ZnCl2-mediated stereoselective addition of terminal alkynes to D-(+)-mannofuranosyl nitrones

Article abstract of DOI:10.1021/ol052331s

(Chemical Equation Presented) An optimized process for the addition of terminal alkynes to chiral nitrones using ZnCl₂ and NEt₃ in toluene is reported. The new reaction protocol is facile to perform and cost-effective. The resulting

Full text of DOI:10.1021/ol052331s

ORGANIC
LETTERS
2
005
Vol. 7, No. 23
329-5330
ZnCl -Mediated Stereoselective Addition
of Terminal Alkynes to
2
5
D-(+)-Mannofuranosyl Nitrones
Dana Topi c´ , Patrick Aschwanden, Roger F a1 ssler, and Erick M. Carreira*
Laboratorium f u¨ r Organische Chemie, ETH H o¨ nggerberg,
CH-8093 Z u¨ rich, Switzerland
carreira@org.chem.ethz.ch
Received September 26, 2005
ABSTRACT
2 3
An optimized process for the addition of terminal alkynes to chiral nitrones using ZnCl and NEt in toluene is reported. The new reaction
protocol is facile to perform and cost-effective. The resulting optically active propargyl N-hydroxylamines are isolated in good to excellent
yield and high diastereoselectivity.
Optically active propargyl N-hydroxylamines can serve as
versatile building blocks for asymmetric synthesis. They are
moved by treating the products with N-hydroxylamine
1
hydrochloride, a process allowing reisolation and reuse of
5
readily converted to amines and are amenable to further
synthetic elaborations, such as cyclization to furnish 2,3-
the auxiliary.
Our continuing interest in the chemistry of metal alky-
2
3
,6
dihydroisoxazoles. Recently, we reported the first general
nylides prepared in situ from terminal alkynes led us to
search for alternative sources of Zn(II). A preliminary
process for the preparation of optically active propargyl
3
N-hydroxylamines. The method prescribes the use of chiral
2
screening revealed that rigorously dried ZnCl is capable of
inducing the addition of terminal alkynes to N-benzylnitrones.
However, unexpectedly, most of the product propargyl
4
nitrones with a broad range of terminal acetylenes in the
2 3
presence of Zn(OTf) , NEt , and N,N-dimethylethanolamine.
After addition, the chiral controlling group is easily re-
(
5) Lantos, I.; Flisak, J.; Liu, L.; Matsuoka, R.; Mendelson, W.;
(
1) For a review, see: (a) Aschwanden, P.; Carreira, E. M. Addition of
Stevenson, D.; Tubman, K.; Tucker, L.; Zhang, W. Y.; Adams, J.; Sorenson,
M.; Garigipati, R.; Erhardt, K.; Ross, S. J. Org. Chem. 1997, 62, 5385.
(6) (a) Frantz, D. E.; F a¨ ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999,
121, 11245. (b) Frantz, D. E.; F a¨ ssler, R.; Carreira, E. M. J. Am. Chem.
Soc. 2000, 122, 1806. (c) Boyall, D.; Lopez, F.; Sasaki, H.; Carreira, E. M.
Org. Lett. 2000, 2, 4233. (d) Sasaki, H.; Boyall, D.; Carreira, E. M. Helv.
Chim. Acta 2001, 84, 964. (e) El-Sayed, E.; Anand, N. K.; Carreira, E. M.
Org. Lett. 2001, 3, 3017. (f) Anand, N. K.; Carreira, E. M. J. Am. Chem.
Soc. 2001, 123, 9687. (g) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org.
Lett. 2002, 4, 2605. (h) Diez, R. S.; Adger, B.; Carreira, E. M. Tetrahedron
2002, 58, 8341. (i) Reber, S.; Kn o¨ pfel, T. F.; Carreira, E. M. Tetrahedron
2003, 59, 6813. (j) Kn o¨ pfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003,
125, 6054. (k) Fischer, C.; Carreira, E. M. Organic Lett. 2004, 6, 1497. (l)
Kn o¨ pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E.
M. Angew. Chem., Int. Ed. 2004, 43, 5971.
Terminal Acetylides to CdO and CdN Electrophiles. In Acetylene
Chemistry: Chemistry, Biology and Material Science; Diederich, F., Stang,
P. J., Tykwinski, R. R., Eds.; Wiley: Weinheim, 2005.
(
2) Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2,
331.
3) F a¨ ssler, R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2002, 41, 3054.
4) (a) Vasella, A. HelV. Chim. Acta 1977, 60, 1273. (b) Basha, A.; Henry,
R.; McLaughlin, M. A.; Ratajczyk, J. D.; Wittenberger, S. J. J. Org. Chem.
994, 59, 6103. (c) For a detailed review on the use of monosaccharides as
2
(
(
1
chiral auxiliaries for asymmetric synthesis, see: Hale, K. J. Monosaccha-
rides: Use in Synthesis as Chiral Templates. In Second Supplements to the
nd Editon of Rodd’s Chemistry of Carbon Compounds; Sainsbury, M.,
Ed.; Elsevier: Amsterdam, 1993; Vol. IE/F/G, Chapter 23b, p 273.
2
1
0.1021/ol052331s CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/21/2005

