Diastereoselectivity enhancement in the 1,3-cycloaddition of β-lactam aldehydes. Application to the synthesis of enantiopure indolizidinone amino esters

Article abstract of DOI:10.1021/jo051402y

Enantiopure α-alkoxy β-lactam acetaldehydes were prepared via the thiazole-based one-carbon homologation. The 1,3-dipolar cycloaddition reaction involving α-alkoxy β-lactam acetaldehyde-derived azomethine ylides gave with excellent diastereoselectivity hi

Full text of DOI:10.1021/jo051402y

Diastereoselectivity Enhancement in the 1,3-Cycloaddition of
â-Lactam Aldehydes. Application to the Synthesis of Enantiopure
Indolizidinone Amino Esters
Benito Alcaide,*,† Pedro Almendros,*,‡ Mar´ıa C. Redondo,† and M. Pilar Ruiz†
Departamento de Quı´mica Orga´nica I, Facultad de Qu´ımica, Universidad Complutense de Madrid,
28040-Madrid, Spain, and Instituto de Quı´mica Orga´nica General, CSIC, Juan de la Cierva 3,
28006-Madrid, Spain
alcaideb@quim.ucm.es; iqoa392@iqog.csic.es
Received July 7, 2005
Enantiopure R-alkoxy â-lactam acetaldehydes were prepared via the thiazole-based one-carbon
homologation. The 1,3-dipolar cycloaddition reaction involving R-alkoxy â-lactam acetaldehyde-
derived azomethine ylides gave with excellent diastereoselectivity highly functionalized 2-azeti-
dinone-tethered prolines, which were directly used for the first preparation of azabicyclo[4.3.0]-
nonane (indolizidinone) amino esters from â-lactams.
Introduction
azasugars and alkaloids.4 Use of 2-azetidinones as chiral
building blocks in organic synthesis is now well-estab-
lished.5 However, no information was available on the
use of â-lactams as precursors for the synthesis of
indolizidines until we entered this field.6
Indolizidine alkaloids are widely distributed in nature
and frequently possess potent biological activity.1 In
recent years, indolizidine alkaloids as well as related
unnatural compounds have become popular synthetic
targets as a consequence of their bioactivity, moderate
complexity, and the diversity of possible synthetic strate-
gies for their construction.2 In particular, azabicyclo-
[4.3.0]nonane (indolizidinone) amino acids have proven
to behave as conformationally restricted dipeptide mi-
metics.3 1,3-Dipolar cycloaddition employing azomethine
ylides is an important process in organic synthesis,
acquiring a prominent place of synthetic strategy for a
variety of targets, including natural products such as
(3) See, among others: (a) Maison, W.; Prenzel, A. H. G. P. Synthesis
2005, 1031. (b) Sun, H.; Nikolovska-Coleska, Z.; Yang, C.-Y.; Xu, L.;
Liu, M.; Tomita, Y.; Pan, H.; Yoshioka, Y.; Krajewski, K.; Roller, P.
P.; Wang, S. J. Am. Chem. Soc. 2004, 126, 16686. (c) Belvisi, L.;
Colombo, L.; Manzoni, L.; Potenza, D.; Scolastico, C. Synlett 2004, 1449.
(d) Cluzeau, J.; Lubell, W. D. J. Org. Chem. 2004, 69, 1504. (e)
Dragovich, P. S.; Zhou, R.; Prins, T. J. J. Org. Chem. 2002, 67, 741. (f)
Sun, H.; Moeller, K. D. Org. Lett. 2002, 4, 1547. (g) Polyak, F.; Lubell,
W. D. J. Org. Chem. 2001, 66, 1171.
(4) For reviews, see: (a) Husinec, S.; Savic, V. Tetrahedron: Asym-
metry 2005, 16, 2047. (b) Synthetic Applications of 1,3-Dipolar Cy-
cloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; Wiley: New York, 2003; Vol. 59. (c)
Karlsson, S.; Hogberg, H.-E. Org. Prep. Proced. Int. 2001, 33, 103. (d)
Broggini, G.; Zecchi, G. Synthesis 1999, 905. (e) Gothelf, K. V.;
Jorgensen, K. A. Chem. Rev. 1998, 98, 863. For selected references,
see: (f) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2004, 125, 10778.
