Approach to Fully Substituted Cyclic Nitrones from N-Hydroxylactam Derivatives: Development and Application to the Total Synthesis of Cylindricine C

Article abstract of DOI:10.1002/anie.201901049

An approach to cyclic nitrones from N-hydroxylactam derivatives is documented. The nucleophilic addition of an organolithium reagent to an N-OSEM [SEM=2-(trimethylsilyl)ethoxymethyl] lactam forms a five-membered chelated intermediate, which undergoes both elimination and deprotection to give a fully substituted nitrone in a one-pot process. When combined with the N-oxidation of easily available chiral lactams, this method becomes especially useful for the quick synthesis of chiral nitrones in enantio-pure form, enabling the concise total synthesis of cylindricine C.

Full text of DOI:10.1002/anie.201901049

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Accepted Article
Title: Nucleophilic Approach to Fully Substituted Cyclic Nitrones from
N-Hydroxylactam Derivatives: Development and Application to
the Total Synthesis of Cylindricine C
Authors: Shobu Hiraoka, Tsutomu Matsumoto, Koki Matsuzaka,
Takaaki Sato, and Noritaka Chida
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901049
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10.1002/anie.201901049
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Nucleophilic Approach to Fully Substituted Cyclic Nitrones from
N-Hydroxylactam Derivatives: Development and Application to
the Total Synthesis of Cylindricine C
Shobu Hiraoka, Tsutomu Matsumoto, Koki Matsuzaka, Takaaki Sato,* Noritaka Chida*
Abstract: A nucleophilic approach to cyclic nitrones from N-
hydroxylactam derivatives is documented. The nucleophilic addition
Table 1. Optimization of nucleophilic addition to N-hydroxylactam derivative
of an organolithium reagent to an N-OSEM lactam forms a five-
6.[a]
membered chelated intermediate, which undergoes both elimination
and deprotection to give a fully substituted nitrone in a one-pot
process. When combined with the N-oxidation of easily available
chiral lactams, this method becomes especially useful for the quick
synthesis of chiral nitrones in enantio pure form, enabling the concise
total synthesis of cylindricine C.
Entry
6
Acid
Yields [%][b]
7
8
6a
In the past decade, several practical nucleophilic additions to
amides have been reported as promising tools for the synthesis
of multi-substituted amines found in complex alkaloids and
pharmaceuticals.[1-3] To explore a new aspect of this useful
transformation, we recently embarked on a program to pursue a
general strategy for the synthesis of 1,3-dipoles[4] starting from
amides.[2d,e,3s,3i] For example, we reported the iridium-catalyzed
reduction of N-hydroxyamides 1 to give nitrones 2 (Scheme
1A).[2d,e] Our reductive approach allowed for quick access to
acyclic, cyclic and macrocyclic nitrones.
1[c]
2
6a (P = H)
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
CF3CO2H
BF3·Et2O
p-TsOH[d]
p-TsOH[e]
7
0
69
18
0
6b (P = TBS)
6c (P = MOM)
6d (P = BOM)
6e (P = MEM)
6f (P = SEM)
6f (P = SEM)
6f (P = SEM)
6f (P = SEM)
6f (P = SEM)
29
29
17
20
68
8
0
3
40
61
51
0
4
0
5
0
6
0
7
73
74
54
0
0
8
5
0
9
21
71
0
10
0
[a] N-Hydroxyamide derivative 6, n-BuLi (1.2 equiv), DME (0.1 M), –50 °C,
30 min; then acid (3 equiv), RT, 1 h. [b] Yields of isolated compounds were
reported after purification by column chromatography. [c] n-BuLi (2 equiv)
was used. [d] p-TsOH (2 equiv) was used. [e] p-TsOH (5 equiv) was used.
BOM = benzyloxymethyl, DME
methoxyethoxy)methyl, MOM
=
=
1, 2-dimethoxyethane, MEM
methoxymethyl, SEM
=
=
(2-
2-
(trimethylsilyl)ethoxymethyl, TBS = t-butyldimethylsilyl, Ts = toluenesulfonyl.
Scheme 1. (A) Reductive approach to nitrone 2 from N-hydroxyamide 1. (B)
Plan for nucleophilic approach to fully substituted nitrone
5 from N-
hydroxyamide derivative 3.
