Diversity-oriented enantioselective synthesis of highly functionalized cyclic and bicyclic alcohols

Article abstract of DOI:10.1002/chem.201202859

The copper-catalyzed hetero-allylic asymmetric alkylation (h-AAA) of functionalized Grignard reagents that contain alkene or alkyne moieties has been achieved with excellent regio- and enantioselectivity. The corresponding alkylation products were further transformed into a variety of highly functionalized cyclic and bicyclic alcohols with excellent control over the chemo-, regio-, and stereoselectivity. Copyright

Full text of DOI:10.1002/chem.201202859

FULL PAPER
DOI: 10.1002/chem.201202859
Diversity-Oriented Enantioselective Synthesis of Highly Functionalized
Cyclic and Bicyclic Alcohols
Bin Mao,[a] Martꢀn FaÇanꢁs-Mastral,[a] Martin Lutz,[b] and Ben L. Feringa*[a]
Abstract: The copper-catalyzed hetero-allylic asymmetric alkylation (h-AAA) of
functionalized Grignard reagents that contain alkene or alkyne moieties has been
Keywords: alcohols
synthesis · copper · cyclization · cy-
cloaddition
· asymmetric
achieved with excellent regio- and enantioselectivity. The corresponding alkylation
products were further transformed into a variety of highly functionalized cyclic
and bicyclic alcohols with excellent control over the chemo-, regio-, and stereose-
lectivity.
Introduction
alcohols in a concise and efficient manner is still highly chal-
lenging.[3] The development of fully catalytic and highly ster-
eoselective short synthetic procedures for cyclic and bicyclic
alcohols is of particular interest in the context of the diversi-
ty-oriented synthesis[4] of stereochemically complex struc-
tures.
Cyclic and bicyclic alcohols are present in a large number of
natural products and pharmaceuticals (Figure 1).[1] For in-
The copper-catalyzed asymmetric allylic alkylation
(AAA) reaction represents a very powerful tool for the
enantioselective construction of optically active molecules.[5]
Recently, a highly regio- and enantioselective synthesis of
optically active allylic esters through copper-catalyzed
hetero-allylic asymmetric alkylation (h-AAA) with Grignard
reagents has been developed by our group (Scheme 1).[6]
One of the major features of this method is that it provides
access to protected chiral allyl alcohols, in combination with
other functional groups, which allow for further transforma-
tions into a variety of important structures.[6,7]
Figure 1. Bioactive compounds that contain various cyclic and bicyclic al-
cohol groups.
stance, these structural features are often found in the ses-
quiterpenoid family, which possess important biological ac-
tivities, such as antitumor and antimicrobial properties.[2]
The rapid construction of highly functionalized ring struc-
tures and control over the regio- and stereochemistry of
single- or fused-ring systems continue to offer important
synthetic challenges. Methods for the asymmetric synthesis
of cyclic alcohols, including chiral synthons, chiral auxilia-
ries, and Corey–Bakshi–Shibata (CBS) reduction, have been
described; however, the formation of enantiopure bicyclic
Scheme 1. Cu-catalyzed hetero-allylic asymmetric alkylation.
We envisioned that the use of functionalized Grignard re-
agents that contain alkene or alkyne moieties in the Cu-cat-
alyzed h-AAA reaction, in combination with several stereo-
selective cyclization and cycloaddition[8] reactions, could
provide easy access to highly functionalized cyclic or bicyclic
protected alcohols in a concise and enantioselective manner.
Although alkyl-Grignard reagents that contain alkene moi-
eties have already been applied in Cu-catalyzed AAA/RCM
reactions,[9] to the best of our knowledge, there are no exam-
ples of the use of alkyl-Grignard reagents that contain
alkyne moieties[10] in this transformation.
[a] B. Mao, Dr. M. FaÇanꢀs-Mastral, Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry
University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
Fax : (+31)50-363-4296
E-mail: b.l.feringa@rug.nl
[b] Dr. M. Lutz
Bijvoet Center for Biomolecular Research
Utrecht University
Padualaan 8, 3584 CH Utrecht (The Netherlands)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202859.
Chem. Eur. J. 2013, 19, 761 – 770
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761

Owing to the high affinity of copper for triple bonds,[11]
the presence of an alkyne moiety could present a problem
for the regio- or stereocontrol of the Cu-catalyzed AAA re-
action. However, a successful Cu-catalyzed h-AAA[6] with
these particular Grignard reagents would give rise to various
enynes that contain a protected chiral alcohol motif, which
could be further transformed into a wide range of
as the catalytic system, the desired alkylation products 3
were obtained in high yields (up to 96%) with excellent
regio- (>99:1) and enantioselectivities (96–97% ee;
Table 1).
With the isolated products 3 in hand, we attempted the
synthesis of cyclic benzoate esters[13] through ring-closing
highly functionalized ring systems (Scheme 2).
Herein, we report a procedure for h-AAA reac-
tions with this type of Grignard reagent.
Table 1. h-AAA/RCM of cinnamyl substrates.[a]
Starting from vinyl ester 1, efficient Cu-catalyzed
h-AAA with alkene-containing Grignard reagents,
followed by ring-closing olefin metathesis,[12] would
provide cyclic benzoate esters,[13] including the for-
mation of five-, six-, and seven-membered-ring
structures. Relying on the Cu-catalyzed h-AAA
with alkyne-containing Grignard reagents, the re-
sulted enynes could be transformed into optically
active 2,4-dienol esters[14] with different ring sizes
through enyne metathesis.[15] In addition, the
highly stereoselective synthesis of different fused-
ring-functionalized carbobicycles from their corre-
sponding 2,4-dienol esters or internal enyne esters
is feasible through Diels–Alder[16] or Pauson–
Khand[17] reactions. The distinctive features of this
convergent strategy are the highly regio- and enan-
tioselective synthesis of allylic esters and the po-
tential for stereocontrol in later transformations to
afford a variety of cyclic and bicyclic alcohols.
g/a>99:1[b]
85% yield[c]
96% yield[c]
97% ee[d]
n=0
n=1
97% ee[d]
g/a>99:1[b]
89% yield[c]
95% yield[c]
95% ee[d]
97% ee[d]
g/a>99:1[b]
85% yield[c]
83% yield[c]
95% ee[d]
n=2
96% ee[d]
[a] General conditions for the h-AAA reaction: CuBr·SMe2 (5 mol%), (R,R)-(+)-Ta-
niaphos (5.5 mol%), Grignard reagent 2 (2 equiv), CH2Cl2, À708C. [b] Regioselectivi-
1
ty was determined by H NMR spectroscopy of the crude mixture. [c] Yield of isolated
product. [d] Enantiomeric excess was determined by chiral HPLC analysis. [e] The ab-
solute configuration was assigned by comparison of optical rotation with known com-
pounds.[6a]
Results and Discussion
Our initial studies were focused on the copper-cat-
olefin metathesis. When compound 3a was treated with
alyzed h-AAA reactions of substrates 1 with Grignard re-
agents that contain a terminal alkene moiety. Under the op-
timized conditions for the addition of simple alkyl-Grignard
reagents,[6] with CuBr·SMe2 and (R,R)-(+)-Taniaphos (L1)
Grubbs 2nd-generation catalyst (5 mol%), five-membered
carbocycle (S)-4a was obtained in 85% yield and excellent
enantioselectivity (97% ee).[6a] The use of longer alkyl
chains on the Grignard reagent did not affect the outcome
of the reaction and allowed us to access the optically active
six- and seven-membered ring structures 4b and 4c in high
yields (85–89%) with excellent enantioselectivity (95% ee;
Table 1). It should be emphasized that high yields and excel-
lent enantioselectivities were found in all cases under the
optimized conditions. No significant loss of enantioselectivi-
ty took place during the ring-closing step. Unfortunately, ef-
forts to cyclize 1,8-diene esters to make their corresponding
eight-membered carbocycles were not successful with
Grubbs second-generation catalyst, thus leading to recovery
of the starting material.[18]
Next, we turned our attention to the use of challenging
Grignard reagents that contained an alkyne functional
group in the Cu-catalyzed hetero-allylic asymmetric alkyla-
tion (h-AAA) reaction (Table 2). To prevent competitive co-
ordination between the terminal alkyne and the copper(I)
species,[11] trimethylsilyl-protected alkynes were employed.
