Enantioselective synthesis of (L)-Fmoc-α-Me-Lys(Boc)-OH via diastereoselective alkylation of oxazinone as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetlet.2009.09.148

Benzyl (2R,3S)-(-)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (4) was successively alkylated with methyl iodide and 1,4-diiodobutane using a base. In each alkylation step anti-alkylated product formed exclusively. The iodo group was displaced with azide,

Full text of DOI:10.1016/j.tetlet.2009.09.148

Tetrahedron Letters 50 (2009) 6913–6915
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Tetrahedron Letters
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Enantioselective synthesis of (L)-Fmoc-a-Me-Lys(Boc)-OH via
diastereoselective alkylation of oxazinone as a chiral auxiliary
*
Satendra S. Chauhan
Bachem Bioscience Inc., 3700 Horizon Drive, King of Prussia, PA 19406, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzyl (2R,3S)-(ꢀ)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (4) was successively alkylated with
methyl iodide and 1,4-diiodobutane using a base. In each alkylation step anti-alkylated product formed
exclusively. The iodo group was displaced with azide, which served as a precursor for the side-chain
amino function. Catalytic hydrogenation with concomitant cleavage of the chiral auxiliary afforded (L)-
Received 24 August 2009
Accepted 24 September 2009
Available online 1 October 2009
a
-Me-Lys-OH (9) in a total of four steps in good yield. (L)-Fmoc-
from 9 via regioselective benzyloxycarbonylation. Alternately, (L)-Fmoc-
obtained via Staudinger reduction of azide (8) in a total of six steps in good yield.
Ó 2009 Elsevier Ltd. All rights reserved.
a
-Me-Lys(Boc)-OH (16) was obtained
Keywords:
Amino acids
Asymmetric synthesis
Diastereoselective alkylation
Chiral auxiliary
a-Me-Lys(Boc)-OH (16) was
Regioselective protection
1. Introduction
cently, Cativiela et al. have used (1S,2R,4R)-10-(dicyclohexylsulfa-
moyl)isoborneol as
chiral auxiliary14 to synthesize (S)-
methyllysine via chiral cyanopropanoate (3; Fig. 1) in 10 steps.15
In this publication, we report a short and efficient synthesis of
(S)- -methyllysine using William’s oxazinone as a chiral auxiliary
a
a-
Optically pure modified amino acids are valuable building
blocks for the preparation of biologically active peptidomimetics
since they can be utilized to confer stability to peptides against
a
enzymatic degradation.1 In addition, C -alkylated amino acids are
(4).16 Reasons for choosing this chiral auxiliary were: (1) commer-
cial availability, (2) excellent optical purity of the final product, (3)
high reactivity towards unactivated electrophiles, and (4) scalabil-
ity. Furthermore, the side-chain amino function could be orthogo-
nally protected before cleavage of the chiral auxiliary eliminating
the need for regioselective protection of the amino functions in
a
not prone to racemization under basic or acidic conditions due to
lack of abstractable or enolizable
a
a
-hydrogen.2 Furthermore, C -
a
alkylation severely restricts rotation around the N–C (u) and
a
C –C(O) (
bilizes preferred conformations of the peptide backbone.3
The quaternization of the -carbon of -amino acids is rather
challenging due to steric constraints. However, several routes to
optically pure -alkylated
-amino acids have been developed.4–8
w) bonds of the amino acid in a peptide sequence and sta-
a
a
a-methyllysine.
