Highly enantio- and diastereoselective one-pot reactions in aqueous media: Combined asymmetric Rh-catalyzed conjugate addition/metal-mediated allylation

Article abstract of DOI:10.1002/ejoc.200600309

1,3-Disubstituted, enantiopure cyclohexanols have been prepared in very high diastereoselectivities and good yields by a concise one-pot method combining the enantioselective rhodium-catalyzed conjugate addition of arylboronic acids with indium-mediated a

Full text of DOI:10.1002/ejoc.200600309

FULL PAPER
DOI: 10.1002/ejoc.200600309
Highly Enantio- and Diastereoselective One-Pot Reactions in Aqueous Media:
Combined Asymmetric Rh-Catalyzed Conjugate Addition/Metal-Mediated
Allylation
[
a]
[b]
[c][‡]
Ben L. Feringa,[b]
Sara Källström, Richard B. C. Jagt, Reijo Sillanpää,
[b]
[a]
Adriaan J. Minnaard,* and Reko Leino*
Keywords: Asymmetric synthesis / Conjugate addition / Allylation / Diastereoselectivity
1
,3-Disubstituted, enantiopure cyclohexanols have been pre-
with indium-mediated allylation into a highly efficient one-
pot reaction in aqueous media.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
pared in very high diastereoselectivities and good yields by
a concise one-pot method combining the enantioselective
rhodium-catalyzed conjugate addition of arylboronic acids
Introduction
Carbon–carbon bond-forming methods provide the
means for generating more complicated organic compounds
from simpler ones, and constitute the essence of organic
[
1]
synthesis. Due to the great demand for stereochemically
defined products, such as medicines and pesticides, asym-
metric C–C bond formation has become one of the most
important areas of organic synthesis.[2] An essential goal in
asymmetric synthesis is the development of tandem, one-
pot and cascade reactions giving a rapid increase in molecu-
[
3]
lar complexity with minimal isolation and purification.
During the past decade, the rhodium-catalyzed conjugate
addition of aryl- and alkenyl boronic acids, pioneered by Scheme 1.
Miyaura and Hayashi,[4] has emerged as an impressive tool
[5]
for stereoselective chemical synthesis. A number of chiral
ligands, the majority being bidentate in nature, has been
Another important and much scrutinized C–C bond
forming method is the Barbier-type metal-mediated al-
[6]
introduced for these reactions.
have recently shown to give excel-
lent enantioselectivities and fast reactions (Scheme 1).
Monodentate phos-
[
11]
phoramidite ligands[
7–9]
lylation in aqueous media. Due to the relatively high re-
activity of allyl halides, the allylation reaction has turned
out to be the most successful among the large amount of
different nucleophilic addition reactions to carbonyl com-
pounds. Various metals have been found to be effective in
mediating this particular reaction (Scheme 2) and among
them, indium has emerged as the most reactive and effective
[
10]
This class of cheap and easily tunable ligands has also
proven to be successful in the rhodium-catalyzed conjugate
addition of aryl- and vinyltrifluoroborates.[8]
[
12]
[
[
a] Laboratory of Organic Chemistry, Åbo Akademi Univeristy,
one.
20500 Åbo, Finland
Fax: +358-2-2154866
E-mail: reko.leino@abo.fi
b] Department of Organic and Molecular Inorganic Chemistry,
Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
Fax: +31-50-3634296
E-mail: a.j.minnaard@rug.nl
[
[
c] Department of Chemistry, Univeristy of Jyväskylä,
4
0351 Jyväskylä, Finland
‡] X-ray crystallography.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 2.
3826
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3826–3833

Combined Asymmetric Rh-Catalyzed Conjugate Addition/Metal-Mediated Allylation
FULL PAPER
Herein we report our initial efforts in combining these
The one-pot allylation of the conjugate addition prod-
two well-known carbon–carbon bond-forming methods ucts 5–9 (Table 1), directly following the conjugate addition
presented above, namely the rhodium-catalyzed asymmetric step, was performed by in situ formation of the allylindium
conjugate addition of arylboronic acids and the indium-me- species from indium powder and allyl bromide added to the
diated allylation into a highly efficient one-pot reaction se- reaction mixture after cooling it to room temperature. We
quence in aqueous media. Because the conjugate addition were pleased to find that this second step of the one-pot
step is highly enantioselective, this one-pot protocol offers protocol indeed proceeded in a highly diastereoselective
excellent means for the controlled creation of a second fashion and with excellent conversions for ketones 5 and
[
13]
stereogenic center in the molecule. The diastereomerically 6 (Table 1, Entries 1–2).
