Regio- and diastereochemical aspects of the additions of Li or Zn derivatives of methoxypropene to oxazolidines derived from phenylglycinol

Article abstract of DOI:10.1055/s-2006-948167

Diastereoselective additions of methoxypropene-derived lithium and zinc reagents to oxazolidines are investigated. The lithium allylic carbanion reacts with oxazolidines to afford mainly the β-amino alcohols with an enol ether function (γ-adduct) and the

Full text of DOI:10.1055/s-2006-948167

LETTER
1855
Regio- and Diastereochemical Aspects of the Additions of Li or Zn Derivatives
of Methoxypropene to Oxazolidines Derived from Phenylglycinol
A
dditions
e
of
L
i
or
Z
n
a
D
erivative
n
s
of Methoxy
n
propene to O
e
xazolidines Alladoum, Sylvain Roland, Emmanuel Vrancken, Catherine Kadouri-Puchot,* Pierre Mangeney*
Université Pierre et Marie Curie-Paris 6, Laboratoire de Chimie Organique UMR 7611, Institut de Chimie Moléculaire FR 2769,
4 Place Jussieu, Case Courrier 47, 75005 Paris, France
E-mail: kadouri@ccr.jussieu.fr; E-mail: mangeney@ccr.jussieu.fr
Received 29 March 2006
As part of a program aimed at emphasizing the efficiency
Abstract: Diastereoselective additions of methoxypropene-derived
of asymmetric syntheses of enantiopure cyclic amino
lithium and zinc reagents to oxazolidines are investigated. The
lithium allylic carbanion reacts with oxazolidines to afford mainly
the b-amino alcohols with an enol ether function (g-adduct) and the
zinc derivative leads to amino alcohols with an allyl ether function
(a-adduct).
acids9 and azaheterocycles10 from new b-amino alcohols,
we decided to investigate this topic.
The starting oxazolidines 2 (R = n-Pr, i-Pr, t-Bu) or
imines 3 (R = Ph, PhCH=CH) were obtained quantita-
tively by mixing (S)-phenylglycinol with the correspond-
ing aldehydes at room temperature in the presence of
MgSO4. The reactions were monitored by NMR and the
crude materials were used, after filtration and evapora-
tion. As already reported, unsaturated aldehydes yielded
the corresponding imines 3. The imine resulting from the
use of cinnamaldehyde was found to be crystalline and
therefore was purified in this manner.
Key words: oxazolidine, methoxypropene, organolithium and
organozinc reagents, b-amino alcohols
The addition of metallated 1-alkoxy-2-propenes 1 to
prochiral electrophiles such as aldehydes or imines is an
attractive way for the construction of highly valuable in-
termediates in organic synthesis. Indeed, depending on
the regioselectivity of their addition, they can give access
either to the corresponding enol ethers 6 (g-adducts) or
allyl ethers 7 (a-adducts) with the formation of one or two
stereogenic centers.1 If the addition of this type of organo-
metallic reagent to aldehydes has received a considerable
attention,2 little work on the related additions of such sub-
stituted reagents to imines has been reported in the
literature.3–5 Similarly, if the addition of allylic organo-
metallic reagents to imines6,7 or oxazolidines derived
from phenylglycinol8,4b,4c is well documented, there is no
report, to our knowledge, on the use of a-alkoxyallyl
organometallics on these compounds. Such reactions
could lead to synthetically useful amino alcohols 4 or 5
(Scheme 1).
The methyl allyl ether 1 (R¢ = Me) was easily metallated
at –78 °C by s-BuLi in THF. Subsequent addition of the
oxazolidines 2 or imines 3 to this organolithium derivative
afforded a mixture of b-amino alcohols 4a–e (major iso-
mer) and 5a–e (minor isomer). These reactions occurred
with high regio- and diastereoselectivity (see Scheme 2,
conditions a, and Table 1).11
OH
NH
OH
NH
1) conditions
a or b
OMe
Ph
+
Ph
3
2) 2 or 3
R
R
OMe
OMe
5a–e
4a–e
Scheme 2 Reagents and conditions: (a) s-BuLi (3 equiv), THF,
–78 °C; (b) s-BuLi (3 equiv), ZnBr2 (3 equiv), THF, –78 °C to r.t.
