Tandem radical-addition-aldol-type reaction of an α,β- unsaturated oxime ether

Article abstract of DOI:10.1002/anie.200502263

(Chemical Equation Presented) The direct generation of boryl enamine 2 by radical addition to the chiral α,β-unsaturated oxime ether 1 (X = (1 R)-camphorsultam, Bn = benzyl) followed by reaction with aldehydes gave rise to a tandem carbon-carbon bond-form

Full text of DOI:10.1002/anie.200502263

Communications
Tandem Reactions
DOI: 10.1002/anie.200502263
Tandem Radical-Addition–Aldol-Type Reaction
of an a,b-Unsaturated Oxime Ether**
Masafumi Ueda, Hideto Miyabe, Hisako Sugino,
Okiko Miyata, and Takeaki Naito*
Conjugate addition of radical species has been recognized as a
versatile tool for introducing an alkyl group into the
b position of a,b-unsaturated carbonyl compounds,[1] and
the subsequent trapping of the intermediate radical species
with allyltin compounds has been widely studied.[2,3] Tandem
reactions are among the most efficient synthetic methods.
However, those that proceed sequentially through ionic
species sometimes exhibit problematic drawbacks such as
the need for exacting reaction conditions, whereas undesired
polymerization may result from tandem radical reactions.A
combination of radical and ionic processes may alleviate these
problems and could thus be a promising approach.Oshima
and co-workers first demonstrated that a tandem radical
addition–aldol condensation of enones or enals could be
performed via the formation of an intermediate boryl
enolate.[4] Other groups have recently reported tandem
reactions involving radical and ionic processes for the
convenient synthesis of highly complex molecules.[5] How-
ever, there are only limited examples which employ enolate
intermediates formed by a radical addition reaction.The goal
of our work is to develop a highly efficient carbon–carbon
bond-construction method by taking advantage of a novel
hybrid radical–ionic reaction involving the radical addition to
a,b-unsaturated oxime ethers and subsequent ionic trapping
of the resulting N-boryl enamine by aldehydes.
Building upon our syntheses of a- and b-amino acids by
radical addition to oxime ethers,[6] we extended our use of a,b-
unsaturated oxime ether 1 bearing Oppolzerꢀs camphorsul-
tam to the synthesis of g-amino acids (Figure 1).Recent
studies on the radical addition to imines showed that amino-
boranes were effectively formed by trapping of intermediate
aminyl radicals with triethylborane.[7–10] Thus, we expected
[*] M. Ueda, H. Sugino, Dr. O. Miyata, Prof. T. Naito
Kobe Pharmaceutical University
Motoyamakita, Higashinada, Kobe 658-8558 (Japan)
Fax: (+81)78-441-7556
E-mail: taknaito@kobepharma-u.ac.jp
Dr. H. Miyabe
Graduate School of Pharmaceutical Sciences
Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
[**] This work was supported in part by a Grant-in-Aid for Scientific
Research on Priority Areas 17035088 and for Young Scientists (B)
(M.U. and H.M.) from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan and the Science Research
Promotion Fund of the Japan Private School Promotion Foundation
for research grants. M.U. is grateful for a Fuji Photo Film Award in
Synthetic Organic Chemistry, Japan.
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in 97% yield without formation of other regioisomers
(paths b or c).This is the first example of a regioselective
radical addition to a conjugated oxime ether that involves
four electrophilic positions.The diastereomeric purity of 3a
was found to be no less than 97.5:2.5 d.r. by 1H NMR
spectroscopic analysis of the crude product.The absolute
configuration at the newly formed stereocenter was deter-
mined to be S by converting the adduct 3a into the authentic
g-amino acid 4.[11] The stereochemical preference of this
reaction can be rationalized as follows.With regard to the
conformation of (E)-1, the anti (sulfonyl and carbonyl groups)
=
and s-cis (carbonyl group and C C bond) planar rotamer
shown in Scheme 1 should be favored over other rotamers.
