Diastereoselective intermolecular addition of the 1,3-dioxolanyl radical to N-acyl aldohydrazones. Asymmetric synthesis of α-amino acid derivatives

Article abstract of DOI:10.1021/ol034696n

(Matrix presented) N-Acyl aldohydrazones I (R = CO₂Et, alkyl, aryl, and furyl) efficiently trap the 1,3-dioxolanyl radical intermolecularly without external activation at temperatures as low as -78°C. For alkyl aldohydrazones, good diastereoselectivities are obtained in the presence of InCl₃ at low temperature. Elaboration of the adducts (II) allows for the asymmetric synthesis of α-amino acid derivatives.

Full text of DOI:10.1021/ol034696n

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2461-2464
Diastereoselective Intermolecular
Addition of the 1,3-Dioxolanyl Radical to
N-Acyl Aldohydrazones. Asymmetric
Synthesis of r-Amino Acid Derivatives
Marta Ferna´ndez and Ricardo Alonso*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, UniVersidad de
Santiago de Compostela, 15782 Santiago de Compostela, Spain
qoraa@usc.es
Received April 27, 2003
ABSTRACT
N-Acyl aldohydrazones I (R ) CO Et, alkyl, aryl, and furyl) efficiently trap the 1,3-dioxolanyl radical intermolecularly without external activation
2
at temperatures as low as −78 °C. For alkyl aldohydrazones, good diastereoselectivities are obtained in the presence of InCl3 at low temperature.
Elaboration of the adducts (II) allows for the asymmetric synthesis of r-amino acid derivatives.
The intramolecular addition of a carbon-centered radical to
a carbon-nitrogen π bond is sufficiently fast, for a variety
of nitrogen functionalities and ring sizes, to efficiently sustain
a radical chain.1 These additions are in fact incorporated at
present into a range of reliable and extraordinarily useful
synthetic transformations.2-4 The intermolecular radical
addition to CdN π bonds, however, proved to be trouble-
some; e.g., plain aldoxime ethers, which behave as excellent
intramolecular carbon radical traps, were found to be
reluctant to perform intermolecularly.5 With limitations, some
solutions to this problem have been advanced in the last five
years.6 In particular, it was demonstrated that the inter-
molecular addition of carbon radicals is indeed synthetically
useful for a variety of compounds where the CdN bond is
activated by electron-withdrawing substituents.7 Among
them, glyoxylic imine derivatives have attracted the most
attention because their adducts are R-amino acid derivatives,
and their performance as radical traps has been studied for
glyoxylate aldoxime IIIa7e and a variety of acyclic and cyclic
related imines IIIb7f and IIIc7f (Figure 1, route A). While
room still exists for improving yields and/or selectivity, the
(1) Even fully carbon-substituted CdN double bonds intramolecularly
trap alkyl and vinyl radicals in the 1,5-exo ((a) Noya, B.; Alonso, R.
Tetrahedron Lett. 1997, 38, 2745-2748. (b) Noya, B.; Paredes, M. D.;
Ozores, L.; Alonso, R. J. Org. Chem. 2000, 65, 5960-5968.) and 1,6-exo
modes (unpublished).
(2) For a review on free radical cyclizations inVolVing nitrogen, including
a compilation of cyclization and ring-opening rate constants for some
representative cases, see: Fallis, A. G.; Brinza, I. M. Tetrahedron 1997,
53, 17543-17594.
(3) For a review on the addition of carbon-centered radicals to imines
and related compounds, see: Friestad, G. K. Tetrahedron 2001, 57, 5461-
5496.
(4) Although most examples apply to the addition at the C atom of the
CdN bond, intramolecular addition at nitrogen is also known and
synthetically useful; see: (a) Viswanathan, R.; Prabhakaran, E. N.; Plotkin,
M. A.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125, 163-168. (b) Falzon,
C. T.; Ryu, I.; Schiesser, C. H. Chem. Commun. 2002, 2338-2339 and
references therein. See also refs 2 and 3.
