Synthesis of novel enantiopure 4-hydroxypipecolic acid derivatives with a bicyclic β-lactam structure from a common 3-azido-4-oxoazetidine-2- carbaldehyde precursor

Article abstract of DOI:10.1021/jo702405h

(Chemical Equation Presented) Two different stereocontrolled accesses to new 4-hydroxypipecolic acid analogues with a bicyclic β-lactam structure have been developed by using intramolecular reductive amination or allenic hydroamination reactions in 2-azet

Full text of DOI:10.1021/jo702405h

Synthesis of Novel Enantiopure
4-Hydroxypipecolic Acid Derivatives with a
Bicyclic â-Lactam Structure from a Common
3-Azido-4-oxoazetidine-2-carbaldehyde Precursor
Benito Alcaide,*,† Pedro Almendros,*,‡ Amparo Luna,† and
Teresa Mart´ınez del Campo†
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica,
UniVersidad Complutense de Madrid, 28040-Madrid, Spain, and
Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la
CierVa 3, 28006-Madrid, Spain
FIGURE 1. Representative biologically relevant 4-hydroxypipecolic
acids.
In addition to the important medicinal properties of the
â-lactam nucleus,6 the 2-azetidinone skeleton has been exten-
sively used as a template on which to build cyclic structures
fused to the four-membered ring, using the chirality and
functionalization of the â-lactam nucleus as a stereocontrolling
element.7 On the other hand, when designing peptide-based
drugs, the use of conformationally constrained amino acids is
alcaideb@quim.ucm.es; palmendros@iqog.csic.es
ReceiVed NoVember 7, 2007
(3) (a) Sakai, R.; Matsubara, H.; Shimamoto, K.; Jimbo, M.; Kamiya,
H.; Namikoshi, M. J. Nat. Prod. 2003, 66, 784. (b) Ornstein, P. L.; Arnold,
M. B.; Lunn, W. H. W.; Heinz, L. J.; Leander, J. D.; Lodge, D.; Schoepp,
D. D. Bioorg. Med. Chem. Lett. 1998, 8, 389. (c) Skiles, J. W.; Giannousis,
P. P.; Fales, K. R. Bioorg. Med. Chem. Lett. 1996, 6, 963. (d) Mannaioni,
G.; Alesiani, M.; Carla`, V.; Natalini, B.; Marinozzi, M.; Pellicciari, R.;
Moroni, F. Eur. J. Pharmacol. 1994, 251, 201. (e) Pellicciari, R.; Natalini,
B.; Constantino, G.; Garzon, A.; Luneia, R.; Mahmoud, M. R.; Marinozzi,
M.; Roberti, M.; Rosato, G. C.; Shiba, S. A. Farmaco 1993, 48, 151. (f)
Pellicciari, R.; Natalini, B.; Luneia, R.; Marinozzi, M.; Marinella, R.; Rosato,
G. C.; Sadeghpour, B. M.; Snyder, J. P.; Monahan, J. B.; Moroni, F. Med.
Chem. Res. 1992, 2, 491.
(4) (a) Beaulieu, P. L.; Anderson, P. C.; Cameron, D. R.; Croteau, G.;
Gorys, V.; Grand-Maˆıtre, C.; Lamarre, D.; Liard, F.; Paris, W.; Plamondon,
L.; Soucy, F.; Thibeault, D.; Wernic, D.; Yoakim, C. J. Med. Chem. 2000,
43, 1094. (b) Lamarre, D.; Croteau, G.; Bourgon, L.; Thibeault, D.; Wardrop,
E.; Clouette, C.; Vaillancourt, M.; Cohen, E.; Pargellis, C.; Yoakim, C.;
Anderson, P. C. Antimicrob. Agents Chemother. 1997, 41, 965.
