Diastereoselective alkylation of glycinates by assistance of intramolecular potassium-fluorine interactions

Article abstract of DOI:10.1002/chem.200901984

A study was conducted to demonstrate diatereoselective alkylation of glycinates by assistance of intermolecular potassium-fluorine interactions. Preparation of the starting materials for the investigations was carried out from the readily available fluorinated acetophenones. The investigations focused on finding appropriate alkylation conditions after their transformation to the corresponding enolates. The representative starting material was subjected to a solution of a base in THF at -78°C to generate the enolate. The model electrophile, BnBr was introduced in the investigations after stirring for 0.5 hours at the same temperature.

Full text of DOI:10.1002/chem.200901984

COMMUNICATION
DOI: 10.1002/chem.200901984
Diastereoselective Alkylation of Glycinates by Assistance of Intramolecular
Potassium···Fluorine Interactions
Takashi Yamazaki,*[a] Seiji Kawashita,[b] Tomoya Kitazume,[b] and Toshio Kubota[c]
Stereoselective synthesis of a-amino acid derivatives with
natural as well as unnatural structural features has constitut-
ed an important field in synthetic organic chemistry.[1] Vari-
ous types of glycinates have been employed thus far as con-
venient key substrates for the preparation of such target
molecules with exerting effective steric bias usually to esters
or amides[1d] or with utilizing appropriate chiral catalysts.[2]
During our continuing study to clarify the role of fluorine
atoms in organic reactions, we have reported[3] that, as
shown in Scheme 1, an excellent level of diastereoselectivity
(up to 95:5) was attained for the alkylation of a-alkoxyest-
ers by various types of electrophiles; in all of these reac-
tions, the intramolecular interaction of fluorine with a metal
has played a pivotal role. This process can be realized by
conformationally fixing the enolate through formation of a
bicyclo [3.3.0]-type structure. This would allow the appropri-
ate electrophiles to approach exclusively from the re-face of
the enolate as a result of preferable participation of the pro-
R lone pair of the carbonyl a-oxygen and the auxiliary
covers the opposite face. In this communication, we would
like to describe our extension of this strategy to glycinates
(3); this, like the previous a-alkoxy ester examples shown in
Scheme 1, successfully demonstrated the significant impor-
tance of intramolecular metal···F chelation for attainment of
excellent diastereoselectivity.
Preparation of the starting materials (3) was carried out
from the readily available fluorinated acetophenones (1,
Scheme 2). To this end, treatment of the benzylimine of 1d
(n=3)[4] with DBU efficiently catalyzed isomerization
through a [1,3] proton shift as reported by Soloshonok
et al.[4,5] Product 2d was furnished upon hydrolytic workup.
On the other hand, syntheses of 2b (n=1) and 2c (n=2)
were initiated by the similar imine process from the corre-
Scheme 1. Diastereoselective alkylation of CF3-containing esters.
sponding ketones (1b, n=1 and 1c, n=2, respectively)[6]
,
and their NaBH4-mediated reduction followed by regiose-
[a] Prof. T. Yamazaki
Division of Applied Chemistry,
Institute of Symbiotic Sciences and Technology,
Tokyo University of Agriculture and Technology,
2-24-16, Nakamachi, Koganei 184-8588 (Japan)
Fax : (+81)42-388-7038
E-mail: tyamazak@cc.tuat.ac.jp
[b] S. Kawashita, Prof. T. Kitazume
Graduate School of Bioscience and Bioengineering,
Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501 (Japan)
[c] Prof. T. Kubota
Department of Biomolecular Functional Engineering,
Ibaraki University,
Nakanarusawa 4-12-1, Hitachi, Ibaraki 316-8511 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901984.
Scheme 2. Preparation of the starting materials (3).