(g) Viso, A.; Ferna´ndez de la Pradilla, R.; Garc´ıa, A.; Guerrero-
Strachan, C.; Alonso, M.; Tortosa, M.; Flores, A.; Mart´ınez-Ripoll, M.;
Fonseca, I.; Andre´, I.; Rodr´ıguez, A. Chem.-Eur. J. 2003, 9, 2867. (h)
Fishwick, C. W. G.; Grigg, R.; Sridharan, V.; Virica, J. Tetrahedron
2003, 59, 4451. (i) Noguchi, M.; Matsumoto, S.; Shirai, M.; Yamamoto,
H. Tetrahedron 2003, 59, 4123.
† Universidad Complutense de Madrid.
‡ Instituto de Qu´ımica Orga´nica General, CSIC.
(1) Their interesting biological activities include antiviral, antitu-
mor, and glucosidase inhibitions. For selected reviews, see: (a) Michael,
J. P. Nat. Prod. Rep. 2003, 20, 458. (b) Michael, J. P. Nat. Prod. Rep.
2001, 18, 520. (c) Vlietinck, A. J.; De Bruyne, T.; Apers, S.; Pieters, L.
A. Planta Med. 1998, 64, 97. (d) Michael, J. P. Nat. Prod. Rep. 1997,
14, 619. (e) Lidell, J. R. Nat. Prod. Rep. 1996, 13, 187. (f) Robin, D. J.
Nat. Prod. Rep. 1995, 12, 413. (g) Ikeda, M.; Sato, T.; Ishibashi, H.
Heterocycles 1988, 27, 1465.
(2) For recent selected examples, see: (a) Reddy, P. G.; Baskaran,
S. J. Org. Chem. 2004, 69, 3093. (b) Wrobleski, A.; Sahasrabudhe, K.;
Aube´, J. J. Am. Chem. Soc. 2004, 126, 5475. (c) Smith, A. B.; Kim, D.
S. Org. Lett. 2004, 6, 1493. (d) Armstrong, P.; Feutren, S.; McAlonan,
H.; O’Mahony, G.; Stevenson, P. J. Tetrahedron Lett. 2004, 48, 1627.
(e) Hanessian, S.; Sailes, H.; Munro, A.; Therrien, E. J. Org. Chem.
2003, 68, 7219. (f) Harris, J. M.; Padwa, A. J. Org. Chem. 2003, 68,
4371. (g) Gravier-Pelletier, C.; Maton, W.; Le Merrer, Y. Synlett 2003,
333.
(5) For selected reviews, see: (a) Alcaide, B.; Almendros, P. Synlett
2002, 381. (b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Synlett 2001, 1813. (c) Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2001,
30, 226. (d) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377. (e)
Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose, A. K. Heterocycles 1988,
27, 1755.
(6) (a) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Chem.-
Eur. J. 2003, 9, 3415. (b) Alcaide, B.; Almendros, P.; Alonso, J. M.;
Aly, M. F.; Torres, M. R. Synlett 2001, 1531.
10.1021/jo051402y CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/01/2005
8890
J. Org. Chem. 2005, 70, 8890-8894

Enhancement in 1,3-Cycloaddition of â-Lactam Aldehydes
SCHEME 1a
SCHEME 2a
a Key: (i) H2NCH(R5)CO2Me, 4 Å MS, DCM, RT, 2 h. (ii) AgOAc,
Et3N, dipolarophile, toluene, RT.
a Key: (i) TMST, DCM, 0 °C, 16 h. (ii) 2a, 2b: TBSOTf, Et3N,
DMAP, DMF, RT, 5 h; 2c: Me2SO4, TBAI (cat), NaOH (aq 50%)/
DCM (1:1), RT, 24 h. (iii) MeOTf, MeCN, RT, 15 min. (iv) NaBH4,
MeOH, RT, 10 min. (v) MeCN, AgNO3, H2O, RT, 10 min. Yields
are for pure isolated products with correct analytical and spec-
troscopic data.
