Highly enantioselective preparation of tertiary alcohols and amines by copper-mediated diastereoselective allylic SN2′ substitutions

Article abstract of DOI:10.1002/anie.200500672

(Chemical Equation Presented) Trisubstituted allylic pentafluorobenzoates react with diorganozinc reagents in the presence of CuCN·2 LiCl to provide alkenes bearing a chiral quaternary center in α position (> 95 % ee). These alkenes are readily converted into chiral tertiary alcohols or into chiral amino alcohols by a straightforward sequence of ozonolysis followed by Curtius rearrangement (see scheme).

Full text of DOI:10.1002/anie.200500672

Angewandte
Chemie
Asymmetric Synthesis
such as (EtO2C(CH2)3)2Zn[8] reacted in a similar way provid-
ing the corresponding chiral esters 4b (68%, 96% ee) and 4c
(58%, 96% ee) with the same level of enantioselectivity. In all
these substitutions, allylic pentafluorobenzoates were used as
substrates. Other allylic alcohol derivatives such as 2,6-
difluorobenzoate 5c (99% ee) underwent the allylic substitu-
tion with optimum enantioselectivity leading to the E alkene
4d in 85% yield and 98% ee (entry 4). These substrates also
gave excellent results with purely alkyl-substituted allylic
reagents such as 5d (99% ee, entry 5). In this case, the
substitution with Et2Zn provided the E alkene 4e (80%,
96% ee) bearing a quaternary center with three different
alkyl substituents. Although allylic acetates react only slug-
gishly with diorganozinc reagents, in the case of the allylic
acetate 5e (97% ee), which bears small substituents (Me and
Et) at the double bond, an efficient substitution with Pent2Zn
took place providing the E alkene 4 f in 60% yield and
95% ee.
This substitution reaction proceeded with a reliable
transfer of chirality (entries 7 and 8) and was also performed
with secondary diorganozinc reagents like iPr2Zn to furnish
the sterically hindered alkene 4i (73%, 95% ee; entry 9).
Interestingly, functionalized allylic pentafluorobenzoates
such as 5i (99% ee) and 5j (99% ee) provided useful chiral
building blocks like 4j (69%), 4k (90%), and 4l (80%) in
enantiomerically pure form (99% ee; entries 10–12).
With the chiral alkenes of type
Highly Enantioselective Preparation of Tertiary
Alcohols and Amines by Copper-Mediated
Diastereoselective Allylic SN2’ Substitutions**
Helena Leuser, Sylvie Perrone, FrØdØric Liron,
Florian F. Kneisel, and Paul Knochel*
The asymmetric preparation of tertiary alcohols and amines is
an important synthetic problem that has been the subject of
numerous studies.[1,2] Copper-catalyzed SN2’ substitutions are
an excellent method for setting up chiral centers in cyclic and
acyclic systems.[3–5] Only a few of these reactions can be
applied to the construction of quaternary carbon centers.[6]
We have recently reported an efficient anti-SN2’ allylic
substitution reaction with pentafluorobenzoates of trisubsti-
tuted allylic alcohols that produces quaternary centers with
almost complete transfer of the chiral information.[7] Herein,
we report applications of this method for preparing chiral
tertiary alcohols 1 and amines and isocyanates such as 2 and 3,
which bear a tertiary chiral center, with high enantioselectiv-
ity starting from the chiral allylic substitution products 4,
which were obtained from the allylic pentafluorobenzoates 5
(Scheme 1).
4 in hand, we then developed
a
straightforward
oxidation
sequence for the conversion of
chiral alkenes 4 to either the cor-
responding aldehydes 12 or carbox-
ylic acids 13 (Scheme 2). The
former intermediate undergoes
stereoselective
Baeyer–Villiger
rearrangement[9] to afford the
chiral tertiary alcohol 1, and the
latter undergoes stereoselective
Curtius rearrangement[10] leading
Scheme 1. Enantioselective preparation of tertiary alcohols 1, amines 2, and isocyanates 3 bearing a
tertiary chiral carbon center.
