Total synthesis of (±)-gephyrotoxin by amide-selective reductive nucleophilic addition

Article abstract of DOI:10.1002/anie.201308905

A chemoselective approach for the total synthesis of (±)- gephyrotoxin has been developed. The key to success was the utilization of N-methoxyamides, which enabled the direct coupling of the amide with an aldehyde and selective reductive nucleophilic addition to the amide in the presence of a variety of sensitive and electrophilic functional groups, such as a methyl ester. This chemoselective approach minimized the use of protecting-group manipulations and redox reactions, which resulted in the most concise and efficient total synthesis of (±)-gephyrotoxin described to date. Aim for selectivity: A chemoselective approach that utilizes N-methoxyamides has been developed for the total synthesis of (±)-gephyrotoxin. The N-methoxy group enabled the direct coupling of the amide with an aldehyde and amide-selective reductive allylation in the presence of a more electrophilic methyl ester, which resulted in the most concise and efficient total synthesis of (±)-gephyrotoxin described to date.

Full text of DOI:10.1002/anie.201308905

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Communications
DOI: 10.1002/anie.201308905
Total Synthesis Very Important Paper
Total Synthesis of (ꢀ)-Gephyrotoxin by Amide-Selective Reductive
Nucleophilic Addition**
Kenji Shirokane, Takamasa Wada, Makoto Yoritate, Ryo Minamikawa, Nobuaki Takayama,
Takaaki Sato,* and Noritaka Chida*
Dedicated to Professor Larry E. Overman on the occasion of his 70th birthday
Abstract: A chemoselective approach for the total synthesis of
(ꢀ)-gephyrotoxin has been developed. The key to success was
the utilization of N-methoxyamides, which enabled the direct
coupling of the amide with an aldehyde and selective reductive
nucleophilic addition to the amide in the presence of a variety
of sensitive and electrophilic functional groups, such as
Figure 1. Gephyrotoxin (1) and previous total syntheses.
a methyl ester. This chemoselective approach minimized the
use of protecting-group manipulations and redox reactions,
which resulted in the most concise and efficient total synthesis
of (ꢀ)-gephyrotoxin described to date.
atom and the installation of the two distinct side chains
required extra protecting-group manipulations. To overcome
this limitation, we envisioned a chemoselective approach with
an amide-selective nucleophilic addition in the presence of
a more electrophilic methyl ester (Scheme 1). This key
reaction ultimately served to minimize the use of protect-
ing-group manipulations, which resulted in a concise total
synthesis of (ꢀ)-gephyrotoxin (1).
M
odern applications of organic chemistry in industry and
medicine, especially for drug discovery, have resulted in the
need for compounds of ever-increasing complexity. However,
the reaction of a targeted functional group in such complex
molecules often requires extra steps to protect more reactive
functional groups, which results in decreases in the total yield.
To overcome this issue and to achieve step-economic
processes, the development of methods with high chemo-
selectivities, especially for carbon–carbon bond formation,
has become a pivotal goal in synthetic chemistry.[1]
Gephyrotoxin (1) was isolated from skin extracts of
a tropical poison dart frog, Dendrobates histrionicus, and
possesses an array of neurological activities, including mild
muscarinic activity.[2] The groups of Kishi, Hart, and Overman
independently reported landmark total syntheses of gephyr-
otoxin with their own beautiful approaches (Figure 1).[3–6]
However, although we appreciate that their syntheses were
achieved more than 30 years ago, they required a number of
protecting groups. For example, the construction of the three
stereogenic carbon centers that are connected to the nitrogen
Scheme 1. Chemoselective reductive nucleophilic addition to N-
methoxyamides. Boc=tert-butoxycarbonyl, Cbz=benzyloxycarbonyl,
Cp=cyclopentadienyl, MOM=methoxymethyl, Ns=ortho-nitrobenze-
nesulfonyl, THP=2-tetrahydropyranyl, Ts=4-toluenesulfonyl.
[*] K. Shirokane, T. Wada, M. Yoritate, R. Minamikawa, N. Takayama,
Dr. T. Sato, Prof. Dr. N. Chida
Before we focused on the overall synthesis, we needed to
develop a practical amide-selective nucleophilic addition
reaction. Although significant progress has recently been
made in the field of nucleophilic addition to inert amides by
using reactive nucleophiles, including diisobutylaluminum
hydride (DIBAL-H), Grignard reagents, and organolithium
reagents,[7–9] functional-group compatibility still remains an
unsolved issue.[10–12] De Meijere and co-workers reported that
a Kulinkovich-type cyclopropanation of tertiary amides
proceeded chemoselectively in the presence of a sterically
hindered tert-butyl ester.[12b] The groups of Charette[12c] and
Huang[12d] described chemoselective transformations of sec-
ondary amides into ketimines and ketones via highly electro-
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
[**] This research was supported by a Grant-in-Aid for Young Scientists
(B) from MEXT (24750045), the Naito Foundation, and a JSPS
fellowship to K.S. (24·1843). We thank Prof. Larry. E. Overman,
University of California, Irvine, for providing 1H NMR spectra of
related compounds. Prof. Takeshi Noda, Kanagawa Institute of
Technology, is acknowledged for mass spectrometric analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308905.
