Construction of optically active CF3-containing quaternary carbon centers via stereospecific SN2′ reaction

Article abstract of DOI:10.1021/ol0481941

(Chemical Equation Presented) Phosphates from 3-substituted 4,4,4-trifluorobut-2-en-1-ols were found to be effective for construction of CF₃-containing quaternary carbon centers by way of Cu(I)-catalyzed Grignard reactions in the presence of ca

Full text of DOI:10.1021/ol0481941

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4651-4654
Construction of Optically Active
CF3-Containing Quaternary Carbon
Centers via Stereospecific SN2
′
Reaction†
Mitsuo Kimura, Takashi Yamazaki,*,‡ Tomoya Kitazume, and Toshio Kubota§
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology,
4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan, and Department of Materials
Science, Ibaraki UniVersity, 4-12-1 Nakanarusawa Hitachi, 316-85111 Japan
tyamazak@cc.tuat.ac.jp
Received September 7, 2004
ABSTRACT
Phosphates from 3-substituted 4,4,4-trifluorobut-2-en-1-ols were found to be effective for construction of CF3-containing quaternary carbon
centers by way of Cu(I)-catalyzed Grignard reactions in the presence of catalytic amounts of CuCN and trimethylsilyl chloride (TMSCl) in an
anti SN2′ manner.
Since quaternary carbon centers with only carbon atoms were
frequently found as the partial structure of various naturally
occurring biologically active compounds,1 synthetic studies
of such special units in a stereoselective fashion have been
extensively carried out in recent years.2
On the other hand, introduction of fluorine atom(s) into
organic compounds has been known as one of the major
strategies for enhancement or modification of their original
biological activities.3 Thus, from the standpoint of the
pharmaceutical utility of fluorinated materials, it would be
quite intriguing to substitute a methyl moiety at a quaternary
carbon site to a trifluoromethyl (CF3) group; however, very
limited synthetic examples that allowed us to conveniently
assemble requisite molecules have been reported.4 This
situation prompted us to further develop new synthetic
procedures to access such specific structures.5
Recently, we have reported that the CF3-containing allylic
alcohol derivatives such as 1 furnished the substitution
products 2 via the clean anti SN2′ mechanism when treated
with an appropriate Grignard reagent in the presence of
catalytic amounts of CuCN and TMSCl, without any trace
† Dedicated to Professor Iwao Ojima on the occasion of his 60th birthday.
‡ Current address: Department of Applied Chemistry, Tokyo University
of Agriculture and Technology, 2-24-16, Nakamachi, Koganei 184-8588,
Japan.
(3) (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Kukhar’, V. P.;
Soloshonok, V. A.; Eds. Fluorine-containing Amino AcidssSynthesis and
Properties; Wiley: New York, 1995. (c) Ojima, I., McCarthy, J. R., Welch,
J. T., Eds. Biomedical Frontiers of Fluorine Chemistry; ACS Symposium
Series 639; American Chemical Society: Washington, DC, 1996.
(4) For example, see: (a) Todoroki, Y.; Hirai, N.; Koshimizu, K.;
Phytochemistry 1995, 38, 561. (b) Jennings, L. D.; Rayner, D. R.; Jordan,
D. B.; Okonya, J. F.; Basarab, G. S.; Amorose, D. K.; Anaclerio, B. M.;
Lee, J. K.; Schwartz, R. S.; Whitmore, K. A. Bioorg. Med. Chem. 2000, 8,
897.
§ Ibaraki University.
(1) For recent examples, see: (a) Nicolaou, K. C.; Snyder, S. A.; Huang,
X.-H.; Simonsen, K. B.; Koumbis, A. E.; Bigot, A. J. Am. Chem. Soc. 2004,
126, 10162. (b) Cheung, A. K.; Murelli, R.; Snapper, M. L. J. Org. Chem.
2004, 69, 5712. (c) Kodama, S.; Hamashima, Y.; Nishide, K.; Node, M.
Angew. Chem., Int. Ed. 2004, 43, 2659. (d) Ghosh, S.; Rivas, F.; Fischer,
D.; Gonza´lez, M. A.; Theodorakis, E. A. Org. Lett. 2004, 6, 941.
(2) For a review on the construction of quaternary carbon centers, see:
(a) Martin, S. F. Tetrahedron 1980, 36, 419. (b) Fuji, K. Chem. ReV. 1993,
93, 2037. (c) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (d) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105.
(5) (a) Resnati, G. Tetrahedron 1993, 49, 9385. (b) Kitazume, T.;
Yamazaki, T. Top. Curr. Chem. 1997, 193, 91. (c) Iseki, K. Tetrahedron
1998, 54, 13887.
10.1021/ol0481941 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/17/2004

