Enantioselective preparation of 2-aminomethyl carboxylic acid derivatives: Solving the β2-amino acid problem with the chiral auxiliary 4-isopropyl-5,5-diphenyloxazolidin-2-one (DIOZ)

Article abstract of DOI:10.1002/hlca.200390149

Multigram amounts of suitably protected β²-amino acids with 17 of the 20 proteinogenic side chains are prepared by diastereoselective reactions of Li, B, or Ti enolates of the corresponding 3-acyl-4-isopropyl-5,5-diphenyloxazolidin-2-ones (acyl-DIOZ; 1) with appropriate electrophiles (amidomethylation, hydroxyalkylation, (benzyloxycarbonyl)methylation) in yields of 55-90% and with diastereoselectivities of 80 to > 97% (Scheme). The primary products 2-8 thus obtained are converted to protected β²-amino acids by standard procedures (Table 1). Many of the DIOZ derivatives are highly crystalline compounds (31 X-ray crystal structures in Table 2). The chiral auxiliary DIOZ, readily prepared in either enantiomeric form, is recovered with high yield.

Full text of DOI:10.1002/hlca.200390149

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Helvetica Chimica Acta Vol. 86 (2003)
Enantioselective Preparation of 2-Aminomethyl Carboxylic Acid
Derivatives: Solving the b2-Amino Acid Problem with the Chiral Auxiliary
4-Isopropyl-5,5-diphenyloxazolidin-2-one (DIOZ)
Preliminary Communication
by Dieter Seebach*, Laurent Schaeffer1), FranÁois Gessier1), Pascal Bindsch‰dler2), Corinna J‰ger3), Delphine
Josien1), Sascha Kopp2), Ge¬rald Lelais4), Yogesh R. Mahajan4), Peter Micuch1), Radovan Sebesta1), and Bernd
W. Schweizer
Laboratorium f¸r Organische Chemie der Eidgenˆssischen Technischen Hochschule, Hˆnggerberg-HCI,
Wolfgang-Pauli-Strasse 10, CH-8093 Z¸rich
Multigram amounts of suitably protected b2-amino acids with 17 of the 20 proteinogenic side chains are
prepared by diastereoselective reactions of Li, B, or Ti enolates of the corresponding 3-acyl-4-isopropyl-5,5-
diphenyloxazolidin-2-ones (acyl-DIOZ; 1) with appropriate electrophiles (amidomethylation, hydroxyalkyla-
tion, (benzyloxycarbonyl)methylation) in yields of 55 90% and with diastereoselectivities of 80 to > 97%
(Scheme). The primary products 2 8 thus obtained are converted to protected b2-amino acids by standard
procedures (Table 1). Many of the DIOZ derivatives are highly crystalline compounds (31 X-ray crystal
structures in Table 2). The chiral auxiliary DIOZ, readily prepared in either enantiomeric form, is recovered
with high yield.
b-Peptides, which consist of homologs of a-amino acids, have turned out to present
a new world of peptide chemistry. While the functional groups in the chain (the amide
bonds) and in the side chains (of Arg, Asp, Glu, His, Lys, Met, Ser, Thr, Trp, and Tyr)
are identical, there is just an additional backbone CH2 group in each amino acid moiety.
Even this causes dramatic effects: secondary structures differ fundamentally (in
number, shape, size, and polarity) and are more stable and predictable at short chain
length [1][2]; there is total enzymatic stability (against peptidases and proteases) [3],
metabolic stability in rats has been demonstrated [4], even microbial degradation is
slow [5]. On the other hand, the activities of an a-peptidic hormone and of an a-
peptidic amphipathic helix can be mimicked by b-peptides [6], and strong binding of
certain b-peptides to DNA of mammalian cells has been detected [7].
There are two ways of inserting CH2 groups into the backbone of peptides: between
the CˆO group and the a-C-atom ( ! b3-amino acid) or between the a-C-atom and the
N-atom ( ! b2-amino acid), and it turns out that the latter change has the more
intriguing effects, leading to turn structures [2] or to a novel type of helix, which consists
of alternating ten- and twelve-membered H-bonded rings [1][8].
1
)
Postdoctoral fellow at ETH-Z¸rich, financed by ETH Z¸rich, by a grant from the Swiss National Science