To develop the method to provide fully substituted nitrones 5
(R1-R3 = alkyl, aryl), we envisioned a nucleophilic addition to N-
hydroxyamide derivatives 3 using organolithium reagents[2a,b]
instead of hydride reducing agents (Scheme 1B). Treatment of 3
with an organolithium reagent would form the five-membered
chelated intermediate 4. Subsequent addition of an acid in a one-
pot process would initiate both elimination of the hydroxy group
and cleavage of the protecting group to provide fully substituted
nitrone 5. The oxygen atom of 3 could increase the electrophilicity
of the amide carbonyl group, and would prevent double addition
of the organolithium reagent by formation of chelated intermediate
4.[5] In this communication, we reported the nucleophilic
transformation of N-OSEM lactams to fully substituted nitrones,
[*]
S. Hiraoka, T. Matsumoto,+ K. Matsuzaka,+ Prof. Dr. T. Sato, Prof.
Dr. N. Chida
Department of Applied Chemistry
Faculty of Science and Technology, Keio University
3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
E-mail: takaakis@applc.keio.ac.jp, chida@applc.keio.ac.jp
These authors contributed equally to this work.
[+]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201901049
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COMMUNICATION
which are challenging compounds to synthesize by conventional
methods. The method was successfully applied to the total
synthesis of cylindricine C.
at the position of the amide carbonyl, enabling the formation of
both 13 and 16 from N-OSEM lactams 6f and 10, respectively.
Nucleophilic addition to -substituted lactam 11 provided nitrone
17 in 72% yield. In addition to six-membered lactams, five-
membered lactam 12 proved to be a suitable substrate for the
nucleophilic synthesis of nitrones (18: 92%; 19: 71%).
Our nucleophilic approach to fully substituted cyclic nitrones
was first evaluated using N-hydroxylactam derivatives 6 (Table 1).
Treatment of N-hydroxylactam 6a (P = H) with n-butyllithium (2
equiv) at –50 °C, followed by addition of p-TsOH (3 equiv) at room
temperature resulted in the formation of nitrone 7 but in only 7%
yield (Table 1, Entry 1). The starting material 6a was recovered in
69% yield, likely because the first deprotonation of the N-hydroxy
group prevented subsequent nucleophilic addition due to the
formation of the unstable dianionic intermediate. We then
conducted a survey for the proper protecting group, one that does
not inhibit the nucleophilic addition, but is easily cleavable under
the elimination conditions. The reaction of N-OTBS amide 6b
slightly increased the yield of nitrone 7 to 29% yield, along with
recovery of 18% of 6a (Table 1, Entry 2). On the assumption that
the N-OTBS group sterically hindered the nucleophilic addition to
the amide carbonyl, we switched to the MOM group because it is
small and cleavable under acidic conditions. Unfortunately, the
reaction of 6c provided nitrone 7 in 29% yield, and imine 8 was
isolated in 40% yield as a major byproduct (Entry 1, Table 3). As
we expected, use of the small MOM group allowed for nucleophilic
addition and subsequent elimination to generate oxyiminium ion
9 (Scheme 2). However, while nitrone 7 was formed from
oxyiminium ion 9 through acid-mediated cleavage of the MOM
group, imine 8 was produced through unfavorable elimination of
9 during the slow deprotection process. Among acetal-type
protecting groups, the SEM group was the best, giving nitrone 7
in 68% yield (Table 1, Entries 4-6). The reactions with other
Brønsted and Lewis acids resulted in low yields, along with imine
8 (Table 1, Entries 7,8). The amount of p-TsOH was crucial to
promote the cleavage of the SEM group (Table 1, Entries 9,10).
The best result was obtained when using five equivalents of p-
TsOH, giving nitrone 7 in 71% yield.
Scheme 3. Scope of nucleophilic formation of fully substituted cyclic nitrones
from N-hydroxyamide derivatives.
