Asymmetric synthesis of pre-protected α,α-disubstituted amino acids from tert-butanesulfinyl ketimines

Article abstract of DOI:10.1016/S0040-4039(00)02300-5

A method for the asymmetric synthesis of pre-protected α,α-disubstituted amino acids is described. 5-Methylfuryllithium is added into sulfinyl ketimines 1 in the presence of AlMe₃ to afford the sulfinamides 2 in 75-97% yields and with diastereoselectivities ranging from 75:25 to 99:1. Subsequent oxidation with RuCl₃/NaIO₄ affords tert-butanesulfonyl (Bus)-protected α,α-disubstituted amino acids 3 in 62-69% yields. Bus-protected amino acids readily undergo amide bond formation, after which the Bus group can be removed with TfOH/CH₂Cl₂ to afford the free amine.

Full text of DOI:10.1016/S0040-4039(00)02300-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1433–1436
Asymmetric synthesis of pre-protected a,a-disubstituted amino
acids from tert-butanesulfinyl ketimines
George Borg, Masao Chino and Jonathan A. Ellman*
Department of Chemistry, University of California, Berkeley, CA 94720, USA
Received 10 December 2000; revised 12 December 2000; accepted 13 December 2000
Abstract—A method for the asymmetric synthesis of pre-protected a,a-disubstituted amino acids is described. 5-Methylfuryl-
lithium is added into sulfinyl ketimines 1 in the presence of AlMe3 to afford the sulfinamides 2 in 75–97% yields and with
diastereoselectivities ranging from 75:25 to 99:1. Subsequent oxidation with RuCl3/NaIO4 affords tert-butanesulfonyl (Bus)-pro-
tected a,a-disubstituted amino acids 3 in 62–69% yields. Bus-protected amino acids readily undergo amide bond formation, after
which the Bus group can be removed with TfOH/CH2Cl2 to afford the free amine. © 2001 Elsevier Science Ltd. All rights
reserved.
a,a-Disubstituted amino acids have displayed powerful
effects on the conformation and the biological activity
of molecules in which they are incorporated.1 As a
result, a,a-disubstituted amino acids have served as key
components in numerous bioactive peptides, potential
therapeutic agents, and natural products.2 The most
widely used methods for the asymmetric synthesis of
a,a-disubstituted amino acids rely on diastereoselective
enolate alkylation.2 However, this approach prohibits
the general use of poor SN2 substrates, such as aryl
halides or sterically demanding alkylating agents.
Moreover, harsh conditions are often necessary to liber-
ate the free acid from the alkylation product.
with RuCl3(cat.)/NaIO4 affords tert-butanesulfonyl
(Bus)-protected amino acids 3 in two steps from sulfinyl
ketimine 1 (Scheme 1).6
We began by evaluating the 1,2-addition of oxidizable
nucleophiles to sulfinyl ketimine 1a (Eq. (1)). Ketimine
1a was added to furyllithium and 5-methylfuryllithium
under the optimal conditions we have previously
reported, namely, with toluene as solvent and with 1
equiv. of AlMe3 at −78°C.5 Unfortunately, due to the
poor solubility of the furyllithium derivatives in tolu-
ene, poor conversions (530%) were observed even
when the reaction mixtures were allowed to warm to
room temperature prior to quenching. By performing
the reactions at 0°C a good yield (80%) and excellent
diastereoselectivity (99:1 dr) was observed for the addi-
tion of 5-methylfuryllithium and a moderate yield
(55%) and comparable diastereoselectivity was observed
for the addition of furyllithium.
An alternative disconnection is the 1,2-addition of oxi-
dizable carbanions to ketimines.3 We have recently
reported the one-step preparation of sulfinyl ketimines
1 in high yields by condensation of enantiomerically
pure tert-butanesulfinamide with ketones.4 Additions of
organolithiums to 1 proceed cleanly and with high
diastereoselectivities.5 Herein, we report the application
of this methodology to the asymmetric synthesis of
pre-protected a,a-disubstituted amino acids. Specifi-
cally, the high-yielding and diastereoselective 1,2-addi-
tion of 5-methylfuryllithium to 1 followed by oxidation
(1)
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02300-5

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G. Borg et al. / Tetrahedron Letters 42 (2001) 1433–1436
Table 1. 1,2-Addition of 2-methylfuryllithium to sulfinyl ketimines 1 (Scheme 1)
Ketimine
R1
R2
2, Yield (%)
2, dr
3, Yield (%)
1a
1b
1c
1d
1e
Me
Bu
Me
Bu
Ph
Ph
i-Pr
i-Pr
i-Bu
80
87
97
91
75
99:1c
62a
67b
63a
69b
69b
97:3d
94:6d
80:20e
75:25e
Me
a Absolute configuration determined by chemical correlation.8
b Absolute configuration tentatively assigned on the basis of consistent diastereofacial selectivity observed for 1a, 1c and previously reported
1,2-addition reactions to sulfinyl ketimines.5
c Diastereoselection determined by chiral HPLC analysis of the acetamide formed after sulfinyl cleavage.
