Electrophilic Amination of Amino Acids with N-Boc-oxaziridines: Efficient Preparation of N-Orthogonally Diprotected Hydrazino Acids and Piperazic Acid Derivatives

Article abstract of DOI:10.1021/jo035700b

A general two-step preparation of enantiopure N_α,N _β-orthogonally diprotected α-hydrazino acids 1 is developed on a multigram scale. The key reaction is the efficient electrophilic amination of N-benzyl amino acids 6 with N-Boc-oxaziridine 7 and accommodates various functional groups encountered in side chains of amino acids. The cyclic 2,3,4,5-tetrahydro-3-pyridazine carboxylic acid (piperazic acid) derivatives 2 and 3 or the cyclic 3,4-dihydro-3-pyrazolecarboxylate 4 are conveniently prepared from glutamic acid or aspartic acid via orthogonally diprotected α-hydrazino acids 1m and 1n.

Full text of DOI:10.1021/jo035700b

Electr op h ilic Am in a tion of Am in o Acid s w ith N-Boc-oxa zir id in es:
Efficien t P r ep a r a tion of N-Or th ogon a lly Dip r otected Hyd r a zin o
Acid s a n d P ip er a zic Acid Der iva tives
J ean-Christophe Hannachi, J oe¨lle Vidal,* J ean-Christophe Mulatier, and Andre´ Collet
EÄ cole Normale Supe´rieure de Lyon, Ste´re´ochimie et Interactions Mole´culaires, UMR CNRS 5532,
46 Alle´e d’Italie, F 69364 Lyon Cedex 07, France
joelle.vidal@univ-rennes1.fr
Received November 19, 2003
A general two-step preparation of enantiopure NR,Nâ-orthogonally diprotected R-hydrazino acids 1
is developed on a multigram scale. The key reaction is the efficient electrophilic amination of
N-benzyl amino acids 6 with N-Boc-oxaziridine 7 and accommodates various functional groups
encountered in side chains of amino acids. The cyclic 2,3,4,5-tetrahydro-3-pyridazine carboxylic
acid (piperazic acid) derivatives 2 and 3 or the cyclic 3,4-dihydro-3-pyrazolecarboxylate 4 are
conveniently prepared from glutamic acid or aspartic acid via orthogonally diprotected R-hydrazino
acids 1m and 1n .
SCHEME 1. Str u ctu r es Con ta in in g a n
In tr od u ction
N-N-C-CdO F r a gm en t
Chemical modification of the peptide backbone is a
fruitful and well-established tool in the search for bio-
active compounds or elucidation of biological mecha-
nisms.1 Among pseudopeptides or peptidomimetics in-
vestigated in medicinal chemistry, those containing an
N-N-C-CdO fragment have a real potential. This motif
is found in several natural peptide compounds: the
antibiotic negamycine2 or the B6 vitamin antagonist
linatine3 are derivatives of R-hydrazino acids and more
than 20 linear or macrocyclic peptides with remarkable
biological properties contain the piperazic acid residue4,5
(Scheme 1). The L-enantiomer of piperazic acid also
resides within the bicyclic ring system of many bioactive
synthetic products such as cilazapril,6 a drug widely used
in the treatment of hypertension or pranalcasan,7 cur-
rently in phase II clinical trials as an antiinflammatory
agent. Synthetic hydrazinopeptides in which an R-amino
acid residue is replaced by an R-hydrazino acid (Scheme
1) behave as bioactive eledoisin analogues,8,9 turn-mi-
metics,10 or reversible inhibitors of human leukocyte
elastase.11 Hydrazinopeptides bearing an N-terminal
* Current address: Institut de Chimie de Rennes, Synthe`se et
EÄ lectrosynthe`se organiques, UMR CNRS 6510, Campus de Beaulieu,
F 35042 Rennes Cedex, France.
(1) (a) Houben-Weyl: Methods of organic chemistry. Synthesis of
Peptides and Peptidomimetics; Goodman, M., Felix, A., Moroder, L.,
Toniolo, C., Eds.; Georg Thieme Verlag: Stuttgart, Germany, 2002;
Vol. E22c. (b) Gante, J . Angew. Chem., Int. Ed. Eng. 1994, 33, 1699-
1720. (c) Nakanishi, H.; Kahn, M. Pract. Med. Chem. 1996, 571-590.
(d) Goodman, M.; Shao, H. Pure Appl. Chem. 1996, 68, 1303-1306.
(e) Hannessian, S.; McNaughton-Smith G.; Lombart, H.-G.; Lubell, W.
D. Tetrahedron 1997, 53, 12789-12854. (f) Ahn, J .-M.; Boyle, N. A.;
MacDonald, M. T.; J anda, K. D. Mini-Rev. Med. Chem. 2002, 2, 463-
473.
(6) Attwood, M. R.; Hassall, C. H.; Kro¨hn, A.; Lawton, G.; Redshaw,
S. J . Chem. Soc., Perkin Trans. 1 1986, 1011-1019.
(2) Hamada, M.; Takeuchi, T.; Kondo, S.; Ikeda, Y.; Naganawa, H.;
Maeda, K.; Okami, Y.; Umezawa, H. J . Antibiot. 1970, 23, 170-171.
(3) Klosterman, H. J .; Lamoureux, G. L.; Parsons, J . L. Biochemistry
1967, 6, 170-177.
(4) For a review, see: (a) Ciufolini, M.; Xi, N. Chem. Soc. Rev. 1998,
27, 437-445. (b) Hale, K. J .; Cai, J .; Delisser, V.; Manaviazar, S.; Peak,
S. A.; Bhatia, G. S.; Collins, T. C.; J ogiya, N. Tetrahedron 1996, 52,
1047-1068.
(5) Sanglifehrin (a powerful immunosupressant), chloptosin, and
pipalamycin (an apoptosis-inducing agent) are recently discovered
natural macrocyclic peptides containing the piperazic acid residue: (a)
Fehr, T.; Kallen, J .; Oberer, L.; Sanglier, J .-J .; Schilling, W. J . Antibiot.
1999, 52, 474-479. (b) Umezawa, K.; Ikeda, Y.; Uchihata, Y.; Naga-
nawa, H.; Kondo, S. J . Org. Chem. 2000, 65, 459-463. (c) Uchihata,
Y.; Ando, N.; Ikeda, Y.; Kondo, S.; Hamada, M.; Umezawa, K. J .
Antibiot. 2002, 55, 1-5.
(7) (a) Batchelor, M. J .; Bebbington, D.; Bemis, G. W.; Fridman, W.
H.; Gillespie, R. J .; Golec, J . M. C.; Gu, Y.; Lauffer, D. J .; Livingston,
D. J .; Matharu, S. S.; Mullican, M. D.; Murcko, M. A.; Murdoch, R.;
Nyce, P. L.; Robidoux, A. L. C.; Su, M.; Wannamaker, M.; Wilson, K.
P.; Zelle, R. E. PCT Int. Appl. WO 9722619, 1997. (b) Siegmund, B.;
Zeitz, M. IDrugs 2003, 6, 154-158.
(8) (a) Niedrich, H. Chem. Ber. 1967, 100, 3273-3282. (b) Grupe,
R.; Niedrich, H. Chem. Ber. 1967, 100, 3283-3288. (c) Niedrich, H.;
Ko¨ller, G. J . Prakt. Chem. 1974, 316, 729-740.
