Simple access to novel azetidine-containing conformationally restricted amino acids by chemoselective reduction of β-lactams

Article abstract of DOI:10.1016/j.tetlet.2004.01.023

Reduction with diphenylsilane and catalytic amounts of tris(triphenylphosphine)rhodium(I) carbonyl hydride resulted in an efficient, chemoselective method for the transformation of amino-acid-derived β-lactams into the corresponding azetidines, which afte

Full text of DOI:10.1016/j.tetlet.2004.01.023

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2193–2196
Simple access to novel azetidine-containing conformationally
restricted amino acids by chemoselective reduction of b-lactams
a
Guillermo Gerona-Navarro, M Angeles Bonache, Miriam Alıas,
a
b
a
ꢀ
M Jesus Perez de Vega, M Teresa Garcıa-Lopez, Pilar Lopez,
a
a
b
a
a
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
a,
Carlos Cativielab, and Rosario Gonzalez-Muniz
*
*
ꢀ
~
aInstituto de Quꢀımica Mꢀedica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
b
ꢀ
ꢀ
Departamento de Quımica Organica, ICMA, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Received 15 December 2003; revised 7 January 2004; accepted 7 January 2004
Abstract—Reduction with diphenylsilane and catalytic amounts of tris(triphenylphosphine)rhodium(I) carbonyl hydride resulted in
an efficient, chemoselective method for the transformation of amino-acid-derived b-lactams into the corresponding azetidines, which
after removal of the p-methoxybenzyl group, afforded a new family of conformationally restricted amino acids. Phe-derived
compounds were obtained in enantiopure form by combining HPLCresolution of the b-lactam precursor and the above-mentioned
procedure.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Incorporation into peptides of amino acids with
restricted / dihedral angles is a general strategy to
induce reverse turn conformations. This kind of con-
straint could be achieved through Na-Ca-cyclizations
but, with the exception of some a-alkylprolines, scarce
attention has been paid to these kinds of restricted
amino acid derivatives.1;2 In this context, the four-
membered ring of azetidines 2 fixes the / torsion angle
in values of approximately 70ꢁ or )70ꢁ, depending on
the relative configuration at the C2 stereogenic center.
These values are very close to those described for the
corner amino acids in standard b- and c-turns.3 To the
best of our knowledge, only three references in the lit-
erature deal with the synthesis of a-substituted azet-
idine-a-carboxylic acids, related to 2. Thus, the Seebach
group reported the stereoselective synthesis of com-
pounds 2 [R1 ¼ CH(OH)R] by hydroxyalkylation of
enantiopure azetidine-2-carboxylic acid derivatives.4
Alternatively, azetidines 2 (R1 ¼ Et, R2 ¼ R3 ¼ H, and
R1 ¼ Bzl, R2 ¼ Et, R3 ¼ Boc) have been prepared by
Seebach and Kawabata groups following Ca fi Na- and
Na fi Ca-cyclizations of chiral halo amino acid deriva-
tives, respectively.5;6
Recently, we have described a simple method for the
preparation of b-lactams 1,7 with a suitable substitution
pattern that make them attractive precursors of the
corresponding azetidines 2, just by reduction of the
b-lactam ring carbonyl group (Chart 1). However, most
of the methods described for the reduction of b-lactams
to azetidines, LiAlH4, NaBH4–AlCl3 DIBAL-H,
AlClH2, and AlCl2H,8 are not compatible with the
presence of ester groups. In this paper we describe a
straightforward procedure for the chemoselective
reduction of compounds 1 to the corresponding azeti-
dine-containing restricted amino acids 2. A combination
of chiral HPLCresolution of the racemic b-lactam and
the application of the reduction procedure here reported
allowed us to prepare pure R and S enantiomers of a
Phe-derived azetidine.
R1
N
R1
N
CO2R2
R3
CO2R2
R3
Keywords: b-Lactams; Azetidines; Chemoselective reduction; Restric-
ted amino acids; Chiral HPLC; Resolution.