Therefore, the alkyl-radical addition to the re (bottom) face is
favored, presumably resulting from steric interactions with
the axial oxygen of the sulfonyl group.[6c] In marked contrast,
the ethylated product 3a was not formed with the use of
diethylzinc as a radical initiator (Table 1, entry 2).[12] The high
diastereoselectivities and good chemical yields were observed
in the addition of secondary alkyl radicals to (E)-1 (Table 1,
entries 3 and 4).A lower chemical yield was attained with a
bulky tert-butyl radical, but the reaction still proceeded with
high d.r. (> 97.5:2.5; Table 1, entry 5). These observations
indicate that triethylborane acts as an effective reagent for
trapping the intermediate enaminyl radical to form the boryl
enamine 2.
Figure 1. Tandem reaction involving both radical and ionic processes
(X=(1R)-camphorsultam). Bn=benzyl.
that the boryl enamine 2 could be formed by the triethylbor-
ane-promoted radical addition to (E)-1, if the reaction
proceeds regioselectively by path a.
Prior to exploring issues of the tandem process, we first
investigated the regioselectivity in the carbon-radical addition
to conjugated oxime ether (E)-1, which possesses three
radicophilic centers (Scheme 1).The addition of ethyl radical
To confirm the formation of boryl enamine 2, we studied
the 1H NMR spectra and the trapping reaction of boryl
enamine 2 with D2O (Scheme 2).The 1H NMR spectra of the
Scheme 1. Radical addition to conjugated oxime ether (E)-1. Boc=tert-
butyloxycarbonyl.
to (E)-1 was performed in CH2Cl2 at 208C for 20 min with
triethylborane (Table 1, entry 1).The reaction took place
regioselectively at the a position of the carbonyl group
(path a as shown in Figure 1) to give the desired product 3a
Scheme 2. Trapping reaction of boryl enamine with D2O (X=(1R)-cam-
phorsultam).
Table 1: Alkyl-radical addition to conjugated oxime ether (E)-1.[a]
reaction mixture of 1 with triethylborane in CD2Cl2 suggested
the formation of (E)-enamine 2 as shown in Scheme 2.The
deuteration of boryl enamine 2 took place at the b position
(relative to the carbonyl group) to give the product 5 in 64%
yield.Thus, the rationale of the reaction pathway is that the
alkyl radical adds to the a position of the carbonyl group in
(E)-1 to form the intermediate radical A, which is captured by
triethylborane to afford the (E)-boryl enamine 2 and
regenerate an ethyl radical.
Entry
Initiator
RI
Product
Yield [%][b]
d.r.[c]
1
2
3
4
5
Et3B
Et2Zn
Et3B
Et3B
Et3B
none
none
iPrI
sBuI
tBuI
3a
–
3b
3c
3d
97
ND
56
69
28
>97.5:2.5
>97.5:2.5
>97.5:2.5
>97.5:2.5
[a] Reactions were carried out using RI (30 equiv) and Et3B or Et2Zn in
hexane (1.0m, 5 equiv) in CH2Cl2 for 20 min. [b] Isolated yield of the
desired alkylated product (ND=not detected). [c] Diastereomeric ratios
were determined by 1H NMR analysis.
With these results in mind, we next investigated the
tandem radical-addition–aldol-type reaction of an a,b-unsa-
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turated oxime ether by using paraformaldehyde (Scheme 3).
Triethylborane was added to a mixture of 1 and paraformal-
dehyde.The resulting products were the ethylated product 3a
and trans-g-butyrolactone 6 in 53 and 44% yields, respectively
(Table 2, entry 1).The g-butyrolactone 6 was presumably
Scheme 4. Radical-addition–aldol-type reaction of (E)-1 (ratio in paren-
theses is for the yield of the major isomer to that of all other isomers
combined; X=(1R)-camphorsultam).
