Hydroxylamines and sulfinamide as amine components in the Petasis boronic acid-Mannich reaction: Synthesis of N-hydroxy or alkoxy-α- aminocarboxylicacids and N-(tert-butyl sulfinyl)-α-amino carboxylicacids

Article abstract of DOI:10.1016/j.tetlet.2003.09.179

An efficient synthesis of N-hydroxy or alkoxy-α-aminocarboxylic acids and N-(tert-butyl sulfinyl)-α-amino carboxylic acids has been developed from N,O-alkyl or hydroxylamines and tert-butyl sulfinamide utilizing a Petasis boronic acid-Mannich reaction. The scope and limitations of this method have been examined.

Full text of DOI:10.1016/j.tetlet.2003.09.179

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8865–8868
Hydroxylamines and sulfinamide as amine components in the
Petasis boronic acid–Mannich reaction: synthesis of N-hydroxy
or alkoxy-a-aminocarboxylicacids and N-(tert-butyl
sulfinyl)-a-amino carboxylicacids
Dinabandhu Naskar,a,* Amrita Roy,a William L. Seibelb and David E. Portlockb,†
aChembiotek Research International, Block BN, Sector-V, Plot 7, Salt Lake Electronic Complex, Kolkata 700 091, India
bCombinatorial Chemistry Section, Procter & Gamble Pharmaceuticals Health Care Research Center,
8700 Mason Montgomery Road, Mason, OH 45040, USA
Accepted 19 September 2003
Abstract—An efficient synthesis of N-hydroxy or alkoxy-a-aminocarboxylic acids and N-(tert-butyl sulfinyl)-a-amino carboxylic
acids has been developed from N,O-alkyl or hydroxylamines and tert-butyl sulfinamide utilizing a Petasis boronic acid–Mannich
reaction. The scope and limitations of this method have been examined.
© 2003 Elsevier Ltd. All rights reserved.
The development of an efficient synthesis of N-
hydroxy-a-amino acids and derivatives1 thereof repre-
sents a challenging goal in organic synthesis since these
compounds are key intermediates in metabolic path-
ways and can be found in human and animal tumors.1,2
In our earlier report, it was shown that hydrazines can
participate in the Petasis boronic acid–Mannich reac-
tion, providing a powerful and convenient method for
the preparation of a-amino acids3–5 which is quite
useful for the synthesis of combinatorial libraries.6 We
have investigated the scope and limitations of using
substituted hydroxylamines and tert-butyl sulfinamide
as amine components in the Petasis boronic acid–Man-
nich reaction. To the best of our knowledge hydroxyl-
amines and tert-butyl sulfinamide have not previously
been studied as substrates for this reaction.3–5
SN2 displacement8 but such methods are not advanta-
geous. There are relatively few methods for the synthe-
sis of N-hydroxy amino acids. These involve
asymmetric oxyamination,9 oxidation by dioxiranes,10
Mitsunobu condition,11 and oxidation of amines.12
We describe herein an efficient synthesis of N-hydroxy
or alkoxy-a-aminocarboxylic acids and tert-butyl sulfin-
amide by the Petasis boronic acid–Mannich reaction.
Commercially available substrates (1 and 3) were sub-
jected to standard Petasis boronic acid–Mannich reac-
tion conditions, i.e. 1 equiv. each of 1 and 3, glyoxylic
acid monohydrate, and an organoboronic acid stirred
at ambient temperature in DCM (Tables 1 and 2).
When R1=methyl, R2=methyl, R3=aryl (2a–b), the
reactions proceeded in excellent yields, ranging from
95–96% of the corresponding N-alkoxy-a-amino acid
after purification by column chromatography (Table
1).13 When R1=methyl, R2=H, R3=aryl or hetero-
cyclic (2c–d), the reactions afforded good yield of the
desired product in 79–87% after purification. When
R3=aryl containing electron withdrawing group (2e),
the corresponding N-alkoxy-a-amino acid was obtained
in 89% yield after purification. Remarkably, when R1=
benzyl, cyclohexyl and tert-butyl, R2=H, R3=aryl (2f–
h), this reaction gave 41–80% yield after purification by
column chromatography. It was also observed that
General methods for the synthesis of enantiomerically
pure or enriched N-hydroxy-a-amino acids have had
scant mention in the literature until recently.7 Various
methods have already been reported for obtaining N-
hydroxy or alkoxy amino acid esters which can be
converted into the corresponding acid derivatives by
* Corresponding author. E-mail: naskar.d@pg.com, dinabandhu@
chembiotek.com
† Present address: Wright State University, Department of Chemistry,
Dayton, OH 45435, USA.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.179

