Synthesis of Optically Pure Highly Functionalized γ-Lactams via 2-Azetidinone-Tethered Iminophosphoranes

Article abstract of DOI:10.1021/jo035623k

A synthesis of optically pure densely functionalized γ-lactams starting from 2-azetidinone-tethered iminophosphoranes has been developed. Full chirality transfer has been accomplished from the enantiomerically pure 2-azetidinones. The addition of lithium acetylides to 4-oxoazetidine-2-carbaldehydes at -78 °C smoothly yielded propargylic alcohols with excellent diastereoselectivities. Propargylic alcohols were converted to mesylates, which by exposure to sodium azide afforded the corresponding azides. Treatment of β-lactams bearing an azido side chain with triphenylphosphine (TPP) gave λ⁵-phosphazenes (iminophosphoranes, phosphine imines), which were not isolated. The sodium methoxide promoted reaction of the phosphazene β-lactams smoothly provided γ-lactams, through a N1-C2 bond breakage process on the four-membered lactam with concomitant ring expansion, followed by hydrolysis.

Full text of DOI:10.1021/jo035623k

further interesting synthetic transformations renders
these fascinating molecules powerful synthetic building
blocks.5-7 Despite the versatility of the 2-azetidinone
ring,8 synthetic routes to monocyclic γ-lactams from
â-lactams have been scarcely reported.9 We have used
carbonyl â-lactams as chiral templates and recently
shown their manipulation to a variety of potentially
bioactive products.10 In this paper we present a â-lactam-
tethered iminophosphorane-based stereocontrolled access
to enantiopure γ-lactams.
Syn th esis of Op tica lly P u r e High ly
F u n ction a lized γ-La cta m s via
2-Azetid in on e-Teth er ed
Im in op h osp h or a n es
Benito Alcaide,*,† Pedro Almendros,*,‡ and
J ose M. Alonso†
Departamento de Quı´mica Orga´nica I,
Facultad de Qu´ımica, Universidad Complutense,
28040 Madrid. Spain, and Instituto de Qu´ımica Orga´nica
General, CSIC, J uan de la Cierva 3, 28006 Madrid, Spain
Starting substrates, enantiopure 4-oxoazetidine-2-car-
baldehydes 1a-e, were obtained as single cis-enantiomers
from imines of (R)-2,3-O-isopropylideneglyceraldehyde
through Staudinger reaction with the appropriate alkoxy-
acetyl chloride in the presence of Et3N, followed by seque-
ntial acidic acetonide hydrolysis and oxidative cleavage.10
Coupling reactions of alkynes (and alkynylmetallic
reagents) and aldehydes are important transformations
in organic synthesis as they generate new carbon-carbon
bonds to give propargyl alcohols. Optically active prop-
argylic alcohols serve as versatile building blocks for
asymmetric synthesis, as they are used in diverse areas,
including the synthesis of natural products, pharmaceu-
ticals, and macromolecules.11 Our interest in the use of
4-oxoazetidine-2-carbaldehydes as substrates for addition
reactions10 prompted us to evaluate their alkynylation
reaction with acetylenes. We found particularly attractive
the catalytic activation of the alkyne and subsequent
addition to the carbonyl derivative. However, neither the
Knochel procedure with cesium hydroxide12 nor the
Carreira protocol with zinc triflate/N-methylephedrine13
were amenable to our â-lactam aldehydes. Aldehydes 1
alcaideb@quim.ucm.es; iqoa392@iqog.csic.es
Received November 5, 2003
Abstr a ct: A synthesis of optically pure densely function-
alized γ-lactams starting from 2-azetidinone-tethered imi-
nophosphoranes has been developed. Full chirality transfer
has been accomplished from the enantiomerically pure
2-azetidinones. The addition of lithium acetylides to 4-oxoaze-
tidine-2-carbaldehydes at -78 °C smoothly yielded propar-
gylic alcohols with excellent diastereoselectivities. Propar-
gylic alcohols were converted to mesylates, which by exposure
to sodium azide afforded the corresponding azides. Treat-
ment of â-lactams bearing an azido side chain with triph-
enylphosphine (TPP) gave λ5-phosphazenes (iminophospho-
ranes, phosphine imines), which were not isolated. The
sodium methoxide promoted reaction of the phosphazene
â-lactams smoothly provided γ-lactams, through a N1-C2
bond breakage process on the four-membered lactam with
concomitant ring expansion, followed by hydrolysis.
