Stereoselective conjugate addition of organocuprates to a dehydroalanine derived diketopiperazine

Article abstract of DOI:10.1039/a807618i

An asymmetric synthesis of homochiral α-amino acids has been developed which is based on the conjugate addition of organocuprates to the dehydroalanine equivalent (3S)-N,N′-bis(p-methoxybenzyl)-3-isopropyl-6-methylenepiperazine-2,5-dione 6.

Full text of DOI:10.1039/a807618i

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Stereoselective conjugate addition of organocuprates to a
dehydroalanine derived diketopiperazine
Steven D. Bull, Stephen G. Davies* and Michael D. O’Shea
The Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford, UK OX1 3QY
Received (in Cambridge) 30th September 1998, Accepted 15th October 1998
An asymmetric synthesis of homochiral á-amino acids has
been developed which is based on the conjugate addition
of organocuprates to the dehydroalanine equivalent (3S)-
N,NЈ-bis(p-methoxybenzyl)-3-isopropyl-6-methylenepiper-
azine-2,5-dione 6.
be prepared using methodology that relies on the 1,4-conjugate
addition of organocuprates to the dehydroalanine equivalent
6.4
DKP 1 in THF at Ϫ78 ЊC was deprotonated with n-BuLi,
quenched with paraformaldehyde and the crude reaction mix-
ture refluxed for 1 hour to afford the Michael acceptor (3S)-
N,NЈ-bis(p-methoxybenzyl)-3-isopropyl-6-methylenepiper-
azine-2,5-dione 6 in 92% yield. Addition of preformed lithium
diphenylcyanocuprate to DKP 6 in THF at Ϫ78 ЊC, followed
by quenching with aqueous ammonium chloride, afforded
cis-(3S,6S)-benzylated DKP 7 ([α]D23 = Ϫ235.5, c 1.0, CHCl3)
in greater than 95% de (Scheme 2).5 The versatility of this
A large number of different methods have been developed for
the asymmetric synthesis of non-proteinogenic α-amino acids.1
We have recently reported on a new diketopiperazine (DKP)
based auxiliary, (3S)-N,NЈ-bis(p-methoxybenzyl)-3-isopropyl-
piperazine-2,5-dione 1, the enolate of which adopts a conform-
ation which ensures that alkylation with a range of electrophiles
affords trans-(3S,6R)-DKPs in excellent de. The high des are
the result of a chiral relay effect deriving from the conformation
of the two N-p-methoxybenzyl protecting groups as illustrated
in all the Schemes. Subsequent deprotection of the resultant
DKPs 2 affords the desired (R)-α-amino acids 4 in good yield.2
(S)-α-Amino acids 5 may also be prepared from DKP 1 using
an epimerisation strategy where diastereoselective reproton-
ation of the enolates derived from DKPs 2 with 2,6-di-tert-
butylphenol affords cis-(3S,6R)-DKPs 3 in excellent de
(Scheme 1).3 We now report that cis-(3S,6S)-DKPs 3 may also
OMe
OMe
N
N
O
N
N
O
(i)
O
O
OMe
OMe
OMe
1
6
N
N
O
(ii)
O
OMe
OMe
1
N
N
O
O
(i)
R
MeO
OMe
OMe
7-13
Scheme 2 Reagents and conditions: (i) 1.1 equiv. n-BuLi, THF, Ϫ78 ЊC;
2 equiv. (CH2O)n; ∆; (ii) organocuprate, THF, Ϫ78 ЊC; NH4Cl(aq)
.
N
N
O
N
N
O
3
(ii)
3
6
conjugate addition methodology was further demonstrated by
the addition of a range of organocuprates to DKP 6 to
afford cis-(3S,6S)-DKPs 8–13 in >95% de, all of which
were purified to homogeneity via column chromatography
(Table 1).
6
O
R1
O
R1
OMe
OMe
2
3
DKP 8 was N-deprotected by oxidative removal of the
p-methoxybenzyl groups with ceric ammonium nitrate in
CH3CN–H2O (3:1) and purified by chromatography over
alumina, to afford DKP 14. This DKP 14 was hydrolysed by
refluxing in 6 M HCl, and the resultant mixture of α-amino
acids converted to their methyl esters 15 and 16 by treatment
with HCl and MeOH. The volatile free amine of valine
methyl ester was removed by fractional distillation under high
vacuum,6 followed by hydrolysis of methyl ester 16 to afford
(iii), (iv)
(iii), (iv)
R1
NH2
NH2
R1
+
NH2
CO2H
NH2
+
CO2H
CO2H
CO2H
5
4
homochiral (S)-γ-methylleucine 17 ([α]D23 = ϩ15.7,
c 1.0,
Scheme 1 Reagents and conditions: (i) 1.1 equiv. LHMDS, THF,
Ϫ78 ЊC;
equiv. R1X; (ii) n-BuLi, THF, Ϫ78 ЊC; 2,6-di-tert-
butylphenol; (iii) CAN, CH3CN–H2O; (iv) 6 M HCl; Dowex 50-XH.
CH3CO2H [lit.,7 [α]D23 = ϩ14.9 CH3CO2H]) in 80% yield from
DKP 8. The enantiomeric excess of 17 was confirmed to be
2
J. Chem. Soc., Perkin Trans. 1, 1998, 3657–3658
3657

