Unnatural chiral N - Tert -butanesulfinyl α-amino acid synthesis; A general synthetic strategy to N -boc-phenylalanine analogue alternatives

Article abstract of DOI:10.1055/s-0032-1317298

This work provides a general approach to unnatural chiral N-tert-butanesulfinyl α-amino acid synthesis with high yields and excellent diastereoselectivities (dr up to 98:2). The asymmetric addition of organometallic reagents to N-tert-butylsulfinyl imino acetate proceeded with excellent diastereo- and regioselectivities even on a 10 mmol scale. The sterically constrained 2,6-dimethyltyrosine (Dmt) derivative was also readily prepared from commercially available and inexpensive starting materials through simple steps. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317298

LETTER
▌2559
lUettner natural Chiral N-tert-Butanesulfinyl α-Amino Acid Synthesis; A General
Synthetic Strategy to N-Boc-Phenylalanine Analogue Alternatives
Chiral N-tert-Butanesulfinyl α-Amino Acid Synthesis
Li Lin,a Xu Fu,a Xiaojuan Ma,a Jinlong Zhang,a Rui Wang*a,b
a
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, State Key Laboratory of Applied Organic Chemistry and Institute of
Biochemistry and Molecular Biology, Lanzhou University, Lanzhou, 730000, P. R. of China
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, P. R. of China
Fax +86(931)8912567; E-mail: wangrui@lzu.edu.cn
Received: 17.06.2012; Accepted after revision: 23.08.2012
Grignard-type reagents can occur at both the ester group
Abstract: This work provides a general approach to unnatural chi-
and the imino group of 1. Davis and co-workers obtained
ral N-tert-butanesulfinyl α-amino acid synthesis with high yields
poor yields and regioselectivities by using either BnMgCl
and excellent diastereoselectivities (dr up to 98:2). The asymmetric
addition of organometallic reagents to N-tert-butylsulfinyl imino
or BnZnCl, or BnMgCl combined with ZnCl2 as the nu-
acetate proceeded with excellent diastereo- and regioselectivities cleophile.9a Reports also indicated that either the N-sulfi-
nyl group9a or the tert-butyl group of sulfinyl9e can be
even on a 10 mmol scale. The sterically constrained 2′,6′-dimethyl-
tyrosine (Dmt) derivative was also readily prepared from commer-
readily substituted by the corresponding nucleophile.
cially available and inexpensive starting materials through simple
Rhodium(I)10a and palladium(II)10b,10c catalyzed additions
steps.
of arylboronic acids to chiral N-tert-butanesulfinyl imino
Key words: unnatural α-amino acids, peptides, regioselectivity,
asymmetric synthesis, chiral auxiliaries
esters have been reported. However, these studies were
limited to the synthesis of arylglycine derivatives.10 Thus,
it is highly desirable to find a general and practical nucleo-
philic reagent for direct asymmetric addition to N-sulfinyl
imino acetate 1 for chiral α-amino acid synthesis.
