Formal Synthesis of (-)-Haliclonin A: Stereoselective Construction of an Azabicyclo[3.3.1]nonane Ring System by a Tandem Radical Reaction

Article abstract of DOI:10.1021/acs.orglett.0c01627

A formal synthesis of (-)-haliclonin A, isolated from the marine sponge Haliclona sp. in Korea, is described. The key feature of the synthesis includes the highly stereoselective tandem radical reaction to construct the azabicyclo[3.3.1]nonane core and the enantioselective formation of an all-carbon quaternary center via the Pd-mediated deracemization.

Full text of DOI:10.1021/acs.orglett.0c01627

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Letter
Formal Synthesis of (−)-Haliclonin A: Stereoselective Construction of
an Azabicyclo[3.3.1]nonane Ring System by a Tandem Radical
Reaction
Keita Komine, Yasuhiro Urayama, Taku Hosaka, Yuki Yamashita, Hayato Fukuda, Susumi Hatakeyama,
and Jun Ishihara*
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ABSTRACT: A formal synthesis of (−)-haliclonin A, isolated from
the marine sponge Haliclona sp. in Korea, is described. The key
feature of the synthesis includes the highly stereoselective tandem
radical reaction to construct the azabicyclo[3.3.1]nonane core and
the enantioselective formation of an all-carbon quaternary center via
the Pd-mediated deracemization.
Scheme 1. Tandem Radical Reaction
he marine sponge genus Haliclona is known to produce
numerous biologically active natural products such as
T
depsipeptides and miscellaneous alkaloids.1 In 2009, Oh and
Shin et al. reported the isolation of (−)-haliclonin A (1), a
macrocyclic diamide, from Haliclona sp. in Korea (Figure 1).2
This natural product exhibits moderate antibacterial activity
with a minimum inhibitory concentration (MIC) value of 6.25
μg/mL against Bacillus subtilis, and cytotoxicity against the
K562 leukemia cell line with a half maximal inhibitory
concentration (IC50) of 15.9 μg/mL. Haliclonin A possesses
a fascinating azabicyclo[3.3.1]nonane core with two bridges
that form 15- and 17-membered rings containing an E-alkene
and a (Z,Z)-skipped diene. The significant biological proper-
ties and structural challenges have made haliclonin A an
attractive target for synthesis.3,4 The first total synthesis of
(−)-haliclonin A has been accomplished by Huang’s group in
2016 employing an organocatalytic asymmetric conjugate
addition and a Pd-promoted cyclization to construct the
highly functionalized bicyclic core.3 Another effort toward the
synthesis of 1 has recently been reported by Fukuyama and
Yokoshima et al., which was based on a creative strategy via an
intramolecular cyclopropanation and a conjugate addition of
an organocopper reagent.4c In this context, we are interested in
a tandem radical strategy for the construction of the formidable
highly condensed core. Herein, we report the formal synthesis
of (−)-haliclonin A (1) by a highly stereoselective tandem
radical reaction.
Our radical strategy is shown in Scheme 1. Carbon-centered
radical reactions enable the chemoselective formation of
sterically hindered carbon−carbon bonds in the presence of
various susceptible functional groups.5,6 It was envisaged that,
once nucleophilic carbamoyl radical 2 is generated,7 it would
be captured by an electron-poor enone to form cyclized
intermediate 3 containing an electrophilic radical. The radical
would in turn undergo the second C−C bond formation by the
Received: May 13, 2020
Figure 1. Structure of (−)-haliclonin A (1).
https://dx.doi.org/10.1021/acs.orglett.0c01627
© XXXX American Chemical Society
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A

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Scheme 2. Synthetic Plan
Table 1. Tandem Radical Reaction of 8
yield (%)
entry
concn (M)
condition
19
20
21
a
1
0.1
AIBN, PhH, reflux, 7 h
AIBN, PhH, reflux, 7 h
V-40, PhH, 110 °C, 7 h
V-40, PhCl, 110 °C, 7 h
V-40, PhH, 130 °C, 2 h
V-40, PhCl, 130 °C, 2 h
21
19
55
60
67
73
63
9
13
18
26
8
11
b
2
0.02
0.02
0.02
0.02
0.02
0.02
c d
,
3
4
5
6
7
d
d
13
15
V-40, PhCl, 150 °C, 2 h
b
a
c
Recovery of 8; 47%. Recovery of 8; 61%. Recovery of 8; 19%.
d
Reaction was conducted in a sealed tube.
