N1-C4 β-lactam bond cleavage in the 2-(trimethylsilyl)thiazole addition to β-lactam aldehydes: Asymmetric synthesis of spiranic and tertiary α-alkoxy-γ-keto acid derivatives

Article abstract of DOI:10.1002/ejoc.200700231

Starting substrates, enantiopure spiranic or 3-substituted 3-alkoxy-4-oxoazetidine-2-carbaldehydes, were prepared from (R)-2,3-O- isopropylideneglyceraldehyde derived azetidine-2,3-diones by sequential Barbier-type addition reactions followed by hydroxy f

Full text of DOI:10.1002/ejoc.200700231

FULL PAPER
DOI: 10.1002/ejoc.200700231
N1–C4 β-Lactam Bond Cleavage in the 2-(Trimethylsilyl)thiazole Addition to
β-Lactam Aldehydes: Asymmetric Synthesis of Spiranic and Tertiary
α-Alkoxy-γ-keto Acid Derivatives
Benito Alcaide,*[a] Pedro Almendros,*[b] and María C. Redondo[a]
Keywords: Aldehydes / Asymmetric synthesis / Cleavage reactions / Lactams / Spiro compounds
Starting substrates, enantiopure spiranic or 3-substituted 3-
alkoxy-4-oxoazetidine-2-carbaldehydes, were prepared from
(R)-2,3-O-isopropylideneglyceraldehyde derived azetidine-
2,3-diones by sequential Barbier-type addition reactions fol-
lowed by hydroxy functionalization and aldehyde un-
masking. The reaction between the above β-lactam alde-
hydes and 2-(trimethylsilyl)thiazole (TMST) gave as major
products conformationally constrained α-alkoxy-γ-keto
amides, which can be considered both as aldols as well as
Passerini-type products, by N1–C4 β-lactam bond cleavage.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
tion between sterically encumbered 4-oxoazetidine-2-car-
baldehydes and TMST to obtain enantiopure spiranic and
tertiary α-alkoxy-γ-keto acid derivatives.[7]
Introduction
In addition to being the key structural motif of the β-
lactam antibiotics, the 2-azetidinone skeleton has been rec-
ognized as a useful building block in the synthesis of phar-
maceutically useful products.[1] The strain energy associated
with the β-lactam nucleus makes it susceptible to opening
through cleavage of any of the single bonds of the four-
membered ring.[2] Cleavage of the N1–C4 bond of 4-arylaz-
etidin-2-ones by hydrogenolysis is a very well known meth-
odology developed by Ojima for the synthesis of α-amino
acids and peptidomimetics.[3] More recently, we and others
have established different protocols for the N1–C4 β-lactam
bond breakage leading to cyclic and acyclic compounds.[4]
In connection with our current research interest in the prep-
aration and synthetic utility of β-lactams,[5] we recently
communicated the synthesis of α-alkoxy-γ-keto acid deriva-
tives by N1–C4 bond cleavage when we reacted 2-(trimeth-
ylsilyl)thiazole (TMST) with 4-oxoazetidine-2-carbal-
dehydes.[6] Our previous report was limited primarily to the
use of simple cis- or trans-4-oxoazetidine-2-carbaldehydes
as a coupling partner. As such, we have undertaken a study
of the potential use of more diverse β-lactam aldehydes.
Herein we examine the feasibility and efficiency of the reac-
Results and Discussion
The starting substrates were prepared from azetidine-2,3-
diones by metal-mediated Barbier-type carbonyl addition
reactions in an aqueous environment followed by function-
alization reactions. Azetidine-2,3-diones (+)-1a and (–)-1b,
were efficiently obtained in an optically pure form from
aromatic (R)-2,3-O-isopropylideneglyceraldehyde derived
imines, by the Staudinger reaction with acetoxyacetyl chlo-
ride in the presence of Et3N, followed by sequential transes-
terification and Swern oxidation, following our previously
reported procedure (Scheme 1).[8]
Scheme 1. Stereoselective preparation of azetidine-2,3-diones 1.
Reagents and conditions: a) (i) Et3N, CH2Cl2, room temp.; (ii)
NaOMe, MeOH, room temp.; (iii) (CO)2Cl2, DMSO, Et3N,
CH2Cl2, –78 °C.
