Diastereoselective pentadienylation reaction of protected chiral α- amino aldehydes

Article abstract of DOI:10.1055/s-2000-6500

Diastereoselective pentadienylation of chiral α-amino aldehydes was achieved. The obtained anti amino alcohols can be transformed into dienic imines which undergo Diels-Alder cyclisation to give stereoselectively indolizidines.

Full text of DOI:10.1055/s-2000-6500

242
LETTER
Diastereoselective Pentadienylation Reaction of Protected Chiral a-Amino
Aldehydes
Frédéric Minassian, Nadia Pelloux-Léon, Yannick Vallée*
LEDSS, UMR CNRS-Université Joseph Fourier, B.P. 53X, 38041 Grenoble, France
Fax +33 47651 4382; E-mail: yannick.vallee@ujf-grenoble.fr
Received 27 November 1999
First experiments were run with pentadienylsilane and the
Abstract: Diastereoselective pentadienylation of chiral a-amino al-
simple aldehydes 1a,b (Scheme 2). As expected, only the
dehydes was achieved. The obtained anti amino alcohols can be
linear alcohols 2a,b were isolated. However the observed
transformed into dienic imines which undergo Diels-Alder cyclisa-
tion to give stereoselectively indolizidines.
stereoselectivity (a :63/37; b :53/47)8 was poor and no ef-
fort was made to determine the relative configuration of
the major isomers.
Key words: chiral a-amino aldehydes, pentadienylation, Diels-Al-
der reaction, indolizidines
The allylation reaction of aldehydes has been widely stud-
ied and is recognized as a powerful route to functionalized
alcohols. Many diastereoselective examples of this reac-
tion have been described.1 In contrast, the reaction of pen-
tadienyl anions with aldehydes has been much less
investigated. These reactions can give two types of prod-
ucts (Scheme 1). As early as 1965,2 Miginiac et al. report-
ed that the reaction of pentadienyllithium with aldehydes
leads to mixtures of linear and branched alcohols, whereas
the corresponding zinc reagent regioselectively gives the
branched alcohol. More recently, it has been reported that
treatment of 5-bromo-1,3-pentadiene with indium metal
in the presence of an aldehyde or a ketone results in the
formation of a branched alcohol.3 On the other hand, pen-
tadienylsilanes and stannanes are known to lead exclu-
sively to the linear product.4,5 Such linear dienols can be
further elaborated for use in the synthesis of natural prod-
ucts, in particular using the introduced diene in a Diels-
Alder or hetero-Diels-Alder reaction.6
Scheme 2
More interesting were the results obtained with the two
serinal analogues 3a,b (Scheme 3). Representative results
are summarized in the Table.
Scheme 1
To the best of our knowledge, nothing is known about the
stereoselectivity of pentadienylation reactions leading to
linear alcohols.7 In this note, we present our first results
about the reaction of pentadienyl anion equivalents with
a-chiral aldehydes, especially protected serinals. An ap-
plication of this strategy to the stereoselective synthesis of
indolizidines is also reported.
Scheme 3
When pentadienyllithium9 was reacted with aldehyde 3a
(Garner’s aldehyde,10 entry 1), a mixture of branched and
linear alcohols was obtained. These compounds can be
Synlett 2000, No. 1, 242–244 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective Pentadienylation Reaction of Protected Chiral a-Amino Aldehydes
243
easily separated by liquid chromatography. However, we In order to demonstrate that the alcohols 5 are interesting
were not able to determine the syn/anti ration directly for synthons, we studied their use in a hetero-Diels-Alder re-
the isolated alcohols 5. They were transformed in two action.13 The amine 7anti was obtained by deprotection of
steps11 into the dioxanes 6 for which this ratio can be 6banti (Scheme 4).14 Treatment of 7anti with ethyl glyox-
readily obtain by HPLC. Furthermore, the syn and anti ylate gave the imine 8anti which was relatively stable15
isomers of 6a,b can be separated by preparative liquid and did not undergo a spontaneous [4p+2p] cyclisation.
chromatography. The stereochemistry of the major and However, when treated with trifluoroacetic acid, 8anti
minor isomers were determined by 1H NMR.12 The reac- readily cyclized, via the corresponding iminium, and gave
tions with pentadienylzinc chloride (entries 2,7) gave re- the tricyclic compound 9. This heterocycle was obtained
gioselectively the branched alcohols 4a,b. No attempt at as a mixture of isomers which we were not able to sepa-
determining the syn/anti ratio of these branched alcohols rate. Hydrogenation of 9 gave the indolizidine 10 as a
was made. On the other hand, pentadienyltrimethylsilane mixture of two isomers (ratio 4/1). These isomers were
and pentadienyltributylstannane led exclusively to the lin- separated by liquid chromatography and careful examina-
ear alcohols 5a,b. As in the case of allylation reactions, a tion of their NMR spectra16 shows that the major isomer
promoter had to be used in order to activate the used alde- 10b has a (2R, 3S, 5R, 8aS) configuration whereas the mi-
hyde in these reactions. For the corresponding allylation nor isomer 10a has a (2R, 3S, 5R, 8aR) configuration. For-
reactions, monodentate activators, such as BF3, lead to the mation of the major isomer 10b would result from an
formation of the anti isomer as the major product, whereas attack of the iminium onto the Re-face of the diene, as de-
the use of bidentate Lewis acids, such as MgBr2, gives picted in the Figure. The configuration of carbon 5 seems
mainly the syn isomer.1 As seen from the table (for in- to indicate an endo attack; however, we cannot exclude a
stance entries 3 and 5), the stereoselectivity of the penta- possible epimerization of this stereogenic center after the
dienylation reaction is independent of the used Lewis acid Diels-Alder reaction.
(at least for boron and magnesium). In every cases, the
anti isomer dominates, with a anti/syn ratio around 9/1,
the only exeption being entry 10 in which the ratio is clos-
er to 4/1.
10a and 10b are precursors for various natural indoliz-
idines.17 We are presently studying their chemistry.
Table Synthesis of compounds 4, 5 and 6
The anti selectivity observed in the case of BF3-promoted
reactions can be adequately explained using a simple Fel-
kin-Anh model as in the case of allylation reactions.1
However, we have no precise rational for the anti selectiv-
ity obtained using MgBr2. We think that it might be due to
a late transition state, closer to the final products than in
the case of allylation reactions. If this is the case, even
though it is probably kinetically controlled,1 the anti/syn
Scheme 4
ratio will largely reflect the relative stability of these iso-
mers.
Synlett 2000, No. 2, 242–244 ISSN 0936-5214 © Thieme Stuttgart · New York

