N,N-dialkylhydrazones as the imine component in the Staudinger-like [2+2] cycloaddition to benzyloxyketene

Article abstract of DOI:10.1002/1521-3773(20020301)41:5<831::AID-ANIE831>3.0.CO;2-6

To overcome the limitations of using unstable imines in Staudinger cycloadditions to ketenes, aldehyde N,N-dialkylhydrazones 1 were used as stable imines. This strategy and a fine tuning of the auxiliary result in a straightforward synthesis of cycloadducts 2, deprotected β-lactams 3, and isoserines 4 (see scheme: a) Et₃N, toluene, Δ; b) 1. magnesium monoperoxyphthalate, 2. H₂, Pd/C; c) H⁺).

Full text of DOI:10.1002/1521-3773(20020301)41:5<831::AID-ANIE831>3.0.CO;2-6

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N,N-Dialkylhydrazones as the Imine
Component in the Staudinger-Like [2‡2]
Cycloaddition to Benzyloxyketene**
NR1R2
H
O
N
Et3N, PhMe, ∆
BnO
+
Cl
R
6
1–5
¬
¬
Rosario Fernandez, Ana Ferrete, Jose M. Lassaletta,*
NR1R2
R
NR1R2
R
O
O
¬
O
NR1R2
Ph
Jose M. Llera,* and EloÌsa MartÌn-Zamora
N
N
N
+
+
BnO
BnO
BnO
The presence of a b-lactam ring as a key substructure of the
most widely used family of antibiotics has stimulated consid-
erable activity focused on the development of stereoselective
routes for its synthesis.[1] One of the most popular methods
involves the [2‡2] cycloaddition of ketenes and imines (the
Staudinger reaction),[2] but this straightforward method
suffers limitations imposed by the poor stability of some
imines, such as methanimines (unstable against polymeriza-
tion) and those derived from aliphatic aldehydes (easily
enolizable and thermally unstable). Previously, we reported
the use of formaldehyde N,N-dialkylhydrazones as a stable
class of monomeric methanimines in the asymmetric Stau-
dinger [2‡2] cycloaddition to a-alkoxy- and a-aminoke-
tenes.[3] Stimulated by the promising results obtained in this
particular case, we decided to investigate also the behavior of
higher aldehyde N,N-dialkylhydrazones as a stable class of
enolizable imines in the same context.
(3S,4R)-7–11
(3R,4S)-7–11
(3R,4R)-8
Ph
Ph
O
O
MeO
NR1R2
=
O
O
Ph
Ph
Et
N
N
Et
N
a
b
c
Scheme 1. [2‡2] Cycloadditions of N,N-dialkylhydrazones to benzyloxyke-
tene. 1: R ˆ n-pentyl, 2: R ˆ iBu, 3: R ˆ PhCH2CH2, 4: R ˆ iPr, 5: R ˆ Ph.
Bnˆ benzyl.
Table 1. Synthesis of 1-N,N-dialkylamino-3-benzyloxyazetidin-2-ones 7a 11a,
11b, and 8c.
Entry Hydra-
zone
T
[8C]
Product
Yield
[%][a]
3R,4S: cis:
3S,4R[b] trans[b]
OMe
Et
Et
7a
N
O
1
2
3
1a
2a
3a
80
80
80
85 (70) 82:18
84 (73) 87:13
97 (78) 80:20
98:2
98:2
N
Considering the lack of general approaches for the enan-
tioselective synthesis of 4-alkyl(aryl)-3-hydroxy-b-lactams
and their potential as precursors of bioactive b-amino-a-
hydroxy acids,[4] we focused on the [2‡2] cycloaddition of
BnO
OMe
Et
Et
8a
chiral
aldehyde
hydrazones
to
a-benzyloxyketene
N
N
O
(Scheme 1). Studies started with the reaction of proline-
derived hydrazones 1a 5a with benzyloxyacetylchloride 6
which leads to the desired cycloadducts 7a 11a, respectively,
in excellent yields (84 98%), even for compounds derived
from easily enolizable substrates (Table 1, entries 1 4).
