Highly efficient approach to orthogonally protected (2S,4R)- and (2S,4S)-4-hydroxyornithine

Article abstract of DOI:10.1021/ol0503182

(Chemical Equation Presented) A concise stereoselective approach to both orthogonally protected (25,4A)- and (2S,4S)-4-hydroxyornithine, key constituents of the biphenomycin-and clavalanine-type antibiotics, respectively, has been developed. The approach is based on bis(oxazoline) copper(II)-complex-catalyzed diastereoselective Henry reactions of nitromethane with the homoserine-derived aldehyde 6. The synthesis of this versatile chiral building block has been markedly improved.

Full text of DOI:10.1021/ol0503182

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1423-1426
Highly Efficient Approach to
Orthogonally Protected (2S,4R)- and
(2S,4S)-4-Hydroxyornithine
Franz F. Paintner,* Lars Allmendinger, Gerd Bauschke, and Patricia Klemann
Department Pharmazie, Zentrum fu¨r Pharmaforschung,
Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Butenandtstrasse 5-13,
Haus C, D-81377 Mu¨nchen, Germany
franz.paintner@cup.uni-muenchen.de
Received February 15, 2005
ABSTRACT
A concise stereoselective approach to both orthogonally protected (2S,4R)- and (2S,4S)-4-hydroxyornithine, key constituents of the biphenomycin-
and clavalanine-type antibiotics, respectively, has been developed. The approach is based on bis(oxazoline) copper(II)-complex-catalyzed
diastereoselective Henry reactions of nitromethane with the homoserine-derived aldehyde 6. The synthesis of this versatile chiral building
block has been markedly improved.
4-Hydroxyornithine is a rare amino acid found in lentils1
(e.g., Lens culinaris Medik.) and some members of the genus
Vicia2 (e.g., V. unijuga A. Br.). Moreover, it is a key
constituent of the â-lactam antibiotic clavalanine3 and the
cyclopeptide antibiotics biphenomycin A and B 1.4 The latter
have received considerable attention in recent years due to
their high in vitro and in vivo antibacterial activity against
multiresistant gram-positive pathogens.5
appropriate NR,Nδ,Oγ-protected (2S,4R)-4-hydroxyornithine
building block. While a number of synthetic pathways,
including stereoselective approaches, have been developed
for the synthesis of 4-hydroxyornithine,7 only two approaches
dealt with the synthesis of a derivative bearing NR,Nδ,Oγ-
protection suitable for peptide synthesis. Schmidt et al.
reported a 13 step synthesis starting from (R)-isopropylidene
glyceraldehyde to form the N,O-acetal 2, albeit in low overall
yield.8 More recently, Rudolph et al. described a very concise
(1) (a) Sulser, H.; Stute, R. Experientia 1976, 32, 422-423. (b) Rozan,
P.; Kuo, Y.-H.; Lambein, F. Phytochemistry 2001, 58, 281-289.
(2) (a) Bell, E. A.; Tirimanna, A. S. L. Biochem. J. 1964, 356-358. (b)
Hatanaka, S.; Kaneko, S.; Saito, K.; Ishida, Y. Phytochemistry (Elsevier)
1981, 20, 2291-2292.
(3) Pruess, D. L.; Kellett, M. J. Antibiotics 1983, 36, 208-212.
(4) (a) Martin, J. H.; Mitscher, L. A.; Shu, P.; Porter, J. N.; Bohonos,
N.; DeVoe, S. E.; Patterson, E. L. Antimicrob. Agents Chemother.-1967
1968, 422-425. (b) Ezaki, M.; Iwami, M.; Yamashita, M.; Hashimoto, S.;
Komori, T.; Umehara, K.; Mine, Y.; Kohsaka, M.; Aoki, H.; Imanaka, H.
