Enantioselective total synthesis of (-)-cyathin B2

Full text of DOI:10.1038/ja.2014.23

The Journal of Antibiotics (2014) 67, 483–485
2014 Japan Antibiotics Research Association All rights reserved 0021-8820/14
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Enantioselective total synthesis of (ꢀ)-cyathin B2
Yu Kobayakawa and Masahisa Nakada
The Journal of Antibiotics (2014) 67, 483–485; doi:10.1038/ja.2014.23; published online 2 April 2014
Keywords: cascade; cyathane; cyathin B2; dearomatization; Diels-Alder reaction; enantioselective; total synthesis
Ayer and Lee1 isolated (ꢀ)-cyathin B2 (1) (Scheme 1) as a component The synthesis of 2 features a complete chirality transfer reaction
of various congeners, from Cyathus earlei Lloyd, which is a tropical of alkyne 7 to allene 6 with an organocopper reagent, the highly
or subtropical species of bird’s nest fungus (family Nidulariaceae) stereoselective oxidative dearomatization/intramolecular inverse-
found in Cuba, Puerto Rico, Mexico and Hawaii. It is a cyathane electron demand Diels-Alder reaction cascade from 6 to 5, 1,2-diol
diterpenoid with a cyathane core as the common scaffold, which cleavage of 4 with PhI(OAc)2 to afford 3, and the ring-closing
features a five–six–seven tricyclic ring system with a trans-[6–7] ring metathesis of 3 providing 2.
fusion and two all-carbon quaternary stereogenic centers at the ring
junctions.
The efficient transformations of 2 to 1 would provide a foundation
for the total synthesis of other cyathane diterpenoids. Therefore,
Although
Staphylococcus aureus, certain cyathane diterpenoids and congeners were pursued.
1
shows moderate antibiotic activity against further studies toward the efficient enantioselective total synthesis of 1
show interesting biological activities. For example, (ꢀ)-erinacine E
One of the problems in the transformation of 2 to 1 was the
and (ꢀ)-scabronine A are the potent stimulators of nerve growth removal of the oxygen atom at the C17 position. To achieve it
factor synthesis; moreover, (ꢀ)-erinacine E is a selective agonist of the efficiently, the ketone in the seven-membered ring should remain
k-opioid receptor and a promising substitute for morphine.2
intact, that is, the selective reduction of the aldehyde group was
The therapeutic relevance and synthetic challenges of cyathane necessary to accomplish the transformation. The direct and selective
diterpenoids have attracted great attention over the past decade, and reduction of the aldehyde group to the methyl group was complicated
numerous synthetic studies as well as total syntheses of cyathane by the fact that the reduction of the keto group would also occur
diterpenoids and congeners have been reported,2–19 and review simultaneously.
articles have been published.20
The two carbonyl groups (aldehyde and keto) in 2 are attached to
Although the structure of 1 is relatively simple and its biological the all-carbon quaternary centers, that is, both the carbonyl groups
activity is moderate, the total synthesis of 1 involves a basic problem are located at similar positions. The selective reaction of the more
that needs to be solved, that is, the efficient construction of the reactive aldehyde was expected to be possible by a suitable reaction.
cyathane core that would enable the total syntheses of other cyathane Therefore, we focused on finding a reaction that would be selective for
diterpenoids with potent biological activities. Moreover, although the the reduction of the aldehyde group.
total synthesis of racemic 1 has been reported,12 the enantioselective
total synthesis of 1 has not yet been reported.
We were unable to accomplish the direct and selective reduction of
the aldehyde group in 2 to a methyl group. After extensive studies, the
Thus far, we have accomplished the enantioselective total synthesis reduction of compound 2 with zinc borohydride in tetrahydrofuran
of ( þ )-allocyathin B2,8 (ꢀ)-erinacine B,12 (ꢀ)-erinacine E,14 (ꢀ)- (THF) at ꢀ5 1C for 1 h successfully afforded compound 9 in 99%
scabronines G and A,2 and (ꢀ)-episcabronine A.2 Currently, we are yield (Scheme 2). The keto group in the seven-membered ring
involved in the study of the second-generation total synthesis of remained intact under these reaction conditions. In order to remove
cyathane diterpenoids to elucidate their structure–activity relation- the resultant primary hydroxy group by the Barton–McCombie
ships. Herein, we report the first and efficient enantioselective total deoxygenation method, alcohol 9 was first converted to phenyl
synthesis of 1. thiocarbonate; the subsequent reduction with tributyltin hydride in
Recently, we reported the enantioselective total synthesis of the presence of a catalytic amount of azobisisobutyronitrile (AIBN) in
(ꢀ)-scabronines G and A, and (ꢀ)-episcabronine A via a common toluene at 100 1C successfully afforded compound 10.