(5) For a review on the synthesis of enantiopure pipecolic acid derivatives,
including 4-hydroxypipecolic acids, see: (a) Kadouri-Puchot, C.; Comesse,
S. Amino Acids 2005, 29, 101. For selected references, see: (b) Cordero,
F. M.; Bonollo, S.; Machetti, F.; Brandi, A. Eur. J. Org. Chem. 2006, 3235.
(c) Lloyd, R. C.; Lloyd, M. C.; Smith, M. E. B.; Holt, K. E.; Swift, J. P.;
Keene, P. A.; Taylor, S. J. C.; McCague, R. Tetrahedron 2004, 60, 717.
(d) Marin, J.; Didierjean, C.; Aubry, A.; Casimir, J.-R.; Briand, J.-P.;
Guichard, G. J. Org. Chem. 2004, 69, 130.
(6) For antibiotic uses, see: (a) Singh, G. S. Mini-ReV. Med. Chem. 2004,
4, 69. (b) Singh, G. S. Mini-ReV. Med. Chem. 2004, 4, 93. (c) Niccolai, D.;
Tarsi, L.; Thomas, R. J. Chem. Commun. 1997, 2333. (d) Southgate, R.
Contemp. Org. Synth. 1994, 1, 417. (e) Southgate, R.; Branch, C.; Coulton,
S.; Hunt, E. In Recent Progress in the Chemical Synthesis of Antibiotics
and Related Microbial Products; Lukacs, G., Ed.; Springer: Berlin,
Germany, 1993; Vol. 2, p 621. (f) The Chemistry of â-Lactams; Page, M.
I., Ed.; Chapman and Hall: London, UK, 1992. (g) Chemistry and Biology
of â-Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic: New
York, 1982; Vols. 1-3. For nonantibiotic uses, see: (h) Rothstein, J. D.;
Patel, S.; Regan, M. R.; Haenggeli, C.; Huang, Y. H.; Bergles, D. E.; Jin,
L.; Hoberg, M. D.; Vidensky, S.; Chung, D. S.; Toan, S. V.; Bruijn, L. I.;
Su, Z.-z.; Gupta, P.; Fisher, P. B. Nature 2005, 433, 73. (i) Hogan, P. C.;
Corey, E. J. J. Am. Chem. Soc. 2005, 127, 15386. (j) Clader, J. W. J. Med.
Chem. 2004, 47, 1. (k) Kvaerno, L.; Ritter, T.; Werder, M.; Hauser, H.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 4653. (l) Burnett, D. A.
Curr. Med. Chem. 2004, 11, 1873. (m) Veinberg, G.; Vorona, M.;
Shestakova, I.; Kanepe, I.; Lukevics, E. Curr. Med. Chem. 2003, 10, 1741.
(n) Page, M. I.; Laws, A. P. Tetrahedron 2000, 56, 5631. (o) Haley, T. M.;
Angier, S. J.; Borthwick, A. D.; Singh, R.; Micetich, R. G. Drugs 2000, 3,
512.
Two different stereocontrolled accesses to new 4-hydrox-
ypipecolic acid analogues with a bicyclic â-lactam structure
have been developed by using intramolecular reductive
amination or allenic hydroamination reactions in 2-azetidi-
none-tethered azides. The access to the cyclization precursors
was achieved from 3-azido-4-oxoazetidine-2-carbaldehyde
via metal-mediated carbonyl-allenylation in aqueous envi-
ronment or by organocatalytic direct aldol reaction. The tin
hydride-promoted cyclization of the 2-azetidinone-tethered
azidoallene is totally regioselective for the central allenic
carbon providing a fused piperidine.
4-Hydroxypipecolic acids are naturally occurring nonprotei-
nogenic amino acids which have been isolated from the leaves
of Calliandra pittieri, Strophantus scandeus, and Acacia os-
waldii,1 and are constituents of many biologically active natural
and synthetic products such as depsipeptide antibiotics,2 N-
methyl-D-aspartic acid (NMDA) receptor antagonists,3 and HIV
protease inhibitors such as palinavir (Figure 1).4 Due to the great
interest in these derivatives much effort has been devoted to
their preparation.5
† Universidad Complutense de Madrid.
‡ Instituto de Qu´ımica Orga´nica General.
