Stereoselective synthesis of (+)-nephrosteranic acid, (+)-trans-cognac lactone, and (+)-trans-whisky lactone using a chiral cyclohexadienyl Ti compound

Article abstract of DOI:10.1002/chem.200400237

We present the stereoselective transfer of cyclohexadienyl from 3-metalated 1,4-cyclohexadienes to various aldehydes. Lewis-acid-mediated "allylation" of aldehydes by treatment with 3-silylated and 3-stannylated 1,4-cyclohexadienes could not be achieved with high diastereoselectivity. In contrast, cyclohexadienyl titanium compounds reacted with both aliphatic and aromatic aldehydes with good-to-excellent diastereoselectivities. Reaction of a chiral TADDOL-derived (TADDOL, 2,2-dimethyl-α,α,α′,α′-tetraphenyl-1, 3-dioxolandimethanol) cyclohexadienyl Ti derivative with various aldehydes led to the corresponding homoallylic alcohols with excellent diastereo- and enantioselectivities. Lower selectivities were obtained with chiral β-cyclohexadienyldiisopinocampheylborane. The 1,3-cyclohexadienes are very useful building blocks for the preparation of biologically important γ-butyrolactones. Short efficient syntheses of (+)-nephrosteranic acid, (+)-trans-whisky lactone, and (+)-iram-cognac lactone by desymmetrization of 1,4-cyclohexadiene are described.

Full text of DOI:10.1002/chem.200400237

FULL PAPER
Stereoselective Synthesis of (+)-Nephrosteranic Acid, (+)-trans-Cognac
Lactone, and (+)-trans-Whisky Lactone using a Chiral Cyclohexadienyl Ti
Compound
Florian Schleth,[a, b] Thomas Vogler,[a] Klaus Harms,[a] and Armido Studer*[a, b]
Abstract: We present the stereoselec-
tive transfer of cyclohexadienyl from 3-
metalated 1,4-cyclohexadienes to vari-
ous aldehydes. Lewis-acid-mediated
™allylation∫ of aldehydes by treatment
with 3-silylated and 3-stannylated 1,4-
cyclohexadienes could not be achieved
with high diastereoselectivity. In con-
trast, cyclohexadienyl titanium com-
pounds reacted with both aliphatic and
aromatic aldehydes with good-to-excel-
lent diastereoselectivities. Reaction of
a chiral TADDOL-derived (TADDOL,
2,2-dimethyl-a,a,a’,a’-tetraphenyl-1,3-
dioxolandimethanol) cyclohexadienyl
Ti derivative with various aldehydes
led to the corresponding homoallylic
alcohols with excellent diastereo- and
enantioselectivities. Lower selectivities
were obtained with chiral B-cyclohexa-
dienyldiisopinocampheylborane.
The
1,3-cyclohexadienes are very useful
building blocks for the preparation of
biologically important g-butyrolac-
tones. Short efficient syntheses of (+)-
nephrosteranic acid, (+)-trans-whisky
lactone, and (+)-trans-cognac lactone
by desymmetrization of 1,4-cyclohexa-
diene are described.
Keywords: asymmetric synthesis ¥
cyclohexadienes ¥ lactones ¥ natural
products
titanates
¥ synthetic methods ¥
Introduction
pounds have been reported.[7] Li,[8] Ti-derived compounds,[9]
and other allyl ™metal∫ compounds have also been applied
in asymmetric allylations.
Nucleophilic addition of allyl metals to carbonyl compounds
has been widely used for the introduction of the synthetical-
ly useful allyl moiety. Secondary and tertiary homoallyl alco-
hols have been prepared by this method. Many applications
in complex natural product synthesis have been reported. In
the last fifteen years, many papers on stereoselective allyla-
tion have appeared.[1] Various ™metals∫ have been used in
these processes: Allylation of aldehydes with allyl silanes in
the presence of chiral Lewis acids has been described.[2]
More recently, stereoselective allylation with allyl silanes in
the presence of chiral Lewis bases has been achieved.[3]
Chiral allyl silanes can also be used in stereoselective allyla-
tions.[4] Allyl stannanes in the presence of Lewis acids[5] and
chiral allylboron compounds[6] have been used successfully
for stereoselective allylations. Recently, Lewis-acid-mediat-
ed low-temperature allylations involving allylboron com-
We recently published our first results from studies on the
desymmetrization of chiral cyclohexadiene Ti compound
1.[10] Treatment of this compound with various aldehydes
provided the corresponding 1,3-cyclohexadienes 2 in good
yields with excellent diastereo- and enantioselectivities
[Eq. (1)]. These dienes are very interesting chiral building
[a] Dipl. Chem. F. Schleth, T. Vogler, Dr. K. Harms, Prof. Dr. A. Studer
Fachbereich Chemie der Universit‰t Marburg
Hans-Meerwein-Strasse, 35032 Marburg (Germany)
E-mail: studer@uni-muenster.de
blocks, as has been shown by their use in the synthesis of
nephrosteranic acid. Herein we report the desymmetrization
of metalated cyclohexadienes in full detail. In addition, we
describe the synthesis of (+)-nephrosteranic acid, (+)-trans-
cognac lactone, and (+)-trans-whisky lactone by our new
method.
[b] Dipl. Chem. F. Schleth, Prof. Dr. A. Studer
New address:
Organisch Chemisches-Institut
Westf‰lische Wilhelms Universit‰t
Corrensstrasse 40, 48149 M¸nster (Germany)
Fax : (+49)251-8336523
Chem. Eur. J. 2004, 10, 4171 4185
DOI: 10.1002/chem.200400237
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4171

FULL PAPER
Results and Discussion
Several issues have to be considered to achieve highly ster-
eoselective allylation of aldehydes by using 3-metalated 1,4-
cyclohexadienes. The first problem to be solved is how the
diastereoselectivity of the reaction can be controlled. This
can be achieved by controlling the face selectivity of the
electrophilic attack. By analogy with the parent allylations
involving allyl metal derivatives, it is likely that the face se-
lectivity can be controlled by the choice of metal (open
versus closed transition state). In addition, the effect of pos-
sible metallotropic 1,3 shifts must be considered.[1] A big
challenge for an allylation method that uses 3-metalated 1,4-
cyclohexadienes is the desymmetrization of the 1,4-cyclo-
hexadiene moiety (differentiation of the two enantiotopic
double bonds).[11]
Scheme 1. The various achiral cyclohexadienyl ™metal∫ compounds
tested.
cyclic transition states, to try to increase the diastereoselec-
tivity of the reactions. The Ti compounds were readily pre-
pared from 1,4-cyclohexadiene by lithiation (sBuLi, tetrame-
thylethylenediamine (TMEDA), THF, ꢀ788) and transmeta-
lation by treatment with Ti(O-iPr)4 or Cp2TiCl2. Addition of
6 to propanal at ꢀ788C occurred in excellent yield and with
high selectivity (91%, syn:anti=11:1, entry 9). Use of re-
agent 7, derived from Cp2TiCl2, provided worse results
(entry 10) so all further experiments were conducted with 6
(!2e t).
Our first experiments were conducted with silylated cyclo-
hexadienes.[12,13] Diene 3 was treated with propanal in
CH2Cl2 in the presence of various achiral Lewis acids (LAs,
ꢀ78 258C, Scheme 1) with the aim of producing 2a. When
BF3¥OEt2, SnCl4, or trimethylsilyl triflate (TMS-OTf) was
used as the Lewis acid, the desired product was not ob-
tained. A moderate yield and low syn selectivity were ach-
ieved by using TiCl4 (Table 1, entry 1). Reaction of the
diene with iPrCHO (!2b), tBuCHO (!2c), and PhCHO
(!2d)[14] provided similar results (entries 2 4). We next fo-
cused on the LA-mediated allylation of propanal with stan-
nylated diene 4. It is well known that allyl stannanes are
more reactive nucleophiles than
Linear aliphatic aldehydes provide better selectivities (up
to 13:1) than secondary aliphatic aldehydes (d.r.ꢁ3:1, en-
tries 11 13). Reaction of 6 with pivalaldehyde afforded 2c
the corresponding silanes.[15]
A
satisfactory yield (75%) was ob-
tained with BF3¥OEt2 as the
LA, but syn selectivity re-
mained low (entry 5). The re-
gioisomer 5a, derived from an
LA-mediated 1,3-stannyl shift[3]
and subsequent allylation, was
formed as a byproduct in 13%
yield. A lower yield of the de-
sired product was obtained
when AlCl3 was used as the LA
(entry 6), and 2a was not
formed at all in the presence of
Ti(O-iPr)4, SnCl4, or TMS-OTf.
The BF3¥OEt2-mediated reac-
tion was also conducted with
iPrCHO and PhCHO to afford
2b and 2d in moderate-to-good
yields but with low selectivities
(entries 7 and 8). Regioisomers
5b and 5d were formed in 20
and 33% yield, respectively.
Table 1. Reaction of 3, 4, 6, and 7 with various aldehydes.
M
LA
R
Product
Yield
[%]
d.r.[a]
(syn:anti)
1.4:1[b]
1.6:1[b]
n.d.[c]
1
SiMe3
TiCl4
Et
2a
2b
2c
2d
2a
2a
2b
2d
2a
2a
2e
2b
2 f
2c
2d
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
36
35
11
31
75
25
45
77
91
23
96
91
59
87
99
98
99
96
23
98
96
98
98
94
99
99
89
93
92
2
3
4
SiMe3
SiMe3
SiMe3
TiCl4
TiCl4
TiCl4
iPr
tBu
Ph
1.6:1[b]
1.7:1[b]
2.5:1[b]
1.6:1[b]
1:3[b]
5
6
SnBu3
SnBu3
BF3¥OEt2
AlCl3
Et
Et
7
8
SnBu3
SnBu3
BF3¥OEt2
BF3¥OEt2
iPr
Ph
9
Ti(O-iPr)3
TiCp2Cl
Et
Et
11.0:1[b]
5.1:1[b]
13.3:1[d]
2.9:1[b]
2.7:1[d]
6.5:1[b]
9.0:1[d]
14.4:1[d]
32:1[d]
2.5:1[d]
1.9:1[d]
11.9:1[e]
39:1[d]
21:1[d]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
Ti(O-iPr)3
C11H23
iPr
C6H11
tBu
Ph
ꢀ
4-Me Ph
ꢀ
4-MeO Ph
ꢀ
4-Br Ph
ꢀ
4-NO2 Ph
ꢀ
3-MeO Ph
ꢀ
2-MeO Ph
ꢀ
2-Me Ph
2-Br Ph
2.8:1[d]
13.2:1[d]
2.0:1[e]
9.4:1[e]
2.7:1[e]
1.9:1[e]
1.9:1[e]
ꢀ
furyl
LA-catalyzed allylation of al-
dehydes with allyl stannanes
and allyl silanes proceeds
through an open transition
state.[1] We decided to use cyclo-
hexadienyl titanium compounds,
a-naphthyl
b-naphthyl
PhCH=CH
PhCꢂC
2 s
2t
C9H19CꢂC
[a] d.r., diastereomeric ratio. [b] Ratio determined by 1H NMR spectroscopy. [c] n.d., not determined.
which are known to form rigid [d] Ratio determined by GC analysis. [e] Ratio determined by HPLC analysis.
4172
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org
Chem. Eur. J. 2004, 10, 4171 4185

Cyclohexadienyl Ti in Stereoselective Synthesis
4171 4185
Table 2. Reaction of 1, 9, and 10 with various aldehydes.
in high yield with good stereo-
selectivity (d.r.=6.5:1, en-
try 14). better result was
A
obtained by using benzaldehyde
(d.r.=9:1, entry 15). Treatment
ꢀ
ꢀ
of 4-MeO PhCHO and 4-Me
PhCHO with 6 afforded 2g and
2h, respectively, with excellent
selectivities (d.r.=32:1 for 4-
R
Reagent
Product
Yield
[%]
d.r.
(syn:anti)
e.r.
ꢀ
MeO PhCHO, entries 16 and
1
2
3
4
5
6
7
8
Ph
Ph
Ph
1
9
10
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2d
2d
2d
2g
2h
2i
83
83
40
82
63
94
58
61
56
92
72
96
81
93
86
83
40[d]
49[f]
>99:1[a]
8:1[a]
98:2[a]
ꢀ
17). Allylation of 4-Br PhCHO
90.5:9.5[a]
89.5:10.5[a]
95:5[a]
led to 2i with only moderate
stereocontrol (d.r.=2.5:1, en-
try 18).
mechanism from an ionic to a
single-electron-transfer (SET)
process probably occurred for
this aldehyde.[16] Indeed, reac-
tion of 6 with SET substrate 4-
24:1[a]
>99:1[a]
>99:1[b]
>99:1[a]
>99:1[a]
>99:1[a]
>99:1[a]
>99:1[c]
98:2[a]
ꢀ
4-Me Ph
4-MeO Ph
4-Br Ph
3-MeO Ph
2-MeO Ph
2-Me Ph
2-Br Ph
furyl
a-naphthyl
b-naphthyl
PhCH=CH
PhCꢂC
C9H19CꢂC
Et
95:5[b]
ꢀ
A
change in the
97:3[a]
ꢀ
97:3[b]
ꢀ
2k
2l
>99:1[a]
96:4[a]
ꢀ
ꢀ
9
2m
2n
2o
2p
2q
2r
2 s
2t
2a
2u
>99:1[c]
93:7[b]
ꢀ
10
11
12
13
14
15
16
17
18
>99:1[b]
>99:1[b]
>99:1[b]
>99:1[b]
>99:1[b]
>99:1[a]
>99:1[a]
>99:1[b]
90:10[b]
90:10[b]
99:1[b]
ꢀ
NO2 PhCHO gave 2j with low
selectivity
(d.r.=1.9:1,
en-
try 19). Excellent stereocon-
trol was achieved with ortho-
substituted benzaldehyde deriv-
atives (entries 21 and 22). Use
of the Br congener again result-
ed in only moderate selectivity
(entry 23). Furfural and b-naph-
98.5:1.5[b]
91:9[e]
C5H11
92:8[a]
[a] Ratio determined by GC analysis. [b] Ratio determined by HPLC analysis. [c] Determined by GC analysis
after transformation into 2d (tBuLi, THF, ꢀ788C; H2O). [d] The 1,4-diene 5a was formed as a side product
and could not be separated from the product. 2a:5a=89:11. [e] Determined by GC analysis after oxidation to
(R)-1-phenylethanol. [f] The 1,4-diene 5u was formed as a side product and could not be separated from the
thaldehyde afforded good selec- product. 2u:5u=88:12.
tivities, whereas a-naphthalde-
hyde and cinnamaldehyde pro-
vided moderate selectivities (entries 24 27). Alkynals react-
ed with low selectivity (entries 28 and 29). These syn selec-
tivities can be explained by the occurrence of a six-
membered chair transition state 8 in which the R group of
the aldehyde is located in a pseudoequatorial position.[1]
With a protocol for the diastereoselective addition of 1,4-
cyclohexadienes to aldehydes in hand, we attempted the
challenging task of differentiating between the enantiotopic
double bonds in the cyclohexadienyl Ti compounds. Duthal-
er has successfully used 2,2-dimethyl-a,a,a’,a’-tetraphenyl-
1,3-dioxolandimethanol (TADDOL)-derived[17] allyl Ti de-
rivatives in highly enantioselective allylations.[18] We pre-
pared the analogous chiral Ti cyclohexadienyl compound 1
and found that the reaction of 1 with benzaldehyde (THF,
ꢀ788C) occurs with excellent diastereoselectivity (syn:anti>
99:1). A promising enantioselectivity was also measured
(enantiomeric ratio, e.r.=91:9, chiral GC) but syn-2d was
formed in low yield (19%). Some decomposition of 1 proba-
bly occurred at ꢀ788C; when the same reaction was carried
out at a lower temperature (ꢀ100 to ꢀ1108C, THF/Et2O)
syn-2d was produced in 83% yield (syn:anti>99:1) with
high enantioselectivity (e.r.=98:2, Table 2, entry 1).
Scheme 2. Chiral cyclohexadienes 1, 9, and 10, tested in the desymmetri-
zation of 1,4-cyclohexadiene.
treatment with benzaldehyde under analogous conditions
(40% yield, syn:anti=24:1, entry 3).[20] However, only mod-
erate enantioselectivity was obtained (e.r.(syn)=89.5:10.5).
All further experiments were conducted with Ti derivative
1.
Compound 1 reacted with para, meta, and ortho-substitut-
ed benzaldehyde derivatives with excellent diastereoselectiv-
ity and high enantioselectivity (Table 2, entries 4 10). In
contrast to 6, chiral Ti reagent 1 reacted with Br-substituted
aromatic aldehydes with excellent stereoselectivity (entries 6
and 10). The SET pathway is clearly not a problem in reac-
tions with 1. a-Naphthaldehyde and phenylpropargyl alde-
hyde reacted with 1 with ™perfect∫ stereoselectivity, whilst
furfural and b-naphthaldehyde provided lower, although
good, enantioselectivities and excellent diastereoselectivities
(entries 11 14). Reaction of 1 with alkynals provided the
corresponding dienes in good yields with high stereoselectiv-
We also tested the isopropoxy Ti derivative 9 (Scheme 2)
in the desymmetrization reaction.[19] Compound 9 provided
lower selectivities than 1 upon reaction with benzaldehyde
(83% yield, syn:anti=8:1, e.r.(syn)=90.5:9.5, entry 2).
Chiral B-cyclohexadienyldiisopinocampheylborane (10) af-
forded a moderate yield with good diastereoselectivity upon
Chem. Eur. J. 2004, 10, 4171 4185
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4173