8866
D. Naskar et al. / Tetrahedron Letters 44 (2003) 8865–8868
these compounds slowly decomposed on long standing
at ambient temperature.
the example 4a, the racemic diastereomers (1:1) were
separated by preparative HPLC and characterized by
1
LCMS, H and 13C NMR, and HRMS.14
When R2=aryl, R3=H (4a–e), these reactions pro-
ceeded in very good yields to afford the desired product
in 50–73% yield after purification by column chro-
matography (Table 2).14 When R2=heterocyclic (4f–h),
the reactions also proceeded in good yields to afford
the desired product in 66–68% yield. When the a-keto
acid was varied from R3=H to R3=Me (4i–j), these
reactions afforded only 37–39% yields of the product.
Together, these results suggest the steric environment at
the reaction center plays a significant role in the yield of
the reaction. As expected, the product consisted of a
50:50 mixture of racemic diastereomers (LC–MS). In
In summary, we have demonstrated that hydroxyl-
amines and sulfinamides can serve as amine substrates
for the Petasis boronic acid–Mannich reaction, provid-
ing a practical synthetic route for the preparation of
N-hydroxy or alkoxy-a-aminocarboxylic acids and N-
(tert-butyl sulfinyl)-a-aminocarboxylic acids. These N-
protected amino acids can be activated either as the
acid chloride or with HATU to provide excellent cou-
pling partners for amide bond formation, and should
be versatile intermediates for the synthesis of hindered
peptides and drugs.
Table 1. Petasis boronic acid–Mannich reactions of substituted hydroxylamines

D. Naskar et al. / Tetrahedron Letters 44 (2003) 8865–8868
8867
Table 2. Petasis boronic acid–Mannich reactions of sulfinamide
Chem. Soc. 1999, 121, 5075; (b) Petasis, N. A.; Patel, Z.
D. Tetrahedron Lett. 2000, 41, 9607; (c) Wang, Q.; Finn,
M. G. Org. Lett. 2000, 2, 4063; (d) Berree, F.; Debache,
A.; Marsac, Y.; Carboni, B. Tetrahedron Lett. 2001, 42,
3591, and references cited therein.
References
1. (a) Merino, P.; Castillo, E.; Santiago, F.; Merchan, F. L.;
Tejero, T. J. Org. Chem. 1998, 63, 2371; (b) Merino, P.;
Santiago, F.; Merchan, F.; Tejero, T. J. Org. Chem. 1998,
63, 5627.
2. Ottenheijm, H. C. J.; Herscheid, J. D. M. Chem. Rev.
1986, 86, 697.
3. (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc.
1997, 119, 445; (b) Petasis, N. A.; Goodman, A.;
Zavialov, I. A. Tetrahedron 1997, 53, 16463; (c) Hansen,
T. K.; Schlienger, N.; Hansen, B. S.; Andersen, P. H.;
Bryce, M. R. Tetrahedron 1999, 40, 3651; (d) Jiang, B.;
Yang, C.-G.; Gu, X.-H. Tetrahedron Lett. 2001, 42, 2545.
4. The Petasis boronic acid–Mannich reaction has also been
applied to the synthesis of heterocyclic systems. See: (a)
Batey, R. A.; MacKay, D. B.; Santhakumar, V. J. J. Am.
5. (a) Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetra-
hedron Lett. 2002, 43, 6845; (b) Portlock, D. E.;
Ostaszewski, R.; Naskar, D.; West, L. Tetrahedron Lett.
2003, 44, 603; (c) Portlock, D. E.; Naskar, D.; West, L.;
Ostaszewski, R.; Chen, J. J. Tetrahedron Lett. 2003, 44,
5121.
6. (a) Klopfenstein, S. R.; Chen, J. J.; Golebiowski, A.; Li,
M.; Peng, S. X.; Shao, X. Tetrahedron Lett. 2000, 41,
4835; (b) Schlienger, N.; Bryce, M. R.; Hansen, T. K.
Tetrahedron 2000, 56, 10023; (c) Domling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3168; (d) Bienayme, H.;
Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6,
3321.

