Stereospecificity of the Au(I)-catalyzed reaction of 1-alkynyl-bicyclo[4.1. 0]-heptan-2-ones with nucleophiles

Article abstract of DOI:10.1016/j.tetasy.2010.05.019

The stereospecificity of the Au(I)-catalyzed reaction of 1-alkynyl-bicyclo[4.1.0]-heptan-2-ones with nucleophiles was investigated. The substrates were prepared in non-racemic form (up to 88% ee) through parallel kinetic resolution (CBS reduction) and reo

Full text of DOI:10.1016/j.tetasy.2010.05.019

Tetrahedron: Asymmetry 21 (2010) 1745–1751
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Stereospecificity of the Au(I)-catalyzed reaction of
1-alkynyl-bicyclo[4.1.0]-heptan-2-ones with nucleophiles
*
Stephan Labsch, Shute Ye, Andreas Adler, Jörg-Martin Neudörfl, Hans-Günther Schmalz
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereospecificity of the Au(I)-catalyzed reaction of 1-alkynyl-bicyclo[4.1.0]-heptan-2-ones with
nucleophiles was investigated. The substrates were prepared in non-racemic form (up to 88% ee) through
parallel kinetic resolution (CBS reduction) and reoxidation of the separated diastereomeric alcohols. The
key Au-catalyzed reaction was then found to proceed without significant loss of absolute stereochemical
information; this way, an achiral carbocationic intermediate could be excluded. Thus, a bicyclobutonium-
type intermediate seems to be attacked in a SN2-type fashion by the nucleophile in accordance with
computational predictions.
Received 3 April 2010
Accepted 4 May 2010
Available online 12 June 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
tion of a primary Au(I)-alkyne complex 3 and leading to a late fura-
nyl gold intermediate of type
6
(Scheme 2).3 Subsequent
In the past decade, homogeneous Au-catalysis has attracted
much attention and a variety of powerful new synthetic methods
have been developed to exploit the activation of an alkyne or an al-
lene substructure towards nucleophilic attack by means of Au(I) or
Au(III) species.1 In particular, Au-catalyzed cyclizations have been
frequently exploited in the synthesis of furans and other heterocy-
cles.2 As a contribution to this rapidly growing research field, we
recently reported the gold-catalyzed reaction of 1-(1-alkynyl)-
cyclopropyl ketones with nucleophiles to give substituted furans
computational studies based on density functional theory sug-
gested the key nucleophilic attack to take place on a cationic inter-
mediate of type 4 leading directly to 6.4
R
1
O
AuL
AuL
R
under mild conditions.3 In
a typical case, a 1-alkynyl-bicy-
O
R
4
clo[4.1.0]-heptan-2-one derivative rac-1 was reacted with an alco-
hol in the presence of an in situ prepared phosphane-stabilized
Au(I) catalyst to give a cyclohepteno-[b]furane of type rac-2
(Scheme 1).
AuL
O
R'-OH
- H+
AuL
R
OR'
O
3
6
AuL
R
H+
- AuL
R
O
O
R'OH
2
5
cat. [{Ph3P}Au]OTf
Scheme 2.
OR'
rac-1
rac-2
Nevertheless, the possibility that the primarily formed cyclo-
propyl-oxenium species 4 undergoes ring opening (to form a sec-
ondary carbocation of type 5) prior to nucleophilic attack could
not be ruled out. This is because the energy difference between 4
and 5 was predicted to be small and the formation of cationic inter-
mediates of type 5 was postulated by Zhang et al. to mechanisti-
cally rationalize Au-catalyzed [4+2] annulation reactions of
related substrates.5
Scheme 1. The basic reaction system of this study.
Initially, we proposed two mechanistic alternatives for this
transformation both starting with the (possibly reversible) forma-
* Corresponding author. Tel.: +49 221 470 3063; fax: +49 221 470 3064.
E-mail address: schmalz@uni-koeln.de (H.-G. Schmalz).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.019

1746
S. Labsch et al. / Tetrahedron: Asymmetry 21 (2010) 1745–1751
While theoretical investigations provide meaningful insights
non-racemic compounds. Only in the case of rac-2by did we fail
to analytically resolve the enantiomers with the set of columns
available.
into possible reaction mechanisms, we feel that experimental
probes should always complement such studies. To distinguish be-
tween the two mechanistic pathways discussed above (Scheme 2),
we decided to probe the stereospecificity of the process. The basic
consideration was that the nucleophile attack on a (chiral) inter-
mediate 4 should proceed in a stereospecific (SN2-type) fashion,
while the absolute stereochemical information would be lost if
an achiral intermediate of type 5 was involved. Herein, we disclose
the results of a study using non-racemic substrates, which indeed
demonstrated the reaction to proceed with a high degree of
stereospecificity.
2.2. Synthesis of non-racemic substrates of type 1
In the first approach (Scheme 4) towards the synthesis of sub-
strates of type 1 in enantiomerically enriched form we employed
the literature-reported10 CBS reduction11 of 7 as the chirogenic
step. Using a CBS catalyst derived from (S)-diphenyl-prolinol and
n-butyl boronic acid the (R)-configurated alcohol was obtained
with 93% ee (GC). Subsequent Sonogashira coupling7 afforded the
enyne 9 in high yield. Unfortunately, our attempts to diastereose-
lectively convert 9 into the cyclo-propanated product 10 in a Sim-
mons–Smith-type reaction did not lead to satisfying results. Even
in the best case (Et2Zn/CH2I2)12 the reaction proceeded rather slug-
gishly to give 10 in only low yield (625%).
2. Results and discussion
2.1. Synthesis of racemic substrates as reference samples
Starting from 2-iodo-cyclohexenone 76 the two alkynylated
compounds 8a and 8b were prepared by standard Sonogashira
coupling7,2a and further converted into the racemic substrates
rac-1a and rac-1b, respectively, through Corey–Chaykovsky cyclo-
propanation8 (Scheme 3).
O
OH
Ph
I
a, b
7
9 (93% ee)
O
O
R
I
c
a
Ph
Ph
O
OH
7
8a (R = Ph)
8b (R = nBu)
d
b
R
R
1a
10
O
O
Scheme 4. Reagents and conditions: (a) nBu-(S)-CBS (15 mol %), BH3ꢀMe2S
(1.2 equiv, slow addition over 1.5 h), 15 min, THF, 0 °C, then quench with MeOH,
95%; (b) Cl2Pd(PPh3)2 (3 mol %), CuI (6 mol %), phenylacetylene, diisopropylamine,
overnight, THF, 0 °C to rt, 85%; (c) Et2Zn (2 equiv), ClCH2I (4 equiv), ClCH2CH2Cl,
45 min, 0 °C, 25%; (d) oxidation.
c
OR'
rac-1a R = Ph
rac-1b R = nBu
rac-2
As an alternative entrance to non-racemic substrates of type 1
we then probed the kinetic resolution13 of the racemic ketones
(rac-1a and rac-1b, respectively) again using the CBS reduction.
