New developments in asymmetric Bradsher cycloadditions: Use of chiral dienes

Article abstract of DOI:10.1016/S0040-4039(00)01708-1

Several serinol derivatives have been prepared and condensed following the Zincke reaction with 2,7-naphthyridine. The resulting naphthyridinium salts were engaged in Bradsher cycloadditions with enol ethers and afforded tetracyclic adducts, potential synthetic precursors of manzamine A alkaloid. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01708-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9251–9256
New developments in asymmetric Bradsher cycloadditions:
use of chiral dienes
Dominique Urban, Eric Duval and Yves Langlois*
Laboratoire de Synthe`se des Substances Naturelles, Associe´s au CNRS, Baˆtiment 410, Universite´ de Paris-Sud,
91405 Orsay, France
Received 29 August 2000; accepted 27 September 2000
Abstract
Several serinol derivatives have been prepared and condensed following the Zincke reaction with
2,7-naphthyridine. The resulting naphthyridinium salts were engaged in Bradsher cycloadditions with enol
ethers and afforded tetracyclic adducts, potential synthetic precursors of manzamine A alkaloid. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: cycloaddition; alkaloid.
During the course of preliminary studies toward the total synthesis of cytotoxic alkaloid
Manzamine A 1,1 we demonstrated2,3 the synthetic utility of a Bradsher cycloaddition4 strategy.
An extension of this reaction to its asymmetric counter part has also been developed using chiral
Z-enol ether as chiral dienophiles.5,6 In the present communication, we describe our results in an
alternative asymmetric Bradsher cycloaddition using chiral 2,7-naphthyridinium salts as chiral
dienes.
These salts can be obtained by using the Zincke reaction, the way of choice for the
preparation of pyridinium salts having a chiral carbon directly linked to nitrogen of a pyridine
ring.7 This reaction has also been used in our previous work for the preparation of achiral
functionalised 2,7-naphthyridinium salt 3 obtained by condensation of serinol with 2,7-naph-
thyridine 2. This salt 3, after Bradsher cycloaddition, followed by olefin metathesis, led,
respectively, to compounds 4 and 5, intermediates in a synthetic approach of racemic manza-
mine A 1 (Scheme 1).4 It was anticipated that the application of the Zincke reaction to chiral
serinol derivatives as nucleophiles should give rise to chiral 2,7-naphthyridinium salts, which
could be used in turn in asymmetric Bradsher cycloadditions.
* Corresponding author. Fax: 33 1 69 15 46 79; e-mail: langlois@icmo.u-p.sud.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01708-1

9252
Scheme 1.
(R)-4-Methoxybenzyl serinol 8 was obtained in two steps after trichloroacetimidate alkyla-
tion, followed by LiBH4 reduction of the acid functional group, in 48% overall yield, from the
known methyl N-trifluoromethyl serinate 6.8 (S)-Benzyl serinol 9 was prepared in five steps from
(S)-serine9 following a described procedure (Scheme 2).10
Scheme 2. (a) Cl3C(NH)OPMB, TfOH (cat.), ether. (b) LiBH4, EtOH/THF 1:1. (c) (PhSe)2, Na, THF, HMPA. (d)
CH2N2, Et2O. (e) LiAlH4, THF. (f) TFA, CH2Cl2.
In order to introduce at an early stage of the synthesis a selenoether functional group which
could be used for a radical five-membered ring formation,2 (S)-2-amino 3-phenylselanyl-propan-
1-ol 12 was also prepared. Accordingly, b-lactone 10 was obtained following the Vederas
synthesis11 and subjected to a nucleophilic ring opening affording seleno amino acid 11.12 Amino
acid 11 was then esterified with diazomethane and the resulting ester, after reduction with
LiAlH4 and cleavage of the tert-butyloxycarbonyl group in acidic medium, gave rise to the
anticipated seleno ether derivative 12 in 59% overall yield (Scheme 2).
With serinol derivatives 8, 9 and 12 in hand the study of the Zincke–Bradsher sequence of
reactions was next addressed. Naphthyridinium salts 14, 15 and 16 were prepared in a one-step
procedure. Accordingly, naphthyridine 2, 4-chloro 1,3-dinitrobenzene 13 and serinol derivatives
8, 9 or 12 were heated at 100°C for 16 hours in a 4:1 mixture of water and dioxane affording,
respectively, naphthyridinium salt intermediates 14, 15 and 16 (Scheme 3). These salts which
cannot be purified easily13 and are always contaminated by serinol derivatives are used directly
in the following Bradsher cycloaddition.
Three enol ethers were used as dienophiles in cycloadditions, ethylvinyl ether 17, (1Z)-1-
ethoxy hexa-1,5-diene 183 and (9Z)-10-ethoxy-deca-5,9-dien-1-ol 19. Enol ethers 18 and 19 were
selected for further 13-membered ring elaboration either by metathesis3 or by direct intramolec-

