Mechanistic studies on the catalytic asymmetric mannich-type reaction with dihydroisoquinolines and development of oxidative mannich-type reactions starting from tetrahydroisoquinolines

Article abstract of DOI:10.1021/jo800800y

(Chemical Equation Presented) Detailed mechanistic studies on our recently reported asymmetric addition reactions of malonates to dihydroisoquinolines (DHIQs) catalyzed by chiral Pd(II) complexes were carried out. It was found that an N,O-acetal was gener

Full text of DOI:10.1021/jo800800y

Mechanistic Studies on the Catalytic Asymmetric Mannich-Type
Reaction with Dihydroisoquinolines and Development of Oxidative
Mannich-Type Reactions Starting from Tetrahydroisoquinolines
†
†
†
†
Christian Dubs, Yoshitaka Hamashima, Naoki Sasamoto, Thomas M. Seidel,
†
‡
,†
Shoko Suzuki, Daisuke Hashizume, and Mikiko Sodeoka*
Synthetic Organic Chemistry Laboratory, RIKEN 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, and
Molecular Characterization Team, RIKEN, Hirosawa, Wako 351-0198, Japan
sodeoka@riken.jp
ReceiVed April 15, 2008
Detailed mechanistic studies on our recently reported asymmetric addition reactions of malonates to
dihydroisoquinolines (DHIQs) catalyzed by chiral Pd(II) complexes were carried out. It was found that
an N,O-acetal was generated in situ by the reaction of DHIQ with (Boc) O, and cooperative action of the
2
Pd(II) complex as an acid-base catalyst allowed the formation of a chiral Pd enolate and a reactive
iminium ion via R-fragmentation. The iminium ion was also accessible via oxidation with DDQ as an
oxidant, and a catalytic asymmetric oxidative Mannich-type reaction was achieved with tetrahydroiso-
quinolines (THIQs) as starting materials. This oxidation protocol was applicable to N-acryloyl-protected
THIQs, allowing the efficient synthesis of optically active tetrahydrobenzo[a]quinolizidine derivatives
via intramolecular Michael reaction.
Introduction
SCHEME 1. Representative Methods for the Synthesis of
Optically Active C1-Substituted THIQs
C1-substituted tetrahydroisoquinolines (THIQs) represent an
important family of biologically active alkaloids, and have been
a target for synthetic organic chemists for decades. Various
1
approaches to construct this ring system have been developed
(
Scheme 1), including the Pictet-Spengler reaction, the
Bischler-Napieralski reduction approach, the Pomeranz-Fritsch
cyclization, the deprotonation-alkylation reaction, and addition
reactions of nucleophiles to the CdN bonds of dihydroiso-
2
quinolines (DHIQs). So far, most asymmetric syntheses of these
molecules have relied on the use of optically active starting
materials or chiral auxilaries. Such reactions require a stoichio-
metric amount of chiral sources, and therefore the development
of efficient methods for asymmetric catalysis has also been of
great interest. However, the number of practical catalytic
†
Synthetic Organic Chemistry Laboratory, RIKEN 2-1 Hirosawa.
Molecular Characterization Team, RIKEN.
‡
reactions is still limited. High turnover numbers and excellent
enantioselectivity were achieved in the catalytic asymmetric
(
1) (a) Bentley, K. W. Nat. Prod. Rep. 2001, 18, 148–170. (b) Scott, J. D.;
Williams, R. M. Chem. ReV. 2002, 102, 1669–1730.
1
0.1021/jo800800y CCC: $40.75  2008 American Chemical Society
J. Org. Chem. 2008, 73, 5859–5871 5859
Published on Web 06/26/2008

Dubs et al.
3
transfer hydrogenation of C1-substituted DHIQs. Recently,
intramolecular allylic amination reactions with chiral Pd(0)
complexes were also reported as a powerful method to obtain
C1-vinyl-substituted THIQs in a highly enantioselective man-
4
ner.
In addition to these elegant methodologies, catalytic asym-
metric addition reactions to the CdN bonds of isoquinoline
scaffolds are also important alternative approaches. Several
successful examples of such addition reactions with various
5
6
nucleophiles, including dialkyl zinc, trimethylsilylcyanide,
7
8
9
allylsilanes, terminal alkynes, and carbonyl compounds, have
been reported. Recently, addition reactions with other hetero-
cyclic systems, such as pyridine, to furnish chiral nitrogen-
containing cyclic compounds have also been gaining much
attention, and unique methods have been devised for diaste-
FIGURE 1. Chiral Pd complexes used in this work.
As regards addition reactions of carbonyl compounds to CdN
bonds, great efforts have been made to develop Mannich-type
reactions with acyclic imines, using ingenious chiral basic metal
1
0
reoselective reactions and (catalytic) enantioselective reac-
1
1
tions. Even catalytic asymmetric acyl Pictet-Spengler reac-
tions became feasible with chiral thiourea-based organocatalysts,
although available nucleophilic aromatic rings are limited to
13
complexes and organic catalysts. In striking contrast, reactions
with cyclic imines have been less well studied, and only a few
9
successful examples are known, although many examples of
1
2
only indoles.
diastereoselective reactions with chiral metal enolates were
1
4
reported. This might be due to difficulties associated with the
lower reactivity of cyclic imines and less efficient face
discrimination. Because the nitrogen atom of the cyclic imines
is normally substituted by a simple alkyl group, the electrophi-
licity is insufficient compared with that of acyclic imines having
electron-withdrawing groups such as acyl groups, sulfonyl
groups, and diarylphosphonoyl groups. In addition, the differ-
ence in the steric size of two substituents on the nitrogen is not
large, which makes it difficult to distinguish the two faces of
the cyclic imines. Therefore, a novel system that can provide
not only an appropriate chiral environment but also effective
activation of the imine is highly desirable for the development
of efficient Mannich-type reactions with cyclic imines.
(
2) For excellent general reviews, see: (a) Chrzanowska, M.; Rozwadowska,
M. D. Chem. ReV. 2004, 104, 3341–3370. (b) Rozwadowska, M. D. Heterocycles
994, 39, 903–931. Recent progress in diastereoselective syntheses: (c) Pedrosa,
1
R.; Andr e´ s, C.; Iglesias, J. M. J. Org. Chem. 2001, 66, 243–350. (d) Gonz a´ lez-
Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69, 3875–
3
7
885. (e) Garc ´ı a, E.; Arrasate, S.; Lete, E.; Sotomayor, N. J. Org. Chem. 2005,
0, 10368–10374.
(3) Reduction of DHIQs: (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya,
T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916–4917, and references cited
thereinRecently, the catalytic asymmetric hydrogenation of isoquinolines was
reported: (b) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem.,
Int. Ed. 2006, 45, 2260–2263.
(
4) (a) Ito, K.; Akashi, S.; Saito, B.; Katsuki, T. Synlett 2003, 1809–1812.
(
b) Shi, C.; Ojima, I. Tetrahedron 2007, 63, 8563–8570.
(5) (a) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.; Inomata, K. Chem.
Lett. 1997, 59–60. (b) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.; Inomata,
K. Bull. Chem. Soc. Jpn. 2000, 73, 447–452. (c) Wang, S.; Seto, C. T. Org.
Lett. 2006, 8, 3979–3982.
Previously, we described catalytic asymmetric Mannich-type
reactions of ꢀ-keto esters with acyclic imines using chiral Pd(II)
(
6) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2
001, 123, 10784–10785.
15
complexes 1 (Figure 1). Reaction of 1,3-dicarbonyl compounds
(
7) (a) Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org.
with the Pd complex 1 affords a chiral Pd enolate, accompanied
by the formation of a strong protic acid, and protonation of the
imines is important to promote the reaction efficiently (Scheme
2). On the assumption that less reactive cyclic imines would be
activated by protonation to form an iminium intermediate, we
attempted the reaction of DHIQs with malonates. We finally
found that the reaction of diisopropyl malonate with various
DHIQs proceeded smoothly in the presence of a catalytic amount
Lett. 2006, 8, 1295–1297. Also, the reaction with a chiral allylsilane was
reported: (b) Yamaguchi, R.; Tanaka, M.; Matsuda, T.; Fujita, K. Chem. Commun.
1
999, 2213–2214.
8) (a) Li, Z.; MacLeod, P. D.; Li, C.-J. Tetrahedron: Asymmetry 2006, 17,
90–597. (b) Taylor, A. M.; Schreiber, S. Org. Lett. 2006, 8, 143–146.
9) (a) Murahashi, S.-I.; Imada, Y.; Kawakami, T.; Harada, K.; Yonemushi,
(
5
(
Y.; Tomita, N. J. Am. Chem. Soc. 2002, 124, 2888–2889. (b) Itoh, T.; Yokoya,
M.; Mizauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2003, 5, 4301–4303. (c)
Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
6
700–6704. (d) Frisch, K.; Langda, A.; Saaby, S.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 6058–6063.
10) Recent examples of diastereoselective addition reactions of carbon-
(
centered nucleophiles to other cyclic CdN bonds: (a) Comins, D. L.; Kuethe,
J. T.; Hong, H.; Lakner, F. J.; Concolino, T. E.; Rheingold, A. L. J. Am. Chem.
Soc. 1999, 121, 2651–2652. (b) Charette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829–11830. (c)
Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002, 124, 8184–8185. (d) Legault,
C.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 6360–6361. (e) Poupon, E.;
Francois, D.; Kunesch, N.; Husson, H.-P. J. Org. Chem. 2004, 69, 3836–3841.
(13) (a) Kobayashi, S.; Ueno, M. In ComprehensiVe Asymmetric Catalysis;
JacobsenE. N., ; Pfaltz, A., ; Yamamoto, H., Eds.; Springer: Berlin, 2004;
Supplement 1, Chapter 29.5. (b) Cordova, A. Acc. Chem. Res. 2004, 37, 102–
112. (c) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–2569. (d)
Ferraris, D. Tetrahedron 2007, 63, 9581–9597. (e) Petrini, M.; Torregiani, E.