The one-pot indium-mediated
pure homoallylic alcohols obtained may then serve as valu- allylation of ketone 7 also proceeded with excellent conver-
able chiral building blocks by further functionalization of sion (Table 1, Entry 3). This case, however, showed only
the alcohol moiety or the C–C double bond of the allylic moderate diastereoselectivity. Quite surprising, only moder-
unit, as briefly demonstrated in the present work.
ate conversions were obtained in the one-pot allylation of
and 9 (Table 1, Entries 4 and 5). The complete lack of
8
diastereoselectivity found in the allylation of ketone 9 is not
surprising given the fact that the envelope conformation of
saturated five-membered rings is very flexible and often be-
haves as if the two positions on any carbon atom are the
same. Nevertheless, it must be emphasized that the yields
reported in Table 1 refer to those of pure single diastereoiso-
mers.
In order to examine the scope of the second step of the
consecutive conjugate addition/allylation reactions, we de-
cided to continue our study by a further examination of
different allylating agents for the allylation of 5 (Table 2).
The indium-mediated allylation and methallylation of this
ketone occurred in 2–3 hours at room temperature yielding
Results and Discussion
In the conjugate addition step of the one-pot reaction
sequence presented in this study, the monodentate phos-
phoramidite L was applied and the cyclic ketones 1–4 were
investigated (Figure 1). As reported previously, this particu-
lar ligand L provides full conversion and excellent enantio-
[14]
selectivity when used in combination with Rh(acac)(eth) in
2
dioxane/water at 100 °C.[
10b]
10a–b with full conversion, high yields and very high dia-
stereoselectivities (Table 2, Entries 1 and 2). Unfortunately,
[
3c,11b]
though not surprising,
we found a complete lack of
diastereoselectivity for the third additional stereocenter in
the homoallylic alcohol 10c of the indium-mediated crotyl-
ation. In all other aspects, this reaction showed similar re-
sults compared to the indium-mediated allylation and me-
thallylation reactions (Table 2, Entry 3). The indium-medi-
Figure 1. Structures of the substrates used in the rhodium-cata-
lyzed conjugate addition.
Table 1. The conjugate addition–allylation sequence evaluating different keto substrates for the first part of the one-pot reaction.
Entry
“ArB” (equiv.)
PhB(OH) (2.0)
m,p-(MeO)
(PhBO) (3.0)
Cond.[a]
Product
Conv.[b] [%]
ee[c] [%]
dr[d] [a/b]
Yield[e] [%]
1
2
3
4
5
2
A
A
B
A
A
10
11
12
13
14
100
100
100
68
Ͼ98
96
99
96
85
94:6
62
84
35
38
32
2
C
6
H
3
B(OH)
2
(2.0)
Ͼ99:Ͻ1
73:27
82:18
50:50
3
PhB(OH)
PhB(OH)
2
(2.0)
(2.0)
2
69
[
2
a] Conjugate additions were performed on a 0.2-mmol scale with 3 mol-% Rh(acac)(eth) and 7.5 mol-% L at 100 °C for 3 h. Condition
O as reported in ref.[ . Condition B: 0.5 mL of dioxane, slow addition of water by syringe pump
10b]
A: 1.0 mL of dioxane, 0.1 mL of H
2
100 °C, 2 h), as reported in ref.[ . Allylations were performed at room temp. for 3 h with 2.0 equiv. of indium and allyl bromide,
5h]
(
1
respectively. [b] Conversions were determined by H NMR spectroscopy. [c] ee Values were determined by chiral HPLC. [d] a: axial OH
1
group; b: equatorial OH group. dr values were determined by GC or H NMR spectroscopy. [e] Isolated yields of pure single diastereoiso-
mers shown in Scheme.