A. Studer et al.
FULL PAPER
ities (entries 15 and 16). Linear aliphatic aldehydes such as
propanal and hexanal gave slightly lower yields but excel-
lent diastereoselectivities and good enantioselectivities (en-
tries 17 and 18). The 1,4-dienes 5a and 5u were formed as
side products of these reactions.
The absolute configuration for all the major isomers of
the new compounds was assigned by considering the rearo-
matization of 2a (Pd(OAc)2/Cu(OAc)2, MeOH), which led
to (R)-1-phenyl-ethanol (e.r.=91:9). This reaction shows
that, in analogy to the Duthaler allylation, addition of 1
occurs on the Si face of the aldehyde.
were obtained. Reaction with TMSI and subsequent treat-
ment with PhCHO provided the diene 2d in 70% yield.
TMSCl activation resulted in excellent diastereoselectivity
(syn:anti>99:1) but enantioselectivity dropped slightly
(e.r.=94:6) compared to that achieved with our original
protocol. The best results were obtained with TMSOTf. The
diene 2d was isolated in 71% yield with ™perfect∫ diastereo-
selectivity (syn:anti>99:1) and an enantiomeric ratio of
97:3.
We studied the reactivation of dimer 11 in detail by using
1H NMR spectroscopy. As can be seen in Figure 1a, reaction
of 11 with TMSCl at room temperature produced the corre-
sponding chloride 12a (typical signals: singlet at d=
6.40 ppm and doublets at d=5.10 and 4.93 ppm, respective-
ly). The reaction was stopped after 240 minutes. Along with
the signals corresponding to the desired chloride, a singlet
was observed at d=6.32 ppm, caused by the presence of an
unidentified Ti complex. Doublets occurred at d=5.00 and
4.89 ppm, which indicates that reactivation with TMSCl is
not complete after 4 h. The side product was tentatively as-
signed as silyloxy TADDOLate 12b, which we propose as
an intermediate formed on the way to 12a. A repeat NMR
experiment clearly showed that a reaction time of 13 h is
necessary to complete the transformation of 12b into chlo-
ride 12a (Figure 1b). This long reaction time for the genera-
tion of 12a was taken into account and the original TMSCl
experiment was repeated (TMCSCl and 11 were stirred for
18 h before addition of the lithiated cyclohexadiene). Enan-
tioselectivity increased to 98:2 with this increase in reaction
time.
The stable Ti complex 11 was formed during workup.[21]
Complex 11 is apolar and can readily be isolated by chroma-
tography (60 80%). The complex can also be prepared
from the corresponding chloride 12a by treatment of the
chloride with saturated aqueous NaHCO3. We envisioned
that this complex could be used as a bench-stable precursor
for the chiral cyclohexadienyl Ti complex 1. Since stoichio-
metric amounts of the chiral Ti compound are needed in
each experiment, recovery of this compound is a very impor-
tant issue.
Compound 11 does not react with lithiated cyclohexa-
diene and was therefore transformed in situ into a more re-
active species. The electrophiles TMSCl, TMSI, MeOTf, and
TMSOTf were used to generate the corresponding Ti com-
plexes 12 14. To this end, 11 (in THF/Et2O) was treated
with 2 equiv alkylating reagent (1 3 h) at room temperature.
Transmetalation and desymmetrization were performed by a
method analogous to that described above (Scheme 3), with
benzaldehyde as the aldehyde. In these reactions benzalde-
hyde was used as electrophile.
In contrast to TMSCl reactivation, treatment of 11 with
TMSOTf (!14) leads to complete reactivation after five mi-
nutes (Figure 1c). Reaction of 11 with TMSI to generate 13
is a clean process and is also complete after five minutes
(1H NMR spectra not shown). The allylation reaction with
13 occurs with a lower enantioselectivity than that with 12;
we do not yet understand why.
We initially applied our new method to the synthesis of
nephrosteranic acid.[22] We presented the synthesis of scale-
mic nephrosteranic acid (ee=83.5%) in a previous commu-
nication.[10] Our studies have revealed that alkynals provide
far better stereoselectivities in the key desymmetrization re-
action than aliphatic aldehydes (see Table 2). We therefore
decided to use aldehyde 15[23] in the reaction with 1. Reduc-
tion of the triple bond at a later stage in the synthesis leads
to the desired linear unsaturated alkyl chain of nephroster-
anic acid.
Treatment of 1 with aldehyde 15 provided 2t (83%, syn:
anti>99:1, e.r.=98.5:1.5, see Table 2, entry 16). The Os-
mediated dihydroxylation/diol cleavage protocol reported in
our previous communication could be replaced by a more
convenient ozonolysis to convert 2t into the corresponding
lactol (Scheme 4). The triple bond in the side chain of the
crude lactol was hydrogenated (H2, Pd/C) to form 16. Crude
16 was oxidized to g-butyrolactone 17 under Jones condi-
tions (21% overall, steps b d). Methylation by a literature
procedure[22c] afforded (+)-nephrosteranic acid (89% after
recrystallization, 15.5% overall yield, [a]D25 =++27.38, c=0.97
in CHCl3); ref. [22a]: [a]D25 =+27.28, c=1.45 in CHCl3). We
Scheme 3. Reuse of dimer 11. a) TMSCl, TMSI, or TMSOTf in THF/
Et2O.
Regeneration of the active complex with TMSCl (room
temperature for 3 h) and subsequent transmetalation and re-
action with PhCHO afforded the desired diene 2d in 68%
yield. Diastereoselectivity remained high (syn:anti>99:1)
but enantioselectivity dropped (e.r.=93:7) compared to that
achieved with our original protocol (e.r.=98:2, see Table 2,
entry 1). The desired diene was not formed when MeOTf
was used as the activating species; unidentified products
4174
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4171 4185

Cyclohexadienyl Ti in Stereoselective Synthesis
4171 4185
1
Figure 1. Reactivation of dimer 11 with TMSCl (a and b) and TMSOTf (c) was monitored by H NMR spectroscopy. All experiments were carried out in
[D8]THF.
obtained crystals suitable for x-ray analysis. The structure of
nephrosteranic acid is shown in Figure 2.[24]
Compound 1 was trapped with aldehyde 18a to give diene
19a in 66% yield (syn:anti>99:1; e.r. not determined). Ozo-
nolysis and subsequent hydrogenation gave lactole 20a.
Jones oxidation led to the corresponding acid, which was im-
mediately reduced by addition of BH3¥SMe2 to afford alco-
hol 21a (13% for steps b e). The Appel reaction (!22a,
79%) and radical debromination with our recently intro-
We next applied our method to other g-butyrolactones.
We targeted the compounds trans-whisky and trans-cognac
lactone.[25] The syntheses of these compounds are depicted
in Scheme 5. The first four steps were conducted as de-
scribed for the synthesis of nephrosteranic acid.
Chem. Eur. J. 2004, 10, 4171 4185
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4175

A. Studer et al.
FULL PAPER
duced tin hydride substitute 23[13] gave (+)-trans-whisky lac-
tone (74%; e.r.=97:3, as determined by chiral GC).
The homologous trans-cognac lactone was prepared by
using the same reaction sequence. Reaction of 1 with alde-
hyde 18b gave diene 19b (57%, syn:anti>99:1; e.r. not de-
termined). Ozonolysis, hydrogenation, Jones oxidation, and
reduction by treatment with BH3¥SMe2 afforded alcohol 21b
in 21.5% overall yield (steps b e). The Appel reaction (!
22b, 67%) and dehalogenation (95%) led to trans-cognac
lactone (e.r.=97.5:2.5, chiral GC).
Conclusion
Scheme 4. Synthesis of nephrosteranic acid: a) THF/Et2O, ꢀ100 to
ꢀ1108C; b) O3, Me2S, CH2Cl2, ꢀ788C; c) H2, Pd/C, EtOH; d) CrO3/
H2SO4, acetone; e) NaHMDS, MeI, THF. HMDS=1,1,1,3,3,3-hexame-
thyldisilazane.
We have reported the first examples of stereoselective cyclo-
hexadienyl transfer to aldehydes from 3-metalated 1,4-cyclo-
hexadienes. Cyclohexadienyl transfer from 3-siylated and 3-
stannylated 1,4-cyclohexadienes to aldehydes in the pres-
ence of Lewis acids could not be performed with high selec-
tivity. Cyclohexadienyl Ti coumpounds underwent the same
reaction with excellent diastereoselectivity. Moreover, the
use of chiral cyclohexadienyl Ti TADDOLate 1 allows dif-
ferentiation between the two enantiotopic double bonds of
the corresponding cyclohexadiene. Excellent diastereo- and
enantioselectivities were obtained upon reaction of 1 with
aromatic aldehydes. Lower but still satisfactory selectivities
were obtained with aliphatic aldehydes. Compound 1 react-
ed with alkynals with good enantioselectivities. Alkynals can
be used as surrogates for aliphatic aldehydes.
We have shown that bench-stable dimer 11, which is read-
ily obtained after workup of the cyclohexadienyl transfer,
can be reused. This is an important result since stoichiomet-
ric amounts of Ti complex are needed for the desymmetriza-
tion reactions. The reactivation of 11 can be monitored by
1H NMR spectroscopy. We believe that this protocol can
also be used for the parent Duthaler allylation.
Figure 2. X-ray structure of nephrosteranic acid.
Functionalized 1,3-cyclohexadienes are very useful build-
ing blocks for the preparation of biologically important g-
butyrolactones. (+)-Nephrosteranic acid, (+)-trans-whisky
lactone, and (+)-trans-cognac lactone were successfully pre-
pared by our new method. These functionalized 1,3-cyclo-
hexadienes can be used as substrates in Diels Alder reac-
tions for the preparation of complex rigid compounds. Such
reactions are currently being studied in our laboratory.
Experimental Section
General: All reactions involving air- or moisture-sensitive reagents or in-
termediates were carried out in heat-gun-dried glassware under an argon
atmosphere. THF was freshly distilled from potassium under argon. Di-
ethylether (Et2O) was freshly distilled from K/Na under argon. Dichloro-
methane (CH2Cl2) was freshly distilled from phosphorus(v)oxide (P2O5).
Triethylamine (Et3N) was distilled from CaH2 and stored under argon.
TMEDA was distilled from Na and stored under argon over activated
4-ä molecular sieves. All other solvents and reagents were purified ac-
cording to standard procedures or were used as received from Aldrich or
Fluka. 1H and 13C NMR spectroscopy: Bruker AMX 500, AMX 400, AC
300, or ARX 200 spectrometer; chemical shifts, d, were measured in ppm
relative to CHCl3 (7.26 ppm), which was used as an external standard.
Polarimetry: optical rotations were measured on a Perkin Elmer 241 po-
Scheme 5. Synthesis of trans-whisky lactone and trans-cognac lactone:
a) THF/Et2O, ꢀ100 to ꢀ1108C; b) O3, Me2S, CH2Cl2, ꢀ788C; c) H2, Pd/
C, EtOH; d) CrO3/H2SO4, acetone, room temperature; e) BH3¥SMe2,
THF, 08C; f) CBr4, PPh3, CH2Cl2, room temperature; g) 23, AIBN,
hexane, 808C. AIBN=azobisisobutyronitrile.
4176
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4171 4185

Cyclohexadienyl Ti in Stereoselective Synthesis
4171 4185
larimeter. TLC: Merck silica gel 60 F254 plates; detection with UVlight
or by dipping into a solution of KMnO4 (1.5 g in 400 mL H2O, 5 g
NaHCO3) or a solution of Ce(SO4)2¥H2O (10 g), phosphormolybdic acid
hydrate (25 g), and conc. H2SO4 (60 mL) in H2O (940 mL), followed by
heating. Flash column chromatography (FC): Merck or Fluka silica gel
60 (40 63 mm) at approximately 0.4 bar. GC: Hewlett Packard 5890 chro-
matograph with a Supelco b-DEX 120 (whisky and cognac lactone) or
Supelco g-DEX 120 column (all other compounds). Temperature pro-
gramme (unless otherwise stated) for g-DEX: 5 min at 1258C (T0), then
a temperature gradient: rate, 1.38Cminꢀ1; final temperature, 2008C (TE).
Temperature programme for b-DEX: 1308C (T0), no temperature gradi-
ent. HPLC: Gynkotek UVD160S instrument, High Precision Pump
Model 480, Chiracel OD column, eluent: 2% iPrOH in nhexanes
(1 mLminꢀ1). Retention times recorded when HPLC or GC analysis was
used for the determination of enantiomer ratios are given below with the
details of the relevant experiment. Gynkotek Software (Version 5.50)
was used for data analysis. Melting points: B¸chi 510 apparatus, uncor-
rected. IR spectroscopy: Perkin Elmer 782 or Bruker IFS-200 spectro-
photometer. MS: VG Tribid, Varian CH7 instruments (EI); IonSpec
Ultima, Finnigan MAT TSQ 700, or Finnigan MAT 95S spectrometer
(ESI); m/z (percentage of basis peak) recorded.
General procedure 5 (GP 5): Allylation with titanate 6: Titanium(iv) iso-
propoxide (Ti(O-iPr)4; 1.3 equiv) was added to a solution of cyclohexa-
dienyllithium (1.2 equiv, 0.2m in THF, prepared according to GP 1) at
ꢀ788C. The resulting brown mixture was stirred for 10 min at this tem-
perature. An aldehyde (1.0 equiv) was then added. The brown reaction
mixture was stirred for 1 h at ꢀ788C and turned yellow. Water and
MTBE were added and a white precipitate formed. The mixture was stir-
red for 15 min at room temperature before the phases were separated.
The aqueous layer was extracted twice with MTBE, washed (NaCl, aq.
sat.), and dried (MgSO4). The solvents were removed in vacuo. The alco-
hols 2 were purified by FC.
General procedure 6 (GP 6): Reaction of dimer 11 with various electro-
philes: The electrophile (2.0 mmol) was added to a solution of dimer 11
(1170 mg, 1.0 mmol) in Et2O (10 mL) and THF (2 mL) under argon at
room temperature. The reaction mixture was stirred for 1 18 h then
cooled to ꢀ1108C. A solution of cyclohexadienyllithium (1.90 mmol, pre-
pared according to GP 1) was slowly added and the temperature was
kept below ꢀ1008C. The resulting brown solution was stirred for 20
60 min at ꢀ1108C. Benzaldehyde (101 mg, 0.95 mmol) was added. After
3 h at ꢀ100 to ꢀ1108C the reaction mixture was treated with water
(10 mL). MTBE (20 mL) was added and the reaction mixture was al-
lowed to warm to room temperature. The phases were separated and the
aqueous layer was extracted twice with MTBE. The combined organic
layers were washed with brine and dried (MgSO4). The solvents were re-
moved in vacuo. Alcohol 2d was purified by FC.
General procedure 1 (GP 1): Preparation of cyclohexadienyllithium:
sBuLi (1.08 equiv, 1.3 1.46m in hexanes) and TMEDA (1.08 equiv) were
added to a solution of 1,4-cyclohexadiene (1.0 equiv) in THF (ca. 0.2m)
cooled to ꢀ788C. The resulting yellow solution was stirred for 60 90 min
at this temperature and was then used for transmetalation reactions.
2,5-Cyclohexadienyl(trimethyl)silane (3): Trimethylchlorosilane (9.09 mL,
47 mmol) was added to a solution of cyclohexadienyllithium (43 mmol,
prepared according to GP 1). The yellow reaction mixture decolorized.
The mixture was allowed to warm to room temperature and was then
stirred for 1 h. Water (15 mL) and Et2O (50 mL) were added and the
phases were separated. The aqueous layer was extracted twice with Et2O
(2î20 mL). The combined organic phases were washed with saturated
NH4Cl and NaCl solutions (25 mL each) and dried (MgSO4). The sol-
vents were removed in vacuo. Distillation (698C, 34 mbar) of the residue
yielded silane 3 (5.62 g, 88%) as a clear, colorless liquid. 1H NMR
(200 MHz, CDCl3): d=5.73 5.64 (m, 2H; CH2CH), 5.58 5.50 (m, 2H;
SiCHCH), 2.74 2.64 (m, 2H; CH2CH), 2.28 2.16 (m, 1H; CHSi),
0.03 ppm (s, 6H; Si(CH3)2). The spectral data are in accordance with the
literature values.[26]
General procedure 2 (GP 2): Allylation with titanate 1: A suspension of
CpTiCl3 (2.1 equiv) in dry diethylether (0.1m) was treated with
TADDOL (2.1 equiv) at room temperature under argon, with all mois-
ture excluded. The reaction mixture was stirred for 1 min. A solution of
NEt3 (4.6 equiv) in diethylether (0.5m) was added over a period of
15 min at room temperature and the formation of a white solid was ob-
served. The resulting suspension was stirred at room temperature over-
night. Moisture and oxygen were excluded whilst the precipitate was sep-
arated from the liquid phase and the solid was then washed twice with
dry ether. Solvent was removed in vacuo until a concentration of approx-
imately 0.2m was reached. The resulting solution was cooled to between
ꢀ100 and ꢀ1108C. A solution of cyclohexadienyllithium (2.0 equiv) pre-
pared according to GP 1 was added slowly enough to keep the tempera-
ture below ꢀ1008C. Once all the cyclohexadienyllithium solution had
been added, the brown reaction mixture containing 1 was stirred for
15 min at ꢀ100 to ꢀ1108C. An aldehyde (1.0 equiv) was slowly added
and the temperature was maintained at ꢀ100 to ꢀ1108C. After 3 h at
this temperature the reaction mixture was treated with water (10 mL).
Methyl tbutyl ether (MTBE; 20 mL) was added and the reaction mixture
was allowed to warm to room temperature. The phases were separated
and the aqueous layer was extracted twice with MTBE. The combined
organic layers were washed with brine and dried (MgSO4). The solvents
were removed in vacuo and the alcohols 2 were purified by FC.
2,5-Cyclohexadienyl(tributyl)stannane (4): Tributyltin chloride (4.47 mL,
16.5 mmol) was added to a solution of cyclohexadienyllithium (15 mmol,
prepared according to GP 1) and the yellow reaction mixture decolor-
ized. The mixture was allowed to warm to room temperature and was
stirred for 1 h. Water (15 mL) and Et2O (50 mL) were added and the
phases were separated. The aqueous layer was extracted twice with Et2O
(î20 mL) then the combined organic phases were washed with saturated
NH4Cl and NaCl solutions (25 mL each) and dried (MgSO4). The sol-
vents were removed in vacuo. FC (P/MTBE 50:1) yielded 4 (5.46 g,
99%) as a colorless clear liquid. 1H NMR (200 MHz, CDCl3): d=5.82
5.64 (m, 2H; CH2CH), 5.40 5.28 (m, 2H; SnCHCH), 3.05 2.48 (m, 3H;
CHSn), 1.59 1.19 (m, 18H; Sn((CH2)3CH3)3), 0.96 0.76 ppm (m, 9H;
CH3). 13C NMR (50 MHz, CDCl3): d=128.7, 119.0, 29.2, 27.5, 26.4, 13.7,
10.1, 9.5 ppm. ESI-MS: 369 (12, [M]+), 323 (100), 291 (40), 267 (58), 235
(8), 211 (25), 179 (6), 102 (16).
General procedure 3 (GP 3): Allylation with silane 3: Silane 3 (1.0
1.3 equiv) was added to a solution of an aldehyde (0.1 0.2m) in CH2Cl2
at ꢀ788C. The resulting solution was stirred for 5 min and a Lewis acid
was added. After a given reaction time, the reaction was terminated by
the addition of KF (10% aq. soln.) or NH4Cl (sat. aq.) solution. CH2Cl2
was added and the phases were separated. The aqueous layer was ex-
tracted twice with MTBE. The combined organic layers were washed
with NH4Cl (aq. sat.) and NaCl (aq. sat.) solutions. The resulting mixture
was dried (MgSO4) and the solvents were removed in vacuo. The alco-
hols 2 were purified by FC.
rac-1-Cyclohexa-2,4-dien-1-yl-propan-1-ol (2a): Homoallylic alcohol 2a
was obtained from silane 3 (0.76 g, 5.0 mmol), TiCl4 (0.95 g, 5.0 mmol),
and propanal (0.36 mL, 5.0 mmol) by applying GP 3. FC (P/MTBE 2.5:1)
yielded 2a (247 mg, 36%) as a colorless oil. d.r. (syn:anti)=1.6:1, deter-
mined by GC analysis (T0 =1008C, rate: 0.38Cminꢀ1); retention times:
major diastereoisomer: 23.53 min (both enantiomers), minor diaster-
eoisomer: enantiomer 1: 24.11 min, enantiomer 2: 24.53 min. IR (neat):
n˜ =3375(s), 3037(s), 2962(s), 2934(s), 2876(s), 1462(m), 1429(w), 1410(w),
General procedure 4 (GP 4): Allylation with stannane 4: Stannane 4
(1.0 1.3 equiv) was added to a solution of an aldehyde (0.1 0.2m) in
CH2Cl2 at ꢀ788C. The resulting solution was stirred for 5 min and
BF3¥OEt2 (1.0 1.3 equiv) was added. After 1 h at ꢀ788C, KF (10% aq.
soln.) was added. A white precipitate was removed by filtration 5 min
later and CH2Cl2 was added. The phases were separated and the aqueous
layer was extracted twice with MTBE. The combined organic layers were
washed with NH4Cl (aq. sat.) and NaCl (aq. sat.) solutions. The resulting
mixture was dried (MgSO4) and the solvents were removed in vacuo. The
alcohols 2 were purified by FC.
1376(w), 1109(m), 1065(m), 1037(m), 968(s), 919(m), 686(s) cmꢀ1
.
1H NMR (300 MHz, CDCl3): d=6.04 5.95 (m, 1H; vinyl H), 5.91 5.74
(m, 2H; vinyl H), 5.69 5.63 (m, 1H; vinyl H), 3.60 3.53 (m, 1H; CHOH,
syn isomer), 3.53 3.45 (m, 1H; CHOH, anti isomer), 2.43 2.17 (m, 2H;
CHCH2), 1.64 1.39 (m, 3H; OH, CH2CH3), 0.96 ppm (t, J=7.5 Hz, 3H;
CH3). 13C NMR (75 Hz, CDCl3, syn isomer): d=127.5 (CH), 126.1 (CH),
125.3 (CH), 123.6 (CH), 74.6 (CH), 38.4 (CH), 26.9 (CH2), 23.1 (CH2),
10.1 ppm (CH3). 13C NMR (75 MHz, CDCl3, anti isomer): d=126.3 (CH),
125.6 (CH), 125.4 (CH), 123.9 (CH), 76.4 (CH), 34.9 (CH), 27.0 (CH2),
Chem. Eur. J. 2004, 10, 4171 4185
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4177