Peptides, due to their high specificity and low toxicity,
have attracted growing attention for pharmaceutical appli-
cations. The incorporation of unnatural amino acids can
play a very important role in enhancing the resistance of
peptides to enzymatic degradation and increasing peptide
Nu
Nu
Nu
O
EtO
S
structural diversity as well as bioactivity.1 To obtain di-
verse unnatural amino acids, a variety of methodologies
have been developed2 such as asymmetric Strecker reac-
tion,3 direct functionalization of glycinate,4 chiral tem-
plate directed alkylation of glycinate,5 and asymmetric
addition to glyoxylate imine.6 Among these protocols, di-
rect asymmetric addition of Grignard reagents to glyoxy-
late imines,7 which can afford protected chiral amino
acids, was undoubtedly one of the most practical and con-
venient approaches. However, generally, significant
background reactions always occur, which leads to poor
stereoselectivity caused by the bidentate chelation effect
of the glyoxylate imine. The use of chiral sulfinyl as a chi-
ral auxiliary is a promising solution. Although sulfinyl
imines have been widely exploited in various synthetic
approaches,8 few reports have been disclosed on the
asymmetric synthesis of chiral α-amino acids via the nu-
cleophilic addition to N-sulfinyl imino acetates.9 As an
electrophilic reagent, N-sulfinyl imino acetate (Figure 1)
shows complex reactivity, which always limited the
nucleophile scope. In fact, nucleophilic additions of
N
t-Bu
O
1
Nu
Figure 1 N-tert-Butanesulfinyl imino acetate 1 as a complex electro-
phile
Recently, Knochel and co-workers reported several proto-
cols for the preparation and application of a series of
multi-metallic organometallic reagents (Figure 2).11 An
impressive lithium chloride effect that could be used to
finely tune the nucleophilicity and alkaline properties of
these organozinc halides or organomagnesium halides
was disclosed. Unlike the usual Grignard reagent, these
Knochel reagents are ester-tolerant, highly nucleophilic,
and weakly alkaline.12 Type I/II Knochel reagents,13
which possess the unique properties mentioned above, are
the most easily accessible and the most widely functional
group compatible. There is no need to preactivate magne-
sium or zinc. Although Ellman’s group reported the addi-
tion of Knochel reagents to sulfinyl imine, application of
the reagent to amino acid synthesis was not disclosed.
Herein, we report the highly diastereoselective addition of
Type I Knochel reagents to N-tert-butylsulfinyl imino
acetate 1 for the asymmetric synthesis of chiral α-amino
acids.14
SYNLETT 2012, 23, 2559–2563
Advanced online publication: 21.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317298; Art ID: ST-2012-W0523-L
© Georg Thieme Verlag Stuttgart · New York

2560
L. Lin et al.
LETTER
The applicability of this approach was examined under the
optimal conditions and the results are combined in Table
2. A series of phenylalanine analogue derivatives was suc-
cessfully afforded. All the additions of benzyl zinc 2 to 1
were rapidly accomplished within 20 minutes. In addition,
the stereoselectivity and the yield were not significantly
affected by the concentration of reagent 2. High yield of
3a could also be obtained starting from benzyl bromide
with excellent diastereoselectivity (95:5) (entry 1). Simi-
lar results were observed in the addition of multi-metallic
benzyl zinc with either electron-withdrawing (2d) or elec-
tron-donating (2b and 2c) substitutes and afforded 3b–d
with high yields and excellent dr values (entry 2–4).
Mono-/multi-halide substituted benzyl zinc was also tol-
erated in this approach. The diastereoselectivities as well
as yields were not obviously affected by the substitution
sites. Excellent dr values of 3e–i with moderate to high
yields were obtained (entries 5–10). 1-Naphthylalanine
derivative 3j was also obtained with high yield (94%) and
diastereoselectivity (90:10) (entry 11). The addition of 2j
to 1 proceeded smoothly to give the 4-vinyl phenylalanine
derivative with an excellent dr value (97:3) and good yield
(69%, entry 12), which can potentially be applied as a chi-
ral ligand as well as in peptide immobilization. It was
pleasing to find that arylglycine 3l could also be highly
diastereoselectively synthesized through the present pro-
tocol with a dr of 92:8 and a yield of 60% (entry 13).