This radical strategy allowed us to analyze the synthesis of 1
as illustrated in Scheme 2. For the synthesis of haliclonin A
(1), we selected Huang’s intermediate 53 as a precursor, which
would be accessible from 6 via a N-alkylation and an aldol
reaction between C1 and C10 positions. We assumed that 6
would be derived from 7 by ring-closing metathesis (RCM)
followed by hydrogenation of the resulting alkene. Then, given
the key tandem radical cyclization−allylation reaction8,9 to
secure the azabicyclo[3.3.1]nonane ring system, selenocarba-
mate 8 would be considered as a precursor of 7 via an
additional functional group interconversion. The radical
precursor would be accessible from cyclohexene 9 bearing an
all-carbon quaternary stereogenic center. To synthesize
enantiomerically pure 9, we envisioned an approach from
racemic compound 10 via the Pd-mediated deracemization,
which we have recently developed.10
Scheme 3. Synthesis of 8
Our synthesis began with the preparation of enone 8 with
high enantiopurity (Scheme 3). Commercially available methyl
cyclohex-3-ene-1-carboxylate (11) was alkylated with the
known alkyl iodide 1211 to deliver 13 in quantitative yield.
Compound 13 was converted to lactone 14 by a three-step
sequence involving saponification, iodolactonization, and
elimination in 99% yield. Methanolysis and carbonation
afforded racemic carbonate 10 in 74% yield, which was then
subjected to a Pd-mediated deracemization.10 Thus, racemic
compound 10 was reacted with sodium propionate using 5 mol
% allylpalladium(II) chloride dimer and 15 mol % (S,S)-
DACH-phenyl Trost ligand in CH2Cl2 at ambient temperature
to provide 9 in 94% yield with excellent enantioselectivity
(98% ee)12 as a sole product. After methanolysis of 9, the
resulting (+)-15 was converted to aldehyde 16 via silylation,
DIBAL reduction, and Swern oxidation in good yield.
Reductive amination of 16 with 4-methoxybenzylamine
furnished 17 in 69% yield. Treatment of 17 with triphosgene,
followed by addition of phenylselenide,14 afforded selenocar-
bamate 18 in excellent yield. Compound 18 was then
converted to enone 8 by desilylation and Parikh−Doering
oxidation.
With the required 8 in hand, we then focused on the tandem
radical reaction with allyltributylstannane (Table 1). When
enone 8 was heated under reflux in benzene in the presence of
convex face attack of nucleophilic allylstannane to produce a
suitably functionalized azabicyclo[3.3.1]nonane core 4.
B
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Scheme 4. Synthesis of 28
Scheme 5. Formal Synthesis of (−)-Haliclonin A (1)
furnished 19 in 73% yield (entry 6). However, the reaction at
150 °C decreased the yield to 63% (entry 7).
