A new alternative to the Mannich reaction: Tandem radical addition-cyclization reaction for asymmetric synthesis of γ-butyrolactones and β-amino acids

Article abstract of DOI:10.1021/ol006716g

(Matrix presented) The radical addition-cyclization reaction of substrates having two different radical acceptors such as acrylate and aldoxime ether moieties was studied. This new free radical-mediated Mannich-type reaction proceeded smoothly via a tande

Full text of DOI:10.1021/ol006716g

ORGANIC
LETTERS
2000
Vol. 2, No. 25
4071-4074
A New Alternative to the Mannich
Reaction: Tandem Radical
Addition−Cyclization Reaction for
Asymmetric Synthesis of
γ-Butyrolactones and â-Amino Acids
Hideto Miyabe, Kayoko Fujii, Takuya Goto, and Takeaki Naito*
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe 658-8558, Japan
taknaito@kobepharma-u.ac.jp
Received October 10, 2000
ABSTRACT
The radical addition−cyclization reaction of substrates having two different radical acceptors such as acrylate and aldoxime ether moieties
was studied. This new free radical-mediated Mannich-type reaction proceeded smoothly via a tandem C−C bond-forming process. Furthermore,
the diastereoselective tandem reaction provides the novel method for asymmetric synthesis of γ-butyrolactones and â-amino acid derivatives.
The Mannich reaction is an important method for the
preparation of â-amino carbonyl compounds. The classical
reaction is, however, plagued by a number of serious
disadvantages, and the range of applications is limited.1
Therefore, numerous modern versions of the Mannich
reaction have been developed for overcoming the drawbacks
of the classical method.1 In general, the improved method-
ologies rely on ionic chemistry using preformed electrophiles
such as imines and/or stable nucleophiles such as enolates,
enol ethers, and enamines. We now report a new Mannich-
type reaction based on free radical chemistry,2 which has
been successfully applied to the asymmetric synthesis of
γ-butyrolactones and â-amino acids (Figure 1).3,4
Figure 1. Mannich-type radical reaction.
In studies on the reactivity of various radical acceptors,
we have found that the intermolecular reactivity of acrylate
derivatives as acceptors toward nucleophilic alkyl radical
addition is higher than those of aldoxime ethers but lower
(1) For a review on the Mannich reaction, see: (a) Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (b)
Overmann, L. E.; Ricca, D. J. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol.
2, p 1007. (c) Tramontiti, M.; Angiolini, L. Tetrahedron 1990, 46, 1791.
(2) For reviews on radical reactions, see: (a) Sibi, M. P.; Porter, N. A.
Acc. Chem. Res. 1999, 32, 163. (b) Renaud, P.; Gerster, M. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2562. (c) Giese, B.; Kopping, B.; Go¨bel, T.;
Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. (N.Y.) 1996,
48, 301. (d) Curran, D. P.; Porter, N. A.; Giese, B. In Stereochemistry of
Radical Reactions: Concepts, Guidelines, and Synthetic Applications;
VCH: Weinheim, 1996.
(3) For reviews on asymmetric synthesis of γ-butyrolactones and â-amino
acids, see: (a) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 25, 117.
(b) Cole, D. C. Tetrahedron 1994, 50, 9517. (c) Ogliaruso, M. A.; Wolfe,
J. F. In Synthesis of Lactones and Lactams; John Wiley & Sons: New
York, 1993.
(4) For our studies on asymmetric synthesis of â-amino acids, see:
Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1, 569.
10.1021/ol006716g CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/22/2000