Knochel reagents
type I: RZnX⋅MgCl2⋅LiCl (ref. 11a)
type II: R2Zn⋅MgCl2⋅LiCl (ref. 11a)
type III: RZnX⋅LiCl
type IV: R'MgX⋅LiCl
R = aryl, alkyl; R' = aryl, alkenyl
ester-tolerant
highly nucleophilic
weakly alkaline
(ref. 11b)
(ref. 11c)
Figure 2 Typical multi-metallic organometallic reagents
In our preliminary studies, solvent and temperature effects
were studied in detail to improve the yield and stereose-
lectivity of the model reaction; the results are summarized
in Table 1. All the reactions were accomplished favorably
at –78 °C within 20 min. When the reaction was carried
out in hexane, poor yield (40%) and diastereoselectivity
(74:26 dr) were observed (entry 1). When using CH2Cl2
and toluene as solvents, 3a was afforded with similarly
moderate yields (58 and 51%) and high dr values (93:7
and 92:8) (entries 2 and 3), respectively. Higher yield
(76%) of 3a was afforded when the reaction was conduct-
ed in isopropyl ether but with a lower dr value (89:11) (en-
try 4). The use of methyl tert-butyl ether (MTBE) failed
to improve the result (entry 5). Tetrahydrofuran (THF)
proved to be the optimal solvent, giving 3a with excellent
diastereoselectivity (97:3) and moderate yield (60%) (en-
try 6). Either the yield or the diastereoselectivity of the
model addition decreased sharply at higher reaction tem-
perature (entries 7–9). It was found that the optical rota-
tion of ethyl phenylalaninate hydrochloride derived from
3a was consistent with ethyl L-phenylalaninate hydro-
chloride. Thus, the absolute configuration of 3a was
(Ss,S).
Extensive studies clearly indicated the introduction of
2′,6′-dimethyltyrosine (Dmt) to peptides, especially opi-
oid peptide synthesis, was vital for improving the peptide
structure–activity relationship.15,16 However, commercial
Dmt is very expensive. The asymmetric synthesis of Dmt
was rather limited due to the steric hindrance of the chiral
carbon center.17 One approach involved Rh-catalyzed
asymmetric hydrogenation under harsh conditions,17b–e
and a relatively expensive chiral catalyst was used. An al-
ternative approach involved a Ni-template strategy,17c
which suffered low diastereoselectivity, long linear steps,
and troublesome purification procedures. Chiral (S)-
phenylethylamine-induced asymmetric synthesis of Dmt
was reported recently, but the use of corrosive HI was crit-
ical to release the unprotected Dmt.17d Therefore, the pres-
ent protocol was applied in the asymmetric synthesis of
selectively protected Dmt.
Table 1 Solvent and Temperature Screeninga,b
Bn
O
S
O
S
BnZnCl⋅MgCl2⋅LiCl (2a)
EtO
EtO2C
N
H
t-Bu
N
t-Bu
within 20 min
O
3a
1
Entry
Solvent
Temp. (°C)
Yield (%)c drd
1
2
3
4
5
6
7
8
9
hexane
CH2Cl2
toluene
i-Pr2O
MTBE
THF
–78
–78
–78
–78
–78
–78
–40
–20
0
40
58
51
76
52
60
58
56
44
74:26
93:7
92:8
89:11
88:12
97:3
The synthesis of 2′,6′-dimethyltyrosine (Dmt) is outlined
in Scheme 1. Benzyl halides 5a and 5b were readily pre-
pared from inexpensive and commercially available 4-hy-
droxy benzaldehyde (4) with excellent isolated yield.
Knochel reagent 2m (0.45 M) and 2n (0.22 M) were af-
forded under the typical procedure (see the Supporting In-
formation). The distinctly different concentrations might
be due to the fact that (a) benzyl zinc bromide 2n has a
higher reactivity and nucleophilicity than benzyl zinc
chloride 2m, and cross-coupling of 2n with benzyl bro-
mide might occur, and (b) the large electron-donating ef-
fect of the two sterically hindered methyl groups
associating with the benzyloxy group might cause the
benzyl zinc bromide 2n to be more unstable. This is con-
THF
87:13
82:18
78:22
THF
THF
a Reaction conditions (unless otherwise noted): 1 (0.2 mmol), 2a (0.3
mmol, 0.45 M in THF), solvent (1 mL), 20 min.
b The absolute configuration of 3a was confirmed to be (Ss,S) (see the
Supporting Information).
c Isolated yield of the major diastereomer.
d Determined by 1H NMR analysis of the crude product.
