Asymmetric synthesis of orthogonally protected (2S,4R)- and (2S,4S)-4-hydroxyornithine

Article abstract of DOI:10.1055/s-2003-40840

Synthesis of orthogonally protected (2S, 4R)- and (2S, 4S)-4-hydroxyornithine was reported featuring an asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester (6) by (5S)-N-benzyloxycarbonyl-5-iodomethyl oxazolidine (7). Double stereoselection was examined using chiral ammonium salts as phase transfer catalysts and a substrate-directed chiral induction is documented.

Full text of DOI:10.1055/s-2003-40840

LETTER
1455
Asymmetric Synthesis of Orthogonally Protected (2S,4R)- and (2S,4S)-4-
Hydroxyornithine
Synthesis of
O
rth
e
ogonally P
n
rotecte
d
H
yd
a
roxyornithi
une d Lépine, Anny-Claude Carbonnelle, Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
Received 2 May 2003
recently been developed into a powerful method for the
synthesis of chiral non-racemic amino acids.10–13 Howev-
er, the stereochemistry of the alkylation of 6 with chiral
electrophiles has not been addressed. In examples report-
Abstract: Synthesis of orthogonally protected (2S, 4R)- and (2S,
4S)-4-hydroxyornithine was reported featuring an asymmetric
alkylation of N-(diphenylmethylene)glycine tert-butyl ester (6) by
(5S)-N-benzyloxycarbonyl-5-iodomethyl oxazolidine (7). Double
stereoselection was examined using chiral ammonium salts as phase ed in the literature, the existing asymmetric center is
transfer catalysts and a substrate-directed chiral induction is docu-
generally too far away from the newly created chiral cen-
ter to exert any chiral directing effect.14,15 In connection
mented.
with our interest in the total synthesis of biphenomycin,16
we thought that alkylation of glycine template 6 by
(5S)-N-benzyloxycarbonyl-5-iodomethyl oxazolidine (7)
Key words: amino acid, asymmetric alkylation, double stereo-
selection, glycine template, 4-hydroxyornithine, phase transfer
catalyst
could potentially constitute a rapid access to (2S,4R)-4-
hydroxyornithine (1). Moreover, such an approach would
give us the opportunity to examine in detail the effect of
the vicinal chiral center on the stereochemical course of
the alkylation process. The result of this study is the sub-
ject of the present communication.
The (2S,4R)- (1) and (2S,4S)-4-hydroxyornithine (2) are
key structural units found in macrocyclic antibiotic bi-
phenomycin A and B 3,1 and b-lactam antibiotic claval-
anine (4),2 respectively (Figure 1). The related 4-
hydroxylated a-amino acids such as (2S,4S,6R)-4-hy-
droxy-5-phenylsulfinylnorvaline (5) has also been identi-
fied as a key component of ustiloxin A and B,3 a family of
cyclic peptides with potent antimitotic activity. A number
of synthetic routes including stereoselective approaches
have been developed for the preparation of these non-
proteinogenic amino acids.4–9
Enantioselective alkylation of N-(diphenylmethylene)gly-
cine tert-butyl ester (6) using phase transfer catalysts has
Scheme 1 Reagents and Conditions: a) TsCl, pyridine, r.t., 93%;
b) NaN3, DMSO, 100 °C, 99%; c) H2, Pd/C, MeOH–HCl (10%); d)
CbzOSu, NaHCO3, H2O–dioxane, r.t., 94%; e) TsCl, pyridine, r.t.,
85%; f) dimethoxypropane, acetone, Bf3·OEt2, r.t., 73%; g) NaI, ace-
tone, reflux, 85%.
The (5S)-N-benzyloxycarbonyl-5-iodomethyl oxazoli-
dine (7) was synthesized as shown in Scheme 1. Tosyla-
tion of (S)-1,2-O-isopropylideneglycerol (8) followed by
nucleophilic displacement of tosylate with sodium azide
provided azido derivative 9. Hydrogenolysis under acidic
conditions provided an amino diol that was chemoselec-
tively N-acylated to give carbamate 10. Regioselective to-
sylation of the primary hydroxy group afforded 11, which
was subsequently converted into iodide 7 via a classical
two-step sequence.
Alkylation of 6 with iodide 7 was examined under a set of
conditions varying the temperature, the base, and the cat-
alyst (Scheme 2). The results are summarized in Table 1.
The first experiment was carried out using O-(9)-allyl-
N-(9-anthracenylmethyl)cinchonidinium bromide (14,
Figure 2) as catalyst under Corey’s conditions (CsOH,
Figure 1
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1455,1458,ftx,en;G09703ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1456
R. Lépine et al.
LETTER
Scheme 2
0.56 M in CH2Cl2). When the reaction was performed at
–50 °C, no alkylation product was observed in accord with
the lower reactivity of alkyl halides relative to benzyl
and allyl halides (entry 1). By performing the reaction at
–20 °C, two diastereomers 12 and 13 were obtained in a
ratio of 7/3 (41% yield) in favor of the (2R,4R) stereomer
12 (entry 2). The yield was further increased without
modifying the selectivity when the reaction was carried
out at room temperature under otherwise identical condi-
tions (entry 3). The relative stereochemistry of 12 and 13
was determined by conversion to their known derivatives
(vide infra).
Figure 2
in essentially the same ratio as in the case of catalyst 14,
although the yield was lower. To further tune the structure
of the catalysts, Maruoka’s axially chiral C2-symmetric
spiro ammonium salt 16 was employed. As is seen, the
same diastereoselectivity was once again observed (entry
6). Overall, these results might indicate that the asymme-
tric induction during the alkylation of 6 by iodide 7 was
dictated by the substrate rather than by the catalyst, re-
gardless of the structure and the chirality of the latter
(matched or mismatched).17,18 This consideration prompt-
ed us to examine the alkylation using achiral ammonium
salt as phase transfer catalyst. Indeed, the same diastereo-
selectivity was observed when tetrabutylammonium bro-
mide was used (TBAB) under otherwise identical
conditions (entry 7). Alkylation performed in the absence
The formation of 12 with a 2R absolute configuration as a
major isomer was unexpected since the 2S configuration
was anticipated on the basis of Corey’s empirical model.
To gain more information about this reaction, catalyst 15
derived from cinchonine was synthesized. Using 15 as
catalyst was thought to modify the stereoselectivity since
it is a pseudo-enantiomer of 14. However, as can be seen
(entry 4), the two diastereomers 12 and 13 were produced
Table 1 Conditions for the Alkylation of 6 with Iodide 7a
Entry
Catalyst
14
Base
Temp (°C)
–50
Yield (%)b
Ratio (12/13)c
1
2
3
4
5
6
7
8
9
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
NaOH
0
41
68
32
0
14
–50 then –20
–50 then r.t.
–50 then r.t.
r.t.
7/3
7/3
7/3
14
15
16
16
CsOH·H2O
CsOH·H2O
NaOH
–50 then r.t.
–50 then r.t.
r.t.
55
68
0
7/3
7/3
TBABd
TBAHSd
no
CsOH·H2O
–50 then r.t.
40
7/3
a Concentration of substrate: 0.56 M in CH2Cl2.
b Isolated yield of 12 and 13 after acidic hydrolysis.
c Diastereomerical ratio was deduced from the 1H NMR spectra. The diastereomers were separated by preparative TLC.
d Abbreviations: TBAB = tetrabutylammonium bromide; TBAHS = tetrabutylammonium hydrogensulfate.
Synlett 2003, No. 10, 1455–1458 © Thieme Stuttgart · New York