Under the same conditions as for the Cu-catalyzed h-AAA
discussed above, product 6b was obtained with only modest
Scheme 2. Proposed routes to cyclic and bicyclic esters, with the h-AAA
of functionalized Grignard reagents as the key step.
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Chem. Eur. J. 2013, 19, 761 – 770

Highly Functionalized Cyclic and Bicyclic Alcohols
FULL PAPER
Table 2. Screening of the reaction condition for the copper-catalyzed h-
cinnamyl ester 1b, readily provided alkylation products 6c
in good yields with excellent regio- and enantioselectivity
(>99:1, 96% ee; Scheme 3). Because ferrocenyl ligand L1
turned out not to be an effective ligand for the h-AAA reac-
tion of b-substituted substrate 1c,[6a] we turned our attention
to phosphoramidites[5g] as potential chiral ligands. When the
reaction was carried out with ligand L2, which has been de-
scribed as an optimal ligand for related transformations,[6a,20]
product 6d was obtained with high enantiocontrol (94% ee)
but poor regioselectivity (g/a 1:2; Scheme 3). However,
ligand L3 afforded the desired product 6d with better regio-
selectivity (6:1) and similar enantioselectivity (92% ee).
Optically enriched 2,4-dienols are key structural motifs in
a variety of natural products.[14] Despite the importance and
versatility of these compounds, approaches for their enantio-
selective synthesis have thus far been limited to the lipase-
catalyzed kinetic resolution of racemic dienols.[14b–d] To
obtain their chiral dienol derivatives, trimethylsilyl-protect-
ed allylic ester 6a was subjected to enyne metathesis[15] with
Grubbs 1st-generation catalyst. No reaction was observed
during this process, presumably owing to the steric effects of
the trimethylsilyl group.[15a] Because it is known that enyne
metathesis proceeds better with terminal alkynes,[15a] allylic
products 6 were transformed into their corresponding termi-
nal enynes 7, without compromising their stereochemical in-
tegrity, by treatment with 2 equivalents of tetra-n-butylam-
monium fluoride (TBAF) in THF. Then, we investigated the
ring-closing metathesis of enynes 7 in the presence of cata-
lytic amounts of Grubbs 1st-
AAA reaction with Grignard reagents that contain an alkyne moiety.[a]
Entry
1a/5b
Addition time [h]
g/a[b]
ee of 6b[c] [%]
1
2
3
4
5
1:2
1:2
1:2
1:1.5
1:1.5
0.1
0.5
2
2
4
>99:1
>99:1
>99:1
>99:1
>99:1
36
88
92
94
97
[a] Reactions performed on a 0.32 mmol scale. Compound 5b (1.5m in
Et2O) was diluted with CH2Cl2 and added dropwise. Complete conver-
sion was achieved in all cases. [b] Regioselectivity was determined by
1H NMR spectroscopy of the crude mixture. [c] Enantiomeric excess was
determined by chiral HPLC analysis.
enantioselectivity (36% ee; Table 2, entry 1). Screening of
different reaction parameters indicated that lower amounts
(1.5 equiv) and slower addition (4 h) of the Grignard re-
agent were essential for obtaining compound 6b in a fully
enantioselective manner.[19] It was particularly rewarding to
find that the treatment of 3-bromopropenyl ester 1a with
Grignard reagent 5a under the optimized conditions
(Table 2, entry 5) provided the desired SN2’ product (6a)
with excellent regio- (>99:1) and enantioselectivity (98%
ee; Scheme 3). Grignard reagent 5b, in combination with
generation catalyst under an
ethylene atmosphere (Table 3).
The presence of ethylene was
found to be essential for accel-
erating the reaction to access
diene ester 8.[21] The reaction
of enyne 7a to form five-mem-
bered cyclic 2,4-dienol ester 8a
proceeded
smoothly
and,
again, no erosion of the enan-
tioselectivity was observed
during this transformation.[22]
Homologous
six-membered
dienol ester 8b was prepared
in 87% yield and 96% ee
under the same conditions
(Table 3). Although enyne 7c,
which contained a cinnamyl-
ester moiety, showed slightly
lower reactivity, thus requiring
a longer reaction time, the de-
sired diene product 8c was ob-
tained in 85% yield and 96%
ee. These results indicate that
this strategy of combining
hetero-allylic asymmetric alky-
lation with ring-closing enyne
metathesis is a highly versatile
Scheme 3. Cu-catalyzed h-AAA of Grignard reagents that contain an alkyne moiety.
Chem. Eur. J. 2013, 19, 761 – 770
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763

B. L. Feringa et al.
Table 3. Deprotection of the TMS group, followed by enyne metathesis.
the complete formation of diene ester 8. To our de-
light, chiral intermediate 8 underwent cycloaddi-
tion with dienophile at 1608C in each case to yield
the corresponding cycloadduct 9 as a single diaster-
eomer (Scheme 5).
The relative configuration of the products was
assigned on the basis of 1H NMR and NOESY
analysis of the products (9a and 9b; Figure 2). In
t=24 h
43% yield[a]
98% ee[b]
6a
74% yield[a]
n=0, R=Ph
98% ee[b]
À
each case, NOE correlations between the Ha Hc
À
and Hb Hd protons indicated an anti stereochemi-
À
cal relationship for Ha Hb. This exclusive stereo-
t=24 h
87% yield[a]
96% ee[b]
6b
85% yield[a]
chemical outcome was attributed to the stereogenic
center that was established in the Cu-catalyzed h-
AAA reaction and the facial selectivity of the
Diels–Alder reaction.[24] It should be pointed out
that the enantiomeric excess of the cycloaddition
product was also not compromised during these re-
actions. This sequential stereoselective approach
offers rapid access to enantiomerically pure com-
plex bicyclic molecules.
n=1, R=Ph
97% ee[b]
t=48 h
85% yield[a]
96% ee[b]
6c
83% yield[a]
n=1, R=PhCH=CH
96% ee[b]
[a] Yield of isolated product. [b] Enantiomeric excess was determined by chiral HPLC
analysis. [c] The absolute configuration was assigned by comparison of optical rotation
with known compounds.[14b]
To establish the synthetic compatibility of allylic
esters 6 for the purposes of diversity-oriented syn-
thesis,[4] we also explored the intramolecular
Pauson–Khand (PK) reactions of 1,5-enyne 6a and
method for the enantioselective synthesis of cyclic 2,4-dienol
esters.
Unfortunately, when enyne
7d, which was obtained after
the removal of the TMS group
on compound 6d, was exposed
to the same conditions as dis-
cussed above, an enyne-meta-
thesis reaction with ethylene
proceeded in an intermolecu-
lar fashion to afford the linear
product (8d; Scheme 4). Al-
though a variety of ruthenium
catalysts and different reaction
conditions[21b] were tested, the
reaction did not result in the
formation of the desired prod-
uct.
