Rapid asymmetric synthesis of highly functionalized C5 chiral synthons. Practical preparation of trans-3 -hydroxy-D-proline

Article abstract of DOI:10.1055/s-1998-1921

A stereocontrolled synthesis of (2R, 3R)-3-hydroxyproline 5 has been achieved in 33% overall yield from a prochiral β-ketoester : the methyl 5,5-dimethoxy-3-oxopentanoate 6. The key intermediate is the richly functionalized compound 4 which presented three different oxygenated groups and an anti relationship between the alcohol and the amine.

Full text of DOI:10.1055/s-1998-1921

November 1998
SYNLETT
1279
Rapid Asymmetric Synthesis of Highly Functionalized C5 Chiral Synthons. Practical
Preparation of trans-3 -Hydroxy-D-Proline.
Olivia Poupardin, Christine Greck and Jean-Pierre Genêt
Laboratoire de Synthèse Sélective Organique et Produits Naturels (UMR 7573), Ecole Nationale Supérieure de Chimie de Paris,
11 rue Pierre et Marie Curie, 75231 Paris cédex 05.
Fax : 33 1 44 07 10 62 - e.mail : genet@ext.jussieu.fr
Received 31 July 1998
Abstract : A stereocontrolled synthesis of (2R, 3R)-3-hydroxyproline 5
has been achieved in 33% overall yield from a prochiral β-ketoester :
the methyl 5,5-dimethoxy-3-oxopentanoate 6. The key intermediate is
the richly functionalized compound 4 which presented three different
oxygenated groups and an anti relationship between the alcohol and the
amine.
Scheme 3
Peptide structures with proline components have received considerable
attention over the past few years.(1) trans-3-Hydroxy-L-proline 1 is a
ketoester 6 presented two symmetrical oxygens in γ positions to the
carbonyl group : this could modify the chelation of the ruthenium
complex and influence the enantioselectivity of the reaction.
constituent of naturally occurring peptides such as Mucrorin-D,(2)
Telomycin(3) and has been isolated from mediterranean sponge and
from collagen hydrolysates.(4) The reduced form of 1, the trans-3-
hydroxy-L-prolinol 2, occurs in the seeds of the legume
Castanospernum australe.(5)
Scheme 1
Several syntheses of trans-3-hydroxyproline and prolinol have been
developed in the literature starting from chiral sources such as
pyroglutamic acid,(6) L-serine(7), D-mannitol(8) or L-malic acid.(9)
Under classical conditions (20 bars, 50°C) the asymmetric
hydrogenation of the β-ketoester 6 was carried out in presence of (R)-
BinapRuBr2 (14) or [(R)-BinapRuCl2]2-Et3N(15) and methanol was used
as solvent to avoid secondary reactions such as transacetalisation or
transesterification. The yields did not exceed 50% and substantial
degradation of the substrate was observed. Then, the hydrogenation was
performed at room temperature and atmospheric pressure using 2
molecular % of (R)-BinapRuBr2 generated in situ.(16) Under these mild
conditions, the β-hydroxyester 7 was obtained with 86% yield and the
enantiomeric excess was higher than 95%. The enantiomeric excess was
determinated by chiral gas chromatography.(17)
The key intermediates of our approach are the anti diastereomers 3 and
4 of the methyl 2-amino-3-hydroxy-5,5-dimethoxypentanoate. These
richly functionalized compounds should be useful for the synthesis of
various α-amino-β-hydroxy acids of either (L) or (D) configurations.
The diastereoselective amination was carried out with
dibenzylazodicarboxylate as electrophilic reagent for the amination step
because the conditions of the deprotection of a benzyl carbamate are
compatible with the presence of an acetal function. The zinc enolate was
generated using methyl zinc bromide and lithium diisopropylamide; its
reaction with the dibenzylazodicarboxylate produced the anti
diastereomer 8 with 66% yield and complete diastereoselectivity.
Scheme 2
Recently, Ciufolini et al. reported the synthesis of the N,O diprotected 4
using the Aza-Achmatowicz reaction(10) in several steps from a chiral
furan oxazalone.(11)
In connection to our continued work on the asymmetric synthesis of α-
amino-β-hydroxy acids, our route to 3 and 4 relied on sequential
catalytic hydrogenation and electrophilic amination,(12) we report here a
concise and stereoselective synthesis of the unnatural trans-3-hydroxy-
D-proline.
At this stage, a rapid correlation was done : the benzyl carbamates were
hydrogenolyzed and the crude product was treated with aqueous
trifluoroacetic acid. The tetrahydropyridazine
9 was obtained
quantitatively and its physical data were identical to those reported in
the literature.(18) These results confirmed that the absolute configuration
of 8 was (2R, 3R).(19) 9 is a direct precursor of the unnatural (3R,
4R)-4-hydroxy-2,3,4,5-tetrahydropyridazine carboxylic acid (HPCA).
(2R, 3R)-Hydroxyproline 5 was obtained by cyclisation of 4 prepared
from β-ketoester 6.(13) First, we studied the hydrogenation of 6 in the
presence of ruthenium catalysts. The C5 acetal functionalized β-