Scheme 3. Tandem radical-addition–trapping reaction of boryl enamine
with paraformaldehyde (X=(1R)-camphorsultam).
ment of 8a with benzylamine in the presence of 2-pyridinol
gave an acyclic oxime ether which was reduced to the amino
acid amide 9.[13] The electron-donating and electron-with-
drawing substituents on the aromatic ring of the aldehyde
exhibited no apparent effects on either the chemical yield or
the stereoselectivity, and good yields were attained for both
8b and 8c.2-Furfural and cinnamaldehyde also worked well
under similar reaction conditions.The trans,trans stereo-
selectivity observed for the reaction can be explained by
invoking a six-membered-ring transition state.The sterically
more stable conformer of (E)-boryl enamine reacted with the
Me3Al-activated aldehyde in such a way that 1,3-diaxial
interactions were minimized, and an unfavorable steric
interaction with allylic substituents was avoided.[14]
Table 2: Radical–aldol-type reaction of (E)-1 with paraformaldehyde.[a]
Entry
Lewis acid
T [8C]
Yield [%][b]
Selectivity[c]
6
3a
trans:cis
1
2
3
None
Me3Al
Me3Al
reflux
20
reflux
44
41
72
53
42
–
10:2
10:3
10:3[d]
[a] Reactions were carried out with Et3B in hexane (1.0m, 5 equiv), Me3Al
in hexane (1.0m, 1.2 equiv), and (CH2O)n (1.2 equiv) in CH2Cl2.
1
[b] Isolated yield. [c] Determined by H NMR analysis. [d] Enantiomeric
purity of the trans isomer was found to be 90% ee by HPLC analysis.
Finally, we examined the tandem reaction involving an
addition of isopropyl radical, which occurred by way of an
iodine atom-transfer process, followed by an aldol-type
reaction (Scheme 5).With the use of isopropyl iodide
formed through the diastereoselective addition of ethyl
radical to 1, trapping of boryl enamine 2 with paraformalde-
hyde, and intramolecular lactonization with concomitant
removal of the chiral auxiliary.The relative configuration of
the two substituents on lactone 6 was determined by NOE
interaction experiments.To the best of our knowledge, this
reaction represents the first reported example of the electro-
philic trapping reaction of an unstable N-boryl enamine
generated through a radical process.This tandem reaction
was promoted in the presence of Me3Al (1.2 equiv) as a Lewis
acid.The reaction using Me 3Al under reflux gave the desired
lactone 6 exclusively in 72% yield (Table 2, entry 3).The
enantiomeric purity of trans-g-butyrolactone 6 was found to
be 90% ee by chiral HPLC analysis.The lower stereoselec-
tivity of the tandem reaction (90% ee) than that of the simple
ethyl-radical addition (> 97.5:2.5 d.r.) was attributed to the
higher reaction temperature (reflux) used in the initial radical
reaction step.
The utility of this new tandem radical–ionic reaction was
tested in the asymmetric synthesis of various types of g-
butyrolactones.Thus, we investigated the reaction with
different kinds of aldehydes (Scheme 4).The trapping
reaction of boryl enamine 2 with benzaldehyde gave the
trans,trans isomer 8a as the major product, accompanied by
small amounts of other diastereomers. g-Butyrolactone 8a
was easily converted into g-amino acid derivative 9.Treat-
Scheme 5. Isopropyl-radical-addition–aldol-type reaction of (E)-1 (ratio
in parentheses is for the yield of the major isomer to that of all other
isomers combined).
(20 equiv) as radical precursor and benzaldehyde as trapping
agent, the tandem reaction of (E)-1 proceeded smoothly to
give isopropyl-substituted g-butyrolactone 10 in 61% yield.
In conclusion, we have developed a hybrid type of
reaction that involves a radical addition and an aldol
condensation.This tandem reaction of an a,b-unsaturated
oxime ether provides a powerful synthetic approach to chiral
g-butyrolactones and g-amino acids.
Experimental Section
General procedure for radical-addition–aldol-type reaction of a,b-
unsaturated oxime ether (E)-1: Aldehyde (0.148 mmol) and Me3Al
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Chemie
(1.0m in hexane, 0.148 mL, 0.148 mmol) were added to a solution of
(E)-1 (50 mg, 0.124 mmol) in CH2Cl2 (5 mL) at room temperature
Miyabe, C.Ushiro, M.Ueda, K.Yamakawa, T.Naito,
Chem. 2000, 65, 176; d) H.Miyabe, K.Fujii, T.Naito,
J. Org.
Org.
under a N2 atmosphere.Et B (1.0m in hexane, 0.62 mL, 0.62 mmol)
Biomol. Chem. 2003, 1, 381; e) M.Ueda, H.Miyabe, H.Sugino,
T.Naito, Org. Biomol. Chem. 2005, 3, 1124.