α
OR'
γ
OH
1
X
*
Ph
NH
*
O
R"
OR'
R
R
R
OR'
OR'
N
H
M
Ph
or
6 γ-adduct
4 γ-adduct
X
R''
2
A
OH
X = O
or NR"
OH
N
X
*
Ph
NH
*
Ph
R'O
M
*
R"
*
R
3
B
OR'
OR'
7 α-adduct
5 α-adduct
Scheme 1 Reactivity of metallated allylethers with electrophiles
SYNLETT 2006, No. 12, pp 1855–1858
0
1
.0
8
.2
0
0
6
Advanced online publication: 24.07.2006
DOI: 10.1055/s-2006-948167; Art ID: D09406ST
© Georg Thieme Verlag Stuttgart · New York

1856
J. Alladoum et al.
LETTER
Table 1 Reactions of the Methyl Allyl Ether Lithium Derivative
with Compounds 2 and 3
product 5a (R = n-Pr). The absolute configuration of the
two new stereogenic centers was determined by X-ray
analyses16 of compound 5d17 and of the hydrochloride
salts of 5b and 5c.18 As depicted in Figure 2, use of imine
3 (R = Ph) resulted in the formation of a syn-adduct 5d;
whereas an anti-selectivity was observed when oxazo-
lidines 2 (R = i-Pr or t-Bu) were used to afford amino
alcohols 5b and 5c.
Entry
R
4a–e
4a
Yield (%)a 4:5b
dr of 4b
>95:5
>95:5
>95:5
91:9
1
2
3
4
5
n-Pr
i-Pr
40
62
55
67
40
84:16
4b
4c
91:9
93:7
91:9
95:5
t-Bu
Ph
4d
4e
OH
OH
S
Cinnamyl
>95:5
S
Ph
NH
R
Ph
NH
a Isolated yield of 4a–e.
b Determined by 1H NMR of the crude product.
R
R
S
Ph
R
OMe
5d
OMe
5b (R = i-Pr)
5c (R = t-Bu)
As shown in the Table 1, in all cases, the major regio-
isomer was the g-adduct 4 obtained with an acceptable
isolated yield. Curiously, the poorest regioselectivity was
observed with the linear substituent n-Pr (entry 1). The di-
Figure 2
According to the general behavior of these organometallic
species, the difference of regioselectivity observed
between the Li and the Zn derivatives is not surprising.19
Indeed Li alkoxyallyl reagents are reported generally to
react with carbonyl compounds to give mainly the g-ad-
ducts when their Zn analogues usually react at the a-posi-
tion (Scheme 3).2b
1
astereomeric purity of the g-adducts, measured by H
NMR analysis of the crude product, was found to be good
to excellent. The configuration of the new stereogenic
center and the stereochemistry of the double bond was de-
termined from compound 4d (R = Ph)12 by X-ray analysis
and found to be respectively S and Z (Figure 1).13 We
assume the same configuration for all compounds 4.14
Br
Li
Zn
OH
s-BuLi
1) s-BuLi
OMe
OMe
OMe
S
H
2) ZnBr2
Ph
NH
S
Z
8
1
9
Ph
OMe
4d
γ-adduct
α-adduct
Figure 1
Scheme 3
In a second set of experiments the above reactions were
performed using the zinc reagent, prepared by transmetal-
lation of the corresponding lithium derivative by ZnBr2
(Scheme 2, conditions b). The results obtained are report-
ed in Table 2.15
The configuration of the newly created stereogenic center
in the enol ether derivatives 4 can be assumed to be the re-
sult of a cyclic transition state C (Scheme 4) involving a
metallic species 8 where the Li is located at the a-position
relative to the OMe group. In such a transition state, due
to chelation, this group is in axial position. Accordingly,
the Li species, in a cisoid conformation, adds on the less
hindered face of the E-imine 10. The addition involves the
participation of a chiral Li derivative, which is probably
configurationally unstable.20
Table 2 Reactions of the Methyl Allyl Ether Zinc Derivative with
Compounds 2 and 3
Entry
R
5a–e
5a
Yield (%)a 4:5b
dr of 5b
70:30
95:5
1
2
3
4
n-Pr
i-Pr
t-Bu
Ph
40
58
70
69
>3:97
5b
4:96
>3:97
>3:97
H
S
Ph
OM
N
OH
5c
>95:5
96:4
Li
8
+
O
Li
O
N
R
Ph
5d
S
Ph
NH
R
H
H
a Isolated yield of 5a–d.
b Determined by 1H NMR of the crude product.
