Application of the addition of triorganozincates to N-(tert-butanesulfinyl)imines to the enantioselective synthesis of α-amino acids

Article abstract of DOI:10.1016/j.tetlet.2009.05.008

Highly enantiomerically enriched N-protected α-amino acids can be easily prepared from optically pure N-(tert-butanesulfinyl)imines by a four-step sequence involving: diastereoselective addition of a triorganozincate to the imine, removal of the sulfinyl group, benzoylation of the nitrogen atom of the obtained primary amine and oxidation of one of the substituents on the carbon atom α to the nitrogen. Using the same configuration in the sulfinyl chiral auxiliary, amino acids with the (R) or the (S) configuration can be prepared by choosing the proper combination of imine and organozincate. α,α-Disubstituted α-amino esters with high optical purity can also be prepared by the diastereoselective addition of trialkylzincates to α-imino esters.

Full text of DOI:10.1016/j.tetlet.2009.05.008

Tetrahedron Letters 50 (2009) 4188–4190
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Tetrahedron Letters
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Application of the addition of triorganozincates to
N-(tert-butanesulfinyl)imines to the enantioselective synthesis of a-amino acids
*
*
Raquel Almansa, David Guijarro , Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly enantiomerically enriched N-protected a-amino acids can be easily prepared from optically pure
N-(tert-butanesulfinyl)imines by a four-step sequence involving: diastereoselective addition of a triorg-
anozincate to the imine, removal of the sulfinyl group, benzoylation of the nitrogen atom of the obtained
Received 24 April 2009
Accepted 5 May 2009
Available online 9 May 2009
primary amine and oxidation of one of the substituents on the carbon atom
same configuration in the sulfinyl chiral auxiliary, amino acids with the (R) or the (S) configuration can be
prepared by choosing the proper combination of imine and organozincate. -Disubstituted -amino
esters with high optical purity can also be prepared by the diastereoselective addition of trialkylzincates
to -imino esters.
a to the nitrogen. Using the
Keywords:
Sulfinylimine
Organozincate
Diastereoselective addition
Oxidative cleavage
a
,
a
a
a
Ó 2009 Elsevier Ltd. All rights reserved.
a-Amino acid
The asymmetric synthesis of
a
-amino acids1 is a research field
the nitrogen atom. We have developed a new version of this
method that uses only a catalytic amount of a dialkylzinc to gen-
erate the organozincate.9 Herein we present our preliminary re-
sults on the application of this methodology to the asymmetric
that continues attracting numerous organic chemists due to the
importance of these chiral building blocks for the construction
of natural structures.2 Besides their biological role as constituents
of peptides and proteins,
a-amino acids have found applications
synthesis of a-amino acids.
in the preparation of agrochemical and pharmaceutical com-
pounds2 and are commonly used as chiral auxiliaries and cata-
lysts in a variety of synthetic methods.3 Among the wide range
In our previous work, we found that the triorganozincate gener-
ated by mixing CH2@CHMgBr (1.5 equiv) and Me2Zn (1.7 equiv)
added the vinyl group to benzaldimine 1a (Scheme 1) in a highly
diastereoselective manner.7 This result prompted us to try to apply
of methods available for the synthesis of optically active a-amino
acids, one can encounter several of them which rely on the ster-
eoselective addition of carboxylate synthons to C@N bonds, such
as the Strecker reaction or the Ugi condensation.1a,b Some alke-
nyl,4 aryl4c,5 and heteroaryl4c,5c,6 groups can be considered as
synthetic equivalents for the carboxylic acid, since they can be
oxidatively cleaved to that function. The addition of such oxidiz-
able groups to imines bearing a removable chiral auxiliary with
the aid of organometallic reagents is the key step in several
this addition methodology to the asymmetric synthesis of a-amino
acids, since it was well known that the vinyl group could be oxida-
