A new preparation of homochiral N-protected 5-hydroxy-3-piperidenes, promising chiral building blocks, by palladiumCatalyzed deracemization of their alkyl carbonates

Article abstract of DOI:10.1002/adsc.200600559

The palladium-catalyzed deracemization of N-protected alkyl carbonates of 5-hydroxy-3-piperidenes by use of chiral phosphine ligands is described. A Trost ligand such as (R)-BPA was found to be a suitable chiral ligand for the deracemization, providing N-

Full text of DOI:10.1002/adsc.200600559

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DOI: 10.1002/adsc.200600559
A New Preparation of Homochiral N-Protected 5-Hydroxy-3-
piperidenes, Promising Chiral Building Blocks, by Palladium-
Catalyzed Deracemization of Their Alkyl Carbonates
Hiroki Takahata,a,* Yumiko Suto,a Erina Kato,a Yuichi Yoshimura,a
and Hidekazu Ouchia
a
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan
Fax : (+81)-22-727-0144; e-mail: takahata@tohoku-pharm.ac.jp
Received: October 27, 2006
Dedicated to Professor Masakatsu Shibasaki on his 60th birthday.
Abstract: The palladium-catalyzed deracemization of yields with good to high enantioselectivities. A plau-
N-protected alkyl carbonates of 5-hydroxy-3-piperi- sible mechanism for the reaction is proposed.
denes by use of chiral phosphine ligands is described.
A Trost ligand such as (R)-BPA was found to be a Keywords: chiral building blocks; deracemization;
suitable chiral ligand for the deracemization, provid- N-protected alkyl carbonates of 5-hydroxy-3-piperi-
ing N-protected 5-hydroxy-3-piperidenes in good denes; N-protected 5-hydroxy-3-piperidenes
Introduction
mer is 50%, and the other half may be waste material
(Scheme 1). A solution offering the potential for a
N-Protected 5-hydroxy-3-piperidenes 1 containing an 100% yield is dynamic kinetic resolution (DKR).[5]
allyl alcohol unit, which has the potential for being This procedure combines enantioselective resolution
transformed into a wide variety of functional groups, and in situ racemization thus permitting the undesira-
have been used as (chiral) building blocks for the con- ble enantiomer to be recycled. A similar alternative is
struction of a variety of alkaloids,[1] in medicinal a deracemization process[6] in which, instead of sepa-
chemistry,[2] and other areas.[3] We have previously re- rating the enantiomers, one is converted into the
ported on an efficient synthesis of 1-azasugars using other. A simple deracemization process might argua-
N-protected 5-hydroxy-3-piperidene.[4] Several proce- bly prove to be the most effective.
dures are available for their racemic synthesis from
The palladium-catalyzed deracemization of cyclic
readily available starting materials (pyridine, 3-hy- allyl esters as described by Trost[6d] (Scheme 2) was
droxypyridine and butadiene monoxide). Enantiopure performed to give cycloalkenols in high yields and
forms can be produced by enzyme-mediated kinetic enatioselectivites.[7] A similar deracemization of allylic
resolution, providing greater than 99% ee. However, carbonates using the hydrogen carbonate ion as a nu-
the selective kinetic discrimination between enantio- cleophile has recently been reported by Gais et al.[8]
mers in racemic mixtures has a fatal drawback in that In this paper we describe the preparation of homochi-
the maximum theoretical yield of the desired enantio- ral N-protected 5-hydroxy-3-piperidenes 1, which are
Scheme 1. Formation of chiral products from racemic substrates.
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NaHCO3) of the secondary amine gave the metathesis
precursors 4, together with small amounts of re-
gioisomers 5. Grubbsꢁ catalyst[9] could be used directly
on 4 to afford the ring-closing metathesis products
1a–c in high yields. The methoxycarbonylation of 1a–c
with methyl chloroformate in the presence of pyridine
gave the methyl carbonates of 5-hydroxy-3-piperi-
denes 2a–c. In a similar manner, 1a was converted by
reaction with Boc2O using 1-methylimidazole as a
base to tert-butyl carbonates 3a (Scheme 3).
Scheme 2. Pd-catalyzed deracemization of N-protected alkyl
carbonates of 5-hydroxy-3-piperidene.
useful building blocks for the preparation of biologi-
With the N-protected 5-alkoxycarbonyloxy-3-piper-
cally active nitrogen compounds by the Pd-catalyzed idenes 2 and 3 in hand (Table 1), we investigated the
deracemization of their alkyl carbonates 2 and 3 using palladium-catalyzed deracemization of 2a. According
procedures similar to those reported by Trost[6d] and to Gaisꢁs procedure, treatment of 2a with Pd
CHTREUNG(dba)3-
2A
CHCl3 (2 mol%) using (R)-BPA[10] as a ligand in
Gais.[8]
CH2Cl2/H2O (9:1) gave (R)-1a with>99% ee in 93%
yield in 24 h. Screening experiments were conducted
with 2a using other chiral phosphine ligands [(R)-
PhBPA,[10] (R)-naphthylBPA,[11] (R)-b-3,[12] and (R)-
Results and Discussion
The preparation of racemic N-protected of 5-hydroxy- BINAP] (Figure 1) and the results are shown in
3-piperidenes 1 was carried out by a previously de-
scribed procedure.[4] The regioselective opening of bu-
tadiene monoxide with allylamine, followed by pro-
tection (TsCl/NaHCO3, Boc2O/NaOH, CbzCl/
Scheme 3. Preparation of alkyl carbonates 2 and 3.
Figure 1. Chiral phosphine ligands.
Table 1. Preparation of N-protected 5-alkoxycarbonyloxy-3-piperidenes.
Entry
P
4
Yield [%][a]
5
Yield [%][a]
1
Yield [%][a]
2
Yield [%][a]
3
Yield [%][a]
1
2
3
Ts
Boc
Cbz
4a
4b
4c
74
66
64
5a
5b
5c
6
2
12
1a
1b
1c
98
98
96
2a
2b
2c
99
98
92
3a
-
-
99
-
-
[a]
Isolated yield.