TABLE 1. Silver Acetate-Mediated 1,3-Dipolar
Cycloaddition of r-Alkoxy â-Lactam
Acetaldehyde-Derived Azomethine Ylides
aldehyde R2 R3 R4
R5
adduct 5/6 d.r.b yield (%)c
(+)-3a
(+)-3a
(+)-3a
(+)-3a
(+)-3a
(+)-3b
Ea
E
E
d
H
H
H
d
H
H
E
H
H
H
H
(+)-5a
100:0
95:5
90:10
100:0
100:0
100:0
57
74
56
78
62
61
Recently, the 1,3-dipolar cycloaddition reaction involv-
ing 4-oxoazetidine-2-carbaldehyde-derived azomethine
ylides has been examined.7 However, disappointing di-
astereoselectivities (typically 40% de) were observed. We
reasoned that installation of an extra stereocenter may
improve the diastereoselectivity of the [3 + 2] cycload-
dition. We wish to report here the intermolecular 1,3-
dipolar cycloaddition reaction involving R-alkoxy â-lactam
acetaldehyde-derived azomethine ylides, together with its
application for the asymmetric synthesis of indolizidinone
amino esters.
Me (+)-5b
Me (+)-5c
Me (+)-5d
Me (+)-5e
e
e
E
H
H
(+)-5f
a E ) CO2Me. b The ratio was determined by integration of well-
resolved signals in the 1H NMR spectra of the crude reaction
mixtures before purification. c Yields (%) are for pure isolated
products with correct analytical and spectroscopic data. d Com-
pound (+)-5d was prepared using N-methylmaleimide. e Com-
pound (+)-5e was prepared using N-phenylmaleimide.
Aliphatic aldimines 4, which were obtained in quan-
titative yields and were used for the next step without
further purification, were achieved by reaction of R-alkoxy
â-lactam acetaldehydes 3 with the corresponding R-amino
ester in the presence of 4 Å molecular sieves. Treatment
of alanine (glycine) aldimines 4 derived from the TBSO-
protected aldehydes (+)-3a and (+)-3b with the appropri-
ate dienophile (e.g., N-methylmaleimide, N-phenyl-
maleimide, methyl acrylate, and dimethyl fumarate) in
the presence of AgOAc/Et3N in toluene at room temper-
ature gave cycloadducts 5 (Scheme 2, Table 1) in good
yields (56-78%) with diastereoselectivities ranging from
good (90:10) to complete (single isomer). No further
improvement occurred when the reaction was carried out
in other solvents, neither by using different reagents
(LiBr) nor by using different bases (DBU). Much poorer
diastereoselectivity was observed when the cycloaddition
reaction was carried out in polar solvents (acetonitrile
and DMSO). For example, (+)-5b and (+)-6b were
obtained as a 85:15 mixture in 65% combined yield when
DMSO was used as solvent and triethylamine as base,
whereas in toluene with triethylamine as base the
reaction afforded a 95:5 mixture (74%). The use of LiBr
or DBU resulted in diminished yields. The imino esters
derived from the MeO-protected aldehyde (+)-3c gave a
complex mixture of unidentified products.
The stereochemistry of the products (5 and 6) is based
on the usual selectivity and endo-transition states via
E,E-syn-dipole observed for metallo azomethine ylide
cycloadditions.4 In the current context, the tert-butyldi-
methylsilyloxy group comprises a large substituent. The
reason for the great selectivity for endo-addition to give
adducts 5 compared to endo-addition to give adducts 6
in the examples of Table 1 may be related to an increase
ease of access of the dipolarophile to the metallodipole
from the Re-face (trans to TBSO group). For example,
the E,E-syn-dipoles derived from aldehydes 3 on reacting
Results and Discussion
The starting substrates were prepared with the service
of thiazole as latent formyl group, via the thiazole-based
one-carbon homologation.8 Enantiopure 2-azetidinones
(+)-1a and (+)-1b were obtained as single cis-enanti-
omers from imines of (R)-2,3-O-isopropylideneglyceral-
dehyde, through Staudinger reaction with methoxyacetyl
chloride in the presence of Et3N, followed by sequential
acidic acetonide hydrolysis and oxidative cleavage.9 The
conversion of 4-oxoazetidine-2-carbaldehydes 1 into
R-alkoxy â-lactam acetaldehydes 3 was carried out
through a three-step reaction sequence involving 2-(tri-
methylsilyl)thiazole (TMST) addition,10 hydroxyl protec-
tion to give ethers 2, and aldehyde unmasking. Carbal-
dehydes 3 were obtained as single isomers in reasonable
yields (Scheme 1). It deserves to be mentioned that TMST
addition to 4-oxoazetidine-2-carbaldehydes 1 is not a
trivial process, because we have recently reported that
the addition reaction of TMST to N-aryl-4-oxoazetidine-
2-carbaldehydes gave enantiopure R-alkoxy-γ-keto acid
derivatives via a novel N1-C4 bond breakage of the
â-lactam nucleus.11
(7) (a) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. J. Org.