O
* Corresponding authors. Tel./fax: +34-976-761210 (C.C.), tel.: +34-
91-562-2900; fax: +34-91-5644853 (R.G.); e-mail addresses: cativiel@
posta.unizar.es; iqmg313@iqm.csic.es
1
2
Chart 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.023

2194
G. Gerona-Navarro et al. / Tetrahedron Letters 45 (2004) 2193–2196
The search for appropriate reduction conditions was
performed using the Trp derivative 1a as model com-
pound. All attempts to reduce 1a with diborane9
resulted in complex mixtures of compounds from which,
in the best case, the expected azetidine 2a was obtained
in only 34% yield. Although it has been claimed that the
reduction of tertiary lactams with 9-BBN proceeds
chemoselectively in the presence of esters,10 the appli-
cation of this procedure to compound 1a resulted in the
simultaneous reduction of the b-lactam carbonyl group
and the 4-methyl ester, to give azetidine 4 as the major
product (Chart 2).
Fortunately, much better results were found following
the method described by Ito and co-workers for the
reduction of tertiary amides with diphenylsilane and
rhodium catalysts.11 Following this procedure, azet-
idines 2a–c, and 2h were obtained in 51–64% yield from
the corresponding Trp- and Glu-derived b-lactams 1a–c,
and 1h, respectively (Scheme 1, Table 1). Improved
yields were obtained in the reduction of 2-azetidinones
derived from Phe, Ala, Leu, and Orn. In general, this
reducing method is chemoselective with respect to car-
t
boxylic esters (Me, Bu) and to urethane moieties (Boc,
Z).12;13
Removal of the 1-Pmb group by catalytic hydrogenation
in the presence of Pd(OH)2 as catalyst gave the
1-unsubstituted azetidines 3 (Scheme 1, Table 1).14;15
Compound 3h was obtained along with a 13% of the
1-(10-hydroxy)ethyl derivative 5 (Chart 2), probably
resulting from the addition of 3h to the acetaldehyde
stabilizing the MeOH used as solvent. Due to the reac-
tion conditions needed for the removal of the Pmb
group in derivative 2i are not compatible with the
presence of the benzyloxycarbonyl moiety, this Z-pro-
tected Orn derivative was transformed into the corre-
sponding Boc analogue 2j (H2/Pd–C/Boc2O, 80%), prior
to the transformation to the corresponding 1-unsubsti-
tuted azetidine 3j (Scheme 2).
t
CO2 Bu
HN
t
CO2 Bu
N
OH
OH
Pmb
N
4
5
Me
Chart 2.
R1
R1
N
R1
NH
3
CO2R2
CO2R2
CO2R2
N
H2/Pd(OH)2
HCl
Ph2SiH2
RhH(CO)(PPh3)3
R3
R3
O
With a suitable method for the preparation of the
azetidine-containing amino acids, the next issue we
addressed was the possibility of preparing these com-
pounds in enantiomerically pure form. For that pur-
pose, the HPLCanalytical resolution of Phe derivatives
1
2
a: R1 = CH2In, R2 = Me, R3 = Pmb
b: R1 = CH2In, R2 = tBu, R3 = Bzl
c: R1 = CH2In(Boc), R2 = tBu, R3 = Pmb
d: R1 = CH2Ph, R2 = Me, R3 = Pmb
e: R1 = CH2Ph, R2 = tBu, R3 = Pmb
f: R1 = CH3, R2 = Me, R3 = Bzl
g: R1 = CH2CH(CH3)2, R2 = tBu, R3 = Pmb
h: R1 = (CH2)2CO2 Bu, R2 = tBu, R3 = Pmb
i: R1 = (CH2)3NHZ, R2 = Me, R3 = Pmb
j: R1 = (CH2)3NHBoc, R2 = Me, R3 = Pmb
(Pmb = p-methoxybenzyl)
ZHN
BocHN
BocHN
t
CO2Me
Pmb
CO2Me
Pmb
CO2Me
NH
H2/Pd-C
Boc2O
H2/Pd(OH)2
HCl
N
N
2i
Scheme 2.
3j
2j
Scheme 1.