(5) Substitution at the radical trapping center, the sp2 carbon atom of
the aldoxime, is responsible for slowing and preventing the intermolecular
addition of carbon radicals. In fact, the reaction takes place when the radical
trapping center is unsubstituted, i.e., for formaldehyde-derived aldoxime
ethers (H2CdNOR): (a) Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988,
110, 1631-1633. (b) Hanamoto, T.; Inanaga, J. Tetrahedron Lett. 1991,
32, 3555-3556.
(6) For a detailed account, see ref 3, pp 5481-5492. See also ref 7.
10.1021/ol034696n CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/19/2003

radical-based method for preparing enantiomerically pure
R-amino acid derivatives (Figure 1, route C). The high
stereoinduction reported for the 4-benzyl-2-oxazolidinone
auxiliary8 and the good behavior shown by R-oxygenated
carbon-radicals, particularly the 1,3-dioxolanyl radical, when
they add intermolecularly to CdN bonds9 augured well for
a successful endeavor.
To check route B, we irradiated solutions of hydrazone 1
and benzophenone in methanol, 2-propanol, and 1,3-di-
oxolane at room temperature. According to our expectations,
we indeed obtained adducts 3a, 3b (31%, 55%, unoptimized,
Figure 1B), and 3c (88%, Table 1, entry 1), respectively.10
Table 1. Photoinduced Radical Addition of the 1,3-Dioxolanyl
Radical onto Activated (1) and Inactivated (4a) N-Acyl
Aldohydrazones
entry
T (° C) InCl3 time (h) product (yield)b
drc
1
2
3
4
5
6
1
1
1
4a
4a
4a
rt
3c 88%
1.5:1
4.1:1
4.1:1
1.8:1
4.6:1
-78
-78
rt
-78
-78
0.25
0.5
0.5
4.5
1.25
3c ∼quant
3c 63-72%
5a ∼quant
5a 68%
2 equiv
2 equiv
Figure 1. Route A: glyoxylic imine derivatives (IIIa-c) previ-
ously studied as radical traps for the preparation of R-amino acid
derivatives. For IIIa see ref 7e. For details on the nature of Aux,
R, and R′ in IIIb and IIIc, see ref 7f. Routes B and C: new
synthetic pathways to R-amino acid derivatives now evaluated.
5a 87%
10.1:1d
a For details see Supporting Information. b Isolated yields. c Diastereo-
selectivities were determined by 1H NMR analysis. d Dr ) 99:1 for the
one-pot procedure: see text, Scheme 1, and Table 2, entry 1.
results obtained thus far point out a very important limitation
inherent to the developed methodologies: they are inap-
propriate in their present form for the addition of primary
carbon radicals, i.e., they are limited in practice to the
preparation of â-branched R-amino acids.
We report herein further advances in this area after
exploring: (a) the performance of the glyoxylic hydrazone
1 for the diastereoselective intermolecular trapping of
R-oxygenated carbon radicals, i.e., the potential of 1 as a
precursor of â-oxygenated R-amino acids (Figure 1, route
B), and (b) the addition of the 1,3-dioxolanyl radical to alkyl
and aryl N-acyl hydrazones 4 as a, presumably general, free-
The reaction proceeded quickly (<2 h) in the absence of
external activators, clearly reflecting the combined beneficial
effect of the activating ethoxycarbonyl group in 1 and the
comparatively higher nucleophilicity of radicals 2a-c.11 Such
an effect was particularly notable for the last case, where
the addition of the 1,3-dioxolanyl radical took place even at
-78 °C to efficiently give 3c in only 15 min (Table 1, entry
2).
The stereoselectivity of the addition, studied for 3c, was,
however, low: the small diastereomeric ratio of 1.5:1
(8) Friestad recently introduced 2-oxazolidinones as auxiliaries for the
asymmetric synthesis of amines: (a) Friestad, G. K.; Qin, J. J. Am. Chem.
Soc. 2001, 123, 9922-9923. (b) Friestad, G. K.; Qin, J. J. Am. Chem. Soc.
2000, 122, 8329-8330.
(7) Compounds where a CdN bond activated by electron-withdrawing
substituents successfully traps carbon radicals intermolecularly include the
following. R-Sulfonyl oxime ethers: (a) Kim, S.; Song, H.-J.; Choi, T.-L.;
Yoon, J.-Y. Angew. Chem., Int. Ed. 2001, 40, 2524-2526. (b) Kim, S.;
Yoon, J.-Y. J. Am. Chem. Soc. 1997, 119, 5982-5983. (c) Kim, S.; Lee, I.