Eur. J. Org. Chem. 2006, 3826–3833
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3827

A. J. Minnaard, R. Leino et al.
Table 2. The conjugate addition–allylation sequence testing different substrates for the second part of the one-pot reaction.[a]
FULL PAPER
Entry
Allylating agent
R1
R2
Conv.[b] [%]
dr[c] [a/b]
Yield[d] [%]
1
2
3
4
allyl bromide
H
H
Me
iPr
H
Me
H
100
100
100
65
94:6
95:5
98:2
Ͼ99:Ͻ1
62
75
71
46
methallyl bromide
crotyl bromide
prenyl bromide
H
[
a] Conjugate additions were performed on a 0.2-mmol scale in dioxane/H
2
O, 10:1 with 3 mol-% Rh(acac)(eth)
2
and 7.5 mol-% L at
1
00 °C for 3 h. Allylations were performed at room temp. for 3 h with 2.0 equiv. of indium and allyl bromide, respectively. [b] Conversions
1
1
were determined by H NMR spectroscopy. [c] a: axial OH group; b: equatorial OH group. dr values were determined by GC or H
NMR spectroscopy. [d] Isolated yields of pure single diastereoisomers are shown in the Scheme.
ated prenylation giving 10d showed the highest diastereo- give two distinct doublet-of-doublets with J = 8.0 Hz and
selectivity after a reaction time of 3 hours, however at the J = 14.4 Hz.
[
15]
expense of conversion and yield (Table 2, Entry 4).
The stereochemical assignment of the chiral cyclohex-
The stereochemistry of the homoallylic alcohol products anols 10a and 10aЈ was further supported by single-crystal
could be ascertained by NMR analysis. For the minor equa- X-ray analysis of 10a, confirming the equatorial positioning
[
16]
torial-OH alcohol 10aЈ, formed by an axial attack of the of the allyl group (Figure 3). Compound 10a crystallizes
allylindium, a NOESY cross-peak between the C(7) protons with three molecules in the asymmetric unit, H-bonded as
of the allyl group and the C(3) proton in the cyclohexane shown in Figure 3. From HO3 there is an intermolecular
i
ring is clearly observed (Figure 2). This interaction is not H-bond to O1 (i = x, y+1, x). This results in the formation
observed for the major alcohol 10a with an axial OH group, of H-bonded columns connected only by van der Waals
which is formed through the preferred equatorial approach forces and explains the fiber-like appearance of the crystals
of the allylindium. The configuration of the major and of 10a.
minor diastereomer, respectively, is also supported by coup-
The preferred equatorial attack of the allylindium rea-
ling constant data where the C(7) protons of the freely rot- gent leading to the axial-OH alcohol 10a (Figure 4) con-
ating allyl group of the major diastereomer 10a give rise to forms to the stereoselectivity previously observed for both
a doublet with a coupling of J = 8.0 Hz, while the same allylindium as well as other allylmetal reagents.[17] Forma-
sterically hindered protons of the minor diastereomer 10aЈ tion of the minor equatorial-OH alcohol 10aЈ by axial at-
tack of the allylindium is believed to be hindered by 1,3-
[
17b]
diaxial interactions with bulky reagents.
This is sup-
ported by the increase in diastereoselectivity found in this
study upon switching from allyl bromide to prenyl bromide
(Table 2). Another possibility is that the rather large van der
Waals radius of indium dictates the stereocontrol in cyclic
systems of this kind, making an axial approach of the al-
lylindium species sterically unfavorable, as previously dis-
[
17c]
cussed by Paquette and co-workers.
Despite the successful nature of indium-promoted reac-
tions, their precise mechanism remains unclear. One pos-
sible mechanism is a single electron transfer process pro-
[
11d,18]
posed by Chan and Li (Figure 5, I).
This reaction
pathway involves a radical anion/indium radical cation pair
which is generated by the SET process at the surface of the
indium metal as allyl bromide approaches it. An alternative
pathway involving an allylindium sesquibromide (Figure 5,
II) might overrun the SET mechanism when preformed al-
Figure 2. Assignment of the stereochemistry of the products by
NMR analysis.
[
17d–17e,19]
lylindium reagents are used.
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Combined Asymmetric Rh-Catalyzed Conjugate Addition/Metal-Mediated Allylation
FULL PAPER
Figure 3. ORTEP drawing of 10a.
Figure 4. Equatorial attack of the allylindium reagent is preferred
over axial attack due to steric reasons.
Figure 5. I: Single electron-transfer mechanism. II: Allylindium ses-
quibromide.
