Synthesis of Enantiopure Homoallylic Ethers by Reagent Controlled Facial Selective Allylation of Chiral Ketones

Article abstract of DOI:10.1002/1521-3765(20010105)7:1<161::AID-CHEM161>3.0.CO;2-9

The stereoselective allylation of chiral methyl ketones to give tertiary homoallylic ethers, which can easily be transformed into homoallylic alcohols, is described. Reaction of the enantiopure ketones 8a-d and the racemic ketones 26a-d with the norpseudoephedrine derivative 2 or ent-2 and allylsilane in the presence of a catalytic amount of trifluoromethanesulfonic acid, led to a series of homoallylic ethers with good to excellent diastereoselectivity (85:15 to > 97:3). The allylation is reagent controlled and nearly independent from the stereogenic centers in the substrates. A partial kinetic resolution was observed using the racemic ketones 26a-d. In the reaction of the chiral ketones 8a-d with the achiral reagents ethoxytrimethylsilane and allylsilane only a low diastereoselectivity was observed.

Full text of DOI:10.1002/1521-3765(20010105)7:1<161::AID-CHEM161>3.0.CO;2-9

FULL PAPER
Synthesis of Enantiopure Homoallylic Ethers by Reagent Controlled Facial
Selective Allylation of Chiral Ketones
Lutz F. Tietze,* Berthold Weigand, Ludwig Völkel, Christian Wulff, and Christian Bittner[a]
Dedicated to Professor Horst Kunz on the occasion of his 60th birthday
Abstract: The stereoselective allylation of chiral methyl ketones to give tertiary
homoallylic ethers, which can easily be transformed into homoallylic alcohols, is
described. Reaction of the enantiopure ketones 8a ± d and the racemic ketones 26a ± d
with the norpseudoephedrine derivative 2 or ent-2 and allylsilane in the presence of a
catalytic amount of trifluoromethanesulfonic acid, led to a series of homoallylic
Keywords: amino alcohols ´ double
stereodifferentiation
´ homoallylic
ethers with good to excellent diastereoselectivity (85:15 to >97:3). The allylation is
reagent controlled and nearly independent from the stereogenic centers in the
substrates. A partial kinetic resolution was observed using the racemic ketones
26a ± d. In the reaction of the chiral ketones 8a ± d with the achiral reagents
ethoxytrimethylsilane and allylsilane only a low diastereoselectivity was observed.
alcohols ´ silanes
Ph COCF3
NH
Introduction
OTBDPS
TMSO
+
O
The facial-selective addition of allylmetals to aldehydes or
acetals to obtain enantiopure homoallylic alcohols or ethers is
a widely used process in organic chemistry.[1] Typically, either
1
2
TBDPSO
an equimolar amount of a chiral allyl reagent such as
TMS
, TfOH
Ph COCF3
NH
3
allylboranes and allyltitanium compounds, or chiral acetals
CH2Cl2, -78 o
C
O
or chiral catalysts are employed.[2±5] However, all of these
reagents, which give excellent selectivity with aldehydes, fail
when applied to simple ketones.[6]
4
Na, NH3
OH
Recently we have demonstrated that reaction of aliphatic
aldehydes with allylsilanes in the presence of the trimethyl-
silyl ether of N-trifluoroacetylnorpseudoephedrine (2) and a
catalytic amount of TMSOTf leads to secondary homoallylic
ethers with an asymmetric induction of >99:1.[7] Reductive
cleavage using sodium in liquid ammonia provides the
corresponding enantiopure homoallylic alcohols. In contrast
to the other known allylation methods, this procedure can also
be applied for the stereoselective synthesis of tertiary
homoallylic ethers and alcohols using simple ketones as
starting material;[8] allylation of for example the ketone 1
gives the homoallylic alcohol 5 in ꢀ96% ee through the ether
4 (Scheme 1). Noteworthy, the allylation of ketones and
OTBDPS
5
≥96% ee
Scheme 1. Allylation of ketone 1 with 3 in presence of 2.
aldehydes creates the opposite absolute configuration at the
newly formed stereogenic center due to different reaction
mechanisms.[7, 8]
Reaction of chiral substrates with chiral reagents under
formation of a new stereogenic center usually leads to the
formation of a ªmatched and a mismatched pairº.[9] Rather
frequently only one of the possible diastereomers can be
obtained with high selectivity. It is therefore of great synthetic
relevance whether a procedure allows the selective formation
of the possible diastereomers independent of the configura-
tion of the stereogenic centers in the substrate.[7] For the facial
selective allylation of chiral ketones we prepared the four
[a] Prof. Dr. Dr. h.c. L. F. Tietze, Dipl.-Chem. B. Weigand,
Dipl.-Chem. L. Völkel, Dr. C. Wulff, Dipl.-Chem. C. Bittner
Institut für Organische Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax : (‡ 49)551-399476
E-mail: ltietze@gwdg.de
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161

L. F. Tietze et al.
FULL PAPER
enantiopure methyl ketones 8a ± d (see Scheme 2) containing
at least a stereogenic center in the a- or b-position. In
addition, we also synthesized and employed the racemic
ketones 26a ± d (see Scheme 5) to investigate whether a
kinetic resolution is possible. Finally, we allylated the
enantiopure ketones 8a ± d using achiral reagents to deter-
mine the induced diastereoselectivity in this type of trans-
formation.
obtained from commercially available (R)-3-phenylbutyric
acid (15) by treatment with methyllithium.[15]
For the investigation of the double stereodifferentiation,
the enantiopure methyl ketones 8a ± d were allylated in
presence of the (S,S)- and (R,R)-norpseudoephedrine deriv-
atives 2 and ent-2, respectively, to obtain the diastereomeric
homoallylic ethers 16/17a ± d and 19/20a ± d (Scheme 3). The
allylations were carried out in a domino-type reaction by
mixing two equivalents of the chiral ketones 8a ± d with 2 as
well as ent-2 and 2.5 equivalents allylsilane 3 in dichloro-
methane at ꢁ788C, subsequent addition of a catalytic amount
of TfOH and stirring for 3 d at ꢁ788C.[16] The reaction of
Results and Discussion
Synthesis and allylation of enantiopure aliphatic methyl
ketones 8a ± d: Ketone 8a was obtained from commercially
available (ꢁ)-dihydrocarveol (6) in an overall yield of 88% by
protecting the hydroxyl group with TBDPSCl and subsequent
ozonolysis of the alkenyl moiety (Scheme 2). For comparison
TMS
Ph COCF3
NH
O
, TfOH
3
+
TMSO
R*
CH2Cl2, -78 o
C
8a-d
2
Ph COCF3
NH
Ph COCF3
R*
O
R*
4
O
2
1′
+
+
NH
2′
O
O
1
3
16a-d
17a-d
b
c
Ph COCF3
NH
80%
93%
HO
OR
OH
OTBDPS
9
8a
6
7
R = H
a
18
(95%)
R = TBDPS
TMS
Ph COCF3
NH
O
, TfOH
3
O
OH
+
TMSO
R*
CH2Cl2, -78 o
C
e, f
57%
d
8a-d
ent-2
CHO
84%
R*
R*
Ph COCF3
NH
Ph COCF3
NH
+
+
O
O
10
8b
11
19a-d
20a-d
Ph COCF3
NH
OR1
O
TBDPSO
O
i
HO
R2
64%
12-14
8c
ent-18
12
13 R1 = TBDPS; R2 = OMe
14
1 = TBDPS; R2 = OH
R
1 = H; R2 = OMe
g (88%)
h (81%)
R*:
R
OTBDPS
a
b
Ph
O
Ph
O
OTBDPS
Ph
i
54%
OH
15
8d
c
d
Scheme 2. Synthesis of enantiopure ketones 8a ± d. a) TBDPSCl, imida-
zole, RT; b) O3, CH2Cl2/MeOH, ꢁ788C, PPh3; c) TBAF, THF, RT;
d) MeMgCl, THF, ꢁ788C; e) H2, Pd/C, MeOH, 71%; f) Dess ± Martin
periodinane, CH2Cl2, RT, 80%; g) TBDPSCl, imidazole, THF, RT;
h) NaOH, iPrOH/H2O, 708C; i) MeLi, Et2O, ꢁ788C.
Scheme 3. Allylation of enantiopure ketones 8a ± d in the presence of 2
and ent-2.
unbranched ketones usually proceeds within a few hours,
although in the case of the chiral ketones 8 the reaction is
slower. For comparison of all transformations we therefore
used a reasonable long reaction time. However, in the
reaction of 8a and 2 the allylation was not complete even
after that time. All reactions proceeded rather well with only
small amounts of the alcohols 18 and ent-18 as by-products
and not converted starting material 8a ± d and 2/ent-2. We
have recently found that the two-fold excess of the methyl
ketones can be reduced to one equivalent by using additives,
such as diisopropyl ketone without any loss in reactivity or
8a was deprotected with TBAF ´ 3H2O to give 9.[10] For the
synthesis of 8b, (R)-citronellal (10) was treated with MeMgCl
to yield alcohol 11 which was first hydrogenated and then
oxidized to give 8b in 48% overall yield.[11] The b-silyloxy-
ketone 8c was synthesized from enantiopure b-hydroxyester
12 in 52% yield by protection of the alcohol moiety to give 13,
subsequent saponification, and treatment of carboxylic acid
14 with methyllithium.[12±14] Finally, the methyl ketone 8d
containing a phenyl group at the stereogenic center was
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Chem. Eur. J. 2001, 7, No. 1

Enantiopure Homoallylic Ethers
161±168
selectivity;[8] this procedure, however, failed with ketones
8a ± c. In contrast, in the reactions of 8d the yields of the
homoallylic ethers 16d/17d and 19d/20d could be increased
from 25% to 67% by addition of 10 equivalents diisopropyl
ketone in presence of two equivalents of 2 and ent-2,
respectively. The additive does not undergo an allylation
under the reaction conditions.