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Table 1 Yields and des observed for formation of DKPs 7–13 via
addition of organocuprates to DKP 6
de) was purified by recrystallisation from ether–petrol (1:1) to
afford DKP 8 (632 mg, 1.36 mmol) in 90% yield. [α]D23 = Ϫ198.6
(c 1.0, CHCl3); mp = 112–114 ЊC; 1H NMR (500 MHz, CDCl3)
1.02 (9H, s), 1.12 (3H, d, J 6.7), 1.17 (3H, d, J 6.7), 1.58 (1H,
dd, J 14.4, 2.2), 1.99 (1H, dd, J 14.4, 8.0), 2.16 (1H, m), 3.59
(1H, d, J 6.9), 3.66 (1H, d, J 15.0), 3.73 (1H, d, J 14.6), 3.80
(6H, s), 3.83 (1H, dd, J 8.0, 2.2), 5.32 (1H, d, J 15.0), 5.42 (1H,
d, J 14.6), 6.78–6.84 (4H, m), 6.98–7.02 (2H, m), 7.04–7.09 (2H,
m); 13C NMR (50 MHz, CDCl3) 20.0, 20.6, 29.7, 30.8, 33.8,
45.9, 49.6, 50.0, 65.8, 114.4, 128.0, 128.3, 129.1, 129.3, 159.4,
159.5, 167.1, 168.9.
Isolated yield of
homochiral
DKP (%)
Cuprate
conditions
[α]D23 (c 1.0,
CHCl3)
R
7
8
9
Ph
tBu
Cy
2 PhLi, 2 CuCN
88
90
92
91
91
Ϫ235.5
2 tBuMgCl, 2 CuCN
2 CyMgBr, 2 CuCN
2 nBuLi, 2 CuCN
2 MeLi, 2 CuCN
Ϫ198.6
Ϫ159.4
Ϫ186.7
Ϫ178.2
Ϫ137.8
Ϫ225.3
10 nBu
11 Me
12 Vinyl 2 VinylMgBr, 2 CuCN 87
13 iPr
2 iPrMgBr, 2 CuCN
88
(3S,6S)-3-Isopropyl-6-(2Ј,2Ј-dimethylpropyl)piperazine-2,5-
dione 14
To a solution of DKP 8 (500 mg, 1.22 mmol) in water (3 mL)
and acetonitrile (9 mL) was added ceric ammonium nitrate (4.0
g, 7.32 mmol {6 equiv.}) in one portion. The resultant suspen-
sion was stirred at room temperature for one hour, neutral
alumina added (ca. 1 g), the solvent removed in vacuo, and the
crude residue applied to a column of neutral alumina (gradient
elution with EtOAc–EtOH 1:1→1:4) to afford DKP 14 (255
mg, 1.13 mmol) in 92% yield. [α]D23 = Ϫ53.0 (c 0.94, AcOH);
mp = 205 ЊC (subl.); 1H NMR (500 MHz, DMSO-d6) 0.82 (3H,
d, J 8.1), 0.88 (9H, s), 0.92 (3H, d, J 8.1), 1.37 (1H, dd, J 14.1,
7.5), 1.84 (1H, dd, J 14.1, 3.4), 2.04 (1H, m), 3.52 (1H, dd,
J 4.53, 3.0), 3.72 (1H, ddd, J 6.7, 3.0, 3.0), 7.92 (1H, s), 8.08
(1H, s); 13C NMR (50 MHz, CDCl3) 17.7, 18.8, 29.4, 30.4, 31.2,
48.0, 52.0, 59.8, 167.8, 169.8.
OMe
H
N
O
N
N
O
(i)
O
N
H
O
OMe
8
14
(ii),(iii)
NH2
(S)-ã-Methylleucine 17
A solution of DKP 14 (219 mg, 0.97 mmol) was refluxed in 6 M
HCl (20 mL) overnight, the solvent removed in vacuo and the
residue heated in methanol–HCl (sat.) for a further hour. The
solvents were removed to afford a residue which was neutralised
with NaHCO3 (aq.), extracted with CH2Cl2, dried (MgSO4), and
the solvents again removed in vacuo to afford a mixture of crude
α-amino acid methyl esters 15 and 16. The more volatile valine
methyl ester 15 was removed via distillation at room temper-
ature (0.1 mmHg), and the residual 16 hydrolysed in 2 M HCl
under reflux, to afford (S)-γ-methylleucine 17 as its HCl salt.
Subsequent desalting using Dowex 50X8-200TM ion exchange
resin afforded (S)-γ-methylleucine 17 (129 mg, 0.912 mmol) in
94% yield. [α]D23 = ϩ15.7 (c 1.0, CH3CO2H), [lit.,7 [α]D23 = ϩ14.9
CO2Me
15
+
(iv)
NH2
CO2H
NH2
CO2Me
17
16
Scheme 3 Reagents and conditions: (i) CAN, CH3CN–H2O (3:1);
(ii) 6 M HCl, ∆; (iii) (a) 2 M HCl, MeOH, (b) K2CO3(aq.), (c) separate
by distillation; (iv) 2 M HCl, ∆; Dowex 50X8-200.