(1) (a) Kite, G. C.; Wieringa, J. J. Biochem. Syst. Ecol. 2003, 31, 279.
(b) Kite, G. C.; Ireland, H. Phytochemistry 2002, 59, 163. (c) Evans, S. V.;
Shing, T. K. M.; Aplin, R. T.; Fellows, L. E.; Fleet, G. W. J. Phytochemistry
1985, 24, 2593. (d) Romeo, J. T.; Swain, L. A.; Bleeker, A. B. Phytochem-
istry 1983, 22, 1615. (e) Ahmad, V. U.; Khan, M. A. Phytochemistry 1971,
10, 3339. (f) Schenk, V. W.; Schutte. H. R. Flora 1963, 153, 426. (g) Clark-
Lewis, J. W.; Mortimer P. I. J. Chem. Soc. 1961, 189.
(2) (a) Mukhtar, T. A.; Wright, G. D. Chem. ReV. 2005, 105, 529. (b)
Di Giambattista, M.; Nyssen, E.; Percher, A.; Cocito, C. Biochemistry 1990,
29, 9203. (c) Reed, J. W.; Purvis, M. B.; Kingston, D. G. I.; Blot, A.;
Gossele, F. J. Org. Chem. 1989, 54, 1161. (d) Kessler, H.; Ku¨hn, M.;
Lo¨schner, T. Liebigs Ann. Chem. 1986, 1. (e) Hollstein, U. Chem. ReV.
1974, 74, 625. (f) Vanderhaeghe, H.; Parmentier, G. J. Am. Chem. Soc.
1960, 82, 4414.
(7) For reviews, see: (a) Alcaide, B.; Almendros, P. Curr. Med. Chem.
2004, 11, 1921. (b) Alcaide, B.; Almendros, P. Curr. Org. Chem. 2002, 6,
245.
10.1021/jo702405h CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/16/2008
J. Org. Chem. 2008, 73, 1635-1638
1635

SCHEME 1. Preparation of Azidoallenol 3 and Azidoaldol
4
SCHEME 2. Synthesis of Enantiopure Fused Bicycle 6
a large variety of reported methods.11 It occurred to us that
exposure of the azide moiety of 2-azetidinone-tethered azides
3 and 4 to chemoselective reductive conditions might serve as
a straightforward procedure for the preparation of new bicyclic
4-hydroxypipecolic acid analogues, because under the reaction
conditions the resulting amino group would attack the allene
or aldol functionalities. The allene moiety represents a versatile
and useful building block in organic synthesis, specially in the
area of transition metal-assisted reactions.12 Instead of an alkene
or an alkyne, an allene component is a fascinating substrate in
an aminocyclization reaction because of its unique reactivity
and the synthetic use of the final products.13 However, regi-
oselectivity problems are significant (endo-trig versus exo-dig
versus exo-trig cyclization). Our initial experiments on cycliza-
tion reactions of azidoallenol 3 with Ph3P-H2O or Ph3SnH led
to complications. To circumvent this problem, we decided to
protect the alcohol group of the allenic alcohol as acetate before
subjecting it to the aminocyclization reaction. On this basis,
we first used the Staudinger protocol for the construction of
the fused azacycle. However, when we tried to reduce azide 5
using the triphenylphosphine method,14 a complex reaction
mixture was observed. Fortunately, we found that 2-azetidinone-
tethered azidoallenic acetate 5 when treated at room temperature
with triphenyltin hydride in benzene solution gave in a totally
regioselective fashion the bicyclic 4-hydroxypipecolic acid
analogue 6 through a 6-exo-dig aminocyclization with con-
comitant acetate cleavage (Scheme 2).15
a major strategy.8 Following our ongoing project in â-lactam
chemistry,9 we became interested in the introduction of structural
constraints on the 4-hydroxypipecolic acid nucleus. We report
herein two different stereocontrolled accesses to new 4-hydrox-
ypipecolic acid analogues with a bicyclic â-lactam structure,
which rely on heterocyclization reactions in both a 2-azetidi-
none-tethered azidoallene as well as a 2-azetidinone-tethered
azidoaldol.