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Preparation of Homochiral N-Protected 5-Hydroxy-3-piperidenes
Table 2. Pd-Catalyzed deracemization of 2a using different
chiral phosphine ligands.
Table 4. Influence of N-protected groups in the Pd-catalyzed
deracemization of 2a–d using (R)-BPA.
Entry
2
P
(R)-1, Yield[%][a] (R)-1, ee [%][b]
Entry Ligand
(R)-1a, Yield
(R)-1a, ee
[%][a]
[%][b]
1
2
3
4
2a
2b
2c
Ts
Boc
Cbz
93
94
88
99
94[c]
87
1
2
3
(R)-BPA
(R)-PhBPA
(R)-naphthylB- 80
93
81
99
98
95
2d[d] COOMe 90
99[e]
PA
(3R)-b-3
[a]
Isolated yields.
Determined by chiral HPLC.
Determined by HPLC after conversion of 1b to 1a.
Compound 2d was prepared from 1b in 5 steps (see Ex-
perimental Section).
4
5
6
57
4[c]
85
94
[b]
[c]
[d]
(R)-BINAP
30[d]
99
(R)-BPA[e]
[a]
[b]
[c]
[d]
[e]
Isolated yields.
Determined by chiral HPLC.
[e]
Determined by HPLC after conversion of 1d to 1a.
Compound 2a was recovered in 88% yield.
ee of (S)-1a.
4 mol% (R)-BPA and 1 mol% Pd2ACHTRE(UGN dba)3-CHCl3 were
Third, influence of N-protected groups was ob-
used.
served using CH2Cl2/H2O (9:1) as a solvent and the
results are shown Table 4. The ees for both N-Boc
(R)-1b and N-Cbz (R)-1c were lower than those for
Table 2. In terms of yield and ee, Trostꢁs ligands were N-Ts (R)-1a and N-COOMe (R)-1d. Fortunately, one
approximately the same as (R)-BPA, whereas (R)-b-3, recrystallization of (R)-1b gave>99% ee. It thus ap-
and (R)-BINAP) were less than (R)-BPA.
pears that different N-protected groups have little
The effect of solvents was next examined using (R)- effect on reactivity.
BPA as a catalyst and the results are shown Table 3.
Fourth, reaction times were examined using 2a and
The use of solvents which are less miscible with 2b and the results are shown in Table 5. The reactions
water, such as (CH2Cl)2 and toluene, gave good re- of both 2a and 2b were complete within 6 h.
sults (Table 3, entries 1 and 2). In addition, miscible
Fifth, the effect of OR leaving groups was studied
solvents such as DMF and DMSO led to similar out- using 3a and acetate 6 (Table 6) Although the dera-
comes, although the ees were slightly low (Table 3, en- cemization of 3a gave (R)-1a (81%) with 99% ee, un-
tries 3 and 4). On the other hand, THF and acetoni- reacted (S)-3a was present in 18% yield with 99% ee
trile were not useful. The use of CH2Cl2 gave the best even after an extended reaction time (24 h). Thus, the
ee (Table 2, entry 1).
reaction rate of 3a bearing a sterically bulky O-Boc is
Table 3. Solvent effect of Pd-catalyzed deracemization of 2a using (R)-BPA.
Entry
Solvent
(CH2Cl)2
Toluene
DMF
DMSO
THF
CH3CN
(R)-1a, Yield [%][a]
(R)-1a, ee [%][b]
(S)-2a, Yield [%][a]
(S)-2a, ee [%][b]
1
2
3
4
5
6
A
88
78
99
97
97
95
-
94
77
-
-
-
-
27
82
-
-
-
89 5
72
9
98
12
11
[a]
Isolated yields.
Determined by chiral HPLC.
[b]
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Table 5. Influence of reaction time in the Pd-catalyzed deracemization of 2a and b using (R)-BPA.
Entry
2
Reaction time [h]
(R)-1a, Yield [%][a]
(R)-1a, ee [%][b]
(S)-2a, Yield [%][a]
(S)-2a, ee [%][b]
1
2
3
4
2a
2a
2b
2b
1
6
1.5
6
42
9
30
9
99
49
9
55
9
86
9
58
3
4
4
99
-
[a]
Isolated yields.
Determined by chiral HPLC.
[b]
Table 6. Effect of leaving group.
Entry
Substrate
(R)-1a, Yield [%][a]
(R)-1a, ee [%][b]
(S)-3a or 6 Yield [%][a]
18 (3a)
(S)-3a or 6 ee [%][b]
1
2
3a
6
81
0
99
-
9
9
(
9
6)
9
1[c]
[a]
Isolated yields.
Determined by chiral HPLC.
Absolute configuration remains undetermined.
[b]
[c]
slow. In addition, the reaction of acetate 6 was very Apparently, the nucleophilic attack of a hydrogen car-
sluggish, resulting in 6 being recovered in 99% yield. bonate ion is favored due to the less steric interaction
Finally, the reaction of 2a was carried out in between the right front wall and the incoming nucleo-
CH2Cl2 for 24 h under anhydrous conditions, produc- phile, resulting in an R configuration. Finally, 8 under-
ing (R)-1a in 9% yield (89% ee) accompanied by the goes irreversible decarboxylation, yielding the dera-
recovery of (S)-2a in 69% yield (50% ee). This indi- cemization product (R)-1. The somewhat lower ee ob-
cates that the presence of water is essential for pro- tained using N-Boc 2b and N-Cbz 2c can be attributed
moting the reaction. On the other hand, the use of to an unfavorable steric interaction between the
KHCO3 instead of water gave (R)-1a in 61% yield larger N-protected substituents compared with N-Ts
(91% ee) and (S)-2a in 11% yield (36% ee). This sug- 2a and N-COOCH3 2d and the flap of the chiral pock-
gests that the hydrogen carbonate ion plays a critical ets in intermediate 7.
role in this deracemization.
Considering the above results, we considered a
plausible mechanism for this deracemization accord- Conclusions
ing to the proposal of Trost[13] and Gais[8] (Scheme 4).