Chem. 2001, 66, 1351. (b) Alcaide, B.; Almendros, P.; Alonso, J. M.;
Aly, M. F. Chem. Commun. 2000, 485. (c) Grigg, R.; Thornton-Pett,
M.; Xu, J.; Xu, L.-H. Tetrahedron 1999, 55, 13841.
(8) Dondoni, A.; Marra, A. Chem. Rev. 2004, 104, 2557.
(9) (a) Alcaide, B.; Almendros, P.; Salgado, N. R. J. Org. Chem. 2000,
65, 3310. (b) Alcaide, B.; Almendros, P.; Aragoncillo, C. J. Org. Chem.
2001, 66, 1612.
(10) The observed syn-diastereoselectivity for the TMST addition
step might be tentatively explained by invoking the Felkin-Anh model,
analogously to related addition processes described in our laboratories.
See: (a) Alcaide, B.; Almendros, P.; Rodr´ıguez-Acebes, R. J. Org. Chem.
2005, 70, 2713. (b) Alcaide, B.; Almendros, P.; Alonso, J. M. J. Org.
Chem. 2004, 69, 993. (c) Alcaide, B.; Almendros, P.; Aragoncillo, C.
Chem.-Eur. J. 2002, 8, 1719.
(11) Alcaide, B.; Almendros, P.; Redondo, M. C. Org. Lett. 2004, 6,
1765.
J. Org. Chem, Vol. 70, No. 22, 2005 8891

Alcaide et al.
SCHEME 3
SCHEME 4a
FIGURE 1. Selected NOE data for indolizidinone amino
esters 7a-d.
Configurational Assignment. The stereochemistry
of indolizidinones 7 was established by NMR techniques,
particularly by vicinal proton couplings and qualitative
homonuclear NOE difference spectra. Taking into ac-
count that 2-azetidinone-tethered prolines 5 could be
obtained and cyclized to indolizidinone amino esters 7,
the stereochemistry for compounds 5 was immediately
deduced by comparison with the NOE results of the
bicyclic systems. The cis-stereochemistry of the four-
membered ring is set during the cyclization step to form
the 2-azetidinone ring, and it is transferred unaltered
during the further synthetic steps. Selected NOE en-
hancements that are in agreement with the proposed
stereochemistries are shown in Figure 1. As an example,
irradiation of the H9 hydrogen (indolizidinone number-
ing) in compound (+)-7a resulted in a 5% increment on
the H7 proton. Irradiation of the H1 hydrogen in com-
pound (+)-7a gave a 5% increment both on the H9 proton
and on the less shielded proton of the methylene group.
For (+)-7a, an additional NOE between the H1 hydrogen
and the H7 proton confirmed the H1/H7/H9 all-syn
stereochemical assignment. Besides, irradiation of the
less shielded proton of the methylene group in compound
(+)-7a gave a 5% increment on H3 hydrogen. Similar
figures were observed on performing NOE experiments
in bicycles (+)-7b, (+)-7c, and (+)-7d.
a Key: (i) MeONa, MeOH, RT. Yields are for pure isolated
products with correct analytical and spectroscopic data.
SCHEME 5a
a Key: (i) MeONa, MeOH, RT.
with methyl acrylate led to the corresponding cycload-
ducts 5 (Scheme 3).
With enantiopure highly functionalized 2-azetidinone-
tethered prolines in hand, our aim was to find an
expedient transformation of cycloadducts 5 into indolizi-
dine systems. Transformation of pyrrolidine-N-allyl-â-
lactams 5a-c into indolizidinone amino acid derivatives
7a-c was directly effected at room temperature via a
sodium methoxide rearrangement reaction (Scheme 4).
