Total Synthesis of Neodysiherbaine A via 1,3-Dipolar Cycloaddition of a Chiral Nitrone Template

Article abstract of DOI:10.1021/acs.orglett.7b03092

The total synthesis of neodysiherbaine A was achieved via 1,3-dipolar cycloaddition of a chiral nitrone template with a sugar-derived allyl alcohol in the presence of MgBr₂·OEt₂. This cycloaddition constructed the C2 and C4 asymmetric centers in a single step. Then reductive cleavage, intramolecular S_N2 reaction of the tertiary alcohol, and oxidation of the primary alcohol afforded neodysiherbaine A.

Full text of DOI:10.1021/acs.orglett.7b03092

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Total Synthesis of Neodysiherbaine A via 1,3-Dipolar Cycloaddition
of a Chiral Nitrone Template
Toshihiro Hirai, Kohki Shibata, Yohei Niwano, Masao Shiozaki, Yoshimitsu Hashimoto,
Nobuyoshi Morita, Shintaro Ban, and Osamu Tamura*
Showa Pharmaceutical University, Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
S
* Supporting Information
ABSTRACT: The total synthesis of neodysiherbaine A was achieved via 1,3-dipolar cycloaddition of a chiral nitrone template
with a sugar-derived allyl alcohol in the presence of MgBr2·OEt2. This cycloaddition constructed the C2 and C4 asymmetric
centers in a single step. Then reductive cleavage, intramolecular SN2 reaction of the tertiary alcohol, and oxidation of the primary
alcohol afforded neodysiherbaine A.
ysiherbaine (1)1 and neodysiherbaine A (2)2 were
isolated from the Micronesian sponge Dysidea herbacea
as excitatory amino acids that are selective agonists of non-
NMDA-type glutamate receptors in the central nervous system
(Figure 1). The structural characteristics of these compounds
numbering) in a single operation, and the latter reaction is
challenging because a highly functionalized tertiary alcohol is
used as the nucleophile.
Our retrosynthetic analysis of 2 is shown in Scheme 1.
Inclusion of an additional bond from the C2-amino nitrogen to
D
Scheme 1. Retrosynthetic Analysis of 2
Figure 1. Dysiherbaine and neodysiherbaine A.
include a highly functionalized pyranofuran moiety (C4−C10),
a glutamic acid moiety (C1−C4, C11), and an oxygen-
substituted quaternary center (C4) that connects those two
parts. Intensive efforts to synthesize these compounds have
been made2−5 because of their interesting structural character-
istics and biological activities.
For example, these amino acids exhibit high affinities for
kainate receptors Gluk1 and Gluk2.6,7 Among various synthetic
intermediates for these amino acids8 and their analogues,9
compound 2 and its analogues have proven to be useful tools
for studying the structure and functions of kainate receptors.7c
In this communication, we report a total synthesis of 2
featuring a chelation-controlled cycloaddition of a nitrone with
an allyl alcohol in the presence of magnesium bromide and
tetrahydrofuran ring construction by means of intramolecular
SN2 reaction. The former reaction can construct the stereo-
chemistries at both the 2- and 4-positions (glutamic acid
the C4-oxygen in 2 affords isoxazolidine A, which can be
obtained by cycloaddition of a nitrone. Accordingly, we
planned to utilize a stereocontrolled 1,3-dipolar cycloaddition
in the synthesis of 2. Thus, cycloaddition of fully functionalized
allyl alcohol B with ester-substituted nitrone C would give
isoxazolidine A, whose hydrogenolysis followed by intra-
Received: October 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03092
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
molecular SN2 reaction should afford the target molecule 2. We
chose cyclic nitrone 3 as a chiral and geometry-fixed nitrone
corresponding to C.10−12 Thus, the first task was the synthesis
of the fully functionalized allyl alcohol corresponding to B.
