1
180
Chemistry Letters Vol.37, No.11 (2008)
A DyI -catalyzed Mannich-type Reaction of 1-Methylcyclopropanecarboxylate-type Donors
3
for the Stereoselective Synthesis of Pyrrolidines with Quaternary Stereocenters
ꢀ
ꢀ
Hidetoshi Noda, Sean H. Wiedemann, Shigeki Matsunaga, and Masakatsu Shibasaki
Graduate School of Pharmaceutical Sciences, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received August 27, 2008; CL-080818; E-mail: mshibasa@mol.f.u-tokyo.ac.jp, smatsuna@mol.f.u-tokyo.ac.jp)
Stereoselective synthesis of functionalized pyrrolidines with
Table 1. Optimization of the reaction conditions
all-carbon quaternary stereocenters is described. DyI3 catalyzed
the ring opening of cyclopropanecarboxylate equivalents and
promoted Mannich-type addition of the resulting ꢀ,ꢀ-disubsti-
tuted enolate intermediates to aryl and isomerizable alkyl
imines, giving products in 86–58% yield and >96:4–84:16
diastereoselectivity.
O
O
Ph
N
Cat.
(20 mol %)
Additive
Me
Me
pTs
N
N
N
N
N
+
pTs
Ph
CH Cl
2
2
X
rt, 48 h
X
X = H: 1a
X = Br: 1b
2a
X = H: 3aa
X = Br: 3ba
(3.0 equiv)
Additive
/equiv
Yielda
/%
Entry
1
Cat.
Drb
The stereoselective formation of all-carbon quaternary ster-
eocenters remains a formidable challenge in the field of organic
synthesis. The use of ꢀ,ꢀ-disubstituted enolates in carbon–
carbon bond-forming reactions is a straightforward approach
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1a
1b
ScI3
none
none
trace
9
—
1
LaI3
SmI3
DyI3
YbI2
MgI2
DyI3
>96:4
>96:4
>96:4
>96:4
—
none
none
42
66
to provide ꢀ-carbonyl quaternary stereocenters. In this context,
we recently reported Sc3 -catalyzed direct aldol-type additions
of N-benzoylcyclopropanecarboxamides. Either a mixture of
Sc(OTf)3/TMSCl/NaI or ScI3 alone effectively promoted the
þ
none
none
58
NR
79
Na2SO3 (0.3)
Na SO (0.3)
>96:4
>96:4
c
2
8
DyI3
84
reactions in good diastereoselectivity. Cis selective in situ
2
3
a
generation of ꢀ,ꢀ-disubstituted enolates was the key event in
these reactions. In this paper, we describe an extension of the
system to Mannich-type reactions for the stereoselective synthe-
sis of functionalized pyrrolidines bearing all-carbon quaternary
stereocenters.
Isolated yield after purification by column chromatography.
1
b
c
Determined by H NMR analysis. Reaction time was 30 h.
The optimized reaction conditions were applied to various
aryl and alkyl imines (Table 2). The reactions of aryl imines
2a–2h proceeded in high diastereoselectivity (Entries 1–8,
>96:4–92:8). Aryl imines 2b–2d with electron-withdrawing
para-substituents showed good reactivity, and products 3bb–
3bd were obtained in 86–77% yield (Entries 2–4). With p-Me-
substituted imine 2e, the slow addition of donor 1b over 8 h
was necessary to obtain product 3be in 60% yield after 72 h
(Entry 5). In the case of ortho-substituted imines 2f–2h, donor
1a gave better results than donor 1b (Entries 6–8, 72–66%
yield). In general, alkyl imines, especially linear alkyl imines,
are rather difficult substrates in direct catalytic Mannich-type re-
Since Carreira’s seminal reports on MgI2-catalyzed
0
Mannich-type ring expansion of spiro[cyclopropane-1,3 -
3
oxindoles], various cyclopropane donors, such as cyclopropyl
4
,5
ketones and methylenecyclopropanecarboxamides, have been
shown to participate in nucleophile-initiated direct Mannich-
type reactions. There remains, however, much room for im-
provement in the use of ꢀ-substituted cyclopropanecarbox-
ylate-type donors. On the basis of our previous aldol-type
reactions, we screened various 1-methylcyclopropanecarbonyl
donors and imines using rare earth metal iodides as catalysts.
The combination of N-acylpyrrazole 1 and N-Ts imines 2 gave
9
actions under Brønsted basic reaction conditions due to compet-
itive isomerization into enamides. Thus, it is noteworthy that the
present system was applicable to readily isomerizable alkyl
imines 2i and 2j. Products were obtained in 72–58% yield and
94:6–84:16 diastereoselectivity (Entries 9–11). Catalyst loading
was successfully reduced to 10 mol % without loss of yield and
diastereoselectivity, but the reaction rate decreased (Entry 12).
The use of donors with bulkier ꢀ-substituents than methyl was
not successful. In such cases, cyclopropane ring-opening pro-
ceeded, but subsequent Mannich-type addition to imine 1a did
not proceed, possibly due to steric hindrance. The N-acylpyra-
zole moiety of product 3ba was successfully converted to methyl
6
promising results. Optimization studies of the reaction condi-
tions using donor 1a and imine 2a are summarized in Table 1.
Although ScI3, which was useful in our previous aldol-type re-
action, gave only trace product 3aa (Entry 1), other rare earth
metal iodides promoted the desired ring-opening/Mannich-type
reaction with concomitant pyrrolidine ring closure (Entries 2–5).
Among metal iodide screened, DyI3 gave the best reactivity at
room temperature in CH2Cl2, giving product 3aa in 66% yield
and >96:4 diastereoselectivity (Entry 4). MgI2 was not a suitable
catalyst for the cyclopropane ring opening of 1a under identical
7
ꢁ
10
reaction conditions (Entry 6). Addition of Na2SO3 effectively
improved the yield to 79% without affecting diastereoselectivity
ester by treatment with Er(OTf)3 in MeOH at 50 C (eq 1).
O
Ph
Er(OTf)3
(10 mol %)
Me
O
Ph
N
Entry 7).8 The use of 4-bromo-3,5-dimethylpyrazole as a
template instead of 3,5-dimethylpyrazole further improved the
N
Me
(
N
N
pTs
MeO
ð1Þ
pTs
MeOH, 50 °C
3
0 min
reactivity, and product 3ba was obtained in 84% yield and
96:4 diastereoselectivity after 30 h (Entry 8).
Br
9
3% yield
>
Copyright Ó 2008 The Chemical Society of Japan