Dienols 8 are suitable sub-
strates for Diels–Alder reac-
tions that would give rise to
Scheme 4. Further elaboration of enyne 6d.
important bicyclic scaffolds 9
in
a
diastereoselective fash-
As outlined in
ion.[23]
Scheme 5, we have developed
a one-pot consecutive enyne-
metathesis/Diels–Alder reac-
tion in the presence of diethyl
acetylenedicarboxylate. Opti-
cally enriched terminal enynes
7a and 7b were subjected to
the enyne-metathesis condi-
tions described above; then,
the dienophile was added after
Scheme 5. One-pot consecutive sequence of enyne metathesis and Diels–Alder reactions.
764
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Highly Functionalized Cyclic and Bicyclic Alcohols
FULL PAPER
TMS-substituted a,b-unsaturated ketone. The synthetic di-
versity of this strategy was illustrated by the facile installa-
tion of an all-carbon quaternary stereogenic center[27] on the
bridgehead carbon atom (Scheme 7). Bicyclic pentanone
10a was treated with lithium dimethylcuprate in Et2O at
À208C. After deprotection of the TMS group, the final
product 11 was obtained as a single isomer in 62% yield.
Figure 2. Relevant NOESY correlations in products 9a and 9b.
1,6-enyne
6b
to
afford
functionalized
bicyclo-
ACHTUNGTRENNUNG[3.3.0]pentanones in a stereoselective manner (Scheme 6).
The cobalt-promoted Pauson–Khand reactions of internal
Conclusion
In summary, we have developed a highly regio- (>99:1) and
enantioselective (up to 98% ee) Cu-catalyzed hetero-allylic
asymmetric alkylation (h-AAA) reaction with functionalized
Grignard reagents that contain alkene or alkyne moieties. A
new strategy that was based on the h-AAA reaction, in
combination with ring-closing metathesis (RCM), of dienes
and enynes has been applied for the catalytic enantioselec-
tive synthesis of cyclic allylic esters. In addition, we have
shown the diversity-oriented synthesis of four different ring-
fused [5,6], [6,6], [5,5], and [6,5] bicyclic structures through
Diels–Alder reactions on 2,4-dienol esters or Pauson–Khand
reactions on enyne substrates. The synthetic versatility of
this method was illustrated by the stereocontrolled installa-
tion of an all-carbon quaternary center on the bridgehead
carbon atom of a carbon [5,5] bicyclic structure. The result-
Scheme 6. Intramolecular Pauson–Khand reaction of enynes 6a and 6b.
enynes 6, with 1.1 equivalents
of [Co2(CO)8] in CH2Cl2 at
room temperature, generated
the corresponding hexacarbo-
nyldicobalt complexes. Subse-
quently, the resulting complexes
Scheme 7. Synthesis of an all-carbon quaternary stereogenic center at the bridgehead carbon atom in com-
pound 11.
were transformed into their cor-
responding substituted cyclo-
pentenones 10 in 55–64% yield
with complete diastereoselectiv-
ity and almost-complete enantioselectivity (97–98% ee).
The relative stereochemistry of the two adjacent stereo-
genic centers in compounds 10a and 10b was determined by
1H NMR and NOESY analysis. The observed exo configura-
tion was expected for an intramolecular PK reaction.[25]
Single-crystal X-ray structure determination of compound
10a confirmed this relative configuration (Figure 3). The ab-
solute stereochemistry was established unequivocally by the
Flack parameters (see the Supporting Information).
ing compounds are suitable synthons for the synthesis of
multiscaffold libraries.
Experimental Section
General: All of the experiments were carried out in flame-dried or oven-
dried glassware under an atmosphere of nitrogen (unless otherwise speci-
fied) by using standard Schlenk techniques. Schlenk tubes with screw
caps were equipped with a Teflon-coated magnetic stirrer bar, flame
dried under vacuum, and allowed to return to RT prior to being charged
with the reactants. A manifold that permitted alternation between a ni-
trogen atmosphere and a vacuum was used to control the atmosphere in
the reaction vessel. Column chromatography was performed on silica gel
(Silica-P flash silica gel from Silicycle, size 40–63 mm). TLC was per-
formed on silica gel 60/Kieselguhr F254; the components were visualized
by using UV light and by staining with a solution of KMnO4 (10 g) and
K2CO3 (10 g) in water (500 mL). Mass spectra were recorded on a LTQ
Orbitrap XL mass spectrometer (ESI+/APCI+/APPI+) or a Xevoꢂ G2
The resulting bicyclic compounds 10 possess a high degree
of functionalization, including an ester group and an a-
1
QTof mass spectrometer with DART ionization. H and 13C NMR spectra
were recorded on Varian AMX400 (400 and 100.59 MHz, respectively)
or Varian Unity Plus Varian-500 spectrometers (500 and 125 MHz, re-
spectively) by using CDCl3 as the solvent. Chemical shifts are reported in
Figure 3. Molecular structure of compound 10a in the crystal.[26]
Chem. Eur. J. 2013, 19, 761 – 770
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765

B. L. Feringa et al.
ppm by using the solvent resonance as an internal standard (1H: d=
7.26 ppm, 13C: d=77.0 ppm); the data are reported as follows: chemical
shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=
broad, m=multiplet), coupling constant(s) [Hz], and integration. Optical
rotations were measured in CHCl3 on a Schmidt+Haensch polarimeter
(Polartronic MH8) with a 10 cm cell (c, given in g/100 mL). Conversion
of the reactants was determined by GC (GC, HP6890: MS HP5973) with
an HP5 column (Agilent Technologies, Palo Alto, CA). The regioselectiv-
General procedure for the Ru-catalyzed ring-closing metathesis (RCM)
reaction:[6] Allylic ester 3 (0.6 mmol) was dissolved in degassed CH2Cl2
(12 mL) under
a N2 atmosphere. Grubbs 2nd-generation catalyst
(0.03 mmol) was tipped into the solution and the mixture was heated at
reflux (408C) for 18 h. Then, the mixture was cooled to RT and the sol-
vents were removed under reduced pressure. Purification by column
chromatography on silica gel (Et2O/n-pentane, 1% to 2%) afforded the
desired product 4.
1
ity of the reaction was determined by H NMR spectroscopy of the crude
(À)-(S)-Cyclohex-2-en-1-yl benzoate (4b): According to the general pro-
mixture. Enantioselectivities were determined by HPLC analysis on a
Shimadzu LC-10ADVP HPLC that was equipped with a Shimadzu SPD-
M10AVP diode-array detector. All of the reactions were carried out
under a nitrogen atmosphere by using oven-dried glassware and standard
Schlenk techniques. All solvents were of reagent grade and were dried
and distilled prior to use (if necessary). THF and Et2O were distilled
over Na/benzophenone. Toluene and CH2Cl2 were distilled over calcium
hydride. All of the ligands and CuBr·SMe2 were purchased from Aldrich
and used without further purification. Alkyl bromides, except for 4-
bromo-1-trimethylsilyl-1-butyne[28] and 5-bromo-1-trimethylsilyl-1-pen-
tyne,[28] which were synthesized according to literature procedures, were
purchased from Aldrich. All other commercially available reagents were
used as received. Starting materials 1a, 1b, and 1c were synthesized ac-
cording to the procedure reported by Trombini, Lombardo, and co-work-
ers.[29] Grignard reagents were prepared from their corresponding alkyl
bromides and magnesium turnings in Et2O by following standard proce-
dures. Grignard reagents were titrated by using sec-BuOH and catalytic
amounts of 1,10-phenanthroline. Compounds 3a and 4a have been re-
ported in our previous paper.[6a]
cedure, compound 4b was obtained as a colorless oil (89% yield, 95%
ee). [a]2D0 =À187.3 (c=3.7 in CHCl3); [lit.[13e] (S isomer, 90% ee): [a]2D0
=
1
À164 (c=0.96 in CHCl3)]; H NMR (400 MHz, CDCl3): d=8.31–7.83 (m,
2H), 7.61–7.50 (m, 1H), 7.48–7.34 (m, 2H), 6.11–5.94 (m, 1H), 5.90–5.80
(m, 1H), 5.51 (dd, J=3.4, 1.6 Hz, 1H), 2.15–2.04 (m, 2H), 2.03–1.94 (m,
1H), 1.93–1.77 (m, 2H), 1.77–1.65 ppm (m, 1H); 13C NMR (100 MHz,
CDCl3): d=166.4, 133.1, 133.0, 131.0, 129.8, 128.5, 125.9, 68.8, 28.6, 25.2,
19.2 ppm; HRMS (ESI+): m/z calcd for C13H14O2Na: 225.08860
[M+Na]+; found: 225.04333; enantiomeric excess was determined by
chiral HPLC (Chiralpak AD-H; n-heptane/2-propanol, 99.9:0.1;
0.5 mLminÀ1
;
226 nm; column temperature: 408C): tR (major)=
19.55 min, tR (minor)=18.66 min.