d Diastereoselection determined by chiral HPLC analysis of the benzamide formed after sulfinyl cleavage.
e Diastereoselection determined by 1H NMR.
Scheme 2. (a) HATU, Et3N, DMF, then HCl·Phe-OMe; (b) i. SOC12, CH2Cl2, cat. DMF. ii. HCl·Phe-OMe, Na2CO3/NaHCO3,
CH2Cl2/H2O.
The utility of Bus-protected a,a-disubstituted amino
The generality of the 1,2-addition of 5-methylfuran to
tert-butanesulfinyl ketimines was then investigated
(Table 1).7 Good to high yields were obtained for both
dialkyl and aryl alkyl sulfinyl ketimines. The
diastereoselection was highly dependent on the imine
substitution. Thus, the diastereoselection was very high
for imines with highly differentiated substituents (1a–
1c), but dropped significantly when the substituents
were of similar steric size (1d–1e).
acids as reagents for peptide synthesis was investigated
by coupling amino acid 3c with L-phenylalanine methyl
ester (Scheme 2). Two coupling conditions were evalu-
ated.11 3c was activated in situ with HATU (1.3 equiv.)
and Et3N in DMF and coupled with 2 equiv. of
HCl·Phe-OMe to deliver dipeptide 4 in 82% yield.
Alternatively, 3c could be converted to the acid chloride
and then coupled with HCl·Phe-OMe in H2O/Na2CO3-
12
NaHCO3/CH2Cl2 to deliver 4 in 79% yield. Signifi-
cantly, despite the extremely hindered nature of the
reactants, only 1.1 equiv. of the hydrochloride salt of
phenylalanine methyl ester was required to achieve a
high yield in this reaction. Subsequent cleavage of the
Oxidation of sulfinamide 2a with RuCl3·H2O (1 mol%)
and NaIO4 (15 equiv.) in 1:1:1.5 CH2Cl2/MeCN/H2O6
went to completion in 2 h to afford the Bus-protected
amino acid 3a in 62% yield after acid/base extraction
(Scheme 1, Table 1). When sulfinamide 2c was oxidized
under the same conditions, a 4:1 mixture of Bus-pro-
tected amino acid 3c and the corresponding ketoacid
was isolated after acid/based extraction. It was found
that ketoacid formation could be partially suppressed
(<10%) by oxidation with minimal acetonitrile
(1:0.04:0.7 CH2Cl2/MeCN/H2O), though the reaction
was slower under these conditions (18 h). Acid/base
extraction followed by recrystallization afforded analyt-
ically pure 3c in 63% yield.9,10 Employing these
modified conditions, Bus-protected amino acids 3b, 3d
and 3e were all obtained in good yields (Table 1). To
demonstrate that no racemization occurs during the
oxidation and Bus-protecting group removal steps, 3b
was converted to the (+)- and (−)-MTPA amides of
a-butyl phenylglycine methyl ester by treatment with
diazomethane, Bus deprotection with TfOH/CH2Cl2,6
and derivatization with (+)- or (−)-MTPACl, respec-
tively. From starting carbinamine 2b (97:3 dr), the
MTPA amides were obtained in 97:3 dr as determined
by HPLC analysis establishing that no degradation of
stereochemical purity occurs during this synthesis
sequence.
6
Bus group from dipeptide 4 using TfOH/CH2Cl2
afforded the free amine 5 in 65% yield.13
In conclusion, we have demonstrated the utility of
tert-butanesulfinyl ketimines 1 for the asymmetric syn-
thesis of pre-protected a,a-disubstituted amino acids in
two steps. Carboxylic acid equivalent 5-methylfuryl-
lithium can be added into both aryl alkyl and dialkyl
ketimines in high yield and in moderate to high
diastereoselectivities. The resulting sulfinamides are oxi-
dized with RuCl3(cat.)/NaIO4 to afford Bus-protected
a,a-disubstituted amino acids in 62–69% yields. Bus-
protected a,a-disubstituted amino acids can be acti-
vated either as the acid chloride or with HATU to
provide excellent coupling partners for amide bond
formation, and should be versatile intermediates for the
synthesis of hindered peptides and drugs.
