N -aminoazetidinecarboxylic acid: Direct access to a small-ring hydrazino acid

Article abstract of DOI:10.1021/jo102108t

A short and efficient synthesis of the previously unknown N-aminoazetidinecarboxylic acid has been established using a photochemical [2 + 2] cycloaddition strategy starting from 6-azauracil. Chiral derivatization with a nonracemic oxazolidinone provided a

Full text of DOI:10.1021/jo102108t

pubs.acs.org/joc
acids.3 The specific “aza-substitution” of the β-carbon of a β-
N-Aminoazetidinecarboxylic Acid: Direct Access
to a Small-Ring Hydrazino Acid
amino acid implies an R-hydrazino acid, and oligomers of
these can be perceived as aza-β-peptides. Little work has
been done on such materials, however,4 and the first aza-β-
peptide structures containing 5-membered cyclic R-hydrazi-
no acids (aza-β-prolines) appeared only very recently.5
In keeping with the achievements and developments using
larger rings, cyclobutane β-amino acids (ACBC) (Figure 1)
have now emerged as useful building blocks.6 Oligomers of
cis-ACBC adopt strand-type conformations involving in-
traresidue hydrogen bonds.7 Dipeptides incorporating trans-
ACBC appear to adopt 8-membered hydrogen bond rings,8
while longer oligomers adopt a 12-helix conformation both
in solution and in the solid state.9
ꢀ
Valerie Declerck and David J. Aitken*
ꢁ
ꢀ
Laboratoire de Synthese Organique et Methodologie,
ICMMO (UMR 8182-CNRS), Universiteꢀ Paris-Sud 11,
15 rue Georges Clemenceau, 91405 Orsay cedex, France
david.aitken@u-psud.fr
Received October 25, 2010
FIGURE 1. AAzC, an aza-analogue of ACBC.
A short and efficient synthesis of the previously unknown
N-aminoazetidinecarboxylic acid has been established
using a photochemical [2 þ 2] cycloaddition strategy
starting from 6-azauracil. Chiral derivatization with a
nonracemic oxazolidinone provided access to both en-
antiomers of the title product.
The aza-analogue of ACBC, N-aminoazetidinecarboxylic
acid (AAzC), would appear to be an interesting compound
for continued studies (Figure 1). First, depending on the ring
nitrogen atom’s configuration, AAzC could be analogous to
trans-ACBC, or to cis-ACBC, or perhaps be in a fluxional
mode between these two limits. Furthermore, this additional
backbone nitrogen might behave as a hydrogen bond accep-
tor, serving to stabilize secondary structure in oligomers.4
However, the preparation of AAzC has never been pre-
viously described.
Since the first preparation of hydrazino acids in 1896 by
Traube,10 subsequently developed by Darapsky,11 only a few
methods have been established for their selective synthesis
and the procedures are sometimes difficult to carry out and/
or have a limited scope. A plausible synthetic precursor for a
given hydrazino acid is the corresponding amino acid,
although the transformation is not always straightfor-
ward.4d,5,12 L-Azetidinecarboxylic acid is commercially
available but prohibitively expensive, and the known syn-
thetic routes to this compound involve several steps.13 We
There is a growing interest in cyclic β-amino acids as
building blocks for the preparation of peptidomimetics
which exhibit useful pharmacological activities and for the
construction of molecular architectures displaying strong
self-organization.1 In particular, cyclopentane and cyclohex-
ane β-amino acids have been widely studied, since these
manifolds impart strong structuring propensities within their
oligomers.2 An “aza-replacement” in the peripheral part of
the carbocycle was envisaged by Gellman, who studied
peptides containing pyrrolidine and piperidine β-amino
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Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 13071–13072. (b) Appella,
D. H.; Christianson, L. A.; Klein, D. A.; Richards, M. R.; Powell, D. R.;
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Published on Web 12/23/2010
DOI: 10.1021/jo102108t
r
2010 American Chemical Society

Declerck and Aitken
JOCNote
SCHEME 1. Racemic Synthesis
wished to investigate an intriguing alternative approach
leading directly to AAzC, employing a photochemical [2 þ 2]
cycloaddition reaction to create the 4-membered ring. We
have previously found this strategy fruitful for the elabora-
tion of cyclobutane β-amino acids starting from uracil,14 and
although imines are not generally considered to be good
partners in [2 þ 2] photocycloadditions, there were sufficient
precedents involving nitogen heterocycles15 for us to inves-
tigate this approach.
