Asymmetric Synthesis of Arylalanines via Asymmetric aza-Darzens (ADZ) Reaction

Article abstract of DOI:10.1055/s-2003-41470

(R)-3-Arylalanines may be prepared in high enantiomeric purity from N-dpp imines by a four-step reaction sequence involving asymmetric aza-Darzens reaction, dephosphinylation, hydrogenolysis and hydrolysis. The amino acids thus obtained were of >95% enantiomeric purity.

Full text of DOI:10.1055/s-2003-41470

1898
LETTER
Asymmetric Synthesis of Arylalanines via Asymmetric aza-Darzens (ADZ)
Reaction
A
symmetric Synth
a
esis of
A
ry
o
lalanines via
m
A
symmetric aza-D
i
(
AD
Z
)
E
Reaction . Maguire, Andrew B. McLaren, J. B. Sweeney*
Department of Chemistry, University of Reading, Reading RG6 6AD, UK
Fax +44(118)93786331; E-mail: j.b.sweeney@reading.ac.uk
Received 30 June 2003
The general proposal is shown in Scheme 1: thus, we an-
Abstract: (R)-3-Arylalanines may be prepared in high enantio-
meric purity from N-dpp imines by a four-step reaction sequence in-
volving asymmetric aza-Darzens reaction, dephosphinylation,
hydrogenolysis and hydrolysis. The amino acids thus obtained were
of >95% enantiomeric purity.
ticipated that asymmetric aza-Darzens reaction (ADZ) of
bromoacyl sultam with a range of N-dpp benzaldimines2
would furnish aziridines 1 which would undergo reduc-
tive cleavage in the presence of transition metal catalysts
and hydrogen to give the corresponding arylalanine deriv-
atives 2, which could be hydrolyzed to give the free amino
acids 3. In particular, although it is well known that N-to-
syl aziridines may be hydrogenolyzed in exactly this man-
ner,3 prior to our studies, there were no reports that similar
dpp-aziridines would undergo an analogous reaction.
Key words: aziridine, dpp, hydrogenolysis, (R)-amino acid
Although the focus of intense activity and experimenta-
tion,1 there is still no single, generally-applicable synthet-
ic method to allow the preparation of a wide range of 2-
amino acids (and their derivatives) of high enantiomeric
purity from simple precursors. As part of a synthetic pro-
gramme directed towards the preparation of (2R)-config-
ured heterocyclic analogues of phenylalanines (such as
azatyrosines), we have recently investigated the hydro-
genolysis of N-diphenylphosphinyl (‘N-dpp’) aziridines
to prepare these compounds and we here report that this
methodology does allow efficient entry to a range of non-
proteinogenic phenylalanine analogues in good yield and
with high levels of enantiomeric purity.
We first sought to prepare a proteinogenic amino acid, to
establish the levels of stereocontrol in the proposed reac-
tion sequence. Thus, using our previously-reported asym-
metric aza-Darzens methodology, we prepared cis-
(2¢S,3¢S)-phenyl N-dpp-aziridine (1a)2 and exposed this
compound to a range of hydrogenolytic procedures: none
were successful, with the starting material being recov-
ered in >90% yield under a range of conditions. Given the
known utility of phosphinamides as ligands for asymmet-
ric catalysis,4 we concluded that catalyst poisoning must
be involved and we were encouraged to witness that the
hydrogenolysis of dephosphinylated aziridine 4a pro-
ceeded in virtually quantitative yield in the presence of
Pearlman’s catalyst, to give sultam 5a as a single diastere-
oisomer. Hydrolytic removal of the auxiliary5 gave (S)-
phenylalanine (3a) in excellent yield (60% from 2S-bro-
moacylcamphorsultam) and in >95% ee (as judged from
specific rotation values, Scheme 2).6
Scheme 1 Proposed arylalanine synthesis via aza-Darzens/hydro-
genolysis
Scheme 2 Phenylalanine via aza-Darzens/hydrogenolysis
Synlett 2003, No. 12, Print: 29 09 2003. Web: 19 09 2003.