After demonstrating the efficiency of the one-pot proto-
Thus, the one-pot protocol reported here provides an at-
col described above, the outcome of the combined method tractive and efficient route to chiral cyclohexanol building
was compared with the one carried out in the traditional blocks with two asymmetric centers formed in excellent dia-
[
20]
two-step fashion.
We also wished to compare the out- stereoselectivities. As a demonstration of the further
come of an indium-mediated allylation vs. a Grignard reac- derivatization of these compounds, we converted the homo-
[
21]
tion using allylmagnesium bromide in the second step.
allylic alcohol 10a into the corresponding allyl ether 15 in
The results unambiguously demonstrate the advantages of good yield by deprotonation with sodium hydride and sub-
the one-pot approach (Table 3) in terms of isolated yield. sequent reaction with excess allyl bromide at room tempera-
[
21]
Furthermore, the indium-mediated allylation proved to be ture (Scheme 3). Upon treating a degassed dichlorometh-
far more selective than the Grignard reaction (Table 3, En- ane solution of 15 with the Grubbs’ second-generation ru-
tries 1, 2 and 4 vs. 3 and 5). This is most likely due to the thenium catalyst at room temperature, chiral spirocyclic
properties of the indium metal, as also previously shown by ether 16 was obtained in 60% yield after purification by
Reetz and co-workers in the diastereoselective allylation of column chromatography, leaving a double bond in the ring
[
17d]
3-methylcyclohexanone using indium-ate complexes.
for further derivatization by e.g. dihydroxylation or epoxid-
Eur. J. Org. Chem. 2006, 3826–3833
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3829

A. J. Minnaard, R. Leino et al.
FULL PAPER
Table 3. One-pot protocol vs. traditional methodologies.
Entry
Method[a]
Product
Conv.[b] [%]
dr[c] [a/b]
Yield[d] [%]
1
2
3
4
5
X
Y
Z
X
Z
10a
10a
10a
11
100
100
100
100
84
94:6
94:6
65:35
Ͼ99:Ͻ1
53:47
62
39
33
84
22
11
[
1
a] Conjugate additions were performed on a 0.2 mmol scale in dioxane/H
2
O, 10:1 with 3 mol-% Rh(acac)(eth)
2
and 7.5 mol-% L at
00 °C for 3 h. Method X: One-pot allylation was performed in dioxane/H O, 10:1 at room temp. for 3 h with 2.0 equiv. of indium and
2
allyl bromide, respectively. Method Y: Following isolation of 5, allylation was performed in THF/hexane, 3:1 at room temp. for 3 h with
[
20]
2
.0 equiv. of indium and allyl bromide, respectively, as reported in ref. . Method Z: Following isolation of 5, allylation was performed
O at room temp. for 12 h with 1.2 equiv. of allylmagnesium bromide, as reported in ref.[ . [b] Conversions were determined by H
NMR spectroscopy. [c] a: axial OH group; b: equatorial OH group. dr values were determined by GC or H NMR spectroscopy. [d]
21]
1
in Et
2
1
Isolated yields of pure single diastereoisomers shown in Scheme.
ation.[22] Further work on the utilization of these one-pot rocyclic ethers in good yield, providing an example of the
reaction products is currently in progress.
possibilities emerging from the products of this new one-
pot protocol.
Experimental Section
General Remarks: All reactions were performed under dry nitrogen
or argon using standard Schlenk techniques. 1,4-Dioxane was dis-
tilled from Na and stored under nitrogen. Reagents were used as
1
13
received. H NMR, C NMR and NOESY spectra were recorded
at room temperature in CDCl on Varian or Bruker instruments at
00 MHz, 400 MHz, 500 MHz or 600 MHz. Chemical shifts were
determined relative to residual solvent peaks (CHCl , δ = 7.26 ppm
3
2
3
for proton atoms, δ = 77.23 ppm for carbon atoms). HRMS were
recorded on an AEI MS-902 or a Fisons ZABSpec-oaTOF instru-
ment. Optical rotations were measured with a Schmidt and
Haensch Polartronic MH8 or a Perkin–Elmer 343 polarimeter.
Flash chromatography was performed using silica gel 60 Å (Merck,
230–400 mesh).
Synthesis of Starting Materials: Substrate 2 was synthesized from 4-
piperidone monohydrate hydrochloride and benzyl chloroformate,
following the literature procedure for ethyl 3,4-dihydro-4-oxo-
Scheme 3.