244
F. Minassian et al.
LETTER
J
J
H4H5 = 7-10 Hz for anti dioxanes. 11 For 6b, major isomer :
H4H5 = 9.5 Hz (anti); minor isomer : JH4H5 = 1.5 Hz (syn).
Attributions were confirmed by NOE experiments.
(13) Weinreb, S. M.; Staib, R. R. Tetrahedron 1982, 38, 3087.
Craig, D. Chem. Soc. Rev. 1987, 16, 187. Waldmann, H.
Synthesis 1994, 535. Abraham, H.; Stella, L. Tetrahedron
1992, 48, 9707. Bailey, P. D.; Millwood, P. A.; Smith, P. D.
Chem. Commun. 1998, 635 and references therein.
Figure
(14) Carpino, L. A.; Han, G. Y. J. Am. Chem. Soc. 1970, 92, 5748;
J. Org. Chem. 1972, 37, 3404.
Acknowledgement
(15) In the 1H NMR spectrum, the proton of the HC=N group was
observed as a singlet at 7.73 ppm (300 MHz, CDCl3).
(16) All new compounds gave spectroscopic and analytical data in
agreement with the assigned structures.
We gratefully thank Dr. Marie-Christine Brochier for her help in the
determination of structures by NMR spectroscopy.
10b: [a]D20+5.5 (c 0.8, CHCl3); 1H NMR (C6D6, 500 MHz)
0.93 (t, 3H, J = 7.1Hz, CH3 ester), 1.01-1.06 (m, 2H, 7-H and
8-H), 1.27-1.32 (m, 2H, 1-H and 8-H), 1.36 (s, 3H, CH3
dioxane), 1.43-1.48 (m, 2H, 6-H and 7-H), 1.56 (s, 3H, CH3
dioxane), 1.60-1.67 (m, 1H, 6-H), 2.13-2.20 (m, 1H, 1-H),
3.00-3.10 (m, 2H, 3-H and 8a-H), 3.44 (dd, 1H, J = 11.4 and
2.8Hz, 5-H), 3.74-3.95 (m, 4H, CH2 ester, 2-H and one H of
CH2O), 4.18 (dd, 1H, J = 10.0 and 3.9Hz, one H of CH2O);
13C NMR (CDCl3, 75MHz) 14.14 (CH3 ester), 19.71 (CH3
dioxane), 21.65 (6-C), 23.72 (7-C), 29.51 (CH3 dioxane),
29.67 (8-C), 34.75 (1-C), 54.74 (3-C), 58.11 (8a-C), 60.05 (5-
C), 61.02 (CH2 ester), 66.62 (CH2 dioxane), 74.67 (2-C),
100.10 (C dioxane), 172.14 (C = O).
References and Notes
(1) For a review, see : Fleming, I. In Comprehensive Organic
Synthesis, vol. 2; Trost, B. M. and Fleming, I., Eds;
Heathcock, C. H., vol. Ed.; Pergamon Press: Cambridge,
1991; p. 563.
(2) Miginiac-Croizeleau, L.; Miginiac, P.; Prévost, C. Bull. Soc.
Chim. Fr. 1965, 3560. Gérard, F.; Miginiac, P. Bull. Soc.
Chim. Fr. 1974, 1924.
(3) Woo, S.; Squires, N.; Fallis, A. G. Org. Lett. 1999, 1, 573.
(4) Seyferth, D.; Pornet, J. J. Org. Chem. 1980, 45, 1721. Hosomi,
A.; Saito, M.; Sakurai, H. Tetrahedron Lett. 1980, 21, 3783.
Naruta, Y.; Nagai, N.; Arita, Y.; Maruyama, K. Chem. Lett.
1983, 1683.
(5) Beryllium derivatives : Yasuda, H.; Ohnuma, Y.; Nakamura,