With azabicyclo[3.3.1]nonane core 19 in hand, we next
turned our attention to the completion of the synthesis of
target molecule (Scheme 4). NaBH4 reduction of 19 and
silylation of the resulting alcohol afforded 22 as a 2:1
diastereomeric mixture in 84% yield. Without separation of
the stereoisomers, 22 was then converted to 24 in 80% yield by
a three-step sequence involving Lemieux−Johnson oxidation,16
reductive amination with 3-buten-1-amine hydrochloride (23),
and benzenesulfonylation. Cleavage of the PMB ether of 24
and Nishizawa−Grieco elimination17 gave terminal alkene 7 in
86% yield. RCM reaction of 7 using Grubbs first generation
catalyst (10 mol %) and 1,4-benzoquinone (10 mol %) in
boiling CH2Cl2 and successive hydrogenation allowed the
formation of the 17-membered ring bridge to give 25 in
excellent yield. Desilylation of 25 followed by Dess−Martin
oxidation afforded ketone 6 in 86% yield, which was then
converted to 27 in 59% yield via cleavage of the N-PMB with
CAN, enamine formation with 2618 following Fukuyama’s
protocol,19 and silane reduction. At this stage, the subsequent
mission was to install the C10−C13 fragment, which proved to
be problematic. After considerable experiments, we gratifyingly
found that aldol condensation of 27 with ethyl glyoxylate
provided 28 and 29 in 78% and 21% yields, respectively,
although the major isomer 28 had the Z-configuration at the
2,2′-azodiisobutyronitrile (AIBN), the desired 19 was obtained
in 21% yield, along with isoindolinone 2013 (9% yield) and
butenamide 21 (11% yield) (entry 1). It is clear that products
20 and 21 were generated by the capture of the resulting
carbamoyl radical with the phenyl ring and allylstannane. To
prevent the formation of undesired 20 and 21, we next
examined the reaction at lower reactant concentration and
higher temperatures. When the reaction was performed at 0.02
M concentration of 8, the production of 21 was totally
suppressed, but the yield of 19 was not improved (entry 2). On
the other hand, when the reaction was carried out at 0.02 M
concentration using 1,1′-azobis(cyclohexane-1-carbonitrile)
(V-40) as an initiator at higher temperatures,15 the yield of
19 was dramatically improved (entries 3−7). To our delight, it
was found that the reaction of 8 in chlorobenzene at 130 °C
Δ
1,10-double bond.
Next, we explored the construction of another 15-membered
bridge (Scheme 5). Reduction of 28 with NaBH4 in methanol
according to Soai’s protocol20 successfully provided diol 30 as
a 1:1 diastereomeric mixture in 73% yield. Swern oxidation of
30 afforded ketoaldehyde 3121 in 84% yield. To construct the
C
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11R chiral center, we examined stereoselective allylation under
various conditions. Eventually, when 31 was treated with
allyltributylstannane and magnesium bromide ethyl etherate
(MgBr2·Et2O) in CH2Cl2 at 0 °C according to Linclau’s
method,22 the allylation was found to take place with perfect
chemo- and diastereoselectivities to afford 3323 in excellent
yield. The selective allylation can be rationalized via chelated
intermediate 32 where the re face attack of the allyl nucleophile
is favored by steric reasons. After silylation of 33, all our efforts
for Z-selective RCM24 of 34 using various metathesis catalysts
were totally fruitless, giving only unreacted 34. However, the
RCM reaction in the presence of classic Grubbs first
generation catalyst in boiling CH2Cl2 afforded the desired Z-
product 5 in 27% yield.25 Compound 5, thus obtained,
exhibited spectral properties identical in all respects to those
reported by Huang et al.3 Therefore, the formal synthesis of
(−)-haliclonin A (1) was achieved.
In conclusion, we have developed a novel approach for the
synthesis of (−)-haliclonin A (1) in an enantiomerically pure
form. The present work illustrates an efficient methodology for
the enantio- and diastereoselective construction of highly
functionalized azabicyclo[3.3.1]nonane ring systems which
relies on Pd-mediated deracemization of cyclohexenyl ester
derivatives and the tandem radical cyclization−allylation
process.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grants
JP16J03966 (K.K.), JP19K15568 (K.K.), JP16H05074
(S.H.), and JP18K05126 (J.I.). This work was the result of
using research equipment shared in MEXT project for
promoting public utilization of advanced research infra-
structure (program for supporting introduction of the new
sharing system) Grant JPMXS0422500320.
REFERENCES
■
(1) Zhu, J.; Liu, Y.; Liu, Z.; Wang, H.; Zhang, H. Bioactive
nitrogenous secondary metabolites from the marine sponge genus
Haliclona. Mar. Drugs 2019, 17, 682.
(2) Jang, K. H.; Kang, G. W.; Jeon, J. E.; Lim, C.; Lee, H. S.; Sim, C.
J.; Oh, K. B.; Shin, J. Haliclonin A, a new macrocyclic diamide from
the sponge Haliclona sp. Org. Lett. 2009, 11, 1713−1716.