Having established this expedient synthesis of racemic
N-aminoazetidine carboxylic acid (()-3, we embarked on
its chiral resolution. Esters of (()-5 were prepared by using
a selection of chiral alcohols (menthol, borneol, N-methyl-
ephedrine) but the diastereomeric separation could not be
achieved by either crystallization or chromatography. It
was previously noted that the resolution of cis-ACBC could
be achieved via amide formation with nonracemic R-phenyl-
ethylamine or R-(p-methoxyphenyl)ethylamine.16 However,
condensation of either of these reagents with (()-5 gave
diastereomeric amide mixtures which were very difficult to
separate. Noting a previous successful resolution by Evans,17
we decided to use a chiral oxazolidinone for the resolution of
(()-5. Best results were obtained with pivaloyl chloride to
activate the carboxylic acid of (()-5 as its tert-butyl anhy-
dride, which reacted with the lithium salt of (S)-benzylox-
azolidin-2-one to provide a mixture of the two diastereo-
isomers 6 and 7. These derivatives were easily separated by
chromatography and isolated in 36% and 33% yields,
respectively (Scheme 2).
A solution of commercially available 6-azauracil in an
acetone/water mixture (3:1) was irradiated with a 400 W
medium pressure Hg lamp fitted with a pyrex filter while
ethylene was bubbled slowly through the mixture. After 18 h,
the [2 þ 2] cycloadduct 1 was isolated in 71% yield (Scheme1).
Straightforward treatment of 1 with 0.5 M aqueous NaOH
provided the semicarbazide acid 2 in 97% yield. Hydrolysis
of a semicarbazide moiety generally requires treatment with
acidic or basic media in rather drastic conditions. Our
attempts to perform this transformation on 2 in various
conditions (1 M NaOH, 50 °C, 16 h; concd HCl, reflux, 16 h;
3 M H2SO4, reflux, 16 h) resulted in extensive degradation; at
best the hydrazino acid (()-3 was isolated in only 10% yield.
Attempts to perform the hydrolysis directly on the cyclo-
adduct 1 gave similarly disappointing results. To circumvent
this problem, we sought to improve the leaving group
character of the semicarbazide moiety. Treatment of the
cycloadduct 1 with 1 equiv of Boc2O in the presence of
DMAP allowed the selective introduction of a Boc group
at the N1 position, furnishing derivative 4 in 95% yield.
Gratifyingly, smooth cleavage of the heterocyclic ring en-
sued when compound 4 was treated with 1 M aqueous
NaOH, giving 90% of the Boc-protected hydrazino acid
(()-5. The Boc group was removed with TFA to give the
target N-aminoazetidine carboxylic acid (()-3 in 91% yield.
SCHEME 2. Chiral Resolution Using (S)-Benzyloxazolidin-2-one
One significant advantage of using an oxazolidine
as a chiral derivatizing agent is its facile removal, and
the treatment of each compound 6 and 7 with LiOOH
in aqueous THF allowed smooth and efficient cleavage
of the oxazolidinone auxiliary to furnish the two enantio-
mercially pure Boc-hydrazino acids (þ)-5 and (-)-5 in
quantitative yields. Furthermore, the oxazolidinone was
recovered and could be reused in subsequent resolution
operations (Scheme 3). TFA-mediated Boc group removal
from (þ)-5 and (-)-5 produced (þ)-3 and (-)-3, respec-
tively, in high yields.
(13) For a recent review, see: Couty, F.; Evano, G. Org. Prep. Proced. Int.
2006, 38, 427–465. For a very recent synthesis, see: Bouazaoui, M.;
Martinez, J.; Cavelier, F. Eur. J. Org. Chem. 2009, 2729–2732.
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(14) (a) Mondiere, A.; Peng, R.; Remuson, R.; Aitken, D. J. Tetrahedron
2008, 64, 1088–1093. (b) Fernandes, C.; Gauzy, C.; Yang, Y.; Roy, O.;
Pereira, E.; Faure, S.; Aitken, D. J. Synthesis 2007, 2222–2232. (c) Gauzy, C.;
Saby, B.; Pereira, E.; Faure, S.; Aitken, D. J. Synlett 2006, 1394–1398.