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philic imidoyl triflates. This approach was highly general and
compatible with a variety of sensitive functional groups, such
as esters and ketones. We envisioned a chemoselective
reductive nucleophilic addition to N-methoxyamides
(Scheme 1, 2!5).[13] Exposure of 2 to the Schwartz reagent[14]
is known to produce intermediate 3, which contains a five-
membered chelate ring and gives the corresponding aldehyde
after hydrolysis.[10b,c] However, our method requires addition
of a Lewis acid to 3, which results in the generation of the N-
oxyiminium ion 4. This intermediate would then undergo
nucleophilic addition to give substituted amine 5. The first
key to achieving functional-group compatibility is the high
reactivity of the Schwartz reagent with amide carbonyl
groups. The second important feature of this transformation
is the high electrophilicity of N-oxyiminium ion 4. Our
previous studies revealed that 4 was more electrophilic than
an ordinary N-alkyliminium ion 6, and reacted with mild
nucleophiles.[15,16] Combining both of these unique properties,
our method became high yielding and compatible with
a number of sensitive functional groups.
yields for a variety of substrates (80–98%). For example,
a more reactive aliphatic methyl ester was tolerated (7b,
84%). The nitro group remained intact under the reaction
conditions (7c, 90%). Benzyl and aryl halide moieties within
the substrates had no detrimental effects on the yield (7d,
98%; 7e, 92%). Carbamate moieties were completely differ-
entiated from the N-methoxyamide despite the high struc-
tural similarity; the corresponding products 7 f and 7g were
obtained in 87% and 90% yield, respectively. A sulfonamide
with an acidic proton did not disturb the reaction (7h, 90%,
7I, 80%). Initially, we were concerned that using the
Schwartz reagent would cause olefin-containing substrates
to readily undergo hydrozirconation as a side reaction.
However, the reactions of N-methoxyamides that contain
a cinnamoyl group or a terminal olefin afforded the allylated
products without affecting the olefin moieties (7j, 84%; 7k,
87%). The developed conditions were mildly acidic, but did
not affect acetal groups (7l: 91%; 7m: 84%).
The high electrophilicity of the N-oxyiminium ion enabled
us to use a variety of nucleophiles without deterioration of
chemoselectivity (Table 1). Most nucleophiles, including
allenylstannane and TMSCN, required 10 mol% of Sc(OTf)3,
although the allylation needed 20 mol% (entries 1 and 2).
Mukaiyama-type Mannich reactions with a silyl enol ether or
Our hypothesis was confirmed when allyltributylstannane
and
a catalytic amount of Sc(OTf)3 were employed
(Scheme 2). Treatment of an N-methoxyamide that also
bears a methyl ester with the Schwartz reagent at room
temperature, followed by addition of Sc(OTf)3 (20 mol%)
and allyltributylstannane (1.2 equiv) provided 7a in 86%
yield. A more electrophilic methyl ester did not interfere with
the reaction. This transformation was found to be compatible
with a variety of functional groups and proceeded in high
Table 1: Variation of the nucleophile.[a]
Entry
Nucleophile
Product
Yield[b] [%]
1
2
71
81
3
4
74
78 (d.r.=1.6:1)
5[c]
75
[a] 2a, [Cp2ZrHCl] (1.6 equiv), (CH2Cl)2 (0.1m), RT, 10 min; nucleophile
(1.2 equiv), Sc(OTf)3 (10 mol%), RT, 1 h. [b] Yield of isolated product
after purification by column chromatography. [c] The reaction was
performed with Sc(OTf)3 (20 mol%) at ꢁ408C. TMS=trimethylsilyl,
TIPS=triisopropylsilyl.
a siloxyfuran proceeded in good yields (entries 3 and 4). The
intermolecular Pictet–Spengler-type reaction with N-methyl-
indole was performed at ꢁ408C to give 12 in 75% yield
(entry 5).
With suitable conditions for the chemoselective reductive
nucleophilic addition to N-methoxyamides in hand, we turned
our attention to the total synthesis of gephyrotoxin
(Scheme 3). Our strategy featured utilization of the N-
methoxy group as a reactivity control element, which was
installed along with the requisite nitrogen atom; The con-
densation of 4-pentenoic acid (13) with N-methoxyamine
Scheme 2. Scope of the chemoselective reductive allylation of N-
methoxyamides. Reaction conditions: 2, [Cp2ZrHCl] (1.6 equiv),
(CH2Cl)2 (0.1m), RT, 10 min; then CH2 =CHCH2SnBu3 (1.2 equiv),
Sc(OTf)3 (20 mol%), RT, 1 h. Yields of isolated products after purifica-
tion by column chromatography are given. Tf=trifluoromethanesul-
fonyl.