We were glad to find that a parallel kinetic resolution14 took place
to give a separable mixture of non-racemic diastereomeric alcohols
in both cases (Scheme 5). Under optimized conditions (30 mol % of
CBS catalyst, THF, 0 °C, slow addition of 1.2 equiv of BH3–SMe2) the
(R)-configurated alcohols (10/11 and 12/13, respectively) were iso-
lated with up to 88% ee albeit in rather low yields after careful
chromatographic separation of the diastereomers. To avoid severe
separation problems it proved to be important to ensure full con-
version of the starting ketones.
The two endo-configurated alcohols 10 (88% ee) and 12 (81% ee)
were then oxidized using either Jones or Dess–Martin reagent15 to
afford the desired ketones (+)-1a and (+)-1b, respectively, in good
yields and unchanged enantiomeric purity within the limits of ana-
lytical accuracy (Scheme 5).
Scheme 3. Reagents and conditions: (a) phenylacetylene or 1-hexyne, Cl2Pd(PPh3)2
(1 mol %), CuI (2 mol %), diisopropylamine, 2–4 h, THF, 0 °C to rt, 82% 8a; 53% 8b; (b)
NaH, trimethylsulfoxonium iodide, DMF, 14–16 h, rt, 70% (rac-1a), 43%, rac-1b; (c)
Au[PPh3]OTf (1 mol %), R’OH, (2 equiv), CH2Cl2, 15 min, rt, 80–91%.
The key Au(I)-catalyzed reaction then proceeded smoothly un-
der the established conditions (CH2Cl2, rt, 15 min) employing
(Au[PPh3]OTf)9 as a catalyst, which was generated in situ from
Au[PPh3]Cl and AgOTf after filtering off the AgCl precipitate
formed. Using methanol, tert-butanol or 2-propanol as a nucleo-
philic reaction partner the expected (racemic) furans of type rac-
2 were obtained in good yield as summarized in Table 1. By means
of chiral GC and HPLC, respectively, suitable conditions were then
elaborated to analytically separate the racemic mixtures in almost
all cases as a precondition for the planned investigations using
Table 1
Results of the Au-catalyzed transformations in the racemic series according to step c
in Scheme 3
R0
Product
Yielda (%)
2.3. Configurational assignments
Entry
R
1
2
3
4
5
6
Ph
Ph
Ph
n-Bu
n-Bu
n-Bu
Me
rac-2ax
rac-2ay
rac-2az
rac-2bx
rac-2by
rac-2bz
91
85
82
86
80
80
The relative configuration of the diastereomeric alcohols (10/11
and 12/13, respectively) was unambiguously determined by means
of an X-ray crystal structure analysis of 10 (Fig. 1) and correlation
of NMR data.
The absolute configuration of the chiral ketones 1a and 1b was
assigned by comparison of the experimental and calculated CD
tert-Bu
Propargyl
Me
tert-Bu
Propargyl
a
Isolated yield after chromatographic purification.

S. Labsch et al. / Tetrahedron: Asymmetry 21 (2010) 1745–1751
1747
Ph
Ph
OH
O
b
Ph
O
28%
29%
87%
10 (88% ee)
1a (86% ee)
a
Ph
OH
rac-1a
11 (71% ee)
λ
Bu
Bu
OH
O
c
Bu
O
12%
24%
83%
12 (81% ee)
1b (81% ee)
a
Bu
OH
rac-1b
13 (??% ee)
Scheme 5. Synthesis of the non-racemic ketones 1a and 1b, respectively, through
parallel kinetic resolution. Reagents and conditions: (a) nBu-(S)-CBS (30 mol %),
BH3ꢀMe2S (1.2 equiv, slow addition over 2 h), THF, 0 °C, then quench with MeOH;
chromatographic separation of diastereomers; (b) Jones reagent, acetone, 20 min,
0 °C to rt; (c) Dess–Martin periodane (1.6 equiv), CH2Cl2, 3.5 h, rt.
λ
Figure 2. Experimental (grey) and calculated (black) CD spectra of compounds 1a
(top) 1b (bottom) in MeCN.
Figure 1. Structure of 10 in the crystalline state.
spectra (Fig. 2).16,17 In addition, it could be shown by chiral GC that
compound 10 prepared from rac-1a according to Scheme 5 was
identical to the sample obtained by cyclopropanation of (R)-9
(Scheme 4).
These assignments are also in accordance with the empirical
octand rule18 considering the Cotton effects at ca. 280 nm (corre-
*
sponding to the ketone n-
p transition). Note that one has to be
Figure 3. Application of the octand rule to ketones 1a (top) and 1b (bottom). Left
side: common view along the C@O axis with the sign of the rear octands indicated.
Right: view from above with the signs of the upper octands indicated. Thus, both
compounds are predicted to exhibit a positive Cotton effect at ca. 280 nm because
the alkynyl substituent occupies the (positive) upper front octand in both cases.
aware that a common simplification of the octand rule (reduction
to a quadrant rule by looking along the carbonyl bond axis and
only considering the four rear quadrants) would lead to the wrong
assignment here (Fig. 3, left). Thus, looking from a bird’s eye per-
spective on the ketone (Fig. 3, right) reveals that the octand occu-
pied by the alkynyl substituent actually has a (+)-sign. Thus, a
positive Cotton effect is predicted for both (S,S)-configured ketones
1a and 1b, respectively.
Using either methanol, tert-butanol or propargylic alcohol we
were pleased to obtain the addition products (furans) of type 2
without any significant loss of absolute stereochemical informa-
tion (Table 2).
2.4. The Au-catalyzed key reaction in the non-racemic series
While we did not explicitly prove the absolute configuration of
the resulting compounds of type 2, we confidently assume them to
be (S)-configurated because the observed stereospecificity can only
be explained through a SN2-type attack of the alcohol nucleophile
Finally, the stereospecificity of the Au-catalyzed title reaction
was probed by subjecting the non-racemic ketones 1a and 1b,
respectively, to the established reaction conditions (Scheme 6).

1748
S. Labsch et al. / Tetrahedron: Asymmetry 21 (2010) 1745–1751
hydroxide. All other reagents were purchased from Aldrich, Merck,
R
R
Acros, Fluka, MP, Chemetall or Strem and used without further
purification, unless otherwise indicated. The CBS catalyst used
was prepared from (S)-diphenylprolinol and n-butylboronic acid.
