Synthesis of both enantiomers of conosilane A

Article abstract of DOI:10.1016/j.tetlet.2018.10.066

Conosilane A, an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 isolated from Conocybe siliginea, is a tremulane sesquiterpene with highly oxygenated tetracyclic ring system. In this study, we report the synthesis of both enantiomers of conosilane A. The key steps of this synthesis involve asymmetric aldol reaction, furan-ring oxidation followed by transacetalization and intramolecular reductive Heck-type cyclization.

Full text of DOI:10.1016/j.tetlet.2018.10.066

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Synthesis of both enantiomers of conosilane A
Hironori Okamura, Naoki Mori, Hidenori Watanabe, Hirosato Takikawa
PII:
S0040-4039(18)31298-X
https://doi.org/10.1016/j.tetlet.2018.10.066
TETL 50376
DOI:
Reference:
Tetrahedron Letters
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19 September 2018
25 October 2018
29 October 2018
Please cite this article as: Okamura, H., Mori, N., Watanabe, H., Takikawa, H., Synthesis of both enantiomers of
conosilane A, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.10.066
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Synthesis of both enantiomers of conosilane
A
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Hironori Okamura, Naoki Mori, Hidenori Watanabe and Hirosato Takikawa*

1
Tetrahedron Letters
Synthesis of both enantiomers of conosilane A
Hironori Okamura, Naoki Mori, Hidenori Watanabe and Hirosato Takikawa*
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-
8657, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Conosilane A, an inhibitor of 11-hydroxysteroid dehydrogenase type 1 isolated from Conocybe
siliginea, is a tremulane sesquiterpene with highly oxygenated tetracyclic ring system. In this
study, we report the synthesis of both enantiomers of conosilane A. The key steps of this
synthesis involve asymmetric aldol reaction, furan-ring oxidation followed by transacetalization
and intramolecular reductive Heck-type cyclization.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Conosilane A
Sesquiterpene
Evans aldol reaction
Reductive Heck-type cyclization
Introduction
The mushroom Conocybe siliginea is known as a rich source of
bioactive tremulane-type sesquiterpenes.1 Some of these
compounds have vasodilating activity and inhibitory activity
against 11-hydroxysteroid dehydrogenase type 1 (11-HSD1),
which catalyzes reduction of cortisone to cortisol. In 2012, Yang
et al. isolated conosilane A (1)2 from the culture broth of
Conocybe siliginea as a novel tremulane sesquiterpene with
highly oxygenated tetracyclic ring system (Fig. 1). This
compound has moderate inhibitory activity against enzyme 11-
HSD1. Although racemic synthesis of 1 has been achieved by
Yuan et al. in 2018,3 asymmetric synthesis of 1 has not yet been
reported. In this study, we report the synthesis of both
enantiomers of conosilane A from commercially available
dimedone.
Scheme 1. Synthetic strategy for conosilane A.
Synthesis of aldehyde 6 and oxazolidinone 7 is shown in
Scheme 2. We started the synthesis of 1 from commercially
available dimedone (8), which was converted to the known enol
ether 9 (93%) according to the reported procedure.4 After -
bromination of 9 (77%), the resulting enone was treated with 2-
lithio-1,3-dithiane to give compound 10.5 In this reaction,
addition of a catalytic amount of Mg(OTf)2 (20 mol%) drastically
improved the yield of 10 up to 88%, whereas the yield was less
than 30% without Mg(OTf)2. Aldehyde 6 was prepared by
removal of dithioacetal of 10 on multigram scale (97%). On the
other hand, oxazolidinone 7 was prepared from the known acid
11 in 80% yield.6
Figure 1. Structure of conosilane A (1).
Results and discussion
Our synthetic strategy is shown in Scheme 1. The target
compound 1 would be prepared from 2 via lactone formation.
Construction of C8 quaternary stereocenter of 2 could be
achieved stereoselectively by intramolecular cyclization of 3. The
right segment of 3 would be synthesized by furan-ring oxidation
followed by transacetalization of 4, which would be obtained
from -hydroxyester 5. Formation of the C6–C7 carbon bond in 5
should be accomplished by asymmetric aldol reaction of
aldehyde 6 with oxazolidinone 7.

