Synthesis of optically active α-(allenyl)-and a-substituted-α- (allenyl)glycines

Article abstract of DOI:10.1016/j.tetlet.2010.05.042

The synthesis of various types of optically active α-(allenylsilane- containing)glycines via a chiralitytransferring ester-enolate Claisen rearrangement of α-acyloxy-a-alkynylsilanes is described. The conversion of the rearranged products into the optically active silicon-free α-(allenyl)-and α-substituted-α-(allenyl)glycines was achieved by the removal of the Me₂PhSi-or TMS group from the allene terminus.

Full text of DOI:10.1016/j.tetlet.2010.05.042

Tetrahedron Letters 51 (2010) 3765–3768
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Tetrahedron Letters
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Synthesis of optically active
a
-(allenyl)- and
a-substituted-
a-(allenyl)glycines
*
*
Takuya Okada, Naoko Oda, Hiroyuki Suzuki, Kazuhiko Sakaguchi , Yasufumi Ohfune
Graduate School of Science, Osaka City University, Sugimoto, Osaka 558-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of various types of optically active
transferring ester-enolate Claisen rearrangement of
sion of the rearranged products into the optically active silicon-free
a
a
-(allenylsilane-containing)glycines via a chirality-
-acyloxy- -alkynylsilanes is described. The conver-
-(allenyl)- and -substituted-
Received 9 April 2010
Revised 8 May 2010
Accepted 12 May 2010
Available online 24 May 2010
a
a
a
a-
(allenyl)glycines was achieved by the removal of the Me2PhSi- or TMS group from the allene terminus.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
a
-(Allenyl)glycine
Enolate Claisen rearrangement
-Acyloxy- -alkynylsilane
Allenylsilane
a
a
O
O
Amino acids possessing an allenyl side chain have attracted sig-
nificant attention due to their inhibitory activities to certain en-
zymes as irreversible inhibitors, so-called suicide or mechanism-
NHBoc
R1
R2
HO2C
2S
NHBoc
R1
O
ð1Þ
ð2Þ
enolate Claisen
rearrangement
based inhibitors.1
c-Allenyl-c-aminobutyric acid (1) and a-allenyl
R2
TBS
TBS
TBS
S
3R
E
DOPA (2) are the representative examples, that is, 1 is known to be
an inhibitor of GABA transaminase2 and 2 exhibits a potent inhib-
itory activity against porcine kidney aromatic group amino acid
NHBoc
O
*
decarboxylase (Fig. 1).3 Therefore,
a
-allenyl amino acids are attrac-
R1 NHBoc
R1
*
•
tive candidates for the development of mechanism-based enzyme
inhibitors. However, only a limited number of reports for their syn-
theses including the enantioselective versions have appeared.4
Herein, we describe the enantio- and diastereoselective synthesis
TBS
CO2H
*
R2
R2
6
7
We recently reported the ester-enolate Claisen rearrangement
-acyloxy- -alkenylsilanes having the N-Boc -amino acid ester
as the acyloxy group that afforded vinylsilane-containing -substi-
tuted -amino acids with the complete transfer of the original
of a-substituted-a-(allenyl)glycines 3 and 4, and a-(allenyl)glycine
of
a
a
a
5 using the ester-enolate Claisen rearrangement of
a-acyloxy-a-
a
alkynylsilanes.
a
NH2
R1 NH2
CO2H
R2
R1 NH2
CO2H
R2
•
HO2C
NH2
TBS
•
•
CO2H
HO
HO
4 R1 = R2 = Me
3 R1 = H, alkyl, or aryl
2
5 R1 = R2 = H
1
R2 = alkyl or aryl
Figure 1.
* Corresponding authors. Tel.: +81 6 6605 2571; fax: +81 6 6605 2522 (K.S.).
E-mail address: sakaguch@sci.osaka-cu.ac.jp (K. Sakaguchi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.042