The starting substrate, 3-azido-4-oxoazetidine-2-carbaldehyde
1 (PMP ) 4-MeOC6H4), was prepared in optically pure form
using standard methodology. Enantiopure 2-azetidinone 2 was
obtained following a literature method from the p-anisidine-
derived imine of (R)-2,3-O-isopropylideneglyceraldehyde, through
Staudinger reaction with azidoacetyl chloride in the presence
of Et3N as a single cis-enantiomer.10 Acetonide hydrolysis to
provide the corresponding diol, followed by oxidative cleavage,
smoothly formed 3-azido-4-oxoazetidine-2-carbaldehyde 1 in
excellent yield (Scheme 1). 2-Azetidinone-tethered azidoallenol
3 was regio- and diastereoselectively achieved via indium-
mediated Barbier-type carbonyl-allenylation reaction of â-lac-
tam aldehyde 1 in aqueous media (Scheme 1). The L-proline-
catalyzed direct aldol reaction between carbaldehyde 1 and
acetone afforded adduct 4 as the exclusive isomer (Scheme 1).
Having obtained the monocyclic precursors 3 and 4, the next
stage was set to carry out the key cyclization step. Straightfor-
ward reduction to amines is one of the most attractive synthetic
applications of azides, because they serve as one of the most
reliable ways to introduce an amino substituent onto a carbon
atom. The conversion of azides to amines can be achieved by
(11) For a review on azide reduction methods, see: (a) Amantini, D.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. Org. Prep. Proc. Int. 2002, 34, 109.
For general reviews, see: (b) The Chemistry of the Azido Group; Patai, S.,
Ed.; Wiley: New York, 1971. (c) Azides and Nitrenes: ReactiVity and Utility;
Scriven, E. F. V., Ed.; Academic Press: New York, 1984. (d) Scriven, E.
F. V.; Turnbull, R. Chem. ReV. 1988, 88, 297. (e) Bra¨se, S.; Gil, C.; Knepper,
K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188.
(12) For reviews, see: (a) Ma, S. Chem. ReV. 2005, 105, 2829. (b)
Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2004, 3377. (c) Ma, S. Acc.
Chem. Res. 2003, 36, 701. (d) Bates, R. W.; Satcharoen, V. Chem. Soc.
ReV. 2002, 31, 12. (e) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39,
3590. (f) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem.
ReV. 2000, 100, 3067.
(13) For reviews, see: (a) Modern Allene Chemistry, Krause, N., Hashmi,
A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (b) Widenhoefer,
R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555.
(14) For selected reviews on phosphazene chemistry, see: (a) Fresneda,
P. M.; Molina, P. Synlett 2004, 1. (b) Molina, P.; Vilaplana, M. J. Synthesis
1994, 1197. (c) Eguchi, S.; Yamashita, K.; Matsushita, Y.; Eguchi, S. Org.
Prep. Proced. Int. 1992, 24, 209. (d) Gololobov, Y. G.; Kasukhin, L. F.
Tetrahedron 1992, 48, 1353. (e) Barluenga, J.; Palacios, F. Org. Prep.
Proced. Int. 1991, 23, 1.
(8) (a) Cowell, S. M.; Lee, Y. S.; Cain, J. P.; Hruby, V. J. Curr. Med.
Chem. 2004, 11, 2785. (b) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion,
C. Biopolymers 2001, 60, 396. (c) Venkatraman, J.; Shankaramma, S. C.;
Balaram, P. Chem. ReV. 2001, 101, 3131. The incorporation of cyclic
secondary amino acids has profound effects on the conformation of peptides,
due to the inability of the nitrogen atom to act as a hydrogen bond donor
unless it is located at the N-terminal position of the molecule, and to the
conformational strain imparted by the cyclic structure: (d) Hruby, V. J.;
Al-Obeidi, F.; Kazmierski, W. Biochem. J. 1990, 268, 249.