In a typical procedure the E pentafluorobenzoate 5a
(97% ee, entry 1 of Table 1) was treated with Pent2Zn
(2 equiv) and CuCN·2LiCl (1 equiv) in THF at ꢀ30 to
ꢀ108C for 14 h to afford the expected anti-SN2’ substitution
product 4a (70%, 96% ee) with an almost perfect transfer of
chiral information. Functionalized diorganozinc reagents
to the isocyanates 3, which can be converted to the
corresponding amines 2. In this way the ozonolysis of the
alkene 4d followed by a reductive workup (PPh3, ꢀ78 to
258C, 2 h) provided the aldehyde 12a in 85% overall yield
and 98% ee. Treatment of 12a with MCPBA (3 equiv,
Na2HPO4, CH2Cl2, RT, 2 h) furnished, after saponification
of the intermediate formyl ester, the tertiary alcohol 1a
(70%, 97% ee) with perfect retention of configuration
(entry 1 of Table 2). Alternatively, the conversion of 4d to
the corresponding carboxylic acid 13a (entry 2) was achieved
when the ozonolysis was followed by a Jones oxidation.
Heating 13a with (PhO)2P(O)N3 in toluene for 1 h in the
presence of Et3N afforded an intermediate isocyanate, which
was converted to the corresponding chiral amine 2a (20%
HCl, reflux, 18 h, 65%, 98% ee) with very high retention of
the configuration for the chiral tertiary center.
[*] Dr. H. Leuser, Dipl.-Chem. S. Perrone, Dr. F. Liron, Dr. F. F. Kneisel,
Prof. Dr. P. Knochel
Department Chemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the Deutsche
Forschungsgemeinschaft (DFG), and Merck Research Laboratories
(MSD) for financial support. We also thank Chemetall GmbH
(Frankfurt) and BASF AG (Ludwigshafen) for generous gifts of
chemicals.
These reaction sequences proved to be general, and the
alkenes 4e (96% ee) and 4g (98% ee) afforded the alcohols
1b (76%, 92% ee; entry 3) and 1c (68%, 93% ee; entry 4),
respectively, and the isocyanate 3a (68%, 98% ee). Polyfunc-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 4627 –4631
DOI: 10.1002/anie.200500672
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4627

Communications
Table 1: Products 4 resulting from the copper-mediated anti-SN2’ substitution of pentafluorobenzoates 5 with diorganozinc reagents.
Entry
Allyl substrate
Product
Yield
[%][b]
ee
Entry
Allyl substrate
Product
Yield
[%][b]
ee
(ee [%][a])
[%][a]
(ee [%][a])
[%][a]
1
2
5a (97)
5a (97)
4a: R=Pent
4b: R=(CH2)3CO2Et
70
68
96
96
7
5 f (99)
4g
88
98
3
4
5b (98)
5c (99)
4c
4d
58
85
96
98
8[c]
5g (97)
5h (99)
4h
4i
90
73
95
95
9
5
5d (99)
4e
80
96
10
11
5i (99)
5i (99)
4j: R=Et
4k: R=Pent
69
90
99
99
6
5e (97)
4 f
60
95
12
5j (99)
4l
80
99
[a] The enantiomeric excess was determined by HPLC or GC analysis. In each case the racemic product was also prepared for HPLC or GC calibration.
[b] Yield of analytically pure product. [c] In this case the reaction was performed in a 2:1 THF/N-methylpyrrolidinone.
Scheme 2. Oxidation–rearrangement sequence for the preparation of chiral tertiary alcohols.
tional products such as selectively protected 1,2-diols bearing
a tertiary hydroxyl group can be readily prepared starting
from the chiral homoallylic benzyl ethers 4j (99% ee), 4k
(99% ee) and 4l (99% ee). After ozonolysis, the intermediate
aldehydes 12d (62%, 99% ee; entry 6), 12e (66%, 99% ee;
entry 8), and 12 f (71%, 99% ee; entry 10) were submitted to
the Baeyer–Villiger reaction to provide the mono-protected
diols 1d (70%, 99% ee), 1e (77%, 98% ee), and 1 f (93%,
96% ee), respectively. By performing the Curtius rearrange-
ment on the corresponding carboxylic acids 13c (65%,
99% ee; entry 7), 13d (60%, 99% ee; entry 9), and 13e
(85%, 99% ee; entry 11), we obtained the amino alcohols 2b
(60%, 99% ee), and 2c (88%, 99% ee), respectively, as well
as the isocyanate 3b (79%, 99% ee).