(3) Guo, L.-D.; Huang, X.-Z.; Luo, S.-P.; Cao, W.-S.; Ruan, Y.-P.; Ye,
J.-L.; Huang, P.-Q. Organocatalytic, Asymmetric Total Synthesis of
(−)-Haliclonin A. Angew. Chem., Int. Ed. 2016, 55, 4064−4068.
(4) (a) Luo, S.-P.; Guo, L.-D.; Gao, L.-H.; Li, S.; Huang, P.-Q.
Toward the Total Synthesis of Haliclonin A: Construction of a
Tricyclic Substructure. Chem. - Eur. J. 2013, 19, 87−91. (b) Gao, Y.-J.;
Luo, S.-P.; Ye, J.-L.; Huang, P.-Q. An attempted approach to the
tricyclic core of haliclonin A: Structural elucidation of the final
product by 2D NMR. Chin. Chem. Lett. 2017, 28, 1176−1181.
(c) Orihara, K.; Kawagishi, F.; Yokoshima, S.; Fukuyama, T. Synthetic
Studies of Haliclonin A: Construction of the 3-Azabicyclo[3.3.1]-
nonane Skeleton with a Bridge that Forms the 17-Membered Ring.
Synlett 2018, 29, 769−772.
(5) For a representative review, see: (a) Curran, D. P.; Porter, N. A.;
Giese, B. Stereochemistry of Radical Reactions: Concepts, Guidelines, and
Synthetic Applications; VCH: New York, 1995. For a review on
tandem radical reactions, see: (b) Godineau, E.; Landais, Y. Radical
and Radical-Ionic Multicomponent Processes. Chem. - Eur. J. 2009,
15, 3044−3055.
(6) Urabe, D.; Yamaguchi, H.; Inoue, M. Application of α-Alkoxy
Bridgehead Radical for Coupling of Oxygenated Carbocycles. Org.
Lett. 2011, 13, 4778−4781.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01627.
Experimental details and compound characterization
data (PDF)
(7) For representative examples, see: (a) Herzon, S. B.; Myers, A. G.
Enantioselective Synthesis of Stephacidin B. J. Am. Chem. Soc. 2005,
127, 5342−5344. (b) Gill, G. B.; Pattenden, G.; Reynolds, S. J.
Cobalt-mediated reactions: inter- and intra-molecular additions of
carbamoyl radicals to alkenes in the synthesis of amides and lactams. J.
Chem. Soc., Perkin Trans. 1 1994, 369−378. For a review on acyl and
carbamoyl radicals, see: (c) Chatgilialoglu, C.; Crich, D.; Komatsu,
M.; Ryu, I. Chemistry of Acyl Radicals. Chem. Rev. 1999, 99, 1991−
2070.
AUTHOR INFORMATION
■
Corresponding Author
Jun Ishihara − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan; orcid.org/
0000-0003-3346-3354; Email: jishi@nagasaki-u.ac.jp
Authors
(8) Mizuno, K.; Ikeda, M.; Toda, S.; Otsuji, Y. Regioselective double
vicinal carbon-carbon bond forming reactions of electron-deficient
alkenes by use of allylic stannanes and organoiodo compounds. J. Am.
Chem. Soc. 1988, 110, 1288−1290.
Keita Komine − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan
Yasuhiro Urayama − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan
Taku Hosaka − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan
Yuki Yamashita − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan
Hayato Fukuda − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan; orcid.org/
0000-0003-1636-4469
(9) (a) Tao, D. J.; Slutskyy, Y.; Overman, L. E. Total Synthesis of
(−)-Chromodorolide B. J. Am. Chem. Soc. 2016, 138, 2186−2189.
(b) Brill, Z. G.; Grover, H. K.; Maimone, T. J. Enantioselective
synthesis of an ophiobolin sesterterpene via a programmed radical
cascade. Science 2016, 352, 1078−1082. (c) Hashimoto, S.; Katoh, S.;
Kato, T.; Urabe, D.; Inoue, M. Total Synthesis of Resiniferatoxin
Enabled by Radical-Mediated Three-Component Coupling and 7-
endo Cyclization. J. Am. Chem. Soc. 2017, 139, 16420−16429.