Table 2. Allylation of enantiopure ketones 8a ± d (2 equiv) in the presence
of achiral 21 (1 equiv).
Ketone
Product
Diastereomeric
ratio
Yield/%
[a]
8a
8b
8c
8d
22a
22b
22c
22d
±
±
2.0:1[b]
1.5:1[c]
2.1:1[b]
82
89
75
The obtained facial selectivity in the allylations of 8a ± d
ranged from 85:15 for the reaction of 8d in the presence of
ent-2 to >97:3 for 8c with 2 and ent-2 (Table 1). Noteworthy,
in the reaction of 8a with a stereogenic center in the a-
position, no epimerization did take place. The difference in
the selectivities found for the reactions of 8a ± d with 2 and
ent-2 was either very small or was non-existent, which clearly
indicates a strong reagent control. The ratio of the formed
homoallylic ethers 16a ± d/17a ± d and 19a ± d/20a ± d was
determined by 13C NMR spectroscopy of the crude products.
[a] No conversion. [b] Determination by GC. [c] Determination by
13C NMR spectroscopy.
products is the reaction of racemic chiral substrates with
enantiopure reagents or catalysts by kinetic resolution. For
this purpose we prepared the racemic ketones 26a ± c and
used them together with the commercially available racemic
26d for the allylation in the presence of ent-2
(Scheme 5).[12±15, 18]
Table 1. Synthesis of homoallylic ethers 16a ± d/17a ± d and 19a ± d/20a ± d
from enantiopure ketones 8a ± d (2 equiv) in the presence of 2 and ent-2
(1 equiv).
OR1
O
TBDPSO
O
c
R2
70%
[b]
Ratio[a]
[a]D
Yield/%[c]
rac-26a
Ketone
Reagent
Product
8a
8a
8b
8b
8c
8c
8d
8d
2
16a/17a
19a/20a
16b/17b
19b/20b
16c/17c
19c/20c
16d/17d
19d/20d
97:3
96:4
‡ 11.3
ꢁ 29.0
‡ 24.3
ꢁ 18.0
‡ 11.2
ꢁ 20.0
ꢁ 26.6
‡ 24.3
36 (91)
64 (84)
52 (87)
44 (73)
41 (85)
44 (79)
67 (76)
66 (80)
rac-23 R1 = H; R2 = OMe
a (93%)
b (92%)
ent-2
2
ent-2
2
ent-2
2
ent-2
rac-24 R1 = TBDPS; R2 = OMe
rac-25 R1 = TBDPS; R2 = OH
90:10
89:11
> 97:3
> 97:3
87:13
85:15
Ph
O
Ph
O
rac-26b
O
d
56%
OH
OH
[a] Determination by 13C NMR spectroscopy. [b] c ˆ 0.5 in CHCl3. [c]
rac-27
Yields in brackets are based on recovered starting material.
O
e
71%
Induced diastereoselectivity of the allylation of chiral methyl
ketones 8a ± d with achiral reagents: For comparison we also
performed the allylation of the chiral ketones 8a ± d with
achiral reagents. Reaction of 8b ± d with ethoxytrimethylsi-
lane (21) and allylsilane 3 led to the homoallylic ethers 22b ± d
applying the same conditions as described for the trans-
formations with 2 and ent-2 (Scheme 4).
Ph
Ph
rac-28
rac-26c
O
rac-26d
Scheme 5. Synthesis of racemic ketones rac-26a ± d. a) TBDPSCl, imida-
zole, THF, RT; b) NaOH, iPrOH/H2O, 708C; c) MeLi, Et2O, ꢁ788C;
d) MeLi, Et2O, ꢁ788C; e) MeLi, Et2O, 08C.
TMS
R*
O
O
, TfOH
3
+
R*
TMSO
21
CH2Cl2, -78 o
C
8 a-d
22 a-d
In these reactions four diastereomers were formed. How-
ever, as expected the two isomers 29a ± d and 29-ent-a ± d
were the major or as for the reaction of 26a the only products;
in the other cases three out of the four possible isomers could
be detected by gas chromatography and 13C NMR spectros-
copy (Scheme 6). The ratio of the major and minor isomers 29
and 30 ranged from 89:11 to >97:3, whereas for the major
isomers 29a-d/ent-a ± d a ratio of 1.4:1 to 2.1:1 was observed;
this indicates that under the applied reaction conditions a
partial kinetic resolution did occur (Table 3). Since the kinetic
resolution usually depends on the stage of transformation we
determined the ratio of the major isomers formed in the
allylation of racemic 26c after 12 h, 1 d, 3 d, and 5 d.[17] As
expected, with increasing transformation a decrease of the
kinetic resolution from 1.6:1 to 1.5:1 was observed.
Scheme 4. Allylation of enantiopure ketones 8a ± d in the presence of
achiral 21.
Surprisingly, methyl ketone 8a did not react under these
conditions and only the starting material was recovered. In the
other cases a mixture of diastereomers was formed with a
rather low selectivity ranging from 1.5 to 2.1:1 (Table 2). The
diastereomeric ratios were determined by gas column chro-
matography and 13C NMR spectroscopy. A separation of the
isomers by preparative chromatography was, however, not
possible.
Allylation of racemic chiral ketones 26a ± d in the presence of
ent-2: A general procedure for the synthesis of enantiopure
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163

L. F. Tietze et al.
FULL PAPER
1
d ˆ 1.05 with J ˆ 6.8 Hz is found. The H NMR spectrum of
22d is quite similar to that of 16d, except that the signals for
the ephedrine moiety are missing. Instead signals for the
ethoxy group are found at d ˆ 3.24 as a quartet with J ˆ 7.0 Hz
and at d ˆ 1.04 as a triplet with J ˆ 7.0 Hz for the major
diastereomer.
Conclusion
The described allylation of methyl ketones using the nor-
pseudoephedrine derivative 2 as well as ent-2 and allylsilane 3
is the only method known at this time, which allows the highly
stereoselective preparation of enantiopure tertiary homoal-
lylic ethers and alcohols from simple ketones. The method
shows a strong reagent control allowing a good to excellent
facial selectivity up to >97:3 independent of the stereogenic
centers in the substrate. Thus, the selectivity for the ªmatched
and mismatched pairsº is nearly identical. Using racemic
mixtures of chiral methyl ketones, a partial kinetic resolution
was observed, which, however, is not very pronounced.
Scheme 6. Allylation of ketones rac-26a ± d in the presence of ent-2.
Experimental Section
Table 3. Allylation of racemic chiral ketones 26a ± d (2 equiv) in the
presence of ent-2 (1 equiv) for 3 d.
General aspects: All reactions were performed in flame-dried glassware in
an atmosphere of argon unless noted otherwise. Melting points were
determined on a Mettler FP61 and are uncorrected. Optical rotations were
measured on a Perkin ± Elmer 241 digital polarimeter in a 1 dm cell. IR
spectra were recorded on a Bruker IFS 25 FT-IR instrument and 1H NMR
and 13C NMR spectra with a Bruker AM-300, a Varian VXR-200 or a
Varian VXR-500. Chemical shifts were reported on the d scale relative to
CDCl3 as an internal standard. Mass spectra were measured at 70 eV with a
Varian MAT 311A. GC analysis was carried out with hydrogen as carrier
gas on a DB 1701 column (J&W Scientific, 0.25 mm  50 m). HPLC
analysis was carried out on a Chiralcel OD-R (250 mm, 0.46 cm). TLC
chromatography was performed on precoated silica gel SIL G/UV254
aluminum plates (Macherey Nagel), and silica gel 32 ± 63 (0.032 ±
0.064 mm) (Macherey Nagel) was used for column chromatography.
Microanalyses were carried out by the Mikroanalytisches Labor des
Instituts für Organische Chemie der Universität Göttingen.
Ketone Product
Ratio 29a ± d/ent-29a ± d Ratio 29:30 Yield/%[c]
26a
26b
26c
26d
29a/29-ent-a
1.4:1[a]
> 97:3[a]
92:8[a]
45 (84)
51 (79)
21 (85)[d]
29b/29-ent-b
29c/29-ent-c
29d/29-ent-d
1.5:1[a]
1.5:1[a, b]
2.1:1[a, b]
91:9[a, b]
90:10[a, b] 71
[a] Determination by 13C NMR spectroscopy. [b] Determination by GC.