[a] Departamento de Química Orgánica I, Facultad de Química,
Universidad Complutense de Madrid,
28040 Madrid, Spain
Fax: +34-91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Instituto de Química Orgánica General, Consejo Superior de
Investigaciones Científicas, CSIC,
The conversion of azetidine-2,3-diones (+)-1a[8a] and
(–)-1b into new spiranic or 3-substituted 3-alkoxy-β-lactam
aldehydes (+)-2a and (+)-2b was carried out through a four-
step reaction sequence involving zinc-mediated allylation to
give 3-allyl 3-hydroxy-β-lactams (+)-3a and (+)-3b, hydroxy
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-91-5644853
E-mail: iqoa392@iqog.csic.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 3707–3710
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. Alcaide, P. Almendros, M. C. Redondo
FULL PAPER
Scheme 2. Preparation of spiranic and 3-substituted 3-alkoxy-β-lactam aldehydes 2. Reagents and conditions: (a) Prenyl bromide, Zn,
THF/NH4Cl (aq. satd.) (1:5), 0 °C, 1.5 h. (b) Me2SO4, TBAI, CH2Cl2, NaOH (aq. 50%) (1:1), room temp., 4 h. (c) PTSA, THF/H2O
(1:1), reflux, 2 h. (d) NaIO4, NaHCO3 (aq. satd.), CH2Cl2, room temp., 2 h. (e) Allyl bromide, Zn, THF/NH4Cl (aq. satd.) (1:1), 0 °C,
3 h. (f) Allyl bromide, TBAI, CH2Cl2, NaOH (aq. 50%) (1:1), room temp., 16 h. (g) [Cl2(PCy3)2Ru = CHPh], toluene, reflux, 7 h. (h) 1-
Bromo-2-butyne, In, THF/NH4Cl (aq. satd.) (1:5), room temp., 16 h. (i) AgNO3, acetone/H2O (1:1), reflux, 2 h.
protection to give ethers (+)-4a and (+)-4b, and aldehyde
unmasking by sequential acidic acetonide hydrolysis and
oxidative cleavage. Spirocyclic dyhydropyran-β-lactam alde-
hyde (+)-2c was obtained from azetidine-2,3-dione (+)-1a
by carbonyl allylation to give 3-allyl 3-hydroxy-β-lactam
(+)-3c, treatment with allyl bromide under basic conditions
to afford diene (+)-5 and ring-closing metathesis to achieve
spiranic 2-azetidinone (+)-6, followed by aldehyde un-
masking. Spirocyclic dihydrofuran-β-lactam aldehyde (+)-
2d was obtained from azetidine-2,3-dione (–)-1b by indium-
mediated carbonyl allenylation to give 3-allenyl 3-hydroxy-
β-lactam (+)-7, followed by silver-induced cyclization and
oxidative cleavage of the resulting diol (+)-8. Carbaldehydes
2 were obtained as single isomers in reasonable yields
(Scheme 2).
TMST addition to 4-oxoazetidine-2-carbaldehydes 2 in
dichloromethane resulted in desired enantiopure α-hydroxy
acid derivatives 9a–d possessing quaternary or spiranic car-
bon centers in reasonable isolated yields (Scheme 3); ad-
Scheme 3. Preparation of conformationally constrained enantio-
dition products[9] 10a–d were also obtained, but as a minor
pure α-alkoxy-γ-keto amides 9. Reagents and conditions: a) TMST,
DCM, 0 °C, 16 h.
component. Carbinols 10b–d could be easily separated by
gravity flow chromatography. However, compound 10a
could not be isolated as a pure compound. The observed
syn diastereoselectivity for the TMST addition step might tions, intermediate alkoxide 11 may suffer a 1,2-migration
be tentatively explained by invoking the Felkin–Anh model, of hydrogen with concurrent cleavage of the N1–C4 bond
analogously to related addition processes described in our of the 2-azetidinone ring, affording α-alkoxy-γ-keto acid de-
laboratories.[10]
rivatives 9 (Scheme 4, path A). Alternatively, species 11 may
We propose the mechanism shown in Scheme 4 to ac- accept an electrophile (proton or trimethylsilyl group) to
count for our new ring cleavage. Under the reaction condi- give addition products 10 (Scheme 4, path B).