Art Id.1437-2096,E;2003,0,12,1898,1900,ftx,en;G15203ST.pdf.
DOI: 10.1055/s-2003-41470
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Synthesis of Arylalanines via Asymmetric aza-Darzens (ADZ) Reaction
1899
Having demonstrated that the proposed synthetic route Finally, we have examined the hydrolytic removal of the
was viable, we next examined the scope of the hydro- chiral auxiliary in a representative cross-section of these
genolysis reaction in the preparation of the antipodal se- amino acid derivatives. Thus, reaction of N-(2¢-ami-
ries of amino acids. Thus, a range of cis- and trans- no)acylsultams with lithium hydroxide in THF–water
aziridinyl (2R)-sultams were hydrogenolyzed to give R- proceeded smoothly to give (after lyophilisation and ion-
configured arylalanine derivatives, 5, in good yield exchange chromatography) arylalanines 3a, 3c, 3f, 3k, in
(Table 1). The most general experimental condition in- excellent yield and with high levels of enantiomeric purity
volved reaction with H2 in alcoholic solvent in the pres- (>95% ee, Table 2).
ence of 5 mol% Pd(OH)2 at room temperature and
atmospheric pressure. Slower reactions (entries 6–9) re-
quired the use of elevated hydrogen pressure (5 atm) for
best yields.
Table 1 Preparation of Arylalanines from Aziridinyl Sultams7
In most of the reactions examined, the only significant
product was that of C-3 ring opening, resulting from
cleavage of the benzylic C-N bond. In the case of aziri-
dines bearing an ortho-substituted aryl group, the product
was contaminated with significant amounts of deaminated
products 6. We presume that these compounds arise via C-
2 ring-opening, followed by cleavage of the benzylic C-N
bond; in the case of the ortho-fluorophenyl substrate (en-
tries 3 and 4), the regioselectivity was improved by utiliz-
ing an EtOH–MeOH solvent system for the reaction
though this adaptation did not improve the regiocontrol of
other reactions.
Hydrogenolyses of bromo- and chlorophenyl aziridines 4l
and 4m gave mixtures of products arising from ring open-
ing and/or dehalogenation (Scheme 3). To ascertain the
likely course of the reactions in these cases, each reaction
was stopped after 6 hours and the products were isolated
and analyzed by 1H NMR. In the case of the chlorophenyl
aziridine, the major product was unreacted aziridine with
chlorophenylalanine derivative 5m and the corresponding
dehalogenated compound 5a present in smaller, roughly
equal amounts. The bromophenyl aziridine 4l proved
more reactive: the main product in this case was 5a, i.e.,
both ring opening and dehalogenation had occurred.
Entrya Aryl aziridine (4)
Yield 4 Hydro- Ratio 5:6
/%
genolysis
yield/%
1
cis-Ph (4b)
99
99
82
82
96
96
96
92
92
90
90
87
88
80
79
99
99
51
78
92
46
67
94
92
42
60
60
56
45
65
>99:<1
>99:<1
83:17
2b
3
cis-Ph (4b)
cis-2-F-C6H4 (4c)
cis-2-F-C6H4 (4c)
trans-2-F-C6H4 (4d)
4b
5c
97:3
85:15
6b,c cis-4-F-C6H4 (4e)
7c
cis-4-F-C6H4 (4e)
8b,c trans-2-F3C-C6H4 (4f)
>99:<1
>99:<1
71:29
9c
10b
11
trans-2-F3C-C6H4 (4f)
cis-4-Et-C6H4 (4g)
cis-4-Et-C6H4 (4g)
cis-2-Et-C6H4 (4h)
trans-2-Et-C6H4 (4i)
cis-3-pyridyl (4j)
76:24
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
12
13
14d
15d
cis-3-(2¢-MeO) pyridyl 4k)
a General procedure: aziridines were mixed with Pearlman’s catalyst
(5 mol%), TFA (1 drop) and H2O (1 drop) in EtOH and hydrogenated
at atmospheric pressure for 14 h.
b EtOAc/MeOH (1/1, v/v) used as solvent.
c Reaction carried out under 5 atm H2 for 72 h.
d MeOH used as solvent.