1280
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SYNLETT
(3S, 4S)-HPCA is an aminoacid constituent of the antitumor and anti
HIV peptide antibiotics : luzopeptins.(20)
Acknowledgment: We thank Glaxo-Wellcome France for a grant to
O.P.
References and notes
(1) Hirschmann, R. Angew. Chem., Int. Ed. Eng. 1991, 103, 1305-
1330. Giannis, A.; Kolter, T. ibid 1993, 105, 1303-1326.
(2) Tschesche, R.; Samuel, T.D.; Uhlendorf, J.; Fehlaber, H.W. Chem.
Ber. 1972, 105, 3106-3114
(3) Sheehan, J.C.; Mania, D.; Nakamura, S.; Stock, J.A.; Maeda, K. J.
Am. Chem. Soc. 1968, 90, 462-470.
(4) Irreverre, F.; Morita, K.; Robertson, A.V.; Witkop, B. J. Am.
Chem. Soc. 1963, 85, 2824-2831. Wolff, J.S.; Ogle, J.D.; Logan,
M.A. J. Biol. Chem. 1966, 241, 1300-1308.
(5) Nash, R.J.; Bell, E.A.; Fleet, G.W.J.; Jones, R.H.; Williams, J.M.
J. Chem. Soc., Chem. Comm. 1985, 738-740.
(6) Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett. 1994, 35, 119-
122. Herdeis, C.; Hubmann, H.P.; Lotter, H. Tetrahedron :
Asymmetry 1994, 5, 119-128.
The synthesis of the (2R, 3R)-trans-3-hydroxyproline 5 was then
developed from the α-hydrazino-β-hydroxyester 8. The principal step
was the cleavage of the hydrazine bond. The hydroxyl function was first
protected as t-butyldimethylsilyl ether because we noticed that no
cleavage of the N-N bond could be perfomed in the presence of a free
(7) Dell’Uomo, N.; Di Giovanni, M.C.; Misiti, D.; Zappia, G.; Delle
Monache, G. Tetrahedron : Asymmetry 1996, 7, 181-188.
(8) Mulzer, M.A.; Meier, A.; Bushmann, J.; Luger, P. J. Org. Chem.
1996, 61, 566-572.
alcohol. After hydrogenolysis of the benzyl carbamates (H2, Pd/C),
(9) Durand, J.O.; Larchevêque, M.; Petit, Y. Tetrahedron Lett. 1998,
39, 5743-5746.
(21)
classical conditions such as H2, PtO2
or H2, Raney Ni under
ultrasounds(22) were used to generate the amine, but degradation of the
substrate was observed and no product could be isolated. Then, we tried
to deprotect and cleave the hydrazine simultaneously : 10 was exposed
to H2 in presence of PtO2.H2O in methanol and 45% of the α-
aminoester 11 was recovered after flash chromatography. Using a 1/1
mixture of methanol-water as solvent for these reactions, the yield
increased to 71% of purified compound 11. To our knowledge, we
proposed here the first one pot deprotection-cleavage of the N-N bond
of a diprotected hydrazine derivative.
(10) Ciufolini, M.A.; Hermann, C.Y.W.; Dong, Q.; Shimizu, T.;
Swaminathan, S.; Xi, N. Synlett 1998, 105-114.
(11) Ciufolini, M.A.; Shimizu, T.; Swaminathan, S.; Xi, N.
Tetrahedron Lett. 1997, 38, 4947-4950.
(12) Greck, C.; Genêt, J.P. Synlett 1997, 741-748.
(13) Methyl 5,5-dimethoxy-3-oxopentanoate 6 was easily prepared
from 3,3-dimethoxypropanoic acid by treatment with
carbonyldiimidazole and magnesium monomethylmalonate. See,
Brooks, D.W.; Masamune, S. Angew. Chem., Int. Ed. Engl. 1979,
18, 72-74.
The cyclisation to the proline ring was performed using aqueous
trifluoroacetic acid and the silyl ether was cleaved under these
conditions. The resulting iminium was reduced in situ by H2 in presence
of PtO2.H2O. The trifluoroacetic salt of methyl trans-hydroxy-D-
prolinate 12 was obtained as a crude product and the methyl ester was
saponified without further purification. After elution through an ion
exchange resin column, the (2R, 3R)-trans-3-hydroxyproline 5 was
isolated as a white solid with 84% yield from 11. All physical data of 5
were identical with those reported in the literature.(8, 23)
(14) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109,
5856-5858. Genêt, J.P. Acros Organics Acta 1995, 4-9.
(15) Ikariya, T.; Ischii, Y.; Kawano, H.. Arai, T.; Saburi, M.;
Yoshikawa, S.; Akutagawa, S. J. Chem. Soc., Chem. Comm. 1985,
922-924.
(16) Genêt, J.P.; Ratovelomanana-Vidal, V.; Cano de Andrade, M.C.;
Pfister, X.; Guerreiro, P.; Lenoir, J.Y. Tetrahedron Lett. 1995, 36,
4801-4804.
The unnatural trans-3-hydroxy-D-proline 5 was synthesized in 6 steps
with 33% overall yield from the prochiral β-ketoester 6. Using (S)-
BinapRuBr2 as catalyst in the first step of asymmetric hydrogenation,
the natural trans-hydroxy-L-proline 1 could be obtained in a similar
manner. This diastereoselective route is very efficient for the
preparation of both trans-3-hydroxyprolines.
(17) Methyl(R)-5,5-dimethoxy-3-hydroxypentanoate (7) : Methyl
5,5-dimethoxy-3-oxopentanoate 6 (1.03 g, 5.4 mmol) was diluted
under argon in degassed methanol (10 ml). This solution was
canulated into a Schlenk tube containing the (R)-BinapRuBr2
complex (2 mol%). The system was purged 3 times with hydrogen
and the reaction mixture was stirred under hydrogen (1 atm.) at
RT for 18h. The solution was concentrated under vacuum. The
residue was purified by flash chromatography with cyclohexane/
In conclusion, we proposed in this paper a rapid and stereoselective
synthesis of highly functionalized building blocks 3 and 4. These
compounds presented three oxygenated functionalities at different
oxydation degrees.This route has also opened an access to the (3R, 4R)-
4-hydroxy-2,3,4,5-tetrahydropyridazine methyl carboxylate 9 and to the
trans-3-hydroxy-D-proline 5 in optically- and diastereomerically-pure
form. Both anti enantiomers of each product are available from the β-
ketoester 6. The proposed syntheses are very concise : 4 steps for 9 and
6 steps for 5 from the β-ketoester 6.
20
AcOEt (1:1). Yield: 86%. [α]D = + 15 (c=1, EtOH). C8H16O5
(192.21) calcd C 49.98, H 8.39; found C 49.63, H 8.38. GPC :
Lipodex A, 80°C, flow : 1ml/mn, r.t. : 62.5 mn.
(18) Greck, C.; Bischoff, L.; Genêt, J.P. Tetrahedron : Asymmetry
1995, 6, 1989-1994.
The use of the C5 chiral synthons 3 and 4 in further syntheses are under
(19) Methyl(2R,3R)-5,5-dimethoxy-2-[N,N’-(dibenzyl
carbonyl)
current investigation in our laboratory.
hydrazino]-3-hydroxypentanoate (8) : To 7 (1.7 g, 8.8 mmol) in

