Lewis acid mediated diastereoselective allylation of 3- menthyloxycarbonyl-5,6-dihydropyridin-4-ones

Article abstract of DOI:10.1055/s-1999-2623

Sakurai allylation of menthyl enoates 5a-c afforded adducts 7a-c with low to excellent facial selectivity, depending on the Lewis acid employed to promote this 1,4-nucleophilic addition of allyltrimethylsilane. A chelated model was assumed to explain the

Full text of DOI:10.1055/s-1999-2623

LETTER
405
Lewis Acid Mediated Diastereoselective Allylation of 3-Menthyloxycarbonyl-
5,6-dihydropyridin-4-ones
Sylvie Brocherieux-Lanoy, Hamid Dhimane, Corinne Vanucci-Bacqué, Gérard Lhommet*
Université Pierre et Marie Curie, Laboratoire de Chimie des Hétérocycles, UMR 7611, 4 Place Jussieu, F-75252 Paris Cedex 05, France
Fax 33 (0)1 44 27 30 56; E-mail: lhommet@ccr.jussieu.fr
Received 11 January 1999
Abstract: Sakurai allylation of menthyl enoates 5a-c afforded ad-
ducts 7a-c with low to excellent facial selectivity, depending on the
Lewis acid employed to promote this 1,4-nucleophilic addition of
allyltrimethylsilane. A chelated model was assumed to explain the
observed diastereoselectivity.
Key words: Sakurai allylation, dihydropyridone, stereoselective,
Lewis acid, chiral auxiliaries
Along with our efforts towards the synthesis of enan-
tiopure α-substituted piperidine moieties from naturally
occurring amino acid,1 we are currently investigating a
new access to these structures by means of diastereoselec-
tive reactions using commercially available substrates and
chiral auxiliaries. To this end, we selected conjugate 1,4-
addition on 2,3-dihydro-4-pyridones A (Figure 1) bearing
a menthyloxycarbonyl as the N-protecting group and the
chiral auxiliary. A preliminary study of the Sakurai allyla-
tion of this substrate in the presence of various Lewis ac-
ids and solvents showed almost no facial selectivity,2 as
described recently by Kibayashi et al.3 In order to improve
this selectivity, these authors used more sophisticated
chiral menthyl carbamates. In contrast to this approach,
we decided to introduce the menthyloxycarbonyl group at
the 3-position of the dihydropyridone structures and to in-
vestigate the effect of this substituent on the facial selec-
tivity of the Sakurai allylation of such β-enamino-β-keto
Scheme 1
esters B (Figure 1). Moreover, in view of synthetic appli-
cations, the expected adducts thus obtained are more
prone to regioselective functionalisation than the ana-
logues obtained from dihydropyridone A.
respectively (84-97% yield). Attempts to prepare the di-
hydropyridone 3a by anti elimination starting from α-
chlorinated β-keto ester 2a failed under various condi-
tions,4 probably due to an equatorial orientation of the
chlorine atom. The carbon-carbon double bond introduc-
tion was then performed on β-keto esters 1a-c following
the selenation-oxidative elimination sequence to lead to
compounds 3a-c (46-56% yield). Unfortunately, neither
6
the use of DMAP5 nor of Ti(OiPr)4 as catalysts could pro-
Figure 1
mote the transesterification of ethyl enoates 3a-c to the
corresponding menthyl esters 5a-c. We then envisioned to
As a prelude to this study, we first synthesised the re-
quired dihydropyridones 3b and 5a-c bearing one or two
menthyloxycarbonyl groups at the 1 and/or 3 positions
(Scheme 1). Commercially available 3-carbethoxy-4-pip-
eridone hydrochloride was readily converted to the corre-
sponding benzyl, (+) and (-)-menthyl carbamates 1a-c
obtain 5a-c by a reverse sequence i.e. transesterification
of 1a-c prior to carbon-carbon double bond formation.
The transesterification step proved once again difficult
with the catalysts5, 6 mentioned above which led to 4a-c in
only low yield (30%). However, this reaction proceeded
efficiently (91-96% yield) following the S. Chavan7 con-
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406
S. Brocherieux-Lanoy et al.
LETTER
ditions using the super acid species S.SnO2 as a catalyst
(0.1 eq w/w). Finally, compounds 5a-c were obtained by
selenation/oxidative elimination of 4a-c in 56-82% yield
(Scheme 1).