than those of glyoxylic oxime ethers and BF3-activated
aldoxime ethers.5 As a preliminary study based on these
reactivities, we examined the radical addition-cyclization
reaction of substrates 1A and 1B having two different radical
acceptors such as acrylate and aldoxime ether moieties (eqs
1 and 2).6 Although a wide range of radical reactions of
oxime ethers and hydrazones and several synthetic studies
of oxacycles have been reported,7 the present reaction is the
first example of the reaction between oxime ethers and
alkoxycarbonyl-stabilized radicals.8
The success of this free radical-mediated Mannich-type
reaction reflects the following points: (i) the overall differ-
ence in the intermolecular reactivity of a nucleophilic carbon
radical between two electrophilic radical acceptors in the first
step and (ii) the high reactivity of triethylborane as a trapping
reagent toward a key intermediate aminyl radical, B (Figure
2). A remarkable feature of this reaction is the construction
of two C-C bonds and two chiral centers via a tandem
process. A favorable experimental feature of this method is
that the reaction proceeds smoothly even in the absence of
toxic tin hydride or heavy metals via a route involving an
iodine atom-transfer process.9 However, it is also important
to note the limitation that a primary radical and unstabilized
alkyl radical other than the ethyl radical will not work as R2
radical under the iodine atom-transfer reaction conditions.
Figure 2. Mannich-type tandem radical addition-cylization.
As shown in Scheme 1, the substrates having acrylate and
aldoxime ether moieties were prepared. The chiral substrate
1A was readily prepared from D-mannitol.10
Scheme 1
(5) Unpublished results.
(6) The intermolecular tandem radical addition-addition approach using
three components such as acrylate, aldoxime ether, and alkyl radical was
difficult to achieve, due to the low intermolecular reactivity of a resonance-
stabilized radical, generated by the initial addition of alkyl radical to acrylate,
toward aldoxime ether.
(7) For reviews, see: (a) Naito, T. Heterocycles 1999, 50, 505. (b) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. For some examples of
the radical reaction of oxime ethers, see: (c) Friestad, G. K. Org. Lett.
1999, 1, 1499. (d) Zhang, J.; Clive, D. L. J. J. Org. Chem. 1999, 64, 770.
(e) Keck, G. E.; Wager, T. T.; McHardy, S. F. J. Org. Chem. 1998, 63,
9164. (f) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito,
T. J. Org. Chem. 1998, 63, 4397. (g) Iserloh, U.; Curran, D. P. J. Org.
Chem. 1998, 63, 4711. (h) Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J.
Org. Chem. 1998, 63, 5877. (i) Marco-Contelles, J.; Balme, G.; Bouyssi,
D.; Destabel, C.; Henriet-Bernard, C. D.; Grimaldi, J.; Hatem, J. M. J. Org.
Chem. 1997, 62, 1202. (j) Noya, B.; Alonso, R. Tetrahedron Lett. 1997,
38, 2745. (k) Booth, S. E.; Jenkins, P. R.; Swain, C. J. J. Chem. Soc., Chem.
Commun. 1991, 1248.
(8) For study on the intramolecular reactions of alkoxycarbonyl-stabilized
radicals with electron rich alkene acceptor, see: Russell, G. A.; Li, C.
Tetrahedron Lett. 1996, 37, 2557.
(9) We previously investigated the intermolecular reaction of oxime ethers
via the iodine atom-transfer process between alkyl iodide and ethyl radical
generated from triethylborane as a radical initiator. See: (a) Miyabe, H.;
Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65,
176. (b) Miyabe, H.; Ueda, M.; Yoshioka, N.; Yamakawa, K.; Naito, T.
Tetrahedron 2000, 56, 2413. (c) Miyabe, H.; Yamakawa, K.; Yoshioka,
N.; Naito, T. Tetrahedron 1999, 55, 11209. Bertrand’s group reported the
The results of the radical reaction of 1A are summarized
in Table 1. We initially studied a simple reaction with an
similar studies. See: (d) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella,
L. Synlett 1998, 780. (e) Bertrand, M. P.; L. Feray, L.; Nouguier, R.; Perfetti,
P. Synlett 1999, 1148. (f) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti,
P. J. Org. Chem. 1999, 64, 9189.
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Org. Lett., Vol. 2, No. 25, 2000