Z
R
OMe
R
H
10 (M = Li)
C
4
Scheme 4
Under these conditions, compounds 5a–d, resulting from
an attack of the organozinc reagent at the a-position, were
obtained with moderate to good yields. In three cases, the
reaction was totally regioselective and occurred with a
satisfactory diastereoselectivity, except in the case of
The stereoselection observed with the zinc derivative is
more difficult to rationalize. In the cases where R is an
alkyl group, it can be rationalized by a chair-like transition
state, in which the steric interactions between the R and
Synlett 2006, No. 12, 1855–1858 © Thieme Stuttgart · New York

LETTER
Additions of Li or Zn Derivatives of Methoxypropene to Oxazolidines
1857
Cabal, M.-P.; Turos, E. Organometallics 1995, 14, 4697.
(d) Fiorelli, C.; Maini, L.; Martelli, G.; Savoia, D.; Zazzeta,
C. Tetrahedron 2002, 58, 8679.
the OMe groups are minimized. The attack, involving a
metallic species 9 (Scheme 3) with the zinc located in g-
position and an enol ether in a Z-configuration occurs on
the less hindered face of the E-imine, according to transi-
tion state D (Scheme 5). With R = Ph, different electronic
and/or steric interactions must be taken into account.
Mechanistic studies are currently underway to rationalize
these contrasting results.
(4) For examples of addition of silylated allylmetals to imines,
see: (a) Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1991, 56,
365. (b) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org.
Chem. 2002, 67, 1496. (c) Agami, C.; Comesse, S.;
Kadouri-Puchot, C. J. Org. Chem. 2000, 65, 4435.
(5) For examples of addition of sulfonimidoyl allylmetals to
imines, see: Schleusner, M.; Gais, H.-J.; Koep, S.; Raabe, G.
J. Am. Chem. Soc. 2002, 124, 7789.
(6) For reviews, see: (a) Block, R. Chem. Rev. 1998, 98, 1407.
(b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1987,
8, 1895. (c) Alvaro, G.; Savoia, D. Synlett 2002, 651; and
references cited therein.
(7) (a) For a review, see: Ding, H.; Friestad, G. K. Synthesis
2005, 2815. For recent examples of addition of allylmetals
to imines, see: (b) Bandini, M.; Cozzi, P. G.; Umami-
Ronchi, A.; Villa, M. Tetrahedron 1999, 55, 8103. (c) Van
der Sluis, M.; Dalmolen, J.; de Lange, B.; Kaptein, B.;
Kellogg, R. M.; Broxterman, Q. B. Org. Lett. 2001, 3, 3943.
(d) Lee, C.-L. K.; Ling, H. Y.; Loh, T.-P. J. Org. Chem.
2004, 69, 7787. (e) Badorrey, R.; Cativiela, C.; Diàz-de-
Villegas, M. D.; Diez, R.; Gàlvez, J. A. Eur. J. Org. Chem.
2002, 3763. (f) Okamoto, S.; Fukuhara, K.; Sato, F.
Tetrahedron Lett. 2000, 41, 5561. (g) Gastner, T.; Ishitani,
H.; Akiyama, R.; Kobyashi, S. Angew. Chem. Int. Ed. 2001,
1897. (h) Koriyama, Y.; Nozawa, A.; Hayakawa, R.;
Shimizu, M. Tetrahedron 2002, 58, 9621. (i) Miniejew, C.;
Outurquin, F.; Pannecoucke, X. Tetrahedron 2005, 61, 447.
(8) For examples of addition of allylmetals to oxazolidines, see:
(a) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada,
T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464.
H
O
S
Ph
OH
OM
N
+
9
MeO
N
R
Ph
S
Ph
NH
M
H
R
S
R
R
OMe
5
D
10 M = ZnBr
R = alkyl
Scheme 5
In conclusion, by addition of Li or Zn reagents of methyl
allyl ether to oxazolidines (or imines) derived from phen-
ylglycinol, it is possible to prepare selectively the corre-
sponding a- or g-adducts with a good diastereoselectivity.
Work is in progress to extend this methodology to the
preparation of other substituted b-amino alcohols and to
use them in the asymmetric synthesis of functionalized
heterocycles.
Acknowledgment
(b) Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T.