A. Studer et al.
FULL PAPER
25.7 (CH2), 10.2 ppm (CH3). MS (EI): 138 (1, [M]+), 107 (4), 91 (8), 80
(100), 79 (56), 59 (20), 41 (7); elemental analysis (%) calcd for C9H14O
(138.21): C 78.21, H 10.21; found: C 78.24, H 10.21.
3462(m), 3038(m), 2954(s), 2869(s), 1480(m), 1396(m), 1364(m), 1097(m),
1011(m), 923(w), 704(m), 648(w) cmꢀ1 1H NMR (300 MHz, CDCl3): d=
.
6.04 5.91 (m, 1H; vinyl H), 5.91 5.73 (m, 2H; vinyl H), 5.64 5.53 (m,
1H; vinyl H), 3.40 (brs, 1H; CHOH, anti isomer), 3.19 3.12 (m, 1H;
CHOH, syn isomer), 2.75 2.60 (m, 1H; CH2CH), 2.51 2.20 (m, 2H;
CH2CH), 1.75 (brd, J=4.2 Hz, 1H; OH), 0.94 ppm (s, 9H; C(CH3)3).
13C NMR (75 MHz, CDCl3): d=127.0 (CH), 126.3 (CH), 126.1 (CH),
123.9 (CH), 83.5 (CH), 35.9 (C), 34.4 (CH), 30.1 (CH2), 26.6 ppm (CH3).
MS (EI): 164 (5, [MꢀH2]+), 138 (7), 125 (13), 107 (46), 95 (49), 91 (23),
87 (51), 80 (87) 79 (98), 57 (100), 43 (28), 41 (48). HRMS ([MꢀH2]+):
calcd for C11H16O: 164.1202; found: 164.1195.
Homoallylic alcohol 2a was obtained from stannane
4 (738 mg,
2.0 mmol), BF3¥OEt2 (0.25 mL, 2.0 mmol), and propanal (0.14 mL,
2.0 mmol) by applying GP 4. FC (P/MTBE 2.5:1) yielded 2a (207 mg,
75%) as a colorless oil. d.r. (syn:anti)=1.7:1, determined by 1H NMR
spectroscopy.
GP
4 was used to obtain homoallylic alcohol 2a from stannane 4
(738 mg, 2.0 mmol), AlCl3 (264 mg, 2.0 mmol), and propanal (0.14 mL,
2.0 mmol). FC (P/MTBE 2.5:1) yielded 2a (69 mg, 25%) as a colorless
1
GP 5 was used to obtain homoallylic alcohol 2c from cyclohexadienyl
lilthium (2.4 mmol, prepared according to GP 1), titanium(iv) isopropox-
ide (738 mg, 2.6 mmol), and pivalaldehyde (168 mg, 2.0 mmol). FC (P/
MTBE 10:1) yielded 2c (285 mg, 87%) as a colorless oil. d.r. (syn:anti)=
oil. d.r. (syn:anti)=2.5:1, determined by H NMR spectroscopy.
GP 5 was used to obtain homoallylic alcohol 2a from cyclohexadienyl-
lithium (2.4 mmol, prepared according to GP 1), titanium(iv) isopropox-
ide (738 mg, 2.6 mmol), and propanal (116 mg, 2.0 mmol). FC (P/MTBE
2.5:1) yielded 2a (251 mg, 91%) as a colorless oil. d.r. (syn:anti)=11.0:1,
1
6.5:1, determined by H NMR spectroscopy.
1
rac-1-Cyclohexa-2,4-dien-1-yl-(phenyl)methanol (2d): GP 3 was used to
obtain homoallylic alcohol 2d from silane 3 (304 mg, 2.0 mmol), TiCl4
(0.22 mL, 2.0 mmol), and benzaldehyde (0.20 mL, 2.0 mmol). The reac-
tion was stopped after 5 min by addition of NH4Cl (sat. aq.). FC (P/
MTBE 10:1) yielded 2d (115 mg, 31%) as a colorless solid. d.r. (syn:an-
ti)=1.6:1, determined by 1H NMR spectroscopy. M.p.: 26 288C. IR
(nujol): n˜ =3385(w), 2925(s), 1456(s), 1377(m), 1151(w), 1016(m), 970(m),
determined by H NMR spectroscopy.
(1R)-1-[(1R)-Cyclohexa-2,4-dien-1-yl]propan-1-ol (2a): GP 2 was used
to obtain homoallylic alcohol 2a from CpTiCl3 (976 mg, 4.45 mmol),
TADDOL (2.08 g, 4.45 mmol), NEt3 (990 mg, 1.30 mL, 9.79 mmol), cyclo-
hexadienyllithium (4.20 mmol, prepared according to GP 1), and propa-
nal (122 mg, 2.1 mmol). FC (P/MTBE 10:1) yielded 2a (116 mg, 40%) as
a colorless oil. d.r. (syn:anti)>99:1, determined by GC analysis; retention
times: only diastereoisomer: 27.43 min. GC and NMR analysis showed
that 11% of the product consisted of isomeric cyclohexa-2,5-dienyl-
propan-1-ol (5a; retention time: 28.36 min).
758(m), 701(m), 680(m) cmꢀ1 1H NMR (300 MHz, CDCl3): d=7.43 7.25
.
(m, 5H; Ph-H), 5.99 5.87 (m, 2H; vinyl H), 5.84 5.75 (m, 1H; vinyl H),
5.43 5.33 (m, 1H; vinyl H), 4.66 (d, J=7.6 Hz, 1H; CHOH), 2.71 2.68
(m, 1H; CHCH2), 2.60 2.22 (m, 2H; CHCH2), 2.12 1.92 ppm (m, 1H;
OH). 13C NMR (75 MHz, CDCl3): d=142.9 (C), 128.4 (CH), 128.3 (CH),
127.6 (CH), 127.0 (CH), 126.7 (CH), 126.4 (CH), 126.0 (CH), 125.6
(CH), 123.8 (CH), 75.6 (CH), 40.3 (CH), 24.1 ppm (CH2). MS (EI): 184
(5, [MꢀH2]+), 108 (85), 107 (100), 80 (87), 79 (97), 78 (19), 77 (37).
HRMS ([MꢀH2]+): calcd for C13H12O: 184.0888; found: 184.0886; ele-
mental analysis (%) calcd for C13H14O (186.25): C 83.83, H 7.58; found:
C 83.53, H 7.71.
The enantiomeric ratio was determined after oxidation of 2a to 1-phenyl-
1-propanol: 2a (33 mg, 0.21 mmol) was dissolved in dry methanol
(1 mL). Cu(OAc)2 (13 mg, 0.072 mmol) and Pd(OAc)2 (13 mg,
0.058 mmol) were added to the solution at room temperature. Moisture
was excluded and the reaction mixture was stirred overnight under at-
mospheric conditions. The solvent was removed in vacuo and CH2Cl2
(5 mL) was added. The suspension was filtered through a short silica pad
and the solvent was again removed in vacuo. FC (P/MTBE 10:1) yielded
an analytically pure sample for GC analysis. Enantiomeric ratio=93:7
(GC analysis: T0 =1008C, rate: 0.38Cminꢀ1; retention times: enantiomer
1: 35.66 min, enantiomer 2: 36.34 min). The R enantiomer eluted first
and was the major enantiomer. The retention times were confirmed after
comparison with an authentic sample (Aldrich) of the R enantiomer.
GP 4 was used to obtain homoallylic alcohol 2d from stannane 4
(738 mg, 2.0 mmol), BF3¥OEt2 (0.25 mL, 2.0 mmol), and benzaldehyde
(0.20 mL, 2.0 mmol). FC (P/MTBE 10:1) yielded 2d (430 mg, 77%) as a
colorless solid. d.r. (syn:anti)=1:3, determined by 1H NMR spectroscopy.
GP 5 was used to obtain homoallylic alcohol 2d from cyclohexadienyl-
lithium (12 mmol, prepared according to GP 1), titanium(iv) isopropox-
ide (3.69 g, 13 mmol), and benzaldehyde (1.06 g, 10.0 mmol). FC (P/
MTBE 10:1) yielded 2d (1.85 g, 99%) as a colorless solid. d.r. (syn:an-
ti)=9.0:1, determined by GC analysis; retention times: major diaster-
eoisomer: enantiomer 1: 51.00 min, enantiomer 2: 51.28 min; minor dia-
stereoisomer: enantiomer 1: 52.13 min, enantiomer 2: 52.34 min.
rac-1-Cyclohexa-2,4-dien-1-yl-2-methylpropan-1-ol (2b): GP 3 was used
to obtain homoallylic alcohol 2b from silane 3 (304 mg, 2.0 mmol), TiCl4
(0.22 mL, 2.0 mmol), and isobutyraldehyde (0.18 mL, 2.0 mmol). FC (P/
MTBE 2.5:1) yielded 2b (106 mg, 35%) as a colorless oil. d.r. (syn:
anti)=1.6:1, determined by 1H NMR spectroscopy; IR (neat): n˜ =3436(m),
3037(m), 2960(m), 2872(m), 1468(m), 1386(w), 1131(w), 1007(m),
685(m) cmꢀ1 1H NMR (300 MHz, CDCl3): d=6.04 5.93 (m, 1H; vinyl
.
(S)-(1R)-Cyclohexa-2,4-dien-1-yl-(phenyl)methanol (2d): GP 2 was used
to obtain homoallylic alcohol 2d from CpTiCl3 (584 mg, 2.67 mmol),
TADDOL (1.25 g, 2.67 mmol), NEt3 (594 mg, 0.78 mL, 5.87 mmol), cyclo-
hexadienyllithium (2.52 mmol, prepared according to GP 1), and benzal-
dehyde (134 mg, 1.26 mmol). FC (P/MTBE 10:1) yielded 2d (206 mg,
83%) as a colorless solid. [a]D25 =+160.98 (c=1.01 in CHCl3). d.r. (syn:an-
ti)>99:1; e.r.=98:2, determined by GC analysis.
H), 5.91 5.75 (m, 2H; vinyl H), 5.67 5.53 (m, 1H; vinyl H), 3.38 (t, J=
5.7 Hz, 1H; CHOH, syn isomer), 3.22 (t, J=5.7 Hz, 1H; CHOH, anti
isomer), 2.59 2.08 (m, 2H; CHCH2), 1.86 1.69 (m, 1H; CH(CH3)2), 1.54
(brs, 1H; ROH), 1.03 0.79 ppm (m, 6H; CH(CH3)2). 13C NMR (75 MHz,
CDCl3, syn isomer): d=127.7 (CH), 126.1 (CH), 125.5 (CH), 123.6 (CH),
77.7 (CH), 36.0 (CH), 29.9 (CH), 22.8 (CH2), 16.8 ppm (CH3). 13C NMR
(75 MHz, CDCl3, anti isomer): d=126.4 (CH), 126.3 (CH), 125.6 (CH),
123.9 (CH), 78.0 (CH), 35.9 (CH), 30.2 (CH), 26.4 (CH2), 16.8 ppm
(CH3). MS (EI): 152 (7, [M]+), 150 (5, [MꢀH2]+), 107 (59), 80 (100), 79
(80), 78 (27), 73 (26), 55 (13), 43 (21). HRMS ([M]+): calcd for C10H16O:
152.1201; found: 152.1197.
Reactions involving dimer 11: Homoallylic alcohol 2d was obtained by
using GP 6 with TMSCl (317 mg, 2.0 mmol). The reaction mixture was
stirred for 18 h before the transmetalation step and 20 min before the al-
dehyde was added. FC (P/MTBE 10:1) yielded 2d (60 mg, 32%) as a col-
orless solid. d.r. (syn:anti)>99:1; e.r.=98:2, determined by GC analysis.
GP 4 was used to obtain homoallylic alcohol 2b from stannane 4
(738 mg, 2.0 mmol), BF3¥OEt2 (0.25 mL, 2.0 mmol), and isobutyraldehyde
(0.18 mL, 2.0 mmol). FC (P/MTBE 10:1) yielded 2b (138 mg, 45%) as a
colorless oil. d.r. (syn:anti)=1.6:1, determined by 1H NMR spectroscopy.
Homoallylic alcohol 2d was obtained by using GP 6 with TMSI (400 mg,
2.0 mmol). The reaction mixture was stirred for 1 h before the transmeta-
lation step and 1 h before the aldehyde was added. FC (P/MTBE 10:1)
yielded 2d (123 mg, 70%) as a colorless solid. d.r. (syn:anti)>99:1; e.r.=
94:6, determined by GC analysis.
GP 5 was used to obtain homoallylic alcohol 2b from cyclohexadienyl-
lithium (2.4 mmol, prepared according to GP 1), titanium(iv) isopropox-
ide (738 mg, 2.6 mmol), and isobutyraldehyde (144 mg, 2.0 mmol). FC (P/
MTBE 10:1) yielded 2b (276 mg, 91%) as a colorless oil. d.r. (syn:anti)=
Homoallylic alcohol 2d was obtained by using GP 6 with TMSOTf
(444 mg, 2.0 mmol). The reaction mixture was stirred for 1 h before the
transmetalation step and 1 h before the aldehyde was added. FC (P/
MTBE 10:1) yielded 2d (125 mg, 71%) as a colorless solid. d.r. (syn:an-
ti)>99:1; e.r.=97:3, determined by GC analysis.
1
2.9:1, determined by H NMR spectroscopy.
rac-1-Cyclohexa-2,4-dien-1-yl-2,2-dimethylpropan-1-ol (2c): GP
3 was
used to obtain homoallylic alcohol 2c from silane 3 (304 mg, 2.0 mmol),
TiCl4 (0.22 mL, 2.0 mmol), and pivalaldehyde (0.22 mL, 2.0 mmol). FC
(P/MTBE 10:1) yielded 2c (19 mg, 11%) as a colorless oil. IR (neat): n˜ =
rac-1-Cyclohexa-2,4-dien-1-yl-dodecan-1-ol (2e): GP 5 was used to
obtain homoallylic alcohol 2e from cyclohexadienyllithium (6.0 mmol,
prepared according to GP 1), titanium(iv) isopropoxide (1.85 g,
4178
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4171 4185