[c] Yields are based on ent-2, in brackets are the numbers based on
recovered ent-2. [d] Reaction time: 5 d.
A preparative separation of the isomers and their structure
elucidation was not possible. However, in analogy to the
products obtained from 8a ± d in the presence of ent-2 the
newly formed stereogenic center in 29a ± d and 29-ent-a ± d
should have the R configuration.
(1R,2R,5R)-5-Isopropenyl-2-methyl-1-(tert-butyldiphenylsilanyloxy)-cy-
clohexane (7): A solution of (ꢁ)-dihydrocarveol (6) (1.54 g, 10.0 mmol),
TBDPSCl (3.02 g, 11.0 mmol), and imidazole (1.50 g, 22.0 mmol) in dry
DMF (6 mL) was stirred for 2 h at room temperature. The mixture was
poured into a mixture of CH2Cl2 (100 mL) and water (400 mL). The layers
were separated and the aqueous layer was extracted with CH2Cl2 (3 Â
50 mL) and the combined organic layers were dried over Na2SO4. The
solvent was evaporated in vacuo and the crude product was purified on
Structure elucidation of the homoallylic ethers: The structure
of the obtained homoallylic ethers 16a ± d, 17a ± d, 19a ± d and
20a ± d, as well as 22b ± d, 29a ± d and 30a ± d was determined
1
by H and 13C NMR spectroscopy. The relative configuration
silica gel (n-pentane/tert-butyl methyl ether 10:1) to give
7 (3.73 g,
of the stereogenic centers in the products was correlated to an
X-ray crystallographic analysis obtained for 16d.[19] As
representatives for all new products the H NMR spectra of
9.50 mmol, 95%). [a]2D0 ˆ ꢁ46.38 (c ˆ 1, CHCl3); 1H NMR (200 MHz,
CDCl3): d ˆ 0.72 ± 1.81 (m, 11H), 0.97 (d, J ˆ 6.0 Hz, 3H), 1.07 (s, 9H),
3.20 ± 3.36 (m, 1H), 4.46 ± 4.67 (m, 2H), 7.29 ± 7.78 (m, 10H); 13C NMR
(50.3 MHz, CDCl3): d ˆ 19.36, 19.52, 20.91, 27.06, 30.93, 33.31, 40.43, 40.99,
43.89, 78.41, 108.1, 127.6, 127.4, 129.3, 129.4, 134.4, 135.2, 135.8, 135.8, 136.0,
149.5; IR (film): nĈ 3070, 3050, 3014, 2930, 2858, 1108, 888, 740 cmꢁ1; MS
1
16d and 22d are discussed. The hydrogens at the vinyl group
of 16d resonate at d ˆ 5.02 ± 5.12 and d ˆ 5.68 ± 5.82 as
multiplets; for the methyl group at the newly formed stereo-
genic center a singulet at d ˆ 0.81 is observed, and the
norpseudoephedrine moiety gives signals at d ˆ 4.53 as a
doublet with J ˆ 3.8 Hz and a multiplet at d ˆ 3.98 ± 4.12. The
signals for the phenyl groups are found at d ˆ 7.12 ± 7.32 and
the signal for the NH group at d ˆ 5.97 as a broad doublet with
J ˆ 8.0 Hz. The diastereotopic protons 3-H resonate at d ˆ
2.28 ± 2.36 and 5-H at d ˆ 1.77 ± 2.00. For the benzylic hydro-
gen 6-H a multiplet at d ˆ 2.90 ± 3.10 and for 7-H a doublet at
‡
‡
(70 eV, CI): m/z (%): 410 (100) [M‡NH3‡H] , 802 (20) [2  M‡NH3] .
(1'R,3'R,4'R)-1-{4'-Methylcyclohexyl-3'-(tert-butyldiphenylsilanyloxy)}-
ethanone (8a): Ozone was bubbled through a solution of alkene 7 (1.96 g,
5.00 mmol) in a mixture of CH2Cl2 (100 mL) and MeOH (20 mL) at ꢁ788C
until a blue color remained permanent. The solution was saturated with
nitrogen and PPh3 (1.70 g, 6.47 mmol) in CH2Cl2 (7 mL) was added. The
mixture was stirred for 10 min and then allowed to warm to room
temperature. The solvent was evaporated and the residue purified on silica
gel (n-pentane/tert-butyl methyl ether 9:1) to give the methyl ketone 8a
(1.83 g, 4.65 mmol, 93%). [a]2D0 ˆ ꢁ73.38 (c ˆ 1, CHCl3); 1H NMR
164
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Enantiopure Homoallylic Ethers
161±168
(200 MHz, CDCl3): d ˆ 0.80 ± 2.13 (m, 8H), 0.98 (d, J ˆ 6.5 Hz, 3H), 1.06 (s,
9H), 1.88 (s, 3H), 3.22 ± 3.32 (m, 1H), 7.32 ± 7.72 (m, 10H); 13C-NMR
(50.3 MHz, CDCl3): d ˆ 19.16, 19.45, 27.06, 27.33, 27.68, 32.43, 37.38, 40.08,
50.39, 77.55, 127.4, 127.6, 129.5, 129.7, 135.7, 210.4; IR (film): nĈ 3070, 3050,
2932, 2894, 1710, 1108, 740, 704 cmꢁ1; MS (70 eV, CI): m/z (%): 395 (100)
concentrated in vacuo. The residue was purified by column filtration (n-
pentane/tert-butyl methyl ether 9:1) to give alcohol 11 (1.73 g, 10.2 mmol,
84%). 1H NMR (CDCl3, 200 MHz): d ˆ 0.91 (d, J ˆ 6.0 Hz, 3H), 1.16 ± 1.69
(m, 13H), 1.38 (s, 1H), 1.97 ± 2.01 (m, 2H), 3.82 ± 4.00 (m, 1H), 5.09 (m,
1H).
‡
‡
‡
[M‡H] , 412 (20) [M‡NH3‡H] , 804 (6) [2  M‡NH3] .
(R)-3-(tert-Butyldiphenylsilanyloxy)-butyric acid methyl ester (13):
TBDPSCl (2.37g, 9.59 mmol) was added dropwise at 158C to a solution
of (R)-3-hydroxybutyric acid methyl ester 12 (1.11 g, 9.59 mmol) and
imidazole (1.65g, 23.8 mmol) in anhydrous THF (5 mL) and the reaction
mixture was stirred for 2 h at room temperature. The precipating solid was
filtered and washed with THF (3 Â 10 mL). Water (40 mL) was added to
the combined organic phases and the mixture was concentrated to 40 mL.
EtOAc (40 mL) was added and the organic layer was separated, washed
with water (2 Â 40 mL), and dried over Na2SO4. The solvent was removed
in vacuo and the residue was purified by flash column chromatography
(n-pentane/tert-butyl methyl ether 9:1) to give silyl ether 12 (3.00 g,
8.41 mmol, 88%). 1H NMR (200 MHz, CDCl3): d ˆ 1.05 (s, 9H), 1.11
(d, J ˆ 6.0 Hz, 3H), 2.38 (dd, J1 ˆ 6.0 Hz, J2 ˆ 15.0 Hz, 1H), 2.58
(dd, J1 ˆ 7.4 Hz, J2 ˆ 15.0 Hz, 1H), 3.59 (s, 3H), 4.32 (m, 1H), 7.30 ± 7.76
(m, 10H).
(4R)-4,8-Dimethylnonan-2-one (8b): A solution of alkene 9 (843 mg,
4.94 mmol) in MeOH (90 mL) was hydrogenated under a pressure of 1 atm
H2 in the presence of a catalytic amount of palladium on activated carbon
(300 mg, 5% Pd/C) for 1 h. After removal of the catalyst by filtration over
silica gel and the solution was concentrated in vacuo. The saturated alcohol
was obtained as a colorless liquid (604 mg, 3.51 mmol, 71%). 1H NMR
(200 MHz, CDCl3): d ˆ 0.86 (d, J ˆ 6.5 Hz, 6H), 0.89 (d, J ˆ 6.0 Hz, 3H),
1.08 ± 1.58 (m, 12H), 3.84 ± 3.94 (m, 1H).
A solution of Dess ± Martin periodinane (1.25 g, 2.91 mmol) in CH2Cl2 was
added to a solution of the alcohol (455 mg, 2.64 mmol) in CH2Cl2 at 08C
and stirring was continued for 30 min. The mixture was warmed to room
temperature, Et2O (85 mL) and 1.3m aqueous NaOH (20 mL) was added.