J. Antibiotics 1985, 38, 1453-1461. (c) Chang, C. C.; Morton, G. O.; James,
J. C.; Siegel, M. M.; Kuck, N. A.; Testa, R. T.; Borders, D. B. J. Antibiotics
1991, 44, 674-677.
(5) (a) Lampe, T.; Adelt, I.; Beyer, D.; Brunner, N.; Endermann, R.;
Ehlert, K.; Kroll, H.-P.; von Nussbaum, F.; Raddatz, S.; Rudolph, J.;
Schiffer, G.; Schumacher, A.; Cancho-Grande, Y.; Michels, M.; Weigand,
S. WO 2003106480, 2003; Chem. Abstr. 2004, 140, 59934. (b) Lampe, T.;
Adelt, I.; Beyer, D.; Brunner, N.; Endermann, R.; Ehlert, K.; Kroll, H.-P.;
von Nussbaum, F.; Raddatz, S.; Rudolph, J.; Schiffer, G.; Schumacher, A.
WO 2004012816, 2004; Chem. Abstr. 2004, 140, 164239.
Figure 1.
As part of our program directed toward a convergent total
synthesis of these antibiotics6 and analogues thereof with a
modified biaryl moiety, we sought an efficient access to an
(6) Paintner, F. F.; Go¨rler, K.; Voelter, W. Synlett 2003, 522-526.
10.1021/ol0503182 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/11/2005

access to the TBDMS-protected 4-hydroxyornithine 3 starting
from (S)-N-Boc aspartic acid tert-butyl ester. This approach,
which is based on an initial homologization of the acid side
chain to form an R-nitroketone and its subsequent dia-
stereoselective reduction to the corresponding â-nitro alcohol,
however, also suffers from a low overall yield.5,9
membered cyclic N,O-acetal 9 (Scheme 2). Thus, this crucial
step was reported to proceed in only 42-48% yield by
reacting 7 with excess 2,2-dimethoxypropane (DMP) (10
equiv, CH2Cl2, rt) in the presence of a catalytic amount of
TsOH due to concurrent formation of the corresponding six-
membered cyclic N,O-acetal 10.13,15
Scheme 2. Acid-Catalyzed N,O-Acetal Formation of
N-Boc-Protected (S)-2-Amino-1,4-butandiol 7 with DMP
In this paper, we disclose a short and efficient stereo-
selective approach to both orthogonally NR,Nδ,Oγ-protected
(2S,4R)- and (2S,4S)-4-hydroxyornithine based on an asym-
metric nitroaldol (Henry) reaction of nitromethane with the
homoserine-derived aldehyde 610 (Scheme 1).11
Scheme 1. Retrosynthetic Analysis
In the course of our studies, however, the structure of this
1
byproduct was revised on the basis of H-13C HMBC and
1H-15N HMQC NMR experiments to be the corresponding
seven-membered cyclic O,O-acetal 8. Indeed, this isomer was
shown to be the product of kinetic control, which slowly
equilibrates with 9 under the reported reaction conditions.