Y.; Yoon, J.-Y.; Oh, D. H. J. Am. Chem. Soc. 1996, 118, 5138-5139.
Glyoxylic aldoxime ethers: (d) Miyabe, H.; Nishimura, A.; Ueda, M.; Naito,
T. Chem. Commun. 2002, 1454-1455. (e) Miyabe, H.; Ushiro, C.; Ueda,
M.; Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65, 176-185. Glyoxylic
aldimines: (f) Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.; Perfetti,
P. Tetrahedron 2000, 56, 3951-3961 and references therein. Glyoxylic
aldonitrones: (g) Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata, O.; Naito,
T. Chem. Commun. 2003, 426-427. N-Sulfonylimines: (h) Miyabe, H.;
Ueda, M.; Naito, T. Chem. Commun. 2000, 2059-2060.
(9) We have recently demonstrated that the use of R-oxygenated carbon
radicals in intermolecular radical addition is particularly convenient, so that
even fully carbon-substituted ketoxime ethers efficiently trap them: Torrente,
S.; Alonso, R. Org. Lett. 2001, 3, 1985-1987. In these cases, and as an
additional synthetic advantage, the addition results in higher functionalized
adducts. See also: (a) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa,
Y.; Taga, T.; Tomioka, K. Org. Lett. 2002, 4, 3509-3511. (b) Kim, S.;
Kim, N.; Chung, W.; Cho, C. H. Synlett 2001, 937-940.
(10) For details see Supporting Information.
(11) Use of an external activating agent was found to be mandatory for
the intermolecular addition of plain carbon radicals to inactivated N-
acylhydrazones: see ref 8.
2462
Org. Lett., Vol. 5, No. 14, 2003

obtained at room temperature could only be moderately
increased to 4.1:1 at low temperature, with no further
improvement on adding chelating InCl3 (Table 1, entries
1-3). While we were concerned with the stability of both
the starting hydrazone and the final adduct under the
H-abstracting photochemical conditions, we observed neither
dimerization nor change of the diastereomeric ratio on
prolonged irradiation under the reaction conditions. It thus
appears that the solvent was adequately protecting these
systems from hydrogen abstraction and subsequent side
reactions, making meaningful the use of the same photo-
chemical radical generation procedure for further studies on
diastereoselectivity. For these, we selected hydrazone 4a,
which incorporates not an electron-withdrawing activating
substituent but rather an ethyl group. Although, as expected,
its reactivity against the 1,3-dioxolanyl radical diminished
as compared to 1, the addition still proceeded quickly at room
temperature (0.5 h) and at a convenient rate even at low
temperatures (4.5 h at -78 °C) (Table 1, entries 4 and 5).
Regarding stereoselectivity, it was only slightly higher than
that obtained for 1, both at room temperature and at -78
°C, but now, for 4a, the addition of InCl3 (2 equiv) had a
remarkable effect and the diastereomeric ratio reached a value
of 10.1:1 in a considerably reduced reaction time (Table 1,
compare entries 5 and 6).
derivative 8 allowed for additional stereomeric enrichment
by crystallization and the subsequent preparation of 10 with
properties identical to those of an authentic sample prepared
from pure (R)-2-aminobutyric acid.10,16 It thus follows that
the stereochemical outcome of the reaction results from the
overwhelming preferential addition of the dioxolanyl radical
on the In-chelated N-acyl hydrazone from the opposite face
to the benzyl group.8b,17 Noteworthy, the same face is the
most exposed one for the nonchelated hydrazone, a factor
that undoubtedly contributes to the high net stereochemical
induction observed.