8868
D. Naskar et al. / Tetrahedron Letters 44 (2003) 8865–8868
7. For an excellent recent review, see: (a) Duthaler, R. O.
196 (M+H+); HRMS: 196.096608 [calcd for C10H13NO3
196.097368 (M+H)+].
Tetrahedron 1994, 50, 1539; See also: (b) Williams, R. M.
Synthesis of Optically Acitve h-Amino Acids; Baldwin, J.
E.; Magnus, P. D., Eds.; Oxford: Pergamon Press, 1989.
8. (a) Yasuhiro, C.; Mitsuo, M.; Masaki, O. Bull. Chem.
Soc. Jpn. 1969, 42, 224; (b) Kolasa, T. Can. J. Chem.
1985, 63, 2139; (c) Kolasa, T.; Chimiak, A. Tetrahedron
1977, 33, 3285; (d) Kolasa, T.; Chimiak, A.; Kitowaka,
A. J. Prakt. Chem. 1975, 317, 252; (e) Kolasa, T.;
Chimiak, A. Tetrahedron 1974, 30, 3591; (f) Cook, A. H.;
Slater, C. A. J. Chem. Soc. 1956, 4130; (g) Chimiak, A.
Roczniki Chem. 1968, 42, 225.
9. (a) Oppolzer, W.; Tamura, O. Tetrahedron Lett. 1990, 31,
991; (b) Oppolzer, W.; Tamura, O.; Deerberg, J. Helv.
Chim. Acta 1992, 75, 1965.
10. Detomaso, A.; Curci, R. Tetrahedron Lett. 2001, 42, 755.
11. Hanessian, S.; Yang, R.-Y. Synlett 1995, 633.
12. Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J. J.
Org. Chem. 1990, 55, 1981.
13. General procedure for the Petasis boronic acid–Mannich
reaction of substituted hydroxyl amine 1 to prepare N-
hydroxy or alkoxy-a-aminocarboxylic acids 2 (Table 1):
To a stirred mixture of glyoxylic acid monohydrate (368
mg, 4.0 mmol) in DCM (12 mL) was added N,O-
dimethylhydroxylamine hydrochloride (390 mg, 4.0
mmol) followed by phenyl boronic acid (488 mg, 4.0
mmol). The resulting mixture was stirred at ambient
temperature for 24 h, and after this time, the solid was
filtered and washed with DCM several times, dried under
reduced pressure and purified by column chromatogra-
phy to afford 750 mg (96%) of 2b as a white solid, mp
(Met-TempII): 152–153°C (uncorrected): Rf=0.16 (5%
MeOH:DCM); analytical HPLC: Polaris C18 column
(4.6×250 mm, 3 micron particle size), mobile phase 0.1%
aqueous phosphoric acid/CH3CN linear gradient over 30
min, 1 mL/min, one peak detected by ELS and UV at 214
nm, tR=9.32 min; 1H NMR (MeOH-d4, 300 MHz): l
2.84 (s, 3H), 3.94 (s, 3H), 5.12(s, 1H), 7.49–7.58 (m, 5H);
13C NMR (MeOH-d4, 75 MHz): l 41.49, 62.27, 77.30,
130.75, 131.38, 132.33, 133.11, 170.45; LCMS (ELSD):
14. General procedure for the Petasis boronic acid–Mannich
reaction of sulfinamide 3 to prepare 4 (Table 2): To a
stirred mixture of glyoxylic acid monohydrate (460 mg,
5.0 mmol) in DCM (15 mL) was added (S)-(−)-2-methyl-
2-propanesulfinamide (606 mg, 5.0 mmol) followed by
4-methoxyphenylboronic acid (760 mg, 5.0 mmol). The
resulting mixture was stirred at ambient temperature for
48 h and after this time, the DCM was removed under
reduced pressure. The residue was purified by chromato-
graphy (silica gel, 40% EtOAc:hexanes) to give 1.04 g
(72%) of 4a as a 50:50 mixture of racemic diastereomers.
The diastereomers (A and B) have been separated by
preparative HPLC; [Polaris C18 column (250×500 mm,
10 micron particle size), mobile phase 0.1% aqueous
TFA/CH3CN linear gradient over 55 min, 60 mL/min];
analytical HPLC: Polaris C18 column (4.6×250 mm, 3
micron particle size), mobile phase 0.1% aqueous phos-
phoric acid/CH3CN linear gradient over 30 min, 1 mL/
min, one peak detected by ELS and UV at 220 nm,
tR=9.078 (A), another peak detected by ELS and UV at
220 nm, tR=9.840 (B).
4a(A): Rf=0.13, 10% MeOH:DCM; white solid, mp
(Met-TempII): 140–141°C (uncorrected); 1H NMR
(CD3OD, 300 MHz): l 1.24 (s, 9H), 3.82 (s, 3H), 5.02 (s,
1H), 6.96 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz, 2H); 13
C
NMR (CD3OD, 75 MHz): l 21.83, 54.59, 56.73, 59.63,
113.90, 128.93, 129.98, 160.11, 173.31; LCMS (ELSD):
286 (M+H+); HRMS: 286.110069 [calcd for C13H19NO4S
286.111305 (M+H)+].
4a(B): Rf=0.14, 10% MeOH:DCM; white solid, mp
(Met-TempII): 109–110°C (uncorrected); 1H NMR
(CD3OD, 300 MHz): l 1.24 (s, 9H), 3.80 (s, 3H), 4.96 (s,
1H), 6.93 (d, J=9 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H); 13C
NMR (CD3OD, 75 MHz): l 23.33, 56.16, 57.52 61.85,
115.46, 131.03, 131.53, 161.68, 174.84; LCMS (ELSD):
286 (M+H+); HRMS: 286.110228 [calcd for C13H19NO4S
286.111305 (M+H)+].