Column chromatography was performed with Acros Silica Gel 60
(230–400 mesh). Analytical thin-layer chromatography (TLC) was
performed with commercial aluminum plates coated with Silica
Gel 60-F254 from Merck. Chromatograms were visualized by UV-
light at 254 nm or by staining with a ‘cerium reagent’ (prepared
from 2 g of phosphomolybdic acid, 1 g of cerium(IV) sulfate and
10 mL of concentrated H2SO4 in 90 mL of water) and subsequent
heating. Melting points (mp) were determined with a Büchi 510
apparatus in open capillary tubes and are uncorrected. Nuclear
magnetic resonance (NMR) spectra (1H, 13C) were recorded in
CDCl3 on Bruker instruments DPX 300, AC 300 or DRX 500. Chem-
ical shifts (d) are reported in delta (d) units in parts per million
(ppm) relative to tetramethylsilane (0.00 ppm). The fine structure
of proton signals is given as s (singlet), d (doublet), t (triplet), m
(multiplet) or br (broad). In the case of 13C NMR, APT (attached
proton test) spectra were used to determine the formal multiplicity
C (s), CH (d), CH2 (t), CH3 (q). Infrared spectra (IR) were recorded on
a Perkin–Elmer Paragon 1000 FT-IR spectrometer using the ATR
technique. The intensity of absorption bands is given as s (strong),
m (medium) or w (weak); b additionally indicates broad signals.
Mass spectra (MS) and high resolution mass spectra (HRMS) were
measured with a Varian MAT 711, Finnigan Incos 500 or Finnigan
MAT 95 ST. The spectra were measured under electron impact
(EI) with an ionization potential of 70 eV. Gas-chromatography
with mass selective detection (GC–MS) was carried out using an
Agilent instrument using a 5973 N detector on 30 m ꢁ 0.25 mm
capillary columns (Optima-1-MS from Macherey-Nagel) with H2
as a carrier gas (1.7 mL/min, 1.2 bar). As a routine, the following
temperature programme was used: 50 °C (2 min), then heating
with 25 °C/min to 300 °C (5 min), finally 320 °C (5 min). Enantio-
meric analyses through GC were performed on an Agilent (HP
6890) instrument with FID detection using either a BGB-176SE col-
umn (A) or a 6TBDMS-2,3-Me-b-CD column (B). Enantiomeric anal-
yses through High Performance Liquid Chromatography (HPLC)
were conducted with HPLC units from Merck-Hitachi and Knauer
(UV-detection at 220 nm and 254 nm) using one of the following
columns: Diacel Chiracel OB-H (C), Diacel Chiracel OJ (D), Diacel
Chiralpak AD-H (E), Macherey Nagel Nucleocell (F) and n-Hex/i-
PrOH (90:10 or 95:5) as a solvent. Optical rotations were measured
on a Perkin–Elmer 343 polarimeter at 20 °C using a 10 cm cell. The
solvents and concentrations (in g/100 mL) are indicated.
O
O
R'-OH
1 mol% [{Ph3P}Au]OTf
CH2Cl2, rt, 15 min
OR'
1a R = Ph
2
1b R = nBu
Scheme 6. Stereospecific Au-catalyzed transformation of ketones 1 into furans of
type 2 (compare Table 2).
Table 2
Results of the Au-catalyzed furan synthesis in the non-racemic series according to
Scheme 6
Entry
Substrate
ee (%)
R’OH
Product
ee (%)
Yielda (%)
1
2
3
4
5
1a
1a
1a
1b
1b
85
86
78
79
79
MeOH
2ax
2ay
2az
2bx
2bz
83
83
77
79
80
63
97
68
65
26
tBuOH
HC„CCH2OH
MeOH
HC„CCH2OH
a
Isolated yield after chromatographic purification.
onto a cationic intermediate of type 4, which might also be re-
garded as a bicyclobutonium-type species 4’ (Scheme 7).19
O
O
R
R
AuL
AuL
R'
H
R'
H
O
O
H
H
4
4'
Scheme 7. Stereospecific attack of an alcohol (R0OH) to a bicyclobutonium-type
intermediate 4/40 affording furans of type 2.
The fact that the reaction (Scheme 6) proceeded with a very
high degree of stereospecificity even in the case of tert-butanol
(as a sterically demanding nucleophile) suggests that the forma-
tion of a secondary carbenium ion of type 5 (Scheme 2) is disfa-
voured under the conditions applied. This is in accordance with
the observation that no conversion of the substrate 1 occurs in
the absence of a nucleophile or in the presence of Et3SiH (as a hy-
dride source known to react with carbenium cations).3
3. Conclusions
4.2. 2-Iodocyclohex-2-enone 7
By preparing the 1-alkynyl-bicyclo[4.1.0]-heptan-2-ones 1a and
1b in non-racemic form, we were able to demonstrate the stereo-
specificity of their Au(I)-catalyzed transformation into cyclohepte-
no[b]furans of type 2. This result not only sheds some light to the
mechanistic pathways of the reaction (by excluding an achiral cat-
ionic intermediate) but also opens new perspectives for possible
applications of the methodology in the synthesis of non-racemic
molecules.
A round-bottomed flask was charged subsequently with 400 mL
of THF/water 1:1, cyclohexenone (8 mL, 83 mmol), K2CO3 (13.7 g,
99 mmol), I2 (31.6 g, 125 mmol) and 4-N,N-dimethylaminopyri-
dine (2.02 g, 17 mmol). The mixture was stirred for 4.5 h, diluted
with 800 mL of EtOAc and washed with satd aqueous Na2S2O3
(800 mL) and 1 M aqueous HCl (600 mL). The organic layer was
dried with MgSO4, the solvent evaporated under reduced pressure
and the solid residue was recrystallized from cyHex to yield 10.9 g
of 7 as a colourless solid. The mother liquid was concentrated and
the residue was purified by column chromatography (1:4 EtOAc/
cyHex) to yield additional 5.0 g of 7 (overall yield 15.9 g, 87%).
Compound 7 is thermally labile but could be stored in the freezer
for several months without decomposition. Mp 49–51 °C. IR (neat):
2948 (w), 2866 (w), 1674 (s), 1583 (m), 1313 (m), 1119 (m), 965
4. Experimental
4.1. General
Reactions were carried out under an atmosphere of argon in
oven-dried glassware with magnetic stirring. THF and toluene
were freshly distilled under an argon atmosphere from sodium/
benzophenone. DMF was distilled from calcium hydride and stored
over 3 Å molecular sieves. Methanol was distilled from magnesium
turnings. Triethylamine was distilled and stored over potassium
(m) cmꢂ1 1H NMR: d = 7.78 (m, 1H), 2.69–2.65 (m, 2H, CH3),
.