Tetrahedron Lett. 2002, 43, 2827. (c) Allin, S. M.; Button,
M. A. C.; Baird, R. D. Synlett 1998, 1117. (d) Legros, J.;
Meyer, F.; Coliboeuf, M.; Crousse, B.; Bonnet-Delpon, D.;
Bégué, J.-P. J. Org. Chem. 2003, 68, 6446.
We thank Dr. Boubekeur and Dr. Herson for X-ray analyses of
compounds 4 (R = Ph), 5 (R = Ph) and 5 (R = i-Pr).
References and Notes
(9) (a) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org.
Chem. 2002, 67, 2424. (b) Agami, C.; Comesse, S.; Guesné,
S.; Kadouri-Puchot, C.; Martinon, L. Synlett 2003, 1058.
(10) LemadTalancé, V.; Banide, E.; Bertin, B.; Comesse, S.;
Kadouri-Puchot, C. Tetrahedron Lett. 2005, 46, 8023.
(11) Typical Procedure for the Synthesis of Compounds 4.
s-BuLi (1.3 M in hexane–cyclohexane, 5.2 mL, 6.8 mmol)
was added at –78 °C to a solution of allyl methyl ether (0.60
mL, 6.4 mmol) in THF (10 mL). After stirring for 30 min at
–78 °C a solution of oxazolidine (2 mmol) in THF (10 mL)
was added dropwise. After the reaction was complete, the
mixture was quenched at –78 °C by addition of sat. aq
NH4Cl (15 mL). The aqueous layer was extracted with Et2O
(3 × 15 mL) and the organic layers were combined, dried
over MgSO4 and evaporated. The residue was then purified
by chromatography on silica gel.
(12) Data for Compound 4d (R = Ph): [2S,2 (1S)]-2-(4-
Methoxy-1-phenylbut-3-enylamino)-2-phenylethanol.
Solid, yield 67%; mp 63 °C; [a]D20 +37 (c 1.1, CHCl3). 1H
NMR: d = 7.33–7.20 (m, 10 H), 5.92 (dt, J = 6.3, 1.3 Hz,
1 H), 4.24 (dd, J = 7.3, 6.3 Hz, 1 H), 3.92 (dd, J = 7.1, 4.6
Hz, 1 H), 3.77 (dd, J = 10.6, 4.6 Hz, 1 H), 3.70 (t, J = 6.4 Hz,
1 H), 3.56 (s, 3 H), 3.53 (dd, J = 10.6, 7.3 Hz, 1 H), 2.9
(br d, 1 H), 2.62–2.45 (m, 2 H), 1.78 (ls, 1 H). 13C NMR:
147.7, 144.0, 141.4, 128.5, 128.2, 127.4, 127.1, 127.0,
126.9, 102.5, 65.7, 61.3, 59.6, 59.5, 31.0. IR (CHCl3): 3374,
3031, 2856, 1660, 1109 cm–1. Anal. Calcd for C19H23NO2: C,
76.73; H, 7.80; N, 4.71. Found: C, 76.60; H, 7.83; N, 4.69.
(1) For reviews, see: (a) Werstiuk, N. H. Tetrahedron 1983, 39,
205. (b) Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E.
Chem. Rev. 1999, 99, 665. (c) For a review on
alkoxyallylstannane, see: Marshall, J. A. Chem. Rev. 1996,
96, 31.
(2) For the synthesis and reactivity of metallated allylic ethers,
see for example: (a) Brown, H. C.; Jadhav, P. K.; Bhat, K. S.
J. Am. Chem. Soc. 1988, 110, 1535. (b) Evans, D. A.;
Andrews, G. C.; Buckwalter, B. J. Am. Chem. Soc. 1974, 96,
5560. (c) Still, W. C.; Macdonald, T. L. J. Org. Chem. 1976,
41, 3620. (d) Yamamoto, Y.; Yatagai, H.; Saito, Y.;
Maruyama, K. J. Org. Chem. 1984, 49, 1096.
(e) Yamamoto, Y.; Saito, Y.; Maruyama, K. J. Organomet.
Chem. 1985, 292, 311. (f) Wuts, P. G. M.; Bigelow, S. S. J.
Org. Chem. 1982, 47, 2498. (g) Zschage, O.; Hoppe, D.