synthetic intermediate
yield starting from
2
a
in 16 steps and with 35% overall
The tert-butyldiphenylsilyl (TBDPS) group in 10 was removed
known compound 8
(Scheme 1).2 by TBAF; the oxidation of the resultant primary alcohol group
Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, Tokyo, Japan
Correspondence: Professor M Nakada, Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo
169-8555, Japan.
E-mail: mnakada@waseda.jp
Received 4 December 2013; revised 13 February 2014; accepted 27 February 2014; published online 2 April 2014

Synthesis of (ꢀ)-cyathin B2
Y Kobayakawa and M Nakada
484
Scheme 2 First enantioselective total synthesis of (ꢀ)-cyathin B2 (1).
EXPERIMENTAL PROCEDURE
(ꢀ)-(3aS,5aR,8E,10aR)-8-(tert-butyldiphenylsilyloxymethyl)-
2,3,3a,4,5,5a,6,7,10,10a-decahydro-3a-hydroxymethyl-1-isopropyl-
5a-methyl-6-oxocyclohepta[e]indene (9)
To a stirred solution of 2 (88.1mg, 0.159 mmol) in THF (5.0ml) was added
Zn(BH4)2 (0.5M in THF, 0.38ml, 0.191mmol, 1.2 equiv) dropwise at ꢀ201C,
and the reaction mixture was stirred at ꢀ51C for 30 min. After the reaction was
completed, the reaction was quenched by adding saturated aqueous NH4Cl
solution (5ml). The aqueous layer was extracted with EtOAc (20 mlꢁ 2). The
combined organic layer was washed with water (20ml), brine (20ml), dried
over Na2SO4, and evaporated. The residue was purified by flash chromato-
graphy (hexane/ethyl acetate¼ 5/1) to afford 9 (87.1 mg, 99%) as a colorless oil:
Rf ¼ 0.67 (hexane/ethyl acetate ¼ 2/1); 1H NMR (400MHz, CDCl3) d
7.72–7.61 (4H, m), 7.47–7.33 (6H, m), 5.72–5.65 (1H, m), 4.07 (1H, d,
J ¼ 13.3Hz), 4.03 (1H, d, J ¼ 13.3Hz), 3.84 (1H, d, J ¼ 10.4 Hz), 3.78 (1H, d,
J ¼ 13.6Hz), 3.44 (1H, d, J ¼ 10.4Hz), 3.15 (1H, d, J ¼ 13.6Hz), 3.07 (1H,
sept, J ¼ 6.8 Hz), 2.70–2.53 (3H, m), 2.45-2.32 (2H, m), 2.06 (1H, ddd,
J ¼ 14.2, 8.2, 5.5 Hz), 1.86 (1H, dt, J ¼ 13.7, 4.6 Hz), 1.71 (1H, ddd, J ¼ 13.7,
4.6, 2.3 Hz), 1.62–1.42 (2H, m), 1.28–1.21 (2H, m), 1.08 (3H, s), 1.07 (9H, s),
1.03 (3H, d, J ¼ 6.8 Hz), 1.03 (3H, d, J ¼ 6.8 Hz); 13C NMR (100MHz, CDCl3)
d 210.4, 146.1, 135.5, 135.5, 133.4, 131.1, 130.7, 129.7, 127.7, 123.8, 68.3, 66.3,
55.1, 54.2, 40.6, 39.1, 33.5, 32.9, 31.8, 30.0, 29.5, 27.2, 26.8, 22.2, 21.6, 19.3,
Scheme 1 Structure of the key intermediate
2
for total syntheses of
(ꢀ)-cyathin B2 (1), (ꢀ)-scabronines G and A, and (ꢀ)-episcabronine A.
with Dess–Martin periodinane reagent afforded the final product,
1. The 1H NMR, 13C NMR, IR and HRMS spectral data of
1 completely matched with those reported by Ayer and Lee1
and Kim and Cha,16 thus confirming the formation of 1. They
did not report the [a]D and melting point of 1 because Cha and
co-workers reported the total synthesis of racemic cyathin B2;
therefore, herein we report the [a]D and melting point of 1 for the
first time.