The organic layer was separated, washed with water (25 mL), 1.3m aqueous
NaOH (20 mL), and dried over Na2SO4. After removal of the solvent, the
residue was purified by column chromatography (n-pentane/tert-butyl
(R)-3-(tert-Butyldiphenylsilanyloxy)-butyric acid (14): Ester 13 (2.75 g,
7.71 mmol) and NaOH (0.62 g, 15.4 mmol) were dissolved in isopropanol
(155 mL) and water (55 mL) and heated to 708C for 2 h with stirring. The
mixture was cooled to ambient temperature and treated with 1n aqueous
HCl (250 mL) and extracted with Et2O (4 Â 100 mL). The combined
organic layers were dried over Na2SO4 and the solvent was removed in
vacuo to give carboxylic acid 14 (2.16 g, 6.31 mmol, 81%) as a white solid
which was used without further purification. M.p. 1158C (pentane, tert-
butyl methyl ether); [a]D20 ˆ ‡1.88 (c ˆ 1, CHCl3); 1H NMR (200 MHz,
CDCl3): d ˆ 1.04 (s, 9H), 1.14 (d, J ˆ 6.3 Hz, 3H), 2.43 (dd, J1 ˆ 6.0 Hz, J2 ˆ
15.0 Hz,1H), 2.55 (dd, J1 ˆ 6.0 Hz, J2 ˆ 15.0 Hz, 1H), 4.27 (m, 1H), 7.36 ±
7.70 (m, 10H); 13C NMR (50.3 MHz, CDCl3): d ˆ 19.14, 23.36, 26.84, 44.05,
66.64, 127.4, 127.5, 129.6, 129.7, 135.7, 176.9.
methyl ether 9:1) to give ketone 8b (360 mg, 2.11 mmol, 80%). [a]D20
ˆ
‡9.58 (c ˆ 1, CHCl3); 1H NMR (200 MHz, CDCl3): d ˆ 0.77 (d, J ˆ 6.0 Hz,
6H), 0.80 (d, J ˆ 6.5 Hz, 3H), 0.98 ± 1.25 (m, 6H), 1.30 ± 1.51 (m, 1H), 1.82 ±
1.94 (m, 1H), 2.04 (s, 3H), 2.12 (dd, J1 ˆ 8.0 Hz, J2 ˆ 16.0 Hz, 1H), 2.32 (dd,
J1 ˆ 7.0 Hz, J2 ˆ 16.0 Hz, 1H); 13C NMR (50.3 MHz, CDCl3): d ˆ 19.82,
22.57, 22.67, 24.72, 27.93, 29.27, 30.35, 37.15, 39.08, 51.26, 208.7.
(R)-4-(tert-Butyldiphenylsilanyloxy)-pentan-2-one (8c): A 1.6m solution
of methyllithium in Et2O (8.00 mL, 12.8 mmol) was added dropwise within
30 min at ꢁ788C under stirring to a solution of 14 (2.00 g, 5.84 mmol) in
anhydrous Et2O (80 mL). Stirring was continued for 30 min, the mixture
was warmed to 08C and then quenched by addition of saturated aqueous
NH4Cl (100 mL). The layers were separated and the aqueous layer was
extracted with Et2O (4 Â 30 mL). The combined organic extracts were
washed with brine and dried over Na2SO4, the solvent was evaporated, and
the residue was purified by column chromatography (n-pentane/tert-butyl
methyl ether 15:1). Ketone 8c was obtained as a colorless oil (1.27 g,
3.73 mmol, 64%). [a]2D0 ˆ ꢁ2.58 (c ˆ 1, CHCl3); 1H NMR (200 MHz,
CDCl3): d ˆ 1.03 (s, 9H), 1.09 (d, J ˆ 6.0 Hz, 3H), 2.05 (s, 3H), 2.46 (dd,
J1 ˆ 6.0 Hz, J2 ˆ 15.0 Hz, 1H), 2.64 (dd, J1 ˆ 6.0 Hz, J2 ˆ 15.0 Hz, 1H), 4.31
(m, 1H), 7.37 ± 7.59 (m, 10H); 13C NMR (50.3 MHz, CDCl3): d ˆ 19.14,
23.61, 26.90, 30.98, 53.19, 66.46, 127.4, 127.6, 129.5, 129.7, 135.7, 207.2; IR
rac-3-(tert-Butyldiphenylsilanyloxy)-butyric acid ethyl ester (rac-24): Re-
action of rac-3-hydroxybutyric acid ethyl ester (rac-23, 2.00 g, 15.1 mmol)
with TBDPSCl was performed as described for 13 to give rac-24 as a
colorless oil (5.21 g, 14.1 mmol, 93%). 1H NMR (200 MHz, CDCl3): d ˆ
1.05 (s, 9H), 1.12 (d, J ˆ 7.5 Hz, 3H), 1.20 (t, J ˆ 8.0 Hz, 3H), 2.38 (dd, J1 ˆ
6.5 Hz, J2 ˆ 15.0 Hz, 1H), 2.76 (dd, J1 ˆ 7.5 Hz, J2 ˆ 15.0 Hz, 1H), 4.06 (q,
J ˆ 8.0 Hz, 2H), 4.36 (m, 1H), 7.30 ± 7.78 (m, 10H); 13C NMR (50.3 MHz,
CDCl3): d ˆ 14.08, 19.12, 23.56, 26.82, 44.59, 60.15, 66.83, 127.5, 127.5, 129.5,
129.5, 135.7, 171.3.
ˆ
(film): nĈ 3070, 3056, 2962, 2932, 2894, 1716 (C O), 1470, 1372, 1426, 1134,
rac-3-(tert-Butyldiphenylsilanyloxy)-butyric acid (rac-25): A solution of
rac-24 (3.70 g, 10.00 mmol) and NaOH (1.13 g, 28.0 mmol) in isopropanol
(200 mL) and water (60 mL) was stirred for 4 h at 608C. The workup was
carried out as described for 14 to give carboxylic acid rac-25 (3.17 g,
9.15 mmol, 92%) as a colorless solid.
1108, 1020, 740, 704 cmꢁ1
.
(S)-4-Phenyl-2-pentanone (8d):
A 1.6m solution of methyllithium
(12.6 mL, 20.1 mmol) was added dropwise at ꢁ788C with stirring for
30 min to a solution of (S)-3-phenylbutric acid (15, 1.50 g, 9.13 mmol) in dry
Et2O. Stirring was continued for 30 min and the mixture was allowed to
warm to 08C. Saturated aqueous NH4Cl solution (135 mL) was added, the
organic layer separated, the aqueous layer extracted with Et2O (4 Â
50 mL), and the combined organic extracts washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography (n-pentane/tert-butyl methyl ether 9:1) to give ketone 8d
(815 mg, 5.02 mmol, 54%) as a colorless liquid. [a]2D0 ˆ ‡40.08 (c ˆ 0.5,
rac-4-(tert-Butyldiphenylsilanyloxy)-pentan-2-one (rac-26a): Reaction of
rac-25 (2.00 g, 5.84 mmol) in anhydrous Et2O (80 mL) with 1.6m solution
methyllithium (6.00 mL, 12.8 mmol) as described for 8c gave rac-26a
(1.39 g, 4.08 mmol, 70%) as a colorless solid. M.p. 428C (pentane, tert-butyl
methyl ether).
rac-4-Phenyl-2-pentanone (rac-26b): Reaction of rac-3-phenylbutyric acid
(rac-27, 1.64 g, 10.0 mmol) with a 1.6m solution of methyllithium in Et2O
(13.8 mL, 22.0 mmol) as described for 8d gave rac-26b as a colorless oil
(5.61 mmol, 910 mg, 56%).
1
CHCl3); H NMR (200 MHz, CDCl3): d ˆ 1.27 (d, J ˆ 7.0 Hz, 3H), 2.06 (s,
3H), 2.64 (dd, J1 ˆ 8.0 Hz, J2 ˆ 16.5 Hz, 1H), 2.77 (dd, J1 ˆ 6.5 Hz, J2 ˆ
16.5 Hz, 1H), 3.32 (m, 1H), 7.15 ± 7.34 (m, 5H); 13C NMR (CDCl3,
50.3 MHz): d ˆ 21.99, 30.54, 35.41, 51.94, 126.2, 126.7, 128.4, 146.1, 207.8.
rac-3-Phenyl-2-pentanone (rac-26c): Reaction of rac-2-phenylbutyric acid
(rac-28, 1.64 g, 10.0 mmol) in Et2O (120 mL) with
a 1.6m solution
(1R,3R,5R)-1-(3-Hydroxy-4-methylcyclohexyl)-ethanone (9): Tetrabutyl-
methyllithium (13.3 mL, 22.2 mmol) as described for 8d gave rac-26c
(1.15 g, 7.08 mmol, 71%) after column chromatography (n-pentane/tert-
butyl methyl ether 9:1) as a colorless liquid. H NMR (200 MHz, CDCl3):
d ˆ 0.83 (t, J ˆ 7.5 Hz, 3H), 1.71 (ddq, J1 ˆ 6.0 Hz, J2 ˆ 7.5 Hz, J3 ˆ 14.0 Hz,
1H), 2.05 (s, 3H), 2.11 (ddq, J1 ˆ 6.5 Hz J2 ˆ 7.5 Hz, J3 ˆ 14.0 Hz, 1H), 3.52
(t, J ˆ 7.5 Hz, 3H), 7.17 ± 7.46 (m, 5H).
ammonium fluoride trihydrate (158 mg, 0.50 mmol) was added to
a
1
solution of silyl ether 8a (100 mg, 0.25 mmol) in THF and stirring was
continued for 3 h. The solvent was evaporated in vacuo and the crude
product was purified by column chromatography on silica gel to give 9
(31 mg, 0.20 mmol, 80%).