As an application of this methodology, we prepared the
chiral 1,2-diol 14, which is a key intermediate in the synthesis
of the combined NK1 and NK2 tachykinin receptor antagonist
(Scheme 3).[11] Thus, the SN2’ substitution of 5i with (PivO-
(CH2)3)2Zn in the presence of CuCN·2LiCl provided the
chiral alkene 15 in 60% yield and 98% ee. The ozonolysis of
15 followed by reductive workup afforded the chiral aldehyde
in 76% yield and 98% ee. Baeyer–Villiger oxidation of 16 in
the presence of NaH2PO4 in CH2Cl2 followed by the
saponification of the two ester functions gave the diol 17 in
70% yield. Quantitative protection of the remote primary
hydroxy function as a TBDMS-silyl ether provided an
intermediate alcohol, which underwent hydrogenolysis over
Pd/C in 2-propanol (H2 (1 atm), 258C, 1 h) to furnish the
4628
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Chemie
Table 2: Tertiary alcohols 1 obtained by oxidation followed by Baeyer–Villiger rearrangement and chiral isocyanates 3 and amines 2 obtained by
oxidation followed by Curtius rearrangement.
Entry
Alkene
Intermediate
Yield [%][b]
ee [%][a]
Product
Yield [%][b]
ee [%][a]
1
4d
12a
85
98
1a
70
97
2
3
4d
4e
4g
4g
4j
13a
12b
12c
13b
12d
13c
12e
13d
12 f
13e
79
63
65
68
62
65
66
60
71
85
98
96
98
98
99
99
99
99
99
99
2a
1b
1c
3a
1d
2b
1e
2c
1 f
65
76
68
68
70
60
77
88
93
79
98
92
93
98
99
99
98
99
96
99
4
5
6
7
4j
8
4k
4k
4l
9
10
11
4l
3b
[a] The enantiomeric excess was determined by HPLC or GC analysis. In each case the racemic product was also prepared for HPLC or GC calibration.
[b] Yield of isolated analytically pure product.
Experimental Section
expected product 14, an intermediate in the synthesis of a
Typical procedure for the copper(i)-mediated allylic substitution of
fluorobenzoates with dialkylzinc reagents: 4d:[7a]: Pent2Zn (2.35 mL,
11.3 mmol, 2.4 equiv) was added at ꢀ308C to a solution of CuCN·2-
LiCl (5.6 mL, 5.6 mmol, 1.2 equiv, 1m in THF) stirred under argon.
The resulting mixture was stirred for 0.5 h at ꢀ308C, then 5c
(4.7 mmol in THF (2 mL), 1.0 equiv) was added dropwise. The
reaction mixture was allowed to warm to ꢀ108C within 1.5 h and was
stirred at ꢀ108C for 14 h. The reaction mixture was quenched by
addition of aq. sat. NH4Cl (5 mL) and was then poured into 25% aq.
ammonia (2 mL), aq. sat. NH4Cl (100 mL), and Et2O (100 mL). After
extraction with Et2O (3 ” 100 mL), the combined extracts were
washed with brine (100 mL) and dried (MgSO4). The solvents were
tachykinin receptor antagonist.
In summary, we have developed
a straightforward
sequence for the synthesis of tertiary alcohols with high
enantioselectivity. We have shown that a Curtius rearrange-
ment on the corresponding chiral carboxylic acids provides a
stereoselective approach to amines bearing a tertiary center
and to amino alcohol derivatives. Further applications of this
method to the preparation of polyfunctional chiral building
blocks are currently underway in our laboratories.