[7] a) H.Miyabe, R.Shibata, C.Ushiro, T.Naito, Tetrahedron Lett.
1998, 39, 631; b) H.Miyabe, M.Ueda, N.Yoshioka, T.Naito,
3
was then added dropwise to the reaction mixture at reflux.After
stirring at reflux for 3 h, the reaction mixture was diluted with
saturated aqueous NaHSO3 and then extracted with EtOAc.The
organic phase was washed with saturated aqueous NaHCO3 and
brine, dried over MgSO4, and concentrated at decreased pressure.
Purification of the residue by preparative TLC (hexane/EtOAc 5:1)
afforded the desired g-butyrolactones.
Synlett 1999, 465; c) H.Miyabe, M.Ueda, T.Naito,
Commun. 2000, 2059.
Chem.
[8] For reviews, see: a) G.K.Friestad, Tetrahedron 2001, 57, 5461;
b) H.Miyabe, M.Ueda, T.Naito, Synlett 2004, 1140.
[9] a) M.P.Bertrand, L.Feray, R.Nouguier, L.Stella, Synlett 1998,
780; b) M.P.Bertrand, L.Feray, R.Nouguier, P.Perfetti,
J. Org.
Received: June 28, 2005
Chem. 1999, 64, 918; c) M.P.Bertrand, S.Coantic, L.Feray, R.
Nouguier, P.Perfetti, Tetrahedron 2000, 56, 3951.
Published online: August 26, 2005
[10] a) G.K. Friestad, J. Qin, J. Am. Chem. Soc. 2000, 122, 8329;
b) G.K. Friestad, J. Qin, J. Am. Chem. Soc. 2001, 123, 9922;
Keywords: asymmetric synthesis · boranes · enamines ·
oxime ethers · radical reactions
.
c) G.K.Friestad, Y.Shen, E.L.Ruggles,
Angew. Chem. 2003,
115, 5215; Angew. Chem. Int. Ed. 2003, 42, 5061.
[11] S.Azam, AA. .DꢀSouza, PB. .Wyatt,
J. Chem. Soc. Perkin
[1] a) P.Renaud, M.Gerster, Angew. Chem. 1998, 110, 2704; Angew.
Chem. Int. Ed. 1998, 37, 2562; b) M.P.Sibi, N.A.Porter, Acc.
Chem. Res. 1999, 32, 163; c) Radicals in Organic Synthesis,
Trans. 1 1996, 621.
[12] Ryu and Komatsu reported that Et2Zn can serve as a radical
initiator in the absence of O2.See: I.Ryu, F.Araki, S.Minakata,
M.Komatsu, Tetrahedron Lett. 1998, 39, 6335.
Vols. 1 and
2 (Ed:s. P.Renaud, MP..Sibi), Wiley-VCH,
Weinheim, 2001; d) MP. .Sibi, S.Manyem, J.Zimmerman,
Chem. Rev. 2003, 103, 3263; e) M.P.Sibi, S.Manyem, Tetrahe-
dron 2000, 56, 8033.
[13] a) D.S. Tan, M.A. Foley, M.D. Shair, S.L. Schreiber,
J. Am.
Chem. Soc. 1999, 121, 9073; b) H.T.Openshaw, N.Whittaker, J.
Chem. Soc. C 1969, 89.
[2] For selected examples of tandem radical allylation, see: a) D.P.
[14] Bahmanyar and Houk reported a theoretical study of the aldol
reaction of an enamine with acetaldehyde.Although there are
two possible conformations of the six-membered ring transition
state involving an equatorial or axial methyl group on acetal-
dehyde, the two conformations are predicted to be equal in
energy.See: S.Bahmanyar, K.N.Houk, J. Am. Chem. Soc. 2001,
123, 11273.