(9) (a) Oehme, P.; Bergmann, J .; Niedrich, H.; J ung, F.; Menzel, G.;
Eichsta¨dt, M.; Rudel, M. Acta Biol. Med. Ger. 1970, 25, 613-625. (b)
Oehme, P.; Katzwinkel, S.; Vogt, W. E.; Niedrich, H. Experientia 1973,
29, 947-948.
(10) Review: Kahn M. Synlett 1993, 821-826.
(11) Guy, L.; Vidal, J .; Collet, A.; Amour, A.; Reboud-Ravaux M. J .
Med. Chem. 1998, 41, 4833-4843.
10.1021/jo035700b CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/27/2004
J . Org. Chem. 2004, 69, 2367-2373
2367

Hannachi et al.
TABLE 1. P r ep a r a tion of Nr,Nâ-Dip r otected
L-Hyd r a zin o Acid 1a -m
SCHEME 2
L-hydrazino acid
derivative
acid (yield from 5) (yield from 6)
N-benzylamino
entry
Ri
CH(CH3)2
1
2
3
4
5
6
7
8
9
6a a (74%)
6ba (77%)
6cb
1a (48%)
1b (81%)
1c (52%)
1d c (63%)
1ed (40%)
1fe (71%)
1gf,g (91%)
1h g (41%)
1i (46%)
CH3
(S)-CH(CH3)CH2CH3
3-methyleneindole
(CH2)4NHCO2Bzl
CH2C6H4-pOBzl
(CH2)3S(O)CH3
CH2CONH2
6d a (72%)
6ea (65%)
6fa (52%)
6ga (75%)
6h a (53%)
6ia (73%)
6j (57%)
6k (86%)
6lb
(CH2)2CO2H
10 (CH2)2CO2CH3
11 CH2CO2Bzl
12 CH2OH
1je,h (71%)
1k e (56%)
1l (57%)
13 (CH2)3OH
6m (71%)
1m e (60%)
a
b
Prepared according to ref 23. Commercially available. c The
d
product was isolated as its hexylamine salt. The product was
achiral hydrazinoacetic acid residue prove to display
anticancer properties12 or to be very useful intermediates
in the preparation of lipopeptides,13 clustered glycoside-
antigen conjugates,14 or synthetic mannose receptor
ligands grafted on vesicles.15
From a structural point of view, we have shown that
the introduction of an N-N-C-CdO fragment in a
peptide chain induces a conformational bias, called a
hydrazino turn,16 which folds the peptide backbone locally
by way of a well-defined intramolecular bifurcated H-
bonding (Scheme 1). Such a folding is also found in
oligomers of NR-substituted hydrazino acetic acid.17 In
addition, recent quantum and molecular mechanics
calculations reveal that oligomers of R-hydrazino acids18
may adopt a wide variety of secondary structures and
thus may behave as foldamers.19
isolated as its dibenzylamine salt. e The product was isolated as
its dicyclohexylamine salt. f Mixture of the two diastereomeric
g
h
sulfoxides. The product was not recrystallized. See ref 22.
library of enantiopure NR-benzyl-Nâ-Boc-R-hydrazino
acids 1a -n from L-amino acids 5a -m (Scheme 2). The
key step rests on our methodology of electrophilic ami-
nation by oxaziridines21 and allows a smooth reaction on
a multigram scale between benzyl amino acids 6a -m and
the highly reactive N-Boc-oxaziridine 7.22 A convenient
transformation of synthons 1m and 1n into piperazic acid
derivatives 2-4 is also presented.
Resu lts a n d Discu ssion
Syn th esis of N-Or th ogon a lly Dip r otected Hy-
d r a zin o Acid s 1a -m . Orthogonal protection of both R-
and â-nitrogens was necessary in order to make synthons
1 compatible with conventional peptide synthesis.11 Our
synthetic strategy relied on delivering the NâH-Boc group
by electrophilic amination with oxaziridine 722 to an
easily available enantiopure amino acid derivative. At
this stage, the alternative was to introduce the NR-
protecting group before or after the electrophilic amina-
tion step. As we showed21a that electrophilic amination
was cleaner with secondary amines over primary amines
and proceeded faster when amines were more basic, we
chose N-benzyl rather than Z-protected R-amino acids as
nucleophilic precursor to 1 (Scheme 2).
Recently, we reported that incorporation of L-R-hy-
drazino acids in peptides is generally best accomplished
by means of NR,Nâ-orthogonally bis-protected derivatives
1 using conventional peptide synthesis methods11 (Scheme
2). As yet, diversity of R-hydrazino acids introduced in
synthetic hydrazinopeptides has been limited to aliphatic
or aromatic side chains (Ri ) H, Me, CH2Ph, iPr, sBu).8-15
To carry on further structural or biological studies about
pseudopeptides containing an N-N-C-CdO fragment,
we needed a general and short access to synthons 120
bearing diversely functionalized side chains. We wish to
report here an efficient two-step procedure leading to a
(12) Bouget, K.; Aubin, S.; Delcros, J .-G.; Arlot-Bonnemains Y.;
Baudy-Floc’h, M. Biorg. Med. Chem. 2003, 11, 4881-4889.
(13) Bonnet, D.; Ollivier, N.; Gras-Masse, H.; Melnyk, O. J . Org.
Chem. 2001, 66, 443-449.
(14) Grandjean, C.; Gras-Masse, H.; Melnyk, O. Chem. Eur. J . 2001,
7, 203-239.
(15) Chenevier, P.; Grandjean, C.; Loing, E.; Malingue, F.; Angyalosi,
G.; Gras-Masse, H.; Roux, D.; Melnyck, O. Bourel-Bonnet, L. J . Chem.
Soc., Chem. Commun. 2002, 2446-2447.
(16) (a) Aubry, A.; Bayeul, D.; Mangeot, J .-P.; Vidal, J .; Ste´rin, S.;
Collet, A.; Lecoq, A.; Marraud, M. Biopolymers 1991, 31, 793-801. (b)
Zerkout, S.; Dupont, V.; Aubry, A.; Vidal, J .; Collet, A.; Vicherat, A.;
Marraud M. Int. J . Pept. Prot. Res. 1994, 44, 378. (c) Aubry, A.;
Mangeot, J . P.; Vidal, J .; Collet, A.; Zerkout, S.; Lecoq, A.; Marraud
M. Int. J . Pept. Prot. Res. 1994, 43, 305. (d) Marraud, M.; Boussard,
G.; Vanderesse, R.; Collet, A.; Vidal, J .; Aubry, A. Actualite´s Chim.
The´r. 22nd Ser., 1995-96, 67-82.
(17) Cheguillaume A.; Salau¨n, A.; Sinbandhit, S.; Potel, M.; Gall,
P.; Baudy-Floc’h, M.; Le Grel, P. J . Org. Chem. 2001, 66, 4923-4929.
(18) Gu¨nther, R.; Hofmann, H.-J . J . Am. Chem. Soc. 2001, 123, 247-
255.
L-Benzyl amino acids 6a -m were prepared by reduc-
tive alkylation of enantiopure amino acids 5a -m . Quitt’s
method23 using benzaldehyde, NaBH4, and NaOH in
water generally gave good yields (Table 1, entries 1-9)
(20) For recent preparations of R-hydrazino acid derivatives, see:
(a) Oguz, U.; Guilbeau, G. G.; McLaughlin, M. L. Tetrahedron Lett.
2002, 43, 2873-2875. (b) Portlock, D. E.; Naskar, D.; West, L.; Li, M.