Synlett 2007, 159–186. (f) Shibasaki, M.; Matsunaga, S. J. Organomet. Chem.
2006, 691, 2089–2100.
(
f) Focken, T.; Charette, A. B. Org. Lett. 2006, 8, 2985–2988. (g) Turcaud, S.;
(14) For selected examples of diastereoselective Mannich-type reactions of
chiral metal enolates with cyclic imines and iminium ions see: (a) Nagao, Y.;
Kumagai, T.; Tatami, S.; Abe, T.; Kuramoto, Y.; Taga, T.; Aoyagi, S.; Nagase,
Y.; Ochiai, M.; Inoue, Y.; Fujita, E. J. Am. Chem. Soc. 1986, 108, 4673–4675.
(b) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi, S.; Fujita, E. J. Am. Chem.
Soc. 1988, 110, 289–291. (c) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi,
S.; Fujita, E. J. Org. Chem. 1990, 55, 1148–1156. (d) Matsumura, Y.; Kanda,
Y.; Shirai, K.; Onomura, O.; Maki, T. Org. Lett. 1999, 1, 175–178. (e)
Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000,
56, 7411–7422. (f) Pilli, R. A.; B o¨ ckelmann, M. A.; Alves, C. F. J. Braz. Chem.
Soc. 2001, 12, 634–651. (g) Barrag a´ n, E.; Olivo, H. F.; Romero-Ortega, M.;
Sarduy, S. J. Org. Chem. 2005, 70, 4214–4217. (h) Olivo, H. F.; Tovar-Miranda,
R.; Barrag a´ n, E. J. Org. Chem. 2006, 71, 3287–3290.
Sierecki, E.; Martens, T.; Royer, J. J. Org. Chem. 2007, 72, 4882–4885. (h)
Yamada, S.; Inoue, M. Org. Lett. 2007, 9, 1477–1480.
(
11) Recent examples of (catalytic) enantioselective addition reactions of
carbon-centered nucleophiles to other cyclic CdN bonds: (a) Nakamura, M.;
Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 1996, 118, 8489–8490. (b) Ichikawa,
E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2004, 126, 11808–11809. (c) Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki,
M. Synlett 2005, 1491–1508. (d) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc.
2006, 128, 9646–9647. (e) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem.
Soc. 2007, 129, 6686–6687. (f) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem.
Soc. 2007, 129, 9300–9301.
(
12) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558–
1
1
0559. (b) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
086–1087. (c) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N.
(15) (a) Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi,
N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005, 44, 1525–1529. (b) Sodeoka,
M.; Hamashima, Y. Pure Appl. Chem. 2006, 78, 477–494.
J. Am. Chem. Soc. 2007, 129, 13404–13405.
5
860 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of Optically ActiVe C1-Substituted THIQs
1
6,17
SCHEME 2. Reaction of ꢀ-Keto Esters with Acyclic Imines
catalysts.
In the first part, the mechanism of the reaction
with DHIQs in the presence of (Boc)2O is discussed. These
studies indicate that the reaction proceeds via the formation of
N,O-acetals, and consecutive R-fragmentation gives the reactive
iminium ion intermediate. On the basis of these results, we
attempted the direct generation of the iminium ion intermediate
starting from N-Boc-protected THIQs or free THIQs. In the
second part, a novel catalytic asymmetric oxidatiVe Mannich-
type reaction, in which the iminium ion intermediate is formed
via oxidation with DDQ as an oxidant, is described (Scheme 3,
eq 2).
SCHEME 3. Mannich-Type Reaction To Give Optically
Active THIQs
Results and Discussion
1
. Catalytic Asymmetric Addition Reactions of Malonates
15
to DHIQs. Motivated by our previous results, we attempted
the reaction with DHIQs (4) using malonates (5) as nucleophiles
in the presence of a catalytic amount of the Pd complex 1. After
examining various reaction conditions, we developed a highly
enantioselective catalytic reaction to afford the corresponding
1
6
C1-substituted tetrahydroisoquinoline derivatives. According
to an optimized procedure, DHIQs in CH2Cl2 were first treated
with (Boc)2O (6a) at room temperature, and the catalyst (2 mol
%
) and the malonate were added to the resulting mixture at 0
SCHEME 4. The Influence of the Reaction Procedure on
the Reaction Efficiency
°
C. The best enantioselectivity was observed when 1a and
diisopropyl malonate 5a were used. This reaction was found to
be applicable to substrates having various substitutents on the
1
8
aromatic ring. The results are summarized in Table 1. In
addition to a simple DHIQ 4a (entry 1), substrates with electron-
donating substituents (entries 2-7) and electron-withdrawing
substituents (entry 8) were available, and the reaction was
1
9
completed within several hours in most cases, affording 7 in
high yield with good to excellent enantioselectivity (∼98% yield,
∼
97% ee). Interestingly, the substrates with neighboring meth-
oxy groups (4e and 4f) underwent the reaction without difficulty
despite the possible bidentate coordination of the dimethoxy
moiety to the catalyst (entries 5 and 6). Although the substrate
4g with a methoxy group at the C8 position was expected to
suffer severe steric repulsion, the reaction proceeded smoothly,
affording 7g in 94% yield with 82% ee (entry 7). For 4e and
SCHEME 5. Proposed Catalytic Cycle
4
f, the catalyst loading could be reduced to 0.5 mol % without
significant loss of reaction efficiency (entries 5 and 6). In the
case of 7e, a single recrystallization from ethyl acetate gave 7e
with 99% ee.
At the beginning of this project, we observed that the addition
order of the reagents was extremely important for promoting
the reaction. Thus, when DHIQ 4a was mixed with diethyl
malonate (5b) in the presence of 1b, the desired product was
not obtained at all, even if (Boc)2O was added to trap the free
amine of the addition product (Scheme 4a). But, a slight
modification of the procedure gave the desired coupling product
(
16) Part of this work was reported as a communication: Sasamoto, N.;
Dubs, C.; Hamashima, Y.; Sodeoka, M., J. Am. Chem. Soc. 2006, 128, 14010-
4011.
17) For preparation of the Pd complexes 1-3 see: Fujii, A.; Hagiwara, E.;
Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450-5458.
18) DIHQs were prepared according to the known procedures: (a) Pelletier,
1
(
(
J. C.; Cava, M. P. J. Org. Chem. 1987, 52, 616–622. (b) Rohluff, J. C.; Dyson,
N. H.; Gardner, J. O.; Alfredson, T. V.; Sparacino, M. L.; Robinson, J., III J.
Org. Chem. 1993, 58, 1935–1938. (c) Clark, R. D.; Repke, D. B.; Berger, J.;
Nelson, J. T.; Kilpatrick, A. T.; Brown, C. M.; MacKinnon, A. C.; Clague, R. U.;
Spedding, M. J. Med. Chem. 1991, 34, 705–717. (d) Huang, W.-J.; Singh, O. V.;
Chen, C.-H.; Chiou, S.-Y.; Lee, S.-S. HelV. Chim. Acta 2002, 85, 1069–1078.
of [{(R)-dm-segphos}Pd(H2O)2](OTf)2 to furnish C1-substituted
optically active THIQs with up to 97% ee (Scheme 3, eq 1).
Herein we describe full details of catalytic asymmetric
Mannich-type reactions of malonates with in situ-formed
iminium ions of DHIQs using chiral Pd(II) complexes as
(
e) Fecik, R. A.; Devasthale, P.; Pillai, S.; Keschavarz-Shokri, A.; Shen, L.;
Mitscher, L. A. J. Med. Chem. 2005, 48, 1229–1236.
(19) All compounds 7a-l exist as a mixture of rotamers. See ref 16.
J. Org. Chem. Vol. 73, No. 15, 2008 5861

Dubs et al.
TABLE 1. Catalytic Asymmetric Addition Reactions to Various
SCHEME 6. Reaction of 4a with 6a
a
f
DHIQs –
complex (3-type) is generated after deprotonation then reacts
with the malonate to form the palladium enolate 11, and
subsequent nucleophilic attack of the enolate on the iminium
2
1
ion gives the desired product 7. In spite of the formation of
the highly reactive iminium species, high asymmetric induction
was observed under mild reaction conditions (0 °C to room
temperature), which may be attributed to simultaneous dual
activation by the Pd complex as an acid-base catalyst.
This reaction mechanism is supported by the following
experimental data:
(
1) Formation of N,O-acetal 9: The reaction of 4a with 6a
in DCM led to the complete formation of the carbonate 8a in
5 min (Scheme 6). The resulting 8a then slowly decarboxylated
1
to give the N,O-acetal 9a, but the reaction did not reach
completion even after a prolonged time. However, mixing 4a
and 6a in toluene at 100 °C gave 9a exclusively. Like all the
coupling products 7, 9a exists as a mixture of two rotamers at
room temperature in CDCl3. The conversion of 8a to 9a was
also promoted by the addition of 1a. A control experiment
showed that the addition of a catalytic amount of TfOH is also
effective for this purpose. Upon addition of a catalytic amount
of 1a to a DCM solution of 8a, violent bubbling (decarboxy-
lation) was observed and the formation of 9a was complete in
less than 15 min.
1
In Figure 2, the aromatic regions of the H NMR spectra of
a
Reaction conditions: 0.15 mmol of 4, 0.225 mmol of 5a, 0.225
b
mmol of 6a, 2 mol % of 1a in 0.15 mL of DCM at 0 °C. Isolated
yield after flash column chromatography. Determined by HPLC (see
ref 16). 1 mol % 1a. 0.5 mol % 1a. After recrystallization from
ethyl acetate. 5 mol % 1a.
c
d
e
f
g
in high yield. Premixing 4a with 6a for 1 h at room temperature,
followed by the addition of 5b and 1b, gave the product 7i with
moderate enantioselectivity (Scheme 4b). Initially, we antici-
pated that the reaction with DHIQs would proceed in a similar
fashion to that which we had reported for the reaction of ꢀ-keto
1
5
esters with acyclic imines (Scheme 2). We proposed that
the imine would be activated by a proton generated during the
formation of the chiral Pd enolate, which was considered to be
crucial for the reaction. In the present reaction, however, the
initial results (Scheme 4) suggested a different mechanism.
