Control of diastereofacial discrimination in the conjugate addition to 5-phenyl-1,3-dioxolan-4-yl substituted propenoate

Article abstract of DOI:10.1016/S0957-4166(00)00353-0

The conjugate addition of methylcuprates and methyllithium to ethyl 5-phenyl-1,3-dioxolan-4-yl-2-propenoate was investigated. It was found that the stereoselectivity is highly dependent on the reagent used. In reactions with stabilized methylcuprates, the

Full text of DOI:10.1016/S0957-4166(00)00353-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3849–3853
Control of diastereofacial discrimination in the conjugate
addition to 5-phenyl-1,3-dioxolan-4-yl substituted
propenoate
Arvydas Stoncˇius,† Christian Alexander Mast and Norbert Sewald*
Organic and Bioorganic Chemistry, Faculty of Chemistry, University of Bielefeld, PO Box 100131,
D-33501 Bielefeld, Germany
Received 23 August 2000; accepted 1 September 2000
Abstract
The conjugate addition of methylcuprates and methyllithium to ethyl 5-phenyl-1,3-dioxolan-4-yl-2-
propenoate was investigated. It was found that the stereoselectivity is highly dependent on the reagent
used. In reactions with stabilized methylcuprates, the anti-1,4-addition product is mainly formed, whereas
syn-diastereoselectivity is observed in the reaction with methyllithium. Additions of methyllithium were
optimized with respect to solvent and additives. © 2000 Elsevier Science Ltd. All rights reserved.
The asymmetric conjugate addition of carbon nucleophiles is an important method for the
formation of carbonꢀcarbon bonds and plays an important role in the synthesis of natural
products.1 However, the divergent results regarding the diastereoselectivity of addition reactions
e.g. to g-alkoxy substituted enoates, render the interpretation and prediction of the stereochem-
ical outcome difficult. Alkyl or silyl substituents on the g-oxygen modulate the electron donor
capability of this group and, consequently, change the reaction pathway from a chelated to a
non-chelated transition state.2,3
A different situation may occur when the g-alkoxy group is incorporated into a dioxolane
ring.4 We found predominant syn-selectivity upon addition of chiral secondary lithium amides
to dioxolan-4-yl substituted E-configured enoates.5 The diastereoselective conjugate addition of
organolithium and organocopper reagents to glyceraldehyde-derived a,b-unsaturated ketones
and esters has been examined by Leonard et al.6 While alkyl and vinyllithium compounds yield
mainly syn-1,4-adducts with dioxolan-4-yl substituted E-configured enoates, extensive decompo-
sition is reported for additions of organocopper reagents to a,b-unsaturated esters.
* Corresponding author. E-mail: norbert.sewald@uni-bielefeld.de
†
Permanent address: University of Vilnius, Department of Organic Chemistry, Naugarduko 24, LT-2006 Vilnius,
Lithuania.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00353-0

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We examined the diastereoselectivity of the 1,4-addition of methyllithium and several methyl-
copper reagents to ethyl (2E)-3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]-2-propenoate
2 (Scheme 2) and found a profound difference in the diastereofacial discrimination among the
organometallic reagents used. Enantiomerically pure 2 was prepared by asymmetric
dihydroxylation7 of dienoate 1,8 subsequent protection of the diol mixture and chromatographic
separation of the regioisomers 2 and 3 (Scheme 1).
Scheme 1. (i) (DHQD)2–PHAL (1.0 mol%), K2OsO4·2H2O (1.0 mol%), K3[Fe(CN)6], K2CO3, MeSO2NH2, t-BuOH/
H2O (1:1, v:v), 0°C; (ii) (MeO)2CMe2/Me2CO (1:1, v:v), p-TosOH, rt
Scheme 2. (i) Reagents see Table 1
Initially various methylcopper reagents—reagents of choice in a similar synthesis11—were
generated from methyllithium and reacted with enoate 2 (Table 1, entries 1–4). The relative
configurations of the 1,4-addition products (4-anti, 5-syn) were assigned by NOE-DIFF experi-
ments with the corresponding g-lactones (Scheme 3). In lactone 6, derived from anti-addition
product 4, an enhancement was observed between the methyl group and H-5, and correspond-
ingly no enhancement between methyl and benzylic protons was detected. In lactone 7, derived
from syn-addition product 5, a significant enhancement between the methyl group and the
benzylic proton was observed, whereas no enhancement between the methyl group and H-5 was
detected.