Chem. Eur. J. 2009, 15, 11461 – 11464
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11461

lective hydrogenolysis[7] furnished the desired products. Con-
densation of 2 with bromoacetate afforded the desired sub-
strates (3) by the action of NaH in an HMPA solvent. It is
possible that such harsh conditions were required because of
the decreased nucleophilicity of the fluorinated amines 2b–
d; this was caused by attachment of the strongly electron-
withdrawing fluorinated methyl groups[8] and is experimen-
tally supported by the ready reaction of the nonfluorinated
2a (n=0) with bromoacetate under the usual mild method
(Et3N/CH2Cl2, RT; 53% yield).[9]
With glycinates 3a–d, which possess various numbers of
fluorine atoms, in hand, our interest was focused on finding
appropriate alkylation conditions after their transformation
to the corresponding enolates. The representative starting
material 3d was subjected to a solution of a base in THF at
À788C to generate the enolate. After stirring for 0.5 h at the
same temperature, the model electrophile, BnBr, was intro-
duced (Table 1). Although quantitative recovery of the start-
excess KHMDS led to predominant formation of the di-
AHCTUNGTREGaNNUN lkylated ester 8a, the short reaction time after addition of
BnBr successfully prevented the production of 8a and fur-
nished the desired product 4d in a comparable yield to the
case of entry 6 (entry 10).
At the next stage, the reaction conditions either in en-
tries 6 or 10 in Table 1 were applied to different electro-
philes; the results of this study are collected in Table 2. Use
Table 2. Reaction of 3d with various electrophiles.[a]
Isolated yield [%]
Diastereomeric
ratio[b]
Entry
EX
4
8
3d
1[c,d]
2
BnBr
MeI
MeI
70 (a)
91 (b)
44
61
53 (c)
72
0[b]
8[b]
12[b]
0
38
0
16[b]
2[b]
35
91:9
90:10
87:13
90:10
86:14
83:17
–
Table 1. Investigation of reaction conditions.
3[d]
4[c]
5
MeI
20
allylBr
allylBr
allylCl
BuBr
6[b]
12[b]
66
6[c]
7
8
0
0
0
0
83
–
Amount [equiv]
19F NMR Yield [%]
[a] Compound 3d was added to a solution of 2.0 equiv of KHMDS in
THF at À788C. After 0.5 h, 2.0 equiv of an electrophile (EX) was intro-
duced and the reaction was allowed to continue for 1 min unless other-
wise noted. [b] Determined by 19F NMR spectroscopy. [c] 1.0 equiv of
KHMDS was used. [d] 1.0 equiv of an electrophile was used.
Entry
Base
LDA
Base
BnBr
4a
8a
3d
1
2[a]
3[a]
4
5
6
1.0
2.0
2.0
2.0
2.0
1.0
1.5
2.0
2.0
2.0
2.0
1.0
0
0
0
0
0
quant
0
LHMDS
NaHMDS
1.0
1.0
2.0
1.0
1.5
1.0
2.0
2.0
2.0
0
0
14
61
65
16
0
19
0
12
39
20
7
0
0
KHMDS
81
64
63
37
76
26
0
21
0
56
0
0
7
8
9
of KHMDS (1 equiv) and MeI (2 equiv) afforded 4b with
excellent product selectivity (entry 4), and by increasing of
the amount of base to 2 equiv (entry 2), a much better iso-
lated yield of 4b was attained with a small amount of a,a-di-
methylated 8b. By employing 1 equiv of KHMDS and
2 equiv of allylBr excellent selectivity of 4c (entry 6) was
obtained, but 2 equiv of a base promoted further allylation
and yielded a substantial quantity of 8c (entry 5). The less
reactive allylCl (entry 7) and the nonactivated electrophile,
BuBr (entry 8), were found to be totally inappropriate for
this process; this suggests that the enolate derived from 3d
is only moderately reactive.
With these good alkylation results for the trifluorinated
compounds (3d) in hand, other enolate species with a differ-
ent number of fluorine atoms were employed for similar re-
actions with three representative electrophiles: BnBr, MeI,
and allylBr (Table 3). Good to high chemical yields and high
to excellent diastereoselectivities were obtained in every in-
stance as long as enolates possessed at least one fluorine
atom, but the diastereoselectivity dropped to as low as 2%
for the substrate 3a without this special element. This ten-
dency is identical to the one we have previously observed
for the a-alkoxy esters shown in Scheme 1, and was the
result of fixation of the enolate conformations. The strong
10[b]
11[c]
[a] A complex mixture was obtained. [b] The reaction mixture was
quenched 1 min after addition of BnBr. [c] Toluene was employed as a
solvent.
ing material 3d was confirmed in cases in which 1.0 equiv of
LDA was used (entry 1), complex 19F NMR spectra were ob-
served for the crude product after deprotonation with
2 equiv of LDA without addition of BnBr (entry 2); this in-
dicated that an excess amount of LDA was likely to cause
defluorinative decomposition of 3d.[10] In spite of similar un-
favorable results with LHMDS[10] and NaHMDS (entries 3–
5), the situation was drastically altered only by changing the
counter cation to potassium. Thus, as shown in entry 6,
1.0 equiv of KHMDS was found to be sufficient to furnish
the desired monoalkylation product 4d in high yield without
contamination by the a,a-disubstituted compound 8a (in-
stead, a small amount of the substrate 3d was recovered).