Curran, W.Shen, J.Zhang, T.A.Heffnerm,
J. Am. Chem. Soc.
1990, 112, 6738; b) B.Giese, M.Zehnder, M.Roth, H-.G.Zeitz,
J. Am. Chem. Soc. 1990, 112, 6741; c) N.A.Porter, I.J.Rose-
nstein, R.A.Breyer, J.D.Bruhnke, W.-X.Wu, A.T.McPhail,
Am. Chem. Soc. 1992, 114, 7664; d) J.H.Wu, R.Radinov, N.A.
Porter, J. Am. Chem. Soc. 1995, 117, 11029; e) M.P.Sibi, J.Ji, J.
Org. Chem. 1996, 61, 6090; f) M.P.Sibi, J.Chen, J. Am. Chem.
Soc. 2001, 123, 9472.
J.
[3] For selected examples of tandem radical reaction, see: a) D.P.
Curran, M.-H. Chen, E. Spletzer, C. M. Seong, C.-T. Chang, J.
Am. Chem. Soc. 1989, 111, 8872; b) J.Marco-Contelles, Chem.
Commun. 1996, 2629; c) K.Takai, N.Matsukawa, A.Takahashi,
T.Fujii, Angew. Chem. 1998, 110, 160; Angew. Chem. Int. Ed.
1998, 37, 152; d) C.Aïssa, A-.L.Dhimane, M.Malacria, Angew.
Chem. 2002, 114, 3418; Angew. Chem. Int. Ed. 2002, 41, 3284;
e) S.Yamago, M.Miyoshi, H.Miyazoe, J.Yoshida,
Angew.
Chem. 2002, 114, 1465; Angew. Chem. Int. Ed. 2002, 41, 1407;
f) K.Takasu, H.Ohsato, J.Kuroyanagi, M.Ihara, J. Org. Chem.
2002, 67, 6001; g) A.Demircan, P.J.Parsons, Eur. J. Org. Chem.
2003, 1729; h) K.Tsuchii, M.Doi, T.Hirao, A.Ogawa,
Chem. 2003, 115, 3614; Angew. Chem. Int. Ed. 2003, 42, 3490;
i) F.Denes, F.Chemla, J.F.Normant, Angew. Chem. 2003, 115,
Angew.
4177; Angew. Chem. Int. Ed. 2003, 42, 4043; j) K.Miura, M.
Tojino, N.Fujisawa, A.Hosomi, I.Ryu, Angew. Chem. 2004, 116,
2477; Angew. Chem. Int. Ed. 2004, 43, 2423; k) M.Tojino, Y.
Uenoyama, T.Fukuyama, I.Ryu, Chem. Commun. 2004, 2482;
l) Y.Uenoyama, T.Fukuyama, O.Nobuta, H.Matsubara, I.Ryu,
Angew. Chem. 2005, 117, 1099; Angew. Chem. Int. Ed. 2005, 44,
1075.
[4] a) K.Nozaki, K.Oshima, K.Utimoto, Tetrahedron Lett. 1988, 29,
1041; b) K.Nozaki, K.Oshima, K.Utimoto,
Bull. Chem. Soc.
Jpn. 1991, 64, 403.
[5] a) S.Bazin, L.Feray, D.Siri, J-.V.Naubron, M.P.Bertrand,
Chem. Commun. 2002, 2506; b) S.Chandrasekhar, C.Narsih-
mulu, N.R. Reddy, M.S. Reddy, Tetrahedron Lett. 2003, 44,
2583; c) H.Miyabe, R.Asada, K.Yoshida, Y.Takemoto, Synlett
2004, 540; d) Y.Yamamoto, S.Nakano, H.Maekawa, I,
Nishiguchi, Org. Lett. 2004, 6, 799; e) S.Bazin, L.Feray, N.
Vanthuyne, M.P.Bertrand, Tetrahedron 2005, 61, 4261.
[6] a) H.Miyabe, C.Ushiro, T.Naito, Chem. Commun. 1997, 1789;
b) H.Miyabe, K.Fujii, T.Naito,
Org. Lett. 1999, 1, 569; c) H.
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