(À)-(S)-Cyclohept-2-en-1-yl benzoate (4c): According to the general pro-
cedure, compound 4c was obtained as a colorless oil (85% yield, 95%
ee). [a]2D0 =À37.4 (c=2.3 in CHCl3); [lit.,[13e] (S isomer, 97% ee): [a]2D0
=
À52 (c=0.85 in CHCl3)]; 1H NMR (400 MHz, CDCl3): d=8.15–8.00 (m,
2H), 7.64–7.51 (m, 1H), 7.49–7.35 (m, 2H), 5.95–5.85 (m, 1H), 5.83–5.76
(m, 1H), 5.71–5.63 (m, 1H), 2.33–2.21 (m, 1H), 2.20–2.09 (m, 1H), 2.07–
1.93 (m, 2H), 1.90–1.66 (m, 3H), 1.53–1.45 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d=166.1, 133.7, 133.0, 132.2, 130.9, 129.8, 128.5, 74.9,
33.1, 28.8, 26.9, 26.8 ppm; HRMS (ESI+): m/z calcd for C14H16O2Na:
337.12304 [M+Na]+; found: 337.12205; enantiomeric excess was deter-
mined by chiral HPLC (Chiralpak AS-H; n-heptane/2-propanol, 99.9:0.1;
General procedure for the copper catalyzed hetero-allylic asymmetric al-
kylation[6] with Grignard reagents that contain terminal alkene groups: A
solution of Grignard reagent 2 (0.64 mmol, 2 equiv) in Et2O was added
dropwise over 5 min to a homogeneous, stirring solution of the allylic
bromide (0.32 mmol), CuBr·SMe2 (5.0 mol%), and L1 (5.5 mol%) in
CH2Cl2 (3.5 mL) at À708C under a nitrogen atmosphere. The reaction
mixture was stirred at the indicated temperature until it had gone to
completion (typically overnight) and was then quenched with MeOH
(5 mL). The reaction mixture was allow to warm to RT and a saturated
aqueous solution of NH4Cl (5 mL) was added. The mixture was parti-
tioned between CH2Cl2 (5 mL) and water. The organic layer was dried
(MgSO4), filtered, and the solvent was evaporated under vacuum. Purifi-
cation by flash column chromatography on silica gel (Et2O/n-pentane,
1% to 2%) afforded pure product 3 as a colorless oil.
0.5 mLminÀ1
;
226 nm; column temperature: 408C): tR (major)=
11.60 min, tR (minor)=10.50 min.
General procedure for the copper-catalyzed hetero-allylic asymmetric al-
kylation[6] with Grignard reagents that contain alkyne groups: Method A.
A solution of Grignard reagent 5 (0.48 mmol, 1.5 equiv) in Et2O (1.5m
and 1.6m for 5a and 5b, respectively) was diluted with CH2Cl2 (combined
volume of 1 mL) and added dropwise over 4 h to a homogeneous, stirring
solution of the allylic bromide (0.32 mmol), CuBr·SMe2 (5.0 mol%), and
L1 (5.5 mol%) in CH2Cl2 (3.2 mL) at À808C under a nitrogen atmos-
phere. The reaction mixture was stirred at the indicated temperature
until it had gone to completion (typically overnight) and was quenched
with MeOH (5 mL). The mixture was allowed to warm to RT and a satu-
rated aqueous solution of NH4Cl (5 mL) was added. The mixture was
partitioned between CH2Cl2 and water. The organic layer was dried over
MgSO4, filtered, and the solvent was evaporated under vacuum. Purifica-
tion by flash column chromatography on silica gel (Et2O/n-pentane, 1%
to 2%) to afford the product (6) as a colorless oil.
(+)-(S)-Octa-1,7-dien-3-yl benzoate (3b): According to the general pro-
cedure, compound 3b was obtained as a colorless oil (95% yield, 97%
ee). [a]2D0 =+33.2 (c=3.6 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
8.07 (d, J=7.9 Hz, 2H), 7.56 (t, J=6.9 Hz, 1H), 7.45 (t, J=7.6 Hz, 2H),
5.99–5.68 (m, 2H), 5.62–5.44 (m, 1H), 5.33 (d, J=17.2 Hz, 1H), 5.21 (d,
J=10.5 Hz, 1H), 5.04 (s, 1H), 5.00–4.88 (m, 1H), 2.11 (q, J=7.0 Hz,
2H), 1.90–1.67 (m, 2H), 1.52 ppm (dd, J=15.2, 7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=166.1, 138.5, 136.7, 133.1, 130.0, 129.8 (2ꢃC),
128.6 (2ꢃC), 116.9, 115.1, 75.4, 34.0, 33.7, 24.6 ppm; HRMS (ESI+): m/z
calcd for C15H18O2Na: 253.11990 [M+Na]+; found: 253.12015; enantio-
meric excess was determined by chiral HPLC (Chiralpak OB-H; n-hep-
tane/2-propanol, 99:1; 0.5 mLminÀ1; 224 nm; column temperature: 408C):
tR (major)=9.94 min, tR (minor)=11.54 min.
Method B. A solution of Grignard reagent 5b (0.38 mmol, 1.2 equiv) in
Et2O (1.6m) was diluted with CH2Cl2 (combined volume of 1 mL) and
added dropwise over 4 h to a homogeneous, stirring solution of allylic
bromide 1c (0.32 mmol), copper(I) thiophene-2-carboxylate (CuTC,
3.0 mol%), and L2 (3.3 mol%) in CH2Cl2 (3.2 mL) at À808C under a ni-
trogen atmosphere. The remaining steps were the same as those descri-
bed in Method A.
(+)-(S)-Nona-1,8-dien-3-yl benzoate (3c): According to the general pro-
cedure, compound 3c was obtained as a colorless oil (83% yield, 96%
ee). [a]2D0 =+21.4 (c=3.4 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
8.10–8.00 (m, 2H), 7.61–7.51 (m, 1H), 7.45 (m, 2H), 5.89 (ddd, J=14.4,
10.3, 5.1 Hz, 1H), 5.84–5.69 (m, 1H), 5.49 (ddd, J=12.2, 6.1, 1.1 Hz, 1H),
5.38–5.28 (m, 1H), 5.20 (dt, J=10.5, 1.2 Hz, 1H), 5.07–4.87 (m, 2H),
2.10–2.03 (m, 2H), 1.88–1.66 (m, 2H), 1.52–1.34 ppm (m, 4H); 13C NMR
(100 MHz, CDCl3): d=166.1, 138.9, 136.8, 133.1, 130.8, 129.8, 128.6,
116.9, 114.7, 75.5, 34.4, 33.8, 28.9, 24.8 ppm; HRMS (ESI+): m/z calcd
for C16H20O2Na: 267.13555 [M+Na]+; found: 267.13507; enantiomeric
excess was determined by chiral HPLC (Chiralpak OB-H; n-heptane/2-
propanol, 98:2; 0.5 mLminÀ1; 226 nm; column temperature: 408C): tR
(major)=8.68 min, tR (minor)=10.00 min.