Allyl alcohol 7 was expected to be suitable, since one of the
hydroxyl groups distinguished by the different protective group
(benzyl group) can be transformed into a leaving group
(Scheme 2). Considering the stereochemistry of 7, we selected
Table 1. Cycloaddition of Nitrone 3 with Allyl Alcohol 7
yield
a
entry
conditions
(%)
8a:8b
b
Scheme 2. Preparation of Allyl Alcohol 7
1
MgBr2·OEt2 (1.5 equiv), 3 h
MgBr2·OEt2 (1.5 equiv), 5 h
MgBr2·OEt2 (4.5 equiv), 5 days
MgBr2·OEt2 (4.5 equiv), 2-propanol (4.5 equiv),
5 days
−
−
c
2
30
48
80
50:50
>95:<5
>95:<5
3
d
4
5
none, 50 °C, 3 days
89
12:88
a
Unless otherwise specified, all reactions were carried out using 3 (50
mg) and 7 (130 mg, 1.5 equiv) in ClCH2CH2Cl at room temperature.
b
c
CH2Cl2 was used as the solvent. The reaction was conducted in
d
refluxing ClCH2CH2Cl. 7 (0.66 equiv) was used, and the yield is
based on 7.
acid moiety and construction of the oxygen-substituted
quaternary center with the correct stereochemistries in a single
step.
The details of the stereoselection remain unclear, but 8a may
be formed by MgBr2-promoted cycloaddition.12,14 Reactions of
1,1-disubstituted alkenes with nitrone 3 always give only the
products derived from cycloaddition from the less hindered si
face because of severe steric interaction with the phenyl group
in the re face (Figure 2, E).11c,12b Since the reaction of nitrone 3
methyl α-D-mannopyranoside as the starting material. The
pyranoside was converted to primary alcohol 4 by means of a
known five-step procedure including silane reduction to afford
D.13,4d Swern oxidation of 4 and Wittig reaction with a stable
ylide afforded α,β-unsaturated aldehyde 5. Hydrogenation of 5
followed by Mannich reaction with Eschenmoser’s salt gave
aldehyde 6. Finally, reduction of 6 with DIBAL-H afforded the
key allyl alcohol 7.
Figure 2. Stereoselection of cycloaddition of 3 with 7.
Next, we examined the crucial cycloaddition (Table 1). First,
a small excess amount of allyl alcohol 7 was used, as is usual.12
Treatment of nitrone 3 (1 equiv) with alcohol 7 (1.5 equiv) in
the presence of MgBr2·OEt2 (1.5 equiv) at room temperature
resulted in recovery of the starting materials (entry 1). Reaction
in refluxing 1,2-dichloroethane gave a 1:1 mixture of 8a and 8b
in 30% yield (entry 2). Taking into account possible
coordination of MgBr2 to the protected hydroxyl groups of
the allyl alcohol, a larger amount of MgBr2·OEt2 was used, and
a higher ratio of 8a was obtained (entry 3). After intensive
experimentation, the use of an excess of nitrone 3 (1.5 equiv)
over allyl alcohol 7 (1.0 equiv) and addition of 2-propanol14c,e
were found to provide a high yield of 8a, probably because of
the improved solubility of MgBr2 (entry 4). In contrast to these
reactions, reaction of nitrone 3 with alcohol 7 in the absence of
MgBr2 afforded 8b as the major isomer (entry 5). On the basis
of these results, practical cycloaddition (multigram scale) was
conducted using allyl alcohol 7 (1 equiv), nitrone 3 (2.6 equiv),
and MgBr2·OEt2 (7.4 equiv) in the presence of 2-propanol (7.4
equiv) in 1,2-dichloroethane to provide exclusively the desired
cycloadduct 8a in 85% yield along with recovery of unreacted
nitrone 3 (see the Supporting Information). It is noteworthy
that this cycloaddition enabled the incorporation of the amino
and alkene 7 simultaneously forms two bonds, the reaction
proceeds via geometry F. The endo-oriented R1 group
apparently occupies a closer position to the nitrone ring than
does the R2 group. When the hydroxymethyl group lies in the
endo position (R1 = CH2OH) in the presence of MgBr2, the R1
group plays the role of a very bulky substituent by wearing
MgBr2 that also coordinates with nitrone oxygen, which
generates stereorepulsion of the nitrone ring. Accordingly, the
hydroxymethyl group occupies the exo position (R2
=
CH2OH), and MgBr2 forms chelation between the hydroxyl
group and nitrone oxygen (G), providing 8a.12b In the case of
the thermal reaction (Table 1, entry 5), the bulky sugar-derived
substituent occupies the exo position (R2) in F to give 8b
predominantly.12b
With the cycloadduct 8a in hand, we next focused on the