With the nucleophilic formation of fully substituted cyclic
nitrones in hand, we turned our attention to the total synthesis of
cylindricine C (20) (Scheme 4).[6] Cylindricines were isolated from
the ascidian Clavelina cylindrica found off the coast of
Tasmania.[7]
These
natural
products
consist
of
a
perhydropyrrolo[2,1-j]quinolone ring system found in a large
family of tricyclic marine alkaloids,[8] some of which possess
biological activities such as in the cytotoxic assay against Vero
cells[9] and the brine shrimp bioassay.[7a] To achieve the total
synthesis of cylindricine C (20), we envisioned a strategy to give
fully substituted nitrone 23 in enantio pure form through N-
oxidation of chiral lactam 21 and subsequent nucleophilic addition
to N-hydroxylactam 22. Subsequent [3+2]-cycloaddition of fully
substituted nitrone 23 would form aza-spirocycle 24, which is
embedded in cylindricine C (20).
Scheme 2. Possible mechanism to provide imine 8 from N-OMOM lactam 6c.
The scope of the nucleophilic formation of nitrones from the
N-OSEM lactams was then surveyed (Scheme 3). In addition to
n-butyllithium, various organolithium reagents were effective,
such as those with methyl and phenyl groups (13: 96%; 14: 69%).
Although the yield was moderate, the i-propyl group was installed
in spite of the large steric hindrance (15: 48%). Nucleophilic
addition of phenyllithium to lactam 10 provided nitrone 16 in 69%
yield. It is noteworthy that our method can overcome the
regioselective issue in the synthesis of cyclic nitrones. For
example, regiodivergent formation of both nitrones 13 and 16 by
the conventional oxidation of 2-methyl-6-phenylpiperidine[4f] is
highly challenging. However, our method can generate nitrones
Scheme 4. Synthetic plan toward enantioselective total synthesis of cylindricine
C (20). TBDPS = tert-butyldiphenylsilyl
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Scheme 5. Enantioselective total synthesis of cylindricine C (20). bpy = 2,2-bipyridyl, DMAP = 4-(N,N-dimethylamino)pyridine, mCPBA = meta-chloroperbenzoic
acid, TBAF = tetrabutylammonium fluoride.
Our total synthesis commenced with the preparation of chiral
nitrone 23 from easily available known lactam 21[10] (Scheme 5).
The N-oxidation of lactam 21 to give N-hydroxylactam 22 proved
to be highly challenging. For example, conventional N-oxidation
of lactams using MoOPH [MoO5·HMPA][11] resulted in the
recovery of lactam 21. After extensive study, we found that
successful oxidation was accomplished via O-methylimidate 25
as follows.[12] First, O-methylation of lactam 21 with Meerwein’s
aminoaldehyde 30 without epimerization. Addition of the turbo
Grignard-type acetylide to aldehyde 30 gave propargylic alcohol
31,[16,17] which underwent the second Iwabuchi oxidation and
attendant aza-Michael cyclization to form dihydro-4-pyridone 32
(37%, 3 steps). Finally, cleavage of the TBDPS group of 32
followed by hydroxyl-directed reduction[6j,k] completed the total
synthesis of cylindricine C (20). Our synthetic sample was found
to be indistinguishable from a natural sample based on 1H NMR,
13C NMR, HRMS, and IR data.
–
reagent [Me3O+BF4 ] provided O-methylimidate 25 in 95% yield.
Oxidation of the resulting imidate 25 with mCPBA generated
methoxyoxaziridine 26, which was treated with MeOH/H2O and
oxalic acid to give N-hydroxyamine 27. Subsequent basification
with K2CO3 in a one-pot process promoted recyclization, affording
N-hydroxylactam 22 in 80% yield. After conversion of 22 to the
SEM ether, nucleophilic addition was achieved by using a hexenyl
lithium reagent under our optimized conditions to provide chiral
nitrone 23 in 84% yield. It is noteworthy that the concise synthesis
of fully substituted nitrones in enantio pure form is still limited in
current organic synthesis, especially for those possessing a
stereocenter adjacent to the nitrogen atom.[13] However, our
sequence involving N-oxidation of lactams and subsequent
nucleophilic addition demonstrated that a variety of chiral nitrones
are now accessible from easily available chiral N-H lactams.
In summary, we have developed a nucleophilic approach to
fully substituted cyclic nitrones from N-hydroxylactam derivatives.