(+)-(S)-7-(Trimethylsilyl)hept-1-en-6-yn-3-yl benzoate (6a): According to
the general procedure Method A, compound 6a was obtained as a color-
less oil (74% yield, 98% ee). [a]2D0 =+14.2 (c=1.3 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=8.06 (dd, J=9.8, 1.6 Hz, 1H), 7.61–7.51 (m, 1H),
7.44 (t, J=6.8 Hz, 1H), 5.98–5.79 (m, 1H), 5.57 (dd, J=12.4, 6.6 Hz,
1H), 5.35 (d, J=16.0 Hz, 1H), 5.24 (d, J=10.6 Hz, 1H), 2.36 (t, J=
7.5 Hz, 1H), 2.14–1.87 (m, 1H), 0.13 ppm (s, 4H); 13C NMR (100 MHz,
CDCl3): d=165.6, 135.7, 132.9, 130.3, 129.6, 129.6, 128.3, 117.2, 105.9,
85.3, 74.1, 33.3, 16.0, 0.0 ppm; HRMS (ESI+): m/z calcd for
C17H22O2SiNa: 309.12813 [M+Na]+; found: 309.12846; enantiomeric
excess was determined by chiral HPLC (Chiralpak AS-H; n-heptane/2-
766
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 761 – 770

Highly Functionalized Cyclic and Bicyclic Alcohols
FULL PAPER
propanol, 99.9:0.1; 0.5 mLminÀ1; 226 nm; column temperature: 408C): tR
(major)=11.60 min, tR (minor)=10.50 min.
1.78–1.52 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=165.7, 136.2,
132.9, 130.4, 129.6, 128.3, 116.9, 83.8, 74.7, 68.8, 33.3, 24.0, 18.2 ppm;
HRMS (ESI+): m/z calcd for C15H16O2Na: 251.10425 [M+Na]+; found:
251.10459; enantiomeric excess was determined by chiral HPLC (Chiral-
pak OB-H; n-heptane/2-propanol, 98:2; 0.5 mLminÀ1; 226 nm; column
temperature: 408C): tR (major)=13.95 min, tR (minor)=16.48 min.
(+)-(S)-8-(Trimethylsilyl)oct-1-en-7-yn-3-yl benzoate (6b): According to
the general procedure Method A, compound 6b was obtained as a color-
less oil (84% yield, 97% ee). [a]2D0 =+10.1 (c=5.7 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=8.20–7.91 (m, 2H), 7.63–7.51 (m, 1H), 7.50–7.32
(m, 2H), 6.11–5.77 (m, 1H), 5.53 (dd, J=12.7, 6.3 Hz, 1H), 5.34 (d, J=
17.2 Hz, 1H), 5.22 (d, J=10.6 Hz, 1H), 2.28 (t, J=7.1 Hz, 2H), 2.01–1.81
(m, 2H), 1.75–1.54 (m, 2H), 0.14 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=165.8, 136.3, 132.9, 130.4, 129.6, 128.3, 116.8, 106.7, 85.0, 74.7,
33.3, 24.2, 19.7, 0.1 ppm; HRMS (ESI+): m/z calcd for C18H24O2SiNa:
323.14378 [M+Na]+; found: 323.14404; enantiomeric excess was deter-
mined by chiral HPLC (Chiralpak AD-H; n-heptane/2-propanol,
99.9:0.1; 0.5 mLminÀ1; 226 nm; column temperature: 408C): tR (major)=
13.80 min, tR (minor)=12.98 min.
(+)-(S)-Oct-1-en-7-yn-3-yl cinnamate (7c): According to the general pro-
cedure, compound 7c was obtained as a colorless oil (83% yield, 96%
ee). [a]2D0 =+33 (c=1.1 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.70
(d, J=16.0 Hz, 1H), 7.60–7.48 (m, 2H), 7.45–7.36 (m, 3H), 6.46 (d, J=
16.0 Hz, 1H), 5.85 (ddd, J=17.0, 10.5, 6.3 Hz, 1H), 5.41 (dd, J=13.0,
6.2 Hz, 1H), 5.31 (dt, J=17.2, 1.3 Hz, 1H), 5.21 (dt, J=10.5, 1.2 Hz, 1H),
2.25 (td, J=7.0, 2.6 Hz, 2H), 1.97 (s, 1H), 1.88–1.78 (m, 2H), 1.70–
1.57 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=166.2, 144.9, 136.3,
134.4, 130.3, 128.9, 128.1, 118.2, 116.9, 83.9, 74.3, 68.7, 33.2, 24.0,
18.2 ppm; HRMS (ESI+): m/z calcd for C17H18O2Na: 277.11990
[M+Na]+; found: 277.12027; enantiomeric excess was determined by
(+)-(S)-8-(Trimethylsilyl)oct-1-en-7-yn-3-yl cinnamate (6c): According to
the general procedure Method A, compound 6c was obtained as a color-
less oil (75% yield, 96% ee). [a]2D0 =+16.0 (c=0.4 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.70 (d, J=16.0 Hz, 1H), 7.60–7.47 (m, 2H),
7.44–7.29 (m, 3H), 6.46 (d, J=16.0 Hz, 1H), 5.90–5.78 (m, 1H), 5.41 (d,
J=5.9 Hz, 1H), 5.31 (d, J=15.9 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H), 2.30–
2.24 (m, 2H), 1.80 (t, J=6.6 Hz, 2H), 1.68–1.52 (m, 2H), 0.13 ppm (s,
9H); 13C NMR (100 MHz, CDCl3): d=166.8, 144.8, 136.3, 134.4, 130.3,
128.9, 128.1, 118.3, 116.8, 106.7, 85.0, 74.3, 33.3, 24.2, 19.6, 0.1 ppm;
HRMS (ESI+): m/z calcd for C20H26O2SiNa: 349.15943 [M+Na]+; found:
349.15943; enantiomeric excess was determined by chiral HPLC (Chiral-
pak AD-H; n-heptane/2-propanol, 99/1; 0.5 mLminÀ1; 270 nm; column
temperature: 408C): tR (major)=14.48 min, tR (minor)=12.64 min.
chiral HPLC (Chiralpak OJ-H; n-heptane/2-propanol, 99:1; 0.5 mLminÀ1
;
270 nm; column temperature: 408C): tR (major)=31.19 min, tR (minor)=
35.12 min.
General procedure for the Ru-catalyzed eneyne-metathesis reaction:[7a]
Compound 7 was dissolved in degassed CH2Cl2 (0.05m) and Grubbs 1st-
generation catalyst (10 mol%) was added to the solution in two portions.
The reaction mixture was heated at reflux under an ethylene atmosphere
(1 atm, balloon) until it had gone to completion (24–48 h), as indicated
by GCMS. The mixture was filtered through a pad of silica, concentrated
under vacuum, and purified by column chromatography on silica gel
(Et2O/n-pentane, 1% to 2%) to yield the desired product (8) as a color-
less oil.