1
6
(2H)-pyridinecarboxylate, and was obtained as a white solid in
4% yield.[ Spectral data were in accordance with literature.
23]
[24]
Conclusions
Arylboroxines were prepared from the corresponding arylboronic
acids by heating at 300 °C in vacuo.[ Phosphoramidite ligand (S)-
25]
To summarize, we have developed a viable method for
the highly diastereoselective construction of two new ste-
reocenters in an efficient manner by consecutive, one-pot
rhodium-catalyzed asymmetric conjugate addition and in-
dium-mediated allylation in aqueous media. Furthermore,
we have shown that the indium-mediated allylation is far
more selective in this particular reaction than the corre-
sponding Grignard reaction with allylmagnesium bromide.
Finally, the one-pot reaction products obtained may be fur-
3
L was prepared from the corresponding H8-bis-β-naphthol, PCl ,
[
10b]
and diethylamine according to a previously reported procedure.
One-pot Procedure: Standard reaction for Table 2; In a Schlenk
tube flushed with nitrogen, Rh(acac)(eth) (1.55 mg, 6 µmol) and
phosphoramidite L (5.93 mg, 15 µmol) were dissolved in dioxane
1 mL). Water (0.1 mL) was added, and the resulting solution was
stirred 5 min at room temperature. Cyclohexenone (20 µL,
.2 mmol) and phenylboronic acid (48.8 mg, 0.4 mmol) were added
to the solution, and the mixture was heated to 100 °C. The resulting
2
(
0
ther utilized as chiral building blocks. Subsequent etherifi- solution was stirred for 3 hours at 100 °C and subsequently cooled
cation followed by ring-closing metathesis gives chiral spi- to room temperature. Indium (46 mg, 0.4 mmol) and allyl bromide
3830
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3826–3833

Combined Asymmetric Rh-Catalyzed Conjugate Addition/Metal-Mediated Allylation
FULL PAPER
(
35 µL, 0.4 mmol) were added. The mixture was stirred for an ad-
ditional 3 hours at room temperature followed by quenching with
satd. NaHCO , extraction with diethyl ether and washing with
1 H) ppm. 13C NMR (50.3 MHz, CDCl
37.4, 43.7, 47.3, 54.3, 69.9, 109.1, 109.7, 116.9, 117.7, 131.8, 138.4,
145.7, 147.3 ppm. HRMS calcd. for 276.1725, found 276.1734.
3
): δ = 20.3, 32.1, 35.1,
3
water. The organic phase was passed through a pad of silica gel.
The crude mixture was purified by flash chromatography and sub-
jected to analysis.
Procedure for the Synthesis of 12: In a Schlenk tube flushed with
2
nitrogen, Rh(acac)(eth) (1.55 mg, 6 µmol) and phosphoramidite L
(
5.93 mg, 15 µmol) were dissolved in dioxane (0.5 mL). After stir-
(
5
=
1R,3S)-1-Allyl-3-phenylcyclohexanol (10a): White solid. M.p. 52–
4 °C. R = 0.63 (10% EtOAc in pentane). [α] = +10.0 (CHCl , c
0.10). 1H NMR (400 MHz, CDCl
): δ = 1.34–1.53 (m, 4 H), and the resulting mixture was stirred at reflux with slow addition
ring for 15 min at room temperature, substrate 2 (46.2 mg,
0.2 mmol) and phenylboroxine (187.0 mg, 0.6 mmol) were added,
f
D
3
3
1
1
1
.67–1.93 (m, 5 H), 2.25 (d, J = 8.0 Hz, 2 H), 2.97 (tt, J = 3.2,
2.4 Hz, 1 H), 5.14 (dd, J = 1.2, 17.2 Hz, 1 H), 5.17 (dd, J = 1.2,
of a 20 vol.-% solution of water in 1,4-dioxane by syringe pump
(0.1 mL/h). After 2 h it was cooled to room temperature and in-
0.4 Hz, 1 H), 5.91 (ddt, J = 8.0, 10.0, 17.2 Hz, 1 H), 7.18–7.33 dium (46 mg, 0.4 mmol) and allyl bromide (35 µL, 0.4 mmol) were
(
3
m, 5 H) ppm. 13C NMR (50.3 MHz, CDCl
3
): δ = 20.3, 32.0, 35.1,
7.7, 43.4, 47.4, 69.8, 117.7, 124.5, 125.4, 126.9, 131.8, 145.6 ppm.