To attain higher conversion, we have investigated conditions
that use varying amounts of KHMDS and BnBr. Although
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running title
COMMUNICATION
strated the unanimous diastereoisomeric preference of 4a,
6a, and 7a. On the basis of these results, we assumed other
alkylation products with a fluorinated auxiliary also consist-
ed of the same (R*,S*)[13] diastereomers as the major com-
ponents. From the crystallographic analysis data it was
found that the NH in 10 contained the short contacts both
with F and C=O of 231.3 and 250.6 pm, respectively; this un-
ambiguously supported the intramolecular hydrogen bond-
ing with 36 and 21 pm shorter atomic distances than the sum
of their van der Waals radii.[15]
This reaction was mechanistically elucidated by using the
mono- and dianionic species, 11b and 12b, respectively, with
a monofluorinated auxiliary. On the basis of our previous re-
sults with a-alkoxy-type substrates, 11b was expected to
form a Z enolate with an intramolecular interaction be-
tween potassium and the nitrogen lone pair. Two representa-
tive epimeric conformers on nitrogen, 11b-1 and -2, could
be considered. If both conformers formed a bicyclo [3.3.0]
system due to the additional K···F interaction, the phenyl
moiety of 11b-1 would cover the enolate re (top) face; this
would cause increased steric hindrance on this side. In 11b-
2, the 2-fluoro-1-phenylethyl moiety, which is located at the
bottom si face, would not have such an unfavorable interac-
tion because the phenyl group points outside. As a result,
11b-2 would be the more preferable conformation to accept
electrophiles at the re face for the selective construction of
alkylated products. This would also be the case for the di-
Scheme 3. Clarification of stereochemical relationship (some hydrogen
atoms are omitted for clarity).
intramolecular chelation between potassium and fluorine
consistently accounted for the stereoselectivity obtained.[11]
The relative stereostructure of the benzylated products
was determined as follows (Scheme 3). The chromatographi-
cally separated major isomer of 7a was treated with LAH at
08C to RT to furnish the already reported aminoalcohol 9[12]
in 69% yield. The reduction in refluxing THF was also car-
ried out on monofluorinated 6a, and led to reductive cleav-
AHCTUNGTREGaNNNU nionic 12b. The only differences in this case would be the
À
À
covalent and coordinating K N and K O bonds, respective-
ly, and the presence of an additional K atom. Such close
similarity (Scheme 4) allows consideration of the same
mechanism as for 11b and electrophiles predominantly ap-
proached from the same face.
À
age of the C F bond in addition to the usual ester transfor-
mation and afforded the same product, 9, with the same
(R*,R*)[13] stereochemical relationship, which was concluded
1
by comparison of their H NMR spectra. In the case of the
trifluorinated material 4a, good crystals appropriate for X-
ray analysis were obtained by its direct derivatization into
the corresponding pyrrolidine amide 10.[14] It appeared that
amide 10, which was obtained from the major isomer of 4a,
possessed (R*,S*)[13] stereochemistry; this clearly demon-
Table 3. Reaction of 3 with various electrophiles.[a]
BnBr[b] (a)
Yield
DS[c]
[% de]
MeI[b] (b)
yield
DS[c]
[% de]
AllylBr[b] (c)
Yield
DS[c]
[% de]
n
[%]
G
[%]
G
[%]
ACHTUNGTRENNUNG
3 (4)
2 (5)
1 (6)
0 (7)
70[d]
61
68
82
76
80
22
61
60
55
66
80
80
72
32
72
64
51
75
66
68
60
2
68
[a] 1.0 equiv of KHMDS and 2.0 equiv of EX were used. [b] EX em-
ployed. [c] DS determined by 19F NMR spectroscopy. [d] 1.0 equiv of
BnBr was employed.