(+)-(S)-2-Methyl-8-(trimethylsilyl)oct-1-en-7-yn-3-yl benzoate (6d): Ac-
cording to the general procedure Method B, compound 6d was obtained
as a colorless oil (72% yield, 92% ee). [a]2D0 =+13.0 (c=1.9 in CHCl3);
1H NMR (400 MHz, CDCl3): d=8.07 (dd, J=8.1, 1.0 Hz, 2H), 7.64–7.52
(m, 1H), 7.45 (t, J=7.6 Hz, 2H), 5.44 (t, J=6.5 Hz, 1H), 5.05 (s, 1H),
4.94 (s, 1H), 2.28 (t, J=6.9 Hz, 2H), 1.91 (dt, J=14.4, 4.7 Hz, 2H), 1.81
(s, 3H), 1.70–1.52 (m, 2H), 0.14 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=165.71, 142.9, 132.9, 130.5, 129.6, 128.3, 112.8, 106.7, 85.1,
77.3, 31.7, 24.3, 19.6, 18.2, 0.1 ppm; HRMS (APCI+): m/z calcd for
C19H27O2Si: 315.17748 [M+H]+; found: 315.17749; enantiomeric excess
was determined by chiral HPLC (Chiralpak AD-H; n-heptane/2-propa-
(À)-(S)-3-Vinylcyclopent-2-en-1-yl benzoate (8a): According to the gen-
eral procedure, compound 8a was obtained as a colorless oil (43% yield,
98% ee). [a]2D0 =À145.4 (c=3.2 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=8.06–7.95 (m, 2H), 7.53 (dd, J=10.5, 4.3 Hz, 1H), 7.39–7.46 (m, 2H),
6.62 (dd, J=17.5, 10.6 Hz, 1H), 6.04–5.93 (m, 1H), 5.88 (s, 1H), 5.29 (d,
J=17.5 Hz, 1H), 5.25 (d, J=10.7 Hz, 1H), 2.76–2.65 (m, 1H), 2.41–2.55
(m, 2H), 2.07 ppm (ddd, J=8.7, 6.4, 3.6 Hz, 1H); 13C NMR (101 MHz,
CDCl3): d=166.4, 148.2, 132.8, 132.7, 130.7, 129.6, 128.2, 127.8, 117.5,
81.0, 30.1, 29.2 ppm; MS (TOF, DART): m/z calcd for C14H14O2: 215.1028
[M+H]+; found: 215.0989; enantiomeric excess was determined by chiral
nol, 99.9:0.1; 0.5 mLminÀ1
; 226 nm; column temperature: 408C): tR
HPLC (Chiralpak OB-H; n-heptane/2-propanol, 99:1; 0.5 mLminÀ1
;
(major)=14.62 min, tR (minor)=12.83 min.
226 nm; column temperature: 408C): tR (major)=17.73 min, tR (minor)=
General procedure for the deprotection of the trimethylsilyl (TMS) al-
kynes: In a round-bottomed flask, TBAF (1.0m in THF, 2.0 equiv) was
added dropwise to a solution of allylic ester 6 (1.0 equiv) in dry THF
(0.05m) at 08C. The mixture was allowed to warm to RT over 1 h. The re-
action was quenched with water and extracted with Et2O (3ꢃ10 mL).
The combined organic extracts were dried over MgSO4, filtered, and con-
centrated under vacuum. The crude material was purified by column
chromatography on silica gel (Et2O/n-pentane, 1% to 2%) to yield the
desired product (7).
11.67 min.
(À)-(S)-3-Vinylcyclohex-2-en-1-yl benzoate (8b): According to the gener-
al procedure, compound 8b was obtained as a colorless oil (87% yield,
96% ee). [a]2D0 =À204 (c=5.5 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=8.08–8.02 (m, 2H), 7.64–7.50 (m, 1H), 7.49–7.28 (m, 2H), 6.38 (dd,
J=17.5, 10.7 Hz, 1H), 5.86 (d, J=3.5 Hz, 1H), 5.62 (d, J=4.3 Hz, 1H),
5.27 (d, J=17.5 Hz, 1H), 5.09 (d, J=10.8 Hz, 1H), 2.30 (dt, J=17.3,
5.7 Hz, 1H), 2.23–2.09 (m, 1H), 2.06–1.83 (m, 3H), 1.83–1.70 ppm (m,
2H); 13C NMR (100 MHz, CDCl3): d=166.2, 140.7, 139.0, 132.8, 130.7,
130.5, 129.6, 128.3, 126.4, 113.5, 69.5, 28.4, 23.6, 19.1 ppm; HRMS
(ESI+): m/z calcd for C15H16O2Na: 251.10425 [M+Na]+; found:
251.10461; enantiomeric excess was determined by chiral HPLC (Chiral-
pak OB-H; n-heptane/2-propanol, 99:1; 0.5 mLminÀ1; 226 nm; column
temperature: 408C): tR (major)=15.08 min, tR (minor)=10.45 min.
(+)-(S)-Hept-1-en-6-yn-3-yl benzoate (7a): According to the general pro-
cedure, compound 7a was obtained as a colorless oil (74% yield, 98%
ee). [a]2D0 =+15.6 (c=0.8 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
8.16–7.99 (m, 2H), 7.59–7.54 (m, 1H), 7.46–7.43 (m, 2H), 6.01–5.80 (m,
1H), 5.61 (dd, J=12.9, 6.3 Hz, 1H), 5.37 (d, J=17.2 Hz, 1H), 5.25 (d, J=
10.6 Hz, 1H), 2.33 (td, J=7.3, 2.6 Hz, 2H), 2.19–1.85 ppm (m, 3H);
13C NMR (100 MHz, CDCl3): d=165.7, 135.6, 133.0, 130.3, 129.6, 128.4,
117.3, 83.1, 73.9, 69.0, 33.1, 14.6 ppm; HRMS (ESI+): m/z calcd for
C14H14O2Na: 237.08860 [M+Na]+; found: 237.08813; enantiomeric excess
was determined by chiral HPLC (Chiralpak AD-H; n-heptane/2-propa-
(À)-(S)-3-Vinylcyclohex-2-en-1-yl benzoate (8c): According to the gener-
al procedure, compound 8c was obtained as a colorless oil (85% yield,
96% ee). [a]2D0 =À197 (c=3.1 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=7.72 (d, J=16.0 Hz, 1H), 7.55 (dd, J=6.7, 2.8 Hz, 2H), 7.44–7.37 (m,
3H), 6.47 (d, J=16.0 Hz, 1H), 6.41 (dd, J=17.5, 10.8 Hz, 1H), 5.83 (d,
J=3.3 Hz, 1H), 5.54 (d, J=4.0 Hz, 1H), 5.29 (d, J=17.4 Hz, 1H), 5.12
(d, J=10.8 Hz, 1H), 2.31 (dt, J=17.2, 5.6 Hz, 1H), 2.23–2.14 (m, 1H),
2.03–1.70 ppm (m, 4H); 13C NMR (125 MHz, CDCl3): d=169.3, 147.3,
143.4, 141.7, 137.2, 132.9, 131.6, 130.7, 129.1, 121.2, 116.2, 71.6, 31.2, 26.4,
21.5 ppm; HRMS (ESI+): m/z calcd for C17H18O2Na: 277.11990
[M+Na]+; found: 277.12029; enantiomeric excess was determined by
nol, 99:1; 0.5 mLminÀ1
; 226 nm; column temperature: 408C): tR
(major)=17.15 min, tR (minor)=14.71 min.
