Organic Letters
Letter
pyrrolidine with vicinal quaternary−tertiary stereocenters
(Scheme 1b).5 The enantiopurity of the obtained products
was high (91% ee), while the diastereoselectivity was only
modest. Recently, we developed a strategy for the asymmetric
5-exo-dig cyclization of α-amino ester enolates onto hetero-
substituted alkynes via the MOC concept (Scheme 1c).6 This
method provided access to the Cα-substituted proline with
heterosubstituted methylene at the β-position. This trigonal
functionality was eventually transformed into a quaternary
stereocenter during the synthesis of hasubanan alkaloids,
including runanine (Figure 1).6a
Herein, we report the development of an intramolecular
MOC SN2′ reaction of acyclic α-amino ester to form
pyrrolidines with vicinal quaternary−tertiary or quaternary−
quaternary stereocenters (Scheme 1d). This reaction is similar
in concept to the previously reported intramolecular MOC
alkylations.3 However, our approach provides value in addition
to forming pyrrolidine rings because the intramolecular SN2′
reaction of allylic electrophiles would result in a versatile vinyl
functionality and create a new carbon stereocenter generally
with excellent stereocontrol because of allylic strain.7
chloride substrate 1a was treated with KHMDS at −78 °C in
THF, the desired SN2′ product 6 was provided in a high yield
and dr with 92% ee (Table 1, entry 1). The allyl bromide 1b
a
Table 1. Optimization of Reaction Conditions
solvent
(0.02 M)
temp
(°C)
yield
b
ee of 6
d
c
entry substrate
(%)
dr
(%)
1
2
3
4
1a
1b
1a
1a
THF
THF
DMF
THF/DMF
(1:1)
THF/DMF
(1:1)
−78
−78
−60
−60
97
89
82
93
19:1
6:1
10:1
16:1
92
95
>99
>99
e
5
1a
−60
94
14:1
>99
a
b
Reactions were run with 0.1 mmol of 1. Combined yield of 6 and
c
its diastereomer. The ratio was determined by 1H NMR of the crude
mixture. The absolute and relative stereochemistry were tentatively
assigned by analogy to 8c. The enantiomeric excess was determined
To explore the feasibility of this strategy, model substrate 1
was designed (Scheme 2). A Boc group was used as the
d
e
by chiral HPLC analysis. The reaction was run with 1.0 mmol of 1a.
Scheme 2. Representative Scheme for the Synthesis of
a
Substrates 1a and 1b
furnished product 6 with an enantiopurity higher than that
obtained from 1a, but the diastereoselectivity was much lower
(entry 2 vs entry 1). The low diastereoselectivity and instability
of the allyl bromide substrate 1b led us to optimize the
reaction conditions with allyl chloride 1a as a substrate.
Attempts to optimize the reaction conditions with respect to
solvent were conducted. The reaction performed in DMF
provided 6 with almost perfect chirality preservation (>99%
ee), albeit with diminished diastereoselectivity (entry 3). When
the reaction was performed in a THF/DMF mixture (1:1), 6
was obtained with a nearly perfect ee value (>99%) and an
excellent dr (16:1) value (entry 4). Applying these conditions
to a larger scale reaction led to similar results (entry 5).
Additionally, under the conditions of entry 4, the cis geometric
isomer of 1a also provided 6 with >99% ee in a slightly lower
yield (85%) and diastereoselectivity (10:1).
With the optimized reaction conditions in hand, we explored
the substrate scope (Scheme 3). The substrate possessing an
N-Cbz protecting group underwent the reaction to provide
pyrrolidine 8a with excellent chirality preservation in a
significantly increased diastereoselectivity compared to that
of N-Boc-protected substrate 1a. The substrate with an N-Bz
protecting group furnished 8b with diminished enantio- and
diastereoselectivity.
The next exploration of the scope of the reaction under the
identified conditions focused on the influence of the α-
substituent of α-amino esters on the degree of chirality
preservation. With a Boc protecting group, α-amino esters
bearing various α-alkyl groups were smoothly cyclized to afford
the pyrrolidine products in high yield with excellent ee (8c−
8f). Even substrate 7f bearing an additional carbonyl group at
the γ-carbon afforded product 8f in high yield with excellent
ee. Only 7g, prepared from methionine, provided product 8g
in diminished yield and ee. Substrate 7h with the ethyl ester
group gave a dr value much lower than that of substrate 1a
with the bulkier tert-butyl ester group, suggesting that the
bulkiness of the ester group has a significant effect on the
diastereoselectivity. Notably, products bearing vicinal quater-
a
Reagents and conditions: (a) (i) NaHCO3 (aq), CH2Cl2, rt, 1 h; (ii)
DNsCl (1.1 equiv), pyridine (3 equiv), CH2Cl2, rt, 12 h, 92%; (b) 3
(1.1 equiv), DIAD (1.5 equiv), PPh3 (2 equiv), benzene, rt, 1 h, 99%;
(c) thioglycolic acid (1.5 equiv), Et3N (3 equiv), CH2Cl2, rt, 2 h, then
Boc2O (2 equiv), Et3N (2 equiv), rt, 48 h, 95%; (d) K2CO3 (2 equiv),
MeOH, rt, 2 h; (e) PPh3 (2 equiv), hexachloro-2-propanone (1.5
equiv, for 1a) or CBr4 (1.5 equiv, for 1b), CH2Cl2, rt, 2 h, 96% for 1a
(two steps), 97% for 1b (two steps). DNsCl = 2,4-dinitrobenzene-
sulfonyl chloride, DIAD = diisopropyl azodicarboxylate.
protecting group on the nitrogen because it is preferable in the
generation of an axially chiral amino ester enolate inter-
mediate.4 Compound 1 was prepared from L-phenylalanine
tert-butyl ester in five steps without noticeable racemization, as
shown in Scheme 2. The introduction of an alkyl substituent
on the amino group was realized by Fukuyama−Mitsunobu
alkylation.8 For this, the α-amino group of phenylalanine was
first condensed with the 2,4-dinitrobenzenesulfonyl (DNs)
group to afford 2. Under the Mitsunobu reaction conditions, 2
was coupled with (E)-5-hydroxypent-2-en-1-yl acetate (3).
The DNs group was then replaced with the Boc group using a
one-pot operation to provide 5. The acetate group of 5 was
removed, and the resulting allyl alcohol was halogenated to
provide substrates 1a and 1b, which were enantiomerically
pure (>99%).
After several bases and conditions were screened, we
obtained a promising result with KHMDS. When the allyl
B
Org. Lett. XXXX, XXX, XXX−XXX
Chung, Yundong