Nitrogen heterocycles comprise the vast majority of
medicinals on the market today. Highly substituted
lactam rings possess diverse biological activity, and much
recent attention has focused on excitatory amino acid
chemistry, particularly as a result of the drive to better
understand CNS function in mammalian systems.1 It has
recently also been shown that densely functionalized
pyrrolidinones, such as lactacystin2 and pramamicin,3
exhibit potent and selective activity in proteasome inac-
tivation and may find application in the development of
selective therapeutic agents for important parasitic infec-
tions.4 In addition, the pyrrolidinone (γ-lactam) function-
ality is a prevalent theme in various natural product
syntheses, and serves as a crucial intermediate for
numerous natural products. On the other hand, the
importance of 2-azetidinones as synthetic intermediates
has been widely recognized in organic synthesis. This
usefulness is based on the impressive variety of trans-
formations which can be derived from this system,
because ring cleavage of any of the four single bonds of
the â-lactam system is enhanced by ring strain. Selective
bond cleavage of the 2-azetidinone ring coupled with
(5) For reviews, see: (a) Ojima, I. The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH Publishers: New York, 1993; p 197.
(b) Ojima, I. Adv. Asymmetric Synth. 1995, 1, 95. (c) Palomo, C.;
Aizpurua, J . M.; Ganboa, I.; Oiarbide, M. Amino Acids 1999, 16, 321.
(d) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Oiarbide, M. Synlett 2001,
1813.
(6) For a review on the â-lactam synthon method, see: Ojima, I.;
Delaloge, F. Chem. Soc. Rev. 1997, 26, 377.
(7) For reviews, see: (a) Alcaide, B.; Almendros, P. Synlett 2002,
381. (b) Manhas, M. S.; Wagle, D. R.; Chiang, J .; Bose, A. K.
Heterocycles 1988, 27, 1755.
(8) For the applications of 4-oxoazetidine-2-carbaldehydes as ef-
ficient chiral synthons, see: (a) Alcaide, B.; Almendros, P. Chem. Soc.
Rev. 2001, 30, 226. For a review on the chemistry of azetidine-2,3-
diones, see: (b) Alcaide, B.; Almendros, P. Org. Prep. Proced. Int. 2001,
33, 315.
(9) (a) Palomo, C.; Coss´ıo, F. P.; Cuevas, C.; Odriozola, J . M.; Ontoria,
J . M. Tetrahedron Lett. 1992, 33, 4827. (b) J ayaraman, M.; Puranik,
V. G.; Bhawal, B. M. Tetrahedron 1996, 52, 9005. (c) Banfi, L.; Guanti,
G.; Rasparini, M. Eur. J . Org. Chem. 2003, 1319. (d) Escalante, J .;
Gonza´lez-Tototzin, M. A. Tetrahedron: Asymmetry 2003, 14, 981.
(10) See, for instance: (a) Alcaide, B.; Almendros, P.; Alonso, J . M.;
Aly, M. F. Chem. Eur. J . 2003, 9, 3415. (b) Alcaide, B.; Almendros, P.;
Pardo, C.; Rodr´ıguez-Ranera, C.; Rodr´ıguez-Vicente, V. J . Org. Chem.