However, compound (+)-5f bearing a benzyl group at the
N1 nitrogen was unreactive. It became evident that the
group attached to the lactam nitrogen plays a crucial role
in this reaction. The attempted transformation of adducts
5 into indolizidines by dissolution in a saturated solution
of HCl(g) in 2-propanol resulted in complex reaction
mixtures. The transformation of proline-â-lactams 5 into
indolizidine derivatives 7 involves the selective amide
bond cleavage of the four-membered ring, followed by
cyclization of the resulting â-amino ester with concomi-
tant ring expansion.
Conclusions
In conclusion, imino esters derived from enantiopure
R-alkoxy â-lactam acetaldehydes gave the 1,3-dipolar
cycloaddition reaction in a highly stereoselective fashion.
The resulting 2-azetidinone-tethered prolines were di-
rectly used for the first preparation of azabicyclo[4.3.0]-
nonane (indolizidinone) amino esters from â-lactams.
Experimental Section
Fused indolizidinone (+)-7d was obtained in moderate
yield from maleimide-derived cycloadduct (+)-5e after
MeONa/MeOH treatment (Scheme 5). It deserves to be
mentioned that the maleimide moiety is not altered
under the basic rearrangement conditions.
General. The same experimental techniques were used as
previously reported.9-11
General Procedure for the Reaction between Alde-
hydes 1 and TMST. A solution of TMST (94 mg, 0.60 mmol)
8892 J. Org. Chem., Vol. 70, No. 22, 2005

Enhancement in 1,3-Cycloaddition of â-Lactam Aldehydes
in anhydrous dichloromethane (0.35 mL) was added dropwise
to a solution cooled at 0 °C of the corresponding 4-oxoazetidine-
2-carbaldehyde 1 (0.50 mmol) in the same solvent (0.5 mL).
The reaction was placed in a 0 °C freezer overnight. The
mixture was extracted with EtOAc, washed with water, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. Chromatography of the residue eluting with ethyl
acetate/hexanes mixtures gave a more polar fraction contain-
ing the corresponding carbinol and a less polar compound, its
trimethylsilyl ether. TBAF (0.63 mL, 2.88 mmol, 1 M solution
in THF) was added dropwise to a solution cooled at 0 °C of
the appropriate trimethylsilyl ether (1.8 mmol) in anhydrous
THF (140 mL). The reaction was stirred a 0 °C for 30 min.
The mixture was extracted with EtOAc, washed with water,
dried over MgSO4, filtered, and concentrated under reduced
pressure to give the corresponding free carbinol in quantitative
yield. No further purification was necessary. Spectroscopic and
analytical data for some representative forms of 2 follow.12
Reaction between 4-Oxoazetidine-2-carbaldehyde (+)-
1a and TMST. From 50 mg (0.42 mmol) of 4-oxoazetidine-2-
carbaldehyde (+)-1a and after chromatography of the residue
eluting with ethyl acetate/hexanes (1:1), two fractions were
obtained. The less polar fraction contained the trimethylsilyl
ether (57 mg, 60%) as a colorless oil. [R]D -12.3 (c 1.4, CHCl3).
1H NMR: δ 0.00 (s, 9H), 3.37 (s, 3H), 3.56 (ddt, 1H, J ) 15.4,
7.3, 1.0 Hz), 4.15 (ddt, 1H, J ) 15.4, 5.1, 1.7 Hz), 4.32 (t, 1H,
J ) 4.9 Hz), 4.43 (d, 1H, J ) 4.6 Hz), 5.00 (m, 2H), 5.12 (d,
1H, J ) 5.2 Hz), 5.39 (m, 1H), 7.20 and 7.66 (d, each 1H, J )
3.2 Hz). 13C NMR: δ 172.4, 167.5, 142.7, 131.0, 119.0, 118.2,
83.0, 70.8, 61.3, 59.2, 43.8, 0.0. IR (CHCl3, cm-1): ν 1742. MS
(ES), m/z: 327 (M+ + 1, 100), 326 (M+, 30). (Anal. Calcd for
C14H22N2O3SSi: C, 51.50; H, 6.79; N, 8.58. Found: C, 51.88;
H, 6.72; N, 8.50.) The more polar fraction contained the free
alcohol (24 mg, 32%) as a colorless oil. [R]D -6.7 (c 1.9, CHCl3).