We finally made a preliminary survey on the scope and
limitations of the method applying the one-pot protocol to
relevant aldehydes 6b-e. Aldehydes 6b and 6c were selected
to study the influence of R-branching, either with alkyl or
with oxygenated substituents, and also because of the
significance of the corresponding amino acids derived from
them. The process worked well for 6b, which afforded adduct
5b with good diastereoselection (dr ) 97:3), thus opening a
new pathway for the asymmetric synthesis of cyclopropyl-
substituted amino acids.18 For the special case of 6c, carrying
a dimethyl acetal function, the overall yield and the stereo-
selectivity were lower than those for 6b but still sufficient
(75%, 95:5) to be of practical synthetic value; thus, good
prospects exist for the application of this methodology to
the preparation of R-acetal R-amino acids.19,20
The process could be done in one pot starting from
propionaldehyde (6a).12 Its treatment with (S)-3-amino-4-
benzyl-1,3-oxazolan-2-one (7S)13 in 1,3-dioxolane in the
presence of catalytic amounts of p-TsOH for 1 h, followed
by UV irradiation (1-1.5 h) in the presence of Ph2CO and
InCl3 at -78 °C, led to 5a (241-681 mg scale) with
improved yields (93-99% overall) and selectivities (dr )
99:1-98:2, Scheme 1). To demonstrate the usefulness of this
As for the aromatic aldehydes 6d and 6e, the reaction was
quick and efficient to render the corresponding adducts in
good yields.21 Chiral induction at the R center was, however,
either nonexistent for 4-methoxy-benzaldehyde or of the
(12) For the nonasymmetric one-pot intermolecular radical addition to
aldimines derived from aromatic aldehydes, see: Yamada, K.; Yamamoto,
Y.; Tomioka, K. Org. Lett. 2003, 5, 1797-1799.
(13) S)-3-Amino-4-benzyl-1,3-oxazolan-2-one (7S) was prepared from
commercial (S)-4-benzyl-1,3-oxazolan-2-one (Supporting Information). For
a recent work on the comparison of electrophilic amination reagents for
N-amination of 2-oxazolidinones, see: Shen, Y.; Friestad, G. K. J. Org.
Chem. 2002, 67, 6236-6239.
Scheme 1
(14) Numerous methods have been reported for the reductive cleavage
of N-N bonds; see: Enders, D.; Lochtman, R.; Meiers, M.; Mu¨ller, S.;
Lazny, R. Synlett 1998, 1182-1184 and references therein.
(15) Deslongchamps and Moreau first reported that aldehyde acetals
reacted with ozone to give esters in high yield: Deslongchamps, P.; Moreau,
C. Can. J. Chem. 1971, 49, 2465-2467. For additional methods, see: Curini,
M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Synlett 1999, 777-779 and
references therein.
(16) Commercially available (R)-2-aminobutanoic acid was converted
to 10 according to: Nosho, Y.; Seki, T.; Kondo, M.; Ohfuji, T.; Tamura,
M.; Okai, H. J. Agric. Food Chem. 1990, 38, 1368-1373.
(17) Access to the enantiomer of 10 would be possible starting with 7R,
accessible in turn from (R)-4-benzyl-1,3-oxazolan-2-one (see ref 13), which
is also commercially available at approximately the same price as its
enantiomer.
(18) First stereocontrolled synthesis of (S)-cleonin and related cyclopro-
pyl-substituted amino acids has been recently published: Esposito, A.; Piras,
P. P.; Ramazzotti, D.; Taddei, M. Org. Lett. 2001, 3, 3273-3275.
(19) For the first asymmetric synthesis of (R)- and (S)-2-amino-3,3-
dimethoxypropanoic acid (R-formylgycine dimethylacetal), including refer-
ences for its previous use in synthesis, see: DeMong, D. E.; Williams, R.
M. Tetrahedron Lett. 2002, 43, 2355-2357.
(20) Although still not tested, controlled oxidation of 5c should only
affect the dioxolane ring, as acyclic dialkoxy acetals react much more slowly
than cyclic ones due to stereoelectronic control: (a) Deslongchamps, P.;
Atlani, P.; Frehel, D.; Malaval, A.; Moreau, C. Can. J. Chem. 1974, 52,
3651-3664. See also: (b) Li, S.; Deslongchamps, P. Tetrahedron Lett. 1993,
34, 7759-7762, (c) Sueda, T.; Fukuda, S.; Ochiai, M. Org. Lett. 2001, 3,
2387-2390. (d) Plesnicˇar, B.; Cerkovnik, J.; Tuttle, T.; Kraka, E.; Cremer,
D. J. Am. Chem. Soc. 2002, 124, 11260-11261 and references therein.
See also ref 15.