A.; Kai, Y.; Yasuoka, N.; Kasai, N. Bull. Chem. Soc. Jpn
1980, 53, 1101.
(6) Bailey, T. R.; Garigipati, R. S.; Morton, J. A.; Weinreb, S. M.
J. Am. Chem. Soc. 1984, 106, 3240. Ainsworth, P. J.; Craig,
D.; Reader, J. C.; Slawin, A. M. Z.; White, A. J. P.; Williams,
D. J. Tetrahedron 1996, 52, 695.
(7) Use of a chiral pentadienyl borane leading to a branched
alcohol : Sugimone, M.; Yamamoto, Y.; Fujii, K.; Ito, Y. J.
Am. Chem. Soc. 1995, 117, 9608.
(8) Ratio determined by HPLC. Column : Nucleosil Sim
250 x 4.6; eluant : cyclohexane/isopropanol: 99.6/0.4.
(9) Bates, R. B.; Gosselink, D. W.; Kaczynski, J. A. Tetrahedron
Lett. 1967, 199.
(10) Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18. 3b was
prepared in a similar way. Full desciption of this new serinal
analogue will be reported elsewhere.
10a: [a]D20+55.8 (c 2.0, CHCl3); 1H NMR (CDCl3, 500MHz)
1.16-1.23 (m, 1H, 8b-H), 1.25 (t, 3H, J = 7.1Hz, CH3 ester),
1.31-1.46 (m, 2H, 1a-H and 7b-H), 1.38 (s included in
preceeding m, 3H, CH3 dioxane), 1.47 (s, 3H, CH3 dioxane),
1.78-1.87 (m, 2H, 1b-H and 6b-H), 1.88-1.98 (m, 2H, 7a-H
and 8a-H), 2.10-2.19 (m, 1H, 6a-H), 2.62 (ddd, 1H, J = 12.0,
8.9 and 4.5Hz, 3-H), 3.00-3.06 (m, 1H, 8a-H), 3.58 (ddd, 1H,
J = 12.0, 8.6 and 4.1Hz, 2-H), 3.67 (dd, 1H, J = 8.9 and 2.1Hz,
5-H), 3.72 (t, 1H, J = 10.8Hz, 1H of CH2O), 3.92 (dd, 1H,
J = 10.8 and 4.5Hz, 1H of CH2O), 4.08-4.18 (m, 2H, CH2
ester); 13C NMR (CDCl3, 75MHz) 14.30 (CH3 ester), 19.29
(CH3 dioxane), 27.68 (6-C), 29.21 (7-C), 29.56 (8-C), 29.60
(CH3 dioxane), 29.95 (1-C), 58.12 (8a-C), 59.50 (3-C), 60.00
(5-C), 60.28 (CH2 ester), 63.13 (CH2 dioxane), 72.40 (2-C),
98.88 (C dioxane), 173.33 (C=O). Attribution of relative
configurations were made using one and two dimensional
NOE experiments in CDCl3 and C6D6.
(17) Michael, J. P. Nat. Prod. Rep. 1997, 619. Yoda, H.; Kawauchi,
M.; Takabe, K. Synlett 1998, 137.
(11) Herold, P. Helv. Chim. Acta 1988, 71, 354. Garner, P.; Park,
J. M. J. Org. Chem. 1988, 53, 2979. Tchertchian, S.; Vallée,
Y. Tetrahedron 1998, 54, 7777.
Article Identifier:
1437-2096,E;2000,0,02,0242,0244,ftx,en;L21799ST.pdf
(12) The coupling constant JH4H5 is characteristic of the
configuration : JH4H5 = 1-2 Hz for syn dioxanes, whereas
Synlett 2000, No. 2, 242–244 ISSN 0936-5214 © Thieme Stuttgart · New York