1H NMR: δ 3.18 (ddt, 1H, J ) 15.3, 7.3, 1.2 Hz), 3.64 (s, 3H),
3.92 (m, 1H), 4.50 (dd, 1H, J ) 4.9, 2.2 Hz), 4.62 (d, 1H, J )
4.9 Hz), 4.85 (m, 2H), 5.23 (t, 1H, J ) 2.5 Hz), 5.29 (m, 1H),
7.23 and 7.65 (d, each 1H, J ) 3.2 Hz). 13C NMR: δ 170.8,
166.8, 142.3, 131.1, 119.1, 118.3, 83.4, 71.2, 61.8, 59.3, 43.9.
IR (CHCl3, cm-1): ν 1741. MS (ES), m/z: 255 (M+ + 1, 100),
254 (M+, 20). (Anal. Calcd for C11H14N2O3S: C, 51.95; H, 5.55;
N, 11.02. Found: C, 51.77; H, 5.49; N, 11.09.)
General Procedure for the TBS Protection of Alco-
hols. Preparation of Silyl Ethers (-)-2a and (-)-2b.
Triethylamine (0.45 mL, 3.2 mmol) and tert-butyldimethylsilyl
trifluoromethane sulfonate (0.50 mL, 2.4 mmol) were sequen-
tially added dropwise via syringe to a solution of the corre-
sponding alcohol (1.6 mmol) and a catalytic amount of 4-(di-
methylamino)pyridine (DMAP) in DMF (4 mL) at 0 °C under
argon. The resulting mixture was allowed to warm to room
temperature and was stirred for 5 h. The crude mixture was
diluted with CH2Cl2 (10 mL) and washed with brine (3 × 5
mL). The organic layer was dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue
eluting with ethyl acetate/hexanes mixtures gave analytically
pure silyl ethers 2.
Silyl Ether (-)-2a. From 42 mg (0.16 mmol) of the
corresponding alcohol, 44 mg (65%) of compound (-)-2a was
obtained as a colorless oil after purification by flash chroma-
tography (hexanes/ethyl acetate, 2/1). [R]D -13.5 (c 0.6, CHCl3).
1H NMR: δ 0.00 and 0.16 (s, each 3H), 0.96 (s, 9H), 3.43 (s,
3H), 3.69 (m, 1H), 4.26 (t, 1H, J ) 4.9 Hz), 4.31 (m, 1H), 4.47
(d, 1H, J ) 4.8 Hz), 5.09 (m, 2H), 5.33 (d, 1H, J ) 5.1 Hz),
5.72 (m, 1H), 7.36 and 7.81 (d, each 1H, J ) 3.2 Hz). 13C
NMR: δ 172.6, 167.6, 142.7, 131.1, 119.1, 118.4, 83.4, 71.2,
61.8, 59.3, 43.9, 25.8, 18.1, -4.5, -4.8. IR (CHCl3, cm-1): ν
1744. MS (ES), m/z: 369 (M+ + 1, 100), 368 (M+, 24). (Anal.
Calcd for C17H28N2O3SSi: C, 55.40; H, 7.66; N, 7.60. Found:
C, 55.68; H, 7.57; N, 7.69.)
General Procedure for the Synthesis of r-Alkoxy
â-Lactam Acetaldehydes 3. A mixture of the corresponding
ether 2 (0.30 mmol), activated 4 Å powdered molecular sieves
(0.3 g), and anhydrous acetonitrile (3 mL) was stirred at room
temperature (RT) for 10 min, before methyl triflate (44 µL,
0.39 mmol) was added. The suspension was stirred at RT for
15 min and then concentrated to dryness without filtering off
the molecular sieves. To a suspension cooled at 0 °C of the
crude N-methylthiazolium salt in methanol (3 mL), NaBH4 (23
mg, 0.60 mmol) was added. The mixture was stirred at RT for
an additional 10 min, diluted with acetone, filtered through a
pad of Celite, and concentrated. A solution of the residue in
dichloromethane (50 mL) was washed with water (5 mL), dried
(MgSO4), and concentrated under reduced pressure. To a
vigorously stirred solution of the resulting thiazolidine in
acetonitrile (3 mL), water (0.3 mL) was added dropwise, and
then AgNO3 (51 mg, 0.30 mmol) was added in one portion. The
mixture was stirred at RT for 10 min, then diluted with 1 M
phosphate buffer at pH 7 (10 mL) and partially concentrated
to remove the organic solvent (bath temperature not exceeding
40 °C). The suspension was extracted with dichloromethane
(3 × 15 mL), and the combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. A solution
of the residue in diethyl ether (30 mL) was filtered through a
pad of Celite and concentrated to afford the corresponding
R-alkoxy acetaldehydes 3 as a colorless oil. The crude product
was used for the next step without any further purification.