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Scheme 3. Total synthesis of (ꢀ)-gephyrotoxin (1). AIBN=2,2’-azobis(isobutyronitrile), DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DIBAL-H=diiso-
butylaluminum hydride, DMF=dimethylformamide, DMSO=dimethylsulfoxide, HMPA=hexamethylphosphoramide.
gave N-methoxyamide 14 in 96% yield. Subsequent cross-
metathesis of 14 with Grubbsꢀ second-generation catalyst at
reflux provided 15 as a mixture of diastereomers in 61% yield
(E/Z = 2.4:1).[17,18] We then attempted the direct coupling of
N-methoxyamide 15 with 4-bromobutanal, followed by intra-
molecular allylation of N-acyl-N-oxyiminium ion 16. The N-
methoxy group played a critical role as a reactivity control
element in this key reaction. In contrast to the reaction of
basic amines, the intermolecular condensation of an ordinary
amide with an aldehyde is very challenging because of the
poor nucleophilicity of the nitrogen atom of the amide.[19] The
assistance of the N-methoxy group, however, increased the
nucleophilicity of the nitrogen atom to render it more
nucleophilic than the oxygen atom and to enable the direct
coupling, which afforded 2,3-cis-piperidone 17 in 79% yield
as a single diastereomer.[20] Interestingly, the identical reac-
tion of the corresponding N-methyl-substituted amide did not
provide the desired lactam. The terminal olefin 17 was then
converted into methyl-Z-enoate 19 (19a/19b = 5.2:1) by
ozonolysis and an olefination developed by Ando and co-
workers.[21] In the following radical cyclization, this Z arrange-
ment of enoate 19 was crucial; 20 was obtained as a single
diastereomer in 97% yield, whereas the transformation of the
corresponding E-enoate gave the product without diastereo-
selectivity (87%, d.r. = 1:1).
would be necessary because no practical protecting group for
esters has been reported. Subsequent protection of the
generated hydroxy group would then be required prior to
the nucleophilic addition, as well as a deprotection after-
wards. On the other hand, our chemoselective reaction gave
the product in a one-pot process, and ultimately removed the
protection/deprotection sequence of the methyl ester from
the total synthesis.
With decahydroquinoline 21 in hand, we turned our
attention to the construction of the pyrrolidine unit
(Scheme 3). Hydroboration of 21 with thexylborane, followed
by a one-pot homologation using the Parikh–Doering oxida-
tion and the Wittig olefination[23] provided E-enoate 23.
Treatment of 23 with activated zinc in AcOH/H2O at 608C
ꢁ
initiated the cleavage of the N O bond, which was followed
by aza-Michael cyclization to form pyrrolidine 24.[24] For
completion of the total synthesis, the installation of the two
distinct side chains was still required. After extensive inves-
tigation, we succeeded in differentiating the two esters in 24
with NaAlH(OtBu)iBu2 (SDBBA).[25] Treatment of 24 with
SDBBA initiated chemoselective partial reduction of the
methyl ester in the presence of the tert-butyl ester to afford
aldehyde 25. Wittig reaction of 25 and subsequent Sonoga-
shira coupling installed the Z-eneyne side chain to give 27.
Finally, reduction of the remaining tert-butyl ester completed
the total synthesis of (ꢀ)-gephyrotoxin (1).
The stage was now set for the key chemoselective
reductive allylation (Scheme 3). Treatment of 20 with
[Cp2ZrHCl] at 08C gave the five-membered chelate, which
underwent subsequent allylation even at ꢁ788C with allyl-
tributylstannane and a catalytic amount of Sc(OTf)3. The
reaction was both chemoselective and stereoselective in the
presence of a methyl ester and afforded 21 in 84% yield
(d.r. = 4.6:1).[22] It is noteworthy that classical nucleophilic
addition in this situation would require a number of extra
steps. First, the reduction of the more electrophilic ester
The present synthesis of (ꢀ)-gephyrotoxin (1) by our
chemoselective approach was accomplished in 14 steps with
an overall yield of 9.4% from commercially available 4-
pentenoic acid, and thus represents the most concise and
efficient synthesis that has been described for (ꢀ)-gephyro-
toxin to date. The key to success was the use of an N-methoxy
group as the reactivity control element. The N-methoxy group
increased the nucleophilicity of the nitrogen atom of the
amide, which enabled the direct coupling of the N-methox-
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[8] We previously reported the non-chemoselective nucleophilic
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need for protecting-group manipulations as well as redox
reactions. We believe that our novel approach will be
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Received: October 12, 2013
Published online: November 29, 2013
Keywords: amides · chemoselectivity · gephyrotoxin ·
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nucleophilic addition · total synthesis
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