(9) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Redondo, M. C. J.
Org. Chem. 2007, 72, 1604. (b) Alcaide, B.; Almendros, P.; Mart´ınez del
Campo, T.; Rodr´ıguez-Acebes, R. AdV. Synth. Catal. 2007, 349, 749. (c)
Alcaide, B.; Almendros, P.; Mart´ınez del Campo, T. Angew. Chem., Int.
Ed. 2006, 45, 4501. (d) Alcaide, B.; Almendros, P.; Rodr´ıguez-Acebes, R.
J. Org. Chem. 2006, 71, 2346. (e) Alcaide, B.; Almendros, P.; Alonso, J.
M. Chem. Eur. J. 2006, 12, 2874. (f) Alcaide, B.; Almendros, P.; Luna,
A.; Torres, M. R. J. Org. Chem. 2006, 71, 4818. (g) Alcaide, B.; Almendros,
P.; Aragoncillo, C.; Redondo, M. C.; Torres, M. R. Chem. Eur. J. 2006,
12, 1539. (h) Alcaide, B.; Almendros, P.; Redondo, M. C. Chem. Commun.
2006, 2616.
(15) Starting from 2-azetidinone-tethered allenol derivatives, we have
recently reported totally regioselective metal-catalyzed cyclization reactions
onto the distal or proximal allene carbon atoms, but not to the central. See:
Alcaide, B.; Almendros, P.; Mart´ınez del Campo, T. Angew. Chem., Int.
Ed. 2007, 46, 6684.
(10) Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.; Kurys, B.
E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas, M. S.; Bose, A. K. J. Org.
Chem. 1988, 53, 4227.
1636 J. Org. Chem., Vol. 73, No. 4, 2008

SCHEME 3. Synthesis of Enantiopure Fused Bicycle 7
FIGURE 3. Transition state model for the L-proline-catalyzed aldol
addition reaction of acetone to â-lactam aldehyde 1.
aldolization step,17 as depicted in Figure 3. Stereoselective
formation of bicycle 7 can be understood on the basis of cis
addition of hydrogen atoms to the less hindered face of the
unsaturated center, since the more accessible side of the
intermediate imine is the face that is not blocked by the â-lactam
ring.
In conclusion, we have described here two different stereo-
controlled routes to new 4-hydroxypipecolic acid analogues with
a bicyclic â-lactam structure. We have shown that combination
of intramolecular reductive amination or allenic hydroamination
reactions in 2-azetidinone-tethered azides may lead to a useful
preparation of the piperidine-fused â-lactam core. The tin
hydride-mediated cyclization of the 2-azetidinone-tethered azi-
doallene is totally regioselective for the central carbon in the
allenic motif. Applications to different heterocycles employing
these aminocyclizations are underway.
Exposure of aldol adduct 4 to the Ph3P-H2O reductive system
did afford a mixture of highly polar compounds, which could
not be characterized. The hydrogenation reaction of azidoaldol
4 performed in the presence of Boc2O revealed through 1H NMR
monitoring the formation of little cyclization product, while the
major components in the mixture were side products. Then it
was decided to carry out reduction of the azide and in situ
cyclization and protection of the resultant secondary amine as
the benzylcarbamate. Interestingly, exposure of compound 4 to
H2 (1 atm) in ethyl acetate at room temperature in the presence
of a catalytic amount of Pd (10% on C) followed by the addition
of benzyl chloroformate provided the 4-hydroxypipecolic acid
analogue 7 with a bicyclic â-lactam structure (Scheme 3).
Experimental Section
General. Melting points were taken using a Gallenkamp ap-
paratus and are uncorrected. 1H NMR and 13C NMR spectra were
recorded on a Bruker Avance-300, Varian VRX-300S, or Bruker
AC-200. NMR spectra were recorded in CDCl3 solutions, except
where otherwise stated. Chemical shifts are given in ppm relative
to TMS (1H, 0.0 ppm) or CDCl3 (13C, 76.9 ppm). Low- and high-
resolution mass spectra were taken on a HP5989A spectrometer,
using the electronic impact (EI) or electrospray modes (ES) unless
otherwise stated. Specific rotation [R]D is given in 10-1 deg cm2
g-1 at 20 °C, and the concentration (c) is expressed in g per 100
mL. All commercially available compounds were used without
further purification. THF was distilled from Na-benzophenone.