(10) Komine, K.; Urayama, Y.; Hosaka, T.; Fukuda, H.;
Hatakeyama, S.; Ishihara, J. New entry to the enantioselective
formation of substituted cyclohexenes bearing an all-carbon
quaternary stereogenic center. Chirality 2020, 32, 273−281.
(11) Bokam, R.; Annam, S. C. V. A. R.; Yalavarthi, N. R.; Gundoju,
N.; Ponnapalli, M. G. Bioinspired First Stereoselective Total Synthesis
of Spinosulfate B. ChemistrySelect 2019, 4, 8911−8914.
Susumi Hatakeyama − Medical Innovation Center, Nagasaki
University, Nagasaki 852-8521, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01627
Notes
(12) The enantiomeric ratio was determined by chiral high-
performance liquid chromatography (HPLC) analysis of (+)-15.
The authors declare no competing financial interest.
D
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The configuration was determined by modified Mosher’s method
after conversion of (+)-15 to the corresponding MTPA esters.
(13) For radical cyclization upon aromatic rings, see: (a) Ly, T.-M.;
Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. A convergent approach to
indolines and indanes. Tetrahedron Lett. 1999, 40, 2533−2536.
(b) Bennasar, M.-L.; Roca, T.; Ferrando, F. Intramolecular reactions
of 2-indolylacyl radicals: cyclisation upon aromatic rings. Tetrahedron
́
Lett. 2004, 45, 5605−5609. (c) Lopez-Valdez, G.; Olguín-Uribe, S.;
Millan-Ortíz, A.; Gamez-Montano, R.; Miranda, L. D. Convenient
̃
access to isoindolinones via carbamoyl radical cyclization. Synthesis of
cichorine and 4-hydroxyisoindolin-1-one natural products. Tetrahe-
dron 2011, 67, 2693−2701.
(14) Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A. The
Organoselenium-mediated reduction of α,β-epoxy ketones, α,β-epoxy
esters, and their congeners to β -hydroxy carbonyl compounds: Novel
methodologies for the synthesis of aldols and their analogues.
Tetrahedron 1997, 53, 12469−12486.
(15) We employed V-40 as a radical initiator in the reactions
performed at high temperature (entries 3−7), because the self-
accelerating decomposition temperature (SADT) of AIBN is 50 °C,
whereas the SADT of V-40 is 80 °C.
(16) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Improved Procedure
for the Oxidative Cleavage of Olefins by OsO4−NaIO4. Org. Lett.
2004, 6, 3217−3219.
(17) Grieco, P. A.; Gilman, S.; Nishizawa, M. Organoselenium
chemistry. A facile one-step synthesis of alkyl aryl selenides from
alcohols. J. Org. Chem. 1976, 41, 1485−1486.
(18) See the Supporting Information for the preparation of 26.
(19) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.;
Fukuyama, T. Total Synthesis of Ecteinascidin 743. J. Am. Chem. Soc.
2002, 124, 6552−6554.
(20) Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Practical
Procedure for the Chemoselective Reduction of Esters by Sodium
Borohydride. Effect of the Slow Addition of Methanol. Bull. Chem.
Soc. Jpn. 1984, 57, 1948−1953.
(21) The stereostructure of 31 was determined by the NOESY
spectrum.
(22) Linclau, B.; Cini, E.; Oakes, C. S.; Josse, S.; Light, M.;
Ironmonger, V. Stereoarrays with an All-Carbon Quaternary Center:
Diastereoselective Desymmetrization of Prochiral Malonaldehydes.
Angew. Chem., Int. Ed. 2012, 51, 1232−1235.
(23) The configuration of 33 was determined by Mosher ester
analysis of the corresponding R- and S-MTPA esters.
(24) Marx, V. M.; Herbert, M. B.; Keitz, B. K.; Grubbs, R. H.
Stereoselective Access to Z and E Macrocycles by Ruthenium-
Catalyzed Z-Selective Ring-Closing Metathesis and Ethenolysis. J. Am.
Chem. Soc. 2013, 135, 94−97.
(25) Two stereoisomers were also generated as an inseparable
mixture.
E
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