2.48–2.43 (m, 2H), 2.15–2.05 (m, 2H). 13C NMR: d = 192.1 (s),
159.4 (d), 103.8 (s), 37.2 (t), 29.9 (t), 22.8 (t). GC–MS: 222 (M+),
135 (100%).

S. Labsch et al. / Tetrahedron: Asymmetry 21 (2010) 1745–1751
1749
4.3. 2-(Phenylethynyl)-cyclohex-2-enone 8a
79.4 (s), 36.2 (t), 30.9 (t), 29.0 (d), 26.7 (s), 21.9 (t), 21.27 (t),
20.95 (t), 18.56 (t), 18.35 (t), 20.95 (t), 13.6 (q). GC–MS: 91
(100%), 190 (M+).
A round-bottomed flask was charged with anhydrous THF
(45 mL), enone
7
(4.4 g, 20 mmol), Cl2Pd(PPh3)2 (140 mg,
0.2 mmol) and CuI (85 mg, 0.4 mmol) and the mixture was cooled
to 0 °C before phenylacetylene (4 mL, 36 mmol) and diisopropyl-
amine (8 mL, 57 mmol) were added. After 2 h at 0 °C the mixture
was diluted with ether (450 mL) and washed with 1 M aqueous
HCl (480 mL). The aqueous phase was extracted with ether
(450 mL) and the combined organic layers were washed with brine
(240 mL) and dried over MgSO4. The solvent was removed under
reduced pressure and the solid residue was purified by column
chromatography (1:4 EtOAc/cyHex) to yield 8a (3.2 g, 82%) as an
orange solid. IR (neat): 3051 (w), 2947 (w), 2860 (w), 1681 (s),
4.7. Kinetic resolution of rac-1b: Preparation of 1-phenyl-
ethynyl-bicyclo[4.1.0]heptan-2-ol 10 and 11
A solution of ketone rac-1a (1.05 g, 5 mmol) in 45 mL of THF was
cooled to 0 °C and a 0.5 M solution of the CBS catalyst in toluene was
added (3 mL, 1.5 mmol). Then a solution of BH3ꢀMe2S in THF (3.0 mL,
6 mmol) was added slowly over a period of 2 h under stirring by
means of a syringe pump. The reaction was then stopped by addition
of a fewmL of MeOH. Removalof all volatilesunder reducedpressure
and column chromatography (5:2 toluene/CH2Cl2) of the oily resi-
due gave the two diastereomers 10 (296 mg, 28%, 88% ee (GC column
A)) and 11 (311 mg, 29%, 71% ee (HPLC column F)).
1488 (m), 1353 (m), 1071 (m), 756 (s), 690 (s) cmꢂ1 1H NMR:
.
d = 7.51–7.48 (m, 2H), 7.36–7.29 (m, 4H), 2.55–2.46 (m, 4H),
2.09–2.01 (m, 2H). 13C NMR: d = 195.5, 154.1, 131.7, 128.3, 128.1,
125.2, 122.8, 92.0, 83.8, 38.1, 26.4, 22.4. GC–MS: 196 (M+).
Compound 11: Rf (5:2 toluene/CH2Cl2) = 0.3. [ ]k (20 °C, CHCl3, c
a
1): [ 589 = +73.4, [ 546 = +88.4, [ 405 = +200.9, [a]365 = +280.4. IR
a]
a
]
a]
(neat): 3388 (b-m), 3071 (w), 3010 (w), 2933 (m), 2857 (m),
4.4. 2-(Hex-1-ynyl)-cyclohex-2-enone 8b
2216 (m), 1949 (w), 1877 (w), 1809 (w), 1678 (w), 1696 (m),
1043 (s), 754 (s), 690 (s) cmꢂ1 1H NMR: d = 7.41–7.38 (m, 2H),
.
Following the procedure described above for the synthesis of
8a, 4.4 g (20 mmol) of 7 was reacted with 1-hexyne (3.2 mL,
26 mmol) for 4 h at rt to give 1.9 g (53%) of 8b as a yellow oil after
chromatography (6:1 toluene/CH2Cl2). IR (neat): 2948 (s), 2930 (s),
7.28–7.25 (m, 3H), 4.16 (t, 1H, J = 3.67 Hz), 2.61 (s, 1H), 2.12–
2.03 (m, 1H), 1.72–1.48 (m, 4H), 1.44–1.33 (m, 1H), 1.18 (dd, 2H,
J = 4.68, J = 9.35 Hz) 0.61 (dd, 1H, J = 4.84 Hz, J = 6.22 Hz). 13C
NMR: d = 131.7 (d), 128.1 (d), 127.8 (d), 123.2 (s), 92.9 (s), 79.2
(s), 66.2 (s), 27.7 (t), 22.4 (t), 20.0 (t), 18.6 (t), 14.8 (t). GC–MS:
194 (100%), 212 (M+). HRMS: calcd for C15H16O = 212.1201, found:
212.120.
2866 (s), 2227 (w), 1683 (s), 1349 (m), 1117 (m) cmꢂ1 1H NMR:
.
d = 7.20 (t, J = 4.4 Hz, 1H), 2.50–2.35 (m, 6H), 2.06–1.97 (m, 2H),
1.58–1.37 (m, 4H), 0.94–0.89 (m, 3H). 13C NMR: d = 196.2 (s),
153.0 (d), 125.5 (s), 93.4 (s), 74.9 (s), 38.1 (t), 30.7 (t), 26.3 (t),
22.4 (t), 22.0 (t), 19.1 (t), 13.6 (q). GC–MS: 134 (100%), 176 (M+).
Compound 10: Rf (5:2 toluene/CH2Cl2) = 0.12. [
1): 546 = ꢂ108.8, 405 = ꢂ242.9,
589 = ꢂ90.5,
ꢂ338.2, [ 334 = ꢂ470.1. IR (neat): 3388 (b-m), 3071 (w), 3010
(w), 2933 (m), 2857 (m), 2216 (m), 1949 (w), 1877(w), 1809 (w),
1678 (w), 1696 (m), 1043 (s), 754 (s), 690 (s) cmꢂ1 1H NMR:
a]k (20 °C, CHCl3,
c
[
a]
[a
]
[
a]
[a
]
365
=
a]
4.5. 1-Phenylethynyl-bicyclo[4.1.0]heptan-2-one rac-1a
.