20O: calcd. C
added. The mixture was stirred for an additional 3 hours at room
temperature after which it was diluted with diethyl ether (2 mL)
and passed through a pad of silica gel. The crude mixture was
purified by flash chromatography and subjected to analysis.
HRMS calcd. for 216.1514, found 216.1520. C15
H
83.28, H 9.32; found C 83.40, H 9.46.
(
6
=
1
8
1
=
(
1S,3S)-1-Allyl-3-phenylcyclohexanol (10aЈ): White solid. M.p. 62–
5 °C. R = 0.35 (10% EtOAc in pentane). [α] = –9.8 (CHCl , c
0.10). 1H NMR (600 MHz, CDCl
): δ = 1.24–1.61 (m, 5 H),
.81–1.96 (m, 4 H), 2.41 (dd, J = 8.0, 14.4 Hz, 1 H), 2.47 (dd, J =
.0, 14.4 Hz, 1 H), 2.66 (tt, J = 3.2, 12.4 Hz, 1 H), 5.19 (dd, J =
Benzyl (2S,4S)-4-Allyl-4-hydroxy-2-phenylpiperidine-1-carboxylate
f
D
3
(
(
12): Light yellow oil. R
= 0.43 (hexane/Et
O, 1:2). [α]
D
= –27.6
f
2
1
3
CHCl
, c = 2.10). H NMR (600 MHz, CDCl
): δ = 1.18 (s, 1 H),
3
3
1.56–1.66 (m, 2 H), 2.02 (dd, J = 7.0, 14.7 Hz, 1 H), 2.22 (d, J =
7.4 Hz, 1 H), 2.37 (d, J = 14.7 Hz, 1 H), 3.37 (dt, J = 3.4, 13.3 Hz,
1 H), 4.21 (d, J = 13.6 Hz, 1 H), 5.11–5.19 (m, 4 H), 5.53 (br. s, 1
.2, 18.0 Hz, 1 H), 5.21 (dd, J = 1.2, 10.8 Hz, 1 H), 5.92 (dddd, J
7.2, 10.8, 14.8, 18.4 Hz, 1 H), 7.20–7.32 (m, 5 H) ppm. 1 C NMR
3
H), 5.86 (ddt, J = 7.7, 10.2, 17.7 Hz, 1 H), 7.22–7.38 (m, 10 H)
150.9 MHz, CDCl
3
): δ = 23.7, 33.8, 38.1, 41.5, 41.8, 45.8, 72.5,
13
ppm. C NMR (150.9 MHz, CDCl
3
): δ = 36.2, 36.8, 39.4, 48.2,
1
2
19.4, 126.4, 127.0, 128.7, 133.6, 146.4 ppm. HRMS calcd. for
16.1514, found 216.1517.
5
1
3
2.3, 67.5, 69.9, 119.6, 125.6, 126.8, 128.0, 128.1, 128.6, 128.9,
32.9, 136.9, 156.2 ppm. HRMS calcd. for 351.1834, found
51.1842.
(
1S,3S)-1-(2-Methylallyl)-3-phenylcyclohexanol (10b): Colorless oil.
= 0.27 (10% EtOAc in hexane). [α] = +13.3 (CHCl , c = 1.04).