2003, 68, 3106. (c) Alcaide, B.; Almendros, P.; Alonso, J . M.; Redondo,
M. C. J . Org. Chem. 2003, 68, 1426. (d) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Eur. J . 2002, 8, 1719. (e) Alcaide, B.; Almendros,
P.; Aragoncillo, C.; Redondo, M. C. Chem. Commun. 2002, 1472. (f)
Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Eur. J . 2002, 8, 3646.
(11) For selected examples, see: (a) Kojima, N.; Maezaki, N.;
Tominaga, H.; Asai, M.; Yanai, M.; Tanaka, T. Chem. Eur. J . 2003, 9,
4980. (b) Marshall, J . A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197. (c)
Trost, B. M.; Krische, M. J . J . Am. Chem. Soc. 1999, 121, 6131. (d)
Tan, L.; Chen, C.-Y.; Tillyer, R. D.; Grabowski, E. J . J .; Reider, P. J .
Angew. Chem., Int. Ed. 1999, 38, 711. (e) Roush, W. R.; Sciotti, R. J .
J . Am. Chem. Soc. 1994, 116, 6457. (f) Marshall, J . A.; Wang, X. J . J .
Org. Chem. 1992, 57, 1242.
† Universidad Complutense.
‡ Instituto de Qu´ımica Orga´nica General.
(1) Moloney, M. G. Nat. Prod. Rep. 1999, 16, 485.
(2) For a review, see: Corey, E. J .; Li, W.-D. Chem. Pharm. Bull.
1999, 47, 1.
(3) Barret, A. G.; Head, J .; Smith, M. L.; Stock, N. S.; White, A. J .
P.; Williams, D. J . J . Org. Chem. 1999, 64, 6005 and references therein.
(4) (a) Saravanan, P.; Corey, E. J . J . Org. Chem. 2003, 68, 2760. (b)
Crane, S. N.; Corey, E. J . Org. Lett. 2001, 3, 1395. (c) Corey, E. J .; Li,
W.-D.; Nagamitsu, T.; Fenteany, G. Tetrahedron 1999, 55, 3305.
10.1021/jo035623k CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/13/2004
J . Org. Chem. 2004, 69, 993-996
993

TABLE 1. Ster eoselective Alk yn yla tion of
4-Oxoa zetid in e-2-ca r ba ld eh yd es
syn/anti yield
F IGURE 1.
entry aldehyde
R1
PMPc
R2
R3
alkynol ratioa
(%)b
1
2
3
4
5
6
7
8
9
(+)-1a
(+)-1a
(+)-1b
(+)-1b
(+)-1c
(+)-1d
(+)-1d
(+)-1e
(+)-1e
PhO Ph
(+)-2a
100:0
100:0
100:0
100:0
100:0
100:0
100:0
70:30
70:30
79
81
66
70
77
64
56
54
42
were almost unreactive under catalytic Carreira’s condi-
tions, while epimerization was observed on the R-amino
aldehyde for the cesium hydroxide-catalyzed reaction.14
Next, we focused our efforts on the alkynylation of alde-
hydes 1 using equimolecular amounts of Lewis acid in
combination with a tertiary amine.15 Despite the claimed
mildness of the procedure promoted by zinc(II) salts in
the presence of triethylamine,16 it was also unfeasible for
R-amino aldehydes 1 because it caused the undesired side
epimerization reaction. Then, we turned our attention to
the classical use of a stoichiometric amount of base, such
as an organolithium reagent, to generate a metal acetyl-
ide. Thus, the addition of lithium(trimethylsilyl)acetylide
or lithium(phenyl)acetylide to 4-oxoazetidine-2-carbal-
dehydes 1a -e in THF at -78 °C smoothly yielded the
propargylic alcohols 2a -i. Importantly, the â-lactam ring
stereochemistry was unaffected by this process.17 Total
diastereoselectivity was generally observed when differ-
ent aldehydes were used (Table 1, entries 1-7). However,
aldehyde (+)-1e bearing a methoxy substituent at C3 and
a 3-butenyl moiety at N1 provided poor diastereoselec-
tivity (70:30) with the same facial preference (Table 1,
entries 8 and 9). The bulkiness of the phenoxy substitu-