Cyclohexadienyl Ti in Stereoselective Synthesis
4171 4185
6.5 mmol), and dodecanal (920 mg, 5 mmol). FC (P/MTBE 10:1) yielded
2e (1.27 g, 96%) as a colorless oil. d.r. (syn:anti)=13.3:1, determined by
GC analysis; retention times: major diastereoisomer: 88.68 min; minor
diastereoisomer: 88.90 min. IR (nujol): n˜ =3355(w), 2959(s), 1463(s),
termined by GC analysis: retention times: major diastereoisomer: enan-
tiomer 1: 54.04 min, enantiomer 2: 54.29 min; minor diastereoisomer:
enantiomer 1: 55.02 min, enantiomer 2: 55.27 min). [a]D25 =+137.28 (c=
1.42 in CHCl3).
1376(m), 1303(w), 1065(w), 970(w), 721(m), 686(w) cmꢀ1
.
1H NMR
rac-Cyclohexa-2,4-dien-1-yl-(4-methoxyphenyl)-methanol (2h): GP 5 was
used to obtain homoallylic alcohol 2h from cyclohexadienyllithium
(2.4 mmol, prepared according to GP 1), titanium(iv) isopropoxide
(738 mg, 2.6 mmol), and 4-methoxybenzaldehyde (272 mg, 2.0 mmol). FC
(P/MTBE 10:1) yielded 2h (428 mg, 99%) as a colorless solid. d.r. (syn:-
anti)=32:1, determined by GC analysis; retention times: major diaster-
eoisomer: enantiomer 1: 70.54 min, enantiomer 2: 70.84 min; minor dia-
stereoisomer: enantiomer 1: 71.56 min, enantiomer 2: 71.80 min. M.p.:
488C. IR (neat): n˜ =3360(w), 2924(s), 1611(m), 1584(m), 1515(m),
1463(s), 1376(m), 1254(m), 1176(w), 1112(w), 1033(m), 970(w), 831(m),
(300 MHz, CDCl3): d=5.98 5.93 (m, 1H; vinyl H), 5.89 5.72 (m, 2H;
vinyl H), 5.66 5.60 (m, 1H; vinyl H), 3.67 3.51 (m; CHOH), 2.42 2.15
(m, 3H), 1.61 1.10 (m, 20H), 0.87 ppm (t, J=6.6 Hz, 3H; CH3).
13C NMR (75 MHz, CDCl3): d=127.6 (CH), 126.2 (CH), 125.5 (CH),
123.7 (CH), 73.5 (CH), 38.9 (CH), 34.2 (CH2), 31.9 (CH2), 29.7 29.6 (5î
CH2), 29.3 (CH2), 26.0 (CH2), 23.1 (CH2), 22.7 (CH2), 14.1 ppm (CH3).
MS (EI): 262 (2, [MꢀH2]+), 108 (85), 111 (15), 97 (29), 83 (33), 80 (100),
69 (12), 57 (22), 43 (14). HRMS ([MꢀH2]+): calcd for C18H30O: 262.2297;
found: 262.2292; elemental analysis (%) calcd for C18H32O (264.45): C
81.75, H 12.20; found: C 81.80, H 12.07.
1
682(m), 568(m) cmꢀ1. H NMR (200 MHz, CDCl3): d=7.28 7.23 (m, 1H;
(1R)-1-[(1R)-Cyclohexa-2,4-dien-1-yl]dodecan-1-ol (2e): GP 2 was used
to obtain homoallylic alcohol 2e from CpTiCl3 (2.53 g, 11.55 mmol),
TADDOL (5.40 g, 11.55 mmol), NEt3 (3.37 mL, 25.41 mmol), cyclohexa-
dienyllithium (11.0 mmol, prepared according to GP 1), and dodecanal
(1.01 g, 5.5 mmol). FC (P/MTBE 10:1) yielded 2e (1.14 g, 79%) as a col-
orless oil. d.r. (syn:anti)>99:1, determined by GC analysis; retention
times: only diastereoisomer: 88.63 min. GC and NMR analysis showed
12% of the product to consist of isomeric 1-cyclohexa-2,5-dien-1-yl-do-
decan-1-ol (5e).
ꢀ
ꢀ
ꢀ
Ar H), 7.26 7.23 (m, 2H; Ar H), 6.90 6.86 (m, 2H; Ar H), 5.97 5.75
(m, 3H; vinyl H), 5.39 5.31 (m, 1H; vinyl H), 4.60 (dd, 1H; J1 =7.5, J2 =
2.8 Hz; CHOH), 4.57 (s, 3H; CH3), 2.70 2.24 (m, 3H), 1.81 ppm (d, 1H,
J=3.0 Hz; OH). 13C NMR (75 MHz, CDCl3): d=135.2 (C), 127.9 (CH),
127.1 (2îCH), 125.9 (CH), 125.4 (CH), 124.4 (C), 123.9 (CH), 113.7 (2î
CH), 75.2 (CH), 55.3 (CH3), 40.4 (CH), 24.4 ppm (CH2). MS (EI): 198 (4,
[MꢀH2O]+), 137 (100), 132 (27), 109 (19), 79 (5). HRMS ([MꢀH2O]+):
calcd for C14H14O: 198.1045; found: 198.1043.
(S)-(1R)-Cyclohexa-2,4-dien-1-yl-(4-methoxyphenyl)methanol (2h): GP
2 was used to obtain homoallylic alcohol 2h from CpTiCl3 (570 mg,
2.60 mmol), TADDOL (1.22 g, 2.60 mmol), NEt3 (578 mg, 0.76 mL,
5.72 mmol), cyclohexadienyllithium (2.48 mmol, prepared according to
GP 1), and 4-methoxybenzaldehyde (1.24 mg, 1.24 mmol). FC (P/MTBE
10:1) yielded 2h (168 mg, 0.78 mmol, 63%) as a colorless solid. d.r. (syn:-
anti)>99:1, determined by GC analysis; retention times: only diaster-
eoisomer: 72.01 min; e.r.=95:5, determined by HPLC analysis; retention
times: enantiomer 1: 25.93 min, enantiomer 2: 27.10 min. [a]D25 =+102.58
(c=1.00 in CHCl3).
rac-Cyclohexa-2,4-dien-1-yl(cyclohexyl)methanol (2 f): GP 5 was used to
obtain homoallylic alcohol 2 f from cyclohexadienyllithium (6.0 mmol,
prepared according to GP 1), titanium(iv) isopropoxide (1.85 g,
6.5 mmol), and dodecanal (920 mg, 5 mmol). FC (P/MTBE 10:1) yielded
2 f (226 mg, 59%) as a colorless oil. d.r. (syn:anti)=2.7:1, determined by
GC analysis; retention times: major diastereoisomer: enantiomer 1:
42.58 min, enantiomer 2: 42.80 min; minor diastereoisomer: 43.22 min
(both enantiomers). IR (nujol): n˜ =3380(brm), 3035(m), 2924(s), 2852(s),
1449(m), 1300(w), 1107(w), 1086(w), 972(w), 704(m), 688(s),
640(m) cmꢀ1 1H NMR (200 MHz, CDCl3): d=6.04 5.56 (m, 4H; vinyl
.
rac-(4-Bromophenyl)-[cyclohexa-2,4-dien-1-yl]methanol (2i): GP 5 was
used to obtain homoallylic alcohol 2i from cyclohexadienyllithium
(2.4 mmol, prepared according to GP 1), titanium(iv) isopropoxide
(738 mg, 2.6 mmol), and 4-bromobenzaldehyde (370 mg, 2.0 mmol). FC
(P/MTBE 10:1) yielded 2i (509 mg, 96%) as a colorless oil. d.r. (syn:an-
ti)=2.5:1, determined by GC analysis; retention times: major diaster-
eoisomer: enantiomer 1: 80.15 min, enantiomer 2: 80.58 min; minor dia-
stereoisomer: enantiomer 1: 81.04 min, enantiomer 2: 82.29 min. IR
(neat): n˜ =3391(brs), 3037(m), 1591(m), 1486(s), 1407(m), 1199(m),
H), 3.50 3.30 (m, 1H; CHOH, syn isomer), 3.27 3.18 (m, 1H; CHOH,
anti isomer), 2.70 2.07 (m, 3H), 1.92 0.82 ppm (m, 12H). 13C NMR
(50 MHz, CDCl3, syn isomer): d=127.4 (CH), 125.7 (CH), 125.1 (CH),
123.3 (CH), 75.8 (CH), 39.1 (CH), 34.8 (CH), 29.2 (CH2), 27.1 (CH2),
25.9 (CH2), 25.7 (CH2), 21.9 ppm (CH2). 13C NMR (50 MHz, CDCl3, anti
isomer): d=127.4 (CH), 125.6 (CH), 125.0 (CH), 122.9 (CH), 75.8 (CH),
39.1 (CH), 34.7 (CH), 29.1 (CH2), 26.9 (CH2), 25.8 (CH2), 25.4 (CH2),
21.9 ppm (CH2). MS (EI): 192 (<1, [M]+), 190 (<1, [MꢀH2]+), 107 (19),
95 (80), 80 (100). HRMS ([M]+): calcd for C13H20O: 192.1514; found:
192.1519.
1071(s), 1009(s), 821(s), 720(m), 638(s) cmꢀ1
.
1H NMR (200 MHz,
ꢀ
ꢀ
CDCl3): d=7.49 7.45 (m, 2H; Ar H), 7.23 7.19 (m, 2H; Ar H), 6.01
5.75 (m, 3H; vinyl H), 5.40 5.33 (m, 1H; vinyl H), 4.62 (dd, 1H, J1 =7.0,
J2 =3.0 Hz; CHOH), 2.66 2.18 (m, 3H), 1.92 ppm (d, 1H, J=3.0 Hz;
OH). 13C NMR (75 MHz, CDCl3): d=141.9 (C), 131.3 (2îCH), 128.4
(2îCH), 128.1 (CH), 126.5 (CH), 125.8 (CH), 123.8 (CH), 121.3 (C),
74.8 (CH), 40.2 (CH), 23.9 ppm (CH2). MS (ESI): 529 ([2M+H]+) (20),
295 (20), 270 (60), 169 (43), 163 (80), 131 (100), 99 (57), 71 (30).
rac-Cyclohexa-2,4-dien-1-yl-(4-methylphenyl)-methanol (2g): GP 5 was
used to obtain homoallylic alcohol 2 g from cyclohexadienyllithium
(2.4 mmol, prepared according to GP 1), titanium(iv) isopropoxide
(738 mg, 2.6 mmol), and 4-methylbenzaldehyde (240 mg, 2.0 mmol). FC
(P/MTBE 10:1) yielded 2 g (394 mg, 98%) as a colorless oil. d.r. (syn:an-
ti)=14.4:1, determined by GC analysis; retention times: major diaster-
eoisomer: enantiomer 1: 54.04 min, enantiomer 2: 54.29 min; minor dia-
stereoisomer: enantiomer 1: 55.02 min, enantiomer 2: 55.27 min. IR
(neat): n˜ =3388(brs), 3036(s), 2920(m), 2864(m), 1514(m), 1427(m),
1409(m), 1373(m), 1048(m), 1016(m), 821(m), 761(m), 722(m), 681(s),
(S)-(4-Bromophenyl)-[(1R)-cyclohexa-2,4-dien-1-yl]methanol (2i): GP 2
was used to obtain homoallylic alcohol 2i from CpTiCl3 (495 mg,
2.26 mmol), TADDOL (1.05 g, 2.26 mmol), NEt3 (0.66 mL, 4.96 mmol),
cyclohexadienyllithium (2.13 mmol, prepared according to GP 1), and 4-
bromobenzaldehyde (197 mg, 1.07 mmol). FC (P/MTBE 10:1) yielded 2i
(265 mg, 1.00 mmol, 94%) as a colorless oil. d.r. (syn:anti)>99:1; e.r.=
97:3, determined by GC analysis; retention times: major diastereoisomer:
enantiomer 1: 80.15 min, enantiomer 2: 80.58 min; minor diastereoisom-
er: enantiomer 1: 81.04 min, enantiomer 2: 82.29 min). [a]D25 =+126.08
(c=1.24 in CHCl3).
1
565(m) cmꢀ1
.
H NMR (300 MHz, CDCl3): d=7.23 7.15 (m, 4H; Ar H),
ꢀ
5.93 5.87 (m, 2H; vinyl H), 5.83 5.78 (m, 1H; vinyl H), 5.39 5.34 (m,
1H; vinyl H), 4.62 4.60 (m; CHOH), 2.69 2.58 (m, 1H; CH2CH), 2.49
2.26 (m, 2H; CH2), 2.35 (s, 3H; CH3); 1.92 ppm (s, 1H; OH). 13C NMR
(75 MHz, CDCl3): d=140.0 (C), 137.2 (C), 129.0 (2îCH), 127.1 (CH),
126.6 (2îCH), 126.0 (CH), 125.4 (CH), 123.8 (CH), 75.4 (CH), 40.3
(CH), 24.2 (CH2), 21.1 ppm (CH3). MS (EI): 198 (<1, [MꢀH2]+), 182
(<1), 167 (2), 121 (100), 93 (58), 91 (21), 80 (26), 77 (30). HRMS
([MꢀH2]+): calcd for C14H14O: 198.1045; found: 198.1049; elemental
analysis (%) calcd for C14H16O (200.28): C 83.96, H 8.05; found: C 83.57,
H 8.20.
rac-Cyclohexa-2,4-dien-1-yl-(3-methoxyphenyl)methanol (2k): GP 5 was
used to obtain homoallylic alcohol 2k from cyclohexadienyllithium
(2.4 mmol, prepared according to GP 1), titanium(iv) isopropoxide
(738 mg, 2.6 mmol), and 3-methoxybenzaldehyde (272 mg, 2.0 mmol). FC
(P/MTBE 10:1) yielded 2k (426 mg, 98%) as a colorless solid. d.r. (syn:
anti)=11.9:1, determined by HPLC analysis; retention times: major dia-
stereoisomer: enantiomer 1: 26.71 min, enantiomer 2: 36.94 min; minor
diastereoisomer: enantiomer 1: 26.71 min, enantiomer 2: 40.79 min. M.p.:
648C. IR (neat): n˜ =3422(brs), 3037(s), 2834(m), 1601(s), 1487(s),
1455(m), 1435(m), 1260(s), 1151(m), 1047(s), 875(w), 781(m), 704(m),
(S)-(1R)-Cyclohexa-2,4-dien-1-yl-(4-methylphenyl)methanol (2 g): GP 2
was used to obtain homoallylic alcohol 2 g from CpTiCl3 (508 mg,
2.32 mmol), TADDOL (1.08 g, 2.32 mmol), NEt3 (0.68 mL, 5.87 mmol),
cyclohexadienyllithium (2.21 mmol, prepared according to GP 1), and 4-
methylbenzaldehyde (133 mg, 1.11 mmol). FC (P/MTBE 10:1) yielded
2 g (182 mg, 82%) as a colorless oil. d.r. (syn:anti)>99:1; e.r.=95:5, de-
Chem. Eur. J. 2004, 10, 4171 4185
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4179