The substrates 2 are converted to p-allyl palladium In summary, the Pd-catalyzed deracemization of alkyl
complex 7 via ionization by (R)-BPA. In the presence carbonates of N-protected 5-hydroxy-3-piperidenes 2
of water, a methyl carbonate ion is attacked by water, using Trostꢁs ligands is described. Among the ligands
generating a hydrogen carbonate ion, which functions examined, (R)-BPA gave good results for substrates
as a true nucleophile.[8] Evidence for this is the result 2a–d, furnishing the corresponding products 1, which
of the reaction conducted in the presence of KHCO3 are promising chiral building blocks for the synthesis
(vide supra). Therefore, intermediate 7 would be of biologically active nitrogen-compounds in good
transformed into the allylic hydrogen carbonate 8. yields with good to high enantioselectivities.
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Preparation of Homochiral N-Protected 5-Hydroxy-3-piperidenes
Scheme 4. A plausible mechanism of Pd-catalyzed deracemization of 2 using (R)-BPA.
ExperimentalSection
Table 8. Specific rotations of deracemization products.
Entry
Product
[a]2D5 (CHCl3)
c [mgmLÀ1]
ee [%[
Melting points were determined on a Mel-Temp melting
point apparatus using an open capillary tube. All melting and
boiling points are uncorrected. Infrared (IR) spectra were re-
corded on a Perkin–Elmer 1600 series FT-IR spectrometer.
Mass spectra (MS) were recorded on a JEOL JMN-DX 303/
JMA-DA 5000 spectrometer. Microanalyses were performed
on a Perkin–Elmer CHN 2400 Elemental Analyzer. Enantio-
meric excesses (ees) were determined by chiral HPLC
(Table 7). Optical rotations were measured with a JASCO
DIP-360 or JASCO P-1020 digital polarimeter (Table 8).
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on JEOL JNM-EX 270 (270 MHz) or JEOL JNM-
AL 400 (400 MHz) spectrometer, using tetramethylsilane as
an internal standard. The following abbreviations are used:
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,
br=broad. Column chromatography was carried out on
Merck silica gel 60 (230–400 mesh) or KANTO Silica Gel
60N (40–50 mm) for flash chromatography.
1
2
3
4
5
6
7
(R)-1a
(S)-2a
(R)-1b
(S)-2b
(R)-1c
(R)-1d
(S)-3a
À98.5
+50.7
À22.2
+46.7
À57.3
À109.0
+42.2
1.20
1.56
1.22
1.78
2.26
1.18
1.55
>99
>99
98
58
87
99
99
1-(N-Allyl-N-p-toluenesulfonylamino)-2-hydroxy-3-
butene (4a) and 2-(N-Allyl-N-p-toluenesulfonyl-
amino)but-3-en-1-ol(5a)
To a solution of allylamine (8.5 mL, 114 mmol) and water
(530 mL) was added butadiene monoxide (3.0 mL,
37.5 mmol) at 158C. The mixture was warmed to 1008C and
stirred for 6 h. The reaction mixture was concentrated under
reduced pressure. The residue was dissolved in ethanol
(150 mL) and NaHCO3 (3.36 g, 40 mmol) and p-toluenesul-
fonyl chloride (7.63 g, 40 mmol) were added at À788C. The
mixture was stirred at room temperature overnight and fil-
tered off on Celite. The residue obtained after evaporation
Table 7. HPLC conditions.
Entry Compound Eluent n-hexane:
Column CHIRAL-
PAK
Flow rate
Retention time
(R)
Retention time
(S)
AcOEt
(mLminÀ1)
1
2
3
4
5
1a
2a
1c
3a
6
3:1
IA
IA
OD
IA
IA
.6 mminin
0.91291.9
0.911.7 min
1.0
0.98.5 min
0.913.6 min
3:1
13.6 min
10.9min
10.8 min
14.7 min
9:1[a]
3:1
12.7 min
3:1
[a]
Eluent is a mixture of n-hexane and 2-propanol.
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of the filtrate was taken up in AcOEt and washed with
brine. The organic solution was dried over MgSO4, filtered,
concentrated under vacuum, and purified by flash column
chromatography on silica gel (n-hexane:AcOEt=2:1) to
give 4a (yield: 7.8 g, 74%) as a colorless oil and 5a (yield:
0.6 g, 6%) as a colorless oil.
Benzyl N-Allyl-N-(2-hydroxy-3-butenyl)carbamate
(4c) and 5c
To a solution of allylamine (8.5 mL, 114 mmol) and water
(530 mL) was added butadiene monoxide (3.0 mL,
37.5 mmol) at 158C. The mixture was warmed to 1008C and
stirred for 6 h. The reaction mixture was concentrated under
reduced pressure. The residue was dissolved in ethanol
(150 mL), then NaHCO3 (3.36 g, 40 mmol) and benzyloxy-
carbonyl chloride (6.82 g, 40 mmol) were added at À788C.
The mixture was stirred at room temperature overnight and
filtered off on Celite. The residue obtained after evapora-
tion of the filtrate was taken up in AcOEt and washed with
brine. The organic solution was dried over MgSO4, filtered,
concentrated under vacuum, and purified by flash column
chromatography on silica gel (n-hexane:AcOEt=2:1~1:2)
to give 4c (yield: 6.2 g, 64%) as a colorless oil and 5c (yield:
1.2 g, 12%) as a colorless oil.
1
4a: H NMR (400 MHz, CDCl3): d=2.43 (s, 3H), 2.66 (br
s, 1H), 3.09(dd, J=14.9, 3.7 Hz, 1H), 3.19 (dd, J=14.9,
8.5 Hz, 1H), 3.90 (ddd, J=33.8, 15.6, 6.4 Hz,2H), 4.27–4.40
(m, 1H), 5.15–5.23 (m, 3H), 5.29–5.38 (m, 1H), 5.54–5.70
(m, 1H), 5.73–5.86 (m, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.72
(d, J=8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.5,
52.4, 53.2, 71.1, 116.5, 119.4, 127.3, 129.8, 132.8, 137.4, 143.6;
IR (KBr): n=1157, 1340 (SO2), 3526 cmÀ1 (OH); EI-MS:
m/z=281 (M+); HR-MS: m/z=281.0989, calcd. for
C14H19NO5S: 281.1086.
