Asymmetric addition of alkoxy ethynyl anion to chiral N-sulfinyl imines

Article abstract of DOI:10.1021/ol302392k

The addition of lithiated ynol ethers to chiral N-sulfinyl imines proceeds in high yield and diastereoselectivity. The selectivity is completely reversed by the addition of boron trifluoride. These alkoxypropargyl sulfinamides can be reduced to afford eno

Full text of DOI:10.1021/ol302392k

ORGANIC
LETTERS
2
012
Vol. 14, No. 19
122–5125
Asymmetric Addition of Alkoxy Ethynyl
Anion to Chiral N‑Sulfinyl Imines
Charlie Verrier, S ꢀe bastien Carret, and Jean-Francois Poisson*
5
D eꢀ partement de Chimie Mol eꢀ culaire (SERCO), UMR-5250, ICMG FR-2607, CNRS,
Universit eꢀ Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France
jean-francois.poisson@ujf-grenoble.fr
Received August 30, 2012
ABSTRACT
The addition of lithiated ynol ethers to chiral N-sulfinyl imines proceeds in high yield and diastereoselectivity. The selectivity is completely
reversed by the addition of boron trifluoride. These alkoxypropargyl sulfinamides can be reduced to afford enol ethers, selectively oxidized to
busyl derivatives, or the ynol ether can be hydrolyzed to afford β-amino esters.
1
Heterosubstituted alkynes such as ynamines, ynamides,
and ynol ethers have received considerable attention over
the past decade due to their particular structure and
synthetic potential as versatile key intermediates in organic
chemistry. While the synthetic utility of ynamides has
electron-rich alkynes have recently found applications
3
in cycloadditions, gold catalysis, or carbocupration. The
ynol ether moiety is generally formed from a pre-existing
function on the molecule, mainly by two methods: from
4
an ester or a carbonyl derivative, or by oxidation of a
2
5
terminal alkyne. In a complementary fashion, the ynol
been particularly studied, their oxygenated analogues,
ynol ethers, are still underexploited. These oxygenated
ether can be introduced by nucleophilic addition of an
alkoxy ethynyl anion to a carbonyl derivative. This second
strategy is very much underdeveloped, with only a few
reports on the addition of lithiated alkoxy ethyne to
(
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P.; Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon, V. Chem.
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M. C.; Hsung, R. P. Org. Lett. 2012, 14, 1768–1771. (f) Dateer, R. B.;
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Hollingworth, G. Bull. Soc. Chim. Fr. 1996, 133, 15–24. (b) Julia, M.;
Saint-Jalmes, V. P.; Verpeaux, J.-N. Synlett 1993, 1993, 233–234.
(c) Pericas, M. A.; Serratosa, F.; Valenti, E. Tetrahedron 1987, 43,
2311–2316. (d) Stang, P. J.; Surber, B. W. J. Am. Chem. Soc. 1985,
107, 1452–1453.
(g) Cao, J.; Xu, Y. P.; Kong, L.; Cui, Y. M.; Hu, Z. Q.; Wang, G. H.;
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77, 1710–1721. (b) Rieder, C. J.; Windberg, K. J.; West, F. G. J. Am.
Chem. Soc. 2009, 131, 7504–7505. (c) Clark, J. S.; Elustondo, F.; Trevitt,
G. P; Boyall, D.; Robertson, J.; Blake, A.; Wilson, C.; Stammen, B.
Tetrahedron 2002, 58, 1973. (d) MaGee, D. I.; Rameseshan, M.; Leach,
J. D. Can. J. Chem. 1995, 73, 2111–2118. (e) Loeffler, A.; Himbert, G.
Synthesis 1992, 495. (f) Raucher, S.; Bray, B. L. J. Org. Chem. 1987, 52,
2332–2333. (g) Tankard, M. H.; Whitehurst, J. S. Tetrahedron 1974, 30,
451–454.