H NMR (600 MHz, CDCl ): δ = 1.35–1.43 (m, 2 H), 1.48–1.52
m, 1 H), 1.62 (br. s, 1 H), 1.69–1.74 (m, 2 H), 1.77–1.85 (m, 2 H),
.85 (s, 3 H), 1.88–1.92 (m, 1 H), 2.22 (d, J = 2.0 Hz, 1 H), 2.97
tt, J = 3.4, 12.5 Hz, 1 H), 4.78 (br. s, 1 H), 4.95 (br. s, 1 H), 7.18–
R
f
D
3
(
(
(
1
1
1R,3S)-1-Allyl-3-phenylcycloheptanol (13): Colorless oil. R
f
= 0.69
, c = 1.14). H NMR
): δ = 1.39–1.44 (m, 2 H), 1.60–1.67 (m, 2 H),
.72–1.85 (m, 5 H), 1.92–1.97 (m, 2 H), 2.20 (dd, J = 7.9, 13.5 Hz,
H), 2.30 (dd, J = 7.2, 13.2 Hz, 1 H), 3.06 (tt, J = 2.8, 11.2 Hz, 1
1
3
1
10% EtOAc in pentane). [α]
600 MHz, CDCl
D 3
= +1.1 (CHCl
(
1
(
7
3
1
3
13
3
.31 (m, 5 H) ppm. C NMR (150.9 MHz, CDCl ): δ = 22.1, 25.7,
H), 5.11 (dd, J = 1.2, 16.4 Hz, 1 H), 5.14 (dd, J = 1.6, 10.8 Hz, 1
3.7, 37.3, 39.5, 45.6, 52.1, 71.6, 115.3, 126.2, 127.2, 128.6, 142.4,
47.4 ppm. HRMS calcd. for 230.1671, found 230.1691.
H), 5.86 (ddt, J = 7.2, 10.0, 16.8 Hz, 1 H), 7.14–7.29 (m, 5 H) ppm.
13
3
C NMR (150.9 MHz, CDCl ): δ = 22.5, 29.2, 38.1, 39.4, 40.8,
4
9.3, 49.7, 74.3, 119.5, 125.8, 126.9, 128.6, 134.0, 150.1 ppm.
(
1S,3S)-1-(1-Methylallyl)-3-phenylcyclohexanol (10c): Colorless oil.
= 0.56 (10% EtOAc in pentane). [α] = +1.7 (CHCl , c = 1.04).
H NMR (600 MHz, CDCl ): δ = 1.05 (d, J = 1.6 Hz, 3 H), 1.07
d, J = 2.0 Hz, 3 H), 1.33–1.90 (m, 18 H), 2.18 (m, 2 H), 2.97 (tt,
J = 3.2, 10.4 Hz, 2 H), 5.07–5.12 (m, 4 H), 5.79–5.87 (m, 2 H),
HRMS calcd. for 230.1671, found 230.1680.
R
f
D
3
1
3
(
(
(
1R,3S)-1-Allyl-3-phenylcyclopentanol (14): Colorless oil. R
10% EtOAc in pentane). [α]
600 MHz, CDCl
f
= 0.69
, c = 0.56). H NMR
): δ = 1.61 (br. s, 1 H), 1.68–1.75 (m, 2 H), 1.78–
.83 (m, 1 H), 1.96–2.01 (m, 1 H), 2.06 (dd, J = 6.8, 13.1 Hz, 1 H),
(
1
D 3
= +12.2 (CHCl
3
7
1
4
1
2
.18–7.32 (m, 10 H) ppm. 13C NMR (150.9 MHz, CDCl
3
): δ =
1
2
5
5
4
4.5, 14.6, 22.0, 22.1, 33.5, 33.6, 33.7, 34.4, 39.4, 39.5, 42.2, 42.9,
9.9, 73.3, 73.4, 116.7, 116.8, 126.1, 126.2, 127.1, 127.2, 128.5,
28.6, 140.3, 147.4, 147.5 ppm. HRMS calcd. for 230.1671, found
30.1680.
.29 (m, 1 H), 2.43 (d, J = 7.4 Hz, 1 H), 3.44–3.50 (m, 1 H), 5.18–
.20 (m, 2 H), 5.92 (ddt, 1 H, J = 7.2, 9.2, 16.8 Hz), 7.18–7.31 (m,
13
3
H) ppm. C NMR (150.9 MHz, CDCl ): δ = 32.9, 39.6, 43.8,
6.7, 48.5, 81.4, 119.3, 126.2, 127.2, 128.6, 134.3, 145.7 ppm.