Angew. Chem. Int. Ed. 2005, 44, 4627 –4631
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Communications
Typical procedure for the oxidation[12] and Curtius rearrange-
ment:[10] 2a: Ozone was passed through a solution of alkene 4d
(432 mg, 2.00 mmol, 1.0 equiv) in acetone (10 mL) at ꢀ788C under N2
until the solution turned blue (3–10 min); excess O3 was removed by a
stream of nitrogen. The reaction mixture was cooled to 08C, and
Jones reagent (2.0 mL, 2.67m, 5.4 mmol, 2.7 equiv) was added
dropwise until the orange color persisted. The mixture was stirred
for 1 h at 208C, then iPrOH (8 mL) was added until the mixture
turned green. The solvents were removed by evaporation, and the
residue was dissolved in water/ (100 mL, 1:4). After acid–base
workup[12c] the desired carboxylic acid 13a (348 mg, 1.58 mmol,
79%) was obtained as a colorless liquid. A mixture of 13a (124 mg,
0.56 mmol, 1.0 equiv), (PhO)2P(O)N3 (231 mg, 0.84 mmol, 1.5 equiv)
and NEt3 (85 mg, 0.84 mmol, 1.5 equiv) in toluene (5 mL) was heated
at refluxfor 2 h. After removal of the solvent by evaporation in vacuo,
the residue was taken up in ether (50 mL) and washed with water (3 ”
50 mL). The organic layer was dried (MgSO4), concentrated in vacuo,
and purified by flash chromatography (pentane/Et2O = 98:2). 1-((2S)-
2-Isocyanatoheptan-2-yl)benzene (120 mg, quant., 98% ee) was
obtained as a colorless liquid. The enantiomeric excess was deter-
mined by GC analysis (column: ChiraldexB-PH; 100 8C const.: tR =
57.8 (S), 61.9 minꢀ1 (R)). 1-((2S)-2-isocyanatoheptan-2-yl)benzene
(50 mg, 0.23 mmol) was heated at refluxin 20% aq. HCl (5 mL) for
24 h. The reaction mixture was partitioned in Et2O and water (4:1),
and the layers were separated. The aqueous layer was treated with
NaOH (20%) and extracted with Et2O (3 ” 80 mL). The organic layer
was dried (MgSO4) and the solvent evaporated in vacuo to give 2a
(30 mg, 0.16 mmol, 65%, 98% ee) as a colorless oil.
Scheme 3. Preparation of the diol 14, an intermediate in the synthesis
of the tachykinin receptor antagonist. a) (PivO(CH2)3)2Zn, CuCN·2LiCl,
THF, ꢀ30!ꢀ108C, 16 h; b) O3, CH2Cl2, ꢀ788C; c) PPh3, RT, 2 h;
d) MCPBA, NaH2PO4, CH2Cl2, RT, 2 h; e) LiOH, MeOH, RT, 5 h;
f) TBDMSCl, imidazole, DMF, RT, 5 h; g) 1 atm H2, Pd/C, iPrOH, RT,
1 h. MCPBA=meta-chloroperbenzoic acid, TBDMS=tert-butyldime-
thylsilyl.
Received: February 22, 2005
removed by evaporation and the residue purified by column
chromatography to yield alkene 4d (855 mg, 3.96 mmol, 85%) as a
colorless liquid.
Keywords: allylic substitution · asymmetric synthesis · copper ·
rearrangements · zinc
.
Typical procedure for the oxidation[12] and Baeyer–Villiger
rearrangement[9] sequence: 1a: Ozone was passed through a solution
of alkene 4d (260 mg, 1.20 mmol, 1.0 equiv) in CH2Cl2 (30 mL) at
ꢀ788C under N2 until the solution turned blue (3–10 min); excess O3
was removed with a stream of N2. PPh3 (408 mg, 1.5 mmol, 1.3 equiv)
was added in one portion, and the mixture was warmed to 208C
within 2 h. The reaction mixture was then diluted with Et2O (10 mL)
and washed with water and brine, and then dried (MgSO4). The
solvents were removed by evaporation in vacuo, and the residue was
purified by column chromatography to give 12a (194 mg, 0.95 mmol,
85%, 98% ee) as a colorless liquid. The enantiomeric excess was
determined by GC analysis (column: ChiraldexB-PH; 100 8C
(30 min), 0.58minꢀ1 until 1208C: tR = 78.3 (R), 79.7 minꢀ1 (S)). To a
solution of aldehyde 12a (163 mg, 0.80 mmol, 1.0 equiv) in CH2Cl2
(2 mL) was added anhydrous MCPBA (260 mg, 1.2 mmol, 1.5 equiv).
The reaction was stirred at room temperature for 24 h before it was
quenched with water and extracted with Et2O (3 ” 50 mL). The
combined organic layers were dried (MgSO4), concentrated in vacuo,
and purified by flash chromatography (pentane/Et2O = 98:2). (2S)-2-
phenylheptan-2-yl formate (123 mg, 70%) was obtained as a colorless
liquid. To a solution of (2S)-2-phenylheptan-2-yl formate (123 mg,
0.56 mmol, 1.0 equiv) in MeOH (2 mL) was added KOH (62 mg,
1.12 mmol, 2.0 equiv). The reaction mixture was stirred at 208C for
1 h, then diluted with Et2O (10 mL), washed with brine, dried
(MgSO4), and concentrated in vacuo. Purification by flash chroma-
tography (pentane/Et2O = 9:1) yielded 1a (75 mg, 0.39 mmol, 70%,
97% ee) as a colorless oil. The enantiomeric excess was determined
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