(d) Roy, O.; Faure, S.; Aitken, D. J. Tetrahedron Lett. 2006, 47, 5981–5984.
(e) Gauzy, C.; Pereira, E.; Faure, S.; Aitken, D. J. Tetrahedron Lett. 2004, 45,
7095–7097. (f) Aitken, D. J.; Gauzy, C.; Pereira, E. Tetrahedron Lett. 2002,
43, 6177–6179.
(15) For a comprehensive review of [2 þ 2] cycloadditions which includes
reactions leading to ring-fused azetidines, see: Crimmins, M. T.; Reinhold,
T. L. In Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons, Inc.:
New York, 1993; Vol. 44, pp 297-588.
(16) Fernandes, C.; Pereira, E.; Faure, S.; Aitken, D. J. J. Org. Chem.
2009, 74, 3217–3220.
(17) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F., Jr.
Tetrahedron 1988, 44, 5525–5540.
J. Org. Chem. Vol. 76, No. 2, 2011 709

Declerck and Aitken
JOCNote
SCHEME 3. Access to Single Enantiomers
observed for (N-Cβ)-(CR-CO) in the octamer of trans-
ACBC.9 The solid state structure also featured an 8-mem-
bered hydrogen-bonded ring, involving the amide NH and
the carbamate CO (with a CdO H;N distance of 2.38 A)
3 3 3
that was further stabilized by the hydrogen donor character
of the ring nitrogen atom with a NR H;N distance of
3 3 3
2.29 A; a “hydrazino turn” was thus clearly in evidence.4a,b,f,18
In summary, we have established a very short and efficient
synthesis of the previously unknown N-aminoazetidinecar-
boxylic acid 3 using a [2 þ 2] photocycloaddition strategy,
which obviates the intermediacy of azetidinecarboxylic acid.
Both enantiomers have been prepared by using a resolution
procedure that employs a chiral oxazolidinone and combines
easy separation with smooth cleavage and recycling of the
resolving agent. A first indication of the noncovalent bond
forming propensity of 3 is suggested by its adoption of a trans
relative configuration, so that the ring nitrogen may contribute
to the stabilization of a “hydrazino turn”. The title compound
should have some significant structuring potential in mixed
peptides with β-amino acids or in other aza-β-peptides.
SCHEME 4. Amide Formation
Experimental Section
1,2,4-Triazabicylo[4.2.0]octane-3,5-dione, 1. A solution of
6-azauracil (2.83 g, 25.0 mmol) in a 1:3 mixture of water and
acetone (1 L) placed in a cylindrical reactor was degassed with
an argon stream for 30 min, and then saturated with ethylene for
30 min. The solution was then irradiated for 18 h with a 400 W
medium-pressure mercury lamp fitted with a Pyrex filter and a
water-cooling jacket while ethylene was bubbled through. The
solution was then evaporated under reduced pressure. Flash
chromatography of the residue (CH2Cl2/MeOH = 98/2) gave a
yellow solid that was washed with a minimum amount of cold
MeOH to leave the cycloadduct 1 (2.49 g, 71%) as a white solid.
Mp 183 °C dec; Rf 0.31 (AcOEt); IR (KBr) ν 3236, 3045, 1713,
1699; 1H NMR (360 MHz, DMSO-d6) δ 1.90 (ddt, 1H, J2 = 10.8
Hz, J3 = 8.5Hz, J3 = 2.3Hz), 2.39 (tt, 1H, J2 = 10.5Hz, J3 = 8.2
Hz), 3.54 (tt, 1H, J3 = 7.4 Hz, J3 = 2.1 Hz), 3.58-3.67 (m, 1H),
4.12 (d, 1H, J3 = 8.1 Hz), 9.02 (s, 1H), 10.58 (s, 1H); 13CNMR (90
MHz, DMSO-d6) δ 20.6, 58.8, 61.5, 152.4, 172.8; HRMS (ESIþ)
calcd for C5H7N3NaO2 [M þ Na]þ 164.0436, found 164.0429.