Tetrahedron Lett. 2002, 43, 6845-6847. (c) Brosse, N.; Pinto, M. F.;
Bodiguel, J .; J amart-Gre´goire, B. J . Org. Chem. 2001, 66, 2869-2873.
(21) (a) For electrophilic amination with oxaziridines, see: Vidal,
J .; Damestoy, S.; Guy, L.; Hannachi, J .-C.; Aubry, A.; Collet, A. Chem.
Eur. J . 1997, 3, 1691-1709. (b) For recent reviews on electrophilic
amination, see: Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J . 2000,
6, 1281-1286. (c) Genet, J . P.; Greck, C.; Lavergne, D. In Modern
amination methods; Ricci, A., Ed.; Wiley-VCH: Weinheim, Germany,
2000; p 65-102.
(22) Vidal, J .; Hannachi, J .-C.; Hourdin, G.; Mulatier, J .-C.; Collet,
A. Tetrahedron Lett. 1998, 39, 8845-8848.
(23) Quitt, P.; Hellerbach, J .; Vogler, K. Helv. Chim. Acta 1963, 46,
327-333.
(19) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180. (b) Hill,
D. J .; Mio, M. J .; Prince, R. B.; Hughes, T. S.; Moore, J . S. Chem. Rev.
2001, 101, 3893-4011.
2368 J . Org. Chem., Vol. 69, No. 7, 2004

Amination of Amino Acids with N-Boc-oxaziridines
SCHEME 3
SCHEME 4. Com p a r a tive P r ep a r a tion s of
N-Dip r otected Am in o-(5)-h yd r oxyn or va lin e 1m a n d
Access to N-Dip r otected Am in oh om oser in e 1n
except for the hydroxide-sensitive esters 6j and 6k or the
water-soluble 6m . To overcome these difficulties, the
intermediate benzylidene imines were prepared in situ
from 5j, 5k , or 5m ; benzaldehyde; and triethylamine in
anhydrous methanol and then reduced by NaBH4 to give
benzyl amino acids 6j, 6k , and 6m in good yields (Table
1, entries 10, 11, and 13).
reaction. So the enantiopurity of compounds 1 was
checked in one case. Only one enantiomer was detected
by chiral column HPLC analysis (Chiralpack OT+) after
CH2N2 derivatization of either crude L-Boc-aminobenzyl-
alanine 1b or D-Boc-aminobenzylalanine 1b.
Electrophilic amination of benzyl amino acids 6 used
N-Boc-3-(trichloromethyl)oxaziridine 7, which was easily
prepared on a large scale (75 g) in two steps from
chloral.22 The reaction was run in CH2Cl2 and in order
to obtain dissolution, benzyl amino acids 6 were con-
verted into their tetramethyl or tetraethylammonium salt
using the corresponding hydroxide. Exothermic reaction
of oxaziridine 7 with 6a salt was very rapid at 4 °C and
gave 1a with 38% yield. The yield was improved to 48%
when the reaction was carried out from -78 °C to room
temperature (Table 1, entry 1). Workup allowed the easy
removal of chloral released during the reaction, so that
crude diprotected hydrazino acids 1a -m were generally
pure enough for most purposes. N-Orthogonally dipro-
tected hydrazino acids 1a -m were either crystalline or
amorphous solids that were stable at 4 °C. After recrys-
tallization or derivatization as the appropriate amine
salt, good yields of crystalline 1a -m were obtained on a
multigram scale, allowing their commercial diffusion by
fine chemical suppliers (Table 1).
The indole side chain of tryptophane 6d did not require
protection, only the secondary amino group being suf-
ficiently reactive to be aminated by oxaziridine 7 (entry
4). We used conventional Z or Bzl protection on the basic
side chain of lysine 6e (primary amine, entry 5) or
tyrosine 6f (phenate,24 entry 6) derivatives. The thio-
ether25 function of N-benzylmethionine needed to be
protected by oxidation to diastereomeric sulfoxides 6g
(entry 7). No protection of the hydroxyl group of serine
6l or δ-hydroxynorvaline 6m derivatives was required
when the reaction conditions were controlled (entries 12,
13). In fact, a small amount of formiate 9 (8%) resulting
from acylation of the hydroxyl function of the side chain
with chloral26 released by oxaziridine 7 during the
amination step (step 2, Scheme 3) was isolated after
column chromatography along with expected compound
8 (65%). This side reaction could easily be avoided when
the temperature was set from -78 to 0 °C for 5 h.
Racemization is not normally a critical problem here,
because the asymmetric center is involved in neither the
reductive alkylation step nor the electrophilic amination
Access to P ip er a zic Acid Der iva tives 2-4. We next
examined the building of the dehydropiperazic acid six-
membered ring from enantiopure diprotected hydrazino
acid 1m . In the literature, the asymmetric synthesis of
the dehydropiperazic acid subunit, which is found in
several bioactive peptides,4 has been achieved in more
than six steps using stereoselective synthesis (trapping
of enolates bearing Evans’ chiral auxiliary with azodi-
carboxylate,27 stereoselective cycloaddition of azodicar-
boxylate to a chiral diene,28 or asymmetric reduction of
a dehydroamino acid followed by nitrosation29). Here, we
present a short access to enantiopure piperazic acid
derivatives 2-4 from commercial L-amino acids 5j or 5k ,
via orthogonally diprotected hydrazino acids 1m or 1n .
Two sequences were investigated in order to prepare
1m (Scheme 4). The first one used the nonproteogenic
δ-hydroxynorvaline 5m , which was prepared from glutam-
ic acid methyl ester 5j according to the method of Barlos30
(Scheme 4, sequence A). This approach required seven
steps from 5j (19% overall yield). Then, a shorter route
to 1m also starting from 5j and using the smooth LiBH4
reduction of methyl ester in N-diprotected aminoglutamic
acid compound 1j was explored (Scheme 4, sequence B).
Synthon 1m was thus obtained on a several-gram scale
with 35% overall yield from 5j. Sequence B was also
successfully applied to aspartic acid benzyl ester 5k and
led to diprotected aminohomoserine 1n in 45% overall
yield.
Next, we carried out oxidation of the hydroxy com-
pound 1m with the mild and selective 1-hydroxy-1,2-
benziodoxol-3(1H)-one 1-oxide (IBX)31 in DMSO solution,
since lactals obtained after PCC or perruthenate (TPAP)
oxidation of N-protected 1,4-amino alcohols are prone to
(27) (a) Nakamura, Y.; Shin, C. G. Chem. Lett. 1992, 49-52. (b)
Nakamura, Y.; Shin, C. G. Bull. Chem. Soc. J pn. 1994, 67, 2151-2161.
(c) Schmidt, U.; Riedl, B. J . Chem. Soc., Chem. Commun. 1992, 1186-
1187. (d) Xi, N.; Alemany, L. B.; Ciufolini, M. J . Am. Chem. Soc. 1998,
120, 80-86.
(24) Alkoxides are efficiently aminated by oxaziridine 7, see: Foot,
O. F.; Knight, D. W. J . Chem. Soc., Chem. Commun. 2000, 975-976.
(25) Thioethers are aminated to sulfilimines by oxaziridines. See
ref 21a and: Armstrong, A.; Cooke, R. S. J . Chem. Soc., Chem.
Commun. 2002, 904-905.