Under optimized conditions (toluene, Et3N, 80 8C for primary
substrates, 1008C for secondary or aromatic substrates),
moderate to good 3R,4S/3S,4R selectivities were found, and
only traces of trans isomers were detected in some cases.
Nevertheless, the collected results were satisfactorily evaluated
because the diastereomers could be separated easily in all
cases, thus allowing the isolation of the optically pure major cis
isomers (3R,4S)-7a (3R,4S)-11a in yields of 70 82%.
BnO
OMe
Et
Et
9a
N
N
O
> 99:1
BnO
Ph
OMe
Et
Et
10a
11a
N
N
O
4
5
4a
5a
100
100
90 (82) 91:9
> 99:1
> 99:1
BnO
OMe
Et
Et
N
N
98 (75) 76:24
O
[*] Dr. J. M. Lassaletta
Instituto de Investigaciones QuÌmicas (CSIC-USe)
Americo Vespuccio s/n
BnO
Ph
Ph
Isla de la Cartuja, 41092Seville (Spain)
Fax : (‡34)95-446-0565
O
O
E-mail: jmlassa@cica.es
O
6
7
5b
2c
100
66
53
< 1:99 > 99:1
¬
Dr. E. MartÌn-Zamora, Dr. R. Fernandez, A. Ferrete
Ph
N
O
O
¬
Dpto. de QuÌmica Organica
N
11b
Universidad de Sevilla (Spain)
Ph
N
BnO
Dr. J. M. Llera
Ph
N
¬
¬
Dpto. de QuÌmica Organica y Farmaceutica
Universidad de Sevilla (Spain)
Fax : (‡34)95-423-3765
O
80
> 99:1
90:10
Ph
8c
E-mail: llera@fafar.us.es
BnO
¬
¬
¬
[**] We thank the Direccion General de Investigacion CientÌfica y Tecnica
(grants BQU 2001-2376 and PPQ 2000-1341) and the Junta de
AndalucÌa for financial support. We also thank the Ministerio de
[a] Yield of isolated product. Values in parentheses correspond to the pure (98% de)
1
major isomer. [b] Determined by means of 13C and H NMR spectroscopy.
¬
Educacion y Ciencia for a doctoral fellowship to A.F.
Angew. Chem. Int. Ed. 2002, 41, No. 5
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1433-7851/02/4105-0831 $ 17.50+.50/0
831

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The behavior of d-mannitol-derived hydrazones[3] was
studied next. However, the reaction of isobutyraldehyde
hydrazone 2b with 6 afforded only compound 12 under a
Table 2. Synthesis of 1-N,N-dialkylamino-3-benzyloxyazetidin-2-ones 8d 11d.
Entry Hydra-
zone
T
[8C]
Product
Yield[a] 3R,4S:
[%]
cis:
3S,4R[b] trans[b]
N
O
Ph
Ph
95:5[c]
85:15
N
1
2
2d
2d
60
80
70
91
> 99:1
> 99:1
O
O
O
O
N
H
O
BnO
BnO
8d
BnO
O
O
N
N
N
O
O
H
3
4
5
3d
3d
3d
rt
60
80
67
83
91
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
91:9
N
N
O
O
Ph
Ph
N
N
9d
13
12
BnO
Ph
O
variety of reaction conditions, thus suggesting that an intra-
molecular H transfer in the zwitterionic intermediate[5] 13
takes place faster than the ring closure to the b-lactam. On the
other hand, the non-enolizable hydrazone 5b reacted with 6
under forcing conditions, to give the desired b-lactam 11b in a
moderate yield (66%), but with excellent stereoselectivity
(Table 1, entry 6). From these results, it appears that the
mannitol-derived C2-symmetric auxiliary offers better induc-
tion in the cycloaddition process than the proline-derived
auxiliary (Table 1, entries 5 and 6), but the lower reactivity of
the former prevents a better result. Considering that steric
factors would hardly explain the observed differences in
behavior, the lack of conformational flexibility in 5b, asso-
ciated with the condensed dioxane rings, was seen as a
possible reason.