The key to success was the use of the SEM group on the N-
hydroxy group, which did not inhibit the nucleophilic addition of
the organolithium reagent, but was easily cleavable during the
acidic elimination process. When combined with N-oxidation of an
easily available chiral lactam, the nucleophilic addition provided a
fully substituted chiral nitrone. This methodology was successfully
used in the total synthesis of cylindricine C. We believe that our
nucleophilic approach will be a general method for the preparation
of highly functionalized chiral nitrones available for the
enantioselective total syntheses of a variety of complex alkaloids.
With chiral nitrone 23 in hand, we turned our attention to the
intramolecular [3+2]-cycloaddition[14] (Scheme 5). A solution of
nitrone 23 in t-BuPh was heated at 150 °C for 3 h, giving a
diastereomeric mixture of two isoxazolidines 24 and 28 in 90%
combined yield. Although poor regioselectivity was observed at
the terminal olefin, the aza-spirocyclic framework 24 was
successfully synthesized. The remaining issue for the total
synthesis was construction of the third piperidinone ring. The
cleavage of the N-O bond with zinc in AcOH/H2O at 45 °C gave
1,3-aminoalcohol 29 in 97% yield. Oxidation of the primary alcohol
in 29 was not a trivial transformation due to the presence of the
secondary amine as well as the potential for epimerization at the
C5 carbon center. However, chemoselective aerobic oxidation
developed by Iwabuchi[15] overcame this challenge to provide
Acknowledgements
This research was supported by a Grant-in-Aid for Scientific
Research (C) from MEXT (18K05127), the Tobe Maki foundation,
and JGC-S Scholarship Foundation.
Keywords: amide • cylindricine • nitrone • nucleophilic addition •
total synthesis
[1]
For reviews and perspectives on nucleophilic addition to amides, see: a)
D. Seebach, Angew. Chem. Int. Ed. 2011, 50, 96–101; Angew. Chem.
2011, 123, 99–105; b) T. Murai, Y. Mutoh, Chem. Lett. 2012, 41, 2–8; c)
V. Pace, W. Holzer, Aust. J. Chem. 2013, 66, 507–510; d) T. Sato, N.
Chida, Org. Biomol. Chem. 2014, 12, 3147–3150; e) V. Pace, W. Holzer,
This article is protected by copyright. All rights reserved.

10.1002/anie.201901049
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COMMUNICATION
B. Olofsson, Adv. Synth. Catal. 2014, 356, 3697–3736; f) A. Volkov, F.
Tinnis, T. Slagbrand, P. Trillo, H. Adolfsson, Chem. Soc. Rev. 2016, 45,
6685–6697; g) D. Kaiser, A. Bauer, M. Lemmerer, N. Maulide, Chem.
Soc. Rev. 2018, 47, 7899–7925; h) P.-Q. Huang, Acta Chim. Sinica 2018,
76, 357–365.
Ciufolini, Angew. Chem. Int. Ed. 2004, 43, 4336–4338; Angew. Chem.
2004, 116, 4436–4438; f) T. Arai, H. Abe, S. Aoyagi, C. Kibayashi,
Tetrahedron Lett. 2004, 45, 5921–5924; g) H. Abe, S. Aoyagi, C.
Kibayashi, J. Am. Chem. Soc. 2005, 127, 1473–1480; h) J. Liu, R. P.
Hsung, S. D. Peters, Org. Lett. 2004, 6, 3989–3992; i) J. Liu, J. J.
Swidorski, S. D. Peters, R. P. Hsung, J. Org. Chem. 2005, 70, 3898–
3902; j) J. J. Swidorski, J. Wang, R. P. Hsung, Org. Lett. 2006, 8, 777–
780; k) J. Wang, J. J. Swidorski, N. Sydorenko, R. P. Hsung, H. A.
Coverdale, J. M. Kuyava, J. Liu, Heterocycles 2006, 70, 423–459; l) T.
Shibuguchi, H. Mihara, A. Kuramochi, S. Sakuraba, T. Ohshima, M.
Shibasaki, Angew. Chem. Int. Ed. 2006, 45, 4635–4637; Angew. Chem.
2006, 118, 4751–4753; m) H. Mihara, T. Shibuguchi, A. Kuramochi, T.
