A Concise Asymmetric Total Synthesis of (+)-Epilupinine

Article abstract of DOI:10.1021/acs.orglett.9b00607

Asymmetric total synthesis of (+)-epilupinine was achieved in just three steps using only commercially available common reagents. The total synthesis involved alkylations of N-nosylamide, ozone oxidation, and sequential reactions of the removal of the nosyl group, intramolecular dehydrative condensation, intramolecular Mannich reaction catalyzed by l-proline, and a reduction.

Full text of DOI:10.1021/acs.orglett.9b00607

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Concise Asymmetric Total Synthesis of (+)-Epilupinine
Tomohiro Tsutsumi, Sangita Karanjit, Atsushi Nakayama, and Kosuke Namba*
Graduate School of Pharmaceutical Science and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1
Shomachi, Tokushima 770-8505, Japan
S
* Supporting Information
ABSTRACT: Asymmetric total synthesis of (+)-epilupinine
was achieved in just three steps using only commercially
available common reagents. The total synthesis involved
alkylations of N-nosylamide, ozone oxidation, and sequential
reactions of the removal of the nosyl group, intramolecular
dehydrative condensation, intramolecular Mannich reaction
catalyzed by L-proline, and a reduction.
Scheme 1. Synthetic Plan of (+)-Epilupinine (1)
uinolizidine alkaloids, which have the octahydro-2H-
Q quinolizine (quinolizidine) skeleton as a structural unit,
are secondary metabolites found mostly in genus Lupinus and
are known to exhibit various potent biological activities that are
mainly cytotoxicity.1 (+)-Epilupinine (1), structurally one of
the simplest quinolizidine alkaloids, was initially considered the
epimerized product of (+)-lupinine2 but was later isolated as a
natural secondary metabolite from various members of the
lupin family.3 1 has been known to exhibit in vitro inhibitory
activity against Leukaemia P-388 and lymphocytic Leukaemia
L1210.4 Recent studies elucidated that the structure of 1
incorporated into various drugs plays an important role as a
pharmacophore.5 For example, the (+)-epilupinine moiety of
antiviral and antimalarial drugs is suggested to behave as a
ligand of 5-HT3, 5-HT4, and sigma receptors.6 Therefore, 1 has
received a great deal of attention from synthetic organic
chemists due to its potent and diverse biological activities and
simple but synthetically cumbersome structure. To date, 15
asymmetric total syntheses of epilupinine4,7 and more than 30
racemic total syntheses8 have been reported. Although these
include efficient chiral syntheses, there remain several points in
need of improvement in the use of an expensive chiral
auxiliary, other steps for the synthesis of starting materials,
cumbersome separation from diastereomer and byproducts, a
greater number of steps, and so on, respectively. The
biosynthetic pathway of (+)-epilupinine (1) is considered to
include the cascade reaction of intramolecular dehydrative
condensation and the Mannich reaction (4 → 2 in Scheme
1),9 and Van Tamelen and Foltz actually synthesized
( )-epilupinine based on the biomimetic cascade reaction in
1960.8o However, development of an asymmetric version of
this cascade reaction that would be the most efficient approach
to (+)-epilupinine has not been achieved for around 60 years
since their racemic total synthesis despite many successful
examples of asymmetric total synthesis. Herein, we report a
development of its asymmetric version and a remarkably
simple total synthesis of (+)-epilupinine (1) in just three steps
from commercially available common reagents as starting
materials.
Our synthetic plan for 1 is outlined in Scheme 1.
(+)-Epilupinine (1) will be readily obtained by the reduction
of the aldehyde moiety of 2. The aldehyde 2 would be
obtained by the Mannich reaction of 3. In this reaction, the
addition of a chiral secondary amine as an organocatalyst is
expected to give optically active 2 via an enamine aldol-type
reaction. The iminium salt 3 would be formed by the
intramolecular dehydrative condensation of either of the
aldehydes of 4 with a secondary amine resulting from the
Received: February 18, 2019
© XXXX American Chemical Society
A
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Letter
deprotection of the nosyl group. It is noteworthy that removal
of the nosyl group in the presence of asymmetric catalyst
followed by reduction in one pot is expected to directly give
(+)-1 from 5 via the biomimetic cascade reaction.