Therefore, a more flexible C2-symmetric hydrazone such as
2c, which has (2S,5S)-diphenylpyrrolidine as the auxiliary, was
synthesized[6] and treated with 6. The desired cycloadduct 8c
was obtained with an excellent (3R,4S/3S,4R) selectivity
(Table 1, entry 7), thus supporting the validity of the hypoth-
esis mentioned above, but the yield (53%) was disappointing,
and the product was contaminated with approximately 10%
of the undesired trans-3R,4R diastereomer. The moderate
reactivity of this system was attributed to a higher steric
6
7
4d
5d
80
80
96
> 99:1
> 99:1
> 99:1
> 99:1
10d
BnO
N
O
100
N
11d
BnO
Ph
[a] Yield of isolated product. [b] Determined by means of 13C and 1H NMR
spectroscopy. [c] Inseparable mixture. The pure cis isomer was obtained after
release of the auxiliary (see Table 3).
case, an optimum reaction temperature of 608C was applied
to the reaction of 6 with aliphatic primary hydrazones 2d and
3d (Table 2, entries 1 and 4), since significant amounts of trans
isomers appeared at 808C (Table 2, entries 2 and 5). The high
reactivity of 2d 5d allows cycloadditions even at room
temperature (Table 2, entry 3), in contrast to all other
hydrazones tested. Secondary (4d) and aromatic (5d) hydra-
zones reacted smoothly with 6 at optimized temperatures of
80 and 1008C,[8] to give the corresponding adducts 10d and
11d in 80 and 96% yield, respectively (Table 2, entries 6
and 7).
À
The key N N bond cleavage, which is required to remove
the auxiliaries, failed under standard reductive conditions.
Fortunately, the oxidative method previously developed by
our group[3] was successfully applied to compounds 7a 11a
and 8d 11d, which reacted with magnesium monoperoxyph-
thalate (MMPP) to afford the deaminated lactams (3R,4S)-
14 (3R,4S)-18 in high yields (Scheme 3, Table 3). Nitrones 19
and 20 were isolated as by-products from 7a 11a and 8d
11d in moderate (ca. 50%) and good (75 80%) yields,[9]
respectively.
ˆ
hindrance around the C N bond, but the suitability of C2-
symmetric auxiliaries in this context was confirmed again in
view of the exhibited selectivity.
An ultimate attempt to improve the results obtained with
hydrazones 1a 5a was therefore based on the strategy
outlined above, but with substrates that contain the sterically
less demanding (2R,5R)-dimethylpyrrolidine as the auxiliary.
As expected, a higher reactivity was observed in the reactions
of 2d 5d[7] with 6, which proceeded smoothly to give the
corresponding cycloadducts 8d 11d in high yields and with
excellent 3R,4S/3S,4R selectivities (Scheme 2, Table 2). In this
R4
O
N
O
NH
MMPP, MeOH
N
R3
R4
R3
+
O
N
N
R
O
N
H
Et3N, PhMe, ∆
+
N
BnO
R
N
BnO
BnO
R
Cl
O
R
14–18
BnO
7–11a,d
19, 20
6
2d–5d
(3R,4S)-8d–11d
de > 98%
7–11a, 19: R3 = CEt2OMe; R4 = H
8–11d, 20: R3 = R4 = Me
Scheme 2. [2‡2] Cycloadditions using (2R,5R)-dimethylpyrrolidine as the
À
auxiliary.
Scheme 3. Oxidative N N bond cleavage. Release of the auxiliary.
832
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1433-7851/02/4105-0832 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 5

COMMUNICATIONS
Table 3. Synthesis of 4-alkyl(aryl)-3-benzyloxyazetidin-2-ones 14 18.