LETTER
Synthesis of Orthogonally Protected Hydroxyornithine
1457
of quaternary ammonium salt was found to give two dia-
stereomers in a similar ratio, but with lower chemical
yields (entry 9).19
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The amino ester 12 and 13 are suitably functionalized for
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17.8 On the other hand, treatment of 13 with 5 N HCl pro-
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72% yield.20 Compound 12 was similarly converted into
products 19 and 20 (Scheme 3).21
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r.t.; b) Boc2O, K2CO3, H2O–dioxane; 55% for two steps; c) 5 N HCl,
CHCl3, r.t., Boc2O, K2CO3, H2O–dioxane; 72% for two steps.
(6) Schmidt, U.; Meyer, R.; Leitenberger, V.; Stäbler, F.;
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In conclusion, we have developed a new access to the pro-
tected (2S,4R)- and (2S,4S)-4-hydroxyornithine. Al-
though the stereoselectivity of the alkylation step was
only moderate, the present study did provide an interest-
ing example of substrate-controlled stereoselective alkyl-
ation of glycine template in the presence of external chiral
sources and urged the development of novel catalyst that
can improve the double stereoselection.22 Previously, low
selectivity of Sharpless asymmetric dihydroxylation of
olefins with stereocenters proximal to the reaction site has
been observed that provided impetus for the development
of new asymmetric process.23
Acknowledgement
(13) O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3.
(14) (a) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett.
1999, 40, 1385. (b) Lygo, B. Tetrahedron Lett. 1999, 40,
1389.
(15) Boisnard, S.; Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2001, 3,
2061.
We thank Professor Maruoka for the gift of catalyst 16 and for the
helpful discussion. Financial support from CNRS is gratefully
acknowledged. R. Lépine thanks the Ministère de l’Enseignement
Supérieur et de la Recherche for a doctoral fellowship.
(16) Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477.
(17) Substrate-directed transformation, see: Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
(18) Double asymmetric induction: (a) Horeau, A.; Kagan, H.
B.; Vigneron, J. P. Bull. Soc. Chim. Fr. 1968, 3795.
(b) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R.
Angew. Chem., Int. Ed. Engl. 1985, 24, 1.
Synlett 2003, No. 10, 1455–1458 © Thieme Stuttgart · New York