(+)-(S)-Oct-1-en-7-yn-3-yl benzoate (7b): According to the general pro-
cedure, compound 7b was obtained as a colorless oil (85% yield, 97%
ee). [a]2D0 =+18.7 (c=3.7 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
8.15–7.97 (m, 2H), 7.63–7.51 (m, 1H), 7.44 (t, J=7.6 Hz, 2H), 5.90 (ddd,
J=16.9, 10.5, 6.2 Hz, 1H), 5.55 (d, J=6.2 Hz, 1H), 5.34 (d, J=17.2 Hz,
1H), 5.22 (d, J=10.5 Hz, 1H), 2.25 (m, 2H), 1.97 (s, 1H), 1.89 (m, 2H),
chiral
HPLC
(Chiralpak
AS-H;
n-heptane/2-propanol,
99:1;
Chem. Eur. J. 2013, 19, 761 – 770
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
767

B. L. Feringa et al.
0.5 mLminÀ1
10.54 min, tR (minor)=14.00 min.
;
221 nm; column temperature: 408C): tR (major)=
m/z calcd for C23H29O6Na: 421.16216 [M+Na]+; found: 421.16245; enan-
tiomeric excess was determined by chiral HPLC (Chiralpak OJ-H; n-hep-
tane/2-propanol, 99:1; 0.5 mLminÀ1; 233 nm; column temperature: 408C):
tR (major)=32.440 min, tR (minor)=28.68 min.
(+)-(S)-2-Methyl-7-methylenenona-1,8-dien-3-yl benzoate (8d): In
a
round-bottomed flask, TBAF (1.0m in THF, 2.0 equiv) was added drop-
wise to a 0.05m solution of allylic ester 6d (1.0 equiv) in dry THF at 08C.
The mixture was allowed to warm to RT over 1 h. The reaction was
quenched with water and extracted with Et2O (3ꢃ10 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated
under vacuum. Then, the corresponding intermediate (7d) was dissolved
in degassed CH2Cl2 (0.05m) and Grubbs 1st-generation catalyst
(10 mol%) was added to the solution in two portions. The reaction mix-
ture was heated at refluxed under an ethylene atmosphere (1 atm, bal-
loon) until it had gone to completion (20 h), as indicated by GCMS. The
mixture was filtered through a pad of silica, concentrated under vacuum,
and purified by column chromatography on silica gel (Et2O/n-pentane,
1% to 2%) to yield the desired product (8d) as a colorless oil (66%
yield). [a]2D0 =+11 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
8.59–7.88 (m, 2H), 7.56 (t, J=7.4 Hz, 1H), 7.44 (t, J=7.6 Hz, 2H), 5.68
(d, J=2.9 Hz, 1H), 5.42 (d, J=6.5 Hz, 1H), 5.39 (d, J=3.0 Hz, 1H), 5.03
(s, 1H), 4.92 (s, 1H), 4.83 (s, 1H), 4.81 (s, 1H), 2.24 (t, J=7.4 Hz, 2H),
1.79 (s, 3H), 1.77–1.66 (m, 2H), 1.57–1.40 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=165.8, 152.9, 151.2, 143.2, 132.8, 130.6, 129.6,
128.3, 125.3, 112.7, 111.5, 77.8, 35.2, 32.3, 23.6, 18.2 ppm; HRMS
(APCI+): m/z calcd for C18H23O2: 271.16926 [M+H]+; found: 271.16884.
General procedure for the Pauson–Khand reaction:[25] A solution of
enyne 6 (1.0 equiv) in dry CH2Cl2 (0.05m) was added to a flask that con-
tained [Co2(CO)8] (1.1 equiv) under a N2 atmosphere. The resulting solu-
tion was stirred at RT for 2 h until the formation of the cobalt complex
was complete (TLC). The solvent was removed under vacuum, the resi-
due was diluted with MeCN (0.025m), and the resulting solution was
heated at 808C until complete consumption of the cobalt complex
(purple color) was observed. The reaction mixture was filtered through a
plug of silica and washed with Et2O. The combined organic solvents were
evaporated and the residue was purified by column chromatography on
silica gel (EtOAc/n-pentane, 5% to 20%) to yield the desired product
(10).
(À)-(1S,6aS)-5-Oxo-4-(trimethylsilyl)-1,2,3,5,6,6a-hexahydropentalen-1-yl
benzoate (10a): According to the general procedure, compound 10a was
obtained as colorless crystals (64% yield, 98% ee). M.p. 85–918C; [a]D20
=
À19 (c=0.8 in CHCl3); 1H NMR (500 MHz, CDCl3): d=8.08 (d, J=
7.4 Hz, 2H), 7.61 (t, J=7.4 Hz, 1H), 7.48 (t, J=7.7 Hz, 2H), 4.99 (dd, J=
17.3, 8.9 Hz, 1H), 3.32–3.18 (m, 1H), 2.94 (ddd, J=18.4, 11.7, 2.5 Hz,
1H), 2.82–2.71 (m, 1H), 2.67 (dd, J=17.9, 6.6 Hz, 1H), 2.64–2.57 (m,
1H), 2.42 (dd, J=17.8, 3.9 Hz, 1H), 2.21 (tt, J=12.7, 8.4 Hz, 1H),
0.24 ppm (s, 9H); 13C NMR (125 MHz, CDCl3): d=215.9, 193.9, 169.1,
141.2, 135.8, 132.6, 132.3, 131.1, 55.3, 44.7, 34.3, 29.3, 1.5 ppm; HRMS
(ESI+): m/z calcd for C18H22O3SiNa: 337.12304 [M+Na]+; found:
337.12205; enantiomeric excess was determined by chiral HPLC (Chiral-
pak AS-H; n-heptane/2-propanol, 99:1; 0.5 mLminÀ1; 229 nm; column
temperature: 408C): tR (major)=12.56 min, tR (minor)=11.75 min.
General procedure for one-pot consecutive enyne-metathesis/Diels–
Alder reactions: The substrate (7a/7b) was dissolved in dry toluene
(0.05m) and Grubbs 1st-generation catalyst (10 mol%) was added to the
solution in two portions (5 mol% at the start and 5 mol% after 6 h). The
mixture was heated at reflux in toluene (808C) under an ethylene atmos-
phere (1 atm, balloon) until complete conversion into dienol ester (8a/
8b) had been achieved, as indicated by TLC. Then, diethyl acetylenedi-
carboxylate (10 equiv) was added dropwise and the resulting solution was
heated at 1608C in a sealed tube until TLC analysis indicated the com-
plete consumption of the diene. Then, the reaction mixture was filtered
through a plug of silica and concentrated under vacuum. The residue was
purified by column chromatography on silica gel (EtOAc/n-pentane,
10% to 20%) to yield the desired product (9a/9b). The stereochemistry
(+)-(7S,7aS)-2-Oxo-3-(trimethylsilyl)-2,4,5,6,7,7a-hexahydro-1H-inden-7-
yl benzoate (10b): According to the general procedure, compound 10b
was obtained as colorless crystals (55% yield, 97% ee). M.p. 79–828C;
[a]2D0 =+166.2 (c=1.0 in CHCl3); 1H NMR (500 MHz, CDCl3): d=8.06
(dd, J=8.0, 0.9 Hz, 2H), 7.60 (dd, J=10.5, 4.3 Hz, 1H), 7.48 (t, J=
7.7 Hz, 2H), 4.78 (td, J=10.9, 4.3 Hz, 1H), 3.06 (d, J=13.8 Hz, 1H),
3.02–2.93 (m, 1H), 2.54 (dd, J=18.7, 6.9 Hz, 1H), 2.37–2.30 (m, 1H),
2.30–2.17 (m, 1H), 2.16–2.07 (m, 1H), 1.85–1.64 (m, 1H), 1.65–1.47 (m,
1H), 0.34–0.02 ppm (m, 9H); 13C NMR (125 MHz, CDCl3): d=211.7,
185.5, 165.9, 139.5, 133.1, 130.2, 129.6, 128.4, 78.5, 49.0, 40.1, 31.2, 30.3,
23.8, À0.4 ppm; HRMS (ESI+): m/z calcd for C19H24O3SiNa: 351.13869
[M+Na]+; found: 351.13911; enantiomeric excess was determined by
chiral HPLC (Chiralpak AD-H; n-heptane/2-propanol, 95:5;
1
of the product was determined by H NMR and NOESY analysis.