Scheme 1
Table 1. Optimization of Reaction Conditions with 6a
amount of the corresponding SN2 products (Scheme 1).6
Because we have already established enzymatic resolution
of the alcoholic part of 1,7 construction of chiral 2 was readily
attained with high optical purity. In this communication, we
would like to report further extension of this SN2′ methodol-
ogy for formation of materials possessing chiral CF3-
containing quaternary carbon centers.
First of all, we have prepared the requisite substrates for
the present purpose, allylic acetates 6 and the corresponding
phosphates 7, by the routine methods as outlined in Scheme
2. The first Horner-Wadsworth-Emmons process afforded
isolated yield (%)
Cu (I)
(equiv)
EtMgBr TMSCl
entry
(equiv)
(equiv)
8a
5a
1
2
3
none
CuCl (0.2)
CuI (0.2)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
2.0
1.5
1.5
1.5
none
none
none
none
none
none
0.6
1.0
1.5
1.0
1.0
<1
<1
4
82a
76
74
28
26
13
20
22
26
23
37
19
20
16
4
CuCN (0.2)
CuCN (0.2)
CuCN (0.2)
CuCN (0.2)
CuCN (0.2)
CuCN (0.2)
CuCN (0.2)
CuCN (0.2)
CuCN (0.4)
CuCN (0.6)
CuCN (1.0)
60
51
14
67
73
68
73
56
72
74
72
5b
6c
7
8
9
10
11
12
13
14
1.0
1.0
1.0
Scheme 2
a Also recovered was 11% of 6a. b Stirred at -78 °C for 30 min and
then stirred at 0 °C for 30 min. A mixture of 8a/9a/10a ) 70:11:19 (by 19
F
NMR) was isolated in 51% yield along with 2% of recovery. c In THF/
Et2O (12:1) solvent. A mixture of 8a/9a/10a ) 2:13:85 (by 19F NMR) was
isolated in 14% yield.
1-4), and other Cu(I) catalysts exclusively afforded the
deprotected alcohol 5a. Reaction at lower temperature (-78
°C) allowed us to obtain larger amounts of the SN2 product
and difluorinated diene (vide infra) possibly because of
retardation of the reductive elimination rate,8 facilitating
isomerization to the sterically less biased form and â-elim-
ination by intramolecular Cu-F interaction, respectively
(entry 5). Similar to the previous case, a quite significant
solvent effect gave rise to suppression of the desired pathway
in THF (entry 6).9 The proportion of the SN2′ product 8a
was increased by addition of TMSCl,10 and 1.0 equiv was
found to be the amount of choice (entries 8 and 10); however,
its contribution was not as effective as the previous case.
Goering reported that although allylic acetates accepted
Grignard attack at their carbonyl carbon under the Cu(I)-
catalyzed conditions, bulkier pivalate or 2,4,6-trimethyl-
benzoate were effective in inhibition of such an unfavorable
process.11 We also employed isobutyrate and pivalate, but
the yield of the SN2′ product was not remarkably affected
(isobutyrate: 72% yield and 11% of 5a; pivalate: 33% yield
and 4% of 5a). On the other hand, exclusive formation of
the SN2′ product was realized in 93% yield by way of the
E/Z mixtures of 4 in an approximate ratio of 8:2 irrespective
of the nature of R1, which was basically constant until they
were derived into 6 and 7. The previously employed
conditions6 for the construction of CF3-containing tertiary
carbon centers were applied to 6a to furnish the desired SN2′
compound 8a in 60% yield along with 28% of deacetylated
allylic alcohol 5a. This side product, not observed at all for
1,6 would be formed as the result of increase of steric
hindrance around the reaction site. This fact apparently
indicated that modulation of the previous conditions was
required for nice adjustment to the present system.
It was easily understood that it is only CuCN that was
effective in obtaining the desired SN2′ product 8a (entries
(8) Ba¨ckvall, J.-E.; Persson, E. S. M.; Bombrun, A. J. Org. Chem. 1994,
59, 4126.
(9) Ba¨ckvall, J.-E.; Selle´n, M.; Grant, B. J. Am. Chem. Soc. 1990, 112,
6615.
(6) (a) Yamazaki, T.; Umetani, H.; Kitazume, T. Tetrahedron Lett. 1997,
38, 6705. (b) Yamazaki, T.; Umetani, H.; Kitazume, Isr. J. Chem. 1999,
39, 193.
(10) Bertz, S. H.; Miao, G.; Rossiter, B. R.; Snyder, J. P. J. Am. Chem.
Soc. 1995, 117, 11023.
(7) Mizutani, K.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 1995, 60,
6046.
(11) Tseng, C. C.; Paisley, S. D.; Goering, H. L. J. Org. Chem. 1986,
51, 2884.
4652
Org. Lett., Vol. 6, No. 25, 2004