1-(tert-Butyloxycarbonyl)-1,2,4-triazabicylo[4.2.0]octane-3,5-
dione, 4. To a suspension of cycloadduct 1 (2.15 g, 15.2 mmol,
1 equiv) in CH3CN (90 mL) was added Boc2O (3.32 g, 15.2 mmol,
1 equiv) and DMAP (18.6 mg, 0.15 mmol, 0.01 equiv). The
mixture was stirred for 14 h at room temperature, then the
solvent was evaporated under reduced pressure. Flash chroma-
tography of the residue (AcOEt/c-C6H12 = 30/70) gave the
bicyclic compound 4 (3.49 g, 95%) as a white solid. Mp 152 °C
dec; Rf 0.45 (AcOEt/c-C6H12 = 50/50); IR (KBr) ν 3160, 3101,
3003, 1746, 1695; 1H NMR (360 MHz, CDCl3) δ 1.54 (s, 9H),
2.11-2.20 (m, 1H), 2.64-2.76 (m, 1H), 3.81-3.96 (m, 2H),
4.41-4.46 (m, 1H), 8.14 (br s, 1H); 13C NMR (90 MHz, CDCl3)
δ 21.7, 28.0, 58.7, 64.7, 84.9, 148.1, 150.3, 171.9; HRMS (ESIþ)
calcd for C10H15N3NaO4 [M þ Na]þ 264.0953, found 264.0955.
1-(tert-Butyloxycarbonylamino)azetidine-2-carboxylic Acid,
(()-5. Bicyclic compound 4 (2.47 g, 10.2 mmol) was treated with
a 1 M aqueous NaOH solution (100 mL). The mixture was
stirred for 14 h at room temperature, then was cooled to 0 °C and
acidified with concentrated HCl to pH 2. The mixture was
extracted with AcOEt (5 ꢀ 50 mL). The combined organic
extracts were dried over MgSO4, filtered, and evaporated under
reduced pressure to give the Boc-hydrazino acid (()-5 (2.00 g,
90%) as a white solid. Mp 135 °C dec; IR (KBr) ν 3231, 2982,
1733, 1647, 1533; 1H NMR (360 MHz, CDCl3) δ 1.44 (s, 9H),
2.06-2.20 (m, 1H), 2.32-2.44 (m, 1H), 3.52-3.64 (m, 1H),
3.65-3.73 (m, 1H), 4.24 (t, 1H, J3 = 8.9 Hz), 6.54 (br s, 1H),
The absolute configuration of these new compounds was
deduced by single crystal X-ray analysis of the amide 8,
which was obtained by condensation of (-)-5 with (R)-R-(p-
methoxyphenyl)ethylamine (Scheme 4). The X-ray structure
(Figure 2) indicated an S configuration for compound (-)-5.
FIGURE 2. X-ray structure of compound 8.
Further examination of the crystal structure revealed a
configurational preference of the ring nitrogen which gives
a trans-like relative configuration, and a dihedral angle
(Nβ-NR)-(CR-CO) of 96.3° which is close to the value
€
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Collet, A.; Vicherat, A.; Marraud, M. Int. J. Pept. Protein Res. 1994, 44, 378–
387. (c) Aubry, A.; Mangeot, J.-P.; Vidal, J.; Collet, A.; Zerkout, S.; Maraud,
M. Int. J. Pept. Protein Res. 1994, 43, 305–311. (d) Marraud, M.; Dupont, V.;
Grand, V.; Zerkout, S.; Lelocq, A.; Boussard, G.; Vidal, J.; Collet, A.;
Aubry, A. Biopolymers 1993, 33, 1135–1148. (e) Aubry, A.; Bayeul, D.;
Mangeot, J.-P.; Vidal, J.; Sterin, S.; Collet, A.; Lecoq, A.; Marraud, M.
Biopolymers 1991, 31, 793–801.
710 J. Org. Chem. Vol. 76, No. 2, 2011

Declerck and Aitken
JOCNote
10.65 (br s, 1H); 13C NMR (90 MHz, CDCl3) δ 19.4, 28.3, 53.7,
69.7, 82.4, 156.6, 173.4; HRMS (ESI-) calcd for C9H15N2O4
[M - H]- 215.1037, found 215.1047. Anal. Calcd for C9H16-
N2O4: C, 49.99; H, 7.46; N, 12.96. Found: C, 49.88; H, 7.44;
N, 12.75.