A round-bottomed flask was charged with DMF (200 mL), NaH
(1.8 g, 44 mmol) and trimethylsulfoxonium iodide (11.5 g,
52 mmol). After 30 min at rt, the enone 8a (7.8 g, 40 mmol) in DMF
(30 mL) was added and stirring was continued for 16 h. Then
1000 mL of water was added, the aqueous phase was extracted with
MTBE (3 ꢁ 200 mL) and the combined organic layers were washed
with satd aqueous NH4Cl (100 mL) and dried over MgSO4. After
removing the solvent under reduced pressure the remaining oil
was purified by column chromatography (1:6 EtOAc/cyHex) to yield
5.9 g (70%) of rac-1a as a white solid. Mp= 52–53 °C. IR (neat): 3044
(w), 2939 (w), 2225 (w), 1693 (s), 1595 (w), 1091 (m), 757 (s), 692 (s)
cmꢂ1. 1H NMR: d = 7.44–7.40 (m, 2H), 7.27–7.24 (m, 3H), 2.43–2.34
(m, 1H), 2.25–1.95(m, 4H), 1.80–1.60(m, 4H). 13CNMR:d = 203.7(s),
131.8 (d), 128.0 (d), 123.2 (s), 89.2 (s), 79.7 (s), 36.3 (s), 29.4 (d), 27.0
(t), 21.3 (t), 21.2 (t), 18.2 (t). GC–MS: 210 (M+).
d = 7.40–7.36 (m, 2H), 7.28–7.24 (m, 3H), 4.33 (dd, 1H, J = 5.69,
J = 9.12 Hz, H-6), 2.06–1.95 (m, 2H), 1.79–1.71 (m, 1H), 1.67–1.59
(1H, H-2), 1.52–1.40 (m, 2H), 1.35–1.21 (m, 2H), 1.10 (dd, 1H,
J = 4.64, J = 9.28 Hz), 0.93 (dd, 1H, J = 4.80, J = 6.52 Hz). 13C NMR:
d = 131.7 (d), 128.2 (d), 127.6 (d), 123.6 (s), 95.4 (s), 76.6 (s), 70.9
(d), 28.9 (t), 24.6 (d), 22.7 (t), 20.0 (t), 19.3 (s), 17.6 (t). GC–MS:
194 (100%), 212 (M+). HRMS: calcd for C15H16O = 212.1201, found:
212.120. For X-ray structure analysis, colourless crystals were ob-
tained from wet CH2Cl2 containing traces of isopropylamine.20
4.8. 1-(Phenylethynyl)-bicyclo[4.1.0]heptan-2-one 1a
A solution of alcohol 10 (135 mg, 0.64 mmol) in 5 mL of acetone
was cooled to 0 °C. Jones reagent was added dropwise until the or-
ange colour persisted. Stirring was continued for 15 min at 0 °C be-
fore the cooling bath was removed and, after five more minutes,
the reaction was stopped by addition of a little i-PrOH. The mixture
was concentrated under reduced pressure and the residue was par-
titioned between water and MTBE. The organic layers were washed
with satd aqueous NaHCO3 and dried over MgSO4. After solvent
evaporation under reduced pressure the residue was purified by
column chromatography (1:10 EtOAc/cyHex) to give 1a as a white
4.6. 1-Hex-1-ynyl-bicyclo[4.1.0]heptan-2-one rac-1b
In analogy to the procedure described above for the synthesis of
rac-1a, NaH (170 mg, 3.9 mmol) and trimethylsulfoxonium iodide
(1.0 g, 4.6 mmol) were first reacted in DMF (15 mL) for 30 min be-
fore the enone 8b (627 mg, 3.6 mmol) in 5 mL of DMF was added.
After 14 h at rt the mixture was partitioned between water (50 mL)
and MTBE (3 ꢁ 20 mL) before the combined organic layers were
washed with satd aqueous NH4Cl (10 mL) and dried over MgSO4.
The solvent was removed under reduced pressure and the remain-
ing oil was purified by column chromatography (1:8 EtOAc/cyHex)
to yield 297 mg (43%) of rac-1b as a yellow oil. IR (neat): 2927 (s),
2860 (m), 1690 (s), 1455 (w), 1350 (w), 1322 (w), 1238 (w), 1135
solid (117 mg, 0.55 mmol, 87%, 86% ee (HPLC column C)). [
(20 °C, CHCl3, 1): 589 = -23.2, 546 = -24.3, 405 = 16.6,
365 = 115.5, [ 334 = 419.3.
a]
k
c
[a
]
[
a]
[a]
[a
]
a]
4.9. Kinetic resolution of rac-1b: preparation of 1-hex-5-ynyl-
bicyclo[4.1.0]heptan-2-ol 12 and 13
(w), 1089 (w), 1017 (w), 913 (w), 814 (w), 746 (w) cmꢂ1 1H NMR
.
d = 2.33 (ddd, J = 4.30 Hz, J = 5.49 Hz, J = 18.21 Hz, 1H), 2.20 (t,
J = 6.99 Hz, 2H), 2.16–1.90 (m, 4H), 1.78–1.55 (m, 3H), 1.52–1.32
(m, 5H), 0.89 (t, J = 7.14 Hz, 3H). 13C NMR d = 204.7 (s), 80.2 (s),
A solution of ketone rac-1b (1.91 g, 10 mmol) in anhydrous THF
(90 mL) was cooled to 0 °C and a 0.5 M solution of the CBS catalyst

1750
S. Labsch et al. / Tetrahedron: Asymmetry 21 (2010) 1745–1751
in toluene was added (6 mL, 3 mmol). Then a solution of BH3ꢀMe2S
in THF (6.0 mL, 12 mmol) was added slowly over a period of 2 h
under stirring by means of a syringe pump. The reaction was then
stopped by addition of a few mL of MeOH. Removal of all volatiles
under reduced pressure and column chromatography (5:2 toluene/
CH2Cl2) of the oily residue gave the two diastereomers 12 (239 mg,
12%, 81% ee (GC column A)) and 13 (461 mg, 24%).
4.13. (S)-5-tert-Butoxy-5,6,7,8-tetrahydro-2-phenyl-4H-
cyclohepta[b]furan 2ay
The reaction of 1a (42 mg, 0.2 mmol, 86% ee) with t-butanol
(27 mg, 0.4 mmol) in the presence of Au[PPh3]OTf (0.00625 M,
0.3 mL, 0.002 mmol) afforded 55 mg (97%, 83% ee (HPLC column
D)) of 2ay as a yellow liquid. [
a] (20 °C, CHCl3, c 1): [a]589 = +7.1,
k
Compound 12: [
ꢂ44.8, [ 405 = ꢂ88.3, [
2932 (s), 2860 (m), 1455(m), 1330 (w), 1253 (w), 1046 (w), 990
(w), 916 (w), 853 (w), 766 (w) cmꢂ1 1H NMR: d = 4.17 (dd, 1H,
a
]
(20 °C, CHCl3, c 1): [
a
]
589 = ꢂ38.1, [
a
]
=
[
a
]
546 = +7.7, [ 405 = +4.6. Rf (1:4 EtOAc/cyHex) = 0.75. IR (neat):
a]
k
546
a
]
a]
365 = ꢂ113.5. IR (neat): 3384 (b-m, OH),
2969 (m), 2928 (m), 2852 (w), 1698 (w), 1601 (w), 1486 (w),
1447 (w), 1361 (m), 1698 (w), 1193 (s), 1053 (s), 1018 (m), 758
.