13.1; IR (ATR) nmax 3445(br), 2930, 2856, 1698, 1427, 1111, 894, 612cmꢀ1
;
HRMS (ESI) [Mþ Na]þ calcd for C36H48NaO3Si: 579.3265, found: 579.3265;
[a]1D9 ꢀ74.9 (c 0.29, CHCl3).
In summary, we accomplished the first enantioselective total
synthesis of (ꢀ)-cyathin B2 (1) via the key intermediate 2 in 21 steps
with 20% overall yield, starting from a known compound 8. The total
synthesis features the chemoselective reduction of the aldehyde group
in the presence of a keto group, and the deoxygenation of the
resultant primary hydroxy group at the C17 position by the Barton–
McCombie protocol. We reported the [a]D and melting point values
of 1 for the first time. The relatively less number of steps and the
overall high yield in the total synthesis of 1 may pave the way for the
enantioselective synthesis of other cyathanes, their congeners and
derivatives, and contribute to the research on their structure–activity
relationships. Further studies are now in progress, and will be
reported in due course.
(ꢀ)-(3aR,5aR,8E,10aR)-8-(tert-butyldiphenylsilyloxymethyl)-
2,3,3a,4,5,5a,6,7,10,10a-decahydro-3a,5a-dimethyl-1-isopropyl-6-
oxocyclohepta[e]indene (10)
To a stirred solution of 9 (85.9 mg, 0.154mmol) in CH2Cl2 (3.0ml) was
added DMAP (37.7 mg, 0.309 mmol, 2.0 equiv) and PhOCSCl (3.1ꢁ 10ꢀ1 ml,
0.231mmol, 1.5 equiv) dropwise at room temperature, and the reaction
mixture was stirred at room temperature for 2 h. After the reaction was
completed, the reaction was quenched by adding saturated aqueous NH4Cl
solution (5ml). The aqueous layer was extracted with EtOAc (10 mlꢁ 2). The
combined organic layer was washed with water (10 ml), brine (10 ml), dried
over Na2SO4, and evaporated. The residue was filtered through a short plug of
silica gel to afford crude product, which was used for the next step without
further purification.
The Journal of Antibiotics

Synthesis of (ꢀ)-cyathin B2
Y Kobayakawa and M Nakada
485
To a stirred solution of the above crude product in toluene (5.0ml) were ACKNOWLEDGEMENTS
added AIBN (10.1mg, 6.16ꢁ 10ꢀ1 mmol, 0.4 equiv) and nBu3SnH (0.20 ml,
This work was financially supported in part by Waseda University Grant for
Special Research Projects, The Grant-in-Aid for Scientific Research on
Innovative Areas ‘Organic Synthesis based on Reaction Integration,
0.770mmol, 5.0 equiv) at room temperature, and the reaction mixture was
stirred at 100 1C for 30min. The reaction mixture was evaporated and the
residue was purified by flash chromatography (hexane/ethyl acetate¼ 50/1 to Development of New Methods and Creation of New Substances’ (no. 2105),
20/1) to afford 10 (56.1 mg, 67% (2 steps)) as a colorless oil:
Rf ¼ 0.81 (hexane/ethyl acetate ¼ 4/1); 1H NMR (400MHz, CDCl3) d
Grant for Scientific Research (B) (25293003) and Grants for Excellent
Graduate Schools (Practical Chemical Wisdom), MEXT, Japan. The fellowship
7.72–7.61 (4H, m), 7.46–7.34 (6H, m), 5.73–5.68 (1H, m), 4.09 (1H, d, for young scientists to YK from JSPS (5515) is also gratefully acknowledged.
J ¼ 13.3Hz), 4.04 (1H, d, J ¼ 13.3Hz), 3.86 (1H, d, J ¼ 13.3 Hz), 3.24 (1H, d,
J ¼ 10.5Hz), 2.97 (1H, sept, J ¼ 6.9 Hz), 2.64 (1H, d, J ¼ 13.3Hz), 2.64–2.53
(2H, m), 2.38–2.63 (2H, m), 1.90 (1H, dt, J ¼ 12.8, 5.5 Hz), 1.70–1.48 (4H, m),
1.23 (1H, ddd, J ¼ 13.3, 4.1, 2.8 Hz), 1.14 (3H, s), 1.08 (9H, s), 1.08 (3H, s),
1
2
Ayer, W. A. & Lee, S. P. Metabolites of bird’s nest fungi. Part 11. Diterpenoid
1.06 (3H, d, J ¼ 6.9 Hz), 1.00 (3H, d, J ¼ 6.9 Hz); 13C NMR (100MHz, CDCl3)
d 211.1, 140.4, 135.7, 135.5, 135.5, 133.4, 130.9, 129.7, 127.6, 124.3, 68.5, 54.5,
49.2, 40.3, 39.3, 38.2, 36.2, 33.0, 30.0, 28.5, 26.9, 26.8, 24.3, 21.8, 21.7, 19.3,
13.0; IR (ATR) nmax 2928, 2855, 1703, 1427, 1251, 1111, 612 cmꢀ1; HRMS
(ESI) [Mþ Na]þ calcd for C36H48NaO2Si: 563.3316, found: 563.3315; [a]D19
ꢀ63.0 (c 1.00, CHCl3).