ent at C3 or the p-methoxyphenyl at N1 on the â-lactam
ring may play a role in ensuring the high selectivity of
this process, while less demanding groups dropped the
diastereoselectivity. The observed syn-diastereoselectivity
might be tentatively explained by invoking the Felkin-
Anh model (Figure 1) analogously to related addition
processes described in our laboratories.8a
PMP
2-propenyl PhO Ph
2-propenyl PhO TMS (+)-2d
PhO TMSd (+)-2b
(+)-2c
PMP
PMP
PMP
BnO Ph
MeO Ph
(+)-2e
(+)-2f
MeO TMS (+)-2g
(+)-2h
3-butenyl MeO TMS (+)-2i
3-butenyl MeO Ph
a
The ratio was determined by integration of well-resolved
signals in the 1H NMR spectra of the crude reaction mixtures
b
before purification. Yield of pure, isolated product with correct
d
analytical and spectral data. c PMP ) 4-MeOC6H4. TMS
)
trimethylsilyl.
SCHEME 1
methanesulfonyl chloride and triethylamine. Mesylates
3 were transformed into azides 4 when treated with NaN3
(Scheme 1). Optimum conditions for the reaction have
been explored and the reaction was found to proceed
smoothly to completion with use of 3 molar equiv of NaN3
in DMF at room temperature overnight.
Formation of iminophosphoranes is a convenient way
of generating nucleophilic amines from organic azides.
It was found that the phosphine imine intermediates
5a -g were formed satisfactorily (we used IR spectroscopy
to follow the disappearance of the azide absorption at
about 2100 cm-1) by reaction of azides 4 with triph-
enylphosphine (Scheme 2).19 Initially, we tried to reduce
azide (+)-4b to amine (+)-6a using the triphenylphos-
phine method, but hydrolysis of the iminophosphorane
was slow and the isolated yield of amine (+)-6a was very
poor (25%) (Scheme 3). Although complete conversion was
observed by TLC and 1H NMR analysis of the crude
reaction mixture, the high polarity of amine 6a and
subsequent high water solubility may be responsible for
the modest isolated yield in the aqueous reaction media.
Studies by Vilarrasa and co-workers have shown that
the phosphazene intermediate can be coupled to acids,
Organic azides are extremely valuable intermediates
for the synthesis of many nitrogen-containing molecules,
including heterocycles and natural products. Our next
target was the synthesis of 2-azetidinone-tethered azides,
because they bear the azido moiety that serves as a latent
amine. The direct conversion of alkynols 2 into the
corresponding azides failed with different reagents such
as NaN3/BF3‚Et2O or DPPA/DBU.18 Then, propargylic
alcohols 2 were converted to mesylates 3 by exposure to
(12) Tzalis, D.; Knochel, P. Angew. Chem,. Int. Ed. 1999, 38, 1463.
(13) Anand, N. K.; Carreira, E. M. J . Am. Chem. Soc. 2001, 123,
9687.
(14) We have reported recently a base-promoted regiospecific C2-
epimerization of cis-4-oxoazetidine-2-carbaldehydes to trans-4-oxoaze-
tidine-2-carbaldehydes. See: Alcaide, B.; Aly, M. F.; Rodr´ıguez, C.;
Rodr´ıguez-Vicente, A. J . Org. Chem. 2000, 65, 3453.
(15) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J . Am. Chem.
Soc. 2000, 122, 1806. (b) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org.
Lett. 2002, 4, 2605.
(16) J iang, B.; Si, Y.-G. Tetrahedron Lett. 2002, 43, 8323.