(4R)-4,8-Dimethylnon-7-en-2-ol (11): A solution of methylmagnesium
chloride (3m, 4.80 mL, 14.6 mmol) in THF was added at ꢁ788C to a
solution of (R)-citronellal (10). After 1 h the reaction mixture was warmed
to 08C and an 20% aqueous solution of NH4Cl (4 mL) was added. The
organic layer was separated and the aqueous layer extracted with Et2O
(4 Â 40 mL). The combined organic extracts were dried over Na2SO4 and
General procedure for the allylation of ketones 8 and 26: Trifluormetha-
nesulfonic acid (0.14 mmol) was added at ꢁ788C with stirring to a solution
of ketones 8a ± d or rac-26a ± d (0.50 mmol), (S,S)- or (R,R)-2-trifluoro-
acetamido-1-trimethylsiloxy-1-phenyl-propane (2 or ent-2, 0.25 mmol) or
ethoxytrimethylsilane (22, 0.25 mmol), and allyltrimethylsilane (3,
0.63 mmol) and stirring was continued at ꢁ788C for 3 d. The reaction
Chem. Eur. J. 2001, 7, No. 1
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0947-6539/01/0701-0165 $ 17.50+.50/0
165

L. F. Tietze et al.
FULL PAPER
was quenched by addition of triethylamine (100 mL) and the mixture
poured into water (5 mL). The organic phase was separated and the
aqueous phase extracted with CH2Cl2 (2 Â 5 mL). The combined organic
phases were washed with brine, dried over Na2SO4, and concentrated in
vacuo. Purification of the residue by column chromatography (n-pentane/
tert-butyl methyl ether 15:1) gave the corresponding homoallylic ethers
16a ± d, 17a ± d, 19a ± d, 20a ± d, 22b ± d, 29a ± d/29-ent-a ± d, and 30a ± d/
30-ent-a ± d, respectively.
(4R,6R,1'R,2'R)-4-Methyl-4-(2'-trifluoroacetamido-1'-phenyl-propoxy)-6-
(tert-butyldiphenylsilanyloxy)-hept-1-ene (19c): According to the general
procedure, reaction of ketone 8c (170 mg, 0.50 mmol) with ent-2 (80 mg,
0.25 mmol) gave the homoallylic ether 19c (69 mg, 0.11 mmol, 44%) as
colorless needles, along with recovered ent-2 (30 mg, 0.09 mmol, 35%).
M.p. 778C (pentane); [a]D20 ˆ ꢁ20.08 (c ˆ 0.5, CHCl3); 1H NMR (200 MHz,
CDCl3): d ˆ 0.84 (s, 3H), 1.11 (d, J ˆ 7.0 Hz, 3H), 1.14 (d, J ˆ 7.0 Hz, 3H),
1.19 (dd, J1 ˆ 14.5 Hz, J2 ˆ 4.0 Hz, 1H), 1.97 (dd, J1 ˆ 14.5 Hz, J2 ˆ 8.5 Hz,
1H), 2.28 (ddd, J1 ˆ 1.0 Hz, J2 ˆ 7.0 Hz, J3 ˆ 13.5 Hz, 1H), 2.36 (dd, J1 ˆ
1.0 Hz, J2 ˆ 7.5 Hz, J3 ˆ 13.5 Hz, 1H), 2.90 (m, 1H), 4.01 (m, 1H), 4.55 (d,
J ˆ 4.0 Hz, 1H), 5.02 ± 5.12 (m, 2H), 5.67 ± 5.81 (m, 1H), 6.30 (brd, J ˆ
8.0 Hz, 1H), 7.10 ± 7.33 (m, 10H); 13C NMR (50.3 MHz, CDCl3): d ˆ 16.73,
19.09, 23.55, 25.67, 26.96, 44.47, 49.81, 51.68, 67.11, 74.27, 78.28, 115.8 (q,
1JCF ˆ 288 Hz), 118.2, 126.6, 127.4, 127.5, 128.6, 129.4, 129.6, 134.1, 141.1,
(4R,1'R,2'R,1''R,3''R,4''R)-4-(2'-Trifluoroacetamido-1'-phenyl-propoxy)-
4-(3''-tert-butyldiphenylsilanyloxy-4''-methyl-cyclohexyl)-pent-1-ene
(19a): According to the general procedure, reaction of ketone 8a (197 mg,
0.50 mmol) with ent-2 (80 mg, 0.25 mmol) gave the homoallylic ether 19a
(106 mg, 0.16 mmol, 64%) as colorless needles, along with recovered ent-2
(20 mg, 0.06 mmol, 20%). M.p. 1818C (pentane); [a]2D0 ˆ ꢁ29.08 (c ˆ 0.5,
CHCl3); 1H NMR (200 MHz, CDCl3): d ˆ 0.49 (s, 3H), 0.64 ± 1.77 (m, 8H),
0.99 (d, J ˆ 6.5 Hz, 3H), 1.03 (s, 9H), 1.09 (d, J ˆ 7.2 Hz, 3H), 2.06 (dd, J1 ˆ
7.0 Hz, J2 ˆ 15.0 Hz, 1H), 2.31 (dd, J1 ˆ 7.5 Hz, J2 ˆ 15.0 Hz, 1H), 3.14 ± 3.24
(m, 1H), 4.07 (m, 1H), 4.48 (d, J ˆ 3.7 Hz, 1H), 4.86 ± 5.01 (m, 2H), 5.45 ±
5.61 (m, 1H), 6.26 (brd, J ˆ 8.0 Hz, 1H), 7.08 ± 7.74 (m, 15H); 13C NMR
(50.3 MHz, CDCl3): d ˆ 16.41, 19.23, 19.50, 21.70, 25.88, 27.08, 32.99, 36.69,
40.60, 40.64, 44.10, 51.59, 73.90, 78.51, 79.94, 115.8 (q, 1JCF ˆ 289 Hz), 117.9,
126.7, 127.3, 127.4, 127.7, 128.2, 129.3, 129.4, 133.6, 135.9, 141.1, 156.3 (q,
2JCF ˆ 37 Hz); IR (KBr): nĈ 3312, 3110, 3074, 3048, 3030, 2962, 2936, 2868,
2865, 1706, 1208, 1188, 1162, 1110, 1092, 1058, 914, 758, 702 cmꢁ1; MS:
2
156.0 (q, JCF ˆ 37 Hz); IR (KBr): nĈ 3302, 3106, 3072, 3044, 2964, 2934,
2896, 2858, 1702, 1214, 1186, 1164, 1108, 1066, 916, 760, 704 cmꢁ1; MS
‡
(70 eV, CI): m/z (%): 629 (100) [M‡NH3‡H] ; C35H44F3NO3Si (611.82):
calcd C 68.71, H 7.24; found C 68.63, H 7.41.
(4S,6R,1'S,2'S)-4-Methyl-4-(2'-trifluoroacetamido-1'-phenyl-propoxy)-6-
(tert-butyldiphenylsilanyloxy)-hept-1-ene (16c): According to the general
procedure, reaction of ketone 8c (170 mg, 0.50 mmol) with 2 (80 mg,
0.25 mmol) gave the homoallylic ether 16c (62 mg, 0.10 mmol, 41%) as
colorless needles, along with recovered 2 (35 mg, 0.11 mmol, 44%). M.p.
818C (pentane); [a]2D0 ˆ ‡11.28 (c ˆ 0.5, CHCl3); 1H NMR (200 MHz,
CDCl3): d ˆ 0.87 (d, J ˆ 6.0 Hz, 3H), 0.91 (s, 3H), 0.91 (s, 9H), 1.10 (d, J ˆ
6.8 Hz, 3H), 1.53 (dd, J1 ˆ 7.2 Hz, Jl ˆ 14.5 Hz, 1H), 1.75 (dd, J1 ˆ 6.0 Hz,
J2 ˆ 14.4 Hz, 1H), 2.24 (ddd, J1 ˆ 1.0 Hz, J2 ˆ 7.0 Hz, J3 ˆ 14.0 Hz, 1H), 2.36
(ddd, J1 ˆ 1.0 Hz, J2 ˆ 7.5 Hz, J3 ˆ 14.0 Hz, 1H), 3.84 ± 4.12 (m, 2H), 4.44 (d,
J ˆ 3.8 Hz, 1H), 4.94 ± 5.06 (m, 2H), 5.57 ± 5.81 (m, 1H), 6.30 (brd, J ˆ
8.0 Hz, 1H), 7.06 ± 7.36 (m, 15H); 13C NMR (50.3 MHz, CDCl3): d ˆ 17.05,
19.12, 24.40, 25.32, 27.00, 43.74, 49.86, 51.82, 66.89, 74.17, 78.25, 115.5 (q,
1JCF ˆ 288 Hz), 118.0, 126.5, 127.3, 127.6, 128.2, 129.4, 129.6, 134.2, 135.9,
‡
(70 eV, CI): m/z (%): 683 (100) [M‡NH3‡H] ; C39H50O3NF3Si (665.35):
calcd C 70.40, H 7.57; found C 70.50, H 7.64.