(26) For formylation of alcohols with chloral, see: Ram, R.; Meher,
N. K. Tetrahedron 2002, 58, 2997-3001.
(28) Aspinall, I. H.; Cowley, P. M.; Mitchell, G.; Stoodley, R. J . J .
Chem. Soc., Chem. Commun. 1993, 1179-1180. (b) Aspinall, I. H.;
Cowley, P. M.; Mitchell, G.; Raynor, C. M.; Stoodley, R. J . J . Chem.
Soc., Perkin Trans. 1 1999, 2591-2599.
(29) Schmidt, U.; Braun, C.; Sutoris, H. Synthesis 1996, 223-229.
(30) Barlos, K.; Mamos, P.; Papaioannou, D.; Patrianakou, S. J .
Chem. Soc., Chem. Commun. 1987, 1583-1584.
J . Org. Chem, Vol. 69, No. 7, 2004 2369

Hannachi et al.
SCHEME 5. P r ep a r a tion of P ip er a zic Der iva tives
2-4 fr om 1m a n d 1n
DMAP resulted in the unexpected formation of carbamic
carbonic anhydride 13, which proved to be unusually
stable. No evolution to the expected N-Boc carbazate35
was observed after prolonged treatment of 13 with DMAP
and thermal decomposition of 13 (studied by differential
scanning calorimetry) occurred at 150 °C. The Fmoc
protecting group was introduced using FmocCl to give
the stable and entirely protected compound 14. Hydro-
genation over Pd on charcoal resulted in both reduction
of the CdN double bond and cleavage of the benzyl NR
protecting group. The resulting unstable product was
derivatized with Sanger’s reagent to yield enantiopure,
crystalline, and stable derivative 12 in 59% overall yield.
All physical data of 12 were in agreement with litera-
ture,36 except melting point, which was significantly
higher.
SCHEME 6. Red u ction of P ip er a zic Der iva tive 3
Con clu sion
In conclusion, a library of enantiopure NR-benzyl-Nâ-
Boc-R-hydrazino acids 1a -n was prepared on a multi-
gram scale according to a two-step sequence, using
reductive alkylation of L-amino acids 5 and subsequent
efficient electrophilic amination with oxaziridine 7. Hy-
droxy-substituted synthons 1m and 1n were also conve-
niently transformed into piperazic acid derivatives 2-4.
The highly functionalized synthons 1a -n or 2 may find
applications in the combinatorial discovery of new bio-
active compounds or the design of stable peptide second-
ary structures containing one or several N-N-C-CdO
fragments. Further introduction of 1a -n or 2 in new
hydrazinopeptides or oligomers of R-hydrazino acids
using conventional peptide synthesis is currently under
investigation in our laboratory.
Exp er im en ta l Section
Gen er a l P r oced u r e for t h e Am in a t ion of N-Ben zyl-
a m in o Acid s 6 by Oxa zir id in e 7. A suspension of the
N-benzylamino acid (10 mmol) in MeOH (20 mL) was treated
at 0 °C with a solution of Me4NOH (or Et4NOH) in MeOH (4.55
mL, 10 mmol). After stirring for 5 min, the solution was
concentrated in vacuo. To the residue dissolved in CH2Cl2 (50
mL) was added dropwise at -78 °C a solution of oxaziridine
722 (2.75 g, 10.5 mmol) in CH2Cl2 (50 mL). The cooling bath
was allowed to warm slowly overnight. In the case of Bzl-Lys-
(ꢀ-Z) 6e, Bzl-Tyr(OBzl) 6f, or Bzl-Met(O) 6g, the reaction
mixture was concentrated in vacuo and the residue was
dissolved in water (120 mL). The basic aqueous phase was
washed with isopropyl ether (25 mL), acidified with KHSO4
(1.36 g) until pH ) 3-4, and then extracted with CH2Cl2 (3 ×
150 mL). In the other cases, the basic aqueous phase (3 × 200
mL) obtained after extraction of the reaction mixture was
washed with CH2Cl2 (25 mL), acidified with KHSO4 (1.36 g)
until pH ) 3-4, and then extracted with CH2Cl2 (3 × 150 mL).
In all cases, the final CH2Cl2 phase was dried over Na2SO4
overoxidation to butyrolactams32 (Scheme 5). Subsequent
treatment with TFA allowed hydrazone formation and
so delivered dehydropiperazic acid 2 in 39% overall yield.
Diazomethane esterification of 1m followed by oxidation
with IBX and TFA treatment resulted in a cleaner
reaction and led to dehydropiperazic acid derivatives 3
in good yield (76%; Scheme 5). Protection of the NR in
compound 8 proved to be essential, since cleavage of the
benzyl group prior to oxidation and then acidic treatment
did not lead to NR-unprotected 3. This sequence was also
successfully applied to analogue 1n and yielded (73%)
derivative 4, which is a useful precursor to a novel class
of proline surrogates33 (Scheme 5).
Reduction of the hydrazone function in 3 was also
investigated (Scheme 6). The use of NaBH3CN yielded
quantitatively 11, which was unstable and spontaneously
reoxidized to 3 (30% of 3 formed within 5 days at 4 °C34).
To improve stability, Nâ protection in 11 was examined.
Reacting Boc2O with 11 in the presence of catalytic
(34) The NR-unprotected analogue of 11 underwent decomposition
to the achiral conjugated hydrazone derivative at room temperature;
see: Paquette, L. A.; Duan, M.; Konetzki, I.; Kempmann, C. J . Am.
Chem. Soc. 2002, 124, 4257-4270.
(35) It was recently shown that carbamic carbonic anhydrides are
unstable intermediates in the formation of N-Boc-carbamates; see:
Basel, Y.; Hassner, A. J . Org. Chem. 2000, 65, 6368-6380.
(36) Bevan, K.; Davies, J . S.; Hassall, C. H.; Morton, R. B.; Phillips,
D. A. S. J . Chem. Soc. C 1971, 514-522. (b) Aspinall, I. H.; Cowley, P.
M.; Mitchell, G.; Stoodley, R. J . J . Chem. Soc., Chem. Commun. 1993,
1179-1180. (c) References 4b and 27b.
(31) For a convenient preparation of IBX (CAUTION: explosive
under impact or heating), see: Frigerio, M.; Santagostino M., Sputore,
S. J . Org. Chem. 1999, 64, 4537-4538.
(32) Olsen, R. K.; Ramasamy, K.; Emery, T. J . Org. Chem. 1984,
49, 3527-3534. (b) Altmann, K.-H. Tetrahedron Lett. 1993, 34, 7721-
7724.
(33) Mish, M. R.; Guerra, F. M.; Carreira, E. M. J . Am. Chem. Soc.
1997, 119, 8379-8380.
(37) De Boer, T. J .; Backer, H. J . Organic Syntheses; J ohn Wiley &
Sons: New York, 1963; Collect. Vol. IV, p 250-253.
2370 J . Org. Chem., Vol. 69, No. 7, 2004

Amination of Amino Acids with N-Boc-oxaziridines
and concentrated in vacuo. The crude product was generally
pure enough for most purpose. It could be either recrystallized
or reacted with an amine to afford a crystalline salt derivative.
138.3, 155.4, 157.0, 177.9. Anal. Calcd for C40H55N3O5 (657.9):
C, 73.03; H, 8.43; N, 6.39. Found: C, 73.07; H, 8.47; N, 6.33.