Table 1. Transformation of b-lactams 1 to azetidines
Entry
Starting compound
Reduction method
2 (%)a
3 (%)a
1
1a
1a
1a
1b
1c
1d
1e
1f
B2H6/THF/65 ꢁC34
9-BBN/THF/65 ꢁC––
––
b
2
––
70c
––
––
93
78
––
––
55d
95e
3
Ph2SiH2/RhH(CO)(PPh3)3/THF/Ar/rt
Ph2SiH2/RhH(CO)(PPh3)3/THF/Ar/rt
Ph2SiH2/RhH(CO)(PPh3)3/THF/Ar/rt
Ph2SiH2/RhH(CO)(PPh3)3/THF/Ar/rt
Ph2SiH2/RhH(CO)(PPh3)3/THF/Ar/rt
Ph2SiH2/RhH(CO)(PPh3)3/THF/Ar/rt
Ph2SiH2/RhH(CO)(PPh3)3/THF/Ar/rt
Ph2SiH2/RhH(CO)(PPh3)3/THF/Ar/rt
Ph2SiH2/RhH(CO)(PPh3)3/THF/Ar/rt
51
58
64
94
90
85
90
62
89
4
5
6
7
8
9
1g
1h
1i
10
11
a Yield of isolated compound.
b 2-Hydroxymethyl azetidine derivative 4 (24%) was obtained as the major compound.
c Hydrogenation performed with Pd black.7a
d Compound 5 (13%) was also isolated.
e Compound 3j obtained from Boc-derivative 2j.

G. Gerona-Navarro et al. / Tetrahedron Letters 45 (2004) 2193–2196
2195
1d, 2d, and 3d was tested on four different silica-bonded
chiral phases.16 Compound 1d could be separated into
their corresponding enantiomers on CSP-1 and CSP-3,
and 2d could be resolved on CSP-2. The best resolution
was achieved for b-lactam 1d using the CSP-1, derived
of mixed 10-undecenoate/3,5-dimethylphenyl-carbamate
of cellulose (Fig. 1A). Therefore, compound 1d was
selected as the most appropriate candidate to carry out
the preparative chromatography. Working in an over-
load mode with the analytical column, the conditions
established at this level were scaled up to preparative
chromatography.17 Thus, enantioseparation of a quasi
racemic mixture of (R)- and (S)-1d18 was achieved by
successive injections, using the peak shaving technique.
In this way, enriched mixtures of each enantiomer of 1d
were obtained (85% and 92% enantiomeric purity of first
and last eluted enantiomers, respectively). Optically
pure compounds were finally obtained by crystallization
of the above-mentioned mixtures19 (Scheme 3, Fig. 1B
and C). The absolute configuration of enantiomerically
pure b-lactams 6d has been previously established.20
Saponification of optically pure enantiomers of 1d to
obtain both enantiomers of 6d and comparison of the
sign of their optical rotation with the values reported in
CO2Me
NH
CO2Me
Pmb
CO2Me
Pmb
N
N
H2/Pd(OH)2
HCl
Ph2SiH2
RhH(CO)(PPh3)3
O
(S)-3d
[α]D = -145.2
(S)-1d
(S)-2d
[α]D = +24.7
(c = 1, CHCl3) (c = 0.04, EtOAc/sat. with HCl)
CO2Me
NH
CO2Me
CO2Me
Pmb
N
N
H2/Pd(OH)2
HCl
Ph2SiH2
RhH(CO)(PPh3)3
O
Pmb
(R)-3d
[α]D = +142.0
(R)-1d
(R)-2d
[α]D = -24.9
(c = 1, CHCl3) (c = 0.07, EtOAc/sat. with HCl)
Scheme 4.
Ref. 20 permitted assignment of the (S)-configuration to
the less retained enantiomer and the (R) stereochemistry
to the more retained enantiomer.21
Once the enantiomerically pure precursors (S)-1d and
(R)-1d were available, they were subjected to the previ-
ously established reducing method, affording 1-Pmb
derivatives (S)-2d and (R)-2d. Finally, removal of Pmb
group in these latter compounds allowed the prepara-
tion of the desired optically pure Phe-derived conform-
ationally constrained amino esters hydrochlorides (S)-3d
and (R)-3d (Scheme 4).