(17) The assignment of the cis-stereochemistry to â-lactams 2a -i
was based on the observed coupling constants of about 5.0 Hz for
methine protons H3 and H4, whereas trans-stereochemistry is con-
sistent with methine coupling constants of ca. 2.0 Hz in their 1H NMR
spectra. The assignment of relative stereochemistry based on the
observed coupling constant for methine protons H3 and H4 is a very
well-established criterium in â-lactam chemistry. See, for example:
Alcaide, B.; Almendros, P.; Salgado, N. R.; Rodriguez-Vincente, A. J .
Org. Chem., 2000, 65, 4453
(18) (a) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre,
D. J .; Grabowski, E. J . J . J . Org. Chem. 1993, 58, 5886. (b) Kumar, H.
M. S.; Reddy, B. V. S.; Anjaneyulu, S.; Yadav, J . S. Tetrahedron Lett.
1998, 39, 7385.
(19) 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.
994 J . Org. Chem., Vol. 69, No. 3, 2004

SCHEME 2
F IGURE 2.
SCHEME 6
SCHEME 3
SCHEME 4
membered lactam with concomitant ring expansion,
followed by hydrolysis. Initially, the selective N1-C2
bond cleavage of the â-lactam nucleus in 2-azetidinone-
tethered iminophosphoranes 5 gave the nonisolable
â-amino-γ-phosphine imino esters 8, which after rear-
rangement under the reaction conditions followed by
hydrolysis of the phosphonium salts 9 yielded the γ-lac-
tams 7 (Scheme 5). The pyrrolidinone formation must be
driven by relief of the strain associated with the four-
membered ring on forming a more stable five-membered
ring. Azacycles 7 showed a single set of signals in their
1H NMR spectra, thus proving that this transformation
proceeded without detectable epimerization.
SCHEME 5
To show the capacity of the method to prepare an array
of γ-lactams bearing stereochemical diversity, the R-pro-
ton of the lactam moiety in the 2-pyrrolidinone nucleus
was regiospecifically epimerized at C3. Previously to the
epimerization reaction, the exocyclic amino group on γ-
lactam (+)-7f was acetylated to give (+)-10. The enantio-
merically pure γ-lactam (+)-11 was obtained in 81% over-
all yield from (+)-7f after sequential treatment with
acetic anhydride and potassium carbonate (Scheme 6).
The stereochemistry of γ-lactams 7 and 10 was estab-
lished by NMR techniques, particularly by vicinal proton
couplings and qualitative homonuclear NOE difference
spectra. The cis-stereochemistry of the four-membered
ring is set during the cyclization step to form the 2-azeti-
dinone ring and it is transferred unaltered during the
further synthetic steps.17 Taking into account that â-lac-
tams 4 could be obtained and cyclized, the stereochem-
istry at the exocyclic stereogenic center for compounds
2-6 was inmediately deduced by comparison with the
NOE results of the cyclic five-membered lactams 7 and
11. For compound (+)-7b the only significant NOE en-
hancement (2%) was observed on H3 upon irradiation on
H5. For compound (+)-11, NOE irradiation of H4 resulted
in a 13% enhancement on H3, while no effect was ob-
served for H5. Thus, an anti,anti-relative stereochemistry
was assigned for compound (+)-7b, while a syn,anti-dis-
position was established for compound (+)-11 (Figure 2).
acid halides, or acid anhydrides to yield an amide in a
straightforward manner.20 It occurred to us that the
Staudinger protocol might serve as a novel one-pot flask
procedure for the direct conversion of 2-azetidinone-
tethered azides into γ-lactams. Indeed, the sequential
treatment of â-lactam azides 4 under meticulously dry
conditions with triphenylphosphine and sodium meth-
oxide, followed by an aqueous workup yielded the enan-
tiopure pyrrolidinones 7 in reasonable yields (Scheme 4).
When applicable, the trimethylsilyl protecting group was
cleaved under the reaction conditions.