3766
T. Okada et al. / Tetrahedron Letters 51 (2010) 3765–3768
Table 1
Enolate Claisen rearrangement of 6 having various amino acid esters
O
LDA (3 equiv)
ZnCl2 (1.2 equiv)
NHBoc
R1 NHBoc
CO2H
O
R1 NH2
CO2H
TFA (30 equiv)
CH2Cl2, rt, 1 h
TBS
•
R1
TBS
•
TBS
R2
THF, -78 ºC to rt, 1 h
R2
R2
6 (>95% ee)
7 (dr = >20 : 1)
3
Entry
R1
R2
Yield of 7a
Yield of 3a
1
2
3
4
5
6
7
H
Me
Bn
Me (6a)
78% (7a)
52% (7b)
46% (7c)
61% (7d)
58% (7e)
55% (7f)
62% (7g)
70% (3a)b
54% (3b)
70% (3c)
60% (3d)
69% (3e)
70% (3f)
87% (3g)b
Me (6b)
Me (6c)
Me (6d)
Me (6e)
Ph (6f)
Ph
Allyl
Me
Me
Cy (6g)
a
Isolated yield after column chromatography.
TMSOTf (3 equiv) and 2,6-lutidine (5 equiv) were used.
b
chirality to the
c
-position (Eq. 1).5 The TBS group in the
a
-alke-
(entries 6 and 7). A high diastereoselectivity (dr = >20:1) was ob-
served in all cases.9 The rearranged products 7b–7g were con-
verted into amino acids 3b–3g by treatment with TFA, respectively.
nylsilane played an important role in the stereoselectivity and
excellent yields due to its chemical stability as well as steric bulk-
iness. We considered that the enolate Claisen rearrangement of the
Our next approach was the synthesis of the silyl group-free
a-
optically active
nylsilane-containing
ity is transferred not only to the allenic central carbon but also to
the -amino acid moiety. The silyl group-free -(allenyl)glycines 4
a
-acyloxy-
a
-alkynylsilane 6 would afford alle-
allenyl- -amino acids using the removable Me2PhSi or TMS group
under mild reaction conditions, since the TBS group attached to the
allene terminus could not be removed under strongly acidic, basic,
or fluoride ion conditions (Scheme 2). The a-acyloxy-a-alkynylsi-
a
a
-amino acids 7, in which the original chiral-
a
a
and 5 would be obtained by the choice of the substituent on the sil-
icon atom (Eq. 2).
lane 8 (>95% ee) containing the Me2PhSi group was treated under
the standard conditions to give the corresponding allene 9 as a sin-
gle diastereomer. Although several attempts to remove the Me2Ph-
Si group using protic acids (TFA, HCl, or HBF4) were unsuccessful,
the treatment with strongly basic conditions (40% KOH in MeOH,
80 °C) was found to be effective for the desilylation without trou-
blesome isomerization of the allene moiety to an alkyne.10 The
removal of the Boc group by TFA gave the novel silyl group-free
Our initial attempt was the enolate Claisen rearrangement of
a-
acyloxy- -alkynyl-tert-butyldimethylsilane 6a possessing Boc-Gly
a
as the acyloxy group (Scheme 1). According to Kazmaier’s proto-
col,6 the preparation of the dianionic ester-enolate from 6a was
performed with LDA in the presence of ZnCl2 at ꢀ78 °C. Upon
warming to room temperature, the rearrangement smoothly pro-
ceeded to give 7a in 78% yield as a single diastereomer. The enan-
tiomeric excess of the rearrangement product was >95%, indicating
that the original chirality was completely transferred to both the
a
-allenyl-
-(Allenyl)glycine (5) has not been found in nature to date, but
is presumed to be a congener of -(propargyl)glycine, a potent
a-amino acid 4 in the optically pure form.
a
a
axial chiral center and
absolute configuration of the
a
-amino acid moiety of the product. The
anti-metabolite of L-Met and L-Leu isolated from the fermentation
broth of an unidentified streptomycete.11 Due to its instability
against the allene isomerization to the alkyne or diene, only one re-
port for the synthesis of 5 in the racemic form has appeared.12 We
a-carbon that was found to be S
was determined by the modified Mosher’s method of the (R)-
and (S)-MTPA amide of 3a.7 The axial chiral center was assigned
to aS in analogous with Kazmaier’s assignment of a similar rear-
rangement product6 together with our proposed stereochemical
outcome of the present rearrangement (vide infra). Conversion into
the protection-free allenylsilane-containing amino acid 3a was
performed using TMSOTf and 2,6-lutidine.8
envisioned that the use of the TMS group at the a-position and al-
kyne terminus would produce 11,13 from which both the silyl
groups attached to the allene moiety could be removed without
the above-mentioned problems (Scheme 3). The rearrangement
of 10 (>95% ee)7 proceeded in a highly stereoselective manner to
give 11 in 50% yield. Several attempts revealed that (1) tetrabutyl-
ammonium fluoride (TBAF) is an efficient reagent to remove the si-
lyl groups, (2) the use of its methyl ester 12 afforded a mixture of
the undesired alkyne 14 and diene 15 (13a:14 = 1:1) even under
neutral conditions, and (3) the undesired CC double bond migra-
tion was prevented by the addition of acetic acid, but the product’s
ee decreased to 26%. The racemization, which occurred during the
Next, we attempted the synthesis of the a-substituted-a-(alle-
nyl)glycines 3b–3g having various substituents (Table 1). The Cla-
isen rearrangement of the alanyl, phenylalanyl, phenylglycyl, and
allylglycyl esters proceeded in a manner similar to that of the gly-
cyl ester 6a to give the corresponding allenes 7b–7e (entries 2–5),
respectively. Other substituents at the alkyne terminus also gave
the corresponding rearranged products 7f and 7g in good yields
O
TMSOTf (3 equiv)
2,6-lutidine (5 equiv)
NHBoc LDA (3 equiv)
NHBoc
CO2H
NH2
CO2H
O
ZnCl2 (1.2 equiv)
TBS
•
TBS
•
aS
S
TBS
)-6a (>95% ee)
CH2Cl2, rt, 2 h
70%
THF, -78 ºC to rt, 1 h
78%
3a (>95% ee)
7a (dr = >20 : 1)
(
S
Scheme 1.