Tetrahedron 1992, 48, 5657. (h) Paulsen, H.; Graeve, C.;
Hoppe, D. Synthesis 1996, 141. (i) Paulsen, H.; Graeve, C.;
Fröhlich, R.; Hoppe, D. Synthesis 1996, 145. (j) Berrien, J.-
F.; Raymond, M.-N.; Moskowitz, H.; Mayrargue, J.
Tetrahedron Lett. 1999, 40, 1313. (k) Ferreira, F.; Herse,
C.; Riguet, E.; Normant, J. F. Tetrahedron Lett. 2000, 41,
1733.
(3) For examples of addition of oxygenated allylmetals to
imines, see: (a) Keinicke, L.; Fristrup, P.; Norrby, P.-O.;
Madsen, R. J. Am. Chem. Soc. 2005, 127, 15756.
(b) Marshall, J. A.; Gill, K.; Seletsky, B. M. Angew. Chem.
Int. Ed. 2000, 953. (c) Jiang, S.; Agoston, G. E.; Chen, T.;
Synlett 2006, No. 12, 1855–1858 © Thieme Stuttgart · New York

1858
J. Alladoum et al.
LETTER
(17) Data for Compound 5d (R = Ph): [2S,2 (2S,1S)]-2-(2-
(13) Atomic coordinates, bond lengths and angles, and thermal
parameters have been deposited at the Cambridge
Crystallographic Data Centre with the deposition number
CCDC 293382.
(14) This stereochemical outcome is well established for the
attack of organometallic reagents onto phenylglycinol-
derived oxazolidines, see, ref. 4b and 6a.
(15) Typical Procedure for the Synthesis of Compounds 5.
s-BuLi (1.3 M in hexane–cyclohexane, 5.2 mL, 6.8 mmol)
was added at –78 °C to a solution of allyl methyl ether (0.60
mL, 6.4 mmol) in THF (10 mL). After stirring for 30 min at
–78 °C, a solution of zinc bromide (1 M in THF, 7.2 mL, 7.2
mmol) was added. The mixture was stirred at –78 °C for 40
min and then a solution of oxazolidine (2 mmol) in THF (10
mL) was added dropwise. After completion, the mixture was
quenched (at –78 °C for 5a and 5d and at r.t. for 5b and 5c)
by addition of sat. aq NH4Cl (20 mL). The aqueous layer was
extracted with Et2O (3 × 20 mL) and the organic layers were
combined, dried over MgSO4 and evaporated. The residue
was purified by chromatography on silica gel.
Methoxy-1-phenylbut-3-enylamino)-2-phenylethanol.
Solid, yield 69%; mp 58 °C; [a]D20 +38 (c 1.1, CHCl3). 1H
NMR: d = 7.32–7.22 (m, 10 H), 5.62–5.54 (m, 1 H), 5.28–
5.20 (m, 2 H), 3.89–3.79 (m, 4 H), 3.61–3.56 (m, 1 H), 3.30
(s, 3 H). 13C NMR: 141.6, 140.4, 135.5, 128.4, 128.3, 128.0,
127.2, 119.1, 86.1, 65.2, 63.8, 61.1, 56.8. IR (CHCl3): 3390,
2925, 1764, 1602, 1453, 1094, 699 cm–1. Anal. Calcd for
C19H23NO2: C, 76.73; H, 7.80; N, 4.71. Found: C, 76.54; H,
7.79; N, 4.54.
(18) We proved that neither racemization nor epimerization
occurred during the formation of the hydrochloride salts.
After a basic treatment (NaOH, 1 M), we recovered free
unchanged starting amino alcohol..
(19) (a) Kuwajima, I.; Nakamura, E. In Comprehensive Organic
Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.;
Pergammon Press: Oxford, 1991, 441–454. (b) Kubota, K.;
Mori, S.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc.
1998, 120, 13334.
(20) (a) Organolithiums in Enantioselective Synthesis; Hodgson,
D. M., Ed.; Springer: Heidelberg, 2003. (b) The Chemistry
of Organolithium Compounds; Rappoport, Z.; Marek, I.,
Eds.; Wiley: New York, 2004.
(16) Atomic coordinates, bond lengths and angles, and thermal
parameters have been deposited at the Cambridge
Crystallographic Data Centre with the deposition numbers
CCDC 602015 for 5b, CCDC 612649 for 5d and CCDC
612650 for 5c.
Synlett 2006, No. 12, 1855–1858 © Thieme Stuttgart · New York