L-N -Be n zyl-N -(t er t -b u t oxyc a r b on yla m in o)m e t h io-
n in e (RS)-S-oxid e 1g. As described above, l-N-benzylme-
thionine (RS)-S-oxide (3.83 g, 15 mmol) and Et4NOH afforded
1g (5.05 g, 91%) as a colorless and solid mixture of two
L-N-Ben zyl-N-(ter t-bu toxyca r bon yla m in o)va lin e 1a . As
described above, L-N-benzylvaline (3.78 g, 18.2 mmol) and Me4-
NOH afforded crude 1a (3.51 g, 59%). Recrystallization from
boiling hexane (70 mL) yielded pure 1a as a colorless solid
diastereomers: [R]25 +7.5 (c 1.3, MeOH); 1H NMR (CDCl3) δ
D
(2.85 g, 48%): mp 108 °C; [R]25D +26.6 (c 1, MeOH) (lit.21a [R]25
1.34 (s, 9H), 2.04-2.28 (m, 2H), 2.60 and 2.63 (2 s, 3H), 3.12
(m, 1H), 3.37-3.48 (m, 2H), 3.99 and 4.06 (AB system, J ) 13
Hz, 2H), 6.86 (br s, 1H), 7.24-7.34 (m, 5H), 11.45 (br s, 1H);
13C NMR (CD3OD) δ 23.4 and 25.0 (two diastereomers), 28.5,
37.7 and 38.3 (two diastereomers), 51.2 and 52.1 (two diaster-
eomers), 62.0, 64.4 and 65.6 (two diastereomers), 81.0, 128.6,
129.3, 130.9, 138.2, 157.7, 174.8 and 174.9 (two diastereomers).
Anal. Calcd for C17H26N2O5S (370.5): C, 55.12; H, 7.07; N, 7.56;
S, 8.65. Found: C, 54.87; H, 7.00; N, 7.84; S, 8.22.
D
+25.6 (c 1, MeOH)). Analytical data were in full agreement
with those reported.21a
L-N-Ben zyl-N-(ter t-bu toxyca r bon yla m in o)a la n in e 1b.
As described above, L-N-benzylalanine (2.69 g, 15 mmol) and
Et4NOH afforded crude 1b (3.71 g, 84%). Recrystallization
from boiling cyclohexane (74 mL) yielded pure 1b as a colorless
solid (3.60 g, 81%): mp 118 °C; [R]25D +22.6 (c 1.2, MeOH); 1H
NMR (CDCl3) δ 1.32 (s, 9H), 1.38 (d, J ) 7 Hz, 3H), 3.64 (q, J
) 7 Hz, 1H), 3.95 (s, 2H), 6.08 (br s, 1H), 7.24-7.37 (m, 5H),
10.21 (br s, 1H); 13C NMR (CDCl3) δ 12.6, 28.0, 60.9, 81.3,
127.9, 128.5, 129.4, 135.6, 156.6, 175.7. Anal. Calcd for
L-N -B e n zy l-N -(t er t -b u t o x y c a r b o n y la m in o )a s p a r -
a gin e 1h . As described above, l-N-benzylasparagine (0.223 g,
1 mmol) and Me4NOH afforded 1h as a colorless glassy solid
(0.158 g, 41%): mp 169 °C; [R]25D -13.6 (c 1, MeOH); 1H NMR
(CDCl3) δ 1.28 (s, 9H), 2.70 (d, J ) 6.5 Hz, 2H), 3.82 (t, J )
6.5 Hz, 1H), 4.06 and 4.14 (AB system, J ) 12.5 Hz, 2H), 6.40
(br s, 1H), 6.67 (br s, 1H), 7.24-7.32 (m, 5H), 8.55 (br s, 1H);
13C NMR (CDCl3) δ 28.0, 35.9, 61.5, 62.8, 80.9, 127.8, 128.3,
129.7, 135.8, 156.9, 173.9, 176.1. Anal. Calcd for C16H23N3O5
(337.4): C, 56.96; H, 6.87; N, 12.46. Found: C, 56.75; H, 7.09;
N, 12.28.
C
15H22N2O4 (294.3): C, 61.21; H, 7.53; N, 9.52. Found: C,
60.95; H, 7.56; N, 9.57.
L-N-Ben zyl-N-(ter t-bu toxycar bon ylam in o)isoleu cin e 1c.
As described above, l-N-benzylisoleucine (4.44 g, 20 mmol) and
Et4NOH afforded crude 1c (4.40 g, 65%). Recrystallization from
boiling hexane (40 mL) yielded pure 1c (3.51 g, 52%). Analyti-
cal data were in full agreement with those reported.11
L -N -B e n z y l-N -(t er t -b u t o x y c a r b o n y la m i n o )t r y p -
top h a n e 1d , Hexyla m in e Sa lt. As described above, L-N-
benzyltryptophane (3.52 g, 12 mmol) and Me4NOH afforded
crude 1d (4.60 g, 93%) as a glassy solid. A portion of this solid
(0.331 g) was dissolved in ether (10 mL) and treated by
hexylamine (0.132 mL, 1 mmol) to yield pure 1d ‚hexylamine
salt as a colorless solid (0.322 g, 63%): mp 142 °C; [R]25D +28.6
(c 1.8, MeOH); 1H NMR (CDCl3,) δ 0.77 (t, J ) 7 Hz, 3H), 1.02-
1.16 (m, 8H), 1.33 (s, 9H), 2.25 (t, J ) 8 Hz, 2H), 3.15 (m, 2H),
3.61 (m, 1H), 3.98 and 3.88 (AB system, J ) 13 Hz, 2H), 6.93-
7.49 (m, 10H), 7.77 (br s, 3H), 9.04 and 9.37 (two rotamers, br
s, 0.27H and 0.73H); 13C NMR (CDCl3) δ (major rotamer) 13.9,
22.4, 26.5, 26.2, 28.0, 28.2, 31.2, 39.4, 61.0, 70.3, 79.8, 111.5,
112.0, 118.4, 118.9, 121.5, 123.5, 127.3, 127.6, 128.1, 129.7,
136.0, 136.4, 156.3, 182.5. Anal. Calcd for C29H42N4O4 (510.7):
C, 68.21; H, 8.29; N, 10.97. Found: C, 68.54; H, 8.17; N, 10.86.
L-N-Ben zyl-N-(ter t-bu toxycar bon ylam in o)glu tam ic Acid
1i. As described above, l-N-benzylglutamic acid (0.238 g, 1
mmol) and Et4NOH (2 mmol) afforded crude 1i (0.278 g, 79%).
Recrystallization from boiling isopropyl ether yielded pure 1i
as a colorless solid (0.162 g, 46%): mp 130 °C; [R]25 +12.2 (c
D
1.3, MeOH); 1H NMR (CDCl3) δ 1.33 (s, 9H), 1.97-2.14 (m,
2H), 2.55-2.78 (m, 2H), 3.51 (br s, 1H), 4.06 (br s, 2H), 6.45
(1H), 7.24-7.44 (m, 5H), 9.62 (br s, 1H); 13C NMR (CDCl3) δ
24.6, 28.0, 30.7, 61.2, 63.8, 80.7, 81.7, 127.7, 128.3, 129.7, 136.8,
155.9, 158.2, 175.8, 179.2. Anal. Calcd for C17H24N2O6 (352.4):
C, 57.94; H, 6.86; N, 7.95. Found: C, 58.14; H, 6.77; N, 7.92.