corresponding phosphate 7a. Previously,6 the usefulness of
this leaving group was demonstrated for the cases when an
acetoxy moiety did not work properly, but we hesitated to
employ it because, from our experience, phosphates some-
times resulted in lower chirality transmission due to their
high leaving ability, probably allowing this process to
proceed in part via the SN1 mechanism.
F2-diene formation became the major pathways along with
the desired route to the SN2′ compounds 8, and the
significantly bulky t-BuMgCl furnished only sluggish results.
When n-C8H17- and PhCH2CH2MgBr were allowed to
react with the phosphate 7c possessing a phenyl group at
the γ-position as R1, a lower level of SN2′ selectivity was
obtained because a bulkier phenyl group would cause severe
steric and/or electronic repulsive interaction with the incom-
ing nucleophilic species. On the other hand, it was intriguing
to note that transformation of the difluorodiene 10 (R1 )
Ph) was not observed for this specific substrate.
In Table 2, the Grignard-based SN2′ reaction of allylic
phosphates 7a-c is summarized. As expected, these sub-
The present reaction mechanism was explained as follows
(Scheme 3). Similar to the case of our recent work, TMSCl
Table 2. SN2′ Reaction of 7 with Various Grignard Reagents
Scheme 3
distributionb
entry substrate
Ra
8
9
10
yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16e
17
18
19
20
7a
7b
7c
Me
Et
i-Pr
i-Bu
t-Bu
Ph
Ph(CH2)2
Me
Et
i-Pr
i-Bu
t-Bu
Ph
Ph(CH2)2
n-C8H17
n-C8H17
i-Bu
t-Bu
Ph
86
>98
39
4
10
73
93
81
94
d
82
>99
47
87
83
83
d
81
>99
96
62
48
27
61
96
<1 <1
44
8
17
6
86
12
97
81
>98
59
79
50
3
8
<1 <1
35
20
38
<1
11
complexation toward cuprates might effectively decrease the
activation energy of reductive elimination due to the â-cation
stabilizing effect of the Si atom.13 Thus, when R and R1 were
small enough in size, R migration would relatively readily
proceed from Int-B to afford the desired products 8. On the
other hand, sterically bulkier alkyl groups rendered this
intermediate more congested and less stable, which would
increase the likelihood of the Cu-F â-elimination6,14 or
isomerization to sterically more favorable Int-C, the latter
of which would eventually give the SN2 products 9. Steric
congestion could also facilitate the attack at the acetate
carbonyl group as an alternative route.
Except for limited cases such as entries 2 and 9 in Table
2, the desired CF3-containing SN2′ products 8 were obtained
only as an inseparable mixture with SN2 and defluorinated
products, 9 and 10, respectively. However, ozonolysis of such
mixtures affected the oxidative cleavage at the CdC bond,
and addition of Me2S eventually led to isolation of the
corresponding aldehydes 11 with a quaternary center at their
R-position without contamination of any other fragments
(Table 3).
6
1
3
97
75
63
33
8
70
3
25 <1
37 <1
67 <1
92 <1
27
<1
<1 >98 <1
68 32 <1
Ph(CH2)2
a In the case of i-Pr, i-Bu, and t-Bu, the corresponding magnesium
chloride was used. b Product distribution was determined by 1H NMR and/
or 19F NMR. c Combined yield. d Complex mixture was obtained. e 6c was
used as the substrate.
strates showed the complete SN2′ selectivity without yielding
the possible regioisomeric SN2 products 9 when reacted with
such primary halide-based reagents as Et- and PhCH2CH2-
MgBr. Predominant formation of the SN2 products 9 was
noticed for PhMgBr probably due to the less potent transfer-
ability of a phenyl group as a ligand.12 As the steric bulkiness
of the Grignard reagents increased, the SN2-type reaction and
At the next stage, we extended this process to the chiral
allylic alcohol 13 (Scheme 4). We have selected ketone 3a
(12) (a) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A.; Parker, D. J.
Org. Chem. 1984, 49, 3928. (b) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski,
J. A. Tetrahedron 1984, 40, 5005.
(13) Lambert, J. B. Tetrahedron 1990, 46, 2677.
(14) Similar type of Cu-F elimination, see: Xu, Y.; Jin, F.; Huang, W.
J. Org. Chem. 1994, 59, 2638.
Org. Lett., Vol. 6, No. 25, 2004
4653