(7) (a) Mak, X. Y.; Ciccolini, R. P.; Robinson, J. M.; Tester, J. W.;
Danheiser, R. L. J. Org. Chem. 2009, 74, 9381–9387. (b) Hashmi,
A. S. K.; Rudolph, M.; Huck, J.; Frey, W.; Bats, J. W.; Hamzi ꢀc , M.
Angew. Chem., Int. Ed. 2009, 48, 5848–5852.
(
3) For selected recent examples, see: (a) Minami, Y.; Shiraishi,
Y.; Yamada, K.; Hiyama, T. J. Am. Chem. Soc. 2012, 134, 6124–6127.
b) Tran, V.; Minehan, T. G.Org. Lett. 2011, 13, 6588–6591. (c)Miyauchi,
Y.; Kobayashi, M.; Tanaka, K. Angew. Chem., Int. Ed. 2011, 50,
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References 6 and 7.
(
1
0.1021/ol302392k r 2012 American Chemical Society
Published on Web 09/20/2012

Our research group has acquired expertise in ynol ether
to sulfinamide 4a. Treatment of dichloroenol ether 1a
with n-butyllithium (2 equiv) followed by the addition of
sulfinyl imine 3a afforded the alkoxypropargylamine 4a
in similar yield and selectivity (dr = 89:11) compared to
the two-step sequence. Overall, this one-pot procedure is
much more attractive in terms of both efficiency and
simplicity, allowing the formation of tert-butyl ynol ether
derivatives.
8
chemistry for the formation of chiral enol ethers. The ynol
ether is conveniently formed by treatment of a dichloroenol
9
ether with two equivalents of n-butyllithium: after a first
deprotonation, the intermediate lithiated species II undergoes
a β-elimination upon warming, leading to a chloroynol ether
III; a subsequent chlorine lithium exchange with a second
equivalent of n-butyllithium leads to the lithiated ethynyl
9
b
ether which can be trapped by electrophiles (Figure 1).
In the present study, we report the unprecedented selective
addition of various ethynyl ether anions to N-sulfinyl
1
imines, offering a variety of useful substrates.
0
Figure 1. Ynol ethers formed from dichloroenol ethers.
We started our study with the synthesis of different
ethynyl ethers. The dichloroenol ethers (1aÀc), obtained
by treatment of trichloethylene with the potassium alk-
oxides, were treated with n-butyllithium followed by hy-
drolysis. The obtainedethynylethers showed verydifferent
stabilities: the cyclohexyl ethyne ether 2a could be purified
by distillation and proved stable for weeks at À15 °C, in
contrast to the benzyl derivative 2b which proved unstable
and the tert-butyl ether 2c that could not be isolated in
a pure form. With pure ynol ether 2a in hand, we studied
its addition to the sulfinyl imine 3a. Using LiHMDS in
hexane as the base, a solvent screening showed that THF
was the most suitable: diethyl ether and pentane gave both
lower yield and selectivity, whereas dichloromethane was
inefficient (Figure 2). Using a THF solution of LiHMDS
led to an increase in yield and selectivity in every solvent;
thereaction in justTHFafforded4awith the bestdiastereo-
selectivity (dr = 91:9) in 92% yield. Surprisingly, the
Grignard derivative led to poorer results in terms of both
efficiency and selectivity. Using n-butyllithium as the base
was nearly as selective, a result that prompted us to
investigate the direct conversion of dichloroenol ether 1a
Figure 2. Optimization of the addition of the ynol ether anion to
chiral N-sulfinyl imines. Ether: diethyl ether. DCM: dichloro-
methane. *Reaction sequence directly from 1a.