ring-closure precursor (Scheme 3). When cycloadduct 8a was
stirred with 20% Pd(OH)2 on charcoal in THF under an
atmosphere of hydrogen at room temperature, hydrogenolysis
of the O-benzyl bond, N−O bond, and N-benzyl bond occurred
simultaneously to generate aminotriol H, which cyclized to
form the γ-lactone. The amino group was protected with a Boc
group, giving N-Boc lactone 9 in 80% yield. After protection of
B
DOI: 10.1021/acs.orglett.7b03092
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formation are known,4a,g,5c this is the first case of THF
construction by employing a highly functionalized tertiary
alcohol as the nucleophile. This success with chloromesylate
11d may be due to the combination of sufficient stability under
the basic conditions, low steric hindrance favoring axial
conformation J, and the high leaving ability of the
chloromesyloxy group.15
Scheme 3. Elaboration of Cycloadduct 8a
To accomplish the synthesis, oxidation of the side chain to
obtain the carboxylic acid is essential. For this purpose,
desilylation of methyl ester 14a and tert-butyl ester 14b was
next examined (Scheme 5). Upon treatment of 14a with HF·
Scheme 5. Synthesis of Neodysiherbaine A (2)
the primary alcohol of 9 to give 10, the secondary hydroxyl
group was sulfonylated to give four kinds of cyclization
precursors: mesylate 11a, tosylate 11b, triflate 11c, and
chloromesylate 11d.
With the four types of sulfonate in hand, the next task was
tetrahydrofuran (THF) formation (Scheme 4). Sulfonates
Scheme 4. Tetrahydrofuran Formation from 11
pyridine, the desired 15a and lactone 16 derived from 15a were
obtained in 20% and 63% yield, respectively. The use of
Bu4N+Ph3SiF2 (TBAT), with less basic F− compared with
−
TBAF, gave only undesired 16 in 83% yield. In contrast to 14a,
utilization of tert-butyl ester 14b greatly suppressed lactone
formation, probably as a result of steric factors. Thus, 14b
underwent desilylation with TBAT to afford primary alcohol
15b, a key intermediate for 2,5d in high yield. Finally, the
synthesis of 2 was achieved via two known steps:5d oxidation of
the primary alcohol followed by removal of all protective
groups of 17 gave neodysiherbaine A (2).
In conclusion, we have accomplished a stereocontrolled total
synthesis of neodysiherbaine A (2) featuring magnesium
bromide-mediated cycloaddition of chiral nitrone template 3
with allyl alcohol 7 bearing a polyoxygenated tetrahydropyran
moiety and tetrahydrofuran construction by an intramolecular
SN2 reaction of a highly stereodemanding tertiary alcohol.
ASSOCIATED CONTENT
* Supporting Information
■
S
11a−d were treated with LiOH (3 equiv) at room temperature
to generate carboxylate I, and then the mixture was heated at 70
°C. In the case of 11a or 11b, no THF formation took place,
although hydrolysis of the lactone proceeded smoothly to give
carboxylate I. Use of triflate 11c led to a complex mixture,
probably because of instability under aqueous basic conditions.
In contrast to these sulfonates, I derived from chloromesylate
11d underwent intramolecular SN2 ring closure to generate
carboxylate K via triaxial conformation J. After acidification of
the mixture with dilute HCl, the organic extract containing acid
12 was treated with trimethylsilyldiazomethane to provide
methyl ester 14a in 78% yield from lactone 11d. When O-tert-
butyl-N,N′-diisopropylisourea (13) was used after workup with
phosphoric acid, tert-butyl ester 14b was obtained in 95% yield
from 11d. Although a few examples of similar SN2-type THF
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03092.
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tamura@ac.shoyaku.ac.jp.
ORCID
Osamu Tamura: 0000-0002-5415-8378
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b03092
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
This work was supported by the Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
Japan, by the MEXT-Supported Program for the Strategic
Research Foundation at Private Universities (2013-2017), and
by JSPS KAKENHI Grant JP17K08221.
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