Scheme 4
Table 3. Ozonolysis of SN2′ Products
distributiona
10 yield of 11b (%)
entry
R1
R
8
9
1
2
3
4
5
PhCH2CH2 Et
>98 <1 <1
76
76
76
88
82
i-Bu
Et
88
96
78 14
8
4
4
<1
8
n-C8H17
i-Bu
Ph
n-C8H17
76 24 <1
a Material distribution was determined by 19F NMR. b Isolated yield based
on the SN2′ starting material.
as the starting material, which was converted to R,â-
unsaturated ketone 12 with exclusive E-selectivity by the
conventional method. Asymmetric reduction of E-12 in the
presence of (R)-BINAL-H gave the allylic alcohol 13 in 91%
ee, whose absolute configuration was expected to be R on
the basis of the already proposed n-π-type electronic repul-
sion in the transition state between the binaphthoxy oxygen
and the unsaturated moiety.15 Subjection of EtMgBr to an
ethereal solution of E-14 in the presence of CuCN and
TMSCl realized complete chirality transmission for the
formation of E-15, which was further transformed into the
R-chiral aldehyde 16 by ozonolysis. Conversion of 16 to
camphorsulfornyl amide 17 was carried out by a four-step
sequence, and the single-crystal X-ray diffraction analysis
of the latter clarified its absolute configuration as R. This
stereochemical output is consistently explained as the result
of the general organocupper anti SN2′ displacement mech-
anism starting from (R)-allylic alcohol 13.16 On the other
hand, the corresponding phosphate instead of the acetate 14
gave a mixture of 15 (E/Z ) 90/10) and the corresponding
SN2 product in a ratio of 91:9, and only 63% of chirality
transmission was observed for E-15 as was expected.
In conclusion, the trisubstituted CF3-containing allylic
derivatives were demonstrated to be good candidates for
efficient construction of quaternary carbon centers via the
SN2′ reaction by treatment with appropriate Grignard reagents
in the presence of CuCN and TMSCl. Moreover, this system
can be readily extended to the chiral version with the aid of
BINAL-H-mediated reduction, which, by way of ozonolysis
of the reaction mixture obtained, eventually realized isolation
of the optically active aldehyde 16 with the CF3-substituted
quaternary carbon center. The scope and limitation of this
method is now under investigation in this laboratory.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for all new
compounds (4-17). This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709.
(16) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063.
OL0481941
4654
Org. Lett., Vol. 6, No. 25, 2004