Ohshima, M. Shibasaki, Heterocycles 2007, 72, 421–438; n) A. C. Flick,
M. J. A. Caballero, A. Padwa, Org. Lett. 2008, 10, 1871–1874; o) A. C.
Flick, M. J. A. Caballero, A. Padwa, Tetrahedron 2010, 66, 3643–3650;
p) T. J. Donohoe, P. M. Brian, G. C. Hargaden, T. J. O’Riordan,
Tetrahedron 2010, 66, 6411–6420; q) G. Lapointe, K. Schenk, P. Renaud,
Org. Lett. 2011, 13, 4774–4777; r) G. Pandey, V. Janakiram, Chem. Eur.
J. 2015, 21, 13120–13126.
[2]
We reported nucleophilic addition to N-hydroxyamides and N-
alkoxyamides. For selected examples, see: a) K. Shirokane, Y. Kurosaki,
T. Sato, N. Chida, Angew. Chem. Int. Ed. 2010, 49, 6369–6372; Angew.
Chem. 2010, 122, 6513–6516; b) Y. Yanagita, H. Nakamura, K.
Shirokane, Y. Kurosaki, T. Sato, N. Chida, Chem. Eur. J. 2013, 19, 678–
684; c) K. Shirokane, T. Wada, M. Yoritate, R. Minamikawa, N.
Takayama, T. Sato, N. Chida, Angew. Chem. Int. Ed. 2014, 53, 512–516;
Angew. Chem. 2014, 126, 522–526; d) S. Katahara, S. Kobayashi, K.
Fujita, T. Matsumoto, T. Sato, N. Chida, J. Am. Chem. Soc. 2016, 138,
5246–5249; e) S. Katahara, S. Kobayashi, K. Fujita, T. Matsumoto, T.
Sato, N. Chida. Bull. Chem. Soc. Jpn. 2017, 90, 893–904; For selected
examples from other groups, see: f) H. Iida, Y. Watanabe, C. Kibayashi,
J. Am. Chem. Soc. 1985, 107, 5534–5535; g) G. Vincent, R. Guillot, C.
Kouklovsky, Angew. Chem. Int. Ed. 2011, 50, 1350–1353; Angew. Chem.
2011, 123, 1386–1389; h) M. Jäkel, J. Qu, T. Schnitzer, G. Helmchen,
Chem. Eur. J. 2013, 19, 16746–16755.
[7]
[8]
a) A. J. Blackman, C. Li, D. C. R. Hockless, B. W. Skelton, A. H. White,
Tetrahedron 1993, 49, 8645–8656; b) C. Li, A. J. Blackman, Aust. J.
Chem. 1994, 47,1355–1361; c) C. Li, A. J. Blackman, Aust. J. Chem.
1995, 48, 955–965.
[3]
For recent selected examples on nucleophilic addition to amides, see: a)
Q. Xia, B. Ganem, Org. Lett. 2001, 3, 485–487; b) T. Murai, Y. Mutoh, Y.
Ohta, M. Murakami, J. Am. Chem. Soc. 2004, 126, 5968–5969; c) T.
Murai, F. Asai, J. Am. Chem. Soc. 2007, 129, 780–781; d) K.-J. Xiao, J.-
M. Luo, K.-Y. Ye, Y. Wang, P.-Q. Huang, Angew. Chem. Int. Ed. 2010,
49, 3037–3040; Angew. Chem. 2010, 122, 3101–3104; e) G. Bélanger,
G. O’Brien, R. Larouche-Gauthier, Org. Lett. 2011, 13, 4268–4271; f) K.-
J. Xiao, A.-E. Wang, P.-Q. Huang, Angew. Chem. Int. Ed. 2012, 51,
8314–8317; Angew. Chem. 2012, 124, 8439–8442. g) A. W. Gregory, A.
Chambers, A. Hawkins, P. Jakubec, D. J. Dixon, Chem. Eur. J. 2015, 21,
111–114; h) F. Tinnis, A. Volkov, T. Slagbrand, H. Adolfsson, Angew.