A. Studer et al.
FULL PAPER
1
684(m) cmꢀ1
.
H NMR (300 MHz, CDCl3): d=7.28 7.23 (m, 1H; Ar H),
anti)=21:1, determined by GC analysis; retention times: major diaster-
eoisomer: enantiomer 1: 55.02 min, enantiomer 2: 55.20 min; minor dia-
stereoisomer: 56.70 min (both enantiomers). M.p.: 48 508C. IR (nujol):
n˜ =3267(brs), 3926(s), 1462(s), 1377(m), 1239(m), 1185(w), 1053(w),
ꢀ
ꢀ
6.91 6.80 (m, 3H; Ar H), 6.05 5.70 (m, 3H; vinyl H), 5.41 5.37 (m, 1H;
vinyl H), 4.62 4.59 (m, 1H; CHOH), 3.80 (s, 3H; CH3), 2.67 2.57 (m,
1H; CHCH2), 2.48 2.24 (m, 2H; CH2), 2.10 2.01 ppm (m, 1H; OH).
13C NMR (75 MHz, CDCl3): d=159.6 (C), 144.6 (C), 129.3 (CH), 127.0
(CH), 126.0 (CH), 125.5 (CH), 123.8 (CH), 119.0 (CH), 113.0 (CH),
112.2 (CH), 75.5 (CH), 55.2 (CH3), 40.3 (CH), 24.1 ppm (CH2). MS (EI):
216 (<1, [M]+), 198 (<1, [MꢀH2O]+), 137 (100), 109 (95), 94 (23), 80
(56), 77 (28). HRMS ([M]+): calcd for C14H16O2: 216.1150; found:
216.1143.
1009(w), 758(w), 726(w), 638(w) cmꢀ1
.
1H NMR (300 MHz, CDCl3): d=
ꢀ
ꢀ
7.50 7.45 (m, 1H; Ar H), 7.27 7.12 (m, 3H; Ar H), 5.94 5.81 (m, 3H;
vinyl H), 5.35 5.30 (m, 1H; vinyl H), 4.98 4.94 (m, 1H; CHOH), 2.69
2.47 (m, 1H), 2.39 2.28 (m, 2H), 2.31 (s, 3H; CH3), 1.98 1.78 ppm (m,
1H; OH). 13C NMR (75 MHz, CDCl3): d=141.1 (C), 135.2 (C), 130.3
(CH), 127.3 (CH), 126.8 (CH), 126.2 (CH), 126.1 (CH), 126.0 (CH),
125.7 (CH), 123.8 (CH), 71.0 (CH), 39.5 (CH3), 24.3 (CH2), 19.4 ppm
(CH3). MS (EI): 182 (<1, [MꢀH2O]+), 121 (100), 93 (44), 80 ppm (38).
HRMS ([MꢀH2O]+): calcd for C14H14: 182.1096; found: 182.1092; ele-
mental analysis (%) calcd for C14H16O (200.28): C 83.96, H 8.05; found:
C 83.59, H 8.25.
rac-Cyclohexa-2,4-dien-1-yl(4-nitrophenyl)methanol (2j): GP 5 was used
to obtain homoallylic alcohol 2j from cyclohexadienyllithium (2.4 mmol,
prepared according to GP 1), titanium(iv) isopropoxide (738 mg,
2.6 mmol), and 4-nitrobenzaldehyde (302 mg, 2.0 mmol). FC (P/MTBE
10:1) yielded 2j (106 mg, 23%) as a yellow oil. d.r. (syn:anti)=1.9:1, de-
termined by GC analysis, rate=58Cminꢀ1; retention times: major diaster-
eoisomer: enantiomer 1: 105.60 min, enantiomer 2: 106.63 min; minor di-
astereoisomer: enantiomer 1: 101.49 min, enantiomer 2: 102.47 min. IR
(neat): n˜ =3410(brs), 3039(m), 2869(m), 1704(m), 1604(w), 1520(m),
1348(m), 1198(m), 1108(m), 1073(m), 1031(m), 1013(m), 857(s), 823(m),
(S)-(1R)-Cyclohexa-2,4-dien-1-yl-(2-methylphenyl)methanol (2m): GP 2
was used to obtain homoallylic alcohol 2 m from CpTiCl3 (554 mg,
2.53 mmol), TADDOL (1.18 g, 2.53 mmol), NEt3 (0.74 mL, 5.55 mmol),
cyclohexadienyllithium (2.39 mmol, prepared according to GP 1), and 2-
methylbenzaldehyde (143 mg, 1.20 mmol). FC (P/MTBE 10:1) yielded
2 m (135 mg, 56%) as a colorless solid. d.r. (syn:anti)>99:1; e.r.=96:4,
determined by GC analysis; retention times: major diastereoisomer:
enantiomer 1: 55.02 min, enantiomer 2: 55.20 min; minor diastereoisom-
er: 56.70 min (both enantiomers). [a]D25 =+152.58 (c=1.01 in CHCl3).
752(m), 701(s) cmꢀ1
.
1H NMR (300 MHz, CDCl3): d=8.24 8.19 (m, 2H;
ꢀ
ꢀ
Ar H), 7.53 7.50 (m, 2H; Ar H), 6.10 5.71 (m, 4H; vinyl H), 4.83 4.76
(m, 1H; CHOH), 2.73 2.12 ppm (m, 4H). 13C NMR (75 MHz, CDCl3):
d=150.3 (C), 147.3 (C), 127.1 (CH), 126.4 (2îCH), 125.7 (CH), 125.0
(CH), 124.1 (CH), 123.7 (2îCH), 74.3 (CH), 40.2 (CH), 23.4 ppm (CH2).
MS (EI): 151 (44), 136 (5), 106 (10), 91 (12), 77 (25), 73 (100), 57 (20), 43
(15).
rac-(2-Bromophenyl)-[cyclohexa-2,4-dien-1-yl]methanol (2n): GP 5 was
used to obtain homoallylic alcohol 2n from cyclohexadienyllithium
(2.4 mmol, prepared according to GP 1), titanium(iv) isopropoxide
(738 mg, 2.6 mmol), and 2-bromobenzaldehyde (370 mg, 2.0 mmol). FC
(P/MTBE 10:1) yielded 2n (519 mg, 98%) as a colorless oil. d.r. (syn:an-
ti)=2.8:1, determined by GC analysis; retention times: major diaster-
eoisomer: 67.86 min (both enantiomers); minor diastereoisomer:
68.98 min (both enantiomers). IR (neat): n˜ =3397(brs), 3037(s), 2934(w),
1567(s), 1468(s), 1409(w), 1195(m), 1122(w), 1094(m), 1017(s), 753(s),
(S)-(1R)-Cyclohexa-2,4-dien-1-yl-(3-methoxyphenyl)methanol (2k): GP
2 was used to obtain homoallylic alcohol 2k from CpTiCl3 (578 mg,
2.63 mmol), TADDOL (1.23 g, 2.63 mmol), NEt3 (0.77 mL, 5.90 mmol),
cyclohexadienyllithium (2.50 mmol, prepared according to GP 1), and 3-
methoxybenzaldehyde (170 mg, 1.25 mmol). FC (P/MTBE 10:1) yielded
2k (156 mg, 0.73 mmol, 58%) as a colorless solid. d.r. (syn:anti)>99:1;
e.r.=97:3, determined by HPLC analysis; retention times: major diaster-
eoisomer: enantiomer 1: 26.71 min, enantiomer 2: 36.94 min; minor dia-
725(m), 684(s) cmꢀ1 1H NMR (300 MHz, CDCl3): d=7.54 7.51 (m, 2H;
.
ꢀ
ꢀ
ꢀ
Ar H), 7.36 7.31 (m, 1H; Ar H), 7.16 7.11 (m, 1H; Ar H), 6.08 5.75
(m, 3H; vinyl H), 5.54 5.49 (m, 1H; vinyl H), 5.15 5.01 (m, 1H;
CHOH), 2.89 2.75 (m, 2H), 2.46 2.12 ppm (m, 3H). 13C NMR (75 MHz,
CDCl3): d=141.2 (C), 132.7 (CH), 128.9 (CH), 128.5 (CH), 127.4 (CH),
126.6 (CH), 126.3 (CH), 125.2 (CH), 123.7 (CH), 122.6 (C), 74.3 (CH),
38.5 (CH), 23.1 ppm (CH2). MS (ESI): 303 ([M+K]+) (5), 289 (12), 270
(20), 242 (50), 231 (17), 195 (18), 186 (25), 169 (35), 163 (73), 142 (60),
131 (100), 99 (62), 71 (42). HRMS: ([M+K]+) calcd for C13H13BrKO:
302.9787; found: 302.9795.
stereoisomer: enantiomer 1: 26.71 min, enantiomer 2: 40.79 min. [a]2D5
+134.48 (c=1.08 in CHCl3).
=
rac-Cyclohexa-2,4-dien-1-yl-(2-methoxyphenyl)methanol (2l): GP 5 was
used to obtain homoallylic alcohol 2l from cyclohexadienyllithium
(2.4 mmol, prepared according to GP 1), titanium(iv) isopropoxide
(738 mg, 2.6 mmol), and 2-methoxybenzaldehyde (272 mg, 2.0 mmol). FC
(P/MTBE 10:1) yielded 2l (415 mg, 96%). d.r. (syn:anti)=39:1, deter-
mined by GC analysis; retention times: major diastereoisomer: enan-
tiomer 1: 61.77 min, enantiomer 2: 61.97 min; minor diastereoisomer:
enantiomer 1: 63.04 min, enantiomer 2: 63.26 min). IR (neat): n˜ =2923(s),
2853(m), 1601(w), 1459(m), 1377(m), 1300(w), 1238(w), 1119(w),
(S)-(2-Bromophenyl)-[(1R)-cyclohexa-2,4-dien-1-yl]methanol (2n): GP 2
was used to obtain homoallylic alcohol 2n from CpTiCl3 (495 mg,
2.26 mmol), TADDOL (1.05 g, 2.26 mmol), NEt3 (0.66 mL, 4.96 mmol),
cyclohexadienyllithium (2.13 mmol, prepared according to GP 1), and 2-
bromobenzaldehyde (197 mg, 1.07 mmol). FC (P/MTBE 10:1) yielded 2n
(261 mg, 92%) as a colorless oil. [a]D25 =+74.88 (c=0.81 in CHCl3).
1020(w), 750(w), 724(w) cmꢀ1
.
1H NMR (300 MHz, CDCl3): d=7.31 7.25
ꢀ
ꢀ
(m, 2H; Ar H), 7.01 6.90 (m, 2H; Ar H), 5.97 5.82 (m, 3H; vinyl H),
5.43 5.39 (m, 1H; vinyl H), 4.82 4.72 (m, 1H; CHOH), 3.88 (s, 3H;
CH3), 2.89 2.70 (m, 2H), 2.56 2.44 (m, 1H), 2.39 2.28 ppm (m, 1H).
13C NMR (75 MHz, CDCl3): d=156.7 (C), 130.3 (C), 128.7 (CH), 128.4
(CH), 127.7 (CH), 126.2 (CH), 125.0 (CH), 123.8 (CH), 120.5 (CH),
110.5 (CH), 73.3 (CH), 55.2 (CH3), 38.5 (CH), 24.2 ppm (CH2). MS (EI):
216 (<1, [M]+), 198 (2, [MꢀH2O]+), 137 (100), 107 (44), 91 (12). HRMS
([M]+): calcd for C14H16O2: 216.1150; found: 216.1150.
To determine the enantiomeric ratio, 2n (100 mg, 0.38 mmol) was dis-
solved in THF (10 mL) and cooled to ꢀ788C. tBuLi (0.64 mL, 1.78m in
hexane, 1.14 mmol, 3 equiv) was added slowly and the reaction mixture
was stirred for two hours at ꢀ788C. Water (3 mL) was added carefully
and the reaction mixture was allowed to warm to room temperature.
MTBE (10 mL) was added and the phases were separated. The aqueous
phase was extracted with MTBE (3î10 mL) and the combined organic
phases were washed with brine and dried over MgSO4. The solvents were
removed by evaporation in vacuo. FC (P/MTBE 10:1) gave 2d (36 mg,
50%). GC analysis of this sample indicated the presence of one single
enantiomer (see above for GC retention times of 2d).
(S)-(1R)-Cyclohexa-2,4-dien-1-yl-(2-methoxyphenyl)methanol (2l): GP 2
was used to obtain homoallylic alcohol 2l from CpTiCl3 (670 mg,
3.05 mmol), TADDOL (1.42 g, 3.05 mmol), NEt3 (0.89 mL, 6.71 mmol),
cyclohexadienyllithium (2.90 mmol, prepared according to GP 1), and 2-
methoxybenzaldehyde (165 mg, 1.21 mmol). FC (P/MTBE 10:1) yielded
2l (159 mg, 61%) as a colorless oil. d.r. (syn:anti)>99:1; e.r.>99:1, deter-
mined by GC analysis; retention times: major diastereoisomer: enan-
tiomer 1: 61.77 min, enantiomer 2: 61.97 min; minor diastereoisomer:
enantiomer 1: 63.04 min, enantiomer 2: 63.26 min. [a]D25 =+124.08 (c=
1.09 in CHCl3).
rac-Cyclohexa-2,4-dien-1-yl-(2-furyl)methanol (2o): GP 5 was used to
obtain homoallylic alcohol 2o from cyclohexadienyllithium (2.4 mmol,
prepared according to GP 1), titanium(iv) isopropoxide (738 mg,
2.6 mmol), and furfural (192 mg, 2.0 mmol). FC (P/MTBE 10:1) yielded
2o (323 mg, 94%) as a yellow oil. d.r. (syn:anti)=13.2:1, determined by
GC analysis; retention times: major diastereoisomer: 31.59 min (both
enantiomers); minor diastereoisomer: 31.96 min (both enantiomers). IR
(neat): n˜ =3403(brs), 3037(s), 2923(w), 1671(w), 1503(m), 1393(w),
rac-Cyclohexa-2,4-dien-1-yl-(2-methylphenyl)methanol (2m): GP 5 was
used to obtain homoallylic alcohol 2m from cyclohexadienyllithium
(2.4 mmol, prepared according to GP 1), titanium(iv) isopropoxide
(738 mg, 2.6 mmol), and 2-methylbenzaldehyde (240 mg, 2.0 mmol). FC
(P/MTBE 10:1) yielded 2m (392 mg, 98%) as a colorless solid. d.r. (syn:
1309(w), 1227(w), 1148(m), 1010(s), 739(m), 678(m) cmꢀ1
.
1H NMR
ꢀ
ꢀ
(300 MHz, CDCl3): d=7.38 (s, 1H; Ar H), 6.34 6.33 (m, 1H; Ar H),
4180
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4171 4185

