962
Chemistry Letters Vol.37, No.9 (2008)
Efficient Entry to the Pyrroloquinoline Core of Martinella Alkaloids
via Novel Base-catalyzed Mukaiyama–Mannich Reaction
Shuhei Ikeda, Masatoshi Shibuya, Naoki Kanoh, and Yoshiharu IwabuchiÃ
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
6-3 Aobayama, Sendai 980-8578
(Received June 16, 2008; CL-080601; E-mail: iwabuchi@mail.pharm.tohoku.ac.jp)
R3
∗
R3
∗
An efficient enantiocontrolled entry to Martinella alkaloids
R2
M
HN
N
R4
∗
was achieved based on the unexpected discovery that a catalytic
amount of KH/dicyclohexyl-18-crown-6 induced an intramolec-
ular Mukaiyama–Mannich reaction of imine 3, leading to a
cascade sequence involving a novel silyl group migration to
furnish the pyrroloquinoline core 6.
R4
h-DA
R4
R3
H
H
N
R2
M
N
R1
9
N
R1
N
R2
R1
ortho-azaxylylene 8
7
Scheme 2. Synthetic plan for the tricyclic core system.
Since its disclosure in 1995,1 the hexahydropyrrolo[3,2-c]-
quinoline core of martinelline (1) and martinellic acid (2) has
posed a considerable challenge to the synthetic community
(Figure 1). More than 20 successful approaches2 have been
documented on the synthesis of the unique heterocyclic system,
several of which culminated in the total syntheses of the natural
products.3 However, few of them allow efficient construction of
the ring system in an enantiocontrolled manner.2b,2d,3a–3c
of imine 3 in a productive way: the reaction always gave a
significant amount of unidentifiable decomposed products.
Learning from these studies, we hypothesized that deprotonation
from the carbamate N–H by a suitable base could give rise to
isomerization of 7 to ortho-azaxylylene 8 which would then
participate in the subsequent intramolecular hetero-Diels–Alder
(h-DA) reaction (Scheme 2).
Efforts to identify conditions that realize the projected
isomerization/h-DA reaction led us to the novel base-catalyzed
reaction system that enables a much more efficient and diaster-
eoselective conversion of 3 to 6 as presented in the following.
As shown in Table 1, our investigations commenced with
low-nucleophilic strong base NaHMDS, but no reaction was
observed (Entry 1). When 3 was treated with a stoichiometric
amount of KH in THF (Entry 2), evolution of H2 was observed
and the color of the solution turned bright yellow. Despite the
marked change in appearance, the expected reaction had not oc-
curred and 3 was recovered. It was suggested that the deprotona-
tion from the carbamate N–H was surely achieved, but in both
cases, the resulting anion formed a stable chelate with the coun-
ter cation, maintaining a situation similar to that of the parent
imine (cf. 13 in Scheme 3). To break down this situation, we
added dicyclohexyl-18-crown-6 (Cy2-18-crown-6)5 and found
its marked effect. Thus, the combination of KH (1.5 equiv)
and Cy2-18-crown-6 (1.5 equiv) provided the desired cycload-
ducts [6 (41%) and 10 (5%)] (Entry 3). After considerable ex-
perimentation, we found that the use of a catalytic amount of
KH/Cy2-18-crown-6 (0.1 equiv each) gave optimal and reprodu-
cible results, providing 6 and 10 in good yield (81%, dr = 77:4,
Entry 4). Gratifyingly, both the yield and the stereoselectivity
were markedly improved compared with our previously reported
We recently reported a novel protocol for the synthesis
of hexahydropyrrolo[3,2-c]quinoline 6 from imine 3,4 where
.
BF3 OEt2 promoted the tandem Mukaiyama–Mannich/hemi-
aminalization sequence (Scheme 1). During this investigation,
2a
´
we reconfirmed Aube’s crucial note indicating that the intra-
molecular hydrogen bonding between the imine and the carba-
mate N–H is formed in closely related substrates and suggesting
that such interaction would render the imine moiety inactive
toward external activation.
We indeed had trouble in controlling the specific activation
NH
HN
Martinelline (1): R =
N
NH2
1
HN
2
H
O
N
Martinellic acid (2): R = H
9b
3
R
O
3a
H
H
N
N
N
4
13
H
NH
Figure 1. Structure of Martinella alkaloids.
TBDPSO
TBSO
MeO2C
BF3•OEt2
(1.5 equiv)
4A MS
OTBDPS
12.5 ppm
HN
N
H
MeO2C
∗
N
.
δ
protocol [BF3 OEt2 (1.5 equiv), 4A MS, CH2Cl2]. The diaster-
OTBS
CH2Cl2
–40 to 0 °C
38%
N
O
Ot-Bu
Boc
eomeric ratio of the products did not reflect the E:Z ratio of
the substrate, which provided insight into the reaction mecha-
nism (vide infra). Use of Lewis bases such as AcOK, AcOLi,6a
and KF resulted in zero conversion (Entries 5–7). The corre-
sponding products were also obtained using KOH, albeit in
low yield (Entry 8).
6 (major isomer)
3 (E:Z = 5:2)
OTBDPS
H
TBSO
MeO2C
MeO2C
OTBDPS
HN
N
H
H
H
N
To gain insight into the reaction mechanism, we carried out
complementary experiments, using other imines 11 and 12
(Chart 1) having an alkyl enol ether or an (E)-alkenyl substitu-
ent. In both cases, no reaction was observed under the optimized
N
O
O
Ot-Bu
TBS
F3B
O
Ot-Bu
F3B
4
5
Scheme 1. Previous result.
Copyright Ó 2008 The Chemical Society of Japan
Ikeda, Shuhei