On the basis of the experimental data described below, we
propose a unique reaction mechanism, as outlined in Scheme
FIGURE 2. 1H NMR in CD
Cl
2
(aromatic region): (a) 4a, (b) 6a +
2
4
a, and (c) 6a + 4a + 1a.
4
a, 8a, and 9a are shown. The shift of the C1 proton signal is
striking [for 4a: 8.32 ppm; for 8a: 7.38 ppm; for 9a: 6.29 and
.39 ppm (mixture of two rotamers)], indicating the stepwise
formation of 9a. Additionally, decarboxylation of 8a promoted
6
5
. The initial reaction of (Boc)2O with DHIQ 4 gives the
carbonate 8, and decarboxylation induced by the catalyst 1 itself
or an acidic proton derived from 1 leads to the formation of the
N,O-acetal 9. Similar formation of N,O-acetals by the reaction
(
20) For the formation of N,O-acetal by the reaction of (Boc)
isoquinoline: see: Ouchi, H.; Saito, H.; Yamamoto, Y.; Takahata, H. Org. Lett.
002, 4, 585–587.
21) The asymmetric addition reaction of malonates to cyclic N,O-acetals
2
O with
2
0
2
of (Boc)2O with isoquinolines was reported in the literature.
R-Fragmentation is induced by the acidic proton released from
a, and t-BuOH and the iminium ion 10 are formed. The PdOH
(
has been reported: Onomura, O.; Kanada, Y.; Nakamura, T.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 2002, 43, 3229–3231.
1
5
862 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of Optically ActiVe C1-Substituted THIQs
SCHEME 7. Formation of 12a and Side Products 13a and
4a
1
SCHEME 8. Side Product Formation at Room Temperature
FIGURE 4. 13C NMR in CD
a + 1a (0.1 equiv), and (c) 9a + 1a (0.2 equiv).
2
2
Cl in the range 65-85 ppm: (a) 9a, (b)
9
by 1a was followed by IR, and the disappearance of one (CO)
was observed (Figure 3). Upon addition of 1a (2 mol %) to 8a
the precursor and the fragmented species is strongly dependent
on the substituent on the nitrogen, the nature of the leaving
2
4
group, and the Lewis acid used for activation.
Generation of 12a is also supported by the following results
(
Scheme 8). At room temperature, the reaction was complete
after only 15 min. But, the Boc-amine 13a (4% yield) and the
amide 14a (4% yield) were isolated as side products, which
were not formed in the reaction performed at 0 °C. These
compounds are considered to be generated via an oxidation-
reduction pathway from the hemiacetal 12a (Scheme 7). It is
likely that 12a reacted with Pd(II) to give 14a together with a
Pd-H species, which then reduced 10a to give 13a. We recently
reported an efficient asymmetric conjugate reduction of enones
using 3b as a catalyst and ethanol as a reductant, in which Pd-H
FIGURE 3. IR monitoring of the reaction of 4a and 6a: black line,
8
a; blue line, 8a + 1a (10 min); red line, 8a + 1a (20 min); and violet
line, 8a + 1a (30 min, 9a).
25
is considered to be a key intermediate.
2
6
(
3) Formation of the Pd-enolate complex 11: Under the
[
(CO) ) 1705, 1736 cm-1 (black line)], the band at 1736 cm
-1
conditions described in Scheme 8, ESI-MS of the reaction
mixture was measured after 5 min. A signal at m/z 1015.2
corresponding to the Pd-enolate complex 11 [{(R)-dm-
-
1
disappeared gradually and the band at 1705 cm shifted to a
smaller wavenumber (1692 cm ). After 30 min, a band at 1692
cm alone remained, which corresponds to 9a (violet line).
2) r-Fragmentation of 9: To examine the further steps of
the reaction, 9a was treated with 1a, and the formation of
-1
-
1
(
(
22) (a) Bloch, R. Chem. ReV. 1998, 98, 1407–1438. (b) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron, 2000, 56, 3817-1856. A general review on
13
t-BuOH was observed by NMR. In Figure 4a, C NMR spectra
of 9a in the range of 65-85 ppm are shown. The carbon signals
attributed to C1 and the quaternary tert-butyl carbons were
observed in this region. Upon the addition of 1a, a new signal
corresponding to t-BuOH appeared, which grew bigger when
additional 1a was added. The other signals, however, did not
change significantly. These observations suggest the formation
of the hemiacetal 12a, which might be in equilibrium with 9a.
This can be understood in terms of R-fragmentation of 9a to
give the iminium ion 10a, followed by a nucleophilic attack by
the hydroxide ion or water molecule coordinated to Pd (Scheme
iminium ion cyclizations: (c) Royer, J.; Bonin, M.; Micouin, L. Chem. ReV.
2
004, 104, 2311–2352.
(
23) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044–1070.
24) Yamamoto, Y.; Nakada, T.; Nemoto, H. J. Am. Chem. Soc. 1992, 114,
21–125.
(
1
(
25) (a) Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8, 4851–
4854. (b) Monguchi, D.; Beemelmanns, T.; Hashizume, D.; Hamashima, Y.;
Sodeoka, M. J. Organomet. Chem. 2008, 693, 867–873.
(
26) For the formation of Pd-enolate complexes of ꢀ-keto esters and
ꢀ
-diketones, see: (a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc.
2002, 124, 11240–11241. (b) Hamashima, Y.; Hotta, D.; Umebayashi, N.;
Tsuchiya, Y.; Suzuki, T.; Sodeoka, M. AdV. Synth. Catal. 2005, 347, 1576–
586. (c) Sodeoka, M.; Hamashima, Y. Bull. Chem. Soc. Jpn. 2005, 78, 941–
1
956. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049–
060. (e) Nama, D.; Pregosin, P. S.; Albinati, A.; Rizzato, S. Organometallics
4
7
). The iminium ion is a powerful intermediate in organic
2
2
2007, 26, 21112121. For the formation of Ru enolate complexes of ꢀ-ketoesters
see: (f) Althaus, M.; Bonaccorsi, C.; Mezzetti, A.; Santoro, F. Organometallics
2006, 25, 3108–3110.
synthesis, and R-fragmentation induced by Lewis or protic
acids is a frequently used method. The equilibrium between
2
3
J. Org. Chem. Vol. 73, No. 15, 2008 5863

Dubs et al.
SCHEME 11. Conversion of 7e and Determination of the
SCHEME 9. Formation of the Pd Enolate 11
Absolute Configuration
Although the exact mechanism of the asymmetric induction
is not clear, the observed absolute configuration correlates to
our proposed model of the Pd enolate complexes (Figure 5).
The bulky i-Pr groups of the malonate would be located away
from the aryl rings of the ligand, creating a new C2 symmetric
environment. The structurally rigid and bulky aromatic ring of
the iminium intermediate 10 points away from the i-Pr group
to avoid steric repulsion (model A vs model B), controlling the
face selection of the CdN bond (model A). The experimental
fact observed during the optimization that changing the size of
malonate 5 had an influence on the enantioselection seems to
be in accord with the proposed transition state model (R ) Et:
SCHEME 10. Comparison between 1b and 3b
7
3% ee; R ) Bn: 66% ee) (Table 2, entries 1-3). Additionally,
a significant effect of the substituent of the ligand was observed
entries 1 and 4-6). It is likely that the methyl substituents on
(
the phenyl ring of the ligand might be important to disfavor
the minor reaction pathway (model B) as a result of increased
steric interaction with the Boc group, thus making the reaction
pathway A more favorable.
+
segphos}Pd(5a-H)] was observed, although a major peak ion
was [{(R)-dm-segphos}Pd(OTf)]+ (m/z 977.1) (Scheme 9a).
2
. Oxidative Mannich-Type Reaction of Malonates to
Although the same enolate complex 11 was also detected in a
solution containing 3a and 5a (Scheme 9b), no corresponding
signal appeared from the mixture of 1a and 5a (Scheme 9c).
Additionally, H/D exchange reaction was observed after the
addition of D2O to a CD2Cl2 solution of 1a and 5a (1:1), and
it took 2 h to achieve 50% disappearance of the acidic methylene
protons of 5a. In contrast, in the case of 3a and 5a, the H/D
exchange was much faster (30 min until completion) (Scheme
THIQs. Because we found that the iminium ion is a key
intermediate, we next became interested in its formation by
oxidative methods starting from the corresponding THIQs
(
Scheme 12). In addition to R-fragmentation, various oxidative
methods have been developed to generate iminium ions,
including the use of chemical oxidizing reagents, photochemical
2
2,23
methods, and electrochemical oxidations.
Such oxidative
coupling reactions would have the great advantage that the
imines 4, preparation of which is often tedious, are no longer
necessary, and instead the readily available and stable 13 can
be used. Notably, since some of the starting imines 4 are
prepared via oxidation of the corresponding amines with NBS
as an oxidant, the direct use of the amines in the asymmetric
Mannich-type reactions would reduce the overall number of
steps necessary for the preparation of 7. This type of oxidative
Mannich reaction has been gaining much attention recently.
Although the number of reports is increasing, no catalytic
asymmetric version of the reaction has yet been reported, to
9
d). These results suggest that the acidic complex 1a induces
R-fragmentation and the deprotonated complex PdOH corre-
sponding to the monomer form of 3a acts as a base to abstract
the R-proton of 5a to give the Pd-enolate complex 11.
Interestingly, in our optimization studies, we found that 3a did
not catalyze the reaction, although 1a actually did, even in
ethanol (Scheme 10). This result suggests that the formation of
the Pd enolate alone is not sufficient for promoting the reaction
and activation of both reactants is essential, highlighting the
importance of the cooperative action of 1a as an acid-base
catalyst.