From a mechanistic point of view, our results could be
explained through a bond breakage process on the four-
(20) (a) Bosch, I.; Urp´ı, F.; Vilarrasa, J . Chem. Commun. 1995, 91.
(b) Bosch, I.; Gonza´lez, A.; Urp´ı, F.; Vilarrasa, J . J . Org. Chem. 1996,
61, 5638. (c) Ariza, X.; Urp´ı, F.; Vilarrasa, J . Tetrahedron Lett. 1999,
40, 7515. (d) Park, S.-D.; Oh, J .-H.; Lim, D. Tetrahedron Lett. 2002,
43, 6309. (e) David, O.; Meester, W. J . N.; Biera¨ugel, H.; Schoemaker,
H. E.; Hiemstra, H.; van Maarseveen, J . H. Angew. Chem., Int. Ed.
2003, 42, 4373.
J . Org. Chem, Vol. 69, No. 3, 2004 995

solution of sodium azide (3.0 mmol) in dimethylformamide (15
mL) at room temperature. The mixture was stirred at room
temperature overnight, and water (5 mL) was added before being
extracted with ethyl acetate (3 × 10 mL). The organic phase
was washed with water (2 × 5 mL), dried (MgSO4), and
concentrated under reduced pressure. Chromatography of the
residue eluting with hexanes/ethyl acetate mixtures gave ana-
lytically pure azides 4. Spectroscopic and analytical data for
some representative pure forms of 4 follow.
In conclusion, treatment of â-lactams bearing an azido
side chain with triphenylphosphine gave 2-azetidinone-
tethered iminophosphoranes, which have been found to
react smoothly with sodium methoxide providing enan-
tiopure γ-lactams. The transformation of â-lactam phos-
phazenes into pyrrolidinones involves the amide bond
cleavage of the â-lactam ring, followed by cyclization of
the resulting â-amino-γ-phosphine imino ester with
concomitant ring expansion, followed by hydrolysis.
P r op a r gylic Azid e (+)-4b. From 127 mg (0.268 mmol) of
methanesulfonate (+)-3b, 97 mg (87%) of compound (+)-4b was
1
obtained as a yellow oil. [R]D +135.3 (c 0.8, CHCl3). H NMR δ
0.02 (s, 9H), 3.75 (s, 3H), 4.48 (dd, 1H, J ) 4.9, 4.1 Hz), 4.75 (d,
1H, J ) 4.1 Hz), 5.38 (d, 1H, J ) 5.1 Hz), 6.77 (m, 2H), 7.00 (m,
3H), 7.24 (m, 2H), 7.41 (m, 2H). 13C NMR δ 162.8, 157.5, 156.9,
129.8, 129.6, 122.5, 119.8, 115.8, 114.3, 97.2, 95.5, 79.4, 59.8,
55.4, 52.1, -0.6. IR (CHCl3, cm-1) ν 2112, 1746. MS (CI), m/z
421 (M+ + 1, 100), 420 (M+, 7). Anal. Calcd for C22H24N4O3Si:
C, 62.83; H, 5.75; N, 13.32. Found: C, 62.90; H, 5.71; N, 13.36.
Gen er a l P r oced u r e for th e P r ep a r a tion of γ-La cta m s 7.
A solution of triphenylphosphine (0.76 mmol) in dichloromethane
(4 mL) was added to a stirred solution of the appropriate azide
4 (0.76 mmol) in dichloromethane (7 mL) at 0 °C, and the
mixture was stirred at room temperature for 3 h. The dichlo-
romethane was removed under reduced pressure and the result-
ing crude iminophosphoranes 5 were solved in anhydrous
methanol (15 mL). Then, sodium methoxide (164 mg, 3.0 mmol)
was added in portions at 0 °C to the methanolic solution of the
corresponding iminophosphorane 5 (0.76 mmol). The reaction
was stirred at room temperature for 2 h and then water was
added (1 mL). The methanol was concentrated under reduced
pressure, the aqueous residue was extracted with ethyl acetate
(4 × 5 mL), the organic layer was 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.