(4S,1'S,2'S,1''R,3''R,4''R)-4-(2'-Trifluoroacetamido-1'-phenyl-propoxy)-4-
(3''-tert-butyldiphenylsilanyloxy-4''-methyl-cyclohexyl)-pent-1-ene (16a):
According to the general procedure, reaction of ketone 8a (197 mg,
0.50 mmol) with 2 (80 mg, 0.25 mmol) gave the homoallylic ether 16a
(60 mg, 0.09 mmol, 36%) as a highly viscous oil, along with recovered 2
(44 mg, 0.14 mmol, 55%). 1H NMR (200 MHz, CDCl3): d ˆ 0.61 (s, 3H),
0.64 ± 1.70 (m, 11H), 0.99 (d, J ˆ 6.5 Hz, 3H), 1.05 (s, 9H), 2.13 (m, 2H),
3.20 ± 3.31 (m, 1H), 3.96 (m, 1H), 4.44 (d, J ˆ 4.0 Hz, 1H), 4.85 ± 4.98 (m,
2H), 5.39 ± 5.55 (m, 1H), 6.24 (brd, J ˆ 8.0 Hz, 1H), 7.04 ± 7.71 (m, 15H);
2
141.2, 156.0 (q, JCF ˆ 37 Hz); IR (KBr): nĈ 3302, 3106, 3072, 3044, 2964,
2934, 2896, 2858, 1702, 1214, 1186, 1164, 1108, 1066, 916, 760, 704 cmꢁ1; MS
‡
(70 eV, CI): m/z (%): 629 (100) [M‡NH3‡H] ; C35H44F3NO3Si (611.82):
calcd C 68.71, H 7.24; found C 68.49, H 7.20.
13C NMR (50.3 MHz, CDCl3): d ˆ 16.21, 19.34, 19.50, 21.87, 26.17, 27.02,
1
32.91, 36.40, 40.41, 40.56, 43.78, 51.55, 73.50, 78.72, 79.79, 115.8 (q, JCF
ˆ
(4R,6S,1'R,2'R)-4-Methyl-4-(2'-trifluoroacetamido-1'-phenyl-propoxy)-6-
phenyl-hept-1-ene (19d): According to the general procedure, reaction of
ketone 8d (81 mg, 0.50 mmol) with ent-2 (80 mg, 0.25 mmol) and diiso-
propylketone (285 mg, 2.50 mmol) gave the homoallylic ether 19d (72 mg,
0.17 mmol, 67%) as colorless needles, along with recovered ent-2 (10 mg,
288 Hz), 117.9, 126.7, 127.6, 128.1, 128.2, 128.4, 129.3, 129.4, 133.6, 141.1,
2
156.4 (q, JCF ˆ 37 Hz); IR (film): nĈ 3330, 3134, 3072, 3030, 2972, 2934,
2894, 2860, 1722, 1210, 1166, 1112, 1078, 1028, 916, 756, 704 cmꢁ1; MS
‡
(70 eV, CI): m/z (%): 683 (100) [M‡NH3‡H] .
30 mmol, 13%). M.p. 908C (pentane, tert-butyl methyl ether); [a]D20
ˆ
(4R,6S,1'R,2'R)-4,6,10-Trimethyl-4-(2'-trifluoroacetamido-1'-phenyl-prop-
oxy)-undec-1-ene (19b): According to the general procedure, reaction of
ketone 8b (85.0 mg, 0.50 mmol) with ent-2 (80 mg, 0.25 mmol) gave the
homoallylic ether 19b (49 mg, 0.11 mmol, 44%) as colorless needles, along
with recovered ent-2 (23 mg, 0.70 mmol, 29%). M.p. 548C (pentane);
[a]2D0 ˆ ꢁ18.08 (c ˆ 0.5, CHCl3); 1H NMR (200 MHz, CDCl3): d ˆ 0.79 ±
1.03 (m, 12H), 1.06 ± 1.73 (m, 13H), 2.32 (m, 2H), 4.08 (m, 1H), 4.60 (d, J ˆ
3.5 Hz, 1H), 5.04 ± 5.10 (m, 2H), 5.70 ± 5.94 (m, 1H), 6.45 (brd, J ˆ 8.0 Hz,
1H), 7.20 ± 7.42 (m, 5H); 13C NMR (50.3 MHz, CDCl3): d ˆ 17.22, 22.00,
22.58, 22.73, 24.02, 24.94, 27.98, 28.66, 39.27, 39.44, 43.64, 47.48, 51.97, 74.37,
‡24.38 (c ˆ 0.5, CHCl3); 1H NMR (200 MHz, CDCl3): d ˆ 0.84 (s, 3H),
1.11 (d, J ˆ 7.0 Hz, 3H), 1.14 (d, J ˆ 7.0 Hz, 3H), 1.19 (dd, J1 ˆ 14.5 Hz, J2 ˆ
4.0 Hz, 1H), 1.97 (dd, J1 ˆ 14.5 Hz, J2 ˆ 8.5 Hz, 1H), 2.28 (ddd, J1 ˆ 1.0 Hz,
J2 ˆ 7.0 Hz, J3 ˆ 13.5 Hz, 1H), 2.36 (dd, J1 ˆ 1.0 Hz, J2 ˆ 7.5 Hz, J3 ˆ 13.5 Hz,
1H), 2.90 (m, 1H), 4.01 (m, 1H), 4.55 (d, J ˆ 4.0 Hz, 1H), 5.02 ± 5.12 (m,
2H), 5.67 ± 5.81 (m, 1H), 6.30 (brd, J ˆ 8.0 Hz, 1H), 7.10 ± 7.33 (m, 10H);
13C NMR (50.3 MHz, CDCl3): d ˆ 16.91, 24.41, 25.61, 35.87, 43.48, 47.64,
1
51.87, 74.44, 79.46, 115.9 (q, JCF ˆ 288 Hz), 118.2, 126.7, 127.0, 127.8, 128.3,
2
128.4, 134.1, 141.3, 148.7, 155.4 (q, JCF ˆ 37 Hz); IR: nĈ 3310, 3084, 3072,
3030, 2970, 2930, 2854, 1702, 1204, 1184, 1164, 1056, 918, 762, 700 cmꢁ1; MS
1
79.75, 115.7 (q, JCF ˆ 288 Hz), 118.1, 126.5, 127.7, 128.3, 134.3, 141.7, 156.4
‡
2
(70 eV, CI): m/z (%): 451 (100) [M‡NH3‡H] .
(q, JCF ˆ 37 Hz); IR (KBr): nĈ 3306, 3078, 3034, 2958, 2928, 2870, 1702,
1568, 1208, 1188, 1164, 914, 756, 702 cmꢁ1; MS (70 eV, CI): m/z (%): 459
(4S,6S,1'S,2'S)-4-Methyl-4-(2'-trifluoroacetamido-1'-phenyl-propoxy)-6-
phenyl-hept-1-ene (16d): According to the general procedure, reaction of
ketone 8d (81 mg, 0.50 mmol) with 2 (80.0 mg, 250 mmol) and diisopropyl
ketone (285 mg, 2.50 mmol) gave the homoallylic ether 16d (72 mg,
0.17 mmol, 66%) as colorless needles along with 2 (8 mg, 0.02 mmol, 10%).
M.p. 728C; [a]2D0 ˆ ꢁ26.68 (c ˆ 0.5, CHCl3); 1H NMR (300 MHz, CDCl3):
d ˆ 0.81 (s, 3H, 4-CH3), 1.05 (d, J ˆ 6.8 Hz, 3H, 7-H3), 1.24 (d, J ˆ 7.2 Hz,
3H, 3'-H2), 1.77 (dd, J1 ˆ 4.0 Hz, J2 ˆ 14.5 Hz, 1H, 5-Ha), 2.00 (dd, J1 ˆ
8.7 Hz, J2 ˆ 14.5 Hz, 1H, 5-Hb), 2.28 (ddd, J1 ˆ 1.0 Hz, J2 ˆ 7.2 Hz, J3 ˆ
13.9 Hz, 1H, 3-Ha), 2.36 (ddd, J1 ˆ 1.0 Hz, J2 ˆ 7.6 Hz, J3 ˆ 13.9 Hz, 1H,
3-Hb), 3.00 (m, 1H, 6-H), 3.98 (m, 1H, 2'-H), 4.53 (d, J ˆ 3.8 Hz, 1H, 1'-H),
5.09 (m, 2H, 1-H2), 5.68 ± 5.82 (m, 1H, 2-H), 5.97 (brd, J ˆ 8.0 Hz, 1H,
‡
‡
(100) [M‡NH3‡H] , 900 (5) [2  M‡NH3‡H] ; C25H38F3NO2 (441.75):
calcd C 68.00, H 8.66; found: C 68.18, H 8.86.