possible risk of peroxide formation; appropriate hazard precau-
tions should be taken. To an ice-cold solution of compound 6
(1.17 g, 3.1 mmol, 1 equiv) in a 1:4 mixture of water and THF
(78 mL) was added a 35% w/w solution of H2O2 (1.6 mL,
18.7 mmol, 6 equiv). The resulting mixture was stirred for 5 min
at 0 °C then a solution of LiOH (149 mg, 6.2 mmol, 2 equiv)
in water (18 mL) was added. The mixture was stirred for
2 h at 0 °C, then 1 M Na2SO3 (40 mL) and saturated NaHCO3
(40 mL) were added successively. THF was removed under
reduced pressure and the aqueous residue was washed with
CH2Cl2 (3ꢀ40 mL) to remove the chiral auxiliary. The aqueous
phase was acidified to pH 1 with concentrated HCl and
extracted with CH2Cl2 (4 ꢀ 40 mL). The combined organic
extracts were dried over MgSO4, filtered, and evaporated
under reduced pressure to give the Boc-hydrazino acid (þ)-5
Chiral Derivatization with (S)-4-Benzyloxazolidin-2-one. To a
cold (-78 °C) solution of Boc-hydrazino acid (()-5 (1.90 g, 8.8
mmol, 1 equiv) and Et3N (1.47 mL, 10.5 mmol, 1.2 equiv) in dry
THF (18 mL) was added dropwise pivaloyl chloride (1.13 mL,
9.2 mmol, 1.05 equiv). The mixture was stirred for 1 h at 0 °C to
form the mixed anhydride, then cooled to -78 °C. In a separate
flask, a cold (ca. -40 °C) solution of (S)-4-benzyl-1,3-oxazoli-
din-2-one (1.55 g, 8.8 mmol, 1 equiv) in THF (18 mL) was
treated with n-BuLi (1.6 M solution in hexanes, 5.48 mL,
8.8 mmol, 1 equiv) and stirred for 5 min. The resulting solution
was added by rapid cannulation to the cooled (-78 °C) solution
of the mixed anhydride. Residual metalated oxazolidinone was
taken up by rinsing with dry THF (2 ꢀ 9 mL), and added to the
cooled reaction mixture; this latter was stirred for 1 h at -78 °C.
After warming to 0 °C, the mixture was diluted with CH2Cl2
(40 mL) and saturated NaHCO3 (20 mL). The organic phase was
collected and the aqueous phase was extracted with CH2Cl2 (4 ꢀ
15 mL). The combined organic phases were washed successively
with saturated NaHCO3 (10 mL) and brine (10 mL), dried over
MgSO4, filtered, and evaporated under reduced pressure. Flash
chromatography of the residue (Et2O/petroleum ether = 75/25)
gave the diastereoisomers 6 (1.18 g, 36%) and 7 (1.09 g, 33%) as
white solids. (S)-4-Benzyl-3-((R)-N-tert-butyloxycarbonylami-
noazetidine-2-carboxyl)oxazolidin-2-one, 6: mp 55 °C dec; Rf
0.75 (Et2O); [R]25D þ146 (c 0.50, CHCl3); IR (film) ν 3385, 3316,
2979, 1785, 1705, 1518, 1386, 1368; 1H NMR (360 MHz, CDCl3)
δ 1.46 (s, 9H), 2.06-2.17 (m, 1H), 2.44-2.55 (m, 1H), 2.85 (dd,
1H, J2 = 13.4 Hz, J3 = 9.3 Hz), 3.30 (dd, 1H, J2 = 13.4 Hz, J3 =
2.6 Hz), 3.61-3.68 (m, 1H), 4.02 (dt, 1H, J3 = 6.1 Hz, J3 = 8.4
Hz), 4.17-4.23 (m, 1H), 4.23-4.31 (m, 1H), 4.65-4.74 (m, 1H),
(647 mg, 96%) as a white solid. Mp 130 °C dec; [R]21 þ22
D
(c 0.50, CHCl3). Spectral data were as for (()-5.
(S)-(1-tert-Butyloxycarbonylamino)azetidine-2-carboxylic Acid,
(-)-5. The above procedure was repeated starting from com-
pound 7 (1.06 g, 2.8 mmol) to give the Boc-hydrazino acid (-)-5
(580 mg, 95%) as a white solid. Mp 130 °C dec; [R]21 -22
D
(c 0.51, CHCl3). Spectral data were as for (()-5.