November 1998
SYNLETT
1281
dry THF (12 ml) at 0°C, was added dropwise a solution of
EtOH). C24H29N2O9 (489.49) calcd C 58.88, H 5.97, N 5.72;
found C 58.87, H 6.06, N 5.81.
MeZnBr (9.7 mmol) prepared from ZnBr2 (2.18 g, 9.7 mmol) in
dry THF (12 ml) and MeLi (6.35 ml, 9.7 mmol, 1.6 M sol. in
Et2O). After stirring for 1h, the mixture was cooled at -78°C and a
solution of lithiumdiisopropylamide (17.6 mmol) in THF was
added dropwise. After further 1h at -78°C, a solution of
dibenzylazodicarboxylate (5.25 g, 17.6 mmol) in THF (24 ml)
was added dropwise. The reaction mixture was stirred until no
more starting material was detectable by TLC (2.5 h.), hydrolysed
at -78°C with a saturated aqueous solution of NH4Cl (30 ml),
warmed at RT, extracted into Et2O, dried and evaporated. The
crude product was purified by flash chromatography eluting with
(20) Konishi, M.; Ohkuma, H.; Sakai, F.; Tsuno, T.; Koshiyama, H.;
Naito, T.; Kawaguchi, H. J. Am. Chem. Soc. 1981, 103, 1241-
1243. Arnold, E.; Clardy, J. J. Am. Chem. Soc. 1981, 103, 1243-
1244.
(21) Claremon, D.A.; Lumma, P.K.; Phillips, P. J. Am. Chem. Soc.
1986, 108, 8265-8266.
(22) Alexakis, A.; Lensen, N.; Mangeney, P. Synlett 1991, 625-626.
(23) Cooper, J.; Gallagher, P.T.; Knight, D.W. J. Chem. Soc. Perkin
Trans I 1993, 1313-1317.
20
20
20
cyclohexane / AcOEt (3:7). Yield : 66%. [α]D = +35 (c=1.24,
5: [α]D = +19 (c=1, H2O); lit.8 [α]D = +18.4 (c=1.2, H2O);
lit.23 [α]D20 = +18.8 (c=0.14, H2O).