyl-6,10-dioxaspiro[4.5]de-
can-2-one (7f)
References
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Fletcher, S. P. Nat. Protoc. 2014, 9, 104. (f) Maciver, E. E.;
Maksymowicz, R. M.; Wilkinson, N.; Roth, P. M. C.; Fletcher, S. P.
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Prepared by the general procedure from [(but-3-en-1-yloxy)meth-
yl]benzene and 8,8-diphenyl-6,10-dioxaspiro[4.5]dec-3-en-2-one
(3b), and purified by flash chromatography (silica gel, 10–20% Et2O–
pentane) to give a yellow oil; yield: 130.3 mg (69%; 89% ee).
HPLC: Chiralpak IA; hexane–i-PrOH (90:10); 1.0 mL/min, λ = 210 nm;
tR = 9.9 min (major enantiomer), tR = 16.0 min (minor enantiomer);
89% ee.
IR (ATR): 2929, 2862, 1748, 1496, 1448, 1278, 1188, 1131, 1049, 752,
699, 642 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.45 (d, J = 7.5 Hz, 2 H), 7.40–7.18 (m,
11 H), 7.09 (d, J = 7.5 Hz, 2 H), 4.64–4.57 (m, 2 H), 4.49 (s, 2 H), 4.33 (d,
J = 11.8 Hz, 1 H), 4.20 (d, J = 12.5 Hz, 1 H), 3.38 (t, J = 6.8 Hz, 2 H), 3.10
(d, J = 17.9 Hz, 1 H), 2.51 (dd, J = 17.9, 8.0 Hz, 1 H), 2.41 (d, J = 17.9 Hz,
1 H), 2.34–2.24 (m, 1 H), 2.13 (dd, J = 17.3, 10.5 Hz, 1 H), 1.63–1.49
(m, 3 H), 1.34–1.12 (m, 3 H).
13C NMR (126 MHz, CDCl3): δ = 213.2, 143.7, 143.4, 138.8, 128.8,
128.7, 128.5, 128.3, 127.8, 127.7, 127.1, 126.6, 104.8, 73.0, 71.0, 70.3,
68.9, 46.1, 45.0, 44.8, 43.4, 30.1, 27.6, 24.7.
HRMS (ESI): m/z [M + H]+ calcd for C31H35O4: 471.25299; found:
471.25290.
[α]25589 = +58.3 (c = 1.1 in CHCl3, 89% ee).
Acknowledgment
The authors thank the EPSRC (EP/H003711/1) for financial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379928.
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(6) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2002, 67, 7244.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2217–2222