Foundation (No. 2000-058831.99), or by financial support from Novartis Pharma AG, Basel.
Part of the Master Theses (Diplomarbeit) of P. B. and of S. K., ETH-Z¸rich, 2003.
Part of Advanced Laboratory Course, ETH-Z¸rich, 2002/2003.
2
3
4
)
)
)
Part of the projected Ph.D. Theses of G. L. and of Y . R. M,. ETH-Z¸rich, 2003.
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Helvetica Chimica Acta Vol. 86 (2003)
1853
While the 20 b3-amino acids with proteinogenic side chains are readily available5)
for solid-phase synthesis by the Fmoc strategy [9], the b2-analogs are not. There are
many recent papers some with bombastically general titles announcing more or less
ingenious preparations of b2-amino acids, and when one looks at the details there are
only the trivial Me, i-Pr, or Bn side chains6).
For our ongoing work on the synthesis of more-complex b2/b3- and all-b2-peptides,
we needed to have ample access to all 20 properly protected b2-amino acids with the
proteinogenic side chains. Thus, ca. 5-g amounts of each were prepared from the N-
acyl-oxazolidin-2-ones 1a 1p7) (Evans methodology; Scheme). Most important was
the Mannich reaction of the Ti-enolates with MeOCH2NHZ [11][12] (1a 1j ! 2a 2j)
and their aldol addition with trioxane ( ! 5, 6). B-Enolates served for aldol addition to
acetaldehyde and to formyl-indol ( ! 3, 4), and Li-enolates were used for the reaction
with ICH2CO2Bn ( ! 7, 8). In Table 1, the conversions of the primary products 2 8 to
C-, N-, and/or side-chain protected b2-amino acids are outlined, together with the
overall yields and leading references to the methods used. Since both enantiomers of
our modified Evans auxiliary [12]8) DIOZ are available, the enantiomers of the
compounds described here are equally well accessible.
One of the advantages of DIOZ is that most of its derivatives are crystalline [13], so
that we could make use of X-ray crystal-structure analyses for safe configurational
assignments (Table 2). Another advantage is the insolubility of the auxiliary itself,
which is readily recovered (ca. 90%) by filtration after cleavage from the products.
All products, the formulae of which are shown in the Scheme and in Table 1, as well
as most of the intermediates (cf. 9 15 in Table 2) formed on the way from the primary
products 1 8 to the amino acids (see Table 1) have been fully characterized (IR, NMR,
[a]D, MS, elemental analyses). This is also true of other DIOZ derivatives 16 32
(Table 2) prepared in the course of our search for alternative general routes to b-amino
acids9).
From the b2-amino acids listed in Table 1, we are in the process of preparing b2-
dipeptides or b2/b3-dipeptides for solid-state fragment coupling [9d]. As in a-peptide
and protein chemistry, the b-amino acids with the functional groups CO2H, NH3,
guanidyl, imidazolyl, OH, SH, CONH2 in the side chain are especially important for
salt-bridge formation, derivatization (cf. phosphorylation, glycosylation etc.), metal
complexation (cf. zinc fingers), disulfide-bridge formation, and strong H-bonding,
effects that we are presently probing in the world of b-peptides.
5
)
We synthesized only Fmoc-b3hCys(Trt)-OH and Fmoc-b3hHis(Trt)-OH. The other 18 Fmoc-b3hXaa(PG)-
OH are commercially available (PG ˆ acid-labile protecting group).
6
7
)
)
For a recent review article on b-amino acid syntheses, see [10].
Most acid derivatives for the preparation of 1a 1p are commercially available; two were prepared by
reductive deamination of the corresponding amino acids (Ile, Met).
Generous supply of DIOZ by the Kilolab of Novartis Pharma AG (Drs. Thomas Leutert and Luigi La
Vecchia, Basel) is gratefully acknowledged. An Organic Syntheses procedure has been checked by the
editors and will appear in the next issue of the series; a copy of the procedure can be requested from the
corresponding author D. S.
8
)
9
)
Details about the results of these investigations will be described elsewhere.