L-N-Ben zyl-N-(ter t-bu toxycar bon ylam in o)aspar tic Acid
4-(Ben zyl Ester ) 1k , Dicycloh exyla m in e Sa lt. L-N-benzyl-
aspartic acid 4-benzyl ester 6k (3.13 g, 10 mmol) was dissolved
in ice-cold water and reacted with ice-cold aqueous Me4NOH.
After lyophilization and as described above, crude 1k (3.93 g,
92%) was obtained. A portion of the crude 1k (0.275 g) in ether
(5 mL) was reacted with dicyclohexylamine (0.130 mL, 0.66
mmol) to yield pure 1k ‚dicyclohexylamine salt as a colorless
L-N-r-Ben zyl-N-E-ben zyloxyca r bon yl-N-r-(ter t-bu toxy-
ca r bon yla m in o)lysin e 1e, Diben zyla m in e Sa lt. As de-
scribed above, l-N-R-benzyl-N-(ꢀ-benzyloxycarbonyl)lysine 6e
(0.200 g, 0.55 mmol) and Et4NOH afforded crude 1e (0.200 g,
75%), which was dissolved in ether (10 mL). Treatment of the
solution by dibenzylamine (0.088 mL, 0.45 mmol) yielded pure
solid (0.231 g, 56%): mp 136 °C; [R]25 +16.7 (c 0.9, MeOH);
D
1H NMR (CDCl3) δ 1.15-1.65 (m, 21H), 1.76 (m, 4H), 1.96-
2.02 (m, 4H), 2.76-2.92 (m, 4H), 3.83 (t, J ) 8 Hz, 1H), 4.05
(br s, 2H), 5.11 (s, 2H), 7.21-7.30 (m, 10H); 13C NMR (CDCl3)
δ 24.7, 25.2, 28.2, 29.0 and 29.1 (two rotamers), 37.1, 52.5,
61.6, 64.0 and 66.0 (two rotamers), 77.6 and 78.7 (two
rotamers), 127.0, 127.9, 128.0, 128.4, 129.3, 136.3, 138.3, 155.2
and 156.5 (two rotamers), 171.6, 176.3. Anal. Calcd for
1e‚dibenzylamine salt as a colorless solid (0.150 g, 40%): mp
1
54 °C; [R]25 +24.7 (c 1.5, MeOH); H NMR (CDCl3) δ 1.20-
D
1.49 (m, 15H), 3.09 (m, 3H), 3.83 (br s, 6H), 5.02 (s, 2H), 5.23
(br s, 1H), 6.99-7.37 (m, 20H); 13C NMR (CDCl3) δ 23.0, 28.0,
28.9, 29.3, 40.0, 50.3, 61.1, 62.2, 66.1, 79.2, 127.0, 127.7, 127.8,
128.2, 128.3, 128.5, 129.0, 129.2, 129.3, 133.6, 136.7, 137.9,
C
35H51N3O6 (609.8): C, 68.94; H, 8.43; N, 6.89. Found: C,
155.6, 156.3, 178.4. Anal. Calcd for
(691.9): C, 69.44; H, 7.43; N, 8.10. Found: C, 69.68; H, 7.42;
N, 7.98.
C40H50N4O6‚0.5H2O
69.04; H, 8.25; N, 6.86.
L-N-Ben zyl-N-(ter t-bu toxyca r bon yla m in o)ser in e 1l. As
described above, L-N-benzylserine (4.68 g, 24 mmol) and Et4-
NOH afforded crude 1l (5.45 g, 73%). Recrystallization from a
mixture of boiling AcOEt (40 mL) and heptane (100 mL)
L-N ,O -D ib e n zy l-N -(t er t -b u t o x y c a r b o n y la m in o )t y -
r osin e 1f, Dicycloh exyla m in e Sa lt. As described above,
L-N,O-dibenzyltyrosine (2.9 g, 8 mmol) and Me4NOH afforded
crude 1f (3.59 g, 94%) as a glassy solid, which was dissolved
in a mixture of ether (15 mL) and hexane (30 mL). Treatment
of the solution by dicyclohexylamine (1.8 mL, 9 mmol) yielded
pure 1f‚dicyclohexylamine salt as a colorless solid (3.73 g,
71%): mp 105 °C; [R]25D +37.3 (c 1.4, MeOH); 1H NMR (CDCl3)
δ 1.16-1.67 (m, 21H), 1.80 (m, 4H), 2.00 (m, 4H), 2.95 (m, 4H),
3.39 (m, 1H), 3.96 (s, 2H), 5.03 (s, 2H), 6.84 (d, J ) 8,5 Hz,
2H), 7.17-7.40 (m, 12H), 7.83 (br s, 1H); 13C NMR (CDCl3) δ
24.7, 25.2, 28.2, 29.1, 29.3, 35.8 and 36.3 (two rotamers), 52.5,
61.8, 69.2, 70.0, 78.7 and 79.0 (two rotamers), 114.1, 126.8,
127.4, 127.8, 128.3, 128.5, 129.3, 130.4, 132.9, 137.4, 137.8,
yielded pure 1l as a colorless solid (4.25 g, 57%): mp 145 °C
(dec); [R]25 +9.6 (c 1.1, MeOH); H NMR (CDCl3) δ 1.30 (s,
1
D
9H), 3.68-4.36 (m, 5H), 6.38 (br s, 1H), 7.23-7.36 (m, 5H);
13C NMR (CDCl3) (two rotamers) δ major and (minor): 28.0
and (27.8), 59.7 and (59.3), 61.5 and (62.3), 66.4 and (67.5),
81.2 and (82.8), 127.8, 128.4, 129.2, 130.0, 136.1 and (136.4),
157.2 and (158.0), 174.2 and (172.8). Anal. Calcd for C15H22N2O5
(310.3): C, 58.05; H, 7.14; N, 9.03. Found: C, 57.63; H, 7.02;
N, 8.95.
L-N-Ben zyl-N-(ter t-bu toxyca r bon yla m in o)-δ-h yd r oxy-
n or va lin e 1m , Dicycloh exyla m in e Sa lt. As described above,
L-N-benzyl-δ-hydroxynorvaline (0.222 g, 1 mmol) and Et4NOH
J . Org. Chem, Vol. 69, No. 7, 2004 2371

Hannachi et al.
were reacted with oxaziridine 7 for 5.5 h from -78 to 0 °C.
Crude 1m (0.338 g, 100%) was then dissolved in AcOEt and
reacted with dicyclohexylamine (0.200 mL, 1 mmol) to yield
pure 1m ‚dicyclohexylamine salt as a colorless solid (0.314 g,
128.5, 128.8, 137.0, 138.0, 175.0. Anal. Calcd. for C12H14N2O2
(218.2): C, 66.04; H, 6.47; N, 12.84. Found: C, 65.53; H, 6.38;
N, 12.84.