(4S,6S,1'S,2'S)-4,6,10-Trimethyl-4-(2'-trifluoroacetamido-1'-phenyl-prop-
oxy)-undec-1-ene (16b): According to the general procedure, reaction of
ketone 8b (85 mg, 0.50 mmol) with
2 (80 mg, 0.25 mmol) gave the
homoallylic ether 16b (57 mg, 0.13 mmol, 52%) as colorless needles, along
with recovered 2 (28 mg, 0.09 mmol, 35%). M.p. 548C (pentane); [a]D20
ˆ
‡24.38 (c ˆ 0.5, CHCl3); 1H NMR (200 MHz, CDCl3): d ˆ 0.80 ± 1.75 (m,
25H), 2.38 (m, 2H), 4.10 (m, 1H), 4.60 (d, J ˆ 4.0 Hz, 1H), 5.07 ± 5.12 (m,
2H), 5.71 ± 5.96 (m, 1H), 6.42 (brd, J ˆ 8.0 Hz, 1H), 7.18 ± 7.46 (m, 5H);
13C NMR (50.3 MHz, CDCl3): d ˆ 17.13, 22.11, 22.56, 22.70, 24.16, 24.87,
N-H), 7.12 ± 7.32 (m, 10H, phenyl-H); 13C NMR (50.3 MHz, CDCl3): d ˆ
1
27.97, 28.56, 39.19, 39.27, 43.86, 47.49, 51.90, 74.29, 79.74, 115.8 (q, JCF
ˆ
1
2
16.72, 24.36, 25.81, 35.80, 43.08, 47.57, 51.59, 74.56, 79.23, 115.7 (q, JCF
ˆ
288 Hz), 118.0, 126.6, 127.7, 128.2, 134.4, 141.5, 156.4 (q, JCF ˆ 37 Hz); IR
(KBr): nĈ 3310, 3106, 3080, 2964, 2932, 2870, 1704, 1640, 1202, 1160, 914,
288 Hz), 118.0, 126.6, 126.9, 128.0, 128.2, 128.4, 134.0, 141.6, 148.8, 156.1 (q,
2JCF ˆ 37 Hz); IR (KBr): nĈ 3340, 3080, 3028, 2968, 2930, 2872, 1704, 1454,
1206, 1178, 1158, 1108, 918, 764, 704 cmꢁ1; MS (70 eV, CI): m/z (%): 451
‡
756, 700 cmꢁ1; MS (70 eV, CI): m/z (%): 459 (100) [M‡NH3‡H] , 900 (5)
‡
[2  M‡NH3‡H] .
166
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Chem. Eur. J. 2001, 7, No. 1

Enantiopure Homoallylic Ethers
161±168
‡
(100) [M‡NH3‡H] ; C25H30F3NO2 (433.50): calcd C 69.26, H 6.98; found C
512 mmol, 51%) as colorless needles, along with recovered ent-2 (72 mg,
0.07 mmol, 28%). M.p. 738C; 1H NMR (200 MHz, CDCl3, mixture of
diastereomers): d ˆ 0.83 (s, 1H), 0.88 (s, 1H), 1.06 ± 1.40 (m, 7H), 1.61 ± 2.12
(m, 2H), 2.29 (ddd, J1 ˆ 1.0 Hz, J2 ˆ 7.5 Hz, J3 ˆ 13.5 Hz, 1H), 2.38 (ddd,
J1 ˆ 1.0 Hz, J2 ˆ 7.5 Hz, J3 ˆ 13.5 Hz, 1H), 2.78 ± 3.10 (m, 1H), 4.00 (m, 1H),
4.52 (d, J ˆ 4.0 Hz, 1H), 4.55 (d, J ˆ 4.2 Hz, 1H), 4.95 ± 5.20 (m, 2H), 5.60 ±
5.87 (m, 1H), 5.96 (brd, J ˆ 8.0 Hz), 6.30 (brd, J ˆ 8.0 Hz), 7.08 ± 7.59 (m,
10H); 13C NMR (125.7 MHz, CDCl3, mixture of diastereomers): d ˆ 16.87,
16.91, 24.41, 24.54, 25.60, 25.96, 35.86, 35.97, 43.18, 43.46, 47.63, 47.69, 51.66,
74.20, 74.42, 74.64, 79.40, 79.46, 115.8 (q, 1JCF ˆ 288 Hz), 117.9, 118.2, 118.3,
125.8, 125.9, 126.5, 126.7, 127.0, 127.7, 127.8, 128.2, 128.3, 128.4, 134.1, 141.3,
68.91, H 6.70.
(6R)-4,6,10-Trimethyl-4-ethoxy-undec-1-ene (22b): According to the gen-
eral procedure, reaction of ketone 8b (324 mg, 2.00 mmol) with 21 (118 mg,
1.00 mmol) gave the diastereomeric homoallylic ethers 22b (197 mg,
0.82 mmol, 82%) as a colorless oil. 1H NMR (200 MHz, CDCl3, mixture
of diastereomers): d ˆ 0.86 (d, J ˆ 6.5 Hz, 6H), 0.94 (d, J ˆ 6.5 Hz, 3H),
1.02 ± 1.70 (m, 16H), 2.20 (ddd, J1 ˆ 1.0 Hz, J2 ˆ 6.0 Hz, J3 ˆ 13.5 Hz, 1H),
2.31 (ddd, J1 ˆ 1.0 Hz, J2 ˆ 5.0 Hz, J3 ˆ 13.0 Hz, 1H), 3.38 (q, J ˆ 7.0 Hz,
2H), 4.97 (m, 2H), 5.70 ± 5.94 (m, 1H); 13C NMR (50.3 MHz, CDCl3,
mixture of diastereomers): d ˆ 15.89, 21.30, 21.49, 22.63, 22.72, 23.62, 23.91,
24.86, 25.27, 27.93, 28.00, 28.59, 38.99, 39.15, 39.26, 39.30, 43.62, 44.63, 56.00,
77.64, 117.0, 134.8, 134.9; IR (film): nĈ 2956, 2928, 2870, 1640, 1446, 1376,
2
141.6, 148.7, 148.9, 156.5 (q, JCF ˆ 37 Hz); IR (KBr): nĈ 3340, 3078, 3031,
2965, 2930, 2872, 1704, 1454, 1206, 1178, 1158, 1107, 921, 767, 701 cmꢁ1; MS
‡
(70 eV, CI): m/z (%): 451 (100) [M‡NH3‡H] ; C25H30F3NO2 (433.50):
1114, 1074, 1016, 846 cmꢁ1
; MS (70 eV, CI): m/z (%): 258 (100)
calcd C 69.26, H 6.98; found C 68.91, H 6.70.
‡
[M‡NH3‡H] ; C16H32O (240.42): calcd C 79.93, H 13.43; found C 8.63,
(4R,5R,1'R,2'R)- and (4R,5S,1'R,2'R)-4-Methyl-4-(2'-trifluoroacetamido-
1'-phenyl-propoxy)-5-phenyl-hept-1-ene (29c and 29-ent-c): According to
the general procedure, reaction of ketone rac-26c (81 mg, 0.50 mmol) with
ent-2 (80 mg, 0.25 mmol) gave after a reaction time of 5 d a diastereomeric
mixture of homoallylic ethers 29c and 29-ent-c (23 mg, 0.05 mmol, 21%) as
colorless needles, along with recovered ent-2 (51 mg, 0.16 mmol, 64%).
M.p. 1038C (pentane); 1H NMR (200 MHz, CDCl3, mixture of diaster-
eomers): d ˆ 0.57 (t, J ˆ 7.0 Hz, 3H, 7-H3), 0.87 (s, 3H, 4-CH3), 1.30 (d, J ˆ
7.5 Hz, 3H, 3'-H3), 1.15 ± 1.28 (m, 2H, 6-H2), 2.38 (m, 2H, 3-H2), 2.53 ± 2.67
(m, 1H, 5-H), 4.25 (m, 1H), 4.76 (d, J ˆ 4.0 Hz, 1H), 4.78 (d, J ˆ 4.0 Hz,
1H), 5.08 ± 5.20 (m, 2H), 5.88 ± 6.02 (m, 1H), 6.36 (brd, J ˆ 7.5 Hz, 1H),
7.08 ± 7.41 (m, 10H); 13C NMR (50.3 MHz, CDCl3, mixture of diastereom-
ers): d ˆ 12.56, 12.78, 13.50, 16.99, 17.13, 21.66, 21.94, 22.13, 23.65, 40.75,
H 13.20.