No evidence has been found for the occurrence of the six-
membered cyclic N,O-acetal 10.16 Furthermore N,O-acetal
9 was shown to exist also in an equilibrium with its 1-methyl-
1-methoxyethyl (MIP) ether derivative 11, a fact not
mentioned in the previous papers.17 In the end, trapping 9
to form 11 allows the overall equilibrium to shift to the
desired five-membered ring system. Accordingly, slight
modification of the reported reaction conditions, i.e., using
2,2-dimethoxypropane as the solvent and addition of 2-meth-
oxypropene (3.0 equiv) to trap liberated methanol, led to 9
in high overall yield (92%) after mild hydrolysis (wet silica
gel, CH2Cl2, rt) of the intermediate MIP ether 11. Finally,
Swern oxidation provided the desired aldehyde 6 in 97%
yield (Scheme 3).14
A simple two-step preparation of building block 6 starting
from readily available N-Boc-protected (S)-2-amino-1,4-
butandiol 712 was previously reported by Ksander and co-
workers.13,14 This commonly used approach, however, suffers
from low regioselectivity in the formation of the five-
(7) (a) Hammarsten, E. Compt. Rend. TraV. Lab. Carlsberg 1916, 11,
223-262. (b) Talbot, G.; Gaudry, R.; Berlinguet, L. Can. J. Chem. 1956,
34, 911-914. (c) Mizusaki, K.; Makisumi, S. Bull. Chem. Soc. Jpn. 1981,
54, 470-472. (d) Jackson, R. F. W.; Wood, A.; Wythes, M. J. Synlett 1990,
735-736. (e) Ha¨usler, J. Liebigs Ann. Chem. 1992, 1231-1237. (f) Jackson,
R. F. W.; Rettie, A. B.; Wood, A.; Wythes, M. J. J. Chem. Soc., Perkin
Trans. 1 1994, 1719-1726. (g) Girard, A.; Greck, C.; Geneˆt, J. P.
Tetrahedron Lett. 1998, 39, 4259-4260. (h) Mues, H.; Kazmaier, U.
Synthesis 2001, 487-498. (i) Le´pine, R.; Carbonnelle, A.-C.; Zhu, J. Synlett
2003, 1455-1458.
(8) Schmidt, U.; Meyer, R.; Leitenberger, V.; Sta¨bler, F.; Lieberknecht,
A. Synthesis 1991, 409-413.
(9) Rudolph, J.; Hanning, F.; Theis, H.; Wischnat, R. Org. Lett. 2001,
3, 3153-3155.
(10) For recent use of this versatile chiral building block, see: (a)
Dondoni, A.; Massi, A.; Minghini, E.; Sabbatini, S.; Bertolasi, V. J. Org.
Chem. 2003, 68, 6172-6183. (b) Catalano, J. G.; Deaton, D. N.; Furfine,
E. S.; Hassell, A. M.; McFayden, R. B.; Miller, A. B.; Miller, L. R.;
Shewchuk, L. M.; Willard, D. H.; Whright, L. L. Bioorg. Med. Chem. Lett.
2004, 14, 275-278. (c) Dondoni, A.; Catozzi, N.; Marra, A. J. Org. Chem.
2004, 69, 5023-5036. (d) Dondoni, A.; Giovanni, P. P.; Massi, A. Org.
Lett. 2004, 6, 2929-2932.
(11) An analogous Henry reaction-based strategy for the synthesis of
4-hydroxyornithine was previously reported by Rudolph et al. (ref 9). This
approach, however, suffers both from an unfavorable stereoselectivity and
from a very low yield in the key nitroaldol reaction step and therefore was
not pursued further.
(13) Ksander, G.; de Jesus, R.; Yuan, A.; Ghai, R. D.; Trapani, A.;
McMartin, C.; Bohacek, R. J. Med. Chem. 1997, 40, 495-505.
(14) For an alternative approach to 6 starting from N-tert-butoxy-
carbonyl-L-aspartic acid γ-benzyl ester, see: Ouerfelli, O.; Ishida, M.;
Shinozaki, H.; Nakanishi, K.; Ohfune, Y. Synlett 1993, 409-410.
(15) Hou, D.-R.; Reibenspies, J. H.; Burgess, K. J. Org. Chem. 2001,
66, 206-215.
(16) Ab initio MO calculations (DFT/B3LYP/6-311G+) showed an
energy difference of about 7.8 kcal/mol between 9 and the six-membered
cyclic N,O-acetal 10, indicating that only traces of this regioisomer are to
be expected.
(12) Although N-Boc-protected (S)-2-amino-1,4-butandiol 7 is com-
mercially available (Aldrich), its relatively high price leads us to recommend
its preparation on a multigram scale from inexpensive L-aspartic acid (see
Supporting Information).