1
5a: H NMR (400 MHz, CDCl3): d=2.26 (br s, 1H), 2.42
(s, 3H), 3.65–3.79(m, 3H), 3.90–4.01 (m, 1H), 4.40–4.47 (m,
1H), 5.01 (d, J=1.3 Hz, 1H), 5.09–5.27 (m, 3H), 5.46–5.59
(m, 1H), 5.80–5.93 (m, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.73
(d, J=8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.4,
47.3, 61.7, 62.5, 117.8, 119.6, 127.2, 129.6, 132.4, 135.4, 137.5,
143.4; IR (KBr): n=1160, 1332 (SO2), 3527 cmÀ1 (OH); EI-
MS: m/z=281 (M+); HR-MS: m/z=281.1110, calcd. for
C14H19NO5S: 281.1086; anal. calcd. for C14H19NO3S: C 59.76,
H 6.81, N 4.98; found: C 59.66, H 6.78, N 5.00.
4c: 1H NMR (600 MHz, CDCl3): d=3.17–3.44 (m, 3H),
3.86–4.09(m, 2H), 4.37 (br s, 1H), 5.15 (s, 5H), 5.31 (dd, J=
56.8, 18.3 Hz, 1H), 5.71–5.90 (m, 2H), 7.27–7.43 (m, 5H);
13C NMR (100 MHz, CDCl3): d=51.0, 53.3, 67.4, 72.1, 115.7,
116.7, 127.7, 127.9, 128.3, 133.3, 136.3, 138.1, 157.5; IR (KBr):
n=1685 (C=O), 3692 cmÀ1 (OH); EI-MS: (m/z)=261 (M+);
HR-MS: m/z=261.1337, calcd. for C15H19NO3: 261.1365.
1
5c: H NMR (400 MHz, CDCl3): d=2.58 (br s, 1H), 3.74
(br d, J=26 Hz, 4H), 4.31–4.47 (m, 1H), 4.96–5.20 (m, 6H),
5.79(br s, 2H), 7.16–7.31 (m, 5H); 13C NMR (100 MHz,
CDCl3): d=48.0, 63.1, 65.7, 67.3, 117.9, 127.7, 127.9, 128.4,
133.6, 134.8, 136.4, 156.6; IR (KBr): n=1683 (C=O), 3447
cmÀ1 (OH); EI-MS: m/z=261 (M+); HR-MS: m/z=
261.1330, calcd. for C15H19NO3: 261.1365.
tert-Butyl N-Allyl-N-(2-hydroxy-3-butenyl)carbamate
(4b) and Benzyl Allyl-1-hydroxybut-3-enylcarbamate
(5b)
To a solution of allylamine (8.5 mL, 114 mmol) and water
(530 mL) was added butadiene monoxide (3.0 mL, 37.5 mmol)
at 158C. The mixture was warmed to 1008C and stirred for
6 h. The reaction mixture was concentrated under reduced
pressure. The residue was dissolved in dioxane (50 mL) and
water (10 mL), then 1 mol/L NaOH (40 mL, 40 mmol) and
(Boc)2O (8.37 g, 40 mmol) were added. The mixture was stir-
red at room temperature overnight. The residue obtained
after evaporation was taken up in Et2O, washed with water,
20% citric acid, and brine. The combined aqueous solutions
were extracted with Et2O. The combined organic solutions
were dried over MgSO4, filtered, concentrated under vacuum,
and purified by flash column chromatography on silica gel (n-
hexane:AcOEt=3:1–1:1) to give 4b (yield: 5.6 g, 66%) as a
colorless oil and 5b (yield: 0.1 g, 2%) as a colorless oil.
4b: 1H NMR (400 MHz, CDCl3): d=1.46 (s, 9H), 1.80–
2.44 (br m, 1H), 3.28 (br s, 2H), 3.86 (br s, 2H), 4.26–4.37
(m, 1H), 5.03–5.20 (m, 3H), 5.33 (d, J=17.1 Hz, 1H), 5.67–
5.90 (m, 2H); 13C NMR (100 MHz, CDCl3): d= 28.3, 51.7,
53.4, 72.7, 80.4, 115.7, 116.4, 133.8, 138.4, 157.6; IR (KBr):
n=1677 (C=O), 3427 cmÀ1 (-OH); EI-MS: m/z=228 (M+ +
1); HR-MS: m/z=227.1538, calcd. for C12H21NO3: 227.1521;
anal. calcd. for C12H21NO3: C 63.41, H 9.31, N 6.16; found:
C 63.10, H 9.52, N 6.28.
(Æ)-N-p-Toluenesulfonyl-5-hydroxy-3-piperidene
[(Æ)-1a]
To a deoxygenated solution of 4a (7.8 g, 27.5 mmol) in
CH2Cl2 (450 mL) under an argon atomosphere was added
bis(tricyclohexylphosphine)benzylidine ruthenium(IV) di-
chloride (679mg, 0.825 mmol, 3 mol%). The solution was
stirred at room temperature overnight, then concentrated
under reduced pressure and the residue was purified by
flash column chromatography on silica gel (n-hexane:A-
cOEt=1:1) to give (Æ)-1a as colorless prisms; yield: 5.7 g
1
(81%); mp 99–1058C (ether). H NMR (400 MHz, CDCl3):
d=1.94 (br d, J=7.3 Hz, 1H), 2.44 (s, 3H), 3.05 (dd, J=3.4,
1.5 Hz, 1H), 3.31–3.40 (m, 2H), 3.77 (dt, J=16.8, 1.9Hz,
1H), 4.20 (br s, 1H), 5.77–5.83 (m, 1H), 5.87–5.94 (m, 1H),
7.34 (d, J=8.3 Hz, 2H), 7.68 (dd, J=6.6, 2.0 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=21.5, 44.9, 50.1, 63.5, 77.2,
77.6, 125.9, 127.7, 128.1, 1À219.8, 133.1, 143.9; IR (KBr): n=
1161, 1323 (SO2), 3529cm (OH); EI-MS: m/z=253 (M+);
HR-MS: m/z=253.0763, calcd. for C12H15NO3S: 253.0773;
anal. calcd. for C12H15NO3S: C 56.90, H 5.97, N, 5.53; found:
C 56.98, H 5.84, N 5.37.