Table 1. Optimization of the Cascade Reaction Leading to
(+)-Epilupinine
To investigate the optimal conditions for the cascade
reaction, we synthesized the dialdehyde 5 as the precursor
(Scheme 2). Treatment of N-nosylamide 6 with 2.0 equiv of 6-
Scheme 2. Synthesis of Cascade Reaction Precursor 5
a
b
c
entry catalyst (mol %)
base
temp (°C) yield (%) ee (%)
1
2
3
4
5
6
7
8
A (20)
B (20)
C (20)
C (50)
D (20)
E (20)
F (20)
G (20)
H (20)
H (100)
I (100)
I (100)
I (100)
J (100)
I (100)
I (100)
I (100)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Triton B
Li2CO3
Me4NOH
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
−15
0
0
0
0
71
−
<5
−
73
61
33
28
trace
−
57
68
61
38
70
35
53
−
61
59
<5
c
8
11
−
de
,
9
30
69
76
28
83
92
25
−
d
10
11
12
13
14
15
16
17
e
bromo-1-hexene 7 and K2CO3 in DMF at 100 °C afforded the
diene 8 in 98% yield. Ozone oxidation of the diene 8 in
dichloromethane at −78 °C proceeded smoothly to give the
dialdehyde 5 in 86% yield. The dialdehyde 5 was sufficiently
stable for purification by silica gel column chromatography.
Having prepared precursor 5, we next examined the cascade
reaction from 5 to 2. Since the cyclization product 2 is unstable
and volatile, the aldehyde 2 was reduced directly to
epilupinine (1) by adding NaBH4 and methanol to the
reaction mixture, and then the yield and ee were determined.10
First, we tried various organocatalysts (A, B, C, G, H, I) in
methanol, obtaining epilupinine 1 in low yield (6−29%) with
moderate ee (<5−59%) after direct reduction of 2 (see
Supporting Information). Although the cascade reaction
proceeded as expected, optimization to increase yield and ee
was required. When the solvent effect on the cascade reaction
catalyzed by Jørgensen’s catalyst A was investigated,11 the use
of CHCl3 was found to increase the chemical yield, although
almost no ee appeared (Table 1, entry 1 and Supporting
Information). Therefore, we further optimized the conditions
of the cascade reaction in CHCl3 (Table 1). Whereas the
addition of MacMillan’s catalyst B7c,12 did not give 1 (entry 2),
Hayashi−Jørgensen catalyst C13 substantially increased the ee
(61%) with a good chemical yield (73%) (entry 3). However,
increasing catalyst C to 50 mol % did not improve either yield
or ee (entry 4). The related catalysts D14 and E15 showed
decline in yield, and almost no ee was observed (entries 5 and
6). In addition, the reaction using catalyst F16 or the
prolineamide G17 did not afford 1 (entries 7 and 8). On the
other hand, the use of D-proline H18 as the catalyst provided an
enantiomer of 1 in 57% yield with 26% ee (entry 9), and
increasing the amount of H to 100 mol % elevated both yield
and ee (entry 10). Since the reaction using D-proline
predominantly afforded (−)-epilupinine, L-proline I was used
in a subsequent investigation. To further increase the ee, a
similar reaction using L-proline was conducted at 0 °C, and the
ee of (+)-1 increased to 76% (entry 11). However, further
decreasing the temperature to −15 °C induced declines in
both yield and the ee (entry 12). Next, when we changed the
base from K2CO3 to Cs2CO3, the ee fortunately increased to
83% (entry 13).19 In addition, the use of previously prepared
cesium salt J further improved the ee to 92% (entry 14).19
f
e
0
−
−
a
The reaction was performed by using 35 mg (0.095 mmol) of 5.
b
c
Isolated yield. Ee was measured by the integral ratio of 19F NMR
after converting 1 to the corresponding Mosher’s ester according to
d
the conventional method. Ee of (−)-epilupinine (enantiomer) is
described. Ee was determined from specific optical rotation. 5.0 g
(13.5 mmol) of 5 were used.
e
f
However, several trials on multigram scale showed 84−86% ee,
even when cesium salt J was used. Although the ee decreased in
gram-scale synthesis, reproducibility over 83% ee was ensured.