8
a,28
our knowledge.
Li et al. have reported various oxidative
Determination of the Absolute Configuration and the
1
6
coupling reactions in which reactive iminium and oxonium
Proposed Transition State Model. As reported previously,
the conversion of 7e to calycotomine 15 was carried out, and
R)-calycotomine was obtained. The absolute configuration of
species are formed either via oxidation with tert-butyl hydro-
2
8a,b
peroxide (TBHP) in the presence of CuBr
or via oxidation
(
1
5 was determined by comparison of the optical rotation with
2c,27
(28) Oxidative Mannich-type reactions: (a) Li, Z.; Li, C.-J. J. Am. Chem.
Soc. 2005, 127, 3672–3673. (b) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173–
3176. (c) Murahashi, S.-i.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc.
the reported value.
This result reveals that the sense of
enantioselection of the present reaction is S-selective (Scheme
1).
2
003, 125, 15312–15313. (d) Murahashi, S.-i.; Komiya, N.; Terai, H. Angew.
1
Chem., Int. Ed. 2005, 44, 6931–6933. (e) Catino, A. J.; Nichols, J. M.; Nettles,
B. J.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128, 5648–5649. (f) Zhang, Y.; Li,
C.-J. Angew. Chem., Int. Ed. 2006, 45, 1949–1952. (g) Matsuo, J.; Tanaki, Y.;
Ishibashi, H. Org. Lett. 2006, 8, 4371–4374. (h) Matsuo, J.; Tanaki, Y.; Ishibashi,
H. Tetrahedron Lett. 2007, 48, 3233–3236.
(27) (a) Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry 1998,
9
, 183–187. For a review on calycotomine see: (b) Kaufmann, T. S. Synthesis
2
005, 339–360. See also ref 2c.
5
864 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of Optically ActiVe C1-Substituted THIQs
FIGURE 5. Proposed transition state model. The naphthyl moieties of the ligand were omitted for clarity.
a
TABLE 2. The Effect of Malonates and Ligands
reaction was carried out at room temperature, the substantial
amount of water induced redox reactions to give the side
products (see Scheme 7). Thus, we prepared anhydrous Pd
complex 2a. Structure determination by X-ray analysis con-
30
firmed that it contained no water molecule. When 2a was used
instead of 1a, the H2O-induced side reactions were suppressed
effectively, and 7e was obtained in better chemical yield (entry
4). The molecular structure of 2a displays a square-planar
geometry of Pd(II) coordinated with two phosphorus atoms and
two oxygen atoms of the trifluoromethanesulfonyl group (Figure
6). Two trifluoromethanesulfonyl groups are positioned in the
open space to avoid unfavorable steric interaction with the
dimethylphenyl group on the ligand. This supports the proposed
structure of the Pd enolate as depicted in Figure 5. In the next
section, we further examined the reaction using nonprotected
THIQs, and full conversion and excellent chemical yield were
achieved using 2a as a catalyst.
b
c
entry
5(R)
1
7
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
5a (i-Pr)
5b (Et)
5c (Bn)
5b (Et)
5b (Et)
5b (Et)
1a
1a
1a
1b
1c
1d
7a
7i
7j
7i
7i
7i
12
3
12
2
1
7
67
quant.
62
quant.
quant.
quant.
80
73
66
44
48
65
a
Reaction conditions: 0.15 mmol of 4a, 0.225 mmol of 5, 0.165
mmol of 6a, 2 mol % of 1 in 0.15 mL of anhydrous EtOH. Isolated
yield after flash column chromatography. Determined by chiral HPLC
b
c
(
see ref 16).
From Amines. Further investigations revealed that the
commercially available amine 14e could be used directly (Table
SCHEME 12. Oxidative Routes to Iminium Ions
4
). Thus, premixing 14e and 6a forms 13e quantitatively and
the concomitantly formed t-BuOH did not have any negative
effect on the reaction. Again, the slow addition of DDQ was
important for high chemical yield and enantioselectivity (entries
1
-3). Finally, the amount of DDQ and 5a could be reduced,
and the desired product 7e was obtained in 97% yield with 86%
ee (entries 5 and 6).
2
8f
Substrate Scope. Under the optimized reaction conditions,
THIQs with different substituents on the aromatic ring were
subjected to the oxidative Mannich-type reaction. The results
are summarized in Table 5. Good results were obtained when
THIQs with electron-donating substituents were used (entries
with DDQ. For example, they reported the oxidative coupling
reaction of malonates with N-phenyl-protected THIQs using the
28b
TBHP/CuBr combination. Inspired by their pioneering work,
we examined our reactions using DDQ as an oxidant, because
we thought that DDQ would minimize the interference with
our Pd-catalyst system compared to that with the THBP/CuBr
2-4), although the reaction of 14g was not so efficient, probably
2
9
due to steric hindrance (entry 5). Unfortunately, however, only
a low yield was observed for 14a (entry 1), and no conversion
occurred in the case of 14h, which has a Br substituent on the
aromatic ring. In contrast to the reaction with the N,O-acetals,
this method is limited to THIQs with electron-donating sub-
stituents. However, for electron-rich substrates, this one-pot
procedure is operationally convenient, and the coupling products
were obtained at a synthetically useful level. It should be noted
that an easily removable protecting group could be used in our
reaction, whereas N-phenyl-substituted substrates have normally
system.
From Isolated N-Boc-Amines. At first, we examined the
reaction of the isolated N-Boc-THIQ 13e. Because DDQ
oxidation of 13e did not occur at 0 °C, the reaction needed to
be carried out at room temperature (Table 3). The addition of
DDQ in one portion into a DCM solution of 13e and 5a
containing 5 mol % of 1a gave 7e in low yield (9%), but with
high enantioselectivity (80% ee) (entry 1). We considered the
low yield to be due to the decomposition of the catalyst and
undesired reactions induced by a high concentration of the
reactive iminium ion. Consequently, we examined the slow
addition of DDQ as a DCM solution. To our delight, the yield
was dramatically increased when DDQ was added slowly over
2
8
been used in the literature.
Proposed Catalytic Cycle. On the basis of the observations
in the case of N,O-acetals, we propose a catalytic cycle of the
31
oxidative Mannich-type reaction as shown in Scheme 13. The
5
h (83%, 86% ee) (entry 2). However, the chemical yield
decreased when the amount of catalyst was reduced to 2 mol
(entry 3). Since 5 mol % of the catalyst was used and the
reaction of 14 with 6a gives the N-Boc-THIQs 13, and oxidation
%
(30) The crystallographic data for 2a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary no. CCDC 673878. These data
can be obtained online free of charge.
(31) A similar reaction mechanism is proposed in ref 28b.
(
29) Indeed, the reaction with CuBr-TBHP as an oxidant did not proceed
at all. Benzoquinone was also ineffective.
J. Org. Chem. Vol. 73, No. 15, 2008 5865

Dubs et al.
a
TABLE 3. Oxidative Mannich-Type Reaction of 13e and 5a
b
c
entry
Pd cat.
DDQ addition
time (h)
yield (%)
ee (%)
1
2
3
1a
1a
1a
2a
one portion
over 5 h
over 5 h
over 5 h
12
7
7
9
83
34
89
80
86
85
81
d
4
7
a
Reaction conditions: 0.15 mmol of 13e, 0.225 mmol of 5a, 5 mol % of Pd catalyst in 0.15 mL of anhydrous DCM; slow addition of DDQ in 1.5
b
c
d
mL of DCM. Isolated yield after flash column chromatography. Determined by chiral HPLC (see ref 16). 2 mol % of 1a.
FIGURE 6. X-ray structure of 2a. Hydrogen atoms are omitted for clarity. Selected distances (Å) and angles (deg) are as follows: Pd(1)-O(5)
2
.1541(2), Pd(1)-O(8) 2.1595(2), Pd(1)-P(2) 2.2305(6), Pd(1)-P(1) 2.2382(6), O(5)-Pd(1)-O(8) 82.67(7), O(5)-Pd(1)-P(2) 172.21(5),
O(8)-Pd(1)-P(2) 93.80(5), O(5)-Pd(1)-P(1) 94.90(5), O(8)-Pd(1)-P(1) 166.63(5), P(2)-Pd(1)-P(1) 90.10(2), C(15)-P(1)-Pd(1) 117.24(7),
C(2)-P(1)-Pd(1) 117.63(7), C(23)-P(1)-Pd(1) 100.75(7), C(39)-P(2)-Pd(1) 111.87(7), C(9)-P(2)-Pd(1) 112.35(7), C(31)-P(2)-Pd(1) 108.62(8),
S(1)-O(1)-Pd(1) 131.00(1), S(2)-O(8)-Pd(1) 117.09(1).
a
TABLE 4. Coupling Reaction of 14e and 5a
b
c
entry
DDQ (equiv)
DDQ addition
5a (equiv)
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
1.1
1.1
1.1
1.4
1.0
1.0
over 5 h
over 2 h
over 10 h
over 10 h
over 10 h
over 10 h
1.5
1.5
1.5
1.5
1.5
1.1
7
4
12
12
12
12
64
41
81
80
91
97
88
75
86
86
86
86
a
Reaction conditions: 0.1 mmol of 14e, 5a, 0.11 mmol of 6a, 5 mol % of 2a in 0.15 mL of anhydrous DCM; slow addition of DDQ in 1.5 mL of
b
c
DCM. Isolated yield after flash column chromatography. Determined by chiral HPLC (see ref 16).
3
2
(
1
hydride abstraction) by DDQ gives the reactive iminium ion
0. The concomitantly formed phenolate anion 15 may act as a
weak base, which facilitates the formation of the Pd enolate
1. Finally, these active species react to give the desired coupling
16 may also interfere with the stereoselectivity of the reaction,
although its exact action is not clear.