(w), 690 (m) cmꢂ1 1H NMR: d = 7.60–7.57 (m, 2H), 7.35–7.33 (m,
.
J = 5.68, J = 9.47 Hz), 2.15 (t, 2H, J = 9.94), 1.96–1.90 (m, 2H),
1.75–1.66 (m, 1H), 1.51–1.18 (m, 9H), 1.00–0.88 (m, 5H), 0.75
(dd, 1H, J = 4.72, J = 6.22 Hz). 13C NMR: d = 85.4 (s), 76.8 (s), 71.4
(d), 31.1 (t), 28.7 (t), 23.8 (d), 22.7 (t), 21.9 (t), 20.3 (t), 19.0 (s),
18.5 (t), 17.2 (t), 13.6 (q). GC–MS: 91 (100%) 192 (M+). HRMS: calcd
for C13H20O = 192.1514, found: 192.151.
2H), 7.21–7.16 (m, 1H), 6.42 (s, 1H), 3.54 (m, 1H), 3.56–3.47 (m,
1H), 2.91–2.84 (m, 1H), 2.71–2.57 (m, 3H), 2.14–1.90 (m, 2H),
1.71–1.55 (m, 2H), 1.22 (s, 9H). 13C NMR: d = 153.2 (s), 150.1 (s),
131.1 (s), 128.5 (d), 126.6 (d), 123.2 (d), 117.2 (s), 108.9 (d), 73.8
(s), 70.9 (d), 40.0 (t), 35.0 (t), 28.3 (q), 24.0 (t). GC–MS: 227
(100%), 284 (M+)
Compound 13:
[
a]
(20 °C, CHCl3,
c
1):
[a]589 = 46.3,
k
[
a
]
546 = 83.6, [ 405 = 121.1, [
a
]
a
]
365 = 163.0. IR (neat): 3388 (bm),
4.14. Synthesis of (S)-5,6,7,8-tetrahydro-2-phenyl-5-(prop-2-
ynyloxy)-4H-cyclohepta[b]furan 2az
3071 (w), 2932 (s), 2853 (m), 1456 (w), 1393 (w), 1333 (w),
1253 (w), 1176 (w), 1116 (w), 1086 (w), 1063 (w), 991 (w), 843
(w) cmꢂ1
.
1H NMR: d = 4.03 (t, 1H, J = 3.95 Hz), 2.54 (s, 1H), 2.18
The reaction of 1a (32 mg, 0.15 mmol, 78% ee) with propargylic
alcohol (17 mg, 0.3 mmol) in the presence of Au[PPh3]OTf
(0.00625 M, 0.23 mL, 0.0015 mmol) afforded 27 mg (68%, 77% ee
(t, 1H, J = 6.94 Hz), 2.05–2.0 (m, 1H), 1.59–1.26 (m, 9H), 1.13–
1.11 (m, 1H), 1.00 (dd, 1H, J = 4.71, J = 9.29 Hz), 0.90 (t, 3H,
J = 7.17 Hz), 0.46 (dd, 1H, J = 4.76, J = 6.27 Hz). 13C NMR: d = 82.9
(s), 79.9 (s), 66.2 (d), 31.1 (t), 27.6 (t), 22.6 (t), 22.0 (t), 20.9 (d),
19.5 (t), 18.5 (t), 18.2 (s), 14.3 (t), 13.6 (q). GC–MS: 91 (100%)
192 (M+). HRMS: calcd for C13H20O = 192.1514, found: 192.151.
(HPLC column E)) of 2az as a liquid. [a] (20 °C, CHCl3, c 1):
k
[
a
]
589 = ꢂ18.9, [
a
]
546 = ꢂ23.5, [ 405 = ꢂ103.1. Rf (1:10 EtOAc /cy-
a
]
Hex) = 0.54. IR (neat): 3292 (w), 2927 (m), 2846 (w), 1676 (w),
1599 (w), 1553 (w), 1483 (w), 1446 (w), 1356 (w), 1080 (s), 932
(w), 932 (w), 813 (w), 759 (s), 691 (w) cmꢂ1 1H NMR: d = 7.60–
.
4.10. 1-Hex-1-ynyl-bicyclo[4.1.0]heptan-2-one 1b
7.57 (m, 2H), 7.36–7.31 (m, 2H), 7.22–7.17 (m, 1H), 6.45 (s, 1H),
4.22 (d, 2H, J = 2.36 Hz), 3.67 (tt, J = 2.91, J = 9.37 Hz), 2.90–2.83
(m, 2H), 2.77–2.71 (m, 1H), 2.68–2.58 (m, 1H), 2.41 (t, 1H,
J = 2.34), 2.25–2.17 (m, 1H), 2.04–1.93 (m, 1H), 1.82–1.56 (m,
2H). 13C NMR: d = 153.1 (s), 150.3 (s), 131.0 (s), 131.0 (d), 126.6
(d), 123.2 (d), 116.4 (s), 108.8 (d), 80.2 (s), 77.2 (d), 73.9 (d), 55.6
(t), 36.0 (t), 31.4 (t), 28.3 (t), 22.8 (t). GC–MS: 266 (100%, M+).
HRMS: calcd for C18H18O2 = 266.1307, found: 266.131.
To a solution of alcohol 12 (212 mg, 1.1 mmol) in 35 mL of
CH2Cl2 were added water (35 lL, 1.2 mmol) and Dess–Martin
periodane (763 mg, 1.8 mmol) and the mixture was stirred for
3 h before a second portion of Dess–Martin periodane was added
(254 mg, 0.6 mmol). After 0.5 h the solution was filtrated through
a small pad of silica and concentrated in vacuo to give the ketone
1b as a yellow oil (174 mg, 0.9 mmol, 83%, 79% ee (GC column
A));
[
a
]
(20 °C, CHCl3,
365 = +29.6.
c
1):
[
a]
589 = ꢂ13.0,
[a
]546 = -13.8,
4.15. Synthesis of (S)-2-butyl-5,6,7,8-tetrahydro-5-methoxy-4H-
cyclohepta[b]furan 2bx
k
[a
]405 = ꢂ1.9, [
a]
4.11. General procedure for the Au(I)-catalyzed key reaction
The reaction of 1b (38 mg, 0.2 mmol, 79% ee) with methanol
(13 mg, 0.4 mmol) in the presence of Au[PPh3]OTf (0.00625 M,
0.3 mL, 0.002 mmol) afforded 29 mg (65%, 79% ee (GC column B))
In a Schlenk-tube the ketone 1 (0.2 mmol) and the alcohol
(0.4 mmol) were dissolved in anhydrous dichloromethane
(0.1 mL) and a solution of freshly prepared Au[PPh3]OTf in CH2Cl2
(0.3 mL) was added. After stirring for 15 min at rt the solvent
was removed under reduced pressure and the product was purified
by column chromatography (1:10 EtOAc/cyHex).
of 2bx as
a
liquid.