(6R)-4-Methyl-4-ethoxy-6-(tert-butyldiphenylsilanyloxy)-hept-1-ene
(22c): According to the general procedure, reaction of ketone 8c (600 mg,
1.76 mmol) with 21 (104 mg, 0.88 mmol) gave the diastereomeric homo-
allylic ethers 22c (320 mg, 0.77 mmol, 89%) as a colorless oil. 1H NMR
(200 MHz, CDCl3, mixture of diastereomers): d ˆ 0.86 (s, 3H, 4-CH3), 0.95
(s, 9H), 0.96 (s, 9H), 1.01 ± 1.32 (m, 6H), 1.55 (dd, J1 ˆ 5.0 Hz, J2 ˆ 15.0 Hz,
1H), 1.68 (dd, J1 ˆ 7.0 Hz, J2 ˆ 15.0 Hz, 1H), 2.01 (ddd, J1 ˆ 1.0 Hz, J2 ˆ
6.0 Hz, J3 ˆ 13.5 Hz, 1H), 2.12 (ddd, J1 ˆ 1.0 Hz, J2 ˆ 5.0 Hz, J3 ˆ 13.5 Hz,
1H), 3.20 (q, J ˆ 7.0 Hz, 2H), 3.22 (q, J ˆ 7.0 Hz, 2H), 4.00 (m, 1H), 4.77 ±
5.03 (m, 2H), 5.48 ± 5.73 (m, 1H), 7.41 ± 7.71 (m, 10H); 13C NMR
(50.3 MHz, CDCl3, mixture of diastereomers): d ˆ 15.75, 19.18, 24.83,
24.97, 26.86, 68.22, 27.05, 47.15, 55.94, 59.73, 67.96, 75.19, 117.2, 127.3, 127.5,
129.5, 134.4, 136.1; IR: nĈ 3070, 3053, 2960, 2932, 2896, 2858, 1428, 1110,
1080, 1004, 914, 740, 704 cmꢁ1; MS (70 eV, CI): m/z (%): 428 (100)
1
41.32, 42.37, 51.51, 51.89, 55.56, 74.65, 80.77, 115.9 (q, JCF ˆ 288 Hz), 117.9,
118.4, 126.4, 126.6, 127.7, 127.8, 128.1, 128.1, 133.9, 134.0, 141.2, 141.4, 156.4
2
(q, JCF ˆ 36 Hz); IR: nĈ 3320, 3086, 3062, 3030, 2968, 2936, 2904, 2882,
‡
[M‡NH3‡H] ; C26H38O2Si (410.67): calcd C 76.04, H 9.33; found C 76.14,
1698, 1204, 1182, 1164, 1076, 1062, 1026, 918, 762, 702 cmꢁ1; MS: (70 eV,
H 9.33.
‡
CI): m/z (%): 451 (100) [M‡NH3‡H] ; C20H28NO2F3 (371.44): calcd C
(6S)-4-Methyl-4-ethoxy-6-phenyl-hept-1-ene (22d): According to the gen-
eral procedure, reaction of ketone 8d (648 mg, 4.00 mmol) with 21 (236 mg,
2.00 mmol) gave the diastereomeric homoallylic ether 22d (350 mg,
1.50 mmol, 75%) as a colorless oil. 1H NMR (200 MHz, CDCl3, mixture
of diastereomers): d ˆ 1.00 (s, 3H), 1.04 (t, J ˆ 7.0 Hz, 3H), 1.27 (d, J ˆ
7.0 Hz, 3H), 1.74 (dd, J1 ˆ 5.5 Hz, J2 ˆ 14.0 Hz, 1H), 1.90 (dd, J1 ˆ 6.0 Hz,
J2 ˆ 14.0 Hz, 1H), 2.16 (ddd, J1 ˆ 1.0 Hz, J2 ˆ 7.5 Hz, J3 ˆ 13.5 Hz, 1H), 2.22
(ddd, J1 ˆ 1.0 Hz, J2 ˆ 8.0 Hz, J3 ˆ 13.5 Hz, 1H), 2.95 (oct, J ˆ 7.0 Hz, 1H),
3.19 ± 3.40 (m, 2H), 4.93 ± 5.05 (m, 2H), 5.63 ± 5.84 (m, 1H), 7.11 ± 7.32 (m,
5H); 13C NMR (50.3 MHz, CDCl3, mixture of diastereomers): d ˆ 15.74,
22.16, 24.01, 24.80, 24.87, 35.42, 35.57, 43.07, 43.67, 45.63, 45.75, 56.05, 56.09,
76.42, 117.2, 125.6, 127.0, 128.3, 134.6, 149.1; IR (film): nĈ 3074, 3026, 2972,
2928, 2872, 1640, 1452, 1374, 1154, 1112, 1074, 918, 762, 700 cmꢁ1; MS
69.26, H 6.98; found C 69.36, H 7.20.
(4R,5R,1'R,2'R)- and (4R,5S,1'R,2'R)-4-Methyl-4-(2'-trifluoroacetamido-
1'-phenyl-propoxy)-5-methyl-hept-1-ene (29d and 29-ent-d): According to
the general procedure, reaction of ketone rac-26d (50 mg, 0.50 mmol) with
ent-2 (80 mg, 0.25 mmol) gave a diastereomeric mixture of homoallylic
ethers 29d and 29-ent-d (66 mg, 0.18 mmol, 71%) as colorless needles. M.p.
508C (pentane); 1H NMR (200 MHz, CDCl3, mixture of diastereomers):
d ˆ 0.64 (t, J ˆ 7.5 Hz, 3H), 0.80 ± 0.99 (m, 9H), 0.91 (s, 3H), 1.16 (d, J ˆ
7.0 Hz, 3H), 1.18 (d, J ˆ 7.0 Hz, 3H), 2.37 (m, 2H), 3.60 (d, J ˆ 3.5 Hz, 1H),
4.09 (m, 1H), 3.56 (d, J ˆ 3.5 Hz, 1H), 5.05 ± 5.16 (m, 2H), 5.74 ± 5.97 (m,
1H), 6.40 (s, 1H), 7.20 ± 7.40 (m, 5H); 13C NMR (50.3 MHz, CDCl3, mixture
of diastereomers): d ˆ 12.47, 12.94, 13.50, 13.61, 16.60, 16.78, 21.62, 21.84,
23.74 23.81, 40.48, 40.57, 42.05, 42.37, 42.57, 51.93, 51.99, 74.38, 81.56, 116.0
(q, 1JCF ˆ 288 Hz), 117.7, 117.8, 117.9, 125.9, 127.1, 128.4, 134.4, 134.6, 141.5,
‡
(70 eV, CI) m/z (%): 250 (100) [M‡NH3‡H] ; C16H24O (232.36): calcd C
2
82.70, H 10.41; found C 82.46, H 10.31.
156.6 (q, JCF ˆ 36 Hz); IR (KBr): nĈ 3070, 3030, 2970, 2938, 2882, 1726,
1704, 1564, 1210, 1186, 1164, 1088, 916, 760, 702 cmꢁ1; MS (70 eV, CI): m/z
(4R,6R,1'R,2'R)- and (4R,6S,1'R,2'R)-4-Methyl-4-(2'-trifluoroacetamido-
1'-phenyl-propoxy)-6-(tert-butyldiphenylsilanyloxy)-hept-1-ene (29a and
29-ent-a): According to the general procedure, reaction of ketone rac-26a
(170 mg, 0.50 mmol) with ent-2 (80.0 mg, 0.25 mmol) gave a diastereomeric
mixture of homoallylic ethers 29a and 29-ent-a (68.0 mg, 112 mmol, 45%)
as colorless needles, along with recovered ent-2 (31 mg, 0.10 mmol, 39%).
1H NMR (200 MHz, CDCl3, mixture of diastereomers): d ˆ 0.77 (s, 3H),
0.94 (s, 3H), 0.92 (d, J ˆ 6.5 Hz, 3H), 0.99 (s, 9H), 1.01 (s, 9H), 1.11 (d, J ˆ
7.0 Hz, 3H), 1.13 (d, J ˆ 7.0 Hz, 3H), 1.57 ± 1.75 (m, 2H), 2.18 ± 2.46 (m,
2H), 3.96 ± 4.08 (m, 2H), 4.47 (d, J ˆ 3.0 Hz, 1H), 4.49 (d, J ˆ 3.0 Hz, 1H),
4.94 ± 5.14 (m, 2H), 5.63 ± 5.80 (m, 1H), 6.32 (brd, J ˆ 8.0 Hz, 1H), 7.08 ±
7.76 (m, 15H); 13C NMR (50.3 MHz, CDCl3, mixture of diastereomers):
‡
(%): 389 (100) [M‡NH3‡H] ; C20H28NO2F3 (371.44): calcd C 64.67, H 7.60;
found C 64.88, H 6.79.
Acknowledgement
The work was generously supported by the Fonds der Chemischen
Industrie. In addition we thank the Wacker-Chemie GmbH for a generous
gift of tert-butyldiphenylchlorosilane and trimethylchlorosilane and the
Knoll AG for a generous gift of norpseudoephedrine.
d ˆ 16.74, 17.06, 19.13, 23.56, 24.40, 25.31, 25.68, 26.97, 43.73, 44.74, 49.65,
1
49.81, 51.67, 51.81, 66.87, 67.11, 74.14, 74.25, 78.22, 78.26, 115.5 (q, JCF
ˆ
288 Hz), 117.9, 118.1, 127.3, 127.5, 127.7, 128.2, 134.9, 135.8, 135.9, 141.2,
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2
156.3 (q, JCF ˆ 37 Hz); IR (film): nĈ 3314, 3070, 3050, 2968, 2934, 2894,
1722, 1704, 1208, 1184, 1164, 1110, 1068 1056, 918, 756, 702 cmꢁ1; MS:
‡
(70 eV, CI): m/z (%): 629 (100) [M‡NH3‡H] .
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Chem. Eur. J. 2001, 7, No. 1
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0947-6539/01/0701-0167 $ 17.50+.50/0
167

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Received: May 4, 2000 [F2466]
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