Asymmetric Synthesis of Tetrahydrobenzo[a]quinolizidine
Derivatives. The tetrahydrobenzo[a]quinolizidine system can be
found in various alkaloids, such as the ipecac alkaloids, which
1
product 7. We suppose that the limited availability of the
substrates is associated with the feasibility of the oxidation of
3, which only proceeds in the case of the electron-rich
3
3,34
include emetine as a prominent member.
As described
above, we normally used a Boc group as a protecting group of
1
substrates. We attribute the lower enantioselectivity compared
to the reaction with N,O-acetals to the difference in the reaction
temperature (0 °C vs rt) and concentration (0.5 M vs gradient
from 0.75 to 0.1 M). In addition, the formed phenolic coproduct
(
32) The initial reaction step in the oxidation with DDQ is believed to be
hydrogen abstraction. See: Fu, P. P.; Harvey, R. G., Chem. ReV., 1978, 78, 317-
61.
33) Fujii, T.; Ohba., M. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1998; Vol 51, pp 271-323.
3
(
5
866 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of Optically ActiVe C1-Substituted THIQs
ad
TABLE 5. Oxidative Mannich-Type Reaction of Various THIQs
SCHEME 14. Formation of the Acryloyl-Protected
Coupling Product
with acryloyl chloride, followed by treatment with suitable
alcohols (Scheme 14). But these compounds were found to be
unstable, being readily converted to the corresponding aldehyde
by hydrolysis during column chromatography. Therefore, we
looked at in situ preparation of the corresponding N,O-acetal
using acryloyl carbonate 18 (Scheme 14). This carbonate was
3
5
prepared according to the literature. Treatment of 18 with 4a
in DCM at 0 °C gave 17, and no N-Boc-protected compound
was observed. To the resulting solution were added the Pd
complex 1a and the malonate 5a. Probably because the
formation of the corresponding iminium ion might be disfavored
by the stronger electron-withdrawing nature of the acryloyl
group, the reaction was slow compared to that of the Boc-
protected substrate. After 16 h, the coupling product 19 was
obtained in 62% yield with as high as 86% ee, indicating that
the acryloyl group is also available in this Mannich-type
reaction.
a
Reaction conditions: 0.1 mmol of 14, 0.11 mmol of 5a, 0.11 mmol
of 6a, 5 mol % of 2a in 0.15 mL of anhydrous DCM; slow addition of
b
DDQ (1.0 equiv) in DCM (1.5 mL) over 10 h. Isolated yield after
flash column chromatography. Determined by chiral HPLC (see ref
6). 10 mol % of 2a.
c
Encouraged by this result, we next examined the oxidative
Mannich-type reaction with N-acryloyl THIQ 20 and its
application to the asymmetric synthesis of the tetrahydroben-
zo[a]quinolizidine system (Scheme 15). The amide 20 was
prepared by the conventional method. The following coupling
reaction using the DDQ procedure gave 21 in high yield with
excellent enantioselectivity (74%, 86% ee). The formation of
the six-membered ring by intramolecular Michael reaction gave
the desired 22 without significant loss of optical purity (83%
ee). Hydrolysis and decarboxylation under a basic condition,
followed by methyl ester formation with TMSCHN2, gave 24
d
1
SCHEME 13. Proposed Reaction Mechanism for the
Oxidative Mannich-Type Reaction
36
as a single diastereomer. The relative configuration of the acid
3
7
2
3 was unequivocally determined by X-ray analysis. The
absolute stereochemistry was assigned by analogy to the case
of 7e. The optical purity of 23 was enriched to 99% by
recrystallization from methanol. It is noteworthy that catalytic
asymmetric synthesis of 24 was achieved starting from N-
acryloyl THIQ 20 and no preparation of the corresponding imine
was necessary, highlighting the usefulness of the DDQ procedure.
the starting materials. If this Boc group can be replaced by an
acryloyl group, it is expected that the coupling product can be
subjected to an intramolecular Michael reaction to construct the
core structure of the tetrahydrobenzo[a]quinolizidine system.
To test this hypothesis, we initially tried to synthesize N-acryloyl
N,O-acetals such as 17 as substrates by the reaction of the imine
Conclusion
We have developed a novel catalytic asymmetric Mannich-
type reaction for the synthesis of optically active C1-substituted
(35) (a) Yamamoto, Y.; Tarbell, D. S. J. Org. Chem. 1971, 36, 2954. (b)
Vansteenkiste, S.; Matthijs, G.; Schacht, E.; Schrijver, F. D.; Damme, M. V.;
Vermeersch, J. Macromol. Rapid Commun. 1999, 20, 333.
(
34) For recent examples, see: (a) Garc ´ı a, E.; Lete, E.; Sotomayor, N. J.
(36) For the synthesis of racemic 24 see: Ihara, M.; Yamada, M.; Ishida, Y.;
Tokunaga, Y.; Fukumoto, K. Heterocycle, 1997, 44, 531-536.
(37) The crystallographic data for 23 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary no. CCDC 670312. These data
can be obtained online free of charge.
Org. Chem. 2006, 71, 6776–6784. (b) Bassas, O.; Llor, N.; Santos, M.-M.; Griera,
R.; Molins, E.; Amat, M.; Bosch, J. Org. Lett. 2005, 7, 2817–2820. (c) Tietze,
L. F.; Rackelmann, N.; M u¨ ller, I. Chem. Eur. J. 2004, 10, 2722–2731. (d)
Kirschbaum, S.; Waldmann, H. J. Org. Chem. 1998, 63, 4936–4946.
J. Org. Chem. Vol. 73, No. 15, 2008 5867

Dubs et al.
SCHEME 15. Synthesis of Tetrahydrobenzo[a]quinolizidine Derivative 24
1
THIQs. The addition reaction of malonates to in situ-formed
iminium ion intermediates of DHIQs proceeded smoothly to
give the coupling product in high yield with good to excellent
enantioselectivity. Mechanistic studies revealed that the reaction
with DHIQs in the presence of (Boc)2O proceeds via the
formation of N,O-acetals, and the chiral Pd complex as an
acid-base catalyst allows the formation of the Pd enolate and
the iminium ions via R-fragmentation of the N,O-acetals. On
the basis of these observations, we succeeded in developing the
oxidative asymmetric Mannich-type reaction of the THIQs using
DDQ as a stoichiometric oxidant. The utility of the second
method was further confirmed by an efficient asymmetric
synthesis of the tetrahydrobenzo[a]quinolizidine system.
The use of N,O-acetals is unique in asymmetric catalysis,
featuring the chiral enolates under acidic conditions. Addition-
ally, the oxidative asymmetric Mannich-type reactions show
great potential to improve the overall efficiency of Mannich-
type reactions as a result of skipping of the separate preparation
of the unstable imines. We believe that the present results
provide a basis for the development of novel asymmetric
reactions.
[{(R)-dm-segphos}Pd(µ-OH)]
CDCl ) δ -2.14 (s, 2H), 2.05 (s, 24H), 2.42 (s, 24H), 5.81 (s, 4H),
.91 (s, 4H), 6.19 (dd, J ) 8.3, 12.9 Hz, 4H), 6.46 (d, J ) 8.3 Hz,
H), 6.80 (s, 12H), 7.25 (s, 4H) [the number of aromatic protons
2 2
(OTf) , 3a: H NMR (400 MHz,
3
5
4
is insufficient due to broadening, but integration between 6.5 and
.5 ppm gave 24.]; P NMR (100 MHz, CDCl
3
1
8
3
, std. 85% H
3 4
PO )
1
9
27
δ 28.6; F NMR (375 MHz, CDCl
408.7 (c 0.30, CH Cl ).
The anhydrous complex 2a was prepared as follows: AgOTf (128
mg, 0.51 mmol, 2.01 equiv) was added to [{(R)-dm-segphos}PdCl
3
, std. TFA) δ -2.10; [R]
D
+
2
2
2
]
(
180.6 mg, 0.25 mmol) in a glovebox. Dry DCM (5 mL) was added
under an N atmosphere, and the resulting mixture was stirred for
2
12 h under shielding from light. After filtration through a membrane
filter (PTFE), the solvent was removed under reduced pressure to
give 2a as a yellow powder (229 mg, 80%). This was stored in a
glovebox and used directly as a catalyst. Recrystallization from
3
CDCl gave yellow needles suitable for X-ray analysis. The 3D
structure of 2a is shown in Figure 6.
1
2
a: H NMR (400 MHz, CDCl
3
) δ 2.30 (s, 12H), 2.36 (s, 12H),
5
8
4
.62 (s, 2H), 5.86 (s, 2H), 6.50 (d, J ) 8.0 Hz, 2H), 6.73 (dd, J )
.0, 12.8 Hz, 2H), 7.13 (s, 2H), 7.18 (s, 2H), 7.40 (d, J ) 12.8 Hz,
3
1
19
H), 7.50 (br s, 4H); P NMR (100 MHz, CDCl
3
) δ 33.5; F NMR
+329.7 (c 0.33, CH Cl ).
A Representative Procedure for the Addition Reaction
with the N,O-Acetal Protocol. The imine 4e (300 mg, 1.57 mmol)
and (Boc) O 6a (513 mg, 2.35 mmol, 1.5 equiv) were dissolved in
26
(
375 MHz, CDCl
3
) δ -1.76; [R]
D
2
2
Experimental Section
Preparation of the Pd Complexes. The aqua complexes 1a and
a were prepared according to the reported procedure. Dropping
2
1
7
3
DCM (1.6 mL) under a nitrogen atmosphere. The resulting mixture
was stirred for 30 min at ambient temperature. Under ice-bath
cooling, diisopropyl malonate 5a (446 µL, 2.35 mmol, 1.5 equiv)
and the Pd complex 1a (18.2 mg, 0.0156 mmol, 1 mol %) were
added successively. After completion of the reaction, ethyl acetate
(5 mL) and brine (5 mL) were added for quenching. The aqueous
layer was extracted with ethyl acetate (3 × 10 mL), and the
a solution of the crude complex in CH
Cl
2 2
into stirred hexane gave
pure 1a as a yellow powder.