We next examined the diastereoselectivity of allylations
of substrates 3b and 5a-c in the presence of various Lewis
acids (Scheme 2). Use of SnCl4 resulted in 1,2-addition of
allyltrimethylsilane leading to an unseparable diastereo-
meric mixture8 of homoallylic alcohols, whereas
BF3∑Et2O and TiCl4 promoted the desired 1,4-addition in
good yield9 with complete regioselectivity (Table 1). With
such Lewis acids, allylation of ethyl enoate 3b, protected
as a menthyl carbamate showed, as expected, no improve-
ment in the facial selectivity (d.e.≤14%, entry a), consis-
tently with the result obtained by using the corresponding
simple dihydropyridone A. However, when the menthy-
loxycarbonyl group was located only at the 3-position, as
in benzyl carbamate 5a, we noticed a marked enhance-
ment of the diastereoselectivity (50≤d.e.≤60%, entries b-
c). We then examined the combined effect of two (+)-
menthyloxycarbonyl groups located both at the 1 and 3
positions. When reacted in the presence of BF3∑Et2O, sub-
strate 5b did not lead to noticeable improvement in the di-
astereoselectivity, which is comparable with the one
observed in the case of compound 5a (entry d). Notewor-
thy was the remarkable facial selectivity, which reached
92% d.e. in the presence of 4 eq of TiCl4 (entry e) in the
case of the Sakurai allylation of dihydropyridone 5b.
Moreover, when the substrate beared two menthyl groups
of opposite configuration (5c) a significant drop in diaste-
reoselectivity was observed either with BF3∑Et2O (entries
d, g) or TiCl4 (entries e, h).
Scheme 2
In order to be able to rationalise these results, we had first
to ascertain the absolute configuration of the major ad-
ducts 6 and 7 resulting from the allylation of compounds
3 and 5 in the presence of TiCl4 (4 eq). To this end, we first
decided to convert compound 7b in five steps to the
known alkaloid: N-methylconiine, as depicted in Scheme
3. Transesterification and subsequent decarbomethoxyla-
tion gave the piperidin-4-one derivative 8 in 59% overall
yield. Treatment of the latter with ethanedithiol in the
presence of BF3∑Et2O led to the corresponding dithioketal
(87% yield) which was readily converted to 2-n-propylpi-
peridine 9 under a hydrogen atmosphere in the presence of
Raney nickel (90% yield). Reduction of the carbamate
moiety with LiAlH4 afforded the corresponding N-meth-
ylpiperidine which was isolated as its hydrochloride salt
10 (84% yield from 9). The physical properties of the lat-
ter (mp = 191-192°C, [α]D22 = - 29.5 (c 0.39, EtOH)) were
in good agreement with those reported for the (-)-(R)-N-
methylconiine hydrochloride.3,10 Accordingly, the major
adduct 7b was proved to have an (R) configuration for the
new generated chiral centre α to the nitrogen atom.
Likewise, a similar sequence of reactions, starting from
adduct 7c, allowed an (R) absolute configuration to be as-
signed to the 2-position of the major diastereoisomer 7c.
Synlett 1999, No. 4, 405–408 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER Lewis Acid Mediated Diastereoselective Allylation of 3-Menthyloxycarbonyl-5,6-dihydropyridin-4-ones
407
Scheme 3
On the other hand, decarbethoxylation of compound 6b
(DMSO, H2O, NaCl) led to a mixture of piperidin-4-ones,
in which the major isomer was epimer 8. Finally, major
isomer of 7a was also shown11 to have an (R) configura-
tion for the new chiral centre.
Taking into account all these results, we suggest a model
susceptible to rationalising the observed facial selectivi-
ties (Scheme 4). Both the nature and the amount of Lewis
acid are crucial for the conversion and the diastereoselec-
Scheme 4
tivity (Table 1). As depicted in Scheme 4, more than one
equivalent of Lewis acid is indeed required to coordinate
both the carbamate and the β-keto ester moieties (entry f).
On the other hand, the use of a bidentate Lewis acid
References and notes
(TiCl4) noticeably increases the diastereoselectivity com-
pared with that obtained with monodentate BF3∑Et2O.12
(1) David, M.; Dhimane, H.; Vanucci-Bacqué, C.; Lhommet, G.
Synlett 1998, 206.
Moreover, we assume an s-cis conformation for both
menthyloxycarbonyl groups. In conformer II which is
favoured due to the steric hindrance between these
groups,13 the N-chiral auxiliary is moved away from the
reactive centre. Therefore, in the case of menthyl enoates
5b-c, the main chiral induction is due to the 3-menthylox-
ycarbonyl moiety. Indeed, the allytrimethylsilane ap-
proach takes place preferentially anti to the isopropyl
substituent of the menthyl ester (Scheme 4). Such a direct-
ing role of the menthyloxycarbonyl group at the 1-posi-
tion is also effective, but to a lesser extend due to its
remoteness from the electrophilic centre (entry a). How-
ever, when both 1,3-menthyloxycarbonyl groups of the
same configuration are present, a synergy was observed
leading to allylation compounds with a high facial selec-
tivity (entry e).