Chem. Int. Ed. 2016, 55, 4562–4566; Angew. Chem. 2016, 128, 4638–
4642; i) P. Q. Huang, Q.-W. Lang, X.-N. Hu, J. Org. Chem. 2016, 81,
10227–10235; j) P.-Q. Huang, W. Ou, F. Han, Chem. Commun. 2016,
52, 11967–11970; k) P. W. Tan, J. Seayad, D. J. Dixon, Angew. Chem.
Int. Ed. 2016, 55, 13436–13440; Angew. Chem. 2016, 128, 13634–
13638; l) M. Sato, H. Azuma, A. Daigaku, S. Sato, K. Takasu, K. Okano,
H. Tokuyama, Angew. Chem. Int. Ed. 2017, 56, 1087–1091; Angew.
Chem. 2017, 129, 1107–1111; m) Á. L. Fuentes de Arriba, E. Lenci, M.
Sonawane, O. Formery, D. J. Dixon, Angew. Chem. Int. Ed. 2017, 56,
3655–3659; Angew. Chem. 2017, 129, 3709–3713; n) L.-G. Xie, D. J.
Dixon, Chem. Sci. 2017, 8, 7492–7497; o) M. Yoritate, Y. Takahashi, H.
Tajima, C. Ogihara, T. Yokoyama, Y. Soda, T. Oishi, T. Sato, N. Chida,
J. Am. Chem. Soc. 2017, 139, 18386–18391; p) L.-G. Xie, D. J. Dixon,
Nature Commun. 2018, 9, 2841; q) W. Qu, F. Han, X.-N. Hu, H. Chen,
P.-Q. Huang, Angew. Chem. Int. Ed. 2018, 57, 11354–11358; Angew.
Chem. 2018, 130, 11524–11528; r) P. Trillo, T. Slagbrand, H. Adolfsson,
Angew. Chem. Int. Ed. 2018, 57, 12347–12351; Angew. Chem. 2018,
130, 12527–12531; s) Y. Takahashi, R. Yoshii, T. Sato, N. Chida, Org.
Lett. 2018, 20, 5705–5708.
For reviews on cylindricines and related alkaloids, see; a) C. Kibayashi,
S. Aoyagi, H. Abe, Bull. Chem. Soc. Jpn. 2003, 76, 2059–2074; b) C.
Kibayashi, Chem. Pharm. Bull. 2005, 53, 1375–1386; c) S. M. Weinreb.
Chem. Rev. 2006, 106, 2531–2549; d) A. Kaga, S. Chiba, Synthesis
2018, 50, 685–699.
[9]
a) A. D. Patil, A. J. Freyer, R. Reichwein, B. Carte, L. B. Killmer, L.
Faucette, R. K. Johnson, D. J. Faulkner, Tetrahedron Lett. 1997, 38,
363–364; b) S. Dutta, H. Abe, S. Aoyagi, C. Kibayashi, K. S. Gates, J.
Am. Chem. Soc. 2005, 127, 15004–15005.
[10] Lactam 21 was obtained by commercially available L-pyroglutaminol in
one step (TBDPSCl, DMF, imidazole, RT, 100%), see: L. Pickering, B. S.
Malhi, P. L. Coe, R. T. Walker, Nucleos. Nucleot. Nucl. 1994, 13, 1493‒
1506.
[11] a) S. A. Matlin, P. G. Sammes, J. Chem. Soc., Chem. Commun. 1972,
1222–1223; b) S. A. Matlin, P. G. Sammes, R. M. Upton, J. Chem. Soc.,
Perkin Trans. 1, 1979, 2481–2487.
[12] The Wade and Aue groups independently reported synthesis of N-
hydroxylactams through oxidation of N-alkylimidates in low yields
(13~27%) due to formation of byproducts such as imines, nitrosos and
oximes. We found that use of oxalic acid was crucial in the ring-opening
step to suppress the generation of these byproducts. a) D. S. C. Black,
R. F. C. Brown, A. M. Wade, Tetrahedron Lett. 1971, 12, 4519–4520; b)
D. Thomas, D. H. Aue, Tetrahedron Lett. 1973, 14, 1807–1810; c) D. H.
Aue, D. Thomas, J. Org. Chem. 1974, 39, 3855–3862; d) A. Drouin, D.
K. Winter, S. Pichette, S. Aubert-Nicol, J. Lessard, C. Spino, J. Org.
Chem. 2011, 76, 164–169.