Spectroscopic and analytical data for some representative
forms of R-alkoxy â-lactam acetaldehydes 3 follow.
r-Alkoxy â-Lactam Acetaldehyde (+)-3a. From 130 mg
(0.30 mmol) of the precursor (-)-2a, 50 mg (56%) of compound
(+)-3a was obtained as a colorless oil. [R]D +9.5 (c 1.0, CHCl3).
1H NMR: δ 0.09 (s, 6H), 0.92 (s, 9H), 3.51 (s, 3H), 3.55 (dd,
1H, J ) 15.5, 7.2 Hz), 3.98 (dd, 1H, J ) 4.4, 3.7 Hz), 4.09 (ddt,
1H, J ) 15.4, 5.5, 1.5 Hz), 4.25 (dd, 1H, J ) 3.6, 0.6 Hz), 4.52
(d, 1H, J ) 4.7 Hz), 5.17 (m, 2H), 5.71 (m, 1H), 9.69 (d, 1H, J
) 0.6 Hz). 13C NMR: δ 210.7, 166.9, 131.1, 119.2, 83.4, 74.7,
59.3, 59.2, 43.7, 25.6, 18.0, -4.6, -5.1. IR (CHCl3, cm-1): ν
1760, 1746. MS (ES), m/z: 314 (M+ + 1, 100), 313 (M+, 15).
(Anal. Calcd for C15H27NO4Si: C, 57.47; H, 8.68; N, 4.47.
Found: C, 57.66; H, 8.60; N, 4.53.)
General Procedure for the Synthesis of Cycloadducts
5. A solution of the appropriate R-alkoxy â-lactam acetaldehyde
3 (1.00 mmol) in dichloromethane (7 mL) was added dropwise
to a stirred solution of 4 Å molecular sieves (2.0 g) and the
corresponding R-amino ester (1.50 mmol) in dichloromethane
(3 mL) at room temperature. After being stirred for 2 h at room
temperature, the mixture was filtered through a plug of Celite.
The solvent was removed under reduced pressure, giving in
quantitative yield imines 4. The crude product was used for
the next step without any further purification. To a solution
of the appropriate imine 4 (1.00 mmol) in toluene (6 mL) were
sequentially added silver acetate (1.20 mmol), the dipolaro-
phile (N-methylmaleimide, N-phenylmaleimide, methyl acry-
late, and dimethyl fumarate) (1.50 mmol), and triethylamine
(1.20 mmol), and the reaction mixture was stirred at room
temperature for 40 h. Saturated aqueous NH4Cl (1 mL) was
added, and the mixture was partitioned between dichlo-
romethane and water. The organic extract was washed with
brine, dried (MgSO4), and concentrated under reduced pres-
sure. Chromatography of the residue eluting with ethyl
acetate/hexanes mixtures gave analytically pure compounds
5. Spectroscopic and analytical data for some representative
pure forms of 5 follow.
Cycloadduct (+)-5a. From 50 mg (0.16 mmol) of the
R-alkoxy â-lactam acetaldehyde (+)-3a, 43 mg (57%) of com-
pound (+)-5a was obtained as a colorless oil after purification
by flash chromatography (hexanes/ethyl acetate, 2/1). [R]D
1
+15.4 (c 1.7, CHCl3). H NMR: δ 0.00 and 0.10 (s, each 3H),
0.73 (s, 9H), 2.35 (m, 2H), 2.52 (br s, 1H), 2.88 (m, 1H), 3.39
(dd, 1H, J ) 9.7, 6.6 Hz), 3.54 (s, 3H), 3.59 (m, 1H), 3.61 and
3.74 (s, each 3H), 3.80 (m, 1H), 3.85 (dd, 1H, J ) 4.9, 1.9 Hz),
(12) Full spectroscopic and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.