(2) Brocherieux-Lanoy, S. PhD Thesis of Université de Paris VI,
4 July 1997.
(3) Sato, M.; Aoyagi, S.; Yago, S.; Kibayashi, C. Tetrahedron
Lett. 1996, 37, 9063.
(4) Treatment of 2a by N,N-dimethylaniline, pyridine or DBU did
not affect the starting material.
(5) Taber, D. F.; Amedio, J. C.; Gulino, F. J. Org. Chem. 1989,
54, 3474.
(6) Seebach, E.; Hungerbühler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Züger, M. Synthesis 1982, 138.
(7) Chavan, S. P.; Zubaidha, P. S.; Dantale, S. W.; Ravindra-
nathan T.; Keshavaraja, A.; Ramaswamy, A. V. Tetrahedron
Lett. 1996, 37, 233.
(8) The diastereoselectivity of the obtained adducts is not yet
ascertained.
(9) Typical procedure for Sakurai allylations : Preparation of 7b.
Compound 5b (1.65g, 3.57 mmol) and allyltrimethylsilane
(2.3 mL, 14.47 mmol) were dissolved in CH2Cl2 (50 mL) at –
78°C under argon atmosphere. Titanium tetrachloride (1.57
mL, 14.3 mmol) was added dropwise via syringe. The reaction
mixture was allowed to warm to – 10°C over 3 hours, then
quenched with an aqueous suspension of NaHCO3 (10 g, 119
mmol in 10 mL of H2O). After warming to room temperature,
water (50 mL) was added and the aqueous layer was extracted
with CH2Cl2 (3 x 100 mL). The combined organic layers were
washed with water (50 mL) and dried over Na2SO4. Evapora-
tion under vacuum gave a yellow oil which was purified by
column chromatography using AcOEt-Cyclohexane (1:4) as
eluent giving pure diastereomeric mixture 7b as a colourless
oil (1.65 g, 92%); IR (neat) 1710, 1680 cm-1 ; 1H NMR (To-
In conclusion, we have devised a dihydropyridone Mich-
ael acceptor 5b bearing simple chiral auxiliaries, which
undergoes Sakurai allylation with modest to excellent di-
astereoselectivity, depending on the Lewis acid used as
the catalyst. Further efforts towards the application of
these results to the total synthesis of naturally occurring
alkaloids are currently under investigation in our Labora-
tory.
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408
S. Brocherieux-Lanoy et al.
LETTER
luene-d8, 250 MHz, 373 K) δ (ppm) : 0.8-1.1 (m, 26H), 1.25-
1.7 (m, 7H), 1.9-2.2 (m, 4H), 2.25-2.55 (m, 2H), 2.55-2.7 (m,
1H), 2.92-3.1 (m, 1H), 4.1-4.25 (m, 1H), 4.78 (td, J = 10.7 and
4.4 Hz, 1H), 4.91 (td, J = 10.7 and 4.4 Hz, 1H), 4.95-5.15 (m,
2H), 5.2-5.35 (m, 1H), 5.85-6.05 (m, 1H), 12.74 and 12.83 (2s,
1H); 13C NMR (Toluene-d8, 62.5 MHz, 373 K) δ (ppm) :
17.05, 17.61, 20.95, 21.13, 22.15, 22.30, 24.59, 25.07, 27.24,
27.74, 28.93, 32.93, 34.93, 35.26, 36.21, 39.55, 41.74, 42.34,
48.25, 48.62, 50.14, 75.49, 75.75, 101.61, 116.50, 136.28,
155.16, 170.93, 171.91; Analysis calcd. for C30H49NO5; C
71.53, H 9.80, N 2.78 ; found C 71.66, H 9.91, N 2.73.
(11) When the reaction mixture of 7a (entry c) was quenched at r.t.
with water, debenzyloxycarbonylation took easily place lead-
ing to the corresponding free amine. The latter was then con-
verted to the (+)-menthyl carbamate 7b, thus allowing the cor-
relation with compound obtained from substrate 5b.
(12) However, Maruaka and coworkers reported recently some ex-
amples of pentacoordinate chelates of boron Lewis acid
(B(C6F5)3). Ooi, T.; Uragushi, D.; Kagoshima, N.; Maruaka,
K. J. Am. Chem. Soc. 1998, 120, 5727.
(13) Similar conformation for the carbamate moiety has been ass-
umed in the case of 1-(8-phenylmenthyl)oxycarbonyl-3-triiso-
propylsilylpyridinium salts derivatives by D. Comins et al:
Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem.
Soc. 1994, 116, 4719.
(10) (a) Lukes, R.; Smetackova, M. M. Collect. Czech. Chem.
Commun. 1934, 6, 231. (b) Comins, D. L.; Hong, H.; Salva-
dor, J. M. J Org. Chem. 1991, 56, 7197.
Synlett 1999, No. 4, 405–408 ISSN 0936-5214 © Thieme Stuttgart · New York