[
a
]
(20 °C, CHCl3,
c
1):
[
a
]
589 = ꢂ2.9,
k
[a]
546 = ꢂ3.8, [
a]
405 = ꢂ13.8, [ 365 = ꢂ23.7. Rf = 0.43 (1:4 EtOAc /
a
]
cyHex). IR (neat): 2929 (s), 2852 (m), 1574 (w), 1455 (w), 1369
(w), 1242 (w), 1188 (w), 1094 (s), 974 (w), 913 (w), 799 (w)
cmꢂ1 1H NMR: d = 5.75 (s, 1H), 3.36 (s, 3H), 3.30–3.22 (m, 1H),
.
2.80–2.65 (m, 2H), 2.65–2.43 (m, 4H), 2.19–2.13 (m, 1H), 1.97–
1.88 (m, 1H), 1.70–1.49 (m, 4H), 1.43–1.26 (m, 2H), 0.92 (t,
J = 7.2 Hz, 3H). 13C NMR: d = 152.8 (s), 150.9 (s), 114.5 (s), 108.3
(d), 80.0 (d), 56.1 (q), 35.8 (t), 31.2 (t), 30.2 (t), 28.1 (t), 27.6 (t),
23.0 (t), 22.3(t), 13.8 (q). GC–MS: 147 (100%), 222 (M+).
4.12. (S)-2-Phenyl-5-methoxy-5,6,7,8-tetrahydro-4H-
cyclohepta[b]furan 2ax
The reaction of 1a (41 mg, 0.2 mmol, 85% ee) with methanol
(13 mg, 0.4 mmol) in the presence of Au[PPh3]OTf (0.00625 M,
0.3 mL, 0.002 mmol) afforded 30 mg (63%, 83% ee (HPLC column
4.16. Synthesis of (S)-5-tert-butoxy-2-butyl-5,6,7,8-tetrahydro-
4H-cyclohepta[b]furan 2by
D)) of 2ax as a liquid. Rf (1:10 EtOAc/cyHex) = 0.45. [
CHCl3, 1): 546 = ꢂ5.0, 405 = ꢂ27.2,
589 = ꢂ3.2,
365 = ꢂ 61.9. IR (neat): 2932 (m), 2853 (w), 1697 (w), 1662
(w), 1602(w), 1447 (m), 1093 (s), 759 (s) cmꢂ1 1H NMR:
a] (20 °C,
k
c
[
a]
[a
]
[a]
[a
]
The reaction of 1b (38 mg, 0.2 mmol, 79% ee) with t-butanol
(27 mg, 0.4 mmol) in the presence of Au[PPh3]OTf (0.00625 M,
.
d = 7.59–7.55 (m, 2H), 7.34–7.29 (m, 2H), 7.20–7.15 (m, 1H), 6.44
(s, 1H), 3.37 (s, 3H, OMe), 3.35–3.26 (m, 1H), 2.90–2.81 (m, 2H),
2.76–2.67 (m, 1H), 2.60–2.52 (m, 1H), 2.22–2.14 (m, 1H), 2.02–
1.91 (m, 1H), 1.78–1.53 (m, 2H). 13C NMR: d = 153.1 (s), 150.2 (s),
131.1 (s), 128.5 (d), 126.6 (d), 123.2 (d), 116.8 (s), 108.9 (d), 79.7
(d), 56.2 (q), 35.8 (t), 31.2 (t), 28.3 (t), 22.8. GC–MS: 242 (100%, M+).
0.3 mL, 0.002 mmol) afforded 42 mg (80%) of 2by as a liquid. [
a]
k
(20 °C, CHCl3, 1): 589 = +7.5; 546 = +9.2; 405 = +16.0.
c
[a
]
[
a]
[a]
Rf = 0.78 (1:4 EtOAc/cyHex). IR (neat): 2962 (m), 2929 (s), 2855
(w), 1574 (w), 1455 (w), 1386 (w), 1360 (m), 1237 (w), 1194 (s),
1053 (s), 1018 (w), 865 (w), 799 (w) cmꢂ1 1H NMR: d = 5.73 (s,
.
1H), 3.50–3.42 (m, 1H), 2.78–2.71 (m, 1H), 2.60–2.47 (m, 5H),

S. Labsch et al. / Tetrahedron: Asymmetry 21 (2010) 1745–1751
1751
3309–3313; (c) Ritter, S.; Hackelöer, K.; Schmalz, H.-G. Heterocycles 2007, 74,
731–742; (d) Weyrauch, J. P.; Hashmi, A. S. K.; Schuster, A.; Hengst, T.; Schetter,
S.; Littmann, A.; Rudolph, M.; Hamzic, M.; Visus, J.; Rominger, F.; Frey, W.; Bats,
J. W. Chem. Eur. J. 2010, 16, 956–963. and references cited therein.
3. Zhang, J.; Schmalz, H.-G. Angew. Chem. 2006, 118, 6856–6859; . Angew. Chem.,
Int. Ed. 2006, 45, 6704–6707.
4. (a) Fang, R.; Su, C.-Y.; Zhao, C.; Phillips, D. L. Organometallics 2009, 28, 741–748;
(b) Zhang, J.; Shen, W.; Li, L.; Li, M. Organometallics 2009, 28, 3129–3139.
5. Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 1814–1815.
6. (a) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.; Wovkulich, P.
M.; Uskokovic´, M. R. Tetrahedron Lett. 1992, 33, 917–918; (b) Krafft, M. E.; Cran,
J. W. Synlett 2005, 8, 1263–1266.
2.10–2.04 (m, 1H), 1.92–1.85 (m, 1H), 1.65–1.53 (m, 4H), 1.43–1.31
(m, 2H), 0.94–0.89 (m, 3H). 13C NMR: d = 152.7 (s), 151.0 (s), 115.1
(s), 108.3 (d), 73.7 (s), 71.2 (d), 40.0 (t), 35.0 (t), 30.3 (t), 28.3 (q),
28.0 (t), 27.6 (t), 24.1 (t), 22.4 (t), 13.8 (q). GC–MS: 57 (100%),
264 (M+). HRMS: calcd for C17H28O2 = 264.2089, found: 264.209.