tively cleaved to the corresponding carboxylic acid.4 Thus, the
addition product 2a was desulfinylated by reaction with a solution
of HCl in methanol10 and the obtained free primary amine was
benzoylated10 with the aim of facilitating the isolation of the final
amino acid. Treatment of benzamide 3a with NaIO4 in the presence
of a catalytic amount of RuCl3 gave N-benzoyl (S)-phenylglycine
with an 88% ee (Scheme 1, Table 1, entry 1). The same reaction
sequence applied to imines 1b and 1c gave the expected protected
amino acids 4b and 4c with enantioselectivities of up to 85%
(Scheme 1, Table 1, entries 3 and 5). Since we have recently found
that the generation of the triorganozincate using only a catalytic
amount of Me2Zn improves results in comparison with the use of
an excess of that reagent,9 we decided to test this addition proce-
dure in our synthesis of amino acids. As it can be seen in Table 1, in
all cases the enantioselectivities obtained in the final benzoylated
amino acids are higher than the ones observed before (entries 2,
4 and 6). It is worth noting that, since Me2(CH2@CH)ZnMgBr and
CH2@CHMgBr have shown opposite diastereoselectivities in their
addition to N-(tert-butanesulfinyl)benzaldimines,7,11 either
methods of preparation of
a-amino acids found in the litera-
ture.4c,d,g,6b Another efficient approach is to introduce these
groups as substituents of the imine substrates.4b,5d,6a,d–f We have
recently reported the highly diastereoselective addition of triorg-
anozincates to N-(tert-butanesulfinyl)imines,7 which are very
useful substrates for the preparation of chiral primary amines.8
By using an excess of a previously formed triorganozincate, very
good yields and diastereoselectivities were obtained in the addi-
tion products, which could be easily transformed into the corre-
sponding enantiomerically enriched amines by desulfinylation of
* Corresponding authors. Fax: +34 965903549 (D.G.).
E-mail addresses: dguijarro@ua.es (D. Guijarro), yus@ua.es (M. Yus).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.008

R. Almansa et al. / Tetrahedron Letters 50 (2009) 4188–4190
4189
O
S
O
S
O
O
i,ii
iii,iv
v
N
t
-Bu
HN
t
-Bu
HN
Ph
HN
Ph
CO2H
Ar
H
Ar
Ar
R
1
2
3
4
a
: Ar = Ph
b: Ar = 4-ClC6H4
c: Ar = 4-MeOC6H4
Scheme 1. Reagents and conditions: (i) Method A: CH2@CHMgBr (1.5 equiv for 1a–b, 2.25 equiv for 1c), Me2Zn (1.7 equiv for 1a–b, 2.5 equiv for 1c), THF, À78 °C; Method B:
CH2@CHMgBr (1.3 equiv), Me2Zn (0.15 equiv), THF, À78 °C; (ii) NH4Cl (aq); (iii) HCl, MeOH; (iv) PhCOCl (2.8 equiv), Et3N (2.8 equiv), CHCl3, 0–20 °C; (v) RuCl3ÁxH2O
(1.2 mol %), NaIO4 (4 equiv), MeCN:H2O:CCl4 (1:1.5:1), 20 °C.
Table 1
Asymmetric synthesis of a-amino acids via the diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl)imines
Entry
Imine
Methoda
Sulfinamide
Yieldc (%)
Benzamide
Yieldf (%)
Amino acid
Yieldg (%)
No.b
drd
No.e
No.e
R
eeh (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1b
1b
1c
1c
1d
1d
1d
1d
1d
1d
1d
5
A
B
A
B
A
B
A
B
A
B
A
B
A
A
Ai
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
2f
2g
6
93
94
82
78
92
90
99
91
83
79
90
98
92
85
96
95:5
98:2
88:12
96:4
93:7
94:6
94:6
97:3
80:20
98:2
93:7
96:4
94:6
91:9
96:4
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
66
65
72
64
64
60
52
41
59
73
59
59
64
—
4a
4a
4b
4b
4c
4c
ent-4d
ent-4d
ent-4e
ent-4e
ent-4f
ent-4f
ent-4g
7
Ph
Ph
95
94
94
89
99
96
75
75
98
98
77
77
96
60f
70f
88
94
76
92
85
86
86
92
58
96
86
92
88
82
92
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
Et
Et
Me2CHCH2
Me2CHCH2
n-C5H11
n-C5H11
i-Pr
3f
3g
—
—
—
5
6
—
—
7
a
Method A: The solution of the triorganozincate prepared by mixing the corresponding Grignard reagent and Me2Zn (see Schemes 1–3) was added to a solution of the
imine (0.5 mmol) in THF (3 mL) at À78 °C and the reaction mixture was stirred for 1 h at the same temperature (see Ref. 7b). Method B: The corresponding Grignard reagent
(1.3 equiv) and Me2Zn (0.15 equiv) were added to the imine in a stepwise procedure (see Ref. 9). The reaction time was 2 h at À78 °C.