addition as the key step for the asymmetric synthesis of
R-amino acids, we transformed 5a into 10 as indicated in
Scheme 1.14,15 Initial conversion of 5a into its benzamide
Org. Lett., Vol. 5, No. 14, 2003
2463

the intermolecular addition quick and efficient, even at low
temperature without requiring external activators. While
further work is needed to reach adequate levels of diaste-
reoselection for acyl-substituted and aromatic systems, the
addition to alkyl aldohydrazones derived from 3-amino-4-
benzyl-1,3-oxazolan-2-one performs adequately to be the
basis for a new method for preparing enantiomerically pure
R-amino acids. The radical addition procedure is convenient
in terms of (a) simplicity, i.e., it is a one-pot operation from
aldehydes, (b) reaction times, between 0.25 and 4 h for the
cases tested, and (c) efficiency, yields from 75 to 99% and
high stereoselectivities. The uses of light and cheap and
benign 1,3-dioxolane22 as both the solvent and the primary
source for the carboxy group are also of environmental
relevance.
Table 2. One-Pot Conversion of Aldehydes into Chiral
R-1,3-Dioxolanyl Amines 5
While we have illustrated the conversion of the radical
adducts into R-amino acids, the 1,3-dioxolane unit is
amenable to a rich array of transformations, rendering
compounds 5 useful precursors of a variety of 1,2-amino-
oxygenated compounds. The addition of the 1,3-dioxolanyl
and related radicals is thus expected to keep receiving
increased attention in organic synthesis.23
Acknowledgment. We thank the DGES/FEDER (Grants
PB98-0606 and BQU2002-01176) and the Xunta de Galicia
(Grants XUGA20905B97 and PGIDT00PXI20901PR, and
a fellowship to M.F.) for funding this work.
a Isolated overall yields after two steps from the aldehyde (except for
5c; see note c). b Diastereoselectivities were determined by 1H NMR
analysis; for details, see Supporting Information. c For 6c, the aldohydrazone
(4c, not shown) was first prepared in refluxing methanol in the presence of
3 Å molecular sieves; then, the radical addition was performed on
chromatographed 4c (96% yield), containing about 5% 4 (R ) CHO).
Supporting Information Available: Preparation proce-
dures for all intermediates and adducts and characterization
data, including NMR spectra (1H, 13C, DEPT), for adducts
3a-c and 5a-e and compounds 8-10. This material is
available free of charge via the Internet at http://pubs.acs.org.
same order as that for activated hydrazone 1 when starting
from furfural.
OL034696N
In summary, the tendencies of photochemically generated
1,3-dioxolanyl radicals and acyl-, alkyl-, aryl-, and furyl-
substituted N-acyl aldohydrazones adequately match to render
(22) For a report on the properties of 1,3-dioxolane, including toxicologi-
cal and environmental issues, see: http://www.epa.gov/chemrtk/dioxlne/
c12846.pdf.
(23) For a treatise, see: (a) Giese, B. Radicals in Organic Synthesis:
Formation of Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986; pp
69-77. Recent work in this field includes: (b) Yoshimitsu, T.; Arano, Y.;
Nagaoka, H. J. Org. Chem. 2003, 68, 625-627. (c) Mosca, R.; Fagnoni,
M.; Mella, M.; Albini, A. Tetrahedron 2001, 57, 10319-10328. (d) Hirano,
K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 2000, 2457-
2458. (e) Manfrotto, C.; Mella, M.; Freccero, M.; Fagnoni, M.; Albini, A.
J. Org. Chem. 1999, 64, 5024-5028.
(21) Aldehydes 6d and 6e were selected as potential precursors of
aromatic and heteroaromatic R-amino acids, preparation of which in
enantiomerically pure form is complicated because of their comparatively
easier base-catalyzed epimerization of the acidic R-methine proton. For a
recent contribution, see: Saaby, S.; Bayo´n, P.; Aburel, P. S.; Jørgensen, K.
A. J. Org. Chem. 2002, 67, 4352-4361.
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