[13] For selected examples on synthesis and application to total synthesis
related to chiral nitrones possessing a stereocenter adjacent to the
nitrogen atom, see: a) M. E. McCallum, G. M. Smith, T. Matsumaru, K.
Kong, J. A. Enquist Jr., J. L. Wood, J. Antibiot. 2016, 69, 331–336; b) K.
Kong, J. A. Enquist Jr., M. E. McCallum, G. M. Smith, T. Matsumaru, E.
Menhaji-Klotz, J. L. Wood, J. Am. Chem. Soc. 2013, 135, 10890–10893.
[14] For synthetic approaches to tricyclic marine alkaloids using [3+2]-
cycloaddtion of nitrones, see; a) K. M. Werner, J. M. de los Santos, S. M.
Weinreb, J. Org. Chem. 1999, 64, 686–687; b) K. M. Werner, J. M. de
los Santos, S. M. Weinreb, M. Shang, J. Org. Chem. 1999, 64, 4865–
4873; c) M. C. Bagley, W. Oppolzer, Tetrahedron: Asymmet. 2000, 11,
2625–2633; d) W. Oppolzer, C. G. Bochet, Tetrahedron: Asymmet. 2000,
11, 4761–4770.
[4]
For selected reviews on synthesis and transformations of nitrones, see:
a) P. N. Confalone, E. M. Huie, In Organic Reactions; Andrew S. Kende,
Ed.; Wiley: New York, NY, 1988; Vol. 36, pp 1–173; b) K. V. Gothelf, K.
A. Jørgensen, Chem. Rev. 1998, 98, 863–909; c) P. de March, M.
Figueredo, J. Font, Heterocycles 1999, 50, 1213–1226; d) S. Kanemasa,
Synlett 2002, 1371–1387; e) M. Bonin, A. Chauveau, L. Micouin, Synlett
2006, 2349–2363; f) J. Revuelta, S. Cicchi, A. Goti, A. Brandi, Synthesis
2007, 485–504; g) H. Pellissier, Tetrahedron 2007, 63, 3235–3285; h) V.
Nair, T. D. Suja, Tetrahedron 2007, 63, 12247–12275; i) L. M. Stanley,
M. P. Sibi, Chem. Rev. 2008, 108, 2887–2902.
[5]
[6]
S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815–3818.
a) B. B. Snider, T. Liu, J. Org. Chem. 1997, 62, 5630–5633; b) G. A.
Molander, M. Rönn, J. Org. Chem. 1999, 64, 5183–5187; c) J. F. Liu, C.
H. Heathcock, J. Org. Chem. 1999, 64, 8263–8266; d) B. M. Trost, M. T.
Rudd, Org. Lett. 2003, 5, 4599–4602; e) S. Canesi, D. Bouchu, M. A.
[15] Y. Sasano, S. Nagasawa, M. Yamazaki, M. Shibuya, J. Park, Y. Iwabuchi,
Angew. Chem. Int. Ed. 2014, 53, 3236–3240; Angew. Chem. 2014, 126,
3300–3304.
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[16] For a selected review on the sp hybridized turbo Grignard, see; R. L.-Y.
[17] The stereochemistry of the secondary alcohol in 31 was determined
Bao, R. Zhao, L. Shi, Chem. Commun. 2015, 51, 6884–6900.
through formation of the carbamate, see the supporting information.
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10.1002/anie.201901049
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Layout 2:
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S. Hiraoka, T. Matsumoto, K.
Matsuzaka, T. Sato,* N. Chida*
Page No. – Page No.
Nucleophilic Approach to Fully
Substituted Cyclic Nitrones from N-
Hydroxylactam Derivatives:
Development and Application to the
Total Synthesis of Cylindricine C
A nucleophilic approach to fully substituted cyclic nitrones from N-hydroxylactam
derivatives is reported. The reaction proceeds through nucleophilic addition of an
organolithium reagent and subsequent elimination in a one-pot process. When
combined with N-oxidation of a chiral lactam, our method allows for utilization of an
easily available lactam as a chiral nitrone equivalent, enabling the enantioselective
total synthesis of cylindricine C.
This article is protected by copyright. All rights reserved.