Cyclohexadienyl Ti in Stereoselective Synthesis
4171 4185
ꢀ
6.26 6.24 (m, 1H; Ar H), 6.05 5.71 (m, 3H; vinyl H), 5.48 5.43 (m, 1H;
enyllithium (2.36 mmol, prepared according to GP 1), and 2-naphtalde-
hyde (188 mg, 1.18 mmol). FC (P/MTBE 10:1) yielded 4j (226 mg,
1.19 mmol, 81%) as a colorless solid. d.r. (syn:anti)>99:1; e.r.=90:10,
determined by HPLC analysis; retention times: major diastereoisomer:
enantiomer 1: 37.38 min, enantiomer 2: 48.24 min; minor diastereoiso-
mer: enantiomer 1: 40.89 min, enantiomer 2: 53.75 min. [a]D25 =+162.88
(c=1.18 in CHCl3).
vinyl H), 4.63 4.61 (m, 1H; CHOH), 2.85 2.73 (m, 1H), 2.47 2.30 (m,
2H), 2.14 1.96 ppm (m, 1H). 13C NMR (75 MHz, CDCl3): d=155.4 (C),
142.9 (CH), 126.2 (CH), 125.7 (CH), 125.5 (CH), 123.9 (CH), 110.2
(CH), 107.3 (CH), 69.0 (CH), 38.0 (CH), 24.2 ppm (CH2). MS (EI): 174
([MꢀH2]+) (<1), 97 (100), 80 (17), 41 (12). HRMS ([MꢀH2]+): calcd for
C11H10O2: 174.0681; found: 174.0676.
(S)-(1R)-Cyclohexa-2,4-dien-1-yl-(2-furyl)methanol (2o): GP 2 was used
to obtain homoallylic alcohol 2o from CpTiCl3 (558 mg, 2.54 mmol),
TADDOL (1.19 g, 2.54 mmol), NEt3 (0.74 mL, 5.59 mmol), cyclohexadie-
nyllithium (2.42 mmol, prepared according to GP 1), and furfural
(116 mg, 1.21 mmol). FC (P/MTBE 10:1) yielded 2o (153 mg, 72%) as a
pale yellow oil. d.r. (syn:anti)=98:2, determined by GC analysis; reten-
tion times: major diastereoisomer: 32.27 min; minor diastereoisomer:
33.18 min; e.r.=93:7, determined by HPLC analysis; retention times:
major diastereoisomer: enantiomer 1: 14.30 min, enantiomer 2:
16.66 min. [a]D25 =+190.68 (c=1.04 in CHCl3).
rac-(2E)-1-[Cyclohexa-2,4-dien-1-yl]-3-phenylprop-2-en-1-ol (2r): GP 5
was used to obtain homoallylic alcohol 2r from cyclohexadienyllithium
(2.4 mmol, prepared according to GP 1), titanium(iv) isopropoxide
(738 mg, 2.6 mmol), and cinnamaldehyde (264 mg, 2.0 mmol). FC (P/
MTBE 10:1) yielded 2r (377 mg, 89%) as a colorless solid. d.r. (syn:an-
ti)=2.7:1, determined by HPLC analysis; retention times: major diaster-
eoisomer: enantiomer 1: 34.20 min, enantiomer 2: 53.59 min; minor dia-
stereoisomer: enantiomer 1: 34.20 min, enantiomer 2: 60.15 min. M.p.:
478C. IR (nujol): n˜ =3396(brm), 3036(w), 2925(s), 2857(s), 1493(m),
1450(s), 1375(m), 1329(m), 1149(m), 1078(w), 1008(w), 968(m), 748(m),
1
683(s) cmꢀ1
.
H NMR (300 MHz, CDCl3): d=7.41 7.22 (m, 5H; Ar H),
ꢀ
rac-Cyclohexa-2,4-dien-1-yl-(1-naphthyl)methanol (2p): GP 5 was used
to obtain homoallylic alcohol 2p from cyclohexadienyllithium (2.4 mmol,
prepared according to GP 1), titanium(iv) isopropoxide (738 mg,
2.6 mmol), and 1-naphthaldehyde (312 mg, 2.0 mmol). FC (P/MTBE
10:1) yielded 2p (428 mg, 99%) as a colorless oil. d.r. (syn:anti)=2.0:1,
determined by HPLC analysis; retention times: major diastereoisomer:
enantiomer 1: 24.02 min, enantiomer 2: 70.58 min; minor diastereoisom-
er: enantiomer 1: 25.23 min, enantiomer 2: 83.94 min. IR (neat): n˜ =
3409(brs), 3038(s), 2974(w), 2938(m), 1690(m), 1597(m), 1511(m),
6.61 (d, 1H, J=15.9 Hz; PhCH=CH), 6.24 (dd, 1H, J1 =15.9, J2 =6.8 Hz;
PhCH=CH), 6.06 5.69 (m, 4H; vinyl H), 4.31 4.27 (m, 1H; CHOH),
2.61 2.50 (m, 1H), 2.38 2.17 (m, 2H), 1.69 ppm (m, 1H, OH). 13C NMR
(75 MHz, CDCl3): d=136.7 (C), 131.7 (CH), 130.6 (CH), 128.6 (CH),
127.7 (CH), 126.5 (CH), 126.1 (CH), 125.6 (CH), 123.8 (CH), 75.6 (CH),
39.3 (CH), 25.3 ppm (CH2). MS (ESI): 315 (100), 289 (36), 250
([MꢀH+K]+) (30), 240 (10), 227 (10), 195 (13), 186 (52), 132 (10), 116
(100). HRMS: ([M+Na]+) calcd for C15H16ONa: 235.1099; found:
235.1094.
1367(s), 1200(m), 1167(m), 1075(m), 996(m), 848(m), 780(m),
1
683(s) cmꢀ1
.
H NMR (300 MHz, CDCl3): d=8.11 8.06 (m, 1H; Ar H),
(1R,2E)-1-[(1R)-Cyclohexa-2,4-dien-1-yl]-3-phenylprop-2-en-1-ol (2r):
GP 2 was used to obtain homoallylic alcohol 2r from CpTiCl3 (544 mg,
2.48 mmol), TADDOL (1.16 g, 2.48 mmol), NEt3 (0.72 mL, 5.45 mmol),
cyclohexadienyllithium (189 mg, 2.36 mmol, prepared according to GP
1), and cinnamaldehyde (156 mg, 1.18 mmol). FC (P/MTBE 10:1) yielded
2r (232 mg, 93%) as a colorless solid. d.r. (syn:anti)>99:1; e.r.=90:10,
determined by HPLC analysis; retention times: major diastereoisomer:
enantiomer 1: 34.20 min, enantiomer 2: 53.59 min; minor diastereoiso-
mer: enantiomer 1: 34.20 min, enantiomer 2: 60.15 min. [a]D25 =+229.98
(c=1.08 in CHCl3).
ꢀ
ꢀ
ꢀ
7.91 7.87 (m, 2H; Ar H), 7.66 7.61 (m, 1H; Ar H), 7.52 7.46 (m, 3H;
Ar H), 6.09 5.71 (m, 3H; vinyl H), 5.48 5.43 (m, 2H; vinyl H, CHOH),
ꢀ
3.01 2.87 (m, 1H), 2.59 2.43 (m, 1H), 2.32 2.10 ppm (m, 2H). 13C NMR
(75 MHz, CDCl3): d=138.3 (C), 133.8 (C), 130.7 (C), 128.9 (CH), 128.1
(CH), 127.3 (CH), 126.6 (CH), 125.8 (CH), 125.6 (CH), 125.4 (CH),
125.2 (CH), 124.1 (CH), 123.7 (CH), 123.3 (CH), 72.1 (CH), 39.6 (CH),
23.9 ppm (CH2). MS (EI): 236 ([M]+) (<1), 218 (2), 158 (50), 133 (16),
129 (100), 78 (13), 75 (45). HRMS: ([M]+) calcd for C17H16O: 236.1201;
found: 236.1199.
(S)-(1R)-Cyclohexa-2,4-dien-1-yl-(1-naphthyl)methanol (2p): GP 2 was
used to obtain homoallylic alcohol 2p from CpTiCl3 (567 mg, 2.59 mmol),
TADDOL (1.21 g, 2.59 mmol), NEt3 (0.76 mL, 5.70 mmol), cyclohexadi-
enyllithium (2.47 mmol, prepared according to GP 1), and 1-naphtalde-
hyde (204 mg, 1.24 mmol). FC (P/MTBE 10:1) yielded 2p (281 mg, 96%)
as a colorless oil. d.r. (syn:anti)>99:1; e.r.>99:1, determined by HPLC
analysis; retention times: major diastereoisomer: enantiomer 1:
24.02 min, enantiomer 2: 70.58 min; minor diastereoisomer: enantiomer
1: 25.23 min, enantiomer 2: 83.94 min. [a]D25 =+91.38 (c=1.00 in CHCl3).
rac-1-[Cyclohexa-2,4-dien-1-yl]-3-phenylprop-2-yn-1-ol (2s): GP 5 was
used to obtian homoallylic alcohol 2s from cyclohexadienyllithium
(2.4 mmol, prepared according to GP 1), titanium(iv) isopropoxide
(738 mg, 2.6 mmol), and phenylpropargyl aldehyde (260 mg, 2.0 mmol).
FC (P/MTBE 10:1) yielded 2s (391 mg, 93%) as a yellow oil. d.r. (syn:
anti)=1.9:1, determined by HPLC analysis; retention times: major dia-
stereoisomer: enantiomer 1: 25.26 min, enantiomer 2: 69.03 min; minor
diastereoisomer: enantiomer 1: 27.68 min, enantiomer 2: 53.06 min. IR
(neat): n˜ =3363(brs), 3038(s), 2867(m), 2231(w), 1597(m), 1490(s),
1442(w), 1429(w), 1409(w), 1371(w), 1328(w), 1070(m), 1036(s), 999(w),
rac-Cyclohexa-2,4-dien-1-yl-(2-naphthyl)methanol (2q): GP 5 was used
to obtain homoallylic alcohol 2q from cyclohexadienyllithium (2.4 mmol,
prepared according to GP 1), titanium(iv) isopropoxide (738 mg,
2.6 mmol), and 2-naphthaldehyde (312 mg, 2.0 mmol). FC (P/MTBE
10:1) yielded 2q (428 mgm 99%) as a colorless solid. d.r. (syn:anti)=
9.4:1, determined by HPLC analysis; retention times: major diaster-
eoisomer: enantiomer 1: 37.38 min, enantiomer 2: 48.24 min; minor dia-
stereoisomer: enantiomer 1: 40.89 min, enantiomer 2: 53.75 min. M.p.:
95 978C. IR (nujol): n˜ =3325(brs), 3033(w), 2926(s), 2859(s), 1464(m),
1376(m), 1341(m), 1150(m), 1028(m), 972(m), 948(m), 857(m), 824(m),
972(m), 757(s), 690(s), 573(w), 525(w), 504(w) cmꢀ1 1H NMR (300 MHz,
.
ꢀ
CDCl3): d=7.43 7.31 (m, 5H; Ar H), 6.03 5.85 (m, 4H; vinyl H), 4.62
4.52 (m, 1H; CHOH), 2.79 2.61 (m, 1H), 2.53 2.31 (m, 2H), 2.11 ppm
(brs, 1H; OH). 13C NMR (75 MHz, CDCl3): d=131.7 (CH), 128.4 (CH),
128.3 (CH), 125.9 (CH), 125.6 (CH), 126.5 (CH), 123.8 (CH), 122.5 (C),
88.9 (C), 86.3 (C), 65.9 (CH), 40.1 (CH), 25.2 ppm (CH2). MS (EI): 210
([M]+; 2), 208 ([MꢀH2]+; 2), 131 (100), 114 (10), 103 (17), 79 (40).
HRMS: ([M]+) calcd for C15H14O: 210.1045; found: 210.1041.
(1S)-1-[(1R)-Cyclohexa-2,4-dien-1-yl]-3-phenylprop-2-yn-1-ol (2s): GP 2
was used to obtain homoallylic alcohol 2s from CpTiCl3 (504 mg,
2.30 mmol), TADDOL (1.08 g, 2.30 mmol), NEt3 (0.67 mL, 5.05 mmol),
cyclohexadienyllithium (2.19 mmol, prepared according to GP 1), and
phenylpropargyl aldehyde (143 mg, 1.10 mmol). FC (P/MTBE 10:1)
yielded 2s (198 mg, 86%) as a yellow oil. d.r. (syn:anti)>99:1; e.r.=99:1,
determined by HPLC analysis; retention times: major diastereoisomer:
enantiomer 1: 25.26 min, enantiomer 2: 69.03 min; minor diastereoiso-
mer: enantiomer 1: 27.68 min, enantiomer 2: 53.06 min. [a]D25 =+219.98
(c=1.12 in CHCl3).
787(m), 741(m), 682(s), 598(w), 479(m) cmꢀ1
.
1H NMR (300 MHz,
ꢀ
ꢀ
CDCl3): d=7.81 7.77 (m, 4H; Ar H), 7.50 7.44 (m, 3H; Ar H), 6.08
5.70 (m, 3H; vinyl H), 5.42 5. 37 (m, 1H; vinyl H), 4.82 4.76 (m, 1H;
CHOH), 2.80 2.70 (m, 1H), 2.55 2.44 (m, 1H), 2.38 2.26 (m, 2H), 2.08
2.03 ppm (m, 1H). 13C NMR (75 MHz, CDCl3): d=140.3 (C), 133.1 (C),
133.0 (C), 128.1 (CH), 127.9 (CH), 127.6 (CH), 126.9 (CH), 126.0 (CH),
125.8 (CH), 125.6 (CH), 125.5 (CH), 125.4 (CH), 124.5 (CH), 123.8
(CH), 75.6 (CH), 40.2 (CH), 24.1 ppm (CH2). MS (EI): 236 ([M]+) (<1),
218 (3), 157 (100), 129 (93), 106 (7), 80 (17). HRMS: ([M]+) calcd for
C17H16O: 236.1201; found: 236.1203; elemental analysis (%) calcd for
C17H16O (236.31): C 86.40, H 6.82; found: C 86.47, H 6.75.
rac-1-[Cyclohexa-2,4-dien-1-yl]dodec-2-yn-1-ol (2t): GP 5 was used to
obtain homoallylic alcohol 2t from cyclohexadienyllithium (2.4 mmol,
prepared according to GP 1), titanium(iv) isopropoxide (738 mg,
2.6 mmol), and dodec-2-yn-1-al (15; 360 mg, 2.0 mmol). FC (P/MTBE
10:1) yielded 2t (480 mg, 92%) as a colorless oil. d.r. (syn:anti)=1.9:1,
(S)-(1R)-Cyclohexa-2,4-dien-1-yl-(2-naphthyl)methanol (2q): GP 2 was
used to obtain homoallylic alcohol 2q from CpTiCl3 (544 mg, 2.48 mmol),
TADDOL (1.16 g, 2.48 mmol), NEt3 (0.72 mL, 5.45 mmol), cyclohexadi-
Chem. Eur. J. 2004, 10, 4171 4185
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4181

A. Studer et al.
FULL PAPER
determined by HPLC analysis; retention times: major diastereoisomer:
enantiomer 1: 28.73 min, enantiomer 2: 39.34 min; minor diastereoiso-
mer: enantiomer 1: 25.00 min, enantiomer 2: 34.52 min. IR (neat): n˜ =
3379(w), 3038(m), 2855(m), 2229(w), 1674(w), 1465(s), 1377(m), 1140(w),
sure. The suspension was passed over a short celite pad and the solvent
was removed in vacuo. The crude product 16 (1.48 g) was used without
further purification in the next step.
Crude lactol 16 (336 mg, 1.24 mmol) was dissolved in acetone (20 mL)
and cooled to 08C. Freshly prepared Jones reagent (2.49 g CrO3, 1.8 mL
H2SO4, 3.6 mL H2O; 20.0 equiv) was cooled to 08C and was added drop-
wise to the reaction mixture. The mixture was stirred for 3 h at 08C then
iPrOH was added carefully to the brownish solution to destroy excess re-
agent. CH2Cl2 (150 mL) and water (50 mL) were added to the dark green
reaction mixture and the phases were separated. The aqueous layer was
extracted four times with CH2Cl2 (4î70 mL). The combined organic
layers were washed four times with water and brine and then dried
(MgSO4). The solvents were removed by evaporation in vacuo. FC
(CH2Cl2/MeOH 10:1) and recrystallization (hexane/iPrOH 98:2) gave
1
1016(m), 970(w), 683(w) cmꢀ1. H NMR (300 MHz, CDCl3): d=6.02 5.96
(m, 1H; vinyl H), 5.91 5.74 (m, 3H; vinyl H), 4.36 4.24 (m, 1H;
CHOH), 2.61 2.46 (m, 1H), 2.43 2.28 (m, 2H), 2.20 (dt, J1 =6.9, J2 =
2.0 Hz, 2H; CꢂCCH2), 1.87 (brs, 1H; OH), 1.54 1.45 (m, 2H), 1.42 1.18
(m, 12H), 0.87 ppm (t, J=6.6 Hz, 3H; CH3). 13C NMR (75 MHz, CDCl3):
d=126.4 (CH), 125.7 (CH), 125.5 (CH), 123.9 (CH), 87.0 (C), 80.2 (C),
65.7 (CH), 40.4 (CH), 31.9 (CH2), 29.5 (CH2), 29.3 (CH2), 29.1 (CH2),
28.8 (CH2), 28.6 (CH2), 25.2 (CH2), 22.6 (CH2), 18.7 (CH2), 14.1 ppm
(CH3). MS (EI): 258 (1, [MꢀH2]+), 105 (2), 95 (4), 83 (7), 80 (57), 79
(48), 78 (38), 70 (100), 55 (8). HRMS: ([MꢀH2]+) calcd for C18H26O:
258.1984; found: 258.1980.
lactone 17 as
a
white solid (75 mg, 21% over all steps). 1H NMR
(1S)-1-[(1R)-Cyclohexa-2,4-dien-1-yl]dodec-2-yn-1-ol (2t): GP
2 was
(500 MHz, CDCl3): d=4.62 (dt, 1H, J1 =7.5, J2 =4.5 Hz), 3.11 3.06 (m,
1H), 2.94 (dd, 1H, J1 =17.9, J2 =8.5 Hz), 2.81 (dd, 1H, J1 =17.9, J2 =
9.6 Hz), 1.84 1.70 (m, 1H), 1.66 1.37 (m, 2H), 1.37 1.20 (m, 17H),
0.88 ppm (t, 3H, J=7.0 Hz). 13C NMR (125 MHz, CDCl3): d=176.3 (C),
174.3 (C), 81.8 (CH), 45.5 (CH), 35.4 (CH), 34.0 (CH), 31.9 (CH), 29.6
(CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.2 (CH2), 29.0 (CH2), 25.2
(CH2), 22.7 (CH2), 14.1 ppm (CH3). MS (EI): 284 ([M]+, 9), 266 (100),
248 (24), 239 (33), 238 (70) 225 (52), 223 (11), 206 (15), 192 (11), 183
(12), 167 (23), 154 (25), 145 (23), 140 (41), 129 (38), 118 (73), 112 (22),
100 (41), 83 (31), 56 (20). HRMS: ([M]+) calcd for C16H28O4: 284.1988;
found: 284.1982.
used to obtain homoallylic alcohol 2t from CpTiCl3 (715 mg, 3.26 mmol),
TADDOL (1.53 g, 3.26 mmol), NEt3 (1.00 mL, 7.18 mmol), cyclohexadie-
nyllithium (3.10 mmol, prepared according to GP 1), and dodec-2-yn-1-al
(15; 279 mg, 1.55 mmol). FC (P/MTBE 10:1) yielded 2t (334 mg, 83%)
as a colorless oil. d.r. (syn:anti)>99:1; e.r.=98.5:1.5, determined by
HPLC analysis; retention times: major diastereoisomer: enantiomer 1:
28.73 min, enantiomer 2: 39.34 min; minor diastereoisomer: enantiomer
1: 25.00 min, enantiomer 2: 34.52 min.
rac-1-[Cyclohexa-2,4-dien-1-yl]hexan-1-ol (2u): GP 5 was used to obtain
homoallylic alcohol 2u from cyclohexadienyllithium (24 mmol, prepared
according to GP 1), titanium(iv) isopropoxide (7.38 g, 26 mmol), and
hexanal (2.00 g, 20 mmol). FC (P/MTBE 7:1) yielded 2u (3.63 g, 96%) as
a colorless oil. d.r. (syn:anti)=28:1, determined by GC analysis; retention
times: major diastereoisomer: enantiomer 1: 44.64 min, enantiomer 2:
44.88 min; minor diastereoisomer: 45.28 min, both enantiomers. IR
(neat): n˜ =3374(brs), 2930(s), 2859(m), 1677(w), 1456(m), 1379(w),
(2R,3S,4S)-(+)-2-Undecyl-4-methyl-5-oxo-tetrahydrofuran-3-carboxylic
acid (nephrosteranic acid): NaHMDS (1.0m in THF, 0.154 mL,
0.154 mmol, 3.6 equiv) was added to a solution of 17 (20 mg, 0.07 mmol)
in THF (1.0 mL) at ꢀ788C over 15 min. After 1 h at ꢀ788C, MeI
(0.042 mL, 0.67 mmol) was added. The mixture was stirred at ꢀ788C for
2 h then the temperature was allowed to rise to ꢀ208C overnight. 2n
HCl (0.75 mL) was added and the mixture was allowed to warm to room
temperature and was then extracted with EtOAc (3î5 mL). The com-
bined organic phases were dried (MgSO4) and concentrated. FC (CHCl3/
MeOH 10:1) and recrystallization (hexane/iPrOH 98:2) gave nephroster-
anic acid (18.7 mg, 89%) as a white crystalline solid. Crystals suitable for
x-ray analysis were obtained from a solution of nephrosteranic acid in
CH2Cl2 laminated with hexane. M.p.: 978C. [a]D25 =+27.38 (c=0.97 in
1
1057(m), 729(w), 700(w) cmꢀ1. H NMR (300 MHz, CDCl3): d=5.99 5.95
(m, 1H; vinyl H), 5.87 5.80 (m, 2H; vinyl H), 5.67 5.62 (m, 1H; vinyl
H), 3.69 3.61 (m, 1H; CHOH), 2.37 2.24 (m, 3H), 1.50 1.30 (m, 8H;
CH2), 0.89 ppm (t, 3H, J=6.6 Hz; CH3). 13C NMR (75 MHz, CDCl3): d=
127.6 (CH), 126.1 (CH), 125.4 (CH), 123.7 (CH), 73.5 (CH), 38.9 (CH),
34.2 (CH2), 31.9 (CH2), 25.6 (CH2), 23.1 (CH2), 22.6 (CH2), 14.0 ppm
(CH3). MS (EI): 180 (4, [M]+), 178 (1, [MꢀH2]+), 107 (78), 94 (26), 93
(28), 81 (58), 78 (100), 77 (47), 68 (13), 61 (27), 56 (15). HRMS: ([M]+)
calcd for C12H20O: 180.1514; found: 180.1523.
1
CHCl3), ref. [22a]: [a]D25 =+27.28 (c=1.45 in CHCl3). H NMR (500 MHz,
CDCl3): d=4.48 (dt, 1H, J1 =8.8, J2 =3.8 Hz), 2.98 (dq, 1H, J1 =11.4, J2 =
ꢀ
6.9 Hz), 2.69 (dd, 1H, J1 =9.7, J2 =10.9 Hz), 1.86 1.79 (m, 1H; Ar H),
(1R)-1-[(1R)-cyclohexa-2,4-dien-1-yl]hexan-1-ol (2u): GP 2 was used to
obtain homoallylic alcohol 2u from CpTiCl3 (812 mg, 3.70 mmol),
TADDOL (1.73 g, 3.70 mmol), NEt3 (1.08 mL, 8.10 mmol), cyclohexadi-
enyllithium (3.50 mmol, prepared according to GP 1), and hexanal
(176 mg, 1.76 mmol). FC (P/MTBE 10:1) yielded 2u (156 mg, 49%) as a
colorless oil. d.r. (syn:anti)>99:1; e.r.=92:8, determined by GC analysis;
retention times: major diastereoisomer: enantiomer 1: 44.64 min, enan-
tiomer 2: 44.88 min; minor diastereoisomer: 45.28 min, both enantiomers.
GC and NMR analysis showed that 12% of the product consisted of iso-
1.74 1.67 (m, 1H), 1.56 1.48 (m, 1H), 1.43 1.22 (m, 17H), 1.36 (d, 3H,
J=6.9 Hz), 0.88 ppm (t, 3H, J=7.0 Hz). 13C NMR (125 MHz, CDCl3):
d=176.6 (C), 175.6 (C), 79.4 (CH), 53.9 (CH), 39.8 (CH), 34.9 (CH), 31.9
(CH), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.2 (CH2), 25.3
(CH2), 22.7 (CH2), 14.5 (CH3), 14.1 ppm (CH3).
Synthesis of (4S,5R)-5-butyl-4-methyldihydrofuran-2(3H)-one (trans-
whisky lactone):
(1S)-1-[(1R)-Cyclohexa-2,4-dien-1-yl]pent-2-yn-1-ol (19a): GP
2 was
meric
[cyclohexa-2,5-dien-1-yl]-hexan-1-ol
(5u; retention
time:
used to obtain homoallylic alcohol 19a from CpTiCl3 (1098 mg,
5.00 mmol), TADDOL (2.34 g, 5.00 mmol), NEt3 (1.53 mL, 11.01 mmol),
cyclohexadienyllithium (4.75 mmol, prepared according to GP 1), and
pent-2-yn-1-al (18a; 195 mg, 2.38 mmol). FC (first FC: P/MTBE 10:1,
second FC: P/acetone 8:1) yielded 19a (334 mg, 66%) as a colorless oil.
The diastereomeric and the enantiomeric ratios could not be determined.
IR (neat): n˜ =3378(s), 3038(w), 2976(m), 2878(m), 2231(w), 1668(w),
45.90 min).
Synthesis of (2R,3S,4S)-(+)-2-undecyl-4-methyl-5-oxo-tetrahydrofuran-
3-carboxylic acid (nephrosteranic acid):
(2R,3S)-(+)-2-undecyl-5-oxo-tetrahydrofuran-3-carboxylic acid (17):
A
solution of 2t (1.00 g, 3.85 mmol, 1.0 equiv) in dry CH2Cl2 (150 mL) was
cooled to ꢀ788C and ozone was bubbled through the solution until a
blue color appeared (ca. 30 min). Oxygen was then bubbled through the
solution until the blue color disappeared (ca. 10 min). Dimethylsulfide
(1.20 g, 19.25 mmol, 5.0 equiv) was added. The reaction mixture was stir-
red for 10 minutes at ꢀ788C and was then allowed to warm to 08C and
stirred overnight at this temperature. The solvents were removed in
vacuo. MTBE (50 mL) and water (30 mL) were added. The phases were
separated and the organic layer was washed with water (25 mL). The
combined aqueous phases were extracted with MTBE (2î100 mL). The
combined organic phases were dried (MgSO4) and the solvents were re-
moved in vacuo.
1454(m), 1318(m), 1141(w), 1017(s), 686(m) cmꢀ1 1H NMR (300 MHz,
.
CDCl3): d=6.03 5.94 (m, 1H; vinyl H), 5.92 5.75 (m, 3H; vinyl H),
4.35 4.25 (m, 1H; CHOH), 2.60 2.43 (m, 1H), 2.42 2.18 (m, 4H), 1.87
(brs, 1H; OH), 1.18 1.11 ppm (m, 3H). 13C NMR (75 MHz, CDCl3): d=
126.3 (CH), 125.8 (CH), 125.5 (CH), 124.0 (CH), 88.2 (C), 79.5 (C), 64.4
(CH), 40.4 (CH), 25.2 (CH2), 13.8 (CH3), 12.8 ppm (CH2). MS (EI): 160
(4, [MꢀH2]+), 83 (47), 80 (46), 79 (100), 77 (20), 55 (43). HRMS:
([MꢀH2]+) calcd for C11H12O: 160.0888; found: 160.0892.
(4R,5R)-5-butyl-4-(hydroxymethyl)dihydrofuran-2(3H)-one (21a): A so-
lution of 19a (843 mg, 5.20 mmol, 1.0 equiv) in dry CH2Cl2 (60 mL) was
cooled to ꢀ788C and ozone was bubbled through the solution until a
blue color could be observed (ca. 45 min). Oxygen was bubbled through
the solution until the blue color disappeared (ca. 15 min). Dimethylsul-
The collected material (1.18 g) was dissolved in EtOH (100 mL). A cata-
lytic amount (ca. 30 mg) of Pd/C was added to the solution. The suspen-
sion was stirred overnight under a hydrogen atmosphere at ambient pres-
4182
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4171 4185