Acknowledgements
This work was supported by the National Science
Foundation. G.B. is grateful for a Pfizer Summer

G. Borg et al. / Tetrahedron Letters 42 (2001) 1433–1436
1435
10. General procedure: RuCl3·H2O (1 mol%) was added to
a mixture of NaIO4 (15 equiv.) in CH2Cl2/MeCN/H2O
(1.0:0.04:0.7), and the mixture was stirred for 1 h. A
solution of 2 in CH2Cl2 was added rapidly to the mix-
ture via cannula. The final concentration of 2 was 0.03
M. Upon completion, as determined by TLC, the mix-
ture was acidified to pH 1 with 1N NaHSO4. The mix-
ture was filtered through a plug of Celite and the
organic layer was separated and washed once with
brine followed by extraction with 5% K2CO3 (3×). The
Undergraduate Research Fellowship. Support for M.C.
from Mitsubishi Chemical Company is gratefully
acknowledged.
References
1. (a) Balaram, P. Curr. Opin. Struct. Biol. 1992, 2, 845–
851; (b) Veber, D. F.; Freidinger, R. M. Trends Neu-
rosci. 1985, 8, 392–396.
2. For reviews on a,a-disubstituted amino acid syntheses,
see: (a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetra-
hedron: Asymmetry 1998, 9, 3517–3599. (b) Williams, R.
M. Synthesis of Optically Active h-Amino Acids; Perga-
mon: Oxford, 1989.
3. Previously, the 1,2-addition of oxidizable carbanions to
aldimines has been applied to the synthesis of a-mono-
substituted amino acids: Alvaro, G.; Martelli, G.;
Savoia, D.; Zoffoli, A. Synthesis 1998, 1773–1777.
4. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.;
Ellman, J. A. J. Org. Chem. 1999, 64, 1278–1284.
5. Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999,
121, 268–269.
aqueous layer was acidified to pH
1 with solid
NaHSO4 and then extracted with EtOAc (3×). The
combined organic portions were dried (Na2SO4) and
concentrated. For amino acid 3c, acid/base extraction
was followed by recrystallization from toluene. Product
characterization for amino acid (R)-3c: IR: 1125, 1305,
1710, 1730, 2979, 3261 cm−1 1H NMR (400 MHz) l
.
0.99 (d, J=6.8, 3H), 1.02 (d, J=6.9, 3H), 1.42 (s, 9H),
1.56 (s, 3H), 2.11 (m, 1H), 4.47 (s, 1H), 10.28 (br s,
1H). 13C NMR (101 MHz) l 16.98, 17.08, 17.33, 24.35,
36.96, 60.15, 65.88, 179.39. Anal. calcd for
C10H21NO4S: C, 47.79; H, 8.42; N, 5.57. Found: C,
47.71; H, 8.30; N, 5.59. The product was determined to
have the (R) configuration upon straightforward con-
6. Bus group: (a) Sun, P.; Weinreb, S. M. J. Org. Chem.
1997, 62, 8604–8608. (b) Gontcharov, A. V.; Liu, H.;
Sharpless, K. B. Org. Lett. 1999, 1, 783–786.
version to a-methyl-
D
-valine methyl ester. [h]2D3 −13.0 (c
-valine methyl ester:
6.1, CHCl3). Lit. for a-methyl-
L
[h]2D3 +13.5 (c 2.4, CHCl3). Tabcheh, M.; El Achqar, A.;
Pappalardo, L.; Roumestant, M.-L.; Viallefont, P. Tet-
rahedron 1991, 47, 4611–4618.