Meth yl (S)-2-Ben zyl-2,3,4,5-tetr a h yd r o-3-p yr id a zin e-
ca r boxyla te 3. L-N-Benzyl-N-(tert-butoxycarbonylamino)-δ-
hydroxynorvaline [obtained after extraction by ether of a
mixture of the dicyclohexylamine salt 1m (4.42 g, 8.5 mmol)
and KHSO4 (1.19 g, 0.5 mmol) in water] was reacted with a
60%): mp 159 °C; [R]25 +39.8 (c 1, MeOH); 1H NMR (CDCl3)
D
δ 1.18-1.46 (m, 25H), 1.80 (m, 4H), 2.00-2.05 (m, 4H), 2.89-
3.01 (m, 2H), 3.23 (m, 1H), 3.56-3.65 (m, 2H), 3.94-4.10 (m,
2H), 7.24-7.37 (m, 5H), 7.87 (br s, 1H); 13C NMR (CDCl3) δ
24.7, 25.2, 27.3, 28.1 and 28.3 (two rotamers), 29.2 and 29.4
(two rotamers), 31.3, 52.6, 61.6, 62.1, 67.5, 79.0, 127.1, 128.0,
129.6, 137.6, 156.1, 179.1. Anal. Calcd for C29H49N3O5 (519.7):
C, 67.02; H, 9.50; N, 8.09. Found: C, 67.10; H, 9.33; N, 8.05.
37
slight excess of CH2N2 in ether. The mixture was concen-
trated in vacuo to give the crude methyl ester 8 as a colorless
solid, which was dissolved in DMSO (25 mL) and reacted with
IBX31 (2.81 g, 10 mmol) for 15 h. The resulting mixture was
diluted with water (50 mL) and CH2Cl2 (200 mL). After
filtration of the solid, the aqueous phase was extracted by CH2-
Cl2. The combined organic phases were washed with water,
dried over Na2SO4, and concentrated in vacuo. The resulting
oily residue was dissolved in CH2Cl2 (80 mL) and reacted with
TFA (4.2 mL, 1.3 mmol) for 4 h at room temperature. The
mixture was washed with water and aqueous saturated
NaHCO3, dried over Na2SO4, and concentrated in vacuo.
Purification by column chromatography (silica gel; ether/
hexane, 1:2) afforded methyl (S)-2-benzyl-2,3,4,5-tetrahydro-
L-N-Ben zyl-N-(ter t-bu toxyca r bon yla m in o)-δ-h yd r oxy-
n or va lin e 1m , Dicycloh exyla m in e Sa lt (by Red u ction of
1j). LiBH4 (0.590 g, 25.6 mmol) was slowly added at 0 °C and
under Ar to a solution in dry THF (30 mL) and dry MeOH
(1.05 mL, 25.6 mmol) of crude L-N-benzyl-N-(tert-butoxycar-
bonylamino)-5-(methyl ester)glutamic acid (4.71 g, 12.8 mmol)
prepared22 from L-N-benzyl-5-(methyl ester)glutamic acid (3.77
g, 15 mmol). The resulting mixture was refluxed for 2.5 h,
cooled to 0 °C, and then slowly poured into a cold mixture of
0.1 M aqueous citric acid (200 mL) and CH2Cl2 (200 mL). The
aqueous phase was extracted by CH2Cl2. The combined organic
phases were dried over Na2SO4 and then concentrated in
vacuo. The residue (4.21 g) was dissolved in diisopropyl ether
(80 mL) and reacted with diclyclohexylamine (2.5 mL, 12.5
mmol) to yield 4.87 g of l-N-benzyl-N-(tert-butoxycarbonyl-
amino)-δ-hydroxynorvaline 1m , dicyclohexylamine salt (62%
from 6j).
3-pyridazinecarboxylate 3 (1.50 g, 76% from 1m ) as a light
1
brown solid: mp 30 °C; [R]25 +13.7 (c 1, MeOH); H NMR
436
(CDCl3) δ 1.94-2.18 (m, 4H), 3.68 (t, J ) 4.5 Hz, 1H), 3.71 (s,
3H), 4.25 and 4.56 (AB system, J ) 14.5 Hz, 2H), 6.65 (t, J )
3 Hz, 1H), 7.24-7.31 (m, 5H); 13C NMR (CDCl3) δ 20.1, 21.7,
51.9, 56.4, 60.3, 127.3, 128.3, 128.62, 135.9, 137.7, 172.0. Anal.
Calcd for C13H16N2O2 (232.3): C, 67.22; H, 6.94; N, 12.06.
Found: C, 67.41; H, 6.97; N, 11.99.
L-N-Ben zyl-N-(ter t-b u t oxyca r b on yla m in o)h om oser -
in e 1n , Diben zyla m in e Sa lt (by Red u ction of 1k ). In the
same way, reduction of crude L-N-benzyl-N-(tert-butoxycarbo-
nylamino)aspartic acid 4-(benzyl ester) (3.93 g) prepared from
L-N-benzylaspartic acid 4-(benzyl ester) (3.13 g, 10 mmol) with
LiBH4 afforded crude 1n (3.5 g). It was dissolved in ether (40
mL) and reacted with dibenzylamine (2 mL, 10. mmol) to yield
2.69 g of 1n ‚dibenzylamine salt (52% from 6k ) as a colorless
Met h yl (S)-2-Ben zyl-3,4-d ih yd r o-3-p yr a zoleca r b oxy-
la te 4. In the same way, L-N-benzyl-N-(tert-butoxycarbonyl-
amino)homoserine 1n , dibenzylamine salt (0.261 g, 0.5 mmol)
afforded 4 (0.080 g, 73% from 1n ) as a light yellow oil: [R]25
D
-193.8 (c 1.1, MeOH); 1H NMR (CDCl3) δ 2.82-3.07 (2H), 3.64
(s, 3H), 3.64 (t, J ) 12 Hz, 1H), 4.30 and 4.39 (AB system, J
) 14 Hz, 2H), 6.67 (s, 1H), 7.14-7.41 (m, 5H); 13C NMR
(CDCl3) δ 38.7, 52.3, 58.8, 64.4, 127.5, 128.3, 129.7, 136.0,
140.9, 171.9. Anal. Calcd. for C12H14N2O2 (218.2): C, 66.04;
H, 6.47; N, 12.84. Found: C, 65.87; H, 6.55; N, 12.64.
solid: mp 124 °C; [R]25 +25.5 (c 1, MeOH); 1H NMR (CDCl3)
D
δ 1.36 (s, 9H), 1.80 (m, 2H), 3.35 (m, 1H), 3.59 (m, 1H), 3.74
(m, 1H), 3.86 (s, 4H), 3.94 (s, 2H), 7.24-7.52 (m, 15H); 13C
NMR (CDCl3) δ 28.1 and 28.3 (two rotamers), 50.5, 60.9, 61.7,
62.7, 65.8 and 66.1 (two rotamers), 80.0 and 80.5 (two
rotamers), 127.4, 128.3, 128.6, 128.8, 129.5, 130.8, 133.5, 137.0
and 137.4 (two rotamers), 155.8 and 156.2 (two rotamers),
177.8. Anal. Calcd for C30H39N3O5 (521.6): C, 69.07; H, 7.54;
N, 8.06. Found: C, 68.89; H, 7.67; N, 8.08.