Benzene, dichloromethane, and triethylamine were distilled from
CaH2. Flame-dried glassware and standard Schlenk techniques were
used for moisture-sensitive reactions. Flash chromatography was
performed using Merck silica gel 60 (230-400 mesh). Identification
of products was made by TLC (Kiesegel 60F-254). UV light (λ )
254 nm), and a vanillin solution in sulfuric acid and 95% EtOH (1
g of vanillin, 5 mL of H2SO4, 150 mL of EtOH) was used to develop
the plates.
FIGURE 2. Model to explain the observed 4,1′-syn stereochemistry
for the allenylation reaction of 3-azido-4-oxoazetidine-2-carbaldehyde
1.
The structure and stereochemistry of compounds 6 and 7 were
assigned by NMR studies. The cis-stereochemistry of the four-
membered ring was set during the cyclization step to form the
2-azetidinone ring, and it was transferred unaltered during
further synthetic steps. The bicyclic structures (by DEPT,
HMQC, HMBC, and COSY) and the stereochemistry (by vicinal
proton couplings and qualitative homonuclear NOE difference
spectra) of fused â-lactams 6 and 7 were established by NMR
one- and two-dimensional techniques. Taking into account that
azidoallenol 3 and azidoaldol 4 could be obtained and cyclized
to bicyclic 4-hydroxypipecolic acid derivatives 6 and 7, the
stereochemistry at the carbinolic stereogenic center for com-
pounds 3 and 4 was immediately deduced by comparison with
the NOE results of the bicyclic â-lactams 6 and 7. The high
diastereoselectivity of the allenylation reaction of 3-azido-4-
oxoazetidine-2-carbaldehyde 1 can be explained by addition of
the organometallic reagent from the less hindered re face of
the carbonyl group following a nonchelated Felkin-Anh model,
as depicted in Figure 2.16 The configuration at the carbinolic
chiral center of the aldol product 4 is consistent with a
Zimmerman-Traxler six-membered-ring chairlike model for the
Procedure for the Intramolecular Allenic Hydroamination
of 2-Azetidinone-Tethered Azide (+)-5. Synthesis of Bicycle (+)-
6. A solution of the 2-azetidinone-tethered azidoallene (+)-5 (75
mg, 0.22 mmol) and triphenyltin hydride (386 mg, 1.10 mmol) in
benzene (1 mL) was stirred at room temperature until complete
disappearance (TLC) of starting material. The solvent was removed
under reduced pressure and 32 mg (53%) of fused adduct (+)-6
was obtained after purification by flash chromatography on silica
(17) For selected reviews, see: (a) Guillena, G.; Na´jera, C. R.; Ramo´n,
D. J. Tetrahedron: Asymmetry 2007, 18, 2249. (b) Modern Aldol Reactions;
Mahrwald, R., Ed.; Wiley-VCH: Weinheim, Germany, 2004. (c) List, B.
Acc. Chem. Res. 2004, 37, 548. (d) Notz, W.; Tanaka, F.; Barbas, C. F., III
Acc. Chem. Res. 2004, 37, 580. (e) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M.
Chem. Soc. ReV. 2004, 33, 65. (f) Alcaide, B.; Almendros, P. Angew. Chem.,
Int. Ed. 2003, 42, 858. (g) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58,
2481. (h) List, B. Tetrahedron 2002, 58, 5573. (i) Alcaide B.; Almendros,
P. Eur. J. Org. Chem. 2002, 1595.
(16) (a) Che´rest, M.; Felkin, H.; Prudent, M.; Anh, N. Tetrahedron Lett.