1458
R. Lépine et al.
LETTER
(19) We thank one of the reviews for pointing out this control
experiment. This result was not unexpected, but it didn’t
allow us to conclude whether the observed stereoselectivity
in the presence of chiral ammonium salt was intrinsic to our
substrate or was the consequence of the lack of the catalyst
assistance.
cm–1; 1H NMR (300 MHz, CDCl3, 293 K) d 1.45 (s, 1 H),
2.32 (m, 1 H), 2.46–2.53 (m, 1 H), 3.30 (dt, 1 H, J1 = 15 Hz,
J2 = 6.3 Hz), 3.52–3.56 (m, 1 H), 4.23 (br d, 1 H, J = 6.8 Hz),
4.75 (br s, 1 H), 5.12–5.18 (m, 4 H), 7.36 (m, 5 H); 13C NMR
(75 MHz, CDCl3) d 28.2, 31.4, 44.6, 49.5, 67.1, 77.2, 80.7,
128.1, 128.2, 128.6, 136.2, 155.3, 156.7, 175.1; MS (EI)
m/z 387 (M + Na), 403 (M + K); [a]D = –18.1 (c 0.57 CHCl3);
[a]D = –22.4 (c 0.5 CHCl3).20
(20) Estiarte, M. A.; Diez, A.; Rubiralta, M.; Jackson, R. F. W.
Tetrahedron 2001, 57, 157.
(21) Compound 17. Rf = 0.5 (eluent: ethyl acetate/heptane = 1/4);
IR (CHCl3) 3444, 3024, 2982, 1712, 1507 cm–1; 1H NMR
(300 MHz, CDCl3, 293 K) d 1.44 (s, 9 H) Hz, 1.46 (s, 9 H),
1.65–1.82 (m, 1 H), 1.93–1.98 (m, 1 H), 3.08–3.17 (ddd, 1
H, J1 = 13.3 Hz, J2 = 7.8 Hz, J3 = 6 Hz), 3.36–3.42 (m, 1 H),
3.91 (m, 1 H), 4.22 (m, 1 H), 5.10 (s, 2 H), 5.26 (m,1 H), 5,39
(m, 1 H), 7,35 (m, 5 H); 13C NMR (75 MHz, CDCl3) d 28.0,
28.3, 38.0, 46.8, 52.1, 66.9, 69.1, 82.3, 82.5, 128.1, 128.2,
128.5, 136.4, 156, 157.1, 171.6; MS (ESI) m/z 461 (M + Na);
[a]D = +9.3 (c 0.9 CHCl3). Compound 18. Rf = 0.41 (eluant:
ethyl acetate/heptane = 1/1); IR (CHCl3) 3445, 1783, 1717
(22) Double stereoselection using matched and mismatched
chiral ammonium catalyst in the alkylation of a Gly-L-Phe
derivative has been documented very recently, see: (a) Ooi,
T.; Tayama, E.; Maruoka, K. Angew. Chem. Int. Ed. 2003,
42, 579. (b) For an earlier example of an achiral quarternary
ammonium salt catalyzed alkylation of a dipeptide, see:
O’Donnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem. Soc.
1996, 118, 6070.
(23) (a) Morikawa, K.; Sharpless, K. B. Tetrahedron Lett. 1993,
34, 5575. (b) Guzman-Perez, A.; Corey, E. J. Tetrahedron
Lett. 1997, 34, 5941.
Synlett 2003, No. 10, 1455–1458 © Thieme Stuttgart · New York