γ-La cta m (+)-7b. From 20 mg (0.047 mmol) of azide (+)-4b,
15 mg (60%) of compound (+)-7b was obtained as a colorless
oil. [R]D +12.9 (c 0.8, CHCl3). 1H NMR δ 2.34 (d, 1H, J ) 2.1
Hz), 3.58 (s, 3H), 4.02 (dd, 1H, J ) 5.1, 2.1 Hz), 4.15 (m, 1H),
4.49 (d, 1H, J ) 5.7 Hz), 5.96 (s, 1H), 6.52 (m, 4H), 6.80 (m,
3H), 7.05 (m, 2H). 13C NMR δ 170.9, 157.9, 153.5, 139.1, 129.4,
122.3, 116.4, 116.1, 114.8, 80.3, 80.2, 63.7, 55.6, 48.4, 29.6. IR
(CHCl3, cm-1) ν 3310, 1750. MS (CI), m/z 323 (M+ + 1, 100),
322 (M+, 9). Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N,
8.69. Found: C, 70.90; H, 5.60; N, 8.74.
Exp er im en ta l Section
Gen er a l. General experimental data and procedures have
been previously reported.10 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, 77.0
ppm). All commercially available compounds were used without
further purification.
Gen er a l P r oced u r e for th e P r ep a r a tion of P r op a r gylic
Alcoh ols 2. A cooled solution of BuLi (3.79 mL, 6.06 mmol, 1.6
M in hexanes) was added dropwise to a stirred solution of the
appropriate acetylene (6.06 mmol) in THF (10 mL) at -78 °C.
After 30 min, the resulting solution was transferred via cannula
to a solution of the corresponding 4-oxoazetidine-2-carbaldehyde
1 (2.02 mmol) in THF (10 mL) cooled at -78 °C, and the mixture
was stirred for 4 h at -78 °C. Saturated aqueous ammonium
chloride (6 mL) was added and the mixture was allowed to warm
to room temperature, before being extracted with ethyl acetate
(3 × 10 mL). The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue eluting with ethyl acetate/hexanes
mixtures gave analytically pure compounds 2. Spectroscopic and
analytical data for some representative pure forms of 2 follow.21
P r op a r gylic Alcoh ol (+)-2b. From 600 mg (2.02 mmol) of
aldehyde (+)-1a , 644 mg (81%) of (+)-2b was obtained as a
colorless oil. [R]D +72.0 (c 0.6, CHCl3). 1H NMR δ 0.01 (s, 9H),
2.49 (d, 1H, J ) 5.5 Hz), 3.81 (s, 3H), 4.66 (t, 1H, J ) 4.9 Hz),
4.95 (t, 1H, J ) 4.8 Hz), 5.40 (d, 1H, J ) 4.9 Hz), 6.77 (m, 2H),
6.95 (m, 3H), 7.20 (m, 2H), 7.47 (m, 2H). 13C NMR δ 163.8, 157.6,
156.8, 130.9, 129.0, 128.9, 127.9, 118.5, 118.3, 92.9, 89.7, 63.2,
59.8, 59.2, 58.0, -0.6. IR (CHCl3, cm-1) ν 3303, 1745. MS (CI),
m/z 396 (M+ + 1, 100), 395 (M+, 12). Anal. Calcd for C22H25NO4-
Si: C, 66.81; H, 6.37; N, 3.54. Found: C, 66.70; H, 6.33; N, 3.52.
Gen er a l P r oced u r e for th e P r ep a r a tion of P r op a r gylic
Meth a n esu lfon a tes 3. Methanesulfonyl chloride (138 mg, 1.20
mmol) and triethylamine (243 mg, 2.40 mmol) were sequentially
added dropwise to a stirred solution of the corresponding
propargylic alcohol (1.0 mmol) in dichloromethane (10 mL) at 0
°C, and the mixture was stirred for 1 h at room temperature.