In summary, we have demonstrated that the use of
diphenylsilane, in the presence of tris(triphenylphos-
phine)-rhodium(I) carbonyl hydride as catalyst, is an
efficient and versatile method for the chemoselective
reduction of b-lactams to azetidines. This procedure was
compatible with the presence of commonly used car-
boxylic acid and amino protecting groups. In the case of
a Phe derivative, HPLCresolution of the racemic
b-lactam precursor, using a noncommercial cellulose-
derived stationary phase, has allowed the preparation of
both enantiomers of the azetidine restricted amino ester
3d in optically pure form. The ability of these con-
strained amino acids to induce folded conformations
upon incorporation into peptides is now under investi-
gation, and will be published in due course.
Figure 1. HPLCanalytical resolution of racemate 1d (A), and resolved
enantiomers (S)-1d (B) and (R)-1d (C). Column: 150 · 4.6 mm ID
containing 3,5-dimethylphenylcarbamate of cellulose (CSP-1). Eluent:
n-hexane/2-propanol 96:4. Flow rate: 0.8 mL/min. UV detection:
210 nm. Chromatographic parameters: k10 ¼ 2:43; a ¼ 1:18; RS ¼ 1:52.
CO2Me
Pmb
CO2H
Pmb
b
N
N
O
O
(S)-1d
[α]D = +30.6
(c = 1, CHCl3)
(S)-6d
[α]D = +47.3
(c = 0.52, CHCl3)
CO2Me
Pmb
N
a
References and notes
O
(R,S)-1d
ꢀ
1. Cativiela, C.; Dıaz-de-Villegas, M. D. Tetrahedron: Asym-
metry 2000, 11, 645–732.
b
CO2Me
N
CO2H
N
2. (a) Thaisrivongs, S.; Pals, D. T.; Lawson, J. A.; Turner, S.
R.; Harris, D. W. J. Med. Chem. 1987, 30, 536–541; (b)
Hinds, M. G.; Welsh, J. H.; Brennand, D. M.; Fischer, J.;
Glennie, M. J.; Richards, N. G. J.; Turner, D. L.;
Robinson, J. A. J. Med. Chem. 1991, 34, 1177–1189; (c)
Fincham, C. I.; Horwell, D. C.; Ratcliffe, G. S.; Rees, D.
C. Bioorg. Med. Chem. Lett. 1992, 2, 403–406; (d) Bisang,
C.; Weber, C.; Inglis, J.; Schiffer, C. A.; van Gunsteren, W.
O
O
Pmb
Pmb
(R)-1d
[α]D = -29.6
(c = 1, CHCl3)
(R)-6d
[α]D = -48.8
(c = 0.51, CHCl3)
Scheme 3. (a): (i) HPLCresolution, (ii) crystallization; (b): (i) 2 N
NaOH, (ii) HCl (pH ¼ 3).

2196
G. Gerona-Navarro et al. / Tetrahedron Letters 45 (2004) 2193–2196
F.; Jelesarov, I.; Bosshard, H. R.; Robinson, J. A. J. Am.
Chem. Soc. 1995, 117, 7904–7915.
3. Rose, G. D.; Gierasch, L. M.; Smith, J. A. Adv. Protein
Chem. 1985, 37, 1–109.
and 40 psi of pressure for 15 h. After filtration of the
catalyst, the solvent was evaporated and the final azetidine
hydrochloride was precipitated with Et2O. Purification by
column chromatography was required in some instances.
15. Selected analytical and spectroscopic data for azetidine 3d:
mp: 118–120 ꢁC(EtOAc/hexane). 1H NMR (200 MHz,
CDCl3): 7.36–7.26 (m, 7H, C6H5 and NHþ2 ), 4.03 (m, 2H,
4-H), 3.78 (s, 3H, OMe), 3.77 (d, 1H, 2-CH2, J ¼ 14:2 Hz),
3.46 (d, 1H, 2-CH2, J ¼ 14:2 Hz), 2.74 (m, 2H, 3-H). Anal.