4.17. Synthesis of (S)-2-butyl-5,6,7,8-tetrahydro-5-(prop-2-
ynyloxy)-4H-cyclohepta[b]furan 2bz
The reaction of 1b (38 mg, 0.2 mmol) with propargylic alcohol
(22 mg, 0.4 mmol) in the presence of Au[PPh3]OTf (0.00625 M,
0.3 mL, 0.002 mmol) afforded 13 mg (26%, 80% ee (GC column A))
7. Sonogashira, K.; Tohda, Y.; Hagihara, N. A. Tetrahedron Lett. 1975, 4467–4470.
8. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867; (b) Cossy, J.;
Furet, N.; BouzBouz, S. Tetrahedron 1995, 51, 11751–11764.
9. (a) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925; (b) Zhang, L. J. Am.
Chem. Soc. 2005, 127, 16804; (c) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8,
2707.
10. Demay, S.; Harms, K.; Knochel, P. Tetrahedron Lett. 1999, 40, 4981–4984.
11. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925–7926; For a review, see Corey, E. J.; Helal, C. J. Angew. Chem.
1998, 110, 2092–2118; . Angew. Chem., Int. Ed. 1998, 37, 1986–2012.
12. For a review on the Simmons–Smith cyclopropation, see: (a) Charette, A. B.;
Beauchemin, A. Org. React. 2001, 58, 1; For the use of Et2Zn/CH2I2, see: (b)
Miyano, S.; Izumi, Y.; Fujii, H.; Hashimoto, H. Synthesis 1977, 700; (c) Denmark,
S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974; (d) El Sheikh, S.; Kausch, N.;
Lex, J.; Neudörfl, J.-M.; Schmalz, H.-G. Synlett 2006, 10, 1527–1530.
13. (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249–330; (b) Keith, J. M.;
Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5–26; (c) Kagan, H. B.
Tetrahedron 2001, 57, 2449–2468.
of 2bz as a liquid. Rf (1:10 EtOAc/cyHex) = 0.52. [
1): 546 = ꢂ2.7, 405 = ꢂ9.6,
589 = ꢂ2.2,
365 = ꢂ31.8. IR (neat): 3293 (w), 3293 (s), 2853 (m), 1770 (w),
1574 (w), 1455 (m), 1360 (w), 1246 (w), 1082 (s), 963 (w), 803
(w) cmꢂ1 1H NMR: d = 5.75 (s, 1H), 4.20 (d, 2H, J = 2.38 Hz), 3.60
a] (20 °C, CHCl3,
k
c
[a]
[
a]
[
a]
[
a]
[
a]
365 = ꢂ17.2,
.
(tt, J = 2.94, J = 9.51 Hz), 2.81–2.49 (m, 6H), 2.39 (t, 1H,
J = 2.37 Hz), 2.22–2.14 (m, 1H), 1.98–1.88 (m, 1H), 1.74–1.52
(m, 4H), 1.36 (dt, 2H, J = 7.34 Hz, J = 14.28 Hz), 0.92 (t, 3H,
J = 7.30). 13C NMR: d = 152.9 (s), 150.9 (s), 114.3 (s), 108.3 (d),
80.3 (s), 77.6 (d), 73.8 (d), 55.5 (t), 36.0 (t), 31.4 (t), 30.2 (t), 28.1
(t), 27.5 (t), 23.0 (s), 22.3 (t), 13.6 (q). GC–MS: 147 (100% peak),
246 (M+). HRMS: calcd for C16H22O2 = 246.1620, found: 246.162.
14. Schmalz, H.-G.; Jope, H. Tetrahedron 1998, 54, 3457–3464.
15. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156; (b) Meyer, S. D.;
Schreiber, S. L. J. Org. Chem. 1994, 59, 7549–7552.
Acknowledgements
16. The CD spectra were calculated through time-dependent density-functional
theory (TDDFT) using GAUSSIAN 03W, the B3LYP functional and the 6-
311++G(2d,2p) basis set.
17. For the calculation of the CD spectra shown in Figure 2 the lowest energy
conformation was used. It should be noted that other low energy conformers of
1b (resulting from rotations within the sidechain or from inversion of the
pseudo-halfchair) also showed positive Cotton effects at 280 nm.
18. Moffitt, W.; Woodward, R. B.; Moscowitz, A.; Klyne, W.; Djerassi, C. J. Am. Chem.
Soc. 1961, 19, 4013–4018.
This work was carried out in the context of Cost D40. We would
like to thank the Chemetall GmbH, Frankfurt, for generous gifts of
chemicals. In addition, we would like to gratefully acknowledge Dr.
Dirk Blunk for valuable advice concerning the calculation of CD
spectra.
19. Olah, G. A.; Prakash, G. K. S.; Rasul, G. J. Am. Chem. Soc. 2008, 130, 9168–9172.
20. X-ray crystal structure of 10: Formula: C15 H16 O1, crystal size:
0.3 ꢁ 0.1 ꢁ 0.03 mm; monocline; space group P21; 100 K; k = 0.71073 Å;
structure determination with direct methods (SHELXS); unit cell:
References
1. Selected reviews: (a) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. 2006, 118,
8064–8105; (b) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403; (c) Jiménez-
Nunez, E.; Echavarren, A. M. Chem. Commun. 2007, 333–346; (d) Shen, H. C.
Tetrahedron 2008, 64, 3885–3903; (e) Hashmi, A. S. K.; Rudolph, M. Chem. Soc.
Rev. 2008, 37, 1766–1775; (f) Arcadi, A. Chem. Rev. 2008, 108, 3266–3325; (g)
Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–3265.
a = 6.3332(3) Å,
c
a = 90°, b = 20.8130(9) Å, b = 96.701(2)°, c = 14.0532(7) Å,
= 90°; Z = 6; space group P21, d (calcd) = 1.150 mg/m3; F(0 0 0) 684;
H-
range: 1.46–25.00°; 3347 independent reflexes;
R indices [1 > 2r (1)]:
R1 = 0.0426, wR2 = 0.0750; residual electron density: 0.174 and ꢂ0.223 eÅꢂ3
.
The crystal structure has been deposited at the Cambridge Crystallographic
Data Centre and allocated the deposition number CCDC 772857.
2. Selected references: (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004,
126, 11164–11165; (b) Ritter, S.; Horino, Y.; Lex, J.; Schmalz, H.-G. Synlett 2006,