The best reaction conditions were next applied to the
addition of dichloroenol ether 1a,b to a variety of sulfinyl
imines (3aÀj) (Scheme 1). The sequence is efficient start-
ing with both the cyclohexyl (1a) and the tert-butyl (1b)
dichloroenol ether, affording the sulfinamides in good
yields and selectivities ranging from 92:8 with p-methox-
ybenzyl sulfinyl imine 3d to a nearly 1:1 mixture with the
p-nitrobenzyl imine 3e. The interesting furan derivative 4d
was formed very efficiently with no influence of the hetero-
atom on the diastereoselectivity. There was no notable
stability differences between the cyclohexyl or the tert-
butyl ynol ethers 4a and 4b: both could be stored neat in
a freezer (À18 °C) for weeks. In contrast, any reactions
attempted with the benzyl derivative 1c led to a crude
addition product which could not be purified, as the
substrate decomposed very quickly. Using primary, sec-
ondary, and tertiary alkyl sulfinyl imines afforded the
addition product in slighlty lower selectivity.
(8) (a) Darses, B.; Greene, A. E.; Poisson, J. F. Org. Lett. 2010, 12,
994–3997. (b) Ceccon, J.; Danoun, G.; Greene, A. E.; Poisson, J. F. Org.
3
Biomol. Chem. 2009, 7, 2029–2031. (c) Reddy, P. V.; Koos, P.; Veyron, A.;
Greene, A. E.; Delair, P. Synlett 2009, 1141–1143. (d) Darses, B.; Greene,
A. E.; Coote, S. C.; Poisson, J. F. Org. Lett. 2008, 10, 821–824. (e) Reddy,
P. V.; Veyron, A.; Koos, P.; Bayle, A.; Greene, A. E.; Delair, P. Org.
Biomol. Chem. 2008, 6, 1170–1172. (f) Ceccon, J.; Greene, A. E.; Poisson,
J. F. Org. Lett. 2006, 8, 4739–4742. (g) Moyano, A.; Charbonnier, F.;
Greene, A. E. J. Org. Chem. 1987, 52, 2919–2922.
The two diastereoisomers are, in all cases, easily sepa-
rated by flash chromatography, and the S ,S relative
S
(9) (a) Darses, B.; Philouze, C.; Greene, A. E.; Poisson, J. F. J. Chem.
configuration of the crystalline major diastereoisomer
4a could be assigned by X-ray analysis (Figure 3). The
formation of this product can be explained by the attack
of the sulfinyl imine by the ynol ether anion through a
Cryst. 2011, 41, 1053–1059. (b) Darses, B.; Milet, A.; Philouze, C.; Greene,
A. E.; Poisson, J. F. Org. Lett. 2008, 10, 4445–4447. (c) Normant, J. Bull.
Soc. Chim. Fr. 1963, 1876.
(
10) For a review, see: Robak, M. T.; Herbage, M. A.; Ellman, J. A.
Chem. Rev. 2010, 110, 3600–3740.
Org. Lett., Vol. 14, No. 19, 2012
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looked for additives in order to reverse the diastereo-
1
0,12
selectivity (Figure 4).
a substantial decrease in selectivity, whereas the S ,R iso-
The addition of DMPU led to
a
Scheme 1. Lithiated Ynol Ether Addition to N-Sulfinyl Imines
S
mer became the major product upon addition of HMPA.
The organozincate, generated by addition of dimethylzinc
to the lithioacetylenic ether, also led to an inversion of
selectivity, but this was still unsatisfactory (dr = 22:78).
Despite the high sensitivity of the acetylenic ether, we
next tested the influence of Lewis acids. The sulfinyl
imine was precomplexed with AlMe , but no reversal of
3
the diastereoselectivity was observed. Switching to boron
trifluoride diethyl etherate was much more reward-
ing, affording the S ,R isomer with a complete inversion
S
of selectivity in an excellent yield, showing an unex-
pected and productive compatibility of ynol ethers with
strong Lewis acids.
a
All yields refer to the combined isolated yield of separated, pure,
diastereoisomers; diastereoisomeric ratios were measured on the
NMR spectra of the crude product.
1
H
six-membered cyclic transition state, where the lithium
coordinated both the amine and the oxygen of the sulf-
oxide, as previously proposed for the addition of other
Figure 4. Influence of additives on diastereoselectivity.
1
1
lithiated species to chiral N-sulfinyl imines.