9253
Scheme 3.
ular N-alkylation. Enol ether 19 was prepared in a six-step sequence as described in Scheme 4.
Commercially available hex-5-yne-1-ol 20 was alkylated, after protection of the hydroxy group,
with formaldehyde affording compound 21. Lindlar selective reduction of the triple bond gave
rise to the Z alcohol derivative 22. Garegg type substitution afforded in moderate yield the
corresponding iodide derivative 23. Alkylation of 23 with the anion resulting from deprotona-
tion of 3-ethoxy propene 24 was performed under transmetallation reaction conditions which
generally increases both yield and g-selectivity.14 However a 1:3 mixture of a and g regioisomers
25 and 26 was obtained in 80% yield. Deprotection gave rise to enol ether 19 and to its
regioisomer 27. This mixture of isomers was not purified at this stage, as far as enol ether 19 is
the only product which is able to react as dienophile in the following Bradsher cycloaddition
(Scheme 4).
Scheme 4. TBSCl, imid., DMF. (b) MeLi, CH2O, THF. (c) Lindlar, quinoline, H2. (d) PPh3, I2, imid, THF. (e)
secBuLi, BaOTf2, THF, −78°C. (f) TBAF, THF.
The results of the Bradsher cycloadditions between naphthyridinium salts 14, 15 and 16 and
enol ethers 17, 18 and 19 are summarised in Scheme 5 and in Table 1. Surprisingly, cycloaddi-
tion between naphthyridinium salts 14 and dienophile 18 (entry 1) afforded in low yield15 an
adduct which proved to be identical to racemic 4. The possible mechanism of this racemisation
will be discussed below. With naphthyridinium salt 15 (entries 2 and 3) yields were in the same
range and the same lack of selectivity was observed, but two couples of isomeric adducts
28a–28b and 29a–29b were isolated.

9254
Scheme 5.
Table 1
Entry
Diene
Dienophile
Solvants
Time
Adducts
Yield (%)
de (%)
1
2
3
4
5
6
7
8
14
15
15
16
16
16
16
16
18
17
19
18
18
19
19
19
tBuOH:H2O=2:1
H2O
Dioxane:H2O=2:1
CH2Cl2:H2O=2:1+SDS
THF:H2O=2:1
THF:H2O=2:1
CH2Cl2:H2O=2:1+SDS
Dioxane:H2O=2:1
3 days
3 h 30
3 days
6 h
4 days
3 days
1 day
3 days
(9)-4
15
10
18
21
16
46
47
60
0
0
0
70
–
72
75
80
28a+28b
29a+29b
30a+30b
31a+31b
31a+31b
31a+31b
31a+31b
More interesting results were observed with naphthyridinium salt 16 (entries 4–8). The
influence of the mixture of solvents is worthy of note. Rate acceleration was observed in a
biphasic medium (CH2Cl2:H2O) in the presence of SDS (entries 4 and 7), but better yield and
selectivity were obtained in dioxane:H2O with compound 19 as dienophile (entry 8). Enol ether
19 which presents an amphiphilic character16 appeared to be the best dienophile during this
study.
The structures of the adducts were established by chemical correlation17 with the known
1
adduct 43 and by H NMR NOE experiments, as indicated in Scheme 5.
The possible mechanism of racemisation leading to racemic compound 4 (entry 1) could be
explained by two Si–Re and Re–Si cycloadditions between 14 and 18, followed by a nucleophilic
attack of the oxygen protected with PMB group with participation of the aromatic moiety on
the iminium intermediate.18 Hydrolysis of the new intermediate should give rise to two isomeric
adducts 4a and 4c. Adduct 4c would be disfavored by steric hindrance and ring opening of the

9255
oxazolidine moiety could give rise to a more stable 4b enantiomer of 4a (Scheme 5).19 With
naphthyridinium salt 15, oxygen is less nucleophile and the iminium intermediate is trapped by
the free alcohol giving rise to the observed mixture of isomers 28a–28b or 29a–29b. The
selectivity observed with naphthyridinium salt 16 (entries 4–8) could be the result of a
stabilisation of the iminium in this salt by selenium and oxygen lone pairs of electrons in the
conformation 16a which should be less reactive. Conformational equilibrium could give rise to
the more reactive conformation 16b in which cycloaddition is favored leading to the major
observed diastereoisomers 30b or 31b (Scheme 6).
Scheme 6.
The encouraging result obtained in Bradsher cycloaddition with nahthyridinium salt 16 and
enol ether 19 allowed the control of the future asymmetric carbons 13 and 13a in manzamine A
1 by using the antipodal (R)-serine as starting material. However, in this case, the third
asymmetric centre on carbon 20a should be reversed during a further stage of the synthesis.
Acknowledgements
We thank the Ministry of Education for a grant to E.D., CNRS, Universite´ de Paris-sud and
Association pour la Recherche sur le Cancer (ARC) for financial support.
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.