(17) Products 8, 9, and 11 were obtained in a ratio of 30:45:25 (as
determined by 1H NMR analysis of the crude reaction product) by treatment
of 7 with DMP (10 equiv) and TsOH (0.1 equiv, CH2Cl2, rt, 36 h) according
to ref 15.
1424
Org. Lett., Vol. 7, No. 7, 2005

catalyst 1422 (5 mol %, THF, -40 °C, 3 days) led to 12
with high diastereoselectivity, albeit in low yield (Table 1,
entry 4).
Scheme 3. Improved Synthesis of Aldehyde 6
Recently, other highly efficient chiral catalysts for asym-
metric Henry reactions have been developed. Thus, Corey23
and Maruoka24 have utilized chiral quaternary ammonium
fluorides as catalysts, while Trost25 has presented a dinuclear
zinc catalyst. Salen-cobalt(II) complexes have been used
by Yamada,26 whereas Jørgensen27 and Evans28 have intro-
duced bis(oxazoline)-copper(II) complexes. The latter seemed
to be the catalysts of choice, at least for aliphatic aldehydes,
with respect to attainable yields and degree of stereoselec-
tivity.
Indeed, application of Evans’ bis(oxazoline) copper(II)
acetate-based catalysts {Cu[(+)-15]}(OAc)2 and in particular
{Cu[(+)-16]}(OAc)2 (5 mol %, EtOH, rt, 5 days) gave the
desired nitro alcohol 12 both with high diastereoselectivity
and in high yield (Table 1, entries 5 and 7). Finally, to
selectively obtain diastereomer 13, aldehyde 6 was reacted
with nitromethane in the presence of the enantiomeric
catalysts {Cu[(-)-15]}(OAc)2 and {Cu[(-)-16]}(OAc)2,
respectively. In these cases, slightly lower stereoselectivities
and yields were observed, reflecting a mismatched pairing
(Table 1, entries 6 and 8).
With key building block 6 in hand, its nitroaldol (Henry)
reaction with nitromethane was examined (Table 1).
LiAlH4-,18 TBAF-,19 as well as t-BuOK-catalyzed20 Henry
reactions led to nitro alcohols 12 and 13 with low dia-
stereoselectivity, reflecting that the existing stereogenic center
is too far away from the newly created one to exert
appreciable asymmetric induction (Table 1, entries 1-3).21
An obvious way of resolving this problem was the introduc-
tion of additional chiral information, i.e., application of a
chiral catalyst. In fact, double stereodifferentiation using
Shibasaki’s well-established heterobimetallic (S)-BINOL
We next turned our attention to the transformation of
â-nitro alcohol 12 into the desired amino acid building
block 4 (Scheme 4).29 Protection of the hydroxyl group as a
Scheme 4. Synthesis of Orthogonally Protected
(2S,4R)-4-Hydroxyornithine 4
Table 1. Diastereoselective Henry Reaction of Aldehyde 6
with Nitromethane
yield ratiob
(%)a 12:13
a Based on recovered starting material.
entry
catalyst
LiAlH4
TBAF
t-BuOK
14
{Cu[(+)-15]}(OAc)2 EtOH, rt
{Cu[(-)-15]}(OAc)2 EtOH, rt
{Cu[(+)-16]}(OAc)2 EtOH, rt
{Cu[(-)-16]}(OAc)2 EtOH, rt
conditions
THF, rt
THF, rt
t-BuOH/THF, 0 °C
THF, -40 °C
1
2
3
4
5
6
7
8
53
33
72
45
87
85
94
91
56:44
43:57
23:77
98:2
92:8
9:91
TIPS ether proceeded smoothly under standard conditions
(TIPSOTf/2,6-lutidine). Reduction of the nitro group was
accomplished using ammonium formate as a hydrogen source
and palladium on carbon as the catalyst to afford the
97:3
8:92
(18) Youn, S. W.; Kim, Y. H. Synlett 2000, 880-882.