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme. Starting Materials N-Acyloxazolidinones 1a 1p and Products 2 8 from the Reaction of N-Acyl-
oxazolidinone Enolates with Electrophiles. For abbreviations, see caption of Table 1; y ˆ yield, ds ˆ diastereo-
selectivity.

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Table 1. Seventeen of the Twenty b2-Amino Acid Derivatives with Proteinogenic Side Chains Prepared from the Primary Products
2
8. All products have (S)-configuration, except for the (R)-b2hSer and (R)-b2hThr derivatives. For the general methodology,
see [11 13] and refs. cit. therein. For previous papers by our group on the preparation of b2-amino acids, see
[1c][2][9d][12][14]6). The preparation of the two missing Asn and Gln derivatives is underway in our laboratory; b2-amino
acid number 20: b2hGlyꢀb3hGly. The abbreviations Boc, Fmoc, Z, Troc, DBU, TFA, Trt are common in peptide chemistry.
ADDP ˆ 1,1'-(azodicarbonyl)dipiperidine, DIAD ˆ diisopropyl azodicarboxylate, DMAP ˆ 4-(dimethylamino)pyridine,
DPPA ˆ diphenylphosphoryl azide, GR ˆ guanidylation reagent ˆ 1,2-bis[(tert-butoxy)carbonyl-1H-pyrazole-1-carboxamidine,
LHMDS ˆ lithium hexamethyldisilazide, Phth ˆ phthaloyl, Su ˆ succinimidyl, TBAF ˆ tetrabutylammonium fluoride,
TBDPS ˆ (tert-butyl)diphenylsilyl, Tf ˆ trifluoromethanesulfonyl, TMSE ˆ 2-(trimethylsilyl)ethyl.
b2-Amino Acid Derivative
Precursor Step(s)
Overall yield [%] References
Z-b2hAla-OH
2a
2e
7
LiOH/THF/H2O
91
1. NaN3/DMF
2. PPh3/GR/THF/H3O
3. LiOH/THF/H2O2
Z-b2hArg(Boc)2-OH
Z-b2hAsp(tBu)-OH
Boc-b2hCys(Trt)-OH
Z-b2hGlu(tBu)-OH
56
32
[15]
1. H2/Pd-C/THF
2. DPPA/NEt3/PhMe
3. BnOH/PhMe
[16]
4. LiOH/THF/H2O2
1. PBu3/ADDP/TrtSH/THF
2. TMSEOLi/THF
3. (NH2CH2)2/BuOH/THF 25
4. Boc2O/MeOH/dioxane
5. TBAF/THF
5
[17][18]
1. H2/Pd-C/THF
2. DPPA/NEt3/PhMe
3. BnOH/PhMe
8
13
[16]
4. LiOH/THF/H2O2
1. BnOLi/THF
2. DIAD/PPh3/HN3/THF
24
Fmoc-b2hHis(Trt)-OH
6
[19]
3. H2/Pd-C/EtOH
4. FmocOSu/Na2CO3/H2O
Z-b2hlle-OH
2i
LiOH/THF/H2O
66
83
1. BnOLi/THF
2. H2/Pd-C/MeOH
3. TsOH/BnOH/benzene
H-b2hLeu-OBn
2c

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Helvetica Chimica Acta Vol. 86 (2003)
Table 1 (cont.)
1. NaN3/DMF
2. Boc2O/Lindlar cat./MeOH
Z-b2hLys(Boc)-OMe
2f
80
80
91
[20]
3. LiBr/DBU/MeOH
Z-b2hMet-OH
2d, 2j
NaOH/THF/MeOH
NaOH/THF/MeOH
Z-b2hPhe-OH
2g
1. NaH/Bu4NI/DMF
2. LiBr/DBU/MeOH
Z-b2h-Pro-OMe
2e
48
1. Isobutylene/CH2Cl2/H2SO4
2. BnOLi/THF
3. (NH2CH2)2/BuOH/THF
H-b2hSer(tBu)-OBn
Z-b2hThr(tBu)-OH
5
3
44
26
[18][21]
[21][22]
1. H2/Pd-C/THF
2. TFA/CH2Cl2
3. Z-Cl/NaHCO3/CH2Cl2
4. Isobutylene/CH2Cl2/H2SO4
5. Bu4NOH/MeCN/H2O
1. BF3 Et2O/Et3SiH/CH2Cl2
2. LiBr/DBU/MeOH
3. Boc2O/DMAP/MeCN
Z-b2hTrp(Boc)-OMe
4
70
[23]
[21]
1. TBAF/THF
2. Isobutylene/CH2Cl2/H2SO4
3. NaOH/THF/H2O
t
Z-b2hTyr(Bu)-OH
2h
2b
52
61
Z-b2hVal-OH
LiOH/THF/H2O

Helvetica Chimica Acta Vol. 86 (2003)
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Table 2. X-Ray Crystal Structures (MOLMOL Presentation), Formulae, and Melting Points (in parentheses) of
DIOZ Derivatives Prepared in the Course of b2-Amino Acid Syntheses. Starting materials 1, primary products 2f,
3, 5, intermediates 9 15 on the way to the b2-amino acid derivatives, and other diphenyl-oxazolidinones 16 32
prepared for b-amino acid syntheses will be described in separate forthcoming papers. The 3-nitro-2-
methylpropanoyl-DIOZ derivative 24 and the imine 26 were prepared by Dr. E. Otchertianova, the N-nitroso-
oxazolidinone 27 by Dr. F. Rossi. Color code: N: blue, O: red, S: yellow, F: green, Cl: magenta, Br: dark green, C
and bonds: gray. Remarkably, the conformation around the Me2CHÀCH bond is identical in all 31 structures
shown: the tertiary H-atom of the i-Pr group points towards the neighboring quasi-equatorial Ph group. Thus, as
pointed out previously, the i-Pr group mimicks a t-Bu group, as far as facial bias of trigonal centers of
substituents at C(3) of the oxazolidinone is concerned (cf. the discussion and a superposition of 27 structures in
[13]). The crystal structure of (S,S)-N-Z-b2hIle-OH (see Table 1) has also been determined. The data sets of the
structures shown in this Table have been deposited with the Cambridge Crystallographic Data Center.

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Table 2 (cont.)

Helvetica Chimica Acta Vol. 86 (2003)
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Table 2 (cont.)

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Table 2 (cont.)

Helvetica Chimica Acta Vol. 86 (2003)
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Received March 14, 2003