(+)-(3S,3aR)-Diethyl-3-(benzoyloxy)-2,3,3a,6-tetrahydro-1H-indene-4,5-
dicarboxylate (9a): According to the general procedure, compound 9a
was obtained as a colorless oil (54% yield, 97% ee). [a]2D0 =+70.2 (c=0.7
1
in CHCl3); H NMR (500 MHz, CDCl3): d=8.08 (d, J=7.4 Hz, 1H), 7.59
(t, J=7.4 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 5.62 (s, 1H), 5.22 (dd, J=
16.5, 7.5 Hz, 1H), 4.19–4.24 (m, 4H), 3.96–4.01 (m, 1H), 3.83–3.89 (m,
1H), 3.62 (d, J=9.2 Hz, 1H), 3.19 (dt, J=22.6, 6.0 Hz, 1H), 2.99 (dd, J=
22.5, 11.9 Hz, 1H), 2.58 (d, J=11.8 Hz, 1H), 2.39–2.48 (m, 2H), 1.85–1.74
(m, 1H), 1.29 (t, J=7.3 Hz, 3H), 1.10 ppm (t, J=7.2 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=171.4, 168.5, 168.4, 141.8, 138.1, 135.8, 132.6,
132.3, 131.1, 130.5, 119.1, 64.0, 63.8, 48.9, 32.4, 32.3, 30.6, 29.5, 16.7,
16.3 ppm; HRMS (ESI+): m/z calcd for C22H25O6: 385.16456 [M+H]+;
found: 385.16560; enantiomeric excess was determined by chiral HPLC
0.5 mLminÀ1
;
228 nm; column temperature: 408C): tR (major)=
14.14 min, tR (minor)=11.34 min.
(+)-(1S,3aR,6aS)-3a-Methyl-5-oxooctahydropentalen-1-yl benzoate (11):
A solution of methyl lithium (1.6m) in dry Et2O (0.62 mL, 1 mmol) was
slowly added to a suspension of CuI (95.2 mg, 0.5 mmol) in Et2O (1 mL)
at 08C under a N2 atmosphere. The resulting mixture was cooled to
À208C and a solution of substrate 10a (15.7 mg, 0.05 mmol) in Et2O
(1 mL) was added dropwise. After stirring at À208C for 4 h, the reaction
mixture was quenched with a saturated aqueous solution of NH4Cl
(4 mL). Then, the organic layer was separated and the aqueous layer was
extracted with Et2O (3ꢃ5 mL). The combined organic layers were con-
centrated under vacuum. The crude mixture was dissolved in dry THF,
TBAF (1m in THF, 0.1 mL, 0.1 mmol) was added dropwise to the solu-
tion at 08C, and the mixture was allowed to warm to RT over 1 h. The or-
ganic solvent was removed under vacuum. The crude material was puri-
fied by column chromatography on silica gel (Et2O/n-pentane, 10% to
20%) to afford the desired product (11) as a colorless oil (62% yield).
(Chiralpak OJ-H; n-heptane/2-propanol, 97:3; 0.5 mLminÀ1
; 232 nm;
column temperature: 408C): tR (major)=10.54 min, tR (minor)=
14.00 min.
(+)-(8S,8aR)-Diethyl-8-(benzoyloxy)-3,5,6,7,8,8a-hexahydronaphthalene-
1,2 dicarboxylate (9b): According to the general procedure, compound
9a was obtained as a colorless oil (68% yield, 96% ee). [a]2D0 =+87 (c=
2.4 in CHCl3); 1H NMR (500 MHz, CDCl3): d=8.05 (dd, J=8.2, 1.2 Hz,
2H), 7.57 (dd, J=10.6, 4.3 Hz, 1H), 7.46 (t, J=7.7 Hz, 2H), 5.58 (s, 1H),
4.90 (td, J=10.7, 4.4 Hz, 1H), 4.20 (dq, J=10.9, 7.1 Hz, 1H), 4.11 (dq,
J=10.9, 7.1 Hz, 1H), 3.80 (dq, J=10.7, 7.2 Hz, 1H), 3.64 (dt, J=11.2,
6.7 Hz, 1H), 3.45 (dq, J=10.7, 7.2 Hz, 1H), 3.18 (dd, J=23.2, 7.3 Hz,
1H), 2.85 (dddd, J=23.2, 6.1, 3.9, 2.3 Hz, 1H), 2.34 (d, J=13.0 Hz, 1H),
2.27 (dd, J=12.5, 3.4 Hz, 1H), 2.02 (t, J=13.0 Hz, 1H), 1.91 (d, J=
13.1 Hz, 1H), 1.71–1.59 (m, 1H), 1.54–1.42 (m, 1H), 1.26 (t, J=7.1 Hz,
3H), 0.78 ppm (t, J=7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=
169.4, 167.3, 165.5, 135.0, 134.6, 133.2, 131.7, 130.2, 129.9, 128.4, 117.5,
77.1, 61.3, 61.2, 45.0, 34.7, 32.9, 28.0, 25.1, 14.2, 13.2 ppm; HRMS (ESI+):
1
[a]2D0 =+23.8 (c=0.7 in CHCl3); H NMR (500 MHz, CDCl3): d=8.06 (d,
J=7.9 Hz, 2H), 7.60 (t, J=7.4 Hz, 1H), 7.48 (t, J=7.7 Hz, 2H), 5.19 (dt,
J=6.2, 3.1 Hz, 1H), 2.75 (ddd, J=11.4, 10.4, 1.6 Hz, 1H), 2.56–2.46 (m,
1H), 2.42–2.21 (m, 4H), 2.13–2.03 (m, 1H), 1.97 (dt, J=13.3, 8.0 Hz,
1H), 1.80 (ddd, J=13.5, 8.0, 5.7 Hz, 1H), 1.39 ppm (s, 1H); 13C NMR
(125 MHz, CDCl3): d=220.9, 168.8, 135.5, 133.0, 132.0, 131.0, 85.6, 55.8,
54.8, 48.7, 45.2, 40.9, 34.1, 31.1 ppm; HRMS (APPI+): m/z calcd for
C16H18O3: 259.13287 [M+H]+; found: 259.13288.
768
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 761 – 770

Highly Functionalized Cyclic and Bicyclic Alcohols
FULL PAPER
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Acknowledgements
Financial support from The Netherlands Organization for Scientific Re-
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fully acknowledged. B.M. thanks the China Scholarship Council for fi-
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that is present on the Grignard reagent to the copper complex. A
faster addition would provide a greater amount of the alkyne in the
reaction solution, which would facilitate the intermolecular coordi-
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[26] CCDC-889474 (10a) contains the supplementary crystallographic
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Received: August 9, 2012
Revised: October 25, 2012
Published online: November 29, 2012
[22] The moderate yield (43%) of isolated product 8a is possibly due to
volatility problems.
770
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Chem. Eur. J. 2013, 19, 761 – 770