a
a
2. Results and discussion
Most notably, the stereogenic centre is constructed by alkylation
of a chiral, nonracemic enolates.9,10 In these reactions, alkylation
occurs from the least-shielded face of the enolate. Furthermore,
in successive dialkylation reactions, the second alkyl group comes
in from the opposite side of the sterically demanding group(s)
present on the chiral auxiliary.6,8
As shown in Scheme 1, benzyl (2R,3S)-(ꢀ)-6-oxo-2,3-diphenyl-
4-morpholinecarboxylate (4) was alkylated twice; first with
methyl iodide and second with 1,4-diiodobutane. Alkylation reac-
tions were optimized in order to achieve highest yields at each
step. The first alkylation of 4 with methyl iodide was attempted
using sodium bis(trimethylsilyl amide) in THF at ꢀ78 °C as re-
ported.16 However, the yield was low and the product required
purification by silica gel column chromatography. The optimum
conditions for alkylation with methyl iodide were comprised of
dissolving 4 and methyl iodide (5 equiv) in THF/HMPA (10:1), gen-
erating enolate at ꢀ78 °C with lithium bis(trimethylsilyl amide)
(1.5 equiv), and allowing the reaction to warm to ambient temper-
ature over the period of 2 h after 1 h at ꢀ78 °C. Aqueous work-up
and evaporation yielded a yellow solid in quantitative yield, which
The first synthesis of D/L-a-methyllysine was reported in 1978
from alanine derivative (1).11 It has been used to study L-lysine up-
take in Escherichia coli and Bacillus sphaericus.12 Later on, the (S)-
isomer of
a-methyllysine was obtained by Gander-Coquoz and
Seebach from (S)-lysine derivatives (2) by exploiting the principle
of self-regeneration of stereocenters (SRS) in rather low yield.13 Re-
* Tel.: +1 610 239 0300; fax: +1 610 239 0800.
E-mail address: schauhan@usbachem.com
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.148

6914
S. S. Chauhan / Tetrahedron Letters 50 (2009) 6913–6915
NH-Boc
H
O
CN
O
OMe
O
N
O
S
O
N
O
N
O
1
O
2
3
Figure 1.
KN(TMS)2
I-(CH2)4-I
LiN(TMS)2
CH3I
O
2
2
5
O
O
3
3
O
N
O
O
N
O
N
O
O
O
O
O
6
5
4
I
NaN3/
DMEU
NH2
O-M+
O
PdCl2
H2
N
O
O
O
R
O
N
I
O
OH
H2N
O
R'
7
O
8
9
R = H or CH3
R' = H or CH2CH2CH2-I
N3
Scheme 1.
contained ꢁ3% of the dialkylated product. The mono-alkylated
product 5 was obtained in 70% yield as a light yellow solid after
recrystallization from 10% EtOAc/hexane.9
It is important to note that in both alkylation reactions only
trans-alkylated product 5 or 6 was formed and no cis-diastereoiso-
mer (i.e., 2R,3S,5R) was detected by HPLC. The high diastereoselec-
tivity of enolate alkylation can be explained by considering the
expected twist-boat conformation that disposes the phenyl ring
at C-3 of enolate 7 in a pseudoaxial orientation, creating steric
shielding of the same face at C-5 position from electrophilic attack
as shown in Scheme 1.
The iodo group of dialkylated product 6 underwent nucleophilic
substitution with sodium azide smoothly and the azide 8 was ob-
tained in 91% yield as a white solid.17 The chiral auxiliary was
cleaved by hydrogenolysis using palladium chloride and hydrogen
gas at 60 psi. The azide group was also reduced under these condi-
Next, we optimized the alkylation of (5S)-5-methyloxazinone
(5) with 1,4-diiodobutane. The best conditions utilized dissolving
5 and 1,4-diiodobutane (10 equiv) in THF/HMPA (10:1) at ambient
temperature, adding potassium bis(trimethylsilyl amide) (7 equiv)
dropwise at ꢀ78 °C, and a reaction time of 4 h at the same temper-
ature. The alkylated product 6 was obtained in quantitative yield as
a dark brown solid (flakes) after aqueous work-up. It was recrystal-
lized from 2% methanol/diisopropyl ether to afford off-white solid
in 70% yield. It should be mentioned that the use of THF solvent
alone with potassium bis(trimethylsilyl amide) as a base resulted
in poor yield.16 Use of lithium bis(trimethylsilyl amide) resulted
in only byproducts.
tions and (L)-a-Me-Lysine (9) was obtained in 84% yield as a dihy-
drochloride salt.9
NH-Boc
O
Boc-HN
H2N
O
O
8-OH-Quinoline
1) CuCO3.Cu(OH)2
2) NaHCO3/(Boc)2O
Cu
NH2
9
OH
H2N
NH-Boc
O
O
10
Scheme 2.