1
{
(R)-dm-segphos}PdCl
2
: H NMR (400 MHz, CDCl
3
) δ 2.24
(
s, 12H), 2.27 (s, 12H), 5.62 (s, 2H), 5.76 (s, 2H), 6.36 (d, J ) 8.4
Hz, 2H), 6.52 (t, J ) 8.4 Hz, 2H), 6.99 (s, 4H), 7.26 (d, J ) 12.4
3
1
3
Hz, 4H), 7.48 (br s, 4H); P NMR (160 MHz, CDCl , std. 85%
2
5
H
3
PO
{(R)-dm-segphos}Pd(H
CDCl ) δ 2.32 (s, 12H), 2.35 (s, 12H), 3.16 (br s, 4H), 5.72 (s,
H), 5.89 (s, 2H), 6.53 (d, J ) 8.0 Hz, 2H), 6.83 (dd, J ) 8.0, 12.9
Hz, 2H), 7.16 (s, 2H), 7.19 (s, 2H), 7.25 (br s, 4H), 7.49 (br s,
4
) δ 27.9; [R]
D
+291.7 (c 0.53, CH
2
Cl
2
).
2 4
combined organic layer was dried over anhydrous Na SO . Evapo-
1
[
2
O)
2
](OTf)
2
, 1a: H NMR (400 MHz,
ration of the solvent under reduced pressure, followed by flash
column chromatography (SiO , hexane-ethyl acetate or hexane-ether
system, ∼6/1) of the residue afforded the desired product 7e as a
white solid (718 mg, 95% yield). The ee was determined to be
94% by chiral HPLC analysis. Full characterization data of the new
compound 7j are listed below. Analytical data of other coupling
products 7 were reported in ref 16.
3
2
2
3
1
19
4
H); P NMR (100 MHz, CDCl
3
, std. 85% H
3
PO
4
) δ 33.3;
F
2
6
NMR (375 MHz, CDCl
CH Cl ).
3
, std. TFA) δ -2.2; [R]
D
+243.2 (c 0.67,
2
2
5
868 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of Optically ActiVe C1-Substituted THIQs
1
Preparation of 7j. This compound exists as a mixture of
14f: White solid. H NMR (400 MHz, CDCl
3
) δ 1.83 (br s, 1H,
3
rotamers in a ratio of 1.3/1 in CDCl at 22 °C. Colorless oil; IR
NH), 2.77 (bt, 2H), 3.11 (bt, 2H), 3.80 (s, 3H), 3.84 (s, 3H), 3.94
-1
1
13
(
(
2
(
1
)
7
2
8
1
1
5
1
neat) 2971, 1731, 1683, 1364, 1293, 1153, 1118 cm ; H NMR
400 MHz, CDCl ) δ 1.45 (s, 9H), 2.65-2.78 (m, 0.56H [major]),
.82-2.94 (m, 1.44H), 3.27-3.39 (m, 0.56H [major]), 3.54-3.61
m, 0.44H [minor]), 3.68-3.72 (m, 0.44H [minor]), 3.88-3.91 (m,
H), 3.96-4.01 (m, 0.56H [major]), 4.90- 5.23 (m, 4H), 5.96 (d, J
6.8 Hz, 0.56H [major]), 6.05 (d, J ) 8.1 Hz, 0.44H [minor])
(s, 2H), 6.72 (d, J ) 8.8 Hz, 1H), 6.74 (d, J ) 8.8 Hz, 1H);
NMR (100 MHz, CDCl ) δ 23.9, 43.6, 47.8, 55.9, 60.0, 110.2,
121.4, 129.0, 146.6, 150.5.
C
3
3
1
14g: White solid. H NMR (400 MHz, CDCl ) δ 2.18 (s, 1H,
3
NH), 2.65 (t, J ) 5.6 Hz, 2H), 3.08 (t, J ) 5.8 Hz, 2H), 3.76 (s,
3H), 3.77 (s, 3H), 3.93 (s, 2H), 6.60 (d, J ) 9.0 Hz, 1H), 6.63 (d,
1
3
13
.04-7.34 (m, 14H); C NMR (100 MHz, CDCl
3
) δ 27.9, 28.1,
J ) 9.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 23.6, 43.0, 43.4,
3
8.3, 28.4, 38.4, 40.3, 53.5, 54.0, 58.8, 59.4, 67.2, 67.3, 67.6, 80.1,
0.6, 126.0, 126.1, 126.8, 126.9, 127.5, 127.6, 128.2, 128.2, 128.3,
28.5, 128.7, 128.8, 134.3, 134.5, 134.6, 134.7, 134.9, 134.9, 135.2,
55.5, 55.6, 106.6, 107.0, 125.0, 125.7, 149.9, 151.2.
Oxidative Mannich-Type Reaction Starting from the N-
Boc-amine 13e. The N-Boc amine 13e (29.3 mg, 0.1 mmol),
diisopropyl malonate 5a (28.5 µL, 0.15 mmol), and the Pd complex
1a or 2a (5 mol %) were dissolved in DCM (0.2 mL) under a
nitrogen atmosphere. DDQ (25 mg, 0.11 mmol) in CH Cl (1.5
54.1, 154.7, 166.6, 166.8, 166.9, 167.0; FAB-LRMS (mNBA) m/z
+
16 [M + 1] ; FAB-HRMS (mNBA) calcd for C31
H
34
O
6
N [M +
2
+
26
] 512.2386, found 512.2384; [R]
D
+25.3 (c 0.34, CH
2
Cl ) (66%
2
2
ee); HPLC (DAICEL CHIRALCEL OD-H, n-hexane/IPA ) 95/5,
mL) was slowly added over 5 h to the reaction mixture with a
syringe pump (addition speed: 0.3 mL/h). After the addition was
complete, the reaction was stirred for an additional 2 h. The mixture
was diluted with ether (4 mL) and filtered through a silica pad with
ether as the eluent. The obtained yellow solution was evaporated
under reduced pressure and the remaining yellow oil was purified
by flash column chromatography (hexane/ether ) 5/1 to 4/1) to
give the desired product 7e (39.8 mg, 83% yield, 86% ee).
A Representative Procedure for the Oxidative Mannich-Type
Reaction Starting from the Amine 14. The amine 14e (19.3 mg,
0.1 mmol) and 6a (25.3 µL, 0.11 mmol) were dissolved in DCM
(0.15 mL) under a nitrogen atmosphere. After 30 min, 5a (20.8
µL, 0.11 mmol) and 2a (5.6 mg 0.005 mmol, 5 mol %) were added,
and DDQ (22.8 mg, 0.1 mmol) dissolved in DCM (1.5 mL) was
added slowly with a syringe pump (addition speed: 0.15 mL/h).
After the addition was complete, the mixture was stirred for an
additional 2 h. The reaction was quenched by the addition of
0
.5 mL/min, 254 nm, τmajor 16.9 mi., τminor 18.3 min.)
Preparation of 13. N-Boc-protected THIQs were prepared by
the reaction of the amines 14 with (Boc)
2 2 2
O in CH Cl and their
NMR spectra were found to be identical with the data reported in
3
8
the literature (13a, 13e).
In Situ Preparation of Carbonate 8a. To an NMR sample tube
containing CD Cl (0.7 mL) were added 4a (13 mg, 0.1 mmol)
and 6a (22 mg, 0.1 mmol). After 10 min, clean formation of 8a
was observed by NMR. Colorless oil; IR (in CH Cl ) 1736, 1705
) δ 1.49 (s, 9H), 1.51
s, 9H), 2.7-2.9 (m, 2H), 3.38 (br s, 1H), 4.04 (br s, 1H), 7.15-7.5
m, 3H), 7.38 (s, 1H), 7.45 (d, J ) 6.2 Hz, 1H); 13C NMR (100
) δ 27.7, 28.3, 28.4, 38.4, 79.7, 80.0, 81.9, 126.6, 127.9,
28.1, 128.8, 132.5, 135.5, 152.9, 153.8; FAB-LRMS (mNBA) m/z
2
2
2
2
-1
1
2 2
cm (both CO); H NMR (400 MHz, CD Cl
(
(
MHz, CDCl
3
1
2
+
32 [10a-OTf] (decarboxylation occurred readily during the FAB-
LRMS measurement).
Preparation of the N,O-Acetal 9a. The imine 4a (13 mg, 0.1
mmol) and 6a (22 mg, 0.1 mmol) were dissolved in toluene, and
the mixture was heated to 90 °C for 1 h. Evaporation of the solvent
under reduced pressure gave 9a. This compound was a mixture of
saturated aqueous NaHCO and the mixture was extracted twice
with ethyl acetate. The combined organic layers were washed with
3
brine and dried over Na SO . Further purification on a silica gel
2
4
column gave 7e (46.6 mg, 0.97 mmol, 97% yield, 86% ee).
Recrystallization from ethyl acetate gave 7e with 99% ee (37 mg,
0.77 mmol, 77% yield).
the rotamers in a ratio of 1.3/1 in CDCl
3
at 24 °C. IR (in CH
692 cm (CO); H NMR (400 MHz, CD Cl ) δ 1.37 (s, 9H),
.45-1.80 (m, 9H), 2.30-2.39 (m, 1H), 2.8-3.1 (m, 1H), 3.4-3.6
2 2
Cl )
-
1
1
1
1
2
2
Preparation of 18. tert-Butyl acryloyl carbonate 18 was obtained
35b
(
[
2
1
1
m, 1H), 3.9-4.3 (m, 1H), 6.29 (s, 0.56H [major]), 6.39 (s, 0.44H
in quantitative yield according to a reported procedure. IR (neat)
2985, 2939, 1795, 1744, 1632, 1405, 1372, 1253, 1199, 1170, 1133
1
3
minor]), 7.1-7.25 (m, 4H); C NMR (100 MHz, CDCl
3
) δ 27.8,
-
1 1
7.9, 28.2, 28.3, 28.6, 28.7, 35.9, 37.3, 74.7, 75.9, 76.9, 79.7, 80.2,
25.9, 126.0, 127.5, 127.6, 128.2, 128.4, 128.7, 129.0, 135.1, 135.2,
cm ; H NMR (300 MHz, CDCl ) δ 1.56 (s, 9H), 6.03 (dd, J )
3
1.5, 10.6 Hz, 1H), 6.12 (dd, J ) 10.6, 16.9 Hz, 1H), 6.55 (dd, J )
13
36.5, 136.5, 152.8, 153.6; FAB-LRMS (mNBA) m/z 232
1.5, 16.9 Hz, 1H); C NMR (75 MHz, CDCl ) δ 27.4, 85.6, 126.8,
3
+
[
10a-OTf] .