b
Product number corresponding to the major diastereoisomer.
c
The crude reaction mixture only showed the mixture of diastereoisomers of the addition products 2 (300 MHz 1H NMR) without any noticeable by-product. The yields are
calculated according to the amount of crude mixture that was obtained after work-up.
d
Diastereomeric ratio determined from the crude reaction mixture by HPLC using a ChiralCel OD-H column. The absolute configuration of the major diastereoisomer was
deduced by removal of the N-sulfinyl group and comparison of the sign of the specific rotation of the free primary amines with the reported data.
e
Product number corresponding to the major enantiomer.
Overall isolated yield for the desulfinylation and the benzoylation steps based on sulfinamide 2 or 6.
Isolated yield after column chromatography (hexane/ethyl acetate/methanol) based on the benzoylated amine 3. All isolated compounds were P95% pure (GC and/or
f
g
300 MHz 1H NMR).
h
Determined for the corresponding methyl ester by HPLC using a ChiralCel OD-H column.
The reaction was performed at À100 °C. The reaction time was 1 h.
i
enantiomer of the amino acid could be prepared by an appropriate
selection of the nucleophile.
cates gave the expected sulfinamides 2d–g in high diastereomeric
ratios (Table 1, entries 7–13). As it was the case with imines 1a–c,
in all cases the diastereoselectivities were higher with a catalytic
generation of the organozincate (Table 1, entries 8, 10 and 12) than
with an excess of it (Table 1, entries 7, 9, 11 and 13), the improve-
ment observed in sulfinamide 2e being especially remarkable (Ta-
ble 1, entries 9 and 10). Sulfinamides 2d–g were then converted
Since the oxidation of the furyl group to a carboxylic acid is also
well documented in the literature,4c,5c,6 we tried an alternative ap-
proach to amino acids with the (R) absolute configuration. The
addition of primary and secondary alkyl groups to the heterocyclic
imine 1d (Scheme 2) through the corresponding alkyldimethylzin-
O
S
O
S
O
O
i,ii
iii,iv
v
N
t
-Bu
HN
t
-Bu
HN
Ph
HN
HO2C
Ph
H
R
R
R
O
O
O
1d
2
3
ent-4
d: R = Et
e
: R = Me2CHCH2
f
: R =
g: R =
n
i
-C5H11
-Pr
Scheme 2. Reagents and conditions: (i) Method A: RMgBr (1.5 equiv), Me2Zn (1.7 equiv), THF, À78 °C. Method B: RMgBr (1.3 equiv), Me2Zn (0.15 equiv), THF, À78 °C; (ii)
NH4Cl (aq); (iii) HCl, MeOH; (iv) PhCOCl (2.8 equiv), Et3N (2.8 equiv), CHCl3, 0–20 °C. (v) RuCl3ÁxH2O (5 mol %), NaIO4 (6 equiv), MeCN:H2O:CCl4 (1.5:1.5:1), 20 °C.

4190
R. Almansa et al. / Tetrahedron Letters 50 (2009) 4188–4190
substrate scope and to find more synthetic applications of this
addition methodology are currently underway in our laboratories.
O
S
O
S
O
i,ii
iii,iv
N
t-Bu
HN
t-Bu
HN
Ph
Acknowledgements
Et
CO2Et
Et
CO2Et
Ph
CO2Et
Ph
Ph
5
6
7
This work was generously supported by the Spanish Ministerio
de Educación y Ciencia (MEC; Grant Nos. CONSOLIDER INGENIO
2010, CSD2007-00006 and CTQ200765218) and the Generalitat
Valenciana (GV/2007/036). R.A. thanks the Spanish Ministerio de
Educación y Ciencia for a predoctoral fellowship. We also thank
MEDALCHEMY S.L. for a gift of chemicals.
