Diastereoselective addition of terminal alkynes to chiral nitrones: Asymmetric synthesis of propargylic N-hydroxylamines

Article abstract of DOI:10.1016/S0957-4166(03)00032-6

1,3-Asymmetric induction in the Et₂Zn-catalyzed addition of terminal alkynes was studied with nitrones bearing a chiral auxiliary on their nitrogen atom. The obtained propargylic N-hydroxylamines were generally isolated in good yields and with satisfactory to excellent diastereoselectivities.

Full text of DOI:10.1016/S0957-4166(03)00032-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 525–528
Diastereoselective addition of terminal alkynes to chiral nitrones:
asymmetric synthesis of propargylic N-hydroxylamines
Samir K. Patel, Sandrine Py, Shashi U. Pandya, Pierre Y. Chavant and Yannick Valle´e*
L.E.D.S.S., UMR 5616 CNRS, Universite´ Joseph Fourier, B.P. 53, 38041 Grenoble, France
Received 18 November 2002; accepted 3 January 2003
Abstract—1,3-Asymmetric induction in the Et2Zn-catalyzed addition of terminal alkynes was studied with nitrones bearing a
chiral auxiliary on their nitrogen atom. The obtained propargylic N-hydroxylamines were generally isolated in good yields and
with satisfactory to excellent diastereoselectivities. © 2003 Elsevier Science Ltd. All rights reserved.
During the course of a program aimed at the develop-
ment of a general method for the asymmetric synthesis
of g-amino-a,b-functionalized acid derivatives, we con-
sidered the direct addition of 3-carbons, highly func-
tionalisable synthons, such as propiolic acid esters or
other functionalized terminal alkynes, to the CꢀN bond
of nitrones.1,2 The obtained functionalized propargylic
N-hydroxylamines represent versatile intermediates for
the synthesis of natural and/or biologically active prod-
ucts.3 In particular, we are interested in the asymmetric
synthesis of PM-94128, a cytotoxic isocoumarin antibi-
otic extracted from the culture broth of Bacillus sp.
PhM-PHD-090 isolated from a marine sediment,4
which showed activity against several tumor cell lines.
However, its relative and absolute configurations are
still unknown, which calls for the development of an
appropriate methodology for its synthesis.
chiral auxiliaries (R* in Scheme 1) b-amino ethers6
derived from 2-(S)-a-phenylglycinol and 2-(S)-valinol,
and a 2,3:5,6-di-O-isopropylidene-protected (D)-man-
nose derivative developed by Vasella and co-workers.7
The recent publication by Carreira et al.8 of results
obtained using Vasella’s auxiliary prompted us to dis-
close our own findings.
The (Z)-aldonitrones 4–5 bearing a chiral auxiliary on
their nitrogen atom were prepared in good yields (69–
93%) by condensation of isovaleraldehyde with the
corresponding N-hydroxylamines in the presence of
MgSO4 (Scheme 2).9 For nitrones 4a–c, the required
chiral N-hydroxylamines were prepared through oxida-
tion of the corresponding amines, in a three-steps
procedure10–12 which proved more efficient (47–73%
overall yield) than the previously described direct oxi-
dation with dibenzoyl peroxide.6,13 Nitrone 5 was
obtained from the 2,3:5,6-di-O-isopropylidene-pro-
Our group has recently developed a new method for the
synthesis of propargylic N-hydroxylamines, involving
the Et2Zn-induced addition of various alkynes to
nitrones.5 This reaction proved highly efficient with a
variety of alkynes and nitrones, and proceeds under
very mild conditions, at room temperature. In the
present letter, we describe our work on an asymmetric
version of this reaction, for which we have selected as
tected (D
)-mannose oxime7 and isovaleraldehyde.
With these enantiopure nitrones in hand, we studied
their reactivity in the Et2Zn-induced addition of alky-
nes, using the conditions developed in our laboratories5
(Scheme 1, Table 1). As anticipated, the addition of a
* Corresponding author. E-mail: syrca.ledss@ujf-grenoble.fr
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00032-6

526
S. K. Patel et al. / Tetrahedron: Asymmetry 14 (2003) 525–528
Scheme 1. Diastereoselective Et2Zn-induced addition of terminal alkynes to chiral nitrones.
Scheme 2. Preparation of chiral nitrones 4–5.
The major diastereomer of the obtained propargylic
simple alkyne (1-hexyne) to the nitrone 4a (entry 1)
proceeded smoothly to afford the corresponding
propargylic N-hydroxylamines in excellent yields and
with a 88:12 diastereomeric ratio. Then we turned our
attention to functional alkynes such as propargylic
ethers and alkyl propiolates, and we found that their
reaction with nitrone 4a was equally efficient (entries
2–4). The addition of t-butyl propiolate to nitrones
(entry 4) is noteworthy as it is the first example of
successful addition of propiolic acid derivatives in non-
basic conditions. This result is remarkable when consid-
ering that the corresponding lithium or magnesium
organometallic species are known to be unstable above
−60°C, and to add sluggishly to electrophiles.
N-hydroxylamines exhibits R absolute configuration at
the new stereocenter, in all cases. This assignment was
ascertained by X-ray analysis of the minor diastereoiso-
mer in one case (entry 4),† and was established on the
basis of NMR studies in the other cases where b-
aminoether auxiliaries were involved (additions to
nitrones 4a–c). The chemical shifts of the propargylic
proton at the new stereocenter was characteristic, in
that it appeared at lower field (Dl ppm 0.5–0.9) in the
major R diastereomer when compared to the minor S
diastereomer. When nitrone 5 was used as the sub-
strate, the absolute configuration of the single N-
hydroxylamine produced was assumed to be R, in
comparison with Carreira’s report.8‡
More than the nature of the alkyne, the nature of the
chiral auxiliary in the nitrone was found to have a
significant effect on the reaction outcome. In particular,
steric hindrance on the nitrogen atom seems to limit the
efficiency of the reaction. When the (S)-valinol-derived
nitrone 4c was used as the substrate (entry 6), the
addition of t-butyl propiolate (as well as 1-hexyne or
3-methoxy-propyne, not shown in Table 1) was very
sluggish, and only traces of the desired adducts were
detected after 72 h, along with unreacted nitrone.
The formation of a chelated transition state6 involving
the coordination of Zn to an heteroatom of the chiral
auxiliary may explain the observed diastereoselectivities
in this reaction, preferential attack occuring at the Si
face of the nitrones.
The use of N-glycosylnitrones was next considered, and
nitrone 5 was prepared according to Vasella’s proce-
dure. To our delight, it was found that 1-hexyne,
propynal diethylacetal, and t-butyl propiolate added
smoothly to this nitrone (entries 7–9), in short reaction
times, and with excellent diastereoselectivities.
† Crystallographic data have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication number
CCDC 195172.
‡ In this paper, the absolute configuration of the products was
ascertained by chemical correlation.

S. K. Patel et al. / Tetrahedron: Asymmetry 14 (2003) 525–528
Table 1. Et2Zn-induced addition of terminal alkynes to nitrones 4a–c and 5a
527
In conclusion, we report an efficient asymmetric synthe-
sis of functional propargylic N-hydroxylamines and
g-N-hydroxy-amino-a,b-acetylenic esters, under mild
conditions. The chiral auxiliaries can be readily
cleaved.6,8 We are currently working on further elabo-
ration of these enantiopure propargylic N-hydroxyl-
amines, for the synthesis of g-amino-a,b-acetylenic, g-
amino-a,b-ethylenic, and g-amino-a,b-dihydroxy acids.
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