5b: 1H NMR (400 MHz, CDCl3): d=1.46 (s, 9H), 2.27–
3.00 (br s, 1H), 3.77 (br d, J=7.1 Hz, 4H), 4.38 (br d, J=
5.6 Hz, 1H), 5.06–5.26 (m, 4H), 5.74–5.96 (m, 2H);
13C NMR (100 MHz, CDCl3): d=28.4, 48.3, 61.1, 63.6, 80.3,
117.5, 134.0, 135.3, 156.3; IR (KBr): n=1694 (C=O), 3437
cmÀ1 (OH); EI-MS: m/z=228 (M+ +1); HR-MS: m/z=
227.1546, calcd. for C12H21NO3: 227.1521.
(Æ)-N-tert-Butoxycalbonyl-5-hydroxy-3-piperidene
[(Æ)-1b]
To a deoxygenated solution of 4b (5.0 g, 22.1 mmol) in
CH2Cl2 (440 mL) under argon atomosphere was added bis-
(tricyclohexylphosphine)benzylidine ruthenium(IV) dichlor-
ide (727.4 mg, 0.884 mmol, 4 mol%). The solution was stir-
690
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Preparation of Homochiral N-Protected 5-Hydroxy-3-piperidenes
red at room temperature overnight, then concentrated
under reduced pressure and the residue was purified by
flash column chromatography on silica gel (n-hexane:
AcOEt=1:1) to give (Æ)-1b as colorless prisms; yield: 4.4 g
(99%); mp 55–568C (n-hexane). 1H NMR (600 MHz,
CDCl3): d=1.44 (s, 9H), 2.46 (br s, 1H), 3.40 (br s, 1H),
3.63 (br s, 1H), 3.80 (dd, J=2.20, 18.9Hz, 1H), 3.89 (br s,
1H), 4.18 (br s, 1H), 5.78 (br s, 1H), 5.84–5.94 (m, 1H);
13C NMR (150 MHz, CDCl3): d=28.3, 42.8, 46.9, 63.5, 80.0,
126.5, 128.3, 155.1; IR (KBr): n=1700 (C=O), 3421 cmÀ1
(OH); EI-MS: m/z=199 (M+); HR-MS: m/z=199.1232,
calcd. for C10H17NO3: 199.1208; anal. calcd. for C10H17NO3:
(0.64 mL, 7.49mmol) in CH 2Cl2 (10 mL) with ice cooling
and then the mixture was stirred at room temperature for
3 h. Ether was added to the mixture. The whole layer was
washed with saturated NH4Cl and brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (n-
hexane:AcOEt=3:1) to give (Æ)-2b as an oil; yield: 480 mg
1
(94%). H NMR (600 MHz, CDCl3): d=1.46 (s, 9H), 3.56
(br d, J=37.7 Hz, 1H), 3.79(s, 5H), 4.08 (br dd, J=85.0,
16.5 Hz, 1H), 5.08 (br d, J=57.5 Hz, 1H), 5.95 (br d, J=
67.0 Hz, 2H); 13C NMR (150 MHz, CDCl3): d=28.3, 42.7,
44.8, 54.8, 69.2,À810.1, 123.1, 131.1, 154.7, 155.2; IR (KBr): n=
C 60.28, H 8.60, N 7.03; found: C 60.37, H 8.57, N 6.87.
1702, 1749cm
(C=O); EI-MS: m/z=256 (M+À1); HR-
MS: m/z=257.1281, calcd. for C12H19NO5: 257.1263; anal.
calcd. for C12H19NO5: C 56.02, H 7.44, N 5.44; found: C
56.18, H 7.38, N 5.43.
(Æ)-N-Benzyloxycarbonyl-5-hydroxy-3-piperidene
[(Æ)-1c]
To a deoxygenated solution of 4c (3.6 g, 13.6 mmol) in
CH2Cl2 (300 mL) under argon atomosphere was added bis-
(tricyclohexylphosphine)benzylidine ruthenium(IV) dichlor-
ide (447.7 mg, 0.544 mmol, 4 mol%). The solution was stir-
red at room temperature overnight, then concentrated
under reduced pressure and the residue was purified by
flash column chromatography on silica gel (n-hexane:
AcOEt=1:1) to give (Æ)-1b as an oil; yield: 3.0 g (96%).
1H NMR (600 MHz, CDCl3): d=2.38 (br s, 1H), 3.46–3.74
(m, 2H), 3.89(br s, 1H), 4.03 (br t, J=20.9Hz, 1H), 4.21
(br d, J=39.6 Hz, 1H), 5.15 (s, 2H), 5.81 (br d, J=44.7 Hz,
1H), 5.91 (d, J=10.3 Hz, 1H), 7.26–7.39(m, 5H); 13C NMR
(150 MHz, CDCl3): d=43.3, 47.5, 47.9, 63.3, 67.3, 126.3,
127.2, 127.9, 128.0, 128.3, 128.4, 136.4, 155.6; IR (KBr): n=
(Æ)-N-Benzyloxycarbonyl-5-methoxycarbonyloxy-3-
piperidene [(Æ)-2c]
Methyl chloroformate (0.39, 5 mmol) was dropwise added to
a solution of 1c (460 mg, 1.9mmol) and pyridine (0.5 mL,
5.7 mmol) in CH2Cl2 (8 mL) with ice cooling and then the
mixture was stirred at room temperature for 3 h. Ether was
added to the mixture. The whole layer was washed with sa-
turated NH4Cl and brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (n-hexane:
AcOEt=3:1) to give (Æ)-2c as an oil; yield: 509mg (92%).
1H NMR (600 MHz, CDCl3): d=3.63 (t, J=13.9Hz, 1H),
3.72ACHTRE(UGN s, 2H), 3.79(s, 1H), 3.82–3.98 (m, 2H), 4.18 (dd, J=
À1
1702 (C=O), 3419cm (OH); EI-MS: m/z=233 (M+); HR-
49.8, 18.7 Hz, 1H), 5.03–5.23 (m, 3H), 5.81 (br d, J=
44.7 Hz, 1H), 5.91 (d, J=10.3 Hz, 1H), 7.26–7.39(m, 5H);
13C NMR (150 MHz, CDCl3): d=43.2, 44.6, 54.8, 60.4, 67.2,
68.8, 123.1, 127.7, 128.5, 129.6, 130.6, 136.5, 155.1; IR (KBr):
n=1707, 1748 cmÀ1 (C=O); EI-MS: m/z=291 (M+); HR-
MS: m/z=291.1095, calcd for C15H17NO5: 291.1107.