Thus, we adopted the conditions of entry 13 for gram-scale
synthesis in terms of chemical yield, ee, and convenience,
because the 83% ee can be further increased by recrystalliza-
tion. On the other hand, the use of Triton B as another base
having a bulky countercation decreased the ee (entry 15), and
Li2CO3 and Me4NOH did not give 1 (entries 16 and 17).
Throughout the optimization study, we did not detect the
formation of diastereomers. Probably, the diastereomers of 2
were readily epimerized under basic conditions. Although we
further examined the reaction conditions such as additives, the
ee could not be increased above 92% (Supporting Informa-
tion).
Next, we tried to increase the ee by recrystallization. Due to
the low recovery rate of free 1 from recrystallization, we tried
to recrystallize 1 in a salt form. Among various acids such as
B
DOI: 10.1021/acs.orglett.9b00607
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carboxylic, sulfonic, and hydrochloric acids,20 we found that
triphenylacetic acid forms a good solid salt with epilupinine.
Then, (+)-epilupinine triphenylacetic acid salt was sufficiently
recrystallized from CHCl3 and diethyl ether, and the resulting
crystals were treated with acid−base distribution to afford salt-
free (+)-epilupinine (1) in 53% yield as an enantiomerically
pure form.21 Thus, enantiomerically pure (+)-epilupinine (1)
was obtained by our three-step total synthesis22 and the
efficient single step construction of (+)-epilupinine (1) from
dialdehyde 5 was established.
We studied the enantioselectivity of a proline-catalyzed
intramolecular Mannich reaction under the Cs2CO3 condition
by Density Functional Theory (DFT) calculation (Figure 1
and Supporting Information). Taking the adduct of a proline-
activated Cs-salt of an iminium cation (A, A′, and A′′) as a
model substrate, we calculated the transition states for the
intramolecular asymmetric Mannich reaction to form a C1−C2
bond. Our calculation result showed that the attack from the
less-hindered Si-face of the sp2 carbon C2 in the six-membered
ring of the iminium cation through TSSi is favored and the
reaction is exergonic, resulting in (+)-epilupinine. However, its
opposite enantiomer resulting from the Re-face attack at C2
needed a high-energy barrier of 5.36 kcal/mol through TSRe
(Figure 1). The transition state TSSi is stabilized by the
formation of low-energy six-membered ring with an O--H
interaction between the H of C2 and O of the carboxylate
group of the catalyst I (Figure 1). The transition state lacks
such interaction in the case of the opposite enantiomer. In
addition, the transition state for formation of one of its
diastereomer (TS′) has a lower energy barrier of 3.63 kcal/mol
compared to TSRe; however, we obtained only enantiomer 1′
and 1 may be due to the epimerization of aldehyde to the most
stable conformer that leads to the formation of (+)-epilupinine
(1). We also compared the reaction profile taking K-salt. The
calculation showed that the distance between C1 and C2 in the
transition state TSSi is 2.55 Å (Cs-salt) and 2.50 Å (K-salt),
respectively; and the gap of activation energy between TSRe
and TSSi is higher in the case of Cs-salt than K-salt due to the
stronger O--H interaction (the O−H distance for Cs-salt is
2.88 Å, and for K-salt it is 3.22 Å, respectively) (Figure 1 and
Supporting Information). This resulted in a slow and highly
enantioselective reaction during our study.
Finally, we applied the established conditions for (+)-epi-
lupinine (1) to the synthesis of related natural products such as
(+)-tashiromine (10) and (+)-trachelanthamidine (12) that
include azabicyclo [4,3,0] and [3.3.0] skeletons, respectively
(Scheme 3). However, the similar reaction of 9 afforded
Scheme 3. Application of the Cascade Reaction to
Related Alkaloids
racemic tashiromine 10 in 23% yield.23 In addition, multiple
products were obtained in the case of 11, and the isolation of
(+)-trachelanthamidine (12) was difficult. Further optimiza-
tion is needed for these related natural products.