obtained at higher temperatures due to higher population of
the reactive conformer of ester moiety. These similar trends
concerning the conformer of ester moiety have also been
reported in the radical cyclization.13
The diastereoselectivity observed for the reaction can be
explained by invoking a favorable conformer minimizing
A1,3-strain effects between the Et3B bonding-oxime ether
group and substituents at the chiral carbon (Figure 3).25
Table 1. Mannich-Type Radical Reaction of 1A
run solvent
R2 T (°C) yield (%)a selectivityb
1c Et
toluene
reflux
20
70
53
64
53
55
68
80
64
56
70
8:1
18:1
12:1
10:1
9:1
2c Et
3c Et
4c Et
5c Et
6d i-Pr
7e i-Pr
toluene
benzene
CH2Cl2
reflux
20
H2O:MeOH, 1:4 reflux
benzene reflux
H2O:MeOH, 1:4 reflux
reflux
9e c-hexyl H2O:MeOH, 1:4 reflux
10f c-pentyl benzene
reflux
12:1
7:1
12:1
8:1
8f c-hexyl benzene
12:1
a Isolated yields of major diastereomer. b Diastereoselectivities were
determined by 1H NMR analysis and indicate the ratio of a major
diastereomer and a second diastereomer. c With Et3B (5 equiv). d With i-PrI
(6 equiv) and Et3B (3 equiv). e With RI (12 equiv) and Et3B (3 equiv).
f With RI (12 equiv) and Et3B (6 equiv).
Figure 3. Stereocontrol in radical cyclization process.
ethyl radical by using triethylborane under several reaction
conditions. The reaction in refluxing toluene proceeded
smoothly to give a major diastereomer, 2Aa, in 70% isolated
yield along with a small amount of the other diastereomers
(run 1).11 The degree of stereoselectivity was shown to be
dependent on the reaction temperature; thus, changing the
temperature to 20 °C led to an increase in diastereoselectivity
to 18:1 (run 2). The treatment in refluxing benzene and CH2-
Cl2 at 20 °C also gave the major diastereomer 2Aa in 64%
and 53% isolated yields, respectively, with moderate dias-
tereoselectivities (runs 3 and 4). From the viewpoint of
elucidating the reaction mechanism, it is important to note
that the tandem reaction proceeded even in aqueous media
(run 5). These observations suggest that the major reaction
pathway is not a route involving the conversion of water-
unstable boryl enolate C into cyclic product D but a tandem
radical route involving the conversion of water-resistant
radical intermediate B into cyclic product D (Figure 2).12 In
marked contrast to the difficulty in achieving the inter-
molecular reactions of aldoxime ethers with the resonance-
stabilized carbon radicals bearing an electron-withdrawing
substituent,6 resonance-stabilized radical A was intramo-
lecularly trapped by an oxime ether group with high
efficiency even under mild conditions. We also investigated
the substituent effect by using the conformationally flexible
substrate 1B (R1 ) H) under similar reaction conditions. The
reaction of 1B proceeded with a slightly low chemical
efficiency to give 2Bb in 44% yield (eq 2);10 thus, the bulky
substituent R1 at the chiral center was important not only
for stereoselectivity but also for efficient cyclization of
intermediate A into D. Additionally, the high yields were
As shown in Scheme 2, the γ-butyrolactone 2Aa was
easily converted to â-amino acid derivative 4 by standard
methods.
Scheme 2
For the asymmetric synthesis of various types of γ-butyro-
lactones, we next investigated the reaction using different
radical precursors RI and Et3B under the iodine atom-transfer
reaction conditions. The isopropyl radical addition to 1A was
run in boiling benzene for 15 min by using isopropyl iodide
(6 equiv) and triethylborane (3 equiv). As expected, the
reaction proceeded smoothly in the absence of tin hydride
to give the isopropylated product 2Ab in 68% yield (run 6).
In our recent studies on the radical addition to highly reactive
acceptors such as glyoxylic oxime ethers and BF3-activated
aldoxime ethers, the competitive addition of an ethyl radical,
generated from triethylborane, was observed as a significant
side reaction.6 In the present reactions, it is noteworthy that
no competitive addition of ethyl radical was observed, due
to the slightly low reactivity of the acrylate moiety on 1A
as a radical acceptor. Other secondary alkyl radicals worked
well under similar reaction conditions, allowing facile
incorporation of structural variety (runs 8-10).
(10) See the Supporting Information for details on the preparation of
1A, 1B, and 4 and experimental procedures.
(11) Radical cascade reaction of oxime ethers was recently reported.
See: Ryu, I.; Kuriyama, H.; Minakata, S.; Komatsu, M.; Yoon, J.-Y.; Kim,
S. J. Am. Chem. Soc. 1999, 121, 12190.
In conclusion, we have shown a new free radical-mediated
Mannich-type reaction via a tandem C-C bond-forming
(12) The reaction between Et3B and the radical R to an ester is less
effective than the corresponding reaction of the radical deriving from ketones
and aldehydes. For the discussions, see: (a) Ollivier, C.; Renaud, P. Angew.
Chem., Int. Ed. 2000, 39, 925. (b) Brown, H. C.; Negishi, E. J. Am. Chem.
Soc. 1971, 93, 3777. (c) Beraud, V.; Gnanou, Y.; Walton, J. C.; Maillard,
B. Tetrahedron Lett. 2000, 41, 1195.
(13) (a) Wang, C.; Russell, G. A. J. Org. Chem. 1999, 64, 2066. (b)
Curran, D. P.; Tamine, J. J. Org. Chem. 1991, 56, 2746.
(14) The absolute configuration of major product 2Aa was determined
by its NOESY spectrum. Stereochemical purity of the major product was
checked by converting 2Aa into MTPA-amide derivative. See the Supporting
Information.
Org. Lett., Vol. 2, No. 25, 2000
4073

process. Furthermore, this tandem reaction provides direct
access to γ-butyrolactones and â-amino acid derivatives.
Japan. H.M. gratefully acknowledges financial support from
Takeda Science Foundation and Fujisawa Foundation, Japan.
Acknowledgment. We thank the Ministry of Education,
Science, Sports and Culture of Japan and the Science
Research Promotion Fund of the Japan Private School
Promotion Foundation for research grants. Partial support
for this work was also provided (to H.M.) by the Nissan
Chemical Industries Award in Synthetic Organic Chemistry,
Supporting Information Available: General experimen-
tal procedures and characterization data for all obtained
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006716G
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Org. Lett., Vol. 2, No. 25, 2000