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Synthesis of Spiranic and Tertiary α-Alkoxy-γ-keto Acid Derivatives
FULL PAPER
25%) as a colorless oil. [α]D = +44.2 (c = 0.8, CHCl3). H NMR
1
(300 MHz, CDCl3, 25 °C): δ = 7.68 (d, J = 3.2 Hz, 1 H), 7.25 (d,
J = 8.8 Hz, 1 H), 7.19 (d, J = 3.2 Hz, 1 H), 6.40 (m, 2 H), 5.78
(dd, J = 22.4, 10.7 Hz, 1 H), 5.19 (d, J = 7.3 Hz, 1 H), 4.91 (m, 2
H), 4.50 (d, J = 7.3 Hz, 1 H), 3.71 and 3.72 (s, each 3 H), 3.69 (s,
3 H), 1.97 (br. s, 1 H), 0.84 and 0.98 (s, each 3 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 175.5, 165.3, 156.9, 154.7, 143.0,
141.8, 126.5, 121.3, 119.2, 115.1, 104.0, 100.1, 99.5, 72.0, 66.2, 58.2,
56.5, 55.5, 42.1, 23.6, 21.3 ppm. IR (CHCl ): ν = 1743 cm–1. MS
˜
3
(ES): m/z (%) = 419 (100) [M + H]+, 418 (17) [M]+. C21H26N2O5S
(418.2): calcd. C 60.27, H 6.26, N 6.69; found C 60.39, H 6.21, N
6.63. The more polar fraction contained quaternary α-alkoxy-γ-
keto carboxamide (–)-9b (47 mg, 62%) as a pale yellow oil. [α]D
=
1
–71.0 (c = 0.6, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ =
8.90 (br. s, 1 H), 8.25 (d, J = 8.5 Hz, 1 H), 8.00 (d, J = 3.2 Hz, 1
H), 7.66 (d, J = 3.2 Hz, 1 H), 6.47 (m, 2 H), 6.18 (dd, J = 17.5,
10.7 Hz, 1 H), 5.10 (m, 2 H), 3.80 and 3.89 (s, each 3 H), 3.73 and
4.13 (d, J = 19.0 Hz, each 1 H), 3.48 (s, 3 H), 1.06 (s, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 190.8, 169.5, 167.1, 156.3, 144.5,
144.0, 126.4, 121.0, 120.5, 113.3, 103.7, 98.7, 85.6, 55.8, 55.7, 54.9,
Scheme 4. Mechanistic explanation for the N1–C4 β-lactam bond
breakage of 3-substituted 3-alkoxy-β-lactam aldehydes 2 under
TMST/carbonyl addition conditions.
Conclusions
45.0, 38.1, 23.0, 22.2 ppm. IR (CHCl ): ν = 1742, 1726 cm–1. MS
˜
3
(EI): m/z (%) = 419 (8) [M + H]+, 418 (30) [M]+, 153 (100).
C21H26N2O5S (418.2): calcd. C 60.27, H 6.26, N 6.69; found C
60.40, H 6.22, N 6.73.
Spiranic as well as 3-substituted 3-alkoxy-β-lactam alde-
hydes, which were obtained from enantiopure azetidine-2,3-
diones, gave preferentially the N1–C4 β-lactam bond cleav-
age product rather than the carbonyl addition product by
reaction with 2-(trimethylsilyl)thiazole. The resulting op-
tically active spiranic and tertiary α-alkoxy-γ-keto acid de-
rivatives, which can be considered both as conformationally
constrained aldols as well as Passerini-type products, can-
not be easily achieved by alternative protocols.
Spiranic α-Alkoxy-γ-keto Carboxamide (–)-9c and β-Lactam (+)-
10c: From 4-oxoazetidine-2-carbaldehyde (+)-2c (70 mg,
0.25 mmol). Chromatography (EtOAc/hexanes, 2:3) gave two frac-
tions. The less polar fraction contained β-lactam (+)-10c (13 mg,
1
12%) as a colorless oil. [α]D = +28.0 (c = 0.8, CHCl3). H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.84 (d, J = 3.3 Hz, 1 H), 7.56 (m,
3 H), 6.77 (d, J = 8.9 Hz, 2 H), 5.83 (s, 2 H), 5.50 (d, J = 6.5 Hz,
each 1 H), 4.57 (d, J = 6.5 Hz, each 1 H), 4.79 and 4.34 (d, J =
16.5 Hz, each 1 H), 3.80 (s, 3 H), 2.63 and 2.36 (d, J = 17.5 Hz,
each 1 H), –0.01 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
δ = 172.3, 165.3, 150.2, 142.7, 131.3, 125.8, 121.0, 120.8, 119.3,
113.8, 82.5, 70.5, 67.2, 65.5, 55.6, 55.4, 28.7, 0.00 ppm. IR (CHCl3):
Experimental Section
General Methods: 1H and 13C NMR spectra were recorded with
a Bruker Avance-300, a Varian VRX-300S, or a Bruker AC-200
instrument. NMR spectra were recorded in CDCl3 solutions, unless
otherwise stated. Chemical shifts are given in ppm relative to TMS
(1H NMR, 0.0 ppm), or CDCl3 (13C NMR, 76.9 ppm). Low and
high resolution mass spectra were recorded with a HP5989A spec-
trometer by using the electronic impact (EI) or electrospray modes
(ES), unless otherwise stated. Specific rotations [α]D are given in
10–1 °cm2 g–1 at 20 °C, and the concentration (c) is expressed in
g100 mL–1. All commercially available compounds were used with-
out further purification.