MS: m/z=233.1055, calcd. for C13H15NO3: 233.1052.
(Æ)-N-p-Toluenesulfonyl-5-methoxycarbonyloxy-3-
piperidene [(Æ)-2a]
Methyl chloroformate (5.0 mL, 64.7 mmol) was dropwise
added to a solution of 1a (4.9g, 19.4 mmol) and pyridine
(6.4 mL, 73.7 mmol) in CH2Cl2 (100 mL) with ice cooling
and then the mixture was stirred at room temperature for
3 h. Ether was added to the mixture. The whole layer was
washed with saturated NH4Cl and brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (n-
hexane:AcOEt=3:1) to give (Æ)-2a as colorless prisms;
yield: 5.5 g (91%); mp 81–858C (ether). 1H NMR
(600 MHz, CDCl3): d=2.43 (s, 3H), 3.30 (dd, J=12.5,
5.5 Hz, 1H), 3.42 (dd, J=12.5, 4.4 Hz, 1H), 3.58 (dd, J=
16.9, 2.2 Hz, 1H), 3.68 (dd, J=17.2, 1.8 Hz, 1H), 3.79(s,
3H), 5.11–5.17 (m, 1H), 5.83–5.87 (m, 1H), 5.90–5.96 (m,
1H), 7.33 (d, J=8.4 Hz, 2H), 7.68 (d, J=1.8 Hz, 2H);
13C NMR (150 MHz, CDCl3): d=21.5, 44.6, 46.2, 54.9, 68.8,
123.7, 127.7, 128.3, 129.8, 133.4, 143.9, 155.1; IR (KBr): n=
1168, 1349(SO 2), 1745 cmÀ1 (C=O); EI-MS: m/z=311
(M+); HR-MS: m/z=311.0793, calcd for C14H17NO5S:
311.0828.
(Æ)-N-p-Toluenesulfonyl-5-tert-butoxycarbonyloxy-3-
piperidene [(Æ)-3a]
A mixture of 1a (507 mg, 2.0 mmol), 1-methylimidazole
(41 mL, 0.5 mmol), and (Boc)2O (1.1 g, 4.9mmol) in CH 2Cl2
(20 mL) was stirred at room temperature overnight. The
mixture was concentrated under reduced pressure. The resi-
due was purified by flash column chromatography on silica
gel (n-hexane:AcOEt=3:1) to give (Æ)-3a as colorless
prisms; yield: 738 mg (99%); mp 119–1208C (ether).
1H NMR (600 MHz, CDCl3): d=0.49(s, 9H), 2.43 (s, 3H),
3.25 (dd, J=12.5, 5.5 Hz, 1H), 3.44 (dd, J=12.1, 4.4 Hz,
1H), 3.61 (ddd, J=33.5, 17.0, 2,6 Hz, 2H), 5.07–5.13 (m,
1H), 5.80–5.86 (m, 1H), 5.86–5.91 (m, 1H), 7.33 (d, J=
8.1 Hz, 2H), 7.64–7.71 (m, 2H); 13C NMR (150 MHz,
CDCl3): d=21.5, 27.7, 44.4, 46.3, 67.8, 82.7, 124.2, 127.7,
129.7, 133.4, 143.8, 152.7. IR (KBr): n=1167, 1278 (SO2),
1731 cmÀ1 (C=O); EI-MS: m/z=353 (M+); HR-MS: m/z=
353.1208, calcd. for C17H23NO5S: 353.1259; anal. calcd. for
C17H23NO5S: C 57.77, H 6.56, N 3.96; found: C 57.50, H
6.34, N 3.87.
(Æ)-N-tert-Butoxycarbonyl-5-methoxycarbonyloxy-3-
piperidene [(Æ)-2b]
Methyl chloroformate (0.5 mL, 6.6 mmol) was dropwise
added to a solution of 1b (399 mg, 2.0 mmol) and pyridine
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Hiroki Takahata et al.
130.3, 138.4, 155.2; IR (KBr): n=1707, 1748 cmÀ1 (C=O);
EI-MS: m/z=215 (M+); HR-MS: m/z=215.0770, calcd for
C9H13NO5: 215.0794.
(Æ)-N-Methoxycarbonyl-5-hydroxy-3-piperidene
[(Æ)-1d]
A mixture of (Æ)-1a, (996 mg, 5 mmol), imidazole (510 mg,
7.5 mmol), DMAP (122 mg, 1 mmol), and tert-butyldiphe-
nylsilyl chloride (1.5 g, 5.5 mmol) in CH2Cl2 (17 mL) was
stirred at room temperature overnight. The reaction mixture
was filtered on celite and the filtrate was washed with brine,
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by flash column chromatography
on silica gel (n-hexane:AcOEt=12:1) to give (Æ)-N-tert-Bu-
toxycarbonyl-5-(tert-butyldiphenylsilyloxy)-3-piperidene as
(Æ)-N-p-Toluenesulfonyl-5-acetoxy-3-piperidene
[(Æ)-6]
Acetyl chloride (0.7 mL, 9.9 mmol) was dropwise added to a
solution of 1a (760 mg, 3.0 mmol) and pyridine (0.96 mL,
11.2 mmol) in CH2Cl2 (15 mL) with ice cooling and then the
mixture was stirred at room temperature for 3 h. Ether was
added to the mixture. The whole layer was washed with sa-
turated NH4Cl and brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (n-hexane:A-
cOEt=3:1) to give (Æ)-6 as a yellow oil; yield: 888 mg
1
an oil; yield: 2.2 g (99%). H NMR (400 MHz, CDCl3): d=
1.07 (s, 9H), 1.40 (s, 9H), 3.20 (br s, 1H), 3.57–3.80 (m, 2H),
3.89(d, J=17.6 Hz, 1H), 4.24 (br s, 1H), 5.67 (br s, 2H),
7.31–7.50 (m, 6H), 7.60–7.73 (m, 4H); 13C NMR (67.5 MHz,
CDCl3): d=19.2, 26.9, 28.4, 42.7, 48.0, 65.2, 79.6, 127.6,
1
(99%). H NMR (400 MHz, CDCl3): d=2.06 (s, 3H), 2.43
127.7, 129.7, 129.7, 135.7, 135.8, 154.7; IR (KBr): n=1702,
(s, 3H), 3.19(ddd, J=12.6, 4.0, 0.7 Hz, 1H), 3.37–3.51 (m,
2H), 3.81 (dt, J=17.1, 1.8 Hz, 1H), 5.20–5.27 (m, 1H), 5.77–
5.84 (m, 1H), 5.89–5.97 (m, 1H), 7.30–7.37 (m, 2H), 7.64–
7.71 (m, 2H); 13C NMR (100 MHz, CDCl3): d=21.1, 21.5,
44.4, 46.6, 65.3, 124.0, 127.7, 128.2, 129.8, 133.5, 143.8, 170.5;
IR (KBr): n=1167, 1352 (SO2), 1738 cmÀ1 (C=O); EI-MS:
m/z=295 (M+); HR-MS: m/z=295.0910, calcd. for
C14H17NO4S: 295.0878; anal.calcd. for C14H17NO4S: C 56.93,
H 5.80, N 4.74; found: C 56.55, H 5.40, N 4.58.