J. Org. Chem, Vol. 70, No. 22, 2005 8893

Alcaide et al.
1
3.94 (dd, 1H, J ) 9.7, 1.9 Hz), 4.28 (ddt, 1H, J ) 15.4, 4.1, 1.7
Hz), 4.33 (d, 1H, J ) 4.9 Hz), 5.16 (m, 2H), 5.73 (m, 1H). 13C
NMR: δ 173.8, 173.4, 167.6, 132.1, 118.6, 83.2, 69.9, 67.5, 59.0,
58.9, 58.1, 52.2, 51.7, 44.7, 44.1, 33.6, 26.3, 18.5, -3.8, -3.9.
IR (CHCl3, cm-1): ν 3334, 1750, 1736. MS (ES), m/z: 471 (M+
+ 1, 100), 470 (M+, 22). (Anal. Calcd for C22H38N2O7Si: C,
56.14; H, 8.14; N, 5.95. Found: C, 56.35; H, 8.07; N, 5.88).
Sodium Methoxide-Promoted Reaction of 2-Azetidi-
none-Tethered Prolines. General Procedure for the
Preparation of Indolizidinone Amino Esters 7. Sodium
methoxide (108.3 mg, 2.0 mmol) was added in portions at 0
°C to a solution of the appropriate 2-azetidinone-tethered
proline (0.50 mmol) in methanol (10 mL). The reaction was
stirred at room temperature until complete disappearance of
the starting material (TLC), and then water was added (1 mL).
The methanol was removed under reduced pressure, and the
aqueous residue was extracted with ethyl acetate (10 × 3 mL).
The organic extract was washed with brine and dried over
MgSO4, and the solvent was removed under reduced pressure.
Chromatography of the residue eluting with ethyl acetate/
hexanes mixtures gave analytically pure compounds 7.
Indolizidinone Amino Ester (+)-7a. From 30 mg (0.06
mmol) of the cycloadduct (+)-5a, 16 mg (55%) of compound
(+)-7a was obtained as a colorless oil after purification by flash
chromatography (hexanes/ethyl acetate, 2/1). [R]D +33.6 (c 0.9,
CHCl3). H NMR: δ 0.14 (br s, 6H), 0.94 (s, 9H), 2.07 (ddd,
1H, J ) 13.1, 9.7, 7.1 Hz), 2.46 (ddd, 1H, J ) 13.0, 8.8, 7.5
Hz), 2.79 (dt, 1H, J ) 10.0, 7.1 Hz), 3.17 (d, 1H, J ) 8.1 Hz),
3.55 (s, 3H), 3.65 (m, 1H), 3.71 and 3.76 (s, each 3H), 3.88 (m,
1H), 4.00 (d, 1H, J ) 5.6 Hz), 4.21 (ddt, 1H, J ) 15.6, 5.4, 1.2
Hz), 4.28 (dd, 1H, J ) 5.8, 1.9 Hz), 4.42 (d, 1H, J ) 5.2 Hz),
5.18 (m, 2H), 5.75 (m, 1H). 13C NMR: δ 174.0, 173.9, 168.3,
131.5, 118.7, 83.3, 69.1, 67.3, 65.1, 59.2, 58.7, 52.4, 52.1, 45.0,
44.9, 29.8, 26.2, 18.3, -3.7, -3.8. IR (CHCl3, cm-1): ν 3336,
1739, 1647. MS (EI), m/z: 471 (M+, 6), 186 (M+ - 284, 100).
(Anal. Calcd for C22H38N2O7Si: C, 56.14; H, 8.14; N, 5.95.
Found: C, 55.98; H, 8.08; N, 6.01.)
Acknowledgment. Support for this work by the
DGI-MCYT (Project BQU2003-07793-C02-01) is grate-
fully acknowledged. M.C.R. thanks the MEC for a
predoctoral grant.
Supporting Information Available: General experimen-
tal procedures as well as spectroscopic and analytical data for
compounds (+)-1a, (+)-1b, (-)-2b, (+)-2c, (+)-3b, (+)-3c, (+)-
5b-f, and (+)-7b-d. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO051402Y
8894 J. Org. Chem., Vol. 70, No. 22, 2005