ν = 1741 cm–1. MS (ES): m/z (%) = 431 (100) [M + H]+, 430 (11)
˜
[M]+. C21H26N2O4SSi (430.6): calcd. C 58.58, H 6.09, N 6.51;
found C 58.47, H 6.06, N 6.55. The more polar fraction contained
spiranic α-alkoxy-γ-keto carboxamide (–)-9c (47 mg, 52%) as a pale
yellow oil. [α]D = –44.0 (c = 0.3, CHCl3). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 8.48 (br. s, 1 H), 7.98 (d, J = 3.0 Hz, 1 H), 7.66
(d, J = 3.0 Hz, 1 H), 7.50 and 6.87 (d, J = 9.0 Hz, each 2 H), 5.85
(m, 2 H), 4.37 and 4.32 (d, J = 16.0 Hz, each 1 H), 3.79 (s, 3 H),
4.16 and 3.65 (d, J = 17.0 Hz, each 1 H), 2.50 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 189.9, 171.4, 167.0, 156.3, 144.7,
130.7, 126.7, 124.6, 122.4, 121.5, 114.1, 75.3, 62.2, 55.5, 40.2,
General Procedure for the Synthesis of Spiranic and Tertiary α-Alk-
oxy-γ-keto Acid Derivatives 9: A solution of TMST (94 mg,
0.60 mmol) in anhydrous dichloromethane (0.35 mL) was added
dropwise to a solution cooled to 0 °C of the corresponding 4-
oxoazetidine-2-carbaldehyde 2 (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 with
MgSO4, filtered, and concentrated under reduced pressure.
Chromatography of the residue (ethyl acetate/hexanes) gave a more
polar fraction containing the corresponding α-alkoxy-γ-keto amide
9, and a less polar compound, containing the free carbinol or its
trimethylsilyl ether 10. Spectroscopic and analytical data for some
representative forms of 9 and 10 follow.[11]
32.5 ppm. IR (CHCl ): ν = 1740, 1724 cm–1. MS (ES): m/z (%) =
˜
3
359 (100) [M + H]+, 358 (23) [M]+. C18H18N2O4S (358.4): calcd. C
60.32, H 5.06, N 7.82; found C 60.44, H 5.03, N 7.78.
Spiranic α-Alkoxy-γ-keto Carboxamide (–)-9d and β-Lactam (+)-
10d: From 4-oxoazetidine-2-carbaldehyde (+)-2d (60 mg,
0.19 mmol). Chromatography (EtOAc/hexanes, 1:3) gave two frac-
tions. The less polar fraction contained β-lactam (+)-10d (15 mg,
1
20%) as a colorless oil. [α]D = +28.0 (c = 0.8, CHCl3). H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.40 (d, J = 8.5 Hz, 1 H), 7.63 and
7.11 (d, J = 3.4 Hz, each 1 H), 6.37 (dd, J = 8.5, 2.4 Hz, 1 H), 6.15
(d, J = 2.4 Hz, 1 H), 5.83 (q, J = 1.8 Hz, 1 H), 5.39 and 5.02 (d, J
= 1.5 Hz, each 1 H), 4.84 (m, 2 H), 3.74 and 3.60 (s, each 3 H),
1.90 (q, J = 1.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
171.2, 167.3, 159.3, 153.3, 139.1, 132.4, 126.9, 124.6, 120.9, 117.1,
103.9, 101.9, 98.6, 75.4, 70.3, 67.0, 55.5, 55.4, 10.9 ppm. IR
Tertiary α-Alkoxy-γ-keto Carboxamide (–)-9b and β-Lactam (+)-
10b: From 4-oxoazetidine-2-carbaldehyde (+)-2b (63 mg,
0.18 mmol). Chromatography (EtOAc/hexanes, 1:3) gave two frac-
tions. The less polar fraction contained β-lactam (+)-10b (20 mg,
(CHCl ): ν = 3342, 1742 cm–1. MS (ES): m/z (%) = 389 (100) [M
˜
3
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B. Alcaide, P. Almendros, M. C. Redondo
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+ H]+, 388 (7) [M]+. C19H20N2O5S (388.4): calcd. C 58.75, H 5.19,
N 7.21; found C 58.85, H 5.16, N 7.17. The more polar fraction
contained spiranic α-alkoxy-γ-keto carboxamide (–)-9d (42 mg,
57%) as a colorless solid. M.p. 118–119 °C (hexanes/ethyl acetate).