T. Okada et al. / Tetrahedron Letters 51 (2010) 3765–3768
3767
O
1) 40% KOH / MeOH
NHBoc
LDA (3 equiv)
ZnCl2 (1.2 equiv)
NH2
CO2H
NHBoc
CO2H
O
80 ºC, 3 h, 56%
•
Me2PhSi
•
Me2PhSi
2) TFA (30 equiv)
CH2Cl2, rt, 1 h, quant
THF, -78 ºC to rt, 1 h
50%
4
9 (dr = >20 : 1)
8 (>95% ee)
Scheme 2.
O
O
LDA (3 equiv)
ZnCl2 (1.2 equiv)
NHBoc
CO2R
NHBoc
TMS
11 R = H
12 R = Me
TMS
+
•
CH2N2
TMS
THF, -78 ºC to rt, 1 h
50%
TMS
10 (>95% ee)
conditions
(a) or (b)
NHBoc
CO2Me
15 (single isomer)
NHBoc
CO2Me
NHBoc
•
+
12
CO2Me
13
14
(a) TBAF (2.5 equiv), pH 7 buffer in THF
rt, 16 h (82%)
13:14:15 = 0:50:50
13 (26% ee)
(b) TBAF (2.5 equiv), 20% AcOH in THF
50 ºC, 3 h (78%)
NH-(S)-MTPA
(b)
CO2Me
TMS
16 (>95% ee)
NH-(S)-MTPA
CO2Me
TMS
•
•
17 (57% ee)
(54% ee after additional 3 h)
TBAF (2.5 equiv)
AcOH (1 equiv)
TMSOTf (8 equiv)
NHBoc
CO2H
2,6-lutidine (12 equiv)
•
11
5 (83% ee)
THF, rt, 16 h
86%
CH2Cl2, rt, 2 h
84%
18 (83% ee)
NHBoc
1. CH2N2
CO2Me
2. H2/Pd-C
78%
19
Scheme 3.
Zn
O
NBoc
O
O
R2
TBS
R1 NHBoc
R1
R1
NHBoc
LDA, ZnCl2
O
A
TBS
•
R1
CO2H
R2
7 (dr = >20 : 1)
TBS
R2
R2
O
6
NBoc
Zn
O
TBS
B
Scheme 4.
desilylation, was ascertained by the use of the diastereomerically
the same conditions as stated above (3), the de of the product 17
homogeneous (S)-MTPA amide 16. Upon treatment of 16 under
decreased to 57%, and its further treatment showed a slight