>99% ee by chiral HPLC analysis of its N-benzyloxycarbonyl
derivative over a CYCLOBOND ITM stationary phase using
CH3CN:TEAA (88:12) as eluant.
In conclusion, addition of organocuprates to Michael
acceptor DKP 6 provides simple access to cis-(3S,6S)-DKPs
5 which are readily deprotected to afford homochiral (S)-α-
amino acids in good yield.
1
(c 1.0, CH3CO2H)]; H NMR (200 MHz, D2O) 0.75 (9H, s),
1.39 (1H, dd, J 14.9, 7.4), 1.70 (1H, dd, J 14.9, 4.8), 3.48 (1H,
dd, J 7.1, 4.8).
Acknowledgements
We would like to thank the EPSRC (MO’S) and Oxford
Asymmetry International Plc (SDB) for their financial support.
Experimental
Selected data for DKP 6
Mp = 88–90 ЊC, [α]D23 = Ϫ129.4 (c 2.3, CHCl3), H NMR (500
Notes and references
1 R. M. Williams, Synthesis of Optically Active α-Amino Acids,
Pergamon Press, Oxford, 1989; R. O. Duthaler, Tetrahedron, 1994,
50, 1540.
2 S. D. Bull, S. G. Davies, S. W. Epstein and, J. V. A. Ouzman, Chem.
Commun., 1998, 659.
3 S. D. Bull, S. G. Davies, S. W. Epstein and J. V. A. Ouzman, Tetra-
hedron: Asymmetry, 1998, 9, 2795.
4 Similar approaches have been adopted by Seebach et al. who
employed a racemic methylene imidazolidinone auxiliary in a
diastereoselective butylcuprate addition (D. Seebach, H. M. Bürger
and C. P. Schickli, Liebigs. Ann. Chem., 1991, 669) and by Hegedus
et al. who used optically active carbamatoacrylates (P. A. Lander and
L. S. Hegedus, J. Am. Chem. Soc., 1994, 116, 8126).
5 The stereochemistry of cis-(3S,6S)-benzylated DKP 7 was assigned
by comparison with an authentic sample prepared de novo from
(S)-phenylalanine and (S)-valine as described in reference 3.
6 C. Deng, U. Groth and U. Schöllkopf, Angew. Chem., Int. Ed. Engl.,
1981, 21, 798; U. Schöllkopf, Pure Appl. Chem., 1983, 55, 1799;
U. Schöllkopf, U. Busse, R. Lonsky and R. Hinrichs, Liebigs. Ann.
Chem., 1986, 2150.
1
MHz, CDCl3) 0.90 (3H, d, J 6.8), 1.04 (3H, d, J 6.8), 2.24 (1H,
m), 3.78 (3H, s), 3.80 (3H, s), 3.89 (1H, d, J 7.5), 3.93 (1H, d,
J 14.7), 4.58 (1H, d, J 14.8), 5.02 (1H, d, J 1.1), 5.13 (1H, d,
J 14.7), 5.40 (1H, d, J 14.8), 5.81 (1H, d, J 1.1), 6.80–6.89 (4H,
m), 7.15–7.20 (4H, m); 13C NMR (50 MHz, CDCl3), 17.4, 19.4,
32.7, 46.9, 48.0, 55.3, 64.5, 104.4, 114.3, 114.4, 128.7, 129.9,
137.7, 159.3, 159.9, 164.7.
(3S,6S)-N,NЈ-Bis(p-methoxybenzyl)-3-isopropyl-6-(2Ј,2Ј-
dimethylpropyl)piperazine-2,5-dione 8
tBuMgCl (1.6 mL, 2 M solution in Et2O) in THF (1.6 mL) was
added to a rapidly stirred suspension of anhydrous copper
cyanide (138 mg, 1.52 mmol) in THF (5 mL) at Ϫ78 ЊC, and the
reaction warmed to Ϫ30 ЊC to afford a homogeneous solution.
The solution was recooled to Ϫ78 ЊC, BF3ؒOEt2 (0.204 mL,
1.92 mmol) added and the reaction stirred for 10 minutes at
Ϫ78 ЊC. DKP 6 (600 mg, 1.47 mmol) was then added, the reac-
tion mixture stirred at Ϫ78 ЊC for 2 hours, quenched with
NH4Cl solution, extracted with ether, dried (MgSO4), and the
solvent removed in vacuum. The crude reaction mixture (>95%
7 J. Pospicek and K. Blaha, Collect. Czech. Chem. Commun., 1987, 514.
Communication 8/07618I
3658
J. Chem. Soc., Perkin Trans. 1, 1998, 3657–3658