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this substrate revealed that ZnCl conveniently affords
optically active propargyl N-hydroxylamines in 94% yield
and 98:2 diastereoselectivity. In contrast to the procedure
employing Zn(OTf) , homogeneous reaction solutions were
2
2
Table 1. ZnCl -Induced Diastereoselective Addition of
Alkynes to N-Mannofuranosylnitronesa
now observed, rendering unnecessary the need for an
additional ligand, such as N,N-dimethylethanolamine, which
we had previously prescribed. The best diastereoselectivity
was observed using toluene as solvent, which additionally
provides the benefit of being an environmentally more
friendly system than the initially published process which
employed dichloromethane.
The optimized reaction conditions were applied to a wide
range of nitrones affording the desired propargyl N-hydroxy-
lamines in good to excellent yield and high diastereoselec-
tivity (Table 1). In a typical reaction, powdered and dried
ZnCl
TMS-acetylene, and NEt
for 15 h. Acidic workup (NH
2
(98% ACS reagent), D-(+)-mannofuranosyl nitrone,
were stirred in toluene at 23 °C
Cl) and purification by flash
3
4
chromatography on silica gel afforded the desired optically
active propargyl N-hydroxylamines. The chiral nitrone
derived from benzaldehyde (Table 1, entry 6) proved to be
insoluble in toluene. Therefore, a mixture of toluene/
CH Cl ) 2:1 was used as solvent, affording the desired
2 2
propargyl N-hydroxylamine in acceptable yield and excellent
diastereoselectivity. In reactions involving the inexpensive
2
-methyl-3-butyne-2-ol, the alkyne could be utilized as the
solvent, affording higher yields than the standard protocol
(
Table 1, entries 7 and 8).
In summary, we have developed an optimized process for
a
A 10-mL Schlenk tube charged with ZnCl2 (102 mg, 0.750 mmol, 1.50
equiv) was put under vacuo and heated to 100-200 °C (heat gun) for 3
min. After the tube was cooled to 23 °C, nitrone (0.500 mmol, 1.00 equiv)
and solvent (1.0 mL) were added. The resulting mixture was stirred until a
homogeneous solution was obtained. TMS-acetylene (74 mg, 0.75 mmol,
the diastereoselective addition of terminal alkynes to chiral
nitrones using ZnCl and NEt in toluene. The new reaction
2
3
1
.5 equiv) and NEt3 (76 mg, 0.75 mmol, 1.5 equiv) were added via syringe,
protocol has considerable advantages over that initially
described as it is facile to perform, cost-effective, and
environmentally friendly. The resulting optically active
propargyl N-hydroxylamines are isolated in good to excellent
yield and high diastereoselectivity and are potentially highly
versatile building blocks for organic synthesis, following
and the resulting solution was stirred at 23 °C for 15 h. Upon completion,
the reaction was quenched with aq NH4Cl (3.0 mL). Workup and purification
by chromatography on silica gel afforded the pure propargyl N-hydroxy-
b
1
lamines. Diastereomeric ratios (dr) were determined by H NMR analysis.
c
d
Toluene/CH2Cl2 ) 2:1 used as solvent. Alkyne used as solvent.
3
removal of the labile auxiliary. In a broader context, the
N-benzylhydroxylamines were prone to cyclization in the
presence of ZnCl , affording the corresponding 2,3-dihy-
observations underscore the ability of simple Zn(II) salts to
participate in alkyne activation and nucleophilic additions.
This sets the stage for further investigations, the results of
which will be reported as they become available.
2
2
droisoxazoles. Interestingly, the use of TMS-acetylene under
these novel reaction conditions led to the desired propargyl
N-benzylhydroxylamines as the sole product. It is likely that
this results from the bulk of the silyl group, which prevents
cyclization.
The addition of TMS-acetylene to the chiral N-manno-
furanosylnitrone derived from cyclohexanecarboxaldehyde
was employed as a test substrate in the examination and
optimization of the reaction conditions. Due to the low
boiling point of TMS-acetylene (52 °C), a slight excess (1.5
equiv) was used to provide optimal yields. The results with
Acknowledgment. E.M.C. is grateful for generous sup-
port from ETH Z u¨ rich (TH-Gesuch) and from F. Hoffmann
LaRoche.
Supporting Information Available: Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL052331S
5330
Org. Lett., Vol. 7, No. 23, 2005