In conclusion, a three-step total synthesis of (+)-epilupinine
(1) from commercially and readily available common reagents
was established. The total synthesis consists of two alkylations
of N-nosylamide, ozone oxidation, the cascade reaction of two
cyclizations, and a reduction. The cascade reaction includes
deprotection of the nosyl group, intramolecular iminium cation
formation, and the intramolecular asymmetric Mannich
reaction. In the asymmetric Mannich reaction, L-proline
cesium salt was found to give the highest enantiomeric excess.
Although a stoichiometric amount of L-proline was needed for
high ee, L-proline is not an expensive organocatalyst and is
recoverable from the reaction mixture. Furthermore, we
Figure 1. (a) Mode of attack on C2 by nucleophilic C1. (b) Energy
profile diagram for formation of enantiomers and diasteromers of
Epilupinine using catalyst I. (c) Optimized transition states for the
Mannich reaction.
C
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(6) (a) Sparatore, A.; Novelli, F.; Sparatore, F. Helv. Chim. Acta
2004, 87, 580−591. (b) Sparatore, A.; Cagnotto, A.; Sparatore, F.
Farmaco 1999, 54, 248−254.
discovered the recrystallization conditions for 1 so that
enantiomerically pure (+)-epilupinine (1) is readily obtained
by this synthesis. Although there have been over 45 examples
of the synthesis of epilupinine, there are fewer steps in this
synthesis than in any conventional synthesis, even including
racemic total synthesis. On the other hand, the application of
this asymmetric cascade reaction to other related natural
products from genus Lupinus is the next challenge, because the
application to the synthesis of (+)-tashiromine (10) and
(+)-trachelanthamidine (12) did not give good results. Further
development of the resulting quinolizidine analogs as the
functional molecules is currently underway in our laboratory.
(7) (a) Park, Y.; Schindler, C. S.; Jacobsen, E. N. J. Am. Chem. Soc.
2016, 138, 14848−14851. (b) Brambilla, M.; Davies, S. G.; Fletcher,
A. M.; Roberts, P. M.; Thomson, J. E.; Zimmer, D. Tetrahedron 2016,
72, 7417−7429. (c) Koley, D.; Krishna, Y.; Srinivas, K.; Khan, A. A.;
Kant, R. Angew. Chem., Int. Ed. 2014, 53, 13196−13200. (d) Thorat,
R. G.; Pansare, S. V. Eur. J. Org. Chem. 2013, 2013, 7282−7285.
(e) Cutter, A. C.; Miller, I. R.; Keily, J. F.; Bellingham, R. K.; Light, M.
E.; Brown, R. C. D. Org. Lett. 2011, 13, 3988−3991. (f) Su, D.; Wang,
X.; Shao, C.; Xu, J.; Zhu, R.; Hu, Y. J. Org. Chem. 2011, 76, 188−194.
(g) Ahari, M.; Perez, A.; Menant, C.; Vasse, J.-L.; Szymoniak, J. Org.
Lett. 2008, 10, 2473−2476. (h) Ma, S.; Ni, B. Chem. - Eur. J. 2004, 10,
3286−3300. (i) Mangeney, P.; Hamon, L.; Raussou, S.; Urbain, N.;
Alexakis, A. Tetrahedron 1998, 54, 10349−10362. (j) Naidu, B. N.;
West, F. G. Tetrahedron 1997, 53, 16565−16574. (k) Morley, C.;
Knight, D. W.; Share, A. C. J. Chem. Soc., Perkin Trans. 1 1994, 2903−
2907. (l) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1994, 116,
8420−8421. (m) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi, S.;
Fujita, E. J. Org. Chem. 1990, 55, 1148−1156. (n) Morley, C.; Knight,
D. W.; Share, A. C. Tetrahedron: Asymmetry 1990, 1, 147−150.
(o) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi, S.; Fujita, E. J.
Am. Chem. Soc. 1988, 110, 289−291.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00607.
Experimental details, computational detail, and 1H
NMR, 13C NMR, and 19F NMR spectra (PDF)
AUTHOR INFORMATION
(8) (a) Koley, D.; Srinivas, K.; Krishna, Y.; Gupta, A. RSC Adv.