3768
T. Okada et al. / Tetrahedron Letters 51 (2010) 3765–3768
2. Castelhano, A. L.; Krantz, A. J. Am. Chem. Soc. 1984, 106, 1877–1879.
3. Castelhano, A. L.; Pliura, D. H.; Taylor, G. J.; Hsieh, K. C.; Krantz, A. J. Am. Chem.
Soc. 1984, 106, 2734–2735.
4. (a) Hamon, D. P. G.; Massy-Westropp, R. A.; Razzino, P. Tetrahedron 1995, 51,
4183–4194; (b) Kagoshima, H.; Uzawa, T.; Akiyama, T. Chem. Lett. 2002, 298–
299.
5. (a) Sakaguchi, K.; Ayabe, M.; Watanabe, Y.; Okada, T.; Kawamura, K.; Shinada,
T.; Ohfune, Y. Tetrahedron 2009, 65, 10355–10364; (b) Sakaguchi, K.; Ayabe, M.;
Watanabe, Y.; Okada, T.; Kawamura, K.; Shinada, T.; Ohfune, Y. Org. Lett. 2008,
10, 5449–5452; (c) Sakaguchi, K.; Yamamoto, M.; Watanabe, Y.; Ohfune, Y.
Tetrahedron Lett. 2007, 48, 4821–4824; (d) Sakaguchi, K.; Yamamoto, M.;
Kawamoto, T.; Yamada, T.; Shinada, T.; Shimamoto, K.; Ohfune, Y. Tetrahedron
Lett. 2004, 45, 5869–5872; (e) Morimoto, Y.; Takaishi, M.; Kinoshita, T.;
Sakaguchi, K.; Shibata, K. Chem. Commun. 2002, 42–43; (f) Sakaguchi, K.;
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decrease in its de (54%). Fortunately, the use of the carboxylic acid-
free 11 in the presence of 1 equiv acetic acid minimized the race-
mization to give 18 in 86% yield (83% ee) in which a small amount
of the alkyne product (ꢁ5%) was contaminated. The absolute con-
figuration at C2 was ascertained by converting it to the known N-
Boc-L
-norvaline-OMe 19.14 Finally, removal of the Boc group of 18
with TMSOTf afforded 5 (84% yield, 83% ee).15
The observed high diastereoselectivity (dr = >20:1) in all cases
can be explained by the preferential formation of the Z-enolate
and subsequent rearrangement via transition state A, in which
the sterically bulky silyl group is oriented in an equatorial position
in a manner similar to an alkyl group reported by Kazmaier6
(Scheme 4). The sterically bulky silyl group would play a key role
in the high diastereoselectivity.5
6. Pioneering work using the ZnCl2-assisted enolate Claisen rearrangement of the
propargyl ester containing the
a-amino acid ester has been reported by
Kazmaier et al., Kazmaier, U.; Gorbitz, C. H. Synthesis 1996, 1489–1493.
7. See, Supplementary data for details.
8. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870–876. In this case, treatment
of 7a with TFA was accompanied by the partial epimerization of the a-position
(dr = 4:1).
9. The mono-anionic enolate Claisen rearrangement of the propionate 20 and
In summary, various types of optically active
containing)glycines, 3a–3g, were synthesized using the dianionic
enolate Claisen rearrangement of -acyloxy- -alkynylsilanes as
the key steps. The Me2PhSi- or TMS group was removable from
the allene terminus to give the silicon-free -(allenyl)glycines 4
and 5. Biological evaluation of the synthetic -(allenyl)glycines
a-(allenylsilane-
a
a
Boc-Pro ester 22 gave the corresponding allenylsilane 21 and 23 (dr = >20:1),
respectively, in moderate yields.
a
O
a
LHMDS (2 equiv)
as well as an application of the present method for the synthesis
of biologically active compounds is currently in progress in our
laboratory.
O
TMSCl (1.2 equiv)
•
TBS
CO2H
TBS
THF, -78 ºC to rt, 1 h
42%
20
21 (dr = >20:1)
Acknowledgment
O
Boc
N
LDA (1.2 equiv)
This study was financially supported by
(16201045 and 19201045) for Scientific Research from the Japan
Society of the Promotion of Science (JSPS).
a Grant-in-Aid
NBoc
CO2H
O
•
TBS
THF, -78 ºC to rt, 1 h
19%
TBS
23 (dr = >20:1)
22
Supplementary data
.
10. Fleming, I.; Dunoguès, J.; Smithers, R. Org. Reactions 1989, 37, 57–575.
11. Scannell, J. P.; Pruess, D. L.; Demny, T. C.; Weiss, F.; Williams, T.; Stempel, A. J.
Antibiot. 1971, 4, 239–244.
12. Castelhano, A. L.; Horne, S.; Taylor, G. J.; Billedeau, R.; Krantz, A. Tetrahedron
1988, 44, 5451–5466.
Supplementary data (full experimental details and characteriza-
tion data of all synthetic compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2010.05.042.
13. Mohamed, M.; Brook, M. A. Collect. Czech. Chem. Commun. 2009, 74, 927–934.
14. Pysh, E. S.; Toniolo, C. J. Am. Chem. Soc. 1977, 99, 6211–6219.
15. Contaminated
a-(propargyl)glycine (ꢁ5%) could not be removed by the
References and notes
repeated recrystallization (H2O, MeOH, EtOH). The ee of 5 was determined
by converting it into 17. Compound 5: mp 173–175 °C (decomp); ½a D26
ꢀ20.2 (c
ꢂ
1. (a) Walsh, C. Tetrahedron 1982, 38, 871–909; (b) Hoffmann-Röder, A.; Krause,
N. Angew. Chem., Int. Ed. 2004, 43, 1196–1216. and references cited therein.
2.00, H2O, 83% ee).