[α]D = –87.0 (c = 1.2, CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C):
δ = 9.07 (br. s, 1 H), 8.22 (d, J = 9.0 Hz, 1 H), 7.99 and 7.66 (d, J
= 3.2 Hz, each 1 H), 6.47 (m, 2 H), 5.62 (q, J = 1.8 Hz, 1 H), 4.74
(m, 2 H), 3.86 and 3.80 (s, each 3 H), 4.11 and 3.69 (d, J = 16.8 Hz,
each 1 H), 1.95 (q, J = 1.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 190.7, 169.5, 167.6, 156.7, 149.8, 145.1, 138.6, 126.9,
122.3, 121.5, 120.3, 104.0, 99.0, 92.8, 75.3, 56.2, 55.9, 43.7,
[4] a) B. Alcaide, P. Almendros, G. Cabrero, M. P. Ruiz, Org. Lett.
2005, 7, 3981; b) P. K. Mandal, L. A. Cabell, J. S. McMurray,
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[5] See, for instance:a) B. Alcaide, P. Almendros, T. Martí-
nez del Campo, Angew. Chem. Int. Ed. 2006, 45, 4501; Angew.
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12.9 ppm. IR (CHCl ): ν = 1739, 1725 cm–1. MS (EI): m/z (%) =
˜
3
389 (15) [M + H]+, 388 (54) [M]+, 208 (100). C19H20N2O5S (388.4):
calcd. C 58.75, H 5.19, N 7.21; found C 58.63, H 5.17, N 7.25.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data and experimental procedures for com-
pounds (–)-1b, 2a–d, 3a–c, (+)-4a, (+)-4b, 5–8, and (–)-9a.
[6] B. Alcaide, P. Almendros, M. C. Redondo, Org. Lett. 2004, 6,
1765.
[7] α-Hydroxy or α-amino acids with a quaternary or spiranic
stereocenter constitute a new class of nonnatural products with
an even more constrained conformation. For selected recent
references, see:a) T. Ooi, K. Fukumoto, K. Maruoka, Angew.
Chem. Int. Ed. 2006, 45, 3839; Angew. Chem. 2006, 118, 3923;
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Bolm, Angew. Chem. Int. Ed. 2004, 43, 5984; Angew. Chem.
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Acknowledgments
Support for this work by the Dirección General de Investigación,
Ministerio de Educación
y
Ciencia (DGI-MEC) (Project
CTQ2006–10292) and Comunidad Autónoma de Madrid-Uni-
versidad Complutense de Madrid (CAM-UCM) (Grant GR69/06)
are gratefully acknowledged. M. C. R. thanks the MEC for a pre-
doctoral grant.
[8] a) B. Alcaide, P. Almendros, C. Aragoncillo, R. Rodríguez-
Acebes, J. Org. Chem. 2001, 66, 5208. For a review on the
chemistry of azetidine-2,3-diones, see: b) B. Alcaide, P. Al-
mendros, Org. Prep. Proced. Int. 2001, 33, 315.
[9] For a review on the addition of thiazole-based organometallic
reagents to carbonyl compounds, see: A. Dondoni, A. Marra,
Chem. Rev. 2004, 104, 2557.
[10] a) B. Alcaide, P. Almendros, J. M. Alonso, J. Org. Chem. 2004,
69, 993; b) B. Alcaide, P. Almendros, C. Aragoncillo, Chem.
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N. R. Salgado, J. Org. Chem. 2000, 65, 3310.
[11] Full spectroscopic and analytical data for compounds not in-
cluded in this Experimental Section are described in the Sup-
porting Information.
[1] For selected reviews, see:a) B. Alcaide, P. Almendros, Curr.
Med. Chem. 2004, 11, 1921; b) A. R. A. S. Deshmukh, B. M.
Bhawal, D. Krishnaswamy, V. V. Govande, B. A. Shinkre, A.
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Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Amino-Acids
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[2] For a review on the selective bond cleavage of the β-lactam
nucleus, see: B. Alcaide, P. Almendros, Synlett 2002, 381.
[3] For reviews, see:a) I. Ojima, F. Delaloge, Chem. Soc. Rev. 1997,
26, 377; b) I. Ojima in Advances in Asymmetric Synthesis (Ed.:
A. Hassner), JAI press, 1995, vol. 1, p. 95; c) I. Ojima, Acc.
Chem. Res. 1995, 28, 383; d) I. Ojima in The Organic Chemistry
of β-Lactams (Ed.: G. George), VCH, New York, 1993, p. 197.
Received: March 15, 2007
Published Online: June 12, 2007
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Eur. J. Org. Chem. 2007, 3707–3710