Ca r ba m ic Ca r bon ic An h yd r id e 13. To methyl (S)-2-
benzyl-2,3,4,5-tetrahydro-3-pyridazinecarboxylate 3 (0.116 g,
0.50 mmol) in acetic acid (1 mL) was added in small portions
sodium cyanoborohydride (0.085 g, 1.4 mmol). The resulting
mixture was stirred for 30 min at room temperature and then
diluted with water (20 mL) and CH2Cl2 (20 mL). Saturated
aqueous NaHCO3 was added until pH ) 8. After usual workup,
the crude product, which was unstable, was dissolved in THF
(1 mL) and immediately reacted with Boc2O (0.218 g, 1 mmol)
in the presence of (dimethylamino)pyridine (7 mg, 0.06 mmol)
and triethylamine (140 mL, 1 mmol) at room temperature. The
mixture was stirred overnight and then diluted with ether and
washed with aqueous citric acid. The organic phase was dried
over Na2SO4 and concentrated in vacuo. The resulting solid
was recrystallized in boiling hexane to give carbamic carbonic
(S)-2-Ben zyl-2,3,4,5-t et r a h yd r o-3-p yr id a zin eca r b ox-
ylic Acid 2. L-N-Benzyl-N-(tert-butoxycarbonylamino)-δ-hy-
droxynorvaline (0.185 g) [obtained after extraction by ether
of a mixture of the dicyclohexylamine salt 1m (0.260 g, 0.5
mmol) and KHSO4 (0.070 g, 0.5 mmol) in water] was dissolved
in DMSO (2 mL) and reacted at room temperature with IBX31
(0.182 g, 0.65 mmol) for 15 h. The resulting mixture was
diluted with water (20 mL) and CH2Cl2 (20 mL). After filtration
of the solid, the aqueous phase was extracted with CH2Cl2.
The combined organic phases were washed with water, dried
over Na2SO4, and concentrated in vacuo. The resulting oily
residue (185 mg) was dissolved in CH2Cl2 (3 mL) and reacted
with TFA (0.1 mL, 1.3 mmol) for 3 h at room temperature.
The resulting mixture was diluted with CH2Cl2 and saturated
NaHCO3. The aqueous phase was washed with CH2Cl2,
acidified to pH 2 by aqueous citric acid, and then extracted by
CH2Cl2. The combined organic phases were dried over Na2-
SO4 and then concentrated in vacuo. The resulting solid (65
mg) was recrystallized in a THF/ether mixture to yield 2 (43
anhydride 13 (0.116 g, 61% from 3): mp 62 °C; IR (KBr): 1728,
1
1742, 1764 cm-1. [R]25 -90.2 (c 1, MeOH); H NMR (CDCl3)
D
δ 1.46-2.15 (m, 13H), 3.17-4.24 (m, 8H), 7.24-7.51 (m, 5H);
13C NMR (CDCl3) δ 18.4, 20.1, 27.6, 37.5, 52.2, 57.6 and
57.7 (two rotamers), 84.0, 127.9, 128.6, 129.0, 129.2, 129.6,
136.0, 148.1, 150.1, 171.5. HRMS (FAB) calcd for C19H27N2O6
(MH+) 379.1869, found 379.1878. Anal. Calcd for C19H26
-
N2O6 (378.4): C, 60.31; H, 6.92; N, 7.40. Found: C, 60.48; H,
6.96; N, 7.40.
Meth yl (S)-1-(9-F lu or en ylm eth oxyca r bon yl)-2-ben zyl-
h exa h yd r o-3-p yr id a zin eca r boxyla te 14. To methyl (S)-2-
benzyl-2,3,4,5-tetrahydro-3-pyridazinecarboxylate 3 (0.141 g,
0.61 mmol) in acetic acid (1.3 mL) was added in small portions
sodium cyanoborohydride (0.104 g, 1.74 mmol). The resulting
mixture was stirred for 30 min at room temperature and then
diluted with water (20 mL) and CH2Cl2 (20 mL). Saturated
aqueous NaHCO3 was added until pH ) 8. After usual workup,
mg, 39%) as white needles: mp 140 °C; [R]25 -18.0 (c 0.55,
D
1
THF); H NMR (CDCl3) δ 1.80-1.85 (m, 1H), 2.09-2.12 (m,
2H), 2.22-2.26 (m, 1H), 3.79 (t, J ) 4.5 Hz, 1H), 4.34 and 4.63
(AB system, J ) 14.5 Hz, 2H), 6.84 (t, J ) 1 Hz, 1H), 7.28-
7.36 (m, 5H); 13C NMR (CDCl3) δ 19.9, 20.2, 56.4, 60.5, 127.6,
2372 J . Org. Chem., Vol. 69, No. 7, 2004

Amination of Amino Acids with N-Boc-oxaziridines
the crude product, which was unstable, was dissolved in CH2-
Cl2 (2 mL) and immediately reacted with FmocCl (0.174 g, 0.67
mmol) in the presence of pyridine (150 µL, 1.85 mmol) for 5 h.
The mixture was diluted with CH2Cl2 and the organic phase
was washed with water and aqueous citric acid, dried over Na2-
SO4, and concentrated in vacuo. Purification by column chro-
matography (silica gel; ether/hexane, 2:3) afforded methyl
(S)-1-(9-fluorenylmethoxycarbonyl)-2-benzylhexahydro-3-py-
dissolved in EtOH (0.5 mL) and reacted for 6 h with triethyl-
amine (0.046 mL, 0.33 mmol) and 2,4-dinitro-1-fluorobenzene
(0.042 mL, 0.33 mmol). Purification by column chromatogra-
phy (silica gel; AcOEt/hexane, 1:3) afforded methyl (S)-1-(2,4-
dinitrophenyl)hexahydro-3-pyridazinecarboxylate 12 (60 mg,
59%) as a yellow solid: mp 115 °C (lit. mp 37-39 °C,36a 96-
97 °C,4b 95-96 °C,27b 94-95 °C36b); [R]25 -365 (c 0.7, MeOH)
D
(lit.4b [R]D +358 (c 0.64, MeOH) for the (R) isomer). 1H and
13C NMR spectra were in full agreement with those reported.36
ridazinecarboxylate 14 (0.203 g, 73% from 3) as a colorless
1
oil: [R]25 -48.8 (c 1, MeOH); H NMR (CDCl3) δ 1.58-2.06
D
(m, 4H), 3.25 (t, J ) 11.5 Hz, 1H), 3.53 (sl, 3H), 3.53-4.33 (m,
7H), 7.24-7.45 and 7.73-7.83 (m, 13H); 13C NMR (CDCl3) δ
18.7, 20.2, 36.6, 47.4, 51.8, 57.1 and 57.8 (two conformers),
67.7, 119.8, 125.4-129.4, 136.4, 141.3, 144.2 and 144.3 (two
conformers), 156.6, 171.7. Anal. Calcd for C28H28N2O4 (456.5):
C, 73.66; H, 6.18; N, 6.14. Found: C, 73.43; H, 6.06; N, 6.16.
Meth yl (S)-1-(2,4-Din itr op h en yl)h exa h yd r o-3-p yr id a -
zin eca r boxyla te 12. A mixture of methyl (S)-2-benzyl-2,3,4,5-
tetrahydro-3-pyridazinecarboxylate 3 (77 mg, 0.33 mmol) and
TFA (0.026 mL, 0.33 mmol) in MeOH (2 mL) was hydrogenated
(1 bar, room temperature) for 17 h in the presence of wet 5%
Pd on charcoal (13 mg, Degussa type E101). After filtration
over Celite and concentration in vacuo, the residue was
Ack n ow led gm en t. Dr S. Piguel (Universite´ de
Rennes 1) is gratefully acknowledged for careful reading
of the manuscript. This manuscript is dedicated to the
memory of Prof. A. Collet, who died on October 26, 1999.
Su p p or tin g In for m a tion Ava ila ble: General methods,
experimental procedures, and characterization data for com-
pounds 5m , 6d , 6f, 6g, 6h , 6i, 6j, 6k , 6m , 8, and 9; HPLC
analysis of 1b; and NMR spectra for 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O035700B
J . Org. Chem, Vol. 69, No. 7, 2004 2373