134.4, 146.9, 160.8.
Conversion to (R)-Calycotomine. Conversion of 7e to 15 was
Procedure for the Addition Reaction with the Acryloyl
Carbonate 18. The DHIQ 4a (13.1 mg, 0.1 mmol) was dissolved
in dry DCM (0.15 mL) under a nitrogen atmosphere. The resulting
solution was cooled to 0 °C and tert-butyl acryloyl carbonate 18
(25.8 mg, 0.15 mmol) in DCM (0.15 mL) was added dropwise.
This mixture was stirred for 15 min, then diisopropyl malonate 5a
(28.5 µL, 0.15 mmol) and 1a (5.8 mg, 0.005 mmol, 5 mol %) were
added, and the resulting mixture was stirred for 16 h at 0 °C.
Saturated aqueous NaCl was added for quenching and the aqueous
layer was extracted with ethyl acetate (3 × 5 mL). The combined
conducted as described in ref 16. The product was found identical
2
c,27
with the reported material by comparison of NMR data.
The
absolute configuration of 15 was determined by comparison of the
optical rotation with the reported value.
Preparation of the Amine 14. The amines 14a and 14e
hydrochloride salt) are commercially available. Other amines 14c,
(
1
4f, and 14g were prepared by a modified Pictet-Spengler
3
9
procedure and the NMR spectra were found to be identical with
the data reported in the literature.
4
0
1
1
4c: Yellow solid. H NMR (400 MHz, CDCl
3
) δ 1.75 (br s,
2 4
organic layers were dried over anhydrous Na SO , and the solvent
1
H, NH), 2.69 (t, J ) 5.6 Hz, 2H), 3.09 (t, J ) 5.8 Hz, 2H), 3.90
was evaporated under reduced pressure. Purification by flash column
chromatography (SiO , hexane-ethyl acetate 3/1) afforded 19 as
a colorless oil (23.2 mg, 0.062 mmol, 62%, 86% ee). This
compound was a mixture of the rotamers in a ratio of 1.9:1 in CDCl
at room temperature. IR (neat) 2981, 2936, 1723, 1650, 1615, 1428,
1
3
(
s, 2H), 5.88 (s, 2H), 6.47 (s, 2H), 6.55 (s, 2H); C NMR (100
MHz, CDCl ) δ 29.3, 43.9, 48.4, 100.4, 106.0, 108.8, 108.8, 127.4,
28.6, 145.5, 145.6.
2
3
1
3
1
375, 1262, 1181, 1160, 1100, 977, 935, 906, 822, 791, 757 cm-
;
1
(
38) For 13a, see: (a) Alonso, E.; Ram o´ n, D. J.; Yus, M. Tetrahedron 1997,
1
H NMR: (400 MHz, CDCl
1
3
) δ 1.07 (d, J ) 6.4 Hz, 1H [minor]),
5
2
3, 14355–14368. For 13e, see: (b) Coppola, G. M. J. Heterocycl. Chem. 1991,
8, 1769–1772.
.11 (d, J ) 6.4 Hz, 1H [minor]), 1.13 (d, J ) 6.0 Hz, 2H [major]),
(39) Sumita, K.; Koumori, M.; Ohno, S. Chem. Pharm. Bull. 1994, 42, 1676–
1.20-1.25 (m, 8H), 2.80-3.10 (m, 2H), 3.34 (ddd, J ) 5.4, 9.5,
1
678.
1
3
[
3.4 Hz, 0.66H [major]), 3.73 (d, J ) 7.2 Hz, 0.34H [minor]),
.80-3.98 (m, 1.34H [major + minor]), 4.47-4.54 (m, 0.66H
(
40) 14c: (a) Ruchirawat, S.; Chaisupakitsin, M.; Patranuwatana, N.; Cashaw,
J. L.; Davis, V. E. Synth. Commun. 1984, 14, 1221–1228. 14f and 14g: (b) Clark,
R. D.; Berger, J.; Garl, P.; Weinhardt, K. K.; Spedding, M.; Kilpatrick, A. T.;
Brown, C. M.; MacKinnon, A. C. J. Med. Chem. 1990, 33, 596–600.
major]), 4.91 (quint, J ) 6.1 Hz, 0.34H [minor]), 4.99-5.07 (m,
1.66H), 5.70 (dd, J ) 1.7, 10.5 Hz, 0.34H [minor]), 5.73 (dd, J )
J. Org. Chem. Vol. 73, No. 15, 2008 5869

Dubs et al.
2
.0, 10.5 Hz, 0.66H [major]), 5.84 (d, J ) 9.2 Hz, 0.66H [major]),
.29 (dd, J ) 2.0, 16.6 Hz, 0.66H [major]), 6.30 (dd, J ) 1.7, 16.6
and the reaction mixture was stirred at 35 °C for 32 h. The solution
was reduced in vacuo and the residue was directly purified by flash
column chromatography (hexane/ethyl acetate ) 3/1 to 2/1) to give
22 as a colorless oil (26.4 mg, 0.062 mmol, 74% yield, 83% ee).
IR (neat) 2978, 2936, 1732, 1712, 1670, 1516, 1464, 1454, 1411,
6
Hz, 0.34H [minor]), 6.43 (d, J ) 7.3 Hz, 0.34H [minor]), 6.59
(
dd, J ) 10.5, 16.6 Hz, 0.34H [minor]), 6.93 (dd, J ) 10.5, 16.6
Hz, 0.66H [major]), 7.10-7.24 (m, 3.66H), 7.43 (d, J ) 7.6 Hz,
1
3
0
2
6
1
.34H [minor]); C NMR (100 MHz, CDCl
3
) δ 21.4, 21.5, 21.6,
-1 1
1
264, 1229, 1195, 1173, 1145, 1121, 1105 cm ; H NMR (400
MHz, CDCl ) δ 0.75 (d, J ) 6.3 Hz, 3H), 1.03 (d, J ) 6.0 Hz,
H), 1.25 (d, J ) 6.3 Hz, 3H), 1.28 (d, J ) 6.3 Hz, 3H), 2.3-2.7
m, 5H), 2.7-2.9 (m, 2H), 3.77 (s, 3H), 3.81 (s, 3H), 4.55 (br d, J
11.8 Hz, 1H), 4.67 (quint, J ) 6.3 Hz, 1H), 5.15 (quint, J ) 6.3
1.6, 21.7, 27.2, 28.6, 37.6, 41.3, 51.4, 54.9, 59.3, 59.5, 69.2, 69.5,
9.8, 70.1, 126.2, 126.4, 126.7, 127.5, 127.7, 127.9, 128.0, 128.1,
28.3, 128.4, 129.2, 133.7, 134.3, 134.7, 134.8, 166.0, 166.3, 166.7;
3
3
(
+
FAB-LRMS (mNBA) m/z 374 [M + 1] ; FAB-HRMS (mNBA)
calcd for C21
)
+
H
27
O
5
NNa [M + Na] 396.1787, found 396.1792;
1
3
Hz, 1H), 5.41 (s, 1H), 6.53 (s, 1H), 6.96 (s, 1H); C NMR (100
MHz, CDCl ) δ 20.9, 21.4, 21.5, 21.6, 28.4, 29.5, 29.8, 40.0, 55.
, 55.9, 58.3, 60.2, 69.3, 69.8, 69.3, 69.8, 111.0, 111.1, 124.5, 129.8,
2
0
[
R]
D
+34.0 (c 0.78, CH Cl ); HPLC (Daicel Chiralcel OD-H,
2
2
3
n-hexane/IPA ) 9/1, 1 mL/min, 280 nm, τminor 40.2 min, τmajor 46.3).
Asymmetric Synthesis of Tetrahydrobenzo[a]quinolizidine
Derivative. 20: The starting material 14e·HCl (1 g, 4.3 mmol)
was suspended in DCM (50 mL). At 0 °C, triethylamine (1.8 mL,
9
1
47.0, 148.0, 168.4, 171.0, 171.8; FAB-LRMS (mNBA) m/z 456
+
[
M + Na] ; FAB-HRMS (mNBA) calcd for C23
H
31
O
7
NNa [M +
+
20
Na] 456.1998, found 456.1996; [R]
D
-15.1 (c 0.41, CHCl ) (83%
3
1
3.0 mmol) was added, and the solution was stirred for 30 min at
ee); HPLC (DAICEL CHIRALPAK AD-H, n-hexane/IPA ) 4/1,
room temperature. Acryloyl chloride (384 µL, 4.73 mmol) was
slowly added at 0 °C, and the reaction mixture was stirred for 1 h
at 0 °C and for 2 h at room temperature. The solution was washed
0
.5 mL/min, 280 nm, τminor 14.4 min, τmajor 15.7 min).