As shown above, we have unambiguously demonstrated
the utility of the intramolecular interaction between fluorine
and potassium. Because of this interaction, a unique confor-
mational fixation of the intermediary enolates occurred, and
this led to diastereoselective alkylation in cases in which at
least one fluorine atom was incorporated in the auxiliary. In
Scheme 4. The possible stable conformation of mono- and dianionic spe-
cies, 11b and 12b, respectively.
Chem. Eur. J. 2009, 15, 11461 – 11464
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www.chemeurj.org
11463

T. Yamazaki et al.
[5] T. Ono, V. P. Kukhar, V. A. Soloshonok, J. Org. Chem. 1996, 61,
6563–6569.
[6] These ketones were synthesized from 1d following to the Uneya-
maꢂs method; a) K. Uneyama, H. Amii, J. Fluorine Chem. 2002, 114,
127–131; b) H. Amii, T. Kobayashi, Y. Hatamoto, K. Uneyama,
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[7] M. Kanai, M. Yasumoto, Y. Kuriyama, K. Inomiya, Y. Katsuhara, K.
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2001, 109, 3–11.
spite of some precedented studies in this field with a-het-
ACHTUNGTRENNUNG
eroatom-containing carbonyl compounds,[16] only a small
number of examples were found in which induction of ste-
reochemistry was realized by a group on an a-heteroatom.[17]
Thus, our result clearly and successfully emphasized the im-
portance of this substrate system. Attainment of higher se-
lectivity and utilization of the products thus obtained are
being investigated in this laboratory.
[9] No reaction occurred between a mixture of 2d and bromoacetate in
the presence of Et3N even under reflux in CHCl3, and 2 equiv of
bromoacetate and NaH in refluxing THF were required for the con-
struction of 3d (67% yield). In cases in which the latter reaction
was performed in an HMPA solvent, 90% yield was attained.
[10] Observation of the 19F NMR spectrum of this crude material afford-
ed clear peaks at around À65 and À71 ppm (from CFCl3), which is
the typical location for the F2C=C structure. It is interesting to note
that defluorination was not observed in cases in which NaHMDS or
KHMDS were employed. See, for example, a) R. Nadano, Y. Iwai,
T. Mori, J. Ichikawa, J. Org. Chem. 2006, 71, 8748–8754; b) H. Ueki,
T. Chiba, T. Yamazaki, T. Kitazume, Tetrahedron 2005, 61, 11141–
11147.
Experimental Section
General procedure for alkylation. A solution of aminoester (1.0 mmol) in
THF (0.5 mL) was added dropwise to a solution of potassium bis(trime-
thylsilyl)amide (2.0 mL as a 0.5m solution in toluene, 1.0 mmol; toluene
was removed under reduced pressure before use) in THF (4 mL) at
À788C. After 10 min, an electrophile (2.0 mmol) in THF (0.5 mL) was
added, and the reaction mixture was stirred for 30 min at the same tem-
perature. The reaction was quenched by the addition of aq. HCl (3m, ca.
0.5 mL) at À788C. After neutralization by sat. aq. NaHCO3 at RT, the re-
sulting solution was extracted with Et2O three times, and the combined
extracts were dried over K2CO3 and concentrated. The desired material
was obtained after purification by silica gel chromatography (10:1
hexane/ethyl acetate).
[11] T. Yamazaki, T. Kitazume in Enantiocontrolled Synthesis of Fluoro-
Organic Compounds (Ed.: V. A. Soloshonok), Wiley, New York,
1999, pp. 575–600.
[12] N. Ikota, K. Achiwa, S. Yamada, Chem. Pharm. Bull. 1983, 31, 887–
894.
[13] Stereochemistry at the benzyl- (thus, a to the carbonyl) and phenyl-
attached carbon atoms was described in this order.
Keywords: alkylation · enolates · fluorine · intramolecular
chelation · stereoselective alkylation
[14] W.-B. Wang, E. J. Roskamp, J. Org. Chem. 1992, 57, 6101–6103.
[15] A. Bondi, J. Phys. Chem. 1964, 68, 441–451.
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Received: July 17, 2009
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Published online: September 24, 2009
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