Ghosez, J. Marchand-Brynaert in Comprehensive Organic Synthesis,
Vol. 5 (Eds.: B. Trost, I. Fleming, L. A. Paquette), Pergamon, Oxford,
1991, p. 85; c) R. Southgate, C. Branch, S. Coulton, E. Hunt in Recent
Progress in Chemical Synthesis of Antibiotics and Related Microbial
Products, Vol. 2 (Ed.: G. Lucas), Springer, Berlin, 1993, p. 2 61; d) R.
Southgate, Contemp. Org. Synth. 1994, 1, 417.
Starting Material
t [h]
Product
Yield [%][a]
[a]2D2[b]
(3R,4S)-7a
(3R,4S)-8a
(3R,4S)-9a
(3R,4S)-10a
(3R,4S)-11a
(3R,4S)-8d[c]
(3R,4S)-9d
(3R,4S)-10d
(3R,4S)-11d
3
(3R,4S)-14
(3R,4S)-15
R,4S)-16
(3R,4S)-17
R,4S)-18
R,4S)-15
R,4S)-16
R,4S)-17
R,4S)-18
78
91
87
88
96
84[d]
84
91
95
‡ 28.9
‡ 33.4
‡ 19.9
‡ 120.4
‡ 96.8
‡ 33.5
‡ 20.9
‡ 120.6
‡ 97.3
2.5
2(3
4
2(3
2(3
2(3
2(3
2(3
[2] H. Staudinger, Justus Liebigs Ann. Chem. 1907, 356, 51.
¬
[3] R. Fernandez, A. Ferrete, J. M. Lassaletta, J. M. Llera, A. Monge,
Angew. Chem. 2000, 112, 3015; Angew. Chem. Int. Ed. 2000, 39,
2893.
[4] C. Palomo, J. M. Aizpurua, I. Ganboa in Enantioselective Synthesis of
b-Aminoacids (Ed.: E. Juaristi), Wiley-VCH, New York, 1997,
chap. 14, p. 279.
[5] a) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Eur. J. Org.
Chem. 1999, 3223; b) F. P. Cossio, J. M. Ugalde, X. Lopez, B. Lecea, C.
Palomo, J. Am. Chem. Soc. 1993, 115, 995; c) F. P. Cossio, A. Arrieta,
B. Lecea, J. M. Ugalde, J. Am. Chem. Soc. 1994, 116, 2085.
[6] Prepared from known (1S,4S)-diphenylbutanediol (D. J. Aldous,
W. M. Dutton, P. G. Steel, Tetrahedron: Asymmetry 2000, 11, 2455)
by mesylation, reaction with hydrazine, and condensation with
isovaleraldehyde (60% overall).
[7] Prepared from known (2S,5S)-hexanediol (J. K. Lieser, Synth. Com-
mun. 1983, 13a, 765) by mesylation, reaction with hydrazine, and
condensation with aldehyde (50 60% overall).
[8] Higher reaction temperatures, which give higher yields of product, can
be applied without the formation of trans isomers in these cases.
[9] The isolation of 20 was possible only when MMPP was used in
stoichiometric amounts. Excess oxidant results in products of over-
oxidation. Details of the scope and mechanism of this deamination
procedure will be published elsewhere. The recycling of the auxiliary
from 20 is currently being investigated.
[10] Review: K. C. Nicolaou, W. M. Dai, R. K. Guy, Angew. Chem. 1994,
106, 38; Angew. Chem. Int. Ed. Engl. 1994, 33, 15.
[11] a) K. Iizuka, T. Kamijo, T. Kubota, K. Akahane, H. Umeyama, Y.
Kiso, J. Med. Chem. 1988, 31, 704; b) H. Sugimura, M. Miura, N.
Yamada, Tetrahedron: Asymmetry 1997, 8, 4089.
[a] Yield of isolated product. [b] c ˆ 1, Cl2CH2. [c] Starting material was a
9:1 mixture of cis:trans isomers. [d] Yield of pure cis product.