Calcd For C12H16ClNO2: C, 59.63; H, 6.67; Cl, 14.67; N,
5.79. Found: C, 59.40; H, 6.55; Cl, 14.03; N, 5.86.
16. Chiral stationary phases (CSPs) were prepared by covalent
bonding of a mixed polysaccharide derivative on allyl silica
gel. CSPs used in this work contained the mixed 10-un-
decenoate/3,5-dimethylphenylcarbamate of cellulose (CSP-1),
10-undecenoate/p-methylbenzoate of cellulose (CSP-2),
10-undecenoate/phenylcarbamate of cellulose (CSP-3)
and 10-undecenoate/3,5-dimethylphenylcarbamate of
amylose (CSP-4) as chiral selectors: (a) Oliveros, L.;
€
4. Seebach, D.; Vettiger, T.; Muller, H.-M.; Plattner, D. A.;
Petter, W. Liebigs Ann. Chem. 1990, 687–695.
5. Seebach, D.; Dziadulewicz, E.; Behrendt, L.; Cantoreggi,
S.; Fitzi, R. Liebigs Ann. Chem. 1989, 1215–1232.
6. While preparing this manuscript, a four-step synthesis of
the Phe-derived azetidine 2 (R1 ¼ Bzl, R2 ¼ Et, R3 ¼ Boc)
was published, but the configuration of the main obtained
isomer was not reported: Kawabata, T.; Kawakami, S.;
Majumdar, S. J. Am. Chem. Soc. 2003, 125, 13012–13013.
7. (a) Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.;
ꢀ
Garcıa-Lopez, M. T.; Gonzalez-Muniz, R. Synlett 2000,
1249–1252; (b) Gerona-Navarro, G.; Bonache, M. A.;
ꢀ
ꢀ
~
ꢀ
Herranz, R.; Garcıa-Lopez, M. T.; Gonzalez-Muniz, R.
J. Org. Chem. 2001, 66, 3538–3547.
ꢀ
ꢀ
~
8. (a) Verkoyen, C.; Rademacher, P. Chem. Ber. 1984, 117,
1659–1670; (b) Yamashita, M.; Ojima, I. J. Am. Chem.
Soc. 1983, 105, 6339; (c) Ojima, I.; Yamato, T.; Naka-
hashi, K. Tetrahedron Lett. 1985, 26, 2035–2038; (d)
Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K. J. Org.
Chem. 1991, 56, 5263–5277; (e) Sudo, A.; Iitaka, Y.; Endo,
T. J. Polym. Sci. Part A: Polym. Chem. 2002, 40, 1912–
1917.
9. (a) Brown, H.; Heim, P. J. Org. Chem. 1973, 38, 912–916;
(b) Adachi, K.; Tsuru, E.; Banjyo, E.; Doe, M.; Shibata,
K.; Yamashita, T. Synthesis 1998, 1623–1626.
10. Collins, C. J.; Lanz, M.; Singaram, B. Tetrahedron Lett.
1999, 40, 3673–3676.
ꢀ
Lopez, P.; Minguillon, C.; Franco, P. J. Liq. Chromatogr.
1995, 18, 1521–1532; (b) Minguillon, C.; Franco, P.;
ꢀ
ꢀ
Oliveros, L.; Lopez, P. J. Chromatogr. A 1996, 728, 407–
414.
17. Preparative resolution of 1d was carried out on a
150 · 20 mm ID column containing the same CSP as
analytical column, 10-undecenoate/3,5-dimethylphenyl-
carbamate of cellulose covalently linked to allyl silica
gel. Although chloroform had led to a lower resolution
factor, elution was performed in a mixture of n-hexane/2-
propanol/chloroform 96:2:2 to increase the sample solu-
bility and, then, the column loadability. Flow rate: 15 mL/
min. UV detection: 254 nm.
18. Although compound 1d could be obtained in an enantio-
selective manner due to the memory of chirality phenom-
enon, for the resolution process it was prepared in almost
racemic form (enantiomeric ratio: 43/57) using a combi-
nation of N-methyl-2-pyrrolidone as solvent and BEMP as
11. Kuwano, R.; Takahashi, M.; Ito, Y. Tetrahedron Lett.
1998, 39, 1017–1020.