Scheme 3. Reagents and conditions: (i) EtMgBr (2.25 equiv), Me2Zn (2.5 equiv),
THF, À78 or À100 °C; (ii) NH4Cl (aq); (iii) HCl, MeOH; (iv) PhCOCl (2.8 equiv), Et3N
(2.8 equiv), CHCl3, 0–20 °C.
into the corresponding primary amines, which were benzoylated
and submitted to oxidation with NaIO4 catalyzed by RuCl3, leading
to the expected N-benzoyl (R)-amino acids ent-4d–g with ee values
of up to 96% (Table 1, entries 7–13). Our methodology is comple-
References and notes
1. (a) Williams, R. M.. In Synthesis of Optically Active a-Amino Acids; Baldwin, J. E.,
Magnus, P. D., Eds.1989; Pergamon Press: Oxford; Vol. 7; (b) Duthaler, R. O.
Tetrahedron 1994, 50, 1539–1650; (c) Wipf, P. Chem. Rev. 1995, 95, 2115–2134;
(d) North, M. Contemp. Org. Synth. 1997, 4, 326–351; (e) Cativiela, C.; Díaz de
Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645–732; (f) Ma, J.-A. Angew.
Chem., Int. Ed. 2003, 42, 4290–4299; (g) Wolkenberg, S. E.; Garbaccio, R. M. Sci.
Synth. 2006, 20a, 385–482.
mentary to other reported approaches to a-amino acids involving
the stereoselective addition of organolithium6a or dialkylzinc6e re-
agents to imines derived from furfural, since we obtain the oppo-
site enantiomer of the final amino acid.
2. (a) Barrett, G. C. Chemistry and Biochemistry of the Amino Acids; Chapman and
Hall: London, 1985; (b) Jones, J. H. In Amino Acids and Peptides; The Royal
Society of Chemistry: London, 1992; Vol. 23.
3. (a) Martens, J. In Topics in Current Chemistry; Boschke, F. L., Ed.; Springer:
Heidelberg, 1984; Vol. 125, pp 167–246; (b) Blaser, H.-U. Chem. Rev. 1992, 92,
935–952; (c) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995.
4. See, for instance: (a) Jumnah, R.; Williams, A. C.; Williams, J. M. J. Synlett 1995,
821–822; (b) Moody, C. J.; Gallagher, P. T.; Lightfoot, A. P.; Slawin, A. M. Z. J. Org.
Chem. 1999, 64, 4419–4425; (c) Cooper, T. S.; Laurent, P.; Moody, C. J.; Takle, A.
K. Org. Biomol. Chem. 2004, 2, 265–276; (d) Collet, M.; Genisson, Y.; Baltas, M.
Tetrahedron: Asymmetry 2007, 18, 1320–1329; (e) Swift, M. D.; Sutherland, A.
Tetrahedron Lett. 2007, 48, 3771–3773; (f) Singh, O. V.; Han, H. Tetrahedron Lett.
2007, 48, 7094–7098; (g) Yoshida, K.; Yamaguchi, K.; Sone, T.; Unno, Y.; Asai,
A.; Yokosawa, H.; Matsuda, A.; Arisawa, M.; Shuto, S. Org. Lett. 2008, 10, 3571–
3574.
In all cases, the two diastereoisomers of sulfinamides 2 were the
only products that could be detected in the crude reaction mix-
tures after the addition of the triorganozincates to imines 1. There-
fore, they could be submitted to the desulfinylation procedure
without further purification, affording the expected primary
amines without any detectable racemization.12 By comparison of
the sign of their specific rotations with the data reported in the lit-
erature, the absolute configuration of the asymmetric carbon
atoms of the major diastereoisomers of 2 could be determined.
The oxidation of benzamides 3 was performed following the liter-
ature procedures.13 The enantiomeric excesses of the N-protected
amino acids 4 and ent-4 were determined for their corresponding
methyl esters14 by HPLC analysis using a ChiralCel OD-H column.
As can be seen in Table 1, in some cases there is a very slight loss
of optical purity (2% maximum) during the whole process from the
imines to the amino acids: the ee values of the final amino acids
match very well with the diastereomeric ratios of the correspond-
ing sulfinamides 2.
5. See, for instance: (a) Bower, J. F.; Jumnah, R.; Williams, A. C.; Williams, J. M. J. J.
Chem. Soc., Perkin Trans.
1 1997, 1411–1420; (b) Veeresa, G.; Datta, A.