Scheme 3 Hydrogenolyses of haloaryl aziridines
Synlett 2003, No. 12, 1898–1900 ISSN 1234-567-89 © Thieme Stuttgart · New York

1900
N. E. Maguire et al.
LETTER
Magomedov, N.; Tedrow, J. S. Angew. Chem. Int. Ed. 2001,
40, 1884. (l) Juhl, K.; Gathergood, N.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2001, 40, 2995. (m) Kawabata, T.;
Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000,
39, 2155. (n) Kawabata, S.; Iwata, N.; Yoneyama, H. Chem.
Lett. 2000, 110. (o) Enders, D.; Shivlock, J. Chem. Soc. Rev.
2000, 29, 359. (p) Ishitani, H.; Komiyama, S.; Hasegawa,
Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762.
(q) Arend, M. Angew. Chem. Int. Ed. 1999, 38, 2873.
(r) Tunge, J. A.; Gately, D. A.; Norton, J. R. J. Am. Chem.
Soc. 1999, 121, 4520. (s) Davis, F. A.; McCoull, W. J. Org.
Chem. 1999, 64, 3396. (t) Horikawa, M.; Busch-Petersen,
J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843.
(u) Myers, A. G.; Gleason, J. L. J. Org. Chem. 1996, 61,
2613. (v) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett.
1994, 35, 7605. (w) Williams, R. M.; Hendrix, J. A. Chem.
Rev. 1992, 92, 889.
Table 2 Hydrolytic Cleavage of Camphorsultam Auxiliary
20
Entrya Ar
Yield (%) [a]D
Ee (%)
98d
1
2
3
4
5
Ph (ent-3a)
87 (60)b
87 (59)
92 (50)
94 (45)
76 (20)
–33.4c
Ph (3a)
+33.26
+24.98
+ 9.1
+53.2
98
4-F-C6H4 (3c)
2-F3C-C6H4 (3f)
3-(2¢-MeO)C5H4N (3k)
99
>95
>95
(2) (a) McLaren, A.; Sweeney, J. B. Org. Lett. 1999, 1, 1339.
(b) Cantrill, A. A.; Hall, L. D.; Jarvis, A. J.; Osborn, H. M.
I.; Raphy, J.; Sweeney, J. Chem. Commun. 1996, 2631.
(3) For reports of aziridine hydrogenolysis, see:
a General procedure: sultams were dissolved in a THF/H2O solution
(1:1, v/v, 5 mL), LiOH monohydrate (2 equiv) added and the solution
stirred at r.t. overnight.
(a) Chandrasekhar, S.; Ahmed, M. Tetrahedron Lett. 1999,
40, 9325. (b) Davis, F. A.; Liu, H.; Reddy, G. V.
Tetrahedron Lett. 1996, 37, 5473. (c) Hwang, G.; Chung, J.;
Lee, W. J. Org. Chem. 1996, 61, 6183. (d) Amrosi, H. D.;
Duzec, W.; Ramm, M.; Jahnisch, K. Tetrahedron Lett. 1994,
35, 7613.
b Overall yield from imine.
c 2¢S-phenylalanine utilized, giving 2S-phenylalanine.
d Assessed from specific rotation values and chiral HPLC.
(4) See, for instance: (a) Cividino, P.; Masson, J.; Molvinger,
K.; Court, J. Tetrahedron: Asymmetry 2000, 11, 3049.
(b) Gamble, M. P.; Smith, A. R. C.; Wills, M. J. Org. Chem.
1998, 63, 6068.
(5) For a review of the methods available for hydrolysis of
acylcamphorsultams, see: Spivey, A. C. Encyclopedia of
Reagents for Organic Synthesis, Vol. 2; Paquette, L. A., Ed.;
Wiley: New York, 1995, 975–981.
Thus, we have demonstrated that an aza-Darzens–hydro-
genolysis–hydrolysis procedure can provide a useful en-
try into a range of phenylalanine analogues, with high
levels of enantiocontrol. We are currently engaged in
determining the scope of this process and extrapolating
our preliminary data to allow the preparation of a range of
biologically significant amino acids.