23: The diester 22 (66.3 mg, 0.15 mmol, 83% ee) was dissolved
in EtOH (6.0 mL), and H O (3 mL) and KOH (64 mg, 7.5 equiv)
2
were added. The reaction was refluxed for 36 h and cooled to
ambient temperature, then all volatiles were removed by evapora-
tion. The residue was dissolved in 1 N NaOH (5 mL) and washed
with saturated aqueous NH
dried over anhydrous Na SO
reduced pressure, followed by flash column chromatography (SiO
hexane-acetone 5:1) afforded 20 as a white solid (840 mg, 79%
yield). This compound was a mixture of the rotamers in a ratio of
4
Cl and brine. The organic phase was
. Evaporation of the solvent under
2
4
2
,
2
twice with Et O, and the organic layer was extracted with 1 N
NaOH. The combined aqueous layers were acidified with 2 N HCl
1
1
.2/1 in CDCl
519, 1460, 1431, 1201, 1120, 1016 cm ; H NMR (400 MHz,
) δ 2.78-2.85 (m, 2H), 3.74-3.88 (m, 8H), 4.65 (s, 0.9H
minor]), 4.72 (s, 1.1H [major]), 5.72 (d, J ) 10.5 Hz, 1H), 6.30
s, 0.45H [minor]), 6.34 (s, 0.55H [major]), 6.57-6.68 (m, 3H);
3
at room temperature. IR (neat) 2840, 1650, 1610,
-1 1
to pH 1-2 and extracted with AcOEt (7 × 5 mL). The combined
CDCl
[
3
2 4
organic layers were dried over Na SO , filtered, and evaporated to
yield the monocarboxylic acid 23 as a white solid (31.9 mg, 0.10
mmol, 66%). Mp 227-229 °C; IR (neat) 2930, 2851, 1972 (br),
(
1
3
3
C NMR (100 MHz, CDCl ) δ 28.3, 29.2, 40.1, 43.7, 44.3, 47.3,
1
1
701, 1564, 1522, 1463, 1448, 1357, 1330, 1288, 1254, 1241, 1227,
5
1
6.0, 108.8, 109.3, 111.1, 111.5, 124.0, 125.1, 125.6, 126.8, 127.7,
27.9, 147.5, 147.7, 165.6, 165.7; FAB-LRMS (mNBA) m/z 270
191, 1122, 1102, 1083, 1042, 1020, 980, 955, 889, 864, 850 cm-
;
1
1
+
3
H NMR (500 MHz, CD OD) δ 2.02-2.15 (m, 2H), 2.39 (ddd, J
[
17 3
M + Na] ; FAB-HRMS (mNBA) calcd for C14H O NNa [M +
+
) 6.0, 9.2, 17.4 Hz, 1H), 2.53 (dt, J ) 6.0, 17.4 Hz, 1H), 2.75 (dt,
J ) 4.6, 16.0 Hz, 1H), 2.92 (ddd, J ) 4.6, 10.1, 16.0 Hz, 1H),
Na] 270.1106, found 270.1107.
2
1: The obtained 20 (247 mg, 1 mmol), 5a (208 µL, 1.1 mmol),
3
.00-3.07 (m, 1H), 3.13 (ddd, J ) 4.6, 10.1, 12.4 Hz, 1H), 3.79
and 2a (112 mg, 10 mol %) were dissolved in DCM (1.5 mL).
DDQ (250 mg, 1.1 mmol) in DCM (15 mL) was slowly added
over 10 h to the reaction mixture with a syringe pump (addition
speed: 1.5 mL/h). After the addition was complete, the mixture
was stirred for an additional 1 h. The reaction was quenched with
saturated aqueous NaHCO
with ethyl acetate. The combined organic layers were washed with
brine and dried over Na SO . The solution was filtered, reduced in
(
s, 3H), 3.81 (s, 3H), 4.37 (dt, J ) 4.6, 12.4 Hz, 1H), 5.05 (d, J )
1
3
7.8 Hz, 1H), 6.78 (s, 1H), 6.87 (s, 1H); C NMR (400 MHz,
CD OD) δ 23.3, 28.2, 30.6, 41.7, 45.0, 56.0, 56.1, 57.1, 107.7,
111.7, 127.7, 128.4, 147.5, 148.2, 169.1, 176.3; ESI-MS (MeOH)
3
+
+
20
3
and the mixture was extracted twice
m/z 306 [M + 1] , FAB-LRMS (Gly) m/z 306 [M + 1] ; [R]
-57.0 (c 0.24, MeOH) (83% ee).
D
2
4
2
4: The acid 23 (14.2 mg, 0.046 mmol) was dissolved in DCM/
MeOH (5/3, 0.8 mL) under a N atmosphere. TMSCHN (1.5 equiv,
5 µL, 2 M in diethyl ether, 0.069 mmol) was added at 0 °C. The
vacuo, and purified by flash column chromatography (hexane/ethyl
acetate ) 4/1 to 3/1) to give 21 as a colorless oil (309 mg, 0.72
mmol, 74% yield, 86% ee). This compound was a mixture of the
2
2
3
mixture was stirred for 3 h while it was allowed to warm to room
temperature. The solvent was removed by evaporation and flash
3
rotamers in a ratio of 2.0/1 in CDCl at room temperature. IR (neat)
-
1 1
2
981, 2936, 1722, 1650, 1611, 1515, 1431, 1255, 1098 cm ; H
column chromatography (SiO
afforded the methyl ester 24 as a colorless oil (12.7 mg, 0.040 mmol,
2
, DCM/MeOH ) 95/5) of the residue
NMR (400 MHz, CDCl
3
) δ 1.08 (d, J ) 6.8 Hz, 1H [minor]), 1.09
(
d, J ) 7.6 Hz, 1H [minor]), 1.15 (d, J ) 6.4 Hz, 2H [major]),
8
1
7%, 83% ee). IR (neat) 2954, 2928, 2854, 1732, 1639, 1519, 1464,
1
6
0
)
1
.18-1.25 (m, 8H), 2.70-2.78 (m, 0.67H [major]), 2.87 (t, J )
.4 Hz, 0.67H [major]), 2.91-3.01 (m, 0.67H), 3.22-3.30 (m,
.67H), 3.72-3.87 (m, 7.67H), 4.53-4.60 (m, 0.67H), 4.90 (q, J
439, 1360, 1331, 1259, 1224, 1167, 1119, 1019 cm- ; H NMR
1 1
(400 MHz, CDCl
3
) δ 2.02-2.18 (m, 2H), 2.39 (ddd, J ) 5.6, 8.4,
6.4 Hz, 0.33H [minor]), 4.97-5.06 (m, 1.67H), 5.67-5.74 (m,
17.2 Hz, 1H), 2.58 (dt, J ) 6.0, 17.2 Hz, 1H), 2.65-2.73 (m, 2H),
2.88-3.07 (m, 3H), 3.80 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H), 4.58
(dt, J ) 4.0, 11.2 Hz, 1H), 5.04 (d, J ) 8.4 Hz, 1H), 6.58 (s, 1H),
.67H), 6.25-6.35 (m, 1.33H), 6.54-6.62 (m, 1.33H), 6.77 (s,
0
(
.67H [major]), 6.90 (dd, J ) 6.4, 16.9 Hz, 0.68H [major]), 7.03
s, 0.32H [minor]); 1 C NMR (100 MHz, CDCl
3
13
3
) δ 21.5, 21.5, 21.6,
6.65 (s, 1H); C NMR (100 MHz, CDCl ) δ 23.6, 28.3, 30.8, 41.3,
3
2
4
1
1
1.6, 21.6 (these peaks are too close to identify), 26.9, 28.3, 37.2,
1.0, 50.9, 54.5, 55.8, 59.5, 59.7, 69.1, 69.4, 69.8, 70.0, 109.6,
10.9, 111.0, 111.5, 125.5, 126.3, 126.5, 127.6, 128.0, 128.2, 147.0,
46.1, 52.5, 55.9, 56.0, 57.1, 107.8, 111.7, 127.8, 128.4, 147.5, 148.1,
+
1
68.9, 174.3; FAB-LRMS (Gly) m/z 320 [M + 1] ; FAB-HRMS
N [M + 1]+ 320.1498, found 320.1501;
(
Gly) calcd for C17
22 5
H O
47.1, 148.1, 148.4, 165.6, 165.9, 166.0, 166.7, 166.8, 166.9; FAB-
20
[
R]
D
-47.0 (c 0.13, DCM) (83% ee); HPLC (Daicel Chiralcel
+
LRMS (mNBA) m/z 456 [M + Na] ; FAB-HRMS (mNBA) calcd
OD-H, n-hexane/IPA ) 4/1, 1 mL/min, 280 nm, τminor 18.3 min,
NNa [M + Na]+ 456.1998, found 456.1998; [R]
63.0 (c 1.98, CHCl ) (86% ee); HPLC (DAICEL CHIRALPAK
AD-H, n-hexane/IPA ) 4/1, 1.0 mL/min, 280 nm, τminor 9.0 min,
major 12.3 min).
20
for C23
H
31
O
7
D
τmajor 20.9 min).
+
3
Acknowledgment. This paper is dedicated to Prof. E. J.
Corey on his 80th birthday. This work was supported by a Grant-
in-Aid for the Encouragement of Young Scientists (B)
τ
2
2: The obtained 21 (36.4 mg, 0.084 mmol) was dissolved in
dry THF (0.3 mL). One grain of NaH (paraffin 60%) was added
5
870 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of Optically ActiVe C1-Substituted THIQs
No. 18790005), a Grant-in-Aid for Scientific Research on
Priority Areas (No. 19028065, “Chemistry of Concerto Cataly-
sis”), Special Project Funding for Basic Science, and a Meiji-
Seika Award in Synthetic Organic Chemistry, Japan (2003).
C.D. is grateful to JSPS and SNF for financial support. We also
thank Dr. Takao Saito of Takasago International Corporation
for generous support.
(
Supporting Information Available: NMR spectra of the Pd
complexes 1a, 2a, and 3a, the new compounds 7j, 18, 19, and
2
1-24, experimental details of X-ray analysis, and crystal-
lographic information files (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JO800800Y
J. Org. Chem. Vol. 73, No. 15, 2008 5871