11

S. S. Chauhan / Tetrahedron Letters 50 (2009) 6913–6915
NH-Cbz NH-Cbz
Fmoc-OSu
Na2CO3
6915
NH-R
Cbz-OSu
NaOH
1) H2; 10% Pd/C
9
OH
OH
2) (Boc)2O/
DIPEA
OH
R-HN
Fmoc-HN
Fmoc-HN
O
O
O
14
15; R = H
16; R = Boc
12; R = H
13; R = Cbz
Scheme 3.
further purification was converted into Fmoc-derivative with Fmoc-
OSu and sodium carbonate as above. Purification of the crude product
as above afforded (L)-Fmoc-a-Me-Lys(Boc)-OH (16) in 59% isolated
yield from azide 8 (three steps). Fmoc-a-Me-Lys(Boc)-OH from both
1) Me3P
1) H2/PdCl2
O
O
strategies showed identical chromatographic23 and spectroscopic
characteristics.24
8
16
O
N
2) Boc-ON
2) Fmoc-OSu
Na2CO3
In conclusion, (L)-a-Me-Lys-OH (9) was obtained from oxazinone
O
(4) as a chiral auxiliary in a total of four steps in 37.4% overall yield.
Regioselective protection of 9 afforded Fmoc-
a
-Me-Lys(Boc)-OH
-Me-Lys(Boc)-OH
17
Scheme 4.
(16) in additional four steps. Besides, Fmoc-
a
NH-Boc
(16)wasobtainedviaStaudingerreductionof theintermediateazide
(8) in a total of six steps in overall good yield (26.3%). Both strategies
afforded the target compound in excellent optical purity (>95%). The
synthesis is short and efficient as the reactions could be monitored
by HPLC and the intermediates could be purified simply by recrystal-
lization without the need for column chromatography.
Having obtained (L)-
tion of the
Scheme 2. Thus, 9 was treated with basic copper carbonate fol-
lowed by treatment with (Boc)2O. The -Boc-protected product
10 was obtained in only 25% yield.18 Cleavage of the copper com-
a
-Me-Lysine (9), we tried selective protec-
e
-amino function via copper complex as shown in
e
References and notes
plex by chelation with 8-hydroxyquinoline afforded (L)-
a-Me-
Lys(Boc)-OH (11) in overall 10% yield.19
1. Ma, J. S. Chim. OGGI 2003, 21, 65–68.
2. Goodman, M.; Ro, S., 5th ed.. In Burger’s Medicinal Chemistry and Drug Discovery;
Wolff, M. E., Ed.; John Wiley & Sons, 1995; Vol. 1, pp 803–861. Chapter 20.
3. Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers (Pept. Sci.) 2001,
60, 396–419.
4. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. 1996, 35, 2708–
2748.
5. Wirth, T. Angew. Chem., Int. Ed. 1997, 36, 225–227.
6. Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517–
3599.
7. Duthaler, R. O. Tetrahedron 1994, 50, 1539–1650.
8. Singh, S. Recent Res. Dev. Org. Chem. 2004, 8, 323–340.
9. Singh, S.; Pennington, M. W. Tetrahedron Lett. 2003, 44, 2683–2685.
10. Singh, S.; Rao, S. J.; Pennington, M. W. J. Org. Chem. 2004, 69, 4551–4554.
11. Bey, P.; Danzan, C.; Dorsselaer, V. V.; Mamona, P.; Jung, M.; Tardif, C. J. Med.
Chem. 1978, 21, 50–55.
Since the yield form copper complex was poor perhaps due to ste-
ric hindrance by -methyl group, we decided to try regioselective
benzyloxycarbonylation of the -amino group of 9. The higher pKa
of the -NH2 (10.5) compared to -NH2 (9.0) renders it more nucle-
ophilic and is known to react selectively, albeit in moderate yield.20
As shown in Scheme 3, (L)- -Me-Lys-OH (9) was treated with
1 N aq NaOH (2 equiv) and Cbz-OSu (1.1 equiv) in acetone at 0 °C
overnight. As expected (L)-H- -Me-Lys(Cbz)-OH (12) was obtained
in 72% yield. Di-Cbz protected product, Cbz- -Me-Lys(Cbz)-OH
a
e
e
a
a
a
a
(13) was also obtained in ꢁ11% yield, but it was easily removed
by washing the acidic aqueous mixture with ethyl acetate. Com-
pound 12 was then treated with Fmoc-OSu and sodium carbonate
in water/dioxane mixture at ambient temperature overnight.21 (L)-
12. Regenstreif, C. A.; Kelland, J. G.; Pansare, S. V.; Vedaras, J. C.; Pickard, M. A. Can.
J. Microbiol. 1986, 32, 522–524.
13. Gander-Coquoz, M.; Seebach, D. Helv. Chim. Acta 1988, 71, 224–236.
14. Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. J. Org. Chem. 1994, 59, 2497–
2505.