Cyclohexadienyl Ti in Stereoselective Synthesis
4171 4185
fide (1.61 g, 26.02 mmol, 5.0 equiv) was added. The reaction mixture was
stirred for 10 minutes at ꢀ788C and was then allowed to warm to 08C,
and was stirred overnight at this temperature. The solvents were removed
in vacuo. Et2O (20 mL), acetone (20 mL), and water (10 mL) were
added. The phases were separated and the organic layer was washed with
water (10 mL). The combined aqueous phases were extracted with
MTBE (3î20 mL). The combined organic phases were dried (MgSO4)
and the solvents were removed in vacuo.
191 mmol, 1.0 equiv), AIBN (9.5 mg, 58 mmol, 0.33 equiv), and diene 23
(102.5 mg, 382 mmol, 2.0 equiv) were dissolved in hexane (1.0 mL) and
heated to 808C in a sealed tube. The reaction mixture was stirred over-
night at 808C. The solvent was removed in vacuo. trans-Whiskylactone
was isolated by FC (P/MTBE 4:1) as a colorless oil (22 mg, 141 mmol,
74%). d.r. (syn:anti)>99:1; e.r.=97:3, determined by GC analysis; reten-
tion times: major diastereoisomer: enantiomer 1: 25.27 min, enantiomer
2: 25.80 min; minor diastereoisomer: enantiomer 1: 32.89 min, enantiom-
er 2: 33.35 min. IR (neat): n˜ =2959(m), 2934(m), 2873(w), 1781(s),
The collected material (864 mg) was dissolved in EtOH (60 mL). A cata-
lytic amount of Pd/C (ca. 20 mg) was added to the solution. The suspen-
sion was stirred overnight under a hydrogen atmosphere at ambient pres-
sure and temperature and was then passed over a short celite pad. The
solvent was removed in vacuo. The crude lactol 20a (804 mg) obtained
by this method was used without further purification in the next step.
1667(m), 1460(w), 1212(m), 1172(m), 985(m) cmꢀ1 1H NMR (400 MHz,
.
CDCl3): d=4.01 (dt, 1H, J1 =7.7, J2 =4.0 Hz; OCH), 2.70 2.60 (m, 1H),
2.25 2.14 (m, 2H), 1.72 1.30 (m, 6H), 1.12 (d, 3H, J=6.4 Hz; CH3),
0.91 ppm (t, 3H, J=6.4 Hz; CH3). 13C NMR (100 MHz, CDCl3): d=176.5
(C), 87.4 (CH), 37.1 (CH2), 36.0 (CH), 33.7 (CH), 27.8 (CH2), 22.4 (CH2),
17.5 (CH3), 13.8 ppm (CH3). MS (ESI): 335 (35, [2M+Na]+), 211 (100),
179 (40, [M+Na]+), 157 (20, [M+H]+). HRMS (ESI): calcd for
C9H16O2Na ([M+Na]+): 179.1048; found: 179.1031.
Lactol 20a (1.19 g, 6.91 mmol) was dissolved in acetone (200 mL) and
cooled to 08C. Freshly prepared Jones reagent (6.90 g CrO3, 4.90 mL
H2SO4, 9.80 mL H2O; 10.0 equiv) was cooled to 08C and added dropwise
to the reaction mixture. The mixture was stirred for 2.25 h at 08C, and
then iPrOH was added carefully to the brownish solution to destroy
excess reagent. CH2Cl2 (100 mL) and water (50 mL) were added to the
reaction mixture and the phases were separated. The aqueous layer was
extracted four times with CH2Cl2 (4î50 mL). The combined organic
layers were dried (MgSO4). After evaporation of the solvents in vacuo,
the lactone acid (1.18 g) corresponding to lactol 20a was obtained as a
yellow oil. This crude product was used without further purification in
the next step.
All data are in accordance with the values reported in the literature.[22a]
Synthesis of (4S,5R)-4-methyl-5-pentyldihydrofuran-2(3H)-one (trans-
cognac lactone):
(1S)-1-[(1R)-Cyclohexa-2,4-dien-1-yl]hex-2-yn-1-ol (19b): GP 2 was used
to obtain homoallylic alcohol 19b from CpTiCl3 (2.19 g, 10.00 mmol),
TADDOL (4.68 g, 10.00 mmol), NEt3 (3.07 mL, 22.00 mmol), cyclohexa-
dienyllithium (9.50 mmol, prepared according to GP 1), and hex-2-yn-1-
al (18b; 456 mg, 4.75 mmol). FC (P/MTBE 10:1) yielded 19b (480 mg,
57%) as a colorless oil. The diastereomeric and the enantiomeric ratios
were not determined. IR (neat): n˜ =3386(brs), 3039(w), 2963(m),
2872(m), 2231(w), 1457(w), 1430(m), 1380(m), 1034(s), 1007(m),
A procedure described by Mori et al.[27] was applied. Crude lactone acid
(266 mg, 1.43 mmol, 1.0 equiv) was dissolved in THF (10 mL) and cooled
to 08C. BH3¥SMe2 (10.0m in THF, 0.18 mL, 1.79 mmol, 1.25 equiv) was
added and the mixture was stirred for 3.5 h at this temperature. The reac-
tion was stopped by the addition of MeOH (ca. 5 mL) and the solvents
were removed in vacuo. The residue was dissolved in MeOH (10 mL)
and the solution was evaporated in vacuo. This procedure was repeated.
The residue was purified by FC (PE/EtOAc 1:1) and the product 21a
was obtained as a colorless oil (38 mg, 0.22 mmol, 13% over all steps).
IR (neat): n˜ =3443(brs), 2934(s), 2872(m), 1771(s), 1467(w), 1195(s),
1
684(s) cmꢀ1. H NMR (300 MHz, CDCl3): d=6.03 5.95 (m, 1H; vinyl H),
5.91 5.74 (m, 3H; vinyl H), 4.33 4.28 (m, 1H; CHOH), 2.61 2.46 (m,
1H), 2.42 2.25 (m, 4H), 2.19 (dt, 2H, J1 =7.0, 5J2 =2.0 Hz; CCH2), 1.96
(brs, 1H; OH), 1.51 (sex, 2H, J=7.2 Hz; CH2CH3), 0.97 ppm (t, 3H, J=
7.5 Hz; CH2CH3). 13C NMR (75 MHz, CDCl3): d=126.4 (CH), 125.7
(CH), 125.4 (CH), 123.9 (CH), 86.7 (C), 80.4 (C), 64.4 (CH), 40.4 (CH),
25.2 (CH2), 22.0 (CH2), 20.7 (CH2), 13.4 ppm (CH3). MS (EI): 174 (3,
[MꢀH2]+), 97 (20), 95 (18), 83 (11), 80 (44), 79 (100), 77 (20), 70 (52), 55
(15), 43 (15), 41 (26). HRMS: ([MꢀH2]+) calcd for C12H14O: 174.1045;
found: 174.1038.
1
1119(m), 1078(w), 982(m), 733(m) cmꢀ1. H NMR (400 MHz, CDCl3): d=
4.36 (dt, 1H, J=7.4, 5.4 Hz; OCH), 3.69 (d, 2H, J=5.8 Hz; OCH2), 2.65
(dd, 1H, J1 =17.5, J2 =8.7 Hz; O=CCHa), 2.44 (dd, 1H, J1 =17.6, J2 =
7.0 Hz; O=CCHb), 2.40 2.34 (m, 1H; CH), 1.80 1.30 (m, 7H; CH2, OH),
0.91 ppm (t, 3H, J=7.2 Hz; CH3). 13C NMR (100 MHz, CDCl3): d=176.5
(C), 82.8 (CH), 63.0 (CH2), 42.5 (CH), 34.9 (CH2), 31.4 (CH2), 27.5
(CH2), 22.4 (CH2), 13.9 ppm (CH3). MS (ESI): 539 (100, [3M+Na]+), 367
(95, [3M+Na]+), 227 (55), 185 (55). HRMS (ESI): calcd for C27H48O9Na
([3M+Na]+): 539.3196; found: 539.3227; calcd for C18H32O6Na
([2M+Na]+): 367.2097; found: 367.2064.
(4R,5R)-4-(Hydroxymethyl)-5-pentyldihydrofuran-2(3H)-one (21b):
A
solution of 19b (1.42 g, 8.07 mmol, 1.0 equiv) in dry CH2Cl2 (80 mL) was
cooled to ꢀ788C and ozone was bubbled through the solution until a
blue color could be observed (ca. 45 min). Oxygen was bubbled through
the solution until the blue color disappeared (ca. 15 min). Dimethylsul-
fide (2.72 g, 43.9 mmol, 5.0 equiv) was added. The reaction mixture was
stirred for 10 minutes at ꢀ788C and was then allowed to warm to 08C
and was stirred overnight at this temperature. The solvents were removed
in vacuo. Et2O (30 mL), acetone (40 mL), and water (20 mL) were added
and the phases separated. The organic layer was washed with water
(20 mL). The combined aqueous phases were extracted with MTBE (3î
40 mL). The combined organic phases were dried (MgSO4) and the sol-
vents were removed in vacuo.
(4S,5R)-4-(Bromomethyl)-5-butyldihydrofuran-2(3H)-one (22a): A pro-
cedure described by Montforts et al.[28] was used. Alcohol 21a (132 mg,
776 mmol, 1.0 equiv) and CBr4 (721 mg, 2.17 mmol, 2.8 equiv) were dis-
solved in CH2Cl2 (70 mL) and cooled to 08C. After 10 min, PPh3 (1.14 g,
4.35 mmol, 5.6 equiv) was added and the ice bath was removed. The reac-
tion mixture turned dark red and was stirred overnight. The mixture was
successively washed with water, HCl (1m in H2O), and a saturated aque-
ous NaHCO3 solution (10 mL each). The phases were separated and the
organic phase dried (MgSO4). The solvent was removed in vacuo. The
residue was purified by chromatography (P/MTBE 2:1) and 22a (144 mg,
615 mmol, 79%) was obtained as a colorless oil. IR (neat): n˜ =2957(s),
2933(s), 2872(m), 1776(s), 1466(w), 1257(m), 1208(m), 1179(s), 1125(w),
A sample of the collected material (1.27 g of 1.52 g) was dissolved in
EtOH (100 mL). A catalytic amount (ca. 30 mg) of Pd/C was added to
the solution. The suspension was stirred vigorously for 60 h in an auto-
clave under hydrogen at a pressure of 20 bar and at ambient temperature.
The suspension was passed over a short celite pad and the solvent was re-
moved in vacuo. The crude lactol 20b (1.53 g) was used without further
purification in the next step.
995(m), 636(m) cmꢀ1 1H NMR (400 MHz, CDCl3): d=4.32 (dt, 1H, J1 =
.
Crude lactol 20b (744 mg, 4.00 mmol) was dissolved in acetone (60 mL)
and was cooled to 08C. Freshly prepared Jones reagent (4.00 g CrO3,
3.60 mL H2SO4, 7.20 mL H2O; 10.0 equiv) was cooled to 08C and added
dropwise to the reaction mixture. The mixture was stirred for 2.25 h at
08C, then iPrOH was added carefully to the brownish solution to destroy
excess reagent. CH2Cl2 (50 mL) and water (20 mL) were added to the re-
action mixture and the phases were separated. The aqueous layer was ex-
tracted four times with CH2Cl2 (4î50 mL). The combined organic layers
were dried (MgSO4) and the solvents were removed by evaporation in
vacuo to give a yellow oil. FC (CHCl3/MeOH/HOAc 70:10:1) yielded
(2R,3S)-5-oxo-2-pentyltetrahydrofuran-3-carboxylic acid (346 mg, 43%).
Analysis of the product provided data identical to those reported in the
7.4, J2 =5.4 Hz; OCH), 3.49 (dd, 1H, J1 =10.6, J2 =5.6 Hz; BrCHa), 3.42
(dd, 1H, J1 =10.7, J2 =6.1 Hz; BrCHb), 2.75 (dd, 1H, J1 =17.2, J2 =
8.2 Hz; O=CCHa), 2.61 2.53 (m, 1H; CH), 2.51 (dd, 1H, J1 =17.1, J2 =
7.0 Hz; O=CCHb), 1.75 1.63 (m, 2H; CH2), 1.54 1.31 (m, 4H; CH2),
0.92 ppm (t, 3H, J=6.9 Hz; CH3). 13C NMR (75 MHz, CDCl3): d=174.9
(C), 83.6 (CH), 42.4 (CH), 34.5 (CH2), 34.0 (CH), 33.6 (CH2), 27.4 (CH2),
22.3 (CH2), 13.8 ppm (CH3). MS (ESI): 491 (25, [2M+Na]+), 291 (100),
257 (45, [M+Na]+), 227 (100), 171 (30, [MꢀBr]+). HRMS (ESI): calcd
for C9H15O2BrNa ([M+Na]+): 257.0153; found: 257.0152.
(4S,5R)-5-Butyl-4-methyldihydrofuran-2(3H)-one (trans-whisky lactone):
A procedure described by Studer et al.[13] was used. Bromide 22a (45 mg,
Chem. Eur. J. 2004, 10, 4171 4185
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4183