The organic phase was washed with water (2 × 5 mL), dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue eluting with hexanes/ethyl acetate
mixtures gave analytically pure methanesulfonates 3. Spectro-
scopic and analytical data for some representative pure forms
of 3 follow.
P r oced u r e for th e P r ep a r a tion of γ-La cta m (+)-11. A
stirred suspension of the γ-lactam (+)-10 (37 mg, 0.098 mmol)
and potassium carbonate (135 mg, 0.98 mmol) in acetonitrile (2
mL) was heated at reflux temperature for 2 h. After cooling to
room temperature, the solid was removed by filtration, and the
filtrate was concentrated under reduced pressure. Chromatog-
raphy of the residue with ethyl acetate gave 30 mg (81%) of
analytically pure compound (+)-11 as a yellow oil.
1
γ-La cta m (+)-11. [R]D +32.7 (c 1.0, CHCl3). H NMR δ 2.49
(s, 3H), 3.59 (s, 3H), 3.69 (s, 3H), 4.17 (m, 1H), 4. 20 (d, 1H, J )
5.7 Hz), 4.52 (d, 1H, J ) 5.6 Hz), 6.57 (m, 2H), 6.74 (m, 2H),
7.33 (m, 5H). 13C NMR δ 171.0, 170.3, 153.4, 139.1, 132.1, 129.1,
128.4, 128.3, 115.3, 114.7, 78.5, 59.3, 56.1, 55.8, 49.4, 25.1. IR
(CHCl3, cm-1) ν 3306, 1748, 1652. MS (CI), m/z 379 (M+ + 1,
100), 378 (M+, 17). Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86;
N, 7.40. Found: C, 69.92; H, 5.83; N, 7.36.
P r op a r gylic Meth a n esu lfon a te (+)-3b. From 54 mg (0.137
mmol) of alcohol (+)-2b, 65 mg (100%) of compound (+)-3b was
1
obtained as a colorless oil. [R]D +51.8 (c 0.7, CHCl3). H NMR δ
0.00 (s, 9H), 2.75 (s, 3H), 3.69 (s, 3H), 4.65 (dd, 1H, J ) 6.7, 5.1
Hz), 5.34 (d, 1H, J ) 5.1 Hz), 5.50 (d, 1H, J ) 6.7 Hz), 7.80 (m,
9H). 13C NMR δ 162.9, 157.6, 157.6, 157.1, 129.8, 129.6, 122.8,
120.0, 116.0, 114.3, 97.6, 97.2, 79.7, 69.9, 59.4, 55.5, 39.1, -0.6.
IR (CHCl3, cm-1) ν 1746, 1354. MS (EI), m/z 474 (M+ + 1, 3),
473 (M+, 100). Anal. Calcd for C23H27NO6SSi: C, 58.33; H, 5.75;
N, 2.96. Found: C, 58.44; H, 5.72; N, 2.94.
Ack n ow led gm en t. We would like to thank the DGI-
MCYT (Project BQU2003-07793-C02-01) for financial
support. J .M.A. thanks the UCM for a predoctoral grant.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for isomerically pure compounds (+)-2a , (+)-
2c-i, (+)-3a , (+)-3c-g, (+)-4a , (+)-4c-g, (+)-6a , (+)-7a , (+)-
7c-g, and (+)-10, as well as experimental procedures for
compounds (+)-6 and (+)-10. This material is available free
of charge via the Internet at http://pubs.acs.org.
Gen er a l P r oced u r e for th e P r ep a r a tion of P r op a r gylic
Azid es 4. A solution of the appropriate methanesulfonate 3 (1.0
mmol) in dimethylformamide (5 mL) was added to a stirred
(21) Full spectroscopic and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.
J O035623K
996 J . Org. Chem., Vol. 69, No. 3, 2004