A. Stoncˇius et al. / Tetrahedron: Asymmetry 11 (2000) 3849–3853
3851
Table 1
Selected results of enoate 2 reactions with methylcopper reagents and methyllithium
No.
Reagent
Solvent
Temperature
(°C)
4:5
Yield of main
isomer (%)
1
29
3
4
5
6
7
8
9
MeCu(CN)Li/BF3·Et2O, 5 eq.
Me2CuLi/Me3SiCl, 1.5 eq.
Me2CuLi·PBu3, 2 eq.
Me2CuLi, 2.5 eq.
MeLi, 1.1 eq.
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
−78
−78
−78
−78
−78
−78
−78
−78
−78
38:1
7:1
2:1
1.9:1
B1:99
B1:99
B1:99
B1:99
B1:99
60a
72b
57a
65a
29a
MeLi, 1.5 eq.
24a
MeLi, 1.5 eq., Me3SiCl, 1.5 eq.c
MeLi, 1.2 eq., Me3SiCl, 1.2 eq.c
55
76 (\85a)
53
MeLi, 2.0 eq., Me3SiCl, 3.0 eq.d Et2O
10
MeLi, 1.2 eq., Me3SiCl, 2.0 eq.d t-BuOMe:Et2O (32:1, v/v) −78
B1:99
46 (51e)
69 (76e)
1110 MeLi, 1.3 eq., Me3SiCl, 2.0 eq.d Hexane:Et2O (4:1, v/v)
−90 to −80 B1:99
a According to GC–MS data.
b ꢀ86% d.e.
c Stepwise, alternating addition of MeLi and Me3SiCl.
d Me3SiCl was added to the reaction mixture before MeLi addition.
1
e According to H NMR data.
Scheme 3.
Mainly 1,4-addition products were formed with organocuprates in moderate to high anti-
selectivity, especially when a Lewis acid or Me3SiCl stabilized methylcopper reagent was used.
The addition of 5 eq. of MeCu(CN)Li/BF3·Et2O leads to diastereomerically pure 4, although a
substantial amount of starting material was detected even after 20 h of reaction time. The
reaction of 2 with 1.5 eq. of Me2CuLi/Me3SiCl proceeds smoothly with satisfactory yield. The
diastereoselectivity of the reaction with PBu3 stabilized methyl cuprate reagent (Me2CuLi) was
found to be similar to that of the reaction with Me2CuLi, although in the presence of PBu3
formation of 1,2-addition and double 1,2-addition products was detected.
Addition of Lewis acid stabilized methylcopper reagents leads to the anti-1,4-addition product
and possibly proceeds due to specific coordination of the copper. In order to change the
character of the coordination, we investigated the addition of methyllithium to 2. Satisfactory
results have been obtained upon addition of methyllithium to similar systems.6 The syn- and the
1,4-selectivity of the methyllithium addition to (2,2-dimethyl-1,3-dioxolan-4-yl)propenoates was
explained by coordination of the lithium atom to the oxygen atoms of the dioxolane ring.