Tetrahedron Lett. 1998, 39, 3069–3070; (c) Hasegawa, M.; Taniyama, D.;
Tomioka, K. Tetrahedron 2000, 56, 10153–10158; (d) Linder, M. R.; Frey, W.
U.; Podlech, J. J. Chem. Soc., Perkin Trans. 1 2001, 2566–2577; (e) Moutevelis-
Minakakis, P.; Sinanoglou, C.; Loukas, V.; Kokotos, G. Synthesis 2005, 933–938.
6. See, for instance: (a) Alvaro, G.; Martelli, G.; Savoia, D.; Zoffoli, A. Synthesis
1998, 1773–1777; (b) Borg, G.; Chino, M.; Ellman, J. A. Tetrahedron Lett. 2001,
42, 1433–1435; (c) Merino, P.; Revuelta, J.; Tejero, T.; Cicchi, S.; Goti, A. Eur. J.
Org. Chem. 2004, 776–782; (d) Demir, A. S.; Sesenoglu, O.; Ulku, D.; Arici, C.
Helv. Chim. Acta 2004, 87, 106–119; (e) Desrosiers, J.-N.; Côté, A.; Charette, A. B.
Tetrahedron 2005, 61, 6186–6192; (f) Enders, D.; Vrettou, M. Synthesis 2006,
2155–2158; (g) Liu, L.-X.; Peng, Q.-L.; Huang, P.-Q. Tetrahedron: Asymmetry
2008, 19, 1200–1203.
7. (a) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2008, 19, 603–
606; (b) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2008, 19,
2484–2491.
8. (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–995; (b)
Ellman, J. A. Pure Appl. Chem. 2003, 75, 39–46; (c) Lin, G.-Q.; Xu, M.-H.; Zhong,
Y.-W.; Sun, X.-W. Acc. Chem. Res. 2008, 41, 831–840.
9. Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron Lett. 2009, 50, 3198–3201.
10. The removal of the sulfinyl group and the benzoylation of the obtained primary
amines were carried out following the procedures previously described by us
(see Ref. 7b).
11. Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883–8904.
12. The ee’s of the free amines were determined after benzoylation and analysis of
the obtained benzamides 3 by HPLC using a ChiralCel OD-H column (see Ref.
7b). The enantiomeric ratios of the free primary amines were equal to the
diastereomeric ratios of the corresponding sulfinamides 2.
13. Oxidative cleavage of the vinyl group: (a) Laschat, S.; Kunz, H. J. Org. Chem.
1991, 56, 5883–5889; Oxidative cleavage of the furyl group: (b) Dondoni, A.;
Franco, S.; Junquera, F.; Merchán, F. L.; Merino, P.; Tejero, T. J. Org. Chem. 1997,
62, 5497–5507.
14. The methyl esters were prepared by treatment of the amino acids 4 or ent-4
with MeI in the presence of K2CO3.
In an attempt to prepare a-amino acids with a quaternary ste-
reogenic centre, the addition of EtMe2ZnMgBr to the imino ester
5 (Scheme 3) was performed at À78 °C and the addition product
6 was obtained with a 91:9 diastereomeric ratio. Desulfinylation
followed by benzoylation afforded the protected amino ester 7
with an 82% ee (Table 1, entry 14). We were glad to see that the
diastereoselectivity of the addition reaction improved to 96:4
when it was carried out at À100 °C, which led to the final amino
ester with a 92% ee (Table 1, entry 15). An interesting point to re-
mark is that a reversal of the diastereoselectivity was observed
when EtMgBr was added to 5 instead of the trialkylzincate
(15:85 diastereomeric ratio at À78 °C).7b Thus, both enantiomers
of the final amino ester could be prepared from the same imine
substrate just by changing the nucleophilic reagent.
In conclusion, the addition of triorganozincates to N-(tert-
butanesulfinyl)imines can be used as a key step in an asymmetric
synthesis of a-amino acids and derivatives. The absolute configura-
tion of the final amino acid can be controlled by an appropriate
choice of the way in which the synthetic equivalent of the carboxy
group is introduced. The methodology is applicable to the synthe-
sis of
using
a
a
,
a
-disubstituted
a-amino acids with high optical purity by
-imino esters as substrates. Further efforts to extend the