Synlett 2012, 23, 2559–2563
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chiral N-tert-Butanesulfinyl α-Amino Acid Synthesis
2561
Table 2 Application Scope in Chiral Amino Acid Derivative Synthesisa
R
O
S
RX + Mg THF, 0 °C
1, THF, –78 °C
RZnX⋅Y
+
40 min
within 20 min
ZnCl2/LiCl
EtO2C
N
H
t-Bu
2
3
R = benzyl, aryl; X = Cl, Br; Y = MgCl2⋅LiCl
Entry
RX
2 (mmol/mL)b
2a′ (0.51)
Product
Yield (%)c
90
drd
Optical rotation
+
Br
Cl
1
2
3a
95:5
2b (0.50)
3b
73
96:4
+
Me
Me
Cl
3
4
2c (0.48)
2d (0.42)
3c
77
64
94:6
94:6
+
+
F3C
Cl
3d
Cl
Cl
Cl
5
2e (0.50)
3e
66
94:6
+
Cl
6
7
8
2f (0.48)
2g (0.51)
2h (0.46)
3f
74
77
82
95:5
96:4
95:5
+
+
+
Cl
Cl
Cl
Cl
Cl
3g
3h
Cl
Br
Br
Cl
Br
9
2i (0.68)
2i′ (0.52)
3i
3i
73
60
92:8
93:7
+
+
10
Cl
11
12
2j (0.52)
2k (0.46)
3j
94
69
90:10
97:3
–
Cl
3k
+
a Reaction conditions: (S)-1 (0.2 mmol), 2 (0.3 mmol in THF), 20 min.
b Separated by filtration and titrated according to the literature method (see the Supporting Information).
c Isolated yield of the major diastereomer.
d Determined by 1H NMR analysis of the crude product.
sistent with the finding that complex products were ob- der acidic conditions, while retaining the ester and not af-
served in the addition of benzyl zinc bromide 2n to fecting the chiral center.18 The carboxyl group was readily
sulfinyl imino acetate (S)-1. When 1.2 equiv of 2m was released upon treatment with LiOH19 to give N-tert-butyl
used instead, selectively protected (S)-Dmt 3m was favor- sulfinyl acid 6 with 90% yield. The phenolic hydroxyl
ably afforded with an excellent dr of 98:2 and 70% yield group of 6 can also be readily released by catalytic hydro-
on a 10 mmol scale. The N-tert-butylsulfinyl group, which genation.
is an equivalent alternative of N-Boc, can be removed un-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2559–2563

2562
L. Lin et al.
LETTER
(3) (a) Yet, L. Angew. Chem. Int. Ed. 2001, 40, 875. (b) Gröger,
H. Chem. Rev. 2003, 103, 2795. (c) Wang, J.; Liu, X.; Feng,
X. Chem. Rev. 2011, 111, 6947.
OH
OBn
OBn
i, ii, iii
iv
(4) (a) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc.
2007, 129, 5364. (b) Zhao, L.; Li, C.-J. Angew. Chem. Int.
Ed. 2008, 47, 7075. (c) Hirner, S.; Panknin, O.; Edefuhr, M.;
Somfai, P. Angew. Chem. Int. Ed. 2008, 47, 1907. (d) Xie, J.;
Huang, Z.-Z. Angew. Chem. Int. Ed. 2010, 49, 10181.
(5) (a) Luo, Y.-C.; Zhang, H.-H.; Wang, Y.; Xu, P.-F. Acc.
Chem. Res. 2010, 43, 1317. (b) See also ref. 2b and
references cited therein
(6) For selected examples, see: (a) Ferraris, D.; Young, B.;
Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548.
(b) Ji, J.-X.; Wu, J.; Chan, A. S. C. Proc. Natl. Acad. Sci.
U.S.A. 2005, 102, 11196. (c) Enders, D.; Seppelt, M.; Beck,
T. Adv. Synth. Catal. 2010, 352, 1413. (d) Huang, G.; Yang,
J.; Zhang, X. Chem. Commun. 2011, 47, 5587.