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A. Stoncˇius et al. / Tetrahedron: Asymmetry 11 (2000) 3849–3853
Our first experiments of methyllithium addition to enoate 2 (Table 1, entries 5 and 6) showed
that the reaction is completely syn-selective, although disappointing in terms of both regioselec-
tivity and yield. Significant amounts of 1,2-addition, double 1,2-addition, 1,2-/1,4-addition
products were formed and considerable amounts of starting material were detected. The
repeated stepwise addition of MeLi and Me3SiCl significantly increased the formation of 5
(Table 1, entry 8). In this procedure only a part (1/4) of the complete quantity of MeLi was
added at once, where each addition step was followed by the addition of the equivalent quantity
of Me3SiCl. However, this procedure was too complicated for synthetic purposes. Our investiga-
tions showed that methyllithium preferably reacts with enoate 2 instead of Me3SiCl at the
reaction temperature (5−78°C) and nearly the same yield of 5 was obtained when Me3SiCl was
added before methyllithium. We also attempted to optimize the yield of syn-selective methyl-
lithium addition to 2 by reducing the coordinative capability of the solvent and by varying the
amount of Me3SiCl (Table 1, entries 9–11). Using t-BuOMe (entry 10) as the solvent leads to
nearly the same result as diethyl ether.12 Compound 5 was obtained in good yield using a
hexane/Et2O-mixture as solvent in the presence of Me3SiCl (Table 1, entry 11). Application of
a non-coordinating solvent enhances the coordinating influence of the dioxolane oxygen atoms
as 1,4-addition directing factor.
In conclusion, the addition of methylcopper reagents to 2 results in the formation of
anti-1,4-addition product 4 with medium to high diastereoselectivity. The syn-1,4-addition
product 5 was obtained exclusively by addition of MeLi to 2.
Acknowledgements
This project was funded by the Saxonian Ministry of Science and Culture, Dresden, by
Deutsche Forschungsgemeinschaft, Bonn (visiting grants to A.S.) and Fonds der Chemischen
Industrie, Frankfurt/Main, which are gratefully acknowledged.
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dried over MgSO4 and evaporated. The residue was chromatographed, hexanes:EtOAc (8:1, v/v) and CHCl3 with
1
2% of EtOAc to give 0.21 g (72%) of 4 (ꢀ86% d.e.). [h]2D8 −0.95 (c 4.2, CHCl3). H NMR (CDCl3): 0.86 (d, 6.8,

A. Stoncˇius et al. / Tetrahedron: Asymmetry 11 (2000) 3849–3853
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3H), 1.25 (t, 7.1, 3H), 1.47 (s, 3H), 1.53 (s, 3H), 2.15 (dd, 15.0, 8.8, 1H), 2.32 (m, 1H), 2.62 (dd, 15.0, 4.0, 1H),
3.77 (dd, 8.3, 5.8, 1H), 4.15 (q, 7.1, 2H), 4.68 (d, 8.2, 1H), 7.20–7.50 (m, 5H).
10. A solution of MeLi (4.43 mmol, 2.77 ml of 1.6 M solution in ether diluted with 6 ml of ether and 5 ml of
n-hexane) was added dropwise over 2.5 h to a stirred solution of 2 (3.41 mmol, 0.94 g) and Me3SiCl (6.81 mmol,
0.74 g, 0.86 ml) in 28 ml of n-hexane at −80 to −90°C. The mixture was stirred for 4 h at −78°C, slowly warmed
up to rt and treated with satd NH4Cl solution (40 ml). All precipitated salts were dissolved by dilution with
water, the phases were separated and the aqueous layer was extracted with n-hexane (4×40 ml). Combined
organic extracts were dried over a mixture of solid NaHCO3 and Na2SO4. Evaporation of the solvent and flash
1
chromatography (hexanes:EtOAc=8:1, v/v) gave 0.69 g (69%) of 5. [h]2D8 +3.3 (c 5.5, CHCl3). H NMR (CDCl3):
1.03 (d, 6.6, 3H), 1.18 (t, 7.1, 3H), 1.48 (s, 3H), 1.54 (s, 3H), 2.19 (dd, 14.8, 9.1, 1H), 2.28 (m, 1H), 2.38 (dd, 14.5,
4.4, 1H), 3.80 (dd, 8.6, 3.3, 1H), 4.07 (q, 7.1, 2H), 4.72 (d, 8.6, 1H), 7.20–7.50 (m, 5H).
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12. 1,2-Addition took place exclusively when THF was used as solvent (not presented in Table 1).
.
.