À1
1749cm
(C=O); EI-MS: m/z=437 (M+); HR-MS; m/z=
437.2369, calcd. for C26H35NO3Si: 437.2386.
A solution of the above silyl ether (1.75 g, 4 mmol) and
CF3COOH (14 mL) in CH2Cl2 (70 mL) was stirred at room
temperature for 2 h. The mixture was concentrated under
reduced pressure. To a solution of the residue in 1,4-dioxane
(50 mL) were added H2O (50 mL), NaHCO3 (3.36 g,
40 mmol), and methyl chloroformate (0.454 g, 4.8 mmol).
The mixture was stirred at room temperature for 3 h and ex-
tracted with AcOEt. The extract was washed with brine,
dried over MgSO4, and concentrated under reduced pres-
sure to leave an oil. To a solution of the oil in THF (5 mL)
was added 1M tetra-n-butylammoniumu fluoride in THF
(5 mL, 5 mmol). The mixture was stirred at room tempera-
ture for 2 h and then concentrated under reduced pressure.
To the residue were CHCl3 and saturated NaHCO3 and the
whole mixture was separated. The organic layer was dried
and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (n-
hexane:AcOEt=1:2) to give 1d as a colorless oil; yield:
0.57 g (91%). 1H NMR (600 MHz, CDCl3): d=2.84 (br s,
1H), 3.34–3.60 (m, 2H), 3.68 (s, 3H), 3.79–3.87 (m, 1H),
3.87–4.06 (m, 1H), 4.17 (d, J=32.8 Hz, 1H), 5.76 (d, J=
33.2 Hz, 1H), 5.88 (dd, J=10.3, 3.5 Hz, 1H); 13C NMR
(150 MHz, CDCl3): d=43.2, 47.4, 52.7, 63.2, 126.1, 128.6,
156.4; IR (KBr): n=1705 (C=O), 3415 cmÀ1 (OH); EI-MS:
m/z=157 (M+); HR-MS: m/z=157.0719, calcd for
C7H11NO3: 157.0739.
GeneralProcedure for Pd-Catayl zed Deracemization
in Tables 2–6
A mixture of Pd2ACHTRE(UGN dba)3·CHCl3 (10.4 mg, 0.01 mmol) and
(R)-BPA (27.6 mg, 0.04 mmol) or other ligands in solvent
(1.8 mL) was stirred for 15 min under argon and then H2O
(0.2 mL) and (Æ)-2a–d, 3a, or 6 (0.5 mmol) were added to
the mixture. The mixture was stirred at room temperature
for 24 h under argon and then diluted with CHCl3. The
whole mixture was dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel (n-hexane:AcOEt=
5:4) to give (R)-1a–d (yields and ees are shown in Tables 2–
6).
Deracemization of 2a under Anhydrous Conditions
A mixture of Pd2ACHTRE(UGN dba)3·CHCl3 (10.4 mg, 0.01 mmol) and
(R)-BPA (27.6 mg, 0.04 mmol) in dry CH2Cl2 (2 mL) was
stirred for 15 min under argon and then (Æ)-2a (0.5 mmol)
was added to the mixture. The mixture was stirred at room
temperature for 24 h under argon and then diluted with
CHCl3. The whole mixture was dried over MgSO4 and con-
centrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (n-hexane:
AcOEt=2:1–1:1) to give (S)-2a (yield: 100 mg, 64%, 50%
ee) and (R)-1a (yield: 25 mg, 9%, 89% ee).
(Æ)-N-Methoxycarbonyl-5-methoxycarbonyloxy-3-
piperidene [(Æ)-2d]
Methyl chloroformate (0.51 mL, 6.7 mmol) was dropwise
added to a solution of 1d (314 mg, 2.0 mmol) and pyridine
(0.65 mL, 7.6 mmol) in CH2Cl2 (10 mL) with ice cooling and
then the mixture was stirred at room temperature for 3 h.
Ether was added to the mixture. The whole layer was
washed with saturated NH4Cl and brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (n-
hexane:AcOEt=3:1) to give (Æ)-2d as an oil; yield: 333 mg
Deracemization of 2a using KHCO3
A mixture of Pd2ACHTRE(UGN dba)3·CHCl3 (10.4 mg, 0.01 mmol) and
(R)-BPA (27.6 mg, 0.04 mmol) in CH2Cl2 (2 mL) was stirred
for 15 min under argon and then KHCO3 (70 mg, 0.7 mmol)
and (Æ)-2a (0.5 mmol) were added to the mixture. The mix-
ture was stirred at room temperature for 24 h under argon
and then diluted with CHCl3. The whole mixture was dried
1
(78%). H NMR (400 MHz, CDCl3): d=3.57–3.69(m, 1H),
3.72 (s, 3H), 3.74–3.93 (m, 5H), 4.11 (br d, J=17.3 Hz, 1H),
5.10 (br d, J=15.4 Hz, 1H), 5.87–6.04 (m, 2H); 13C NMR
(150 MHz, CDCl3): d=43.1, 44.5, 52.8, 54.8, 68.9, 123.3,
692
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Preparation of Homochiral N-Protected 5-Hydroxy-3-piperidenes
over MgSO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography on
silica gel (n-hexane:AcOEt=2:1–1:1) to give (S)-2a (yield:
18 mg, 11%, 36% ee) and (R)-1a (78 mg, 61%, 91% ee).