12. General procedure for the b-lactam reduction: To a
solution of the corresponding azetidinone (5.01 mmol) in
dry THF (5 mL) was added, under Ar atmosphere,
tris(triphenyl-phosphine)rhodium(I) carbonyl hydride
(46 mg, 1%) and diphenylsilane (2.3 mL, 12.5 mmol). After
15 h of reaction at room temperature, the solvent was
evaporated to give a residue that was dissolved in Et2O
and washed twice with 1 M HCl. The aqueous layer was
treated with 2 N NaOH to pH 10 and extracted with
EtOAc. The organic layer was washed with brine and
dried over Na2SO4. Evaporation to dryness afforded the
corresponding 1-Pmb-azetidine that usually did not
required further purification.
13. Selected spectroscopic data for compound 2d: 1H NMR
(300 MHz, CDCl3): d 7.18 and 6.80 (m, 9H, Ar-H), 3.72 (s,
3H, OMe), 3.68 (s, 3H, OMe), 3.67 (d, 1H, 1-CH2,
J ¼ 12:7 Hz), 3.50 (d, 1H, 1-CH2, J ¼ 12:7 Hz), 3.21 (d,
1H, 2-CH2, J ¼ 13:3 Hz), 3.10 (m, 2H, 4-H), 3.09 (d, 1H,
2-CH2, J ¼ 13:3 Hz), 2.41 (m, 1H, 3-H), 2.12 (m, 1H, 3-
H). 13C NMR (75 MHz, CDCl3): d 173.06 (COO), 158.52,
136.50, 130.23, 129.75, 129.55, 128.06, 126.37, 113.55 (Ar),
72.86 (2-C), 55.28 (1-CH2), 55.06 (OMe), 51.17 (OMe),
49.48 (4-C), 40.98 (2-CH2), 25.74 (3-C). ES-MS: 326.4
(M+1)þ.
ꢀ
base: (a) Bonache, M. A.; Gerona-Navarro, G.; Martın-
Martınez, M.; Garcıa-Lopez, M. T.; Lopez, P.; Cativiela,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
C.; Gonzalez-Muniz, R. Synlett 2003, 1007–1011; (b)
Bonache, M. A.; Gerona-Navarro, G.; Garcıa-Aparicio,
~
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
C.; Alıas, M.; Martın-Martınez, M.; Garcıa-Lopez, M. T.;
Lopez, P.; Cativiela, C.; Gonzalez-Muniz, R. Tetrahedron:
ꢀ
ꢀ
~
Asymmetry 2003, 14, 2161–2169.
19. Under the conditions described above, a total of 1 g of 1d
was injected in 3.3 mL of CHCl3 and each run (0.2 mL)
was collected into three separated fractions. The first
combined fraction (245 mg) and the last one (335 mg)
contained mainly one of the enantiomers (85% and 92% of
enantiomeric purity, respectively). The third fraction
(400 mg) was reinjected and similar enantioselectives
mixtures were obtained. Crystallization of the enriched
mixtures in ethanol/hexanes led to the optically pure
compounds. By this procedure 275 and 285 mg of the
first and second eluted enantiomers of 1d can be
obtained.
ꢀ
ꢀ
ꢀ
20. Gerona-Navarro, G.; Garcıa-Lopez, M. T.; Gonzalez-
~
14. General method for the removal of 1-Pmb group: To a
solution of the corresponding 1-(p-methoxy)benzylazet-
idine (3.86 mmol) in MeOH (75 mL) was successively
added HCl 12 M (0.34 mL, 3.86 mmol) and Pd(OH)2 (20%
w/w). The obtained suspension was hydrogenated at 50 ꢁC
Muniz, R. J. Org. Chem. 2002, 67, 3953–3956.
21. Polarimetry data of (S)- and (R)-6d, prepared according to
the HPLCresolution procedure described here, are higher
than those reported in Ref. 20, indicating a more accurate
resolution in this case.