2014, 4, 3934−3937. (b) Pohmakotr, M.; Seubsai, A.; Numeechai, P.;
Tuchinda, P. Synthesis 2008, 2008, 1733−1736. (c) Amorde, S. M.;
Judd, A. S.; Martin, S. F. Org. Lett. 2005, 7, 2031−2033. (d) Molander,
G. A.; Nichols, P. J. J. Org. Chem. 1996, 61, 6040−6043. (e) Cordero,
F. M.; Anichini, B.; Goti, A.; Brandi, A. Tetrahedron 1993, 49, 9867−
9876. (f) Gesson, J. P.; Jacquesy, J. C.; Rambaud, D. Tetrahedron Lett.
1992, 33, 3633−3636. (g) Edstrom, E. D. Tetrahedron Lett. 1991, 32,
5709−5712. (h) Nagasaka, T.; Yamamoto, H.; Hayashi, H.; Kato, H.;
Kawaida, M.; Yamaguchi, K.; Hamaguchi, F. Heterocycles 1989, 29,
■
Corresponding Author
*E-mail: namba@tokushima-u.ac.jp.
ORCID
Kosuke Namba: 0000-0003-1548-5656
Notes
The authors declare no competing financial interest.
́
́
1209−1216. (i) Celerier, J. P.; Haddad, M.; Saliou, C.; Lhommet, G.
Tetrahedron 1989, 45, 6161−6170. (j) Grieco, P. A.; Parker, D. T. J.
Org. Chem. 1988, 53, 3325−3330. (k) Takahata, H.; Yamabe, K.;
Suzuki, T.; Yamazaki, T. Chem. Pharm. Bull. 1986, 34, 4523−4526.
(l) Ihara, M.; Kirihara, T.; Fukumoto, K.; Kametani, T. Heterocycles
1985, 23, 1097−1100. (m) Yamada, Y.; Hatano, K.; Matsui, M. Agric.
Biol. Chem. 1971, 35, 285−286. (n) Winterfeld, K.; Knieps, R. Arch.
Pharm. 1960, 293, 325−333. (o) Van Tamelen, E. E.; Foltz, R. L. J.
Am. Chem. Soc. 1960, 82, 502−503.
ACKNOWLEDGMENTS
■
This work was partially supported by JSPS KAKENHI Grant
Numbers JP16H01156 in Middle Molecular Strategy and
JP16H03292, and JST value program Grant Number
VP29117941288. We acknowledge Tokushima University for
their financial support of the Research Clusters program of
Tokushima University (No. 1703015).
REFERENCES
(9) Robinson, R. The Structural Relations of Natural Products; Oxford
University Press: London, 1955.
(10) The enantiomeric excess of epilupinine 1 was determined by
the integral ratio of 19F NMR after converting 1 to the corresponding
Mosher ester according to the conventional method, as the separable
condition using HPLC could not be established.
(11) (a) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790−4971. (b) Austin,
J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172−1173.
(c) Chong, M. J.; Clarke, I. S.; Koch, I.; Olbach, P. C.; Taylor, N. J.
Tetrahedron: Asymmetry 1995, 6, 409−418.
(12) (a) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39,
79−87. (b) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243−4244.
■
(1) (a) Bunsupa, S.; Yamazaki, M.; Saito, K. Front. Plant Sci. 2012, 3,
239−246. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139−165.
(c) Samanani, N.; Facchini, P. J. Recent Adv. Phytochem. 2006, 40,
53−83.
(2) (a) Sparatore, A.; Tasso, B.; Boido, V.; Sparatore, F. Helv. Chim.
Acta 2005, 88, 245−251. (b) Winterfeld, K.; Holschneider, F. W. Ber.
Dtsch. Chem. Ges. B 1931, 64, 137−150.
(3) (a) Beck, A. B.; Goldspink, B. H.; Knox, J. R. J. Nat. Prod. 1979,
42, 385−398. (b) White, E. P. N. Z. J. Sci. Technol., Sect B 1951, 33,
50−54.
(4) Hua, D. H.; Miao, S. W.; Bravo, A. A.; Takemoto, D. J. Synthesis
1991, 1991, 970−974.