1968, 2199. (b) Anh, N. Top. Curr. Chem. 1980, 88, 114.
J. Org. Chem, Vol. 73, No. 4, 2008 1637

gel using dichloromethane/ethyl acetate (9:1 containing 2% of
triethylamine) as eluent.
by silica gel column chromatography (eluent: ethyl acetate/hexanes,
1:2) to afford bicycle (+)-7 (58 mg, 49% yield).
Bicycle (+)-6. Colorless oil; [R]D +70.7 (c 0.5, CHCl3); 1H NMR
(CDCl3) δ 7.74 (br s, 1H), 7.41 and 6.92 (d, each 2H, J ) 9.0 Hz),
6.12 (dd, 1H, J ) 3.9, 1.7 Hz), 5.99 (d, 1H, J ) 6.3 Hz), 5.22 (m,
1H), 3.82 (s, 3H), 2.16 (s, 3H), 1.26 (s, 3H); 13C NMR (CDCl3) δ
164.9, 157.1, 127.7, 122.0, 119.0, 118.1, 114.7, 96.9, 87.1, 76.9,
55.5, 29.7, 22.7; IR (CHCl3, cm-1) ν 3350, 3320, 1744; MS (ES)
m/z 275 (M+ + 1, 100), 274 (M+, 5). Anal. Calcd for C15H18N2O3:
C, 65.68; H, 6.61; N, 10.21. Found: C, 65.55; H, 6.57; N, 10.28.
Procedure for the Intramolecular Reductive Amination of
2-Azetidinone-Tethered Azide (+)-4. Synthesis of Bicycle (+)-
7. To a solution of the aldol (+)-4 (90 mg, 0.30 mmol) in ethyl
acetate (16 mL) was added 10% Pd/C (15 mg). The suspension
was stirred under H2 (1 atm) over 4 h at room temperature. After
this time, the reaction mixture was filtered through Celite, and the
solvent was evaporated affording the corresponding aminoalcohol.
Benzyl chloroformate (49 µL, 0.36 mmol) was added to a solution
of the above crude aminoalcohol (0.30 mmol) and Na2CO3 (38 mg,
0.36 mmol) in dry dichloromethane (2 mL), and the reaction mixture
was stirred at room temperature for 12 h. The reaction mixture
was treated with water and extracted with dichloromethane, and
the organic layer was dried with anhydrous MgSO4, filtered, and
concentrated in vacuo to afford a crude product, which was purified
Bicycle (+)-7: colorless solid; mp 170-171 °C (hexanes/ethyl
acetate); [R]D +44.2 (c 0.8, CHCl3); 1H NMR δ 7.34 (m, 7H), 6.87
(d, 2H, J ) 9.0 Hz), 6.14 (d, 1H, J ) 10.1 Hz), 5.35 (dd, 1H, J )
10.1, 5.1 Hz), 5.12 (s, 2H), 4.28 (m, 2H), 3.78 (s, 3H), 3.53 (br s,
1H), 2.64 (m, 2H), 2.08 (s, 3H); 13C NMR δ 165.0, 156.8, 155.9,
135.8, 130.5, 128.5, 128.2, 128.1, 120.6, 118.2, 114.5, 114.3, 67.4,
66.0, 59.9, 58.4, 55.4, 47.3, 30.5; IR (CHCl3, cm-1) ν 3330, 1742,
1720; MS (EI) m/z 396 (M+, 9), 149 (100). Anal. Calcd for
C22H24N2O5: C, 66.65; H, 6.10; N, 7.07. Found: C, 66.77; H, 6.05;
N, 7.01.
Acknowledgment. We would like to thank the DGI-MEC
(Project CTQ2006-10292) and CAM-UCM (Grant GR69/06)
for financial support. T.M.C. thanks the MEC for a predoctoral
grant.
Supporting Information Available: Compound characterization
data and experimental procedures for compounds 1 and 3-5, as
1
well as H NMR and 13C NMR spectra for new compounds. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO702405H
1638 J. Org. Chem., Vol. 73, No. 4, 2008