(
1S,3S)-1-(1,1-Dimethylallyl)-3-phenylcyclohexanol (10d): Colorless HRMS calcd. for 202.1358, found 202.1370.
oil. R = 0.79 (10% EtOAc in pentane). [α] = +6.7 (CHCl , c =
): δ = 1.06 (s, 3 H), 1.07 (s, 3
f
D
3
Procedure for the Synthesis of 16: A Schlenk tube flushed with ar-
gon was charged with NaH (14.4 mg, 0.6 mmol) and anhydrous
DMF (0.5 mL) and cooled in an ice bath. To this slurry a solution
of 10a (33.7 mg, 0.2 mmol) in anhydrous DMF (0.5 mL) was
added. The reaction mixture was warmed to room temperature
over the course of 1 h and then recooled on an ice bath and treated
with freshly purified allyl bromide (42 µL, 0.5 mmol, filtered
through a basic alumina column). The reaction mixture was stirred
at room temperature overnight. After 15 h it was again cooled on
an ice bath and quenched by a slow addition of water. The resulting
1
1
.34). H NMR (400 MHz, CDCl
3
H), 1.30–1.88 (m, 9 H), 2.94 (tt, J = 3.2, 12.4 Hz, 1 H), 5.07 (dd,
J = 1.2, 17.2 Hz, 1 H), 5.12 (dd, J = 1.6, 11.2 Hz, 1 H), 6.01 (dd,
J = 10.8, 17.6 Hz, 1 H), 7.18–7.33 (m, 5 H) ppm. 13C NMR
50.3 MHz, CDCl
3.6, 112.5, 124.5, 125.5, 126.9, 143.7, 145.9 ppm. HRMS calcd.
for 244.1827, found 244.1855.
(
7
3
): δ = 20.3, 20.5, 29.4, 31.7, 38.0, 38.2, 42.8,
(
1R,3S)-1-Allyl-3-(3,4-dimethoxyphenyl)cyclohexanol (11): Color-
less oil. R = 0.53 (30% EtOAc in pentane). [α] = +10.3 (CHCl ,
c = 1.74). H NMR (400 MHz, CDCl
f
D
3
1
3
): δ = 1.33–1.47 (m, 4 H), mixture was extracted with diethyl ether, washed with water and
1
1
1
1
.65–1.90 (m, 5 H), 2.24 (d, J = 7.2 Hz, 2 H), 2.90 (tt, J = 3.2, brine, and the organic extracts were dried with MgSO . Filtration
4
2.4 Hz, 1 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 5.13 (dd, J = 1.2, 18.0 Hz,
H), 5.16 (dd, J = 1.2, 9.2 Hz, 1 H), 5.90 (ddt, J = 6.8, 9.6, 17.2 Hz,
H), 6.74 (s, 1 H), 6.75 (d, 1 H, J = 7.6 Hz), 6.81 (d, J = 8.0 Hz,
through a pad of silica followed by concentration in vacuo gave 15
as a colorless liquid, which was used for the next reaction without
further purification.
Eur. J. Org. Chem. 2006, 3826–3833
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3831

A. J. Minnaard, R. Leino et al.
FULL PAPER
In the second step of preparing 16, a Schlenk tube flushed with
argon was charged with a solution of 15 (32.5 mg, 0.13 mmol) in
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Cl (0.7 mL) and degassed using three evacuation/
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12 h the reaction product was purified by flash chromatography by
passing the reaction mixture as such through a silica column af-
fording 16 (21.4 mg, 60%) as a light yellow oil.
[
7] a) M. Van den Berg, A. J. Minnaard, E. P. Schudde, J.
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6R,8S)-8-Phenyl-1-oxaspiro[5,5]undec-3-ene (16): Light yellow oil.
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R
f
D
3
1
3
1
2
4
7
3
1
.33–1.45 (m, 2 H), 1.64–1.69 (m, 1 H), 1.75–1.83 (m, 1 H), 1.89–
.03 (m, 4 H), 2.10–2.13 (m, 1 H), 2.94 (tt, J = 3.3, 12.7 Hz, 1 H),
.13–4.15 (m, 2 H), 5.67–5.70 (m, 1 H), 5.72–5.76 (m, 1 H), 7.17–
.31 (m, 5 H) ppm. C NMR (150.9 MHz, CDCl ): δ = 21.8, 34.1,
3
4.3, 37.1, 39.1, 42.3, 60.5, 71.1, 123.0, 125.3, 126.1, 127.2, 128.6,
47.5 ppm. HRMS calcd. for 228.1514, found 228.1513.
13
[
[
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Supporting Information (see also the footnote on the first page of
3700–3701.
1
13
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3832
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Eur. J. Org. Chem. 2006, 3826–3833

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Received: April 9, 2006
Published Online: June 28, 2006
Eur. J. Org. Chem. 2006, 3826–3833
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3833