Fmoc-
white solid after work-up. It was then hydrogenolyzed over 10%
Pd/C catalyst to afford (L)-Fmoc- -Me-Lys-OH (15) in 73% yield,
a-Me-Lys(Cbz)-OH (14) was obtained in 60% yield as an off-
15. Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A.; Ronco, E. Chirality 2004, 16,
106–111.
a
which was subsequently treated with (Boc)2O and diisopropylethyl
amine in water/dioxane mixture. After work-up and silica gel col-
umn chromatography (dichloromethane/methanol), (L)-Fmoc-a-
Me-Lys(Boc)-OH (16) was obtained in 64% yield (90% pure) as a
white solid. Compound 16 could also be purified by C18 reversed-
phase HPLC using 0.1% TFA containing water/acetonitrile buffers.
Using regioselective benzyloxycarbonylation approach (Scheme
16. Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113, 9276–9286.
17. Oppolzer, W.; Moretti, R.; Zhou, C. Helv. Chim. Acta 1994, 77, 2363–2380.
18. Scott, J. W.; Parker, D.; Parrish, D. R. Synth. Commun. 1981, 11, 303–314.
19. Wiejak, S.; Masiukiewicz, E.; Rzeszotarska, B. Chem. Pharm. Bull. 1999, 47,
1489–1490.
20. Bodanszky, M.; Bodanszky, A. In The Practice of Peptide Synthesis, 2nd ed.;
Springer Verlag Berlin Heidelberg: Germany, 1994; pp 51–52.
21. Atherton, E.; Sheppard, R. C. In Solid Phase Peptide Synthesis; IRL Press: Oxford,
England, 1989; p 61.
3), we obtained Fmoc-a-Me-Lys(Boc)-OH (16) in 20% overall yield
22. Ariza, X.; Urpi, F.; Viladomat, C.; Vilarrasa, J. Tetrahedron Lett. 1998, 39, 9109–
9112.
23. Analytical HPLC was performed on a C18
starting form H- -Me-Lys-OH (8). Our goal was then to improve the
a
, reversed-phase column (Vydac,
yield and reduce the number of steps. Therefore, we adopted an alter-
native strategy using Staudinger reduction as shown in Scheme 4.
Compound 8 was reduced with trimethylphosphine in toluene at
0 °C. The intermediate phosphazene was not isolated but rather re-
acted with Boc-ON in situ.22 Compound 17 was isolated in 92% yield
after flash silica gel column chromatography (hexane/diethyl ether).
The chiral auxiliary was hydrogenolyzed as above with palladium
chloride in methanol containing 10% acetic acid/water (1:1) under
150 ꢂ 4.6 mM, 5
l
). A linear gradient from 5% to 95% buffer B in 45 min was
used. Buffer A consisted of 0.1% TFA in water and buffer B was 0.1% TFA in
acetonitrile. Flow rate was 1.5 mL/min. Compound 16 eluted at 24.4 min under
these conditions.
24. Maldi-Tof-MS (CCA matrix): 505 (C27H34N2O6) (M+Na)+ (35%), 382
(C22H26N2O4) (MꢀBoc)+ (100%). 1H NMR (600 MHz, CD3OD): d 7.80 (2H, d,
J = 7.2 Hz), 7.66 (2H, d, J = 7.2 Hz), 7.39 (2H, t, J = 7.2 Hz), 7.31 (2H, t, J = 7.2 Hz),
4.32 (2H, br, s), 4.21 (1H, t, J = 6.6 Hz), 3.02 (2H, br, m), 1.87 (2H, br, m), 1.47
(3H, s), 1.45 (2H, m), 1.41 (9H, m), 1.40 (2H, m). ½a D24
ꢃ
+1.18 (c 0.25, MeOH).
Anal. (purified by HPLC using C18 reversed-phase column and 0.1% TFA
containing water/acetonitrile buffers) Calcd for C27H34N2O6ꢄ2/3CF3CO2H: C,
60.92; H, 6.21; N, 5.01. Found: C, 60.78, H, 6.14; N, 5.08.
hydrogen atmosphere at 80 psi pressure. (L)-H-a-Me-Lys(Boc)-OH
(11) was obtained as a gray solid in quantitative yield, which without