7. General procedure for 5-methylfuryllithium additions to
sulfinyl ketimines: (a) 5-methylfuryllithium was prepared
by addition of 2.5 M n-BuLi in hexanes (5 equiv.) to a
5 M solution of 2-methylfuran (6 equiv.) in Et2O at
−10°C. The resulting solution was allowed to warm
to room temperature and stirred overnight. (b) To a 1
M solution of sulfinyl ketimine (1 equiv.) in toluene at
0°C was slowly added a 1 M solution of AlMe3 in
toluene (1.1 equiv.). The resulting solution was stirred
for 5 min before it was added over the course of 30
min to a 0°C solution of 5-methylfuryllithium diluted
to 0.5 M with toluene. Stirring was continued at 0°C
for 3–4 h before the mixture was allowed to warm
slowly to room temperature. Saturated aq. Na2SO4 was
added dropwise until gas was no longer evolved upon
addition, and solid MgSO4 was added. The slurry was
stirred for 5 min before it was filtered through a Celite
pad and the filter cake was rinsed with EtOAc. Chro-
matography of the residue left after concentration of
the filtrate afforded sulfinamides 2a–e. Product charac-
terization for sulfinamide (R)-2c: IR: 1064, 1363, 1387,
11. General procedure for coupling of 3c with Phe-OMe:
Method A: HATU (1.3 equiv.) was added to a 0.4 M
solution of amino acid 3c (1 equiv.) and Et3N (4
equiv.) in DMF. After stirring for 1 h, HCl·Phe-OMe
(2 equiv.) was added. Upon completion, as determined
by TLC, the mixture was diluted with 3:1 hexanes/
CH2Cl2 and washed with 1N NaHSO4 (3×). The
organic layer was washed with 0.1 M K2CO3 (3×),
dried (Na2SO4), and concentrated. Chromatography
with 85:15 hexanes/EtOAc afforded dipeptide 4.
Method B: This procedure is a modification of the
reaction conditions reported by Vedejs (Ref. 12). (a) To
a 0.2 M solution of amino acid 3c (1 equiv.) and
SOC12 (3 equiv.) in CH2Cl2 was added a catalytic
amount of DMF. After stirring for 2 h, the solution
was concentrated, dissolved in dry toluene, and concen-
trated again to yield the acid chloride, which was used
without further purification. (b) To a stirred solution of
HCl·Phe-OMe, NaHCO3 (3.2 equiv.), and Na2CO3 (2
equiv.) in 1:1 CH2Cl2:H2O (0.1 M) at 0°C was added a
0.1 M solution of the acid chloride in dry CH2Cl2.
After stirring for 1 h, the reaction mixture was diluted
with hexanes (3:1 hexanes/CH2Cl2 final ratio). The
aqueous layer was washed with 3:1 hexanes/CH2Cl2 (3×).
The combined organic layers were washed once with
0.5% HCl and then brine. Chromatography with 85:15
hexanes/EtOAc afforded dipeptide 4 in 79% yield.
12. N-sulfonyl-protected amino acid chlorides are markedly
more stable than N-carbamate-protected amino acids,
which decompose readily to the considerably less reac-
tive oxazolinones. For the synthesis and application of N-
sulfonyl amino acid chlorides, see: Vedejs, E.; Lin, S.;
Klapars, A.; Wang, J. J. Am. Chem. Soc. 1996, 118,
9796–9797.
1455 cm−1 1H NMR (400 MHz) l 0.76 (d, J=6.8,
.
3H), 0.93 (d, J=6.9, 3H), 1.17 (s, 9H), 1.43 (s, 3H),
2.19–2.25 (m, 4H), 3.37 (s, 1H), 5.83–5.84 (m, 1H), 6.11
(d, J=3.0, 1H). 13C NMR (101 MHz) l 13.57, 16.79,
17.58, 19.12, 22.54, 36.81, 55.72, 59.81, 105.72, 107.28,
151.03, 156.30. Anal. calcd for C14H25NO2S: C, 61.95;
H, 9.28; N, 5.16. Found: C, 61.85; H, 9.27; N, 5.15.
8. Compound 2a was converted to the methyl ester of
a-methyl-D-phenylglycine hydrochloride, and 2c was
converted to the methyl ester of a-methyl valine (see
Ref. 10).
9. Alternatively, the ketoacid could be scavenged from the
product by overnight treatment of the crude material
with 1 equiv. of polystyrene-p-toluenesulfonyl hydrazide
resin in dichloroethane at 40°C.

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G. Borg et al. / Tetrahedron Letters 42 (2001) 1433–1436
13. Deprotection of dipeptide 4 [this procedure is a modifi-
cation of the conditions developed by Weinreb (Ref.
6a)]: To a solution of 4 in anisole (20 equiv.) was added
a 0.4 N solution of TfOH in CH2Cl2 (6 equiv.). After
stirring for 24 h, the mixture was washed with saturated
NaHCO3 (3×). After drying (Na2SO4) and concentra-
tion, chromatography (hexanes/EtOAc) afforded amine
5.
.