(R)-1-Aminoazetidine-2-carboxylic Acid, (þ)-3. TFA (1.15
mL) was added dropwise to a solution of Boc-hydrazino acid
(þ)-5 (108 mg, 0.5 mmol) in CH2Cl2 (3.5 mL). The mixture was
stirred for 30 min at room temperature then the solvent was
evaporated under reduced pressure. The residue was taken up in
water and the resulting solution was deposited on a cation-
exchange column (Dowex 50X8W, Hþ, 50-100 mesh). The
column was washed with H2O until the eluent was neutral,
and the product was then eluted with 1 M NH4OH. Evaporation
(T < 25 °C) of appropriate fractions gave the hydrazino acid
(þ)-3 (57 mg, 98%) as a white solid. Mp 74 °C dec; [R]23D þ138
(c 0.50, H2O); IR (KBr) ν 3429, 1622, 1416, 1312; 1H NMR (360
MHz, D2O) δ 2.22-2.36 (m, 1H), 2.53-2.65 (m, 1H), 3.70-3.81
(m, 1H), 3.93-4.04 (m, 1H), 4.40-4.50 (m, 1H); 13C NMR (90
MHz, D2O) δ 19.2, 54.8, 72.3, 175.1; HRMS (ESI-) calcd for
C4H7N2O2 [M - H]- 115.0513, found 115.0511.
5.56 (t, 1H, J3 = 8.3 Hz), 6.59 (br s, 1H), 7.18-7.37 (m, 5H); 13
C
NMR (90 MHz, CDCl3) δ 19.3, 28.4, 37.8, 53.8, 55.0, 67.0, 67.8,
80.5, 127.4, 129.0, 129.5, 135.1, 153.0, 154.9, 171.8; HRMS
(ESIþ) calcd for C19H25N3NaO5 [M þ Na]þ 398.1686, found
398.1666. (S)-4-Benzyl-3-((S)-N-tert-butyloxycarbonylaminoa-
zetidine-2-carboxyl)oxazolidin-2-one, 7: mp 50 °C dec; Rf 0.33
(Et2O); [R]25D -49 (c 0.50, CHCl3); IR (neat) ν 3387, 3307, 2978,
(S)-1-Aminoazetidine-2-carboxylic Acid, (-)-3. The above
procedure was repeated starting from Boc-hydrazino acid (-)-
5 (108 mg, 0.5 mmol) to give the hydrazino acid (-)-3 (57 mg,
98%) as a white solid. Mp 73 °C dec; [R]23D -138 (c 0.50, H2O).
Spectral data were as for (þ)-3.
1
1785, 1702, 1518, 1386, 1368; H NMR (360 MHz, CDCl3) δ
1.49 (s, 9H), 2.03-2.15 (m, 1H), 2.39-2.51 (m, 1H), 2.82 (dd,
1H, J2 = 13.5 Hz, J3 = 9.6 Hz), 3.37 (dd, 1H, J2 = 13.5 Hz, J3 =
3.2 Hz), 3.59-3.67 (m, 1H), 4.02 (dt, 1H, J3 = 6.3 Hz, J3 = 8.3
Hz), 4.16-4.29 (m, 2H), 4.63-4.72 (m, 1H), 5.60 (t, 1H, J3 = 8.2
Hz), 6.58 (br s, 1H), 7.18-7.37 (m, 5H); 13C NMR (90 MHz,
CDCl3) δ 19.2, 28.5, 37.7, 53.7, 55.1, 67.0, 67.7, 80.6, 127.4,
129.0, 129.5, 135.3, 152.9, 155.0, 171.9; HRMS (ESIþ) calcd for
C19H25N3NaO5 [M þ Na]þ 398.1686, found 398.1674.
ꢀ
Acknowledgment. We are grateful to Dr. Regis Guillot
(ICMMO) for the X-ray diffraction analysis of compound 8.
Supporting Information Available: Experimental details,
1
spectral data, copies of H and 13C NMR spectra for all new
compounds, X-ray structure, and crystal data for compound 8
in CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
(R)-(1-tert-Butyloxycarbonylamino)azetidine-2-carboxylic Acid,
(þ)-5. Caution: The use of hydrogen peroxide in THF presents a
J. Org. Chem. Vol. 76, No. 2, 2011 711