CHO
X
ZnX⋅MgCl2⋅LiCl
2m: X = Cl; 2n: X = Br
4
5a: X = Cl
5b: X = Br
v
O
O
S
t-Bu
CO2H
S
t-Bu
CO2Et
HN
HN
vi
BnO
BnO
3m
6
Scheme 1 2′,6′-Dimethyl tyrosine synthesis. Reagents and condi-
tions: (i) BnBr, K2CO3, acetone, reflux, 3 h; (ii) NaBH4, MeOH, 0 °C,
92% yield from phenol aldehyde 4; (iii) 5a: SOCl2, 1 h in CH2Cl2,
98%; 5b: CBr4, Ph3P, 1 h in THF, 90%; (iv) Mg, ZnCl2/LiCl
(1.1 M/1.5 M in THF), 3 h, 0.45 M for 2m, 0.22 M for 2n; (v) 2n (1.2
equiv), (S)-1 (10 mmol), –78 °C, 30 min, dr 98:2, 70%; (vi) LiOH (1
M, THF–H2O), overnight at r.t., 90%.
(7) Dickstein, J. S.; Kozlowski, M. C. Chem. Soc. Rev. 2008, 37,
1166.
(8) For reviews, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T.
P. Acc. Chem. Res. 2002, 35, 984. (b) Ferreira, F.; Botuha,
C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009, 38,
1162. (c) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W.
Acc. Chem. Res. 2008, 41, 831. (d) Robak, M. T.; Herbage,
M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
(9) (a) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396.
(b) Grigg, R.; McCaffrey, S.; Sridharan, V.; Fishwick, C. W.
G.; Kilner, C.; Korn, S.; Bailey, K.; Blacker, J. Tetrahedron
2006, 62, 12159. (c) Andreassen, T.; Hansen, L.-K.; Gautun,
O. R. Eur. J. Org. Chem. 2008, 4871. (d) Sun, X.; Zheng,
W.; Wei, B.-G. Tetrahedron Lett. 2008, 49, 6195. (e) Gu, C.-
L.; Liu, L.; Wang, D.; Chen, Y.-J. J. Org. Chem. 2009, 74,
5754. (f) Reddy, L. R.; Gupta, A. P.; Liu, Y. J. Org. Chem.
2011, 76, 3409.
(10) (a) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem.
Soc. 2006, 128, 6304. (b) Dai, H.; Lu, X. Org. Lett. 2007, 9,
3077. (c) Dai, H.; Yang, M.; Lu, X. Adv. Synth. Catal. 2008,
350, 249. (d) Li, Y.; Ji, D. M.; Xu, M. H. Org. Biomol.
Chem. 2011, 9, 8452.
(11) For selected examples, see: (a) Metzger, A.; Bernhardt, S.;
Manolikakes, G.; Knochel, P. Angew. Chem. Int. Ed. 2010,
49, 4665. (b) Boudet, N.; Sase, S.; Sinha, P.; Liu, C.-Y.;
Krasovskiy, A.; Knochel, P. J. Am. Chem. Soc. 2007, 129,
12358. (c) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.;
Helm, M.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47,
6802.
In conclusion, we have developed a facile, convenient, re-
liable, and inexpensive synthesis of chiral α-amino acids
using N-tert-butanesulfinyl as the chiral auxiliary. The ad-
dition of various multi-metallic benzyl zinc halides to N-
tert-butanesulfinyl imino ester gave N-tert-butanesulfinyl
amino esters with high yields and excellent diastereose-
lectivities. The amino or carboxyl group of the addition
product can be selectively deprotected under very mild
conditions. Because N-tert-butanesulfinyl amino acids
can be considered as N-Boc-α-amino acids alternatives,
the present approach is potentially very important in pep-
tide synthesis. The protected sterically constrained (S)-
Dmt derivative was also readily prepared from inexpen-
sive and commercially available starting material through
simple steps with a high overall yield on a multigram
scale. Applying the unnatural chiral α-amino acids to re-
lated peptide SAR improvement is under investigation.