Finally, standard transformations of 18 and 14 afforded b-
amino-a-hydroxy acids 24, a side chain of taxol,[10] and 22, a
component of the renin inhibitor KRI-1230[11] and of the
antitumor drug ABT-271,[12] respectively (Scheme 4). These
experiments served not only as illustrative examples of the
synthetic utility of the method, but also confirmed the
absolute configuration assigned to these compounds.[13] The
products with the opposite configuration could be also
prepared by using the enantiomeric (2S,5S)-dimethylpyrroli-
dine[14] as the auxiliary.
O
O
NH2
NH
H2, Pd/C
NH
6N HCl
quant.
COOH
R
BnO
R
HO
R
OH
14: R = iBu
18: R = Ph
22: R = iBu
24: R = Ph
21: R = iBu (85%)
23: R = Ph (72%)
[12] a) L. Li, S. A. Thomas, L. L. Klein, C. M. Yeung, C. J. Maring, D. J.
Grampovnik, P. A. Lartey, J. J. Plattner, J. Med. Chem. 1994, 37, 2655;
b) M. R. Leanna, J. A. DeMattei, W. Li, P. J. Nichols, M. Rasmussen,
H. E. Morton, Org. Lett. 2000, 2, 3627.
Scheme 4. Synthesis of b-amino-a-hydroxy acids.
[13] (2R,3S)-22: [a]2D0 ˆ ‡25.2 (c ˆ 0.6, AcOH); lit: [a]2D5 ˆ ‡26.9 (c ˆ 0.3,
AcOH) (R. L. Johnson, J. Med. Chem. 1982, 25, 605); [a]2D3 ˆ ‡25.6
(c ˆ 0.3, AcOH) (J. M. Chong, K. B. Sharpless, J. Org. Chem. 1985, 50,
1563). (3R,4S)-23: [a]D25 ˆ ‡181.9 (c ˆ 1.3, MeOH); lit: [a]2D4 ˆ 182.0
(c ˆ 1.04, MeOH) (C. E. Song, S. W. Lee, S. Lee, W. Lee, Tetrahedron:
Asymmetry 1998, 9, 983); [a]D25 ˆ ‡193 (c ˆ 1.63, MeOH) (G. I. Georg,
Z. S. Cheruvallath, J. Med. Chem. 1992, 35, 4230).
In summary, the Staudinger cycloaddition of chiral N,N-
dialkylhydrazones to benzyloxyketene appears to be a new
general approach to the enantioselective synthesis of 4-sub-
stituted 3-alkoxyazetidin-2-ones. The (2R,5R)-dimethylpyrro-
lidine substituent is the key element in several aspects: 1) it
confers the needed stability to the starting substrates,
particularly in the aliphatic series; 2) it efficiently controls
the stereochemical course of the reaction; and 3) it behaves as
an efficient protecting group that can be removed easily from
the b-lactam ring.
[14] Available from (2R,5R)-hexanediol: H. Ikeda, E. Sato, T. Sugai, H.
Ohta, Tetrahedron 1996, 52, 8113.
Experimental Section
7
11: Benzyloxyacetyl chloride (6, 4 mmol) in toluene (10 mL) was added
stepwise (8 portions of 0.5 mmol over 3 h) to a solution of hydrazone 1
5
(1 mmol) and Et3N (8 mmol) in dry toluene (5 mL). The mixture was
stirred until completion and purified by chromatography.
14 18: MMPP ¥ 6H2O (0.9 mmol) was added to a solution of 7 11
(0.3 mmol) in MeOH (0.75 mL), and the mixture was stirred at room
temperature until completion.
Received: October 15, 2001
Revised: November 23, 2001 [Z18065]
[1] Reviews: a) R. J. Ternadsky, J. M. Morin, Jr. in The Organic Chemistry
of b-Lactams (Ed.: G. I. Georg), VCH, New York, 1993, p. 2 57; b) L.
Angew. Chem. Int. Ed. 2002, 41, No. 5
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