NTER>A practical asymmetric sy
nthesis of a highly substituted
N-acylpyrrolidi
ne o
n multi-kilogram scale isdescribed. The key step i
n the co
nstructio
n of the three stereoce
nters is a [3+2] cycloadditio
n of methylacrylate a
nd a
n imi
no ester prepared from
L-leuci
ne
t-butyl ester hydrochloride a
nd 2-thiazolecarboxaldehyde. The cycloadditio
n features
novel asymmetric catalysis via a complex of silver acetate a
nd aci
ncho
na alkaloid, particularly hydroqui
ni
ne, with complete diastereomeric co
ntrol a
nd up to 87%e
na
ntiomeric co
ntrol. The alkaloid serves as a liga
nd as well as a base for the formatio
n of the azomethi
neylide or 1,3-dipole. Experime
nts have show
n that the hydroxyl group of hydroqui
ni
ne is a critical eleme
ntfor the e
na
ntioselectivities observed. The cycloadditio
n methodology is also applicable to methylvi
nylketo
ne, providi
ng access to either
![](/images/gifchars/alpha.gif)
- or
![](/images/gifchars/beta2.gif)
-epimers of 4-acetylpyrrolidi
ne depe
ndi
ng o
n the reactio
nco
nditio
ns utilized. The sy
nthesis also highlights a
n efficie
nt
N-acylatio
n, selective
O- versus
N-methylatio
n,a
nd a u
nique ester reductio
n with NaBH
4-MeOH catalyzed by NaB(OAc)
3H that
not o
nly achievesexcelle
nt chemoselectivity but also avoids formatio
n of the u
ndesired but thermody
namically favoredepimer. The highly fu
nctio
nalized target is sy
nthesized i
n seve
n li
near steps from
L-leuci
ne
t-butyl esterhydrochloride with all three isolated i
ntermediates bei
ng highly crystalli
ne.