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(ꢀ)-episcabronine A. Angew. Chem. Int. Ed. Engl. 52, 7569–7573 (2013) and
references cited therein.
3
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9
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To a stirred solution of 10 (10.9 mg, 2.02 ꢁ 10ꢀ2 mmol) and NH4Cl (5.4mg,
0.101mmol, 5 equiv) in THF (2.0ml) was added TBAF (1.0M in THF,
0.72 ml, 0.717 mmol, 3.0 equiv) at 0 1C, and the reaction mixture was stirred at
room temperature for 4 h. The reaction was quenched by adding saturated
aqueous NH4Cl solution (5ml), and the aqueous layer was extracted with
EtOAc (5mlꢁ 3). The combined organic layer was washed with brine (5ml),
dried over Na2SO4, and evaporated. The residue was filtered through a short
plug of silica gel to afford crude alcohol, which was used for the next step
without further purification.
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synthesis of ( )-allocyathin B3. Can. J. Chem. 82, 254–267 (2004).
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To a stirred solution of the above crude alcohol in CH2Cl2 (2.0ml) was
added DMP (17.1 mg, 4.04ꢁ 10ꢀ2 mmol, 2.0 equiv) at 0 1C, and the reaction
mixture was stirred at room temperature for 2 h. After the reaction was
completed, the reaction mixture was diluted with hexane (2.0ml), and the
resulting mixture was directly submitted to flash chromatography (hexane/
ethyl acetate ¼ 4/1) to afford (ꢀ)-cyathin B2 (1) (5.1mg, 84% (2 steps)) as a
colorless solid:
Rf ¼ 0.85 (hexane/ethyl acetate ¼ 2/1); 1H NMR (400MHz, CDCl3) d 9.38
(1H, s), 6.76–6.71 (1H, m), 3.76 (1H, dd, J ¼ 13.7, 2.8 Hz), 3.49 (1H, d,
J ¼ 14.2Hz), 3.30 (1H, dd, J ¼ 12.4, 1.8 Hz), 3.01–2.78 (3H, m), 2.37–2.28 (2H,
m), 1.95 (1H, dt, J ¼ 13.3, 5.5 Hz), 1.71–1.50 (3H, m), 1.27 (1H, ddd, J ¼ 13.3,
4.1, 2.8Hz), 1.12 (3H, s), 1.05 (3H, s), 1.02 (3H, d, J ¼ 6.9 Hz), 1.01 (3H, d,
J ¼ 6.9 Hz); 13C NMR (100 MHz, CDCl3) d 210.8, 192.3, 153.5, 141.1, 135.9,
134.7, 55.1, 49.3, 39.5, 38.0, 35.9, 34.1, 32.9, 31.7, 28.6, 27.1, 24.2, 21.9, 21.6,
Soc. 127, 5334–5335 (2005).
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double catalytic enantioselective alkylation. Nature 453, 1228–1231 (2008).
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Ed. Engl. 48, 5334–5336 (2009).
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G, an inducer of neurotrophic factor production. J. Am. Chem. Soc. 127, 13514–
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12.7; IR (ATR) nmax 2957, 2927, 1690, 1680, 1440, 1251, 1077, 1053cmꢀ1
;
HRMS (ESI) [Mþ Na] þ calcd for C20H28NaO2: 323.1982, found: 323.1982;
20 Enquist, J. A. Jr & Stoltz, B. M. Synthetic efforts toward cyathane diterpenoid natural
products. Nat. Prod. Rep. 26, 661–680 (2009) and references cite therein.
[a]1D9 ꢀ57.7 (c 0.22, CHCl3); mp 57.8–59.11C.
The Journal of Antibiotics