A. Studer et al.
FULL PAPER
literature.[29] A procedure described by Mori et al.[27] was then applied.
The obtained carboxylic acid (30 mg, 150 mmol, 1.0 equiv) was dissolved
in THF (1 mL) and cooled to 08C. BH3¥SMe2 (10.0m in THF, 19 mL,
190 mmol, 1.25 equiv) was added and the mixture was stirred for 3 h at
this temperature. The reaction was terminated by the addition of MeOH
(1 mL) and the solvents were removed in vacuo. The residue was dis-
solved in MeOH (5 mL) and the solvent was evaporated in vacuo. This
procedure was repeated. The residue was purified by FC (PE/EtOAc 1:1)
and 21b was obtained as a colorless oil (14 mg, 75 mmol, 21.5% over all
steps). IR (neat): n˜ =3441(brs), 2933(s), 2872(s), 1770(s), 1467(m),
Acknowledgement
We thank the Deutsche Forschungsgemeinschaft (Grant no. STU 3 1)
and the Fonds der Chemischen Industrie for their support.
[1] Houben-Weyl, Vol. E21b, (Eds.: G. Helmchen, R. W. Hoffmann, J.
Mulzer, E. Schaumann), Thieme, Stuttgart, 1995, pp. 1357 1602; Y.
Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207.
[2] I. Fleming, A. Barbero, D. Walter, Chem. Rev. 1997, 97, 2063; E. J.
Thomas in Allylsilanes in Houben-Weyl, Vol. E21b (Eds.: G. Helm-
chen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart,
1995, p. 1491.
[3] S. E. Denmark, R. A. Stavenger, Acc. Chem. Res. 2000, 33, 432;
S. E. Denmark, J. Fu, J. Am. Chem. Soc. 2001, 123, 9488; A. V.
Malkov, M. Orsini, D. Pernazza, K. W. Muir, V. Langer, P. Meghani,
1202(s), 1118(m), 1077(w), 994(m), 948(w) cmꢀ1 1H NMR (500 MHz,
.
CDCl3): d=4.36 (dt, 1H, J=7.6, J=5.5 Hz; OCH), 3.68 (d, 2H, J=
5.5 Hz; OCH2), 2.64 (dd, 1H, J1 =17.6, J2 =8.9 Hz; O=CCHa), 2.44 (dd,
1H, J1 =17.7, J2 =8.5 Hz; O=CCHb), 2.39 2.34 (m, 1H; CH), 2.00 (brs,
1H; OH), 1.71 1.61 (m, 2H; CH2), 1.55 1.26 (m, 6H; CH2), 0.89 ppm (t,
3H, J=6.9 Hz; CH3). 13C NMR (125 MHz, CDCl3): d=176.7 (C), 83.0
(CH), 62.9 (CH2), 42.5 (CH), 35.2 (CH2), 31.5 (CH2), 31.4 (CH2), 27.5
(CH2), 22.4 (CH2), 13.9 ppm (CH3). MS (ESI): 581 (80, [3M+Na]+), 395
(100,[2M+Na]+), 241 (75), 225 (55, [M+K]+), 209 (35, [M+Na]+), 187
(15, [M+H]+). HRMS (ESI): calcd for C20H36O6Na ([2M+Na]+);
395.2410 found: 395.2426.
¬
P. Kocovsky, Org. Lett. 2002, 4, 1047; A. V. Malkov, L. Dufkova, L.
¬
Farrugia, P. Kocovsky, Angew. Chem. 2003, 115, 3802; Angew. Chem.
Int. Ed. 2003, 42, 3674; S. E. Denmark, J. Fu, Chem. Commun. 2003,
167.
[4] D. R. Schmidt, S. J. O×Malley, J. L. Leighton, J. Am. Chem. Soc.
2003, 125, 1190; K. Kubota, J. L. Leighton, Angew. Chem. 2003, 115,
976; Angew. Chem. Int. Ed. 2003, 42, 946; R. Berger, P. M. A.
Rabbat, J. L. Leighton, J. Am. Chem. Soc. 2003, 125, 9596.
[5] E. J. Thomas in Allylstannanes in Houben-Weyl, Vol. E21b (Eds.: G.
Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme,
Stuttgart, 1995, p. 1508; selected examples: M. Kurosu, M. Lorca,
Tetrahedron Lett. 2002, 43, 1765 and references cited therein; C.-M.
Yu, J.-Y. Lee, B. So, J. Hong, Angew. Chem. 2002, 114, 169; Angew.
Chem. Int. Ed. 2002, 41, 161 and references cited therein.
[6] W. R. Roush in Allylboron Reagents in Houben-Weyl, Vol. E21b
(Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann),
Thieme, Stuttgart, 1995, p. 1410; W. R. Roush, S. Chemler in
Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH, Wein-
heim, 2000, p. 403.
[7] T. Ishiyama, T.-a. Ahiko, N. Miyaura, J. Am. Chem. Soc. 2002, 124,
12414; H. Lachance, X. Lu, M. Gravel, D. G. Hall, J. Am. Chem.
Soc. 2003, 125, 10160. See also: J. W. J. Kennedy, D. G. Hall, Angew.
Chem. 2003, 115, 4880; Angew. Chem. Int. Ed. 2003, 42, 4732.
[8] D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376; Angew. Chem.
Int. Ed. Engl. 1997, 36, 2282.
[9] D. Seebach, B. Weidmann, L. Widler in Titanium and Zirconium
Derivatives in Organic Synthesis in Modern Synthetic Methods (Ed.:
R. Scheffold), Salle und Sauerl‰nder, 1983, Vol. 3, p. 217; b) M. T.
Reetz, Organotitanium Reagents in Organic Synthesis, Springer,
Berlin 1986; c) D. Hoppe in Allyltitanium and Allylzirconium Re-
agents in Houben-Weyl, Vol. E21b (Eds.: G. Helmchen, R. W. Hoff-
mann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1995, 1551.
[10] F. Schleth, A. Studer, Angew. Chem. 2004, 116, 317; Angew. Chem.
Int. Ed. 2004, 43, 313.
[11] For stereoselective dihydroxylations of silylated 1,4-cyclohexadienes,
see: R. Angelaud, O. Babot, T. Charvat, Y. Landais, J. Org. Chem.
1999, 64, 9613.
[12] Allylsilanes have been used successfully in enantioselective allyla-
tions. For examples involving chiral Lewis acids, see: D. R. Gau-
thier, Jr., E. M. Carreira, Angew. Chem. 1996, 108, 2521; Angew.
Chem. Int. Ed. Engl. 1996, 35, 2363.
[13] Silylated cyclohexadienes have been used successfully as tin hydride
substituents in radical chemistry: A. Studer, S. Amrein, Angew.
Chem. 2000, 112, 3196; Angew. Chem. Int. Ed. 2000, 39, 3080; A.
Studer, S. Amrein, F. Schleth, T. Schulte, J. C. Walton, J. Am. Chem.
Soc. 2003, 125, 5726.
[14] The major isomer of 2d was unambiguously assigned as the syn
compound by x-ray analysis. All the other compounds were assigned
by analogy with 2d. CCDC-213624 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB21EZ, UK; fax: (+44)1223-336-033; or deposit@ccdc.
cam.ac.uk).
(4S,5R)-4-(Bromomethyl)-5-pentyldihydrofuran-2(3H)-one (22b): A pro-
cedure described by Montforts et al.[28] was used. Alcohol 21b (76 mg,
409 mmol, 1.0 equiv) and CBr4 (379 mg, 1.14 mmol, 2.8 equiv) were dis-
solved in CH2Cl2 (30 mL) and cooled to 08C. After 10 min, PPh3
(600 mg, 2.29 mmol, 5.6 equiv) was added and the ice bath was removed.
The reaction mixture turned dark red and was stirred overnight. The mix-
ture was successively washed with water, HCl (1m in H2O), and a saturat-
ed aqueous solution of NaHCO3 (5 mL each). The phases were separated
and the organic phase was dried (MgSO4). The solvent was removed in
vacuo. The residue was adsorbed on silica gel and was purified by FC (P/
MTBE 2:1). 22b (68 mg, 273 mmol, 67%) was obtained as a colorless oil.
IR (neat): n˜ =2931(m), 2860(m), 1777(s), 1465(w), 1258(m), 1177(s),
1108(m), 999(m), 617(m) cmꢀ1 1H NMR (500 MHz, CDCl3): d=4.31 (m,
.
1H; OCH), 3.47 (dd, 1H, J1 =10.7, J2 =5.8 Hz; BrCHa), 3.41 (dd, 1H,
J1 =10.5, J2 =6.2 Hz; BrCHb), 2.75 (dd, 1H, J1 =17.4, J2 =8.5 Hz; O=
CCHa), 2.61 2.53 (m, 1H; CH), 2.50 (dd, 1H; J1 =17.4, J2 =7.1 Hz; O=
CCHb), 1.73 1.62 (m, 2H; CH2), 1.54 1.27 (m, 6H; CH2), 0.93 0.88 ppm
(m, 3H; CH3). 13C NMR (125 MHz, CDCl3): d=174.9 (C), 83.7 (CH),
42.4 (CH), 34.9 (CH2), 34.0 (CH), 33.6 (CH2), 31.4 (CH2), 25.0 (CH2),
22.4 (CH2), 13.9 ppm (CH3). MS (ESI): 521 (100, [2M+Na]+), 303 (100),
289 (65, [M+K]+), 273 (25, [M+Na]+), 249 (55, [M+H]+), 223 (100), 201
(72). HRMS (ESI): calcd for C10H17O2BrNa ([M+Na]+): 271.0310;
found: 271.0307.
(4S,5R)-4-methyl-5-pentyldihydrofuran-2(3H)-one (trans-cognac lactone):
A procedure described by Studer et al.[13] was used. Bromide 22b (34 mg,
136 mmol, 1.0 equiv), AIBN (7.5 mg, 46 mmol, 0.33 equiv), and diene 23
(73 mg, 273 mmol, 2.0 equiv) were dissolved in hexane (1.5 mL) and
heated to 808C in a sealed tube. The reaction mixture was stirred over-
night at 808C. The solvent was removed in vacuo. FC (P/MTBE 4:1)
gave trans-cognaclactone as a colorless oil (22 mg, 130 mmol, 95%). d.r.
(syn:anti)>99:1; e.r.=97.5:2.5, determined by GC analysis; retention
times: minor diastereoisomer: enantiomer 1: 21.78 min, enantiomer 2:
22.40 min; major diastereoisomer: enantiomer 1: 35.52 min, enantiomer
2: 36.54 min). IR (neat): n˜ =2958(m), 2933(m), 2861(w), 1779(s),
1669(m), 1458(w), 1210(m), 1169(m), 1107(s), 1003(w), 938(m) cmꢀ1
.
1H NMR (500 MHz, CDCl3): d=4.01 (dt, 1H, J1 =7.7, J2 =3.9 Hz; OCH),
2.73 2.63 (m, 1H; O=CCHa), 2.28 2.15 (m, 2H, CH; O=CCHb); 1.72
1.27 (m, 8H; CH2), 1.14 (d, 3H, J=6.5 Hz; CH3), 0.89 ppm (t, 3H, J=
6.4 Hz; CH3). 13C NMR (125 MHz, CDCl3): d=176.9 (C), 87.5 (CH), 37.1
(CH2), 36.1 (CH), 34.0 (CH2), 31.6 (CH2), 25.4 (CH2), 22.5 (CH2), 17.5
(CH3), 13.6 ppm (CH3). MS (ESI): 376 (80, [2M+Na]+), 307 (35), 225
(90, [M+Na+MeOH]+), 193 (100, [M+Na]+), 171 (20, [M+H]+), 153
(30). HRMS (ESI): calcd for C11H22O3Na ([M+MeOH+Na]+): 225.1467;
found: 225.1460; calcd for C10H19O2 ([M+H]+): 171.1386; found:
171.1299; calcd for C10H18O2Na ([M+Na]+): 193.1205; found: 193.1187.
All data are in accordance with those given in the literature.[22a]
[15] H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66.
4184
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4171 4185

Cyclohexadienyl Ti in Stereoselective Synthesis
4171 4185
[16] R. W. Hoffmann, B. Hˆlzer, Chem. Commun. 2001, 491.
[17] For an excellent review on the use of TADDOLs in asymmetric syn-
thesis, see: D. Seebach, A. K. Beck, A. Heckel, Angew. Chem. 2001,
113, 96; Angew . Chem. Int. Ed. 2001, 40, 92.
[18] A. Hafner, R. O. Duthaler, R. Marti, G. Rihs, P. Rothe-Streit, F.
Schwarzenbach, J. Am. Chem. Soc. 1992, 114, 2321.
[19] D. Seebach, A. K. Beck, S. Roggo, A. Wonnacott, Chem. Ber. 1985,
118, 3673.
[20] For allylations involving B-allyldiisopinocampheylborane, see: H. C.
Brown, P. K. Jadhav, J. Am. Chem. Soc. 1983, 105, 2092.
1cald =1.124 gcmꢀ3 for Z=2, F(000)=328, m=0.078 mmꢀ1, STOE
IPDS-II image plate diffractometer, l=0.71069 ä, T=193(2) K,
6416 reflections, qmax =258, 3044 independent (Rint =0.0479) and
2029 observed reflections [Iꢃ2s(I)], empirical absorption correction
(multiscan method), solution by direct methods (SIR92, a program
for crystal structure solution; A. Altomare, G. Cascarano, C. Giaco-
vazzo, A. Guagliardi, J. Appl. Crystallogr. 1993, 26, 343), anisotropic
refinement (SHELXL-97, a program for crystal structure refine-
ment; release 97-2; G. M. Sheldrick, University of Gˆttingen, Ger-
many), O-bonded hydrogen atoms located and isotropically refined,
other hydrogen atoms at calculated positions with fixed isotropic
temperature factors, 197 refined parameters, R=0.0489 (observed
data), wR2 =0.1393 (independent data).
[21] R. O. Duthaler, A. Hafner, P. L. Alsters, G. Bold, G. Rihs, P. Rothe-
Streit, B. Wyss, Inorg. Chim. Acta 1994, 222, 95.
[22] For recent syntheses of nephrosteranic acid, see: a) H. Takahata, Y.
Uchida, T. Momose, J. Org. Chem. 1995, 60, 5628; b) P. A. Jacobi, P.
Herradura, Can. J. Chem. 2001, 79, 1727; c) M. P. Sibi, P. Liu, J. Ji, S.
Hajra, J.-x. Chen, J. Org. Chem. 2002, 67, 1738; d) R. B. Chhor, B.
Nosse, S. Sˆrgel, C. Bˆhm, M. Seitz, O. Reiser, Chem. Eur. J. 2003,
9, 260; M. T. Barros, C. D. Maycock, M. N. Ventura, Org. Lett. 2003,
5, 4097.
[25] For syntheses, see: ref. [22a]; A. Schlapbach, R. W. Hoffmann, Eur.
J. Org. Chem. 2001, 323; F. Benedetti, C. Forzato, P. Nitti, G. Pitac-
co, E. Valentin, M. Vicario, Tetrahedron: Asymmetry 2001, 12, 505;
P. Bertus, P. Phansavath, V. Ratovelomanana-Vidal, J.-P. GenÜt,
A. R. Touati, T. Homri, B. Ben Hassine, Tetrahedron: Asymmetry
1999, 10, 1369.
[23] C. Harcken, R. Br¸ckner, E. Rank, Chem. Eur. J. 1998, 4, 2342.
[24] CCDC-232209 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK; fax: (+44)1223-336-033; or deposit@ccdc.cam.ac.
uk). Crystallographic data (C17H30O4, Mr =298.41): crystal size:
0.32î0.15î0.05 mm3, monoclinic, space group P21, a=5.4541(7),
b=29.223(2), c=5.5365(5) ä, b=91.522(9)8, V=882.09(16) ä3,
[26] C. Eaborn, R. A. Jackson, R. Pearce, J. Chem. Soc. Perkin Trans. 1
1975, 470.
[27] K. Mori, K. Yamane, Tetrahedron 1982, 38, 2919.
[28] M. Wedel, A. Walter, F.-P. Montforts, Eur. J. Org. Chem. 2001, 1681.
[29] A. Vaupel, P. Knochel, J. Org. Chem. 1996, 61, 5743.
Received: March 12, 2004
Published online: July 14, 2004
Chem. Eur. J. 2004, 10, 4171 4185
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4185