(6) The Dictionary of Organic Compounds, Vol. 5; Chapman
and Hall: London, 1996, 3126.
(7) Representative Experimental Procedure: To cis-
2S,2¢S,3¢S-N-[(3-(phenyl)-2-aziridinyl)carbonyl]bornane-
10,2-sultam (4a) in a EtOAc:MeOH (1:1) mixture (5 mL)
was added a substoichiometric amount of H2O, TFA and
Pd(OH)2 (42 mg, 0.06 mmol). The flask was then pump
filled with hydrogen and stirred at atmospheric pressure and
r.t. overnight. After this time the solution was filtered
through a pad of Celite®, the pad washed with further
MeOH. The solvent was removed in vacuo to afford S-(5a)
as a colourless solid (110 mg, 0.3 mmol, 99%); Rf = 0.46
(EtOAc); [a]D20 +66.7 (c 1, CHCl3). IR (CCl4): nmax = 3019,
2951 (CH), 1672 (C=O), 1334, 1170 (SO2), 756, 721, 702
(Ar) cm–1. 1H NMR (250 MHz, CD3OD): d = 1.05 and 1.20
(6 H, 2 × s), 1.28–1.50 and 1.88–2.15 (7 H, m), 2.89 (1 H,
dd, J = 10.6 Hz, 14.5 Hz), 3.65 (1 H, dd, J = 2.8 Hz, 14.5 Hz),
3.76 and 3.87 (2 H, 2 × d, J = 14.2 Hz), 4.05 (1 H, dd, J = 5.0
Hz, 7.9 Hz), 4.61 (1 H, dd, J = 2.8 Hz, 10.6 Hz), 7.32–7.47
(5 H, m). 13C NMR (60 MHz, CD3OD): d = 20.53, 21.60,
27.59, 33.95, 39.43, 37.90, 46.50, 49.70, 51.08, 53.72,
56.10, 67.26, 129.49, 130.70, 130.92, 135.92, 168.55. MS
(CI): m/z (%) = 363 (33) [MH]+, 271 (22), 120 (100), 91 (13),
58 (4). Found: [MH]+, 363.1732, C19H27N2O3S requires
[MH]+, 363.1743.
Acknowledgment
We thank the University of Reading and EPSRC for financial
support, the helpful comments of Drs. H. M. I. Osborn and A. T.
Russell and we acknowledge the guidance and advice of Mr. G.
Buchman and Mr. E. Blair.
References
(1) For recent reports of methodology directed towards
preparation of a-amino acids, see: (a) O’Donnell, M. J.;
Cooper, J. T.; Mader, M. M. J. Am. Chem. Soc. 2002, 125,
2370. (b) Kobayashi, S.; Matsubara, R.; Nakamura, Y.;
Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2002, 125,
2507. (c) Futatsugi, K.; Yanagisawa, A.; Yamamoto, H.
Chem. Comm. 2002, 566. (d) Lygo, B.; Andrews, B. I.;
Crosby, J.; Peterson, J. A. Tetrahedron Lett. 2002, 43, 8015.
(e) Watanabe, S.; Crodova, A.; Tanaka, F.; Barbas, C. F.
Org. Lett. 2002, 4, 4519. (f) Cordova, A.; Barbas, C. F.
Tetrahedron Lett. 2002, 43, 7749. (g) Chen, J. X.; Tunge, J.
A.; Norton, J. R. J. Org. Chem. 2002, 67, 4366. (h) Lee, S.
K.; Nam, J.; Park, Y. S. Synlett 2002, 790. (i) Hang, J. F.;
Tian, S. K.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2001, 123,
12696. (j) Yanagisawa, A.; Matsuzaki, Y.; Yamamoto, H.
Synlett 2001, 1855. (k) Evans, D. A.; Janey, J. M.;
(8) The Dictionary of Organic Compounds, Vol. 4; Chapman
and Hall: London, 1996, 3126.
Synlett 2003, No. 12, 1898–1900 ISSN 1234-567-89 © Thieme Stuttgart · New York