(19) O¨ hrlein, R.; Ja¨ger, V. Tetrahedron Lett. 1988, 29, 6083-6086.
(20) Hanessian, S.; Brassard, M. Tetrahedron 2004, 60, 7621-7628.
(21) Low stereoselectivity in nitroaldol reactions with aldehydes bearing
a stereogenic center at the â-position has been observed previously. See
ref 9 and references therein.
a Isolated yield. b Determined by HPLC analysis of crude reaction
mixtures.
Org. Lett., Vol. 7, No. 7, 2005
1425

corresponding amine, which was transformed (Z)-OSu/NEt3)
to the Nδ-Z-protected 4-hydroxyornithine derivative 17 in
84% overall yield (three steps). Selective hydrolysis of the
N,O-acetal using several methods (e.g., pyridinium tosylate,
MeOH, 60 °C; I2, MeOH, rt or CeCl3‚7H2O/oxalic acid, rt)
proved to be difficult due to concomitant partial cleavage
of the TIPS ether. Fortunately, we were able to effect this
transformation cleanly and in good yield (64%, 96% based
on recovered starting material) using ethylene glycol/CSA
(THF, 50 °C, 2 days).30 The final oxidation of the amino
alcohol was best accomplished with TEMPO/NaOCl/
NaClO231 to give the desired carboxylic acid 4 {mp 45-47
epimerization. The absolute configuration of product 4 was
established to be 2S,4R by subsequent transformation into
the known γ-lactone 1832 {mp 148-149 °C, lit. mp 143-
145 °C; [R]23 -25.2 (c 0.85, CHCl3), lit. [R]23 -22.4 (c
D
D
0.5, CHCl3)}.
According to this reaction sequence, 13 was converted to
5 {mp 53-55 °C, [R]20 -28.5 (c 1.00, CH2Cl2)} in 57%
D
overall yield (66% based on recovered starting materials) in
five steps.
In conclusion, we have developed a short and highly
efficient approach to orthogonally protected (2S,4R)- and
(2S,4S)-4-hydroxyornithine building blocks 4 and 5, respec-
tively, based on bis(oxazoline) copper(II)-complex-catalyzed
diastereoselective Henry reactions of nitromethane with
aldehyde 6. In addition, a greatly improved procedure for a
multigram synthesis of this valuable chiral building block
and its precursor 9 has been developed.
°C, [R]22 +67.6 (c 1.64, CH2Cl2)} in 83% yield without
D
(22) (a) Sasai, H.; Suzuki, T.; Arai, S.; Shibasaki, M. J. Am. Chem. Soc.
1992, 114, 4418-4420. (b) Sasai, H.; Watanabe, S.; Suzuki, T.; Shibasaki,
M. Org. Synth. 2002, 78, 14-22.
(23) Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999, 38, 1931-
1934.
(24) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054-
2055.
Acknowledgment. We thank Prof. Klaus T. Wanner and
the Deutsche Forschungsgemeinschaft (Project PA 886\1-
1) for generous financial support, Dr. Thomas Wein for
computational studies, and David Schaffert for technical
assistance.
(25) (a) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett.
2002, 4, 2621-2623. (b) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int.
Ed. 2002, 41, 861-863.
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T.; Yamada, T. Chem. Lett. 2004, 33, 614-615. (b) Kogami, Y.; Nakajima,
T.; Ikeno, T.; Yamada, T. Synthesis 2004, 1947-1950.
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(28) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692-12693.
(29) Since â-nitro alcohols 12 and 13 were difficult to separate, 12 was
used as a mixture of diastereomers (97:3). The minor diastereomer could
be easily removed by flash chromatography on silica gel at the stage of the
Nδ-Z-protected â-amino alcohol 17.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0503182
(30) Coleman, R. S.; Richardson, T. E.; Carpenter, A. J. J. Org. Chem.
1998, 63, 5738-5739.
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1426
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