Lett. 2003, 44, 2995–2999; d) D. A. Evans, K. R.
Campos, J. S. Tedrow, F. E. Michael, M. R. Gagne, J.
Am. Chem. Soc. 2000, 122, 7905–7920; e) D. A. Evans,
K. R. Campos, J. S. Tedrow, F. E. Michael, M. R.
Gagne, J.Org. Chem. 1999, 64, 2994–2995.
[4] a) H. Ouchi, Y. Mihara, H. Takahata, J. Org. Chem.
2005, 70, 5207–5214; b) H. Ouchi, Y. Mihara, H. Wata-
nabe, H. Takahata, Tetrahedron Lett. 2004, 45, 7053–
7056.
[5] a) R. Noyori, M. Tokunaga, M. Kitamura, Bull. Chem.
Soc. Jpn. 1995, 63, 36–56; b) K. Szori, G. Szollosi, M.
Bartok, Adv. Synth. Catal. 2006, 348, 515–522; c) A.
Ros, A. Magriz, H. Dietrich, M. Ford, R. Fernandez,
J. M. Lassaletta, Adv. Synth. Catal 2005, 347, 1917–
1920; d) S.Hoffmann M. Nicoletti B. List, J. Am. Chem.
Soc. 2006, 128, 13074–13075; e) S. Akai, K. Tanimoto,
Y. Kanao, M. Egi, T. Yamamoto, Y. Kita, Angew.
Chem. Int. Ed. 2006, 45, 2592–2595.
[6] a) C. J. Dunsmore, R. Carr, T. Fleming, N. J. Turner, J.
Am. Chem. Soc. 2006, 128, 2224–2225; b) J. T. Mohr,
D. C. Behenna, A. M. Harned, B. M. Stoltz, Angew.
Chem. Int. Ed. 2005, 44, 6924–6927; c) B. M. Trost, H.-
C. Tsui, F. D. Toste, J. Am. Chem. Soc. 2000, 122,
3534–3535; d) B. M. Trost, M. G. Organ, J. Am. Chem.
Soc. 1994, 116, 10320–10321.
Acknowledgements
This work was supported, in part, by a Grant-in-Aid for Sci-
entific Research (No. 18590012) and High Technology Re-
search Program from Ministry of Education, Sciences, Sports
and Culture of Japan.
References
[1] a) H. Sakagami, K. Ogasawara, Heterocycles 2001, 54,
43–47; b) H. Sakagami, K. Ogasawara, Synthesis 2000,
521–524; c) H. Sakagami, K. Samizu, T. Kamikubo, K.
Ogasawara, Synlett 1996, 163–164; d) T. Imanishi, K.
Miyashita, A. Nakai, M. Inoue, M. Hanaoka, Chem.
Pharm. Bull. 1983, 31, 1191–1198; e) T. Imanishi, N.
Yagi, H. Shin, M. Hanaoka, Chem. Pharm. Bull. 1982,
30, 4052–4059; f) T. Imanishi, N. Yagi, H. Shin, M. Ha-
naoka, T. Momose, I. Imanishi, Chem. Pharm. Bull.
1982, 30, 3617–3623; g) T. Imanishi, K. Miyashita, A.
Nakai, M. Inoue M. Hanaoka, Chem. Pharm. Bull.
1982, 30, 1521–1524; h) T. Imanishi, H. Shin, N. Yagi,
M. Hanaoka, Tetrahedron Lett. 1980, 21, 3285–3288.
[2] a) B. Musicki, A.-M. Periers, L. Piombo, P. Laurin, M.
Klich, C. Dupuis-Hamelin, P. Lassaigne, A. Bonnefoy,
Tetrahedron Lett. 2003, 44, 9259–9262; b) K. Miyashita,
M. Park, S. Adachi, S. Seki, S. Obika, T. Imanishi,
Bioorg. Med. Chem. Lett. 2002, 12, 1075–1077; c) C.
Morice, M. Domostoj, K. Briner, A. Mann, J. Suffert,
C.-G. Wermuth, Tetrahedron Lett. 2001, 42, 6499–6502.
[3] a) C. J. Easton, C. M. Hughes, E. R. T. Tiekink, C. E.
Lubin, S. G. Paul, G. W. Simpson, Tetrahedron Lett.
1994, 35, 3589–3592; b) J. S. McCallum, L. S. Liebes-
kind, Synthesis 1993, 819–823; c) S. R. Baker, M.
Cases, M. Keenan, R. A. Lewis, P. Tan, Tetrahedron
[7] B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103,
2921–2943.
[8] B. J. Luessem, H.-J. Gais, J. Am. Chem. Soc. 2003, 125,
6066–6067.
[9] R. H. Grubbs, S. Chang, Tetrahedron 1998, 54, 4413–
4450.
[10] B. M. Trost, D. L. Van Vranken, C. Bingel, J. Am.
Chem. Soc. 1992, 114, 9327–9343.
[11] B. M. Trost, R. C. Bunt, R. C. Lemoine, T. L. Calkins, J.
Am. Chem. Soc. 2000, 122, 5968 À5976.
[12] a) K. Shibatomi, Y. Uozumi, Tetrahedron: Asymmetry
2002, 13, 1769–1772; b) Y. Uozumi, H. Tanaka, K. Shi-
batomi, Org. Lett. 2004, 6, 281–283.
[13] B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121,
4545–4554.
Adv. Synth. Catal. 2007, 349, 685 – 693
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
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