(5) (a) Tonelli, M.; Vazzana, I.; Tasso, B.; Boido, V.; Sparatore, F.;
Fermeglia, M.; Paneni, M. S.; Posocco, P.; Pricl, S.; Colla, P. L.; Ibba,
C.; Secci, B.; Collu, G.; Loddo, R. Bioorg. Med. Chem. 2009, 17,
4425−4440. (b) Tonelli, M.; Paglietti, G.; Boido, V.; Sparatore, F.;
Marongiu, F.; Marongiu, E.; LaColla, P.; Loddo, R. Chem. Biodiversity
2008, 5, 2386−2401. (c) Casagrande, M.; Basilico, N.; Parapini, S.;
Romeo, S.; Taramelli, D.; Sparatore, A. Bioorg. Med. Chem. 2008, 16,
6813−6823. (d) Vazzana, I.; Budriesi, R.; Terranova, E.; Ioan, P.;
Ugenti, M. P.; Tasso, B.; Chiarini, A.; Sparatore, F. J. Med. Chem.
2007, 50, 334−343. (e) Sparatore, A.; Basilico, N.; Parapini, S.;
Romeo, S.; Novelli, F.; Sparatore, F.; Taramelli, D. Bioorg. Med. Chem.
2005, 13, 5338−5345. (f) Ercoli, M.; Mina, L.; Boido, C. C.; Boido,
V.; Sparatore, F.; Armani, U.; Piana, A. Farmaco 2004, 59, 101−109.
(13) (a) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.;
Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248−264. (b) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471−
5569. (c) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjarsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296−
18304. (d) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212−4215. (e) Marigo, M.; Wabnitz, T. C.;
Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44,
794−797.
(14) (a) Lattanzi, A. Chem. Commun. 2009, 1452−1463. (b) Kapf-
hammer, J.; Matthes, A. Hoppe-Seyler's Z. Physiol. Chem. 1934, 223,
43−52.
D
DOI: 10.1021/acs.orglett.9b00607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) Jia, Z.-J.; Jiang, H.; Li, J.-L.; Gschwend, B.; Li, Q.-Z.; Yin, X.;
Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am. Chem. Soc. 2011, 133,
5053−5061.
(16) (a) Saha, S.; Moorthy, J. N. J. Org. Chem. 2011, 76, 396−402.
(b) Dahlin, N.; Bøgevig, A.; Adolfsson, H. Adv. Synth. Catal. 2004,
346, 1101−1105.
(17) (a) Dodda, R.; Zhao, C.-G. Org. Lett. 2006, 8, 4911−4914.
(b) Tang, Z.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D.
Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5755−5760.
(18) (a) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res.
2004, 37, 580−591. (b) Cordova, A. Acc. Chem. Res. 2004, 37, 102−
112. (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138−5175. (d) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.;
Ohsawa, A. Org. Lett. 2003, 5, 4301−4304. (e) List, B.; Pojarliev, P.;
Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827−833.
(f) List, B. J. Am. Chem. Soc. 2000, 122, 9336−9337. (g) Eder, U.;
Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496−
497.
(19) The use of 20 mol% of J gave the 66% ee and 38% yield, and the
prepared potassium salt of L-proline did not affect the ee.
(20) HCl, (COOH)2, AcOH, L-tartalic acid, TFA, L-malic acid, D-
mandelic acid, benzoic acid, TsOH, and 10-campher sulfonic acid did
not afford good solid salt for recrystallization.
(21) The peak of enantiomer was not detected by 19F NMR, and the
value of [α]D was identical to that of the literature.
(22) We tried to develop a two-step total synthesis. After ozonolysis
of 5 in CHCl3 at −60 °C, the reaction mixture was directly subjected
to the cascade reaction to give 1. In this one-pot operation, although a
long reaction time was needed, 1 was actually obtained in 57% yield
from 5. However, the ee of 1 was substantially decreased to 49%. After
various examination, we found that the formaldehyde, derived from
ozone oxidation of primary alkenes, disturbs the subsequent reactions.
(23) The formation of tashiromine (10) was confirmed by
comparison with the data from ref 7c.
E
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