The inversion of diastereoselectivity proved general for
all the tested sulfinyl imines 3aÀj, either aromatic or
aliphatic, affording the sulfinamides 5aÀj in excellent yield
(Scheme 2). In addition, in all cases the selectivity is much
higher compared to the reaction without Lewis acid. This
reaction could be performed on gram-scale, with the
formation of 600 mg of sulfinamide 5a (83%) and 1.4 g
of 5b (84%), both still obtained as single diastereoisomers
(dr >2:98).
With these new substrates in hand, their potential
transformations were next investigated. The hydrolysis of
the ynol ethers 4b,j and 5b,j was selectively achieved using
trifluoroacetic acid and methanol in dichoromethane,
affording respectively the β-amino esters 6b,j and 7b,j in
excellent yield as single diastereoisomers (Scheme 3). No
sulfinamide cleavage was observed under these reaction
conditions. The addition of ynol ethers to chiral N-sulfinyl
imines thus affords a direct entry to β-amino acids.
Figure 3. X-ray Ortep of the major diastereoisomer 4a.
As it would be very interesting to synthesize both
isomers from the same enantiomer of the sulfinamide, we
We pursued investigations by a selective reduction of the
triple bond by catalytic hydrogenation leading to the enol
(
11) For the proposed transition states, see the Supporting Informa-
tion. See also: (a) Ferreira, F.; Botuha, C.; Chemla, F.; P ꢀe rez-Luna, A.
Chem. Soc. Rev. 2009, 38, 1162–1186. (b) Chen, X.-Y.; Qiu, X.-L.; Qing,
F.-L. Tetrahedron 2008, 64, 2301–2306.
(12) Jiang, W. L.; Chen, C.; Marinkovic, D.; Tran, J. A.; Chen, C. W.;
Arellano, L. M.; White, N. S.; Tucci, F. C. J. Org. Chem. 2005, 70, 8924.
5
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Org. Lett., Vol. 14, No. 19, 2012

1
3
ether 8b,j (95%, Scheme 4). Finally, we have found that
the selective oxidation of the sulfinamide to the sulfon-
amide, in the presence of the ynol ether, could be cleanly
achieved using DMDO at À20 °C, affording the busyl
protected amine 9b (86%). This transformation offers an
additional option for the derivatization of this class of
compounds.
Scheme 2. Lithiated Ynol Ethers Addition to N-sulfinyl Imines
3
a
aÀj Precomplexed with BF
3
3 OEt2
Scheme 4. Reduction and Oxidation of Alkoxypropargyl
Sulfinamide 5
In conclusion, we have reported the addition of lithiated
ynol ethers to chiral N-sulfinyl imines producing function-
alized alkoxypropargyl sulfinamide in good yield and
selectivity; with or without boron trifluoride, a complete
reversal of the diastereoselectivity is observed. These
new densely functionalized substrates can be selectively
reduced at the triple bond, oxidized at the sulfur, and
upon hydrolysis afford β-amino esters in a very efficient
manner. We are pursuing the study of the reactivity of
these substrates, and the results will be reported in due
course.
Acknowledgment. We thank the CNRS, the University
Joseph Fourier, and the ANR (Project Lycomet ANR-11-
JS-07-006-01) for financial support as well as Dr. C.
Philouze and Dr. B. Baptiste (D ꢀe partement de Chimie
Mol ꢀe culaire) for X-ray analysis. C.V. acknowledges the
Minist ꢁe re de la Recherche for a PhD fellowship.
a
All yields refer to combined isolated yield of separated pure
b
c
diastereoisomers. Performed on 600 mg scale. Reaction on gram scale
synthesis of 1.4 g of 5b).
(
Supporting Information Available. Detailed diastereo-
isomeric ratios for Figures 2 and 4, complete characteriza-
tion data and H and C NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Scheme 3. Synthesis of β-Amino Esters 6 and 7
1
13
(
13) Enol ether 8j was obtained with 10% of over-reduction product.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
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