(12) For detailed comparisons of these reagents, see: Piller, F. M.;
Metzger, A.; Schade, M. A.; Haag, B. A.; Gavryushin, A.;
Knochel, P. Chem.–Eur. J. 2009, 15, 7192.
(13) Addition of these reagents to sulfinyl imine was reported
very recently, see: Buesking, A. W.; Baguley, T. D.; Ellman,
J. A. Org. Lett. 2011, 13, 964.
Acknowledgment
We gratefully acknowledge financial support from NSFC (nos.
21002043, 20932003, and 90813012), and the Key National S & T
Program ‘Major New Drug Development’ of the Ministry of Sci-
ence and Technology (2012ZX09504001-003).
(14) Synthesis of α-trifluoromethyl α-amino acids via the
addition of type I Knochel reagent to (R)-phenylglycinol
methyl ether based imines of trifluoropyruvate has been
reported very recently, see: Yang, J.; Min, Q.-Q.; He, Y.;
Zhang, X. Tetrahedron Lett. 2011, 52, 4675.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
(15) For selected reviews, see: (a) Bryant, S. D.; Jinsmaa, Y.;
Salvadori, S.; Okada, Y.; Lazarus, L. H. Peptide Sci. 2003,
71, 86. (b) Hoye, A. T.; Davoren, J. E.; Wipf, P.; Fink, M. P.;
Kagan, V. E. Acc. Chem. Res. 2008, 41, 87.
(16) For selected examples, see: (a) Harrison, B. A.; Pasternak,
G. W.; Verdine, G. L. J. Med. Chem. 2003, 46, 677.
(b) Berezowska, I.; Chung, N. N.; Lemieux, C.; Wilkes, B.
C.; Schiller, P. W. J. Med. Chem. 2009, 52, 6941.
(c) Yamamoto, T.; Nair, P.; Largent-Milnes, T. M.;
Jacobsen, N. E.; Davis, P.; Ma, S.-W.; Yamamura, H. I.;
References
(1) Liu, W. X.; Wang, R. Med. Res. Rev. 2012, 32, 536.
(2) (a) Nájera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
(b) See the preface in: Soloshonok, V. A.; Izawa, K.
Asymmetric Synthesis and Application of α-Amino Acids;
Vol. 1009; American Chemical Society: Washington DC,
2009.
Synlett 2012, 23, 2559–2563
© Georg Thieme Verlag Stuttgart · New York

LETTER
Vanderah, T. W.; Porreca, F.; Lai, J.; Hruby, V. J. J. Med.
Chiral N-tert-Butanesulfinyl α-Amino Acid Synthesis
2563
2009, 20, 1398. (e) Praquin, C. F. B.; de Koning, P. D.;
Peach, P. J.; Howard, R. M.; Spencer, S. L. Org. Process
Res. Dev. 2011, 15, 1124.
Chem. 2011, 54, 2029.
(17) (a) Abrash, H. I.; Niemann, C. Biochemistry 1963, 2, 947.
(b) Dygos, J. H.; Yonan, E. E.; Scaros, M. G.; Goodmonson,
O. J.; Getman, D. P.; Periana, R. A.; Beck, G. R. Synthesis
1992, 741. (c) Tang, X.; Soloshonok, V. A.; Hruby, V. J.
Tetrahedron: Asymmetry 2000, 11, 2917. (d) Balducci, D.;
Contaldi, S.; Lazzari, I.; Porzi, G. Tetrahedron: Asymmetry
(18) Brak, K.; Barrett, K. T.; Ellman, J. A. J. Org. Chem. 2009,
74, 3606.
(19) Patel, D. V.; VanMiddlesworth, F.; Donaubauer, J.; Gannett,
P.; Sih, C. J. J. Am. Chem. Soc. 1986, 108, 4603.
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