2
Tetrahedron
The synthesis of (7S,8S,12S)-1 is shown in Scheme 4. Both
ketone and hydroxy group of 5 were protected by treatment with
TBSOTf/Et3N. Reduction of the ester with DIBAL followed by
acidic hydrolysis of silyl enol ether afforded 4 in good yield
(78% from 5). The mild oxidation of furan-ring in 4 was
successfully performed by treatment with NBS in MeOH at 0 °C
to give 15, which was directly transacetalized under acidic
conditions to furnish the key intermediate
3 in almost
quantitative yield. Although compound 3 was an anomeric
mixture (3:3 = 2:1), this mixture was used for the next step
without purification.9
Scheme 2. Synthesis of the intermediates 6 and 7. Reagents and conditions:
(a) Br2, CH2Cl2, 0 °C, 2 h, then Et3N, CH2Cl2, 1 h, 77%; (b) 1,3-dithiane, n-
BuLi, Mg(OTf)2 (20 mol%), Et2O, 0 °C, 2 h, 88%; (c) HIO4•2H2O, THF/Et2O,
0 °C to rt, 30 min, 97%; (d) (COCl)2, cat. DMF, CH2Cl2, reflux, 1.5 h, then 12,
n-BuLi, Et2O, −78 °C to rt, 1 h, 80%.
With two units 6 and 7 in hand, aldol reaction between 6 and 7
was investigated (Scheme 3). In our early-phased studies, we
found that the anti-type aldol adduct was preferable to the syn-
adduct for the key intramolecular cyclization (3→2). This might
be due to the steric hindrance caused by the C6 substituent. Thus,
Mg-mediated asymmetric anti-aldol conditions reported by
Evans et al.7 were applied. However, in this reaction, the
diastereoselectivity was not observed, whereas the anti-
selectivity was perfect. The resulting diastereomeric mixture of
13 and 14 was separated by column chromatography to afford 13
(29%) and 14 (50%), respectively. This result was not expected
but allowed us to synthesize both enantiomers of 1 from 13 and
14. The removal of chiral auxiliary of 13 and 14 was performed
by treatment with NaOMe to give 5 (91%) and ent-5 (73%),
respectively. The enantiomeric exesses of both enantiomers were
estimated to be >99% ee by HPLC analysis. The absolute
configuration of 5 was determined by the modified Mosher’s
method.8
Scheme 4. Synthesis of (7S,8S,12S)- and (7R,8R,12R)-1. Reagents and
conditions: (a) TBSOTf, Et3N, CH2Cl2, 0 °C to rt, overnight; (b) DIBAL,
CH2Cl2, −78 °C, 3 h (c) dil. HCl, THF, rt, 5 h, 78% for three steps; (d) NBS,
MeOH, 0 °C, 15 min; (e) p-TsOH•H2O, MeCN, rt, 10 min, 95% in two steps,
3:3 = 2:1; (f) Ni(COD)2, Mg(OTf)2, MeCN, rt, overnight; (g) 3 M HCl,
THF, rt, overnight, 59% in two steps; (h) PDC, MS 4A, CH2Cl2, rt, 24 h, 97%.
With the key intermediate 3 in hand, we examined the
intramolecular cyclization. Initially, radical conditions (n-
Bu3SnH/AIBN in refluxing toluene) was applied, but the yield of
the desired product 2 was low (< 30%). It was likely that the
substrate 3 would be unstable under rather harsh conditions.
Because the milder conditions would be suitable for this reaction,
we then investigated transition metal-mediated reductive Heck-
type cyclization. Pd-mediated conditions were initially attempted,
but the desired 2 was obtained in lower yield (ca. 15%) by
treatment with a catalytic amount of Pd(PPh3)4. After screening
several conditions, the use of a stoichiometric amount of
Ni(COD)2 in MeCN10 led to a significant improvement in yield
(57%). Remarkably, in this reaction, 2 was obtained as a single
isomer with -OMe group, even though the substrate was an
anomeric mixture (3/). The orientation of anomeric OMe
group in 3 was considered crucial for the cyclization, and this
kinetic separation should be due to steric hindrance caused by the
-oriented OMe group in 3. Therefore, addition of a Lewis acid
for the activation of the unreactive 3 was attempted. We
examined various mild Lewis acids, e.g., Zn(OTf)2, Sc(OTf)3,
Scheme 3. Synthesis of 5 and ent-5. Reagents and conditions: (a) MgBr2•
OEt2, Et3N, TMSCl, EtOAc, rt, 24 h; TFA, MeOH, rt, 1 h; (b) NaOMe,
MeOH, 0 °C, 5 min, 91% for 5, 73% for ent-5.

3
Mg(OTf)2, Al(OTf)3, and eventually found that the addition of
Mg(OTf)2 gave the best result (66%). The cyclized product 2 was
immediately treated with 3M HCl in THF to remove protective
found to be effective for this reaction. The overall yields of
(7S,8S,12S)-1 and (7R,8R,12R)-1 were 6.8% and 9.8% in 14
steps, respectively.
groups, affording
a diastereomeric mixture of tetracyclic
hemiacetal 16 (59% in two steps, dr = 4:1). Finally, the synthesis
Supplementary Data
References and Notes
1
of (7S,8S,12S)-1 was accomplished by PDC oxidation of 16. H
and 13C NMR data of the synthetic 1 agreed with those of the
natural product. Specific rotation of the synthetic (7S,8S,12S)-1
26
{[]D −66.3 (c 0.33, MeOH)} also agreed with that of the
1. D.Z. Liu, F. Wang, J.K. Liu, J. Nat. Prod. 70 (2007) 1503–1506.
2. X.Y. Yang, T. Feng, Z.H. Li, Y. Sheng, X. Yin, Y. Leng, J.K. Liu,
Org. Lett. 14 (2012) 5382–5384.
3. Z. Yuan, X. Hu, H. Zhang, L. Liu, P. Chen, M. He, X. Xie, X.
Wang, X. She, Chem. Commun. 54 (2018) 912–915.
4. K. Winska, A. Grudniewska, A. Chojnacka, A. Bialonska, C.
Wawrzenczyk, Tetrahedron: Asymmetry 21 (2010) 670–678.
5. When the reaction was carried out in THF, compound 10 was not
obtained at all.
6. E. Sherman, E.D. Amsturz, J. Am. Chem. Soc. 72 (1950) 2195–
2199.
7. D.A. Evans, J.S. Tedrow, J.T. Shaw, C.W. Downey, J. Am.
Chem. Soc. 124 (2002) 392–393.
19
natural product {[]D −52.4 (c 0.25, MeOH)}. Similarly,
26
starting from ent-5, we also synthesized (7R,8R,12R)-1, {[]D
+59.8 (c 0.38, MeOH)}.
Conclusion
In conclusion, we have achieved the synthesis of both
enantiomers of conosilane A (1) from commercially available
dimedone (8). Highlights of our synthesis include anti-selective
aldol reaction, furan-ring oxidation and stereoselective
intramolecular
cyclization.
Although
the
desired
8. J.A. Dale, H. Mosher, J. Am. Chem. Soc. 95 (1973) 512–519.
9. When the mixture was exposed to silica gel for a long time, the
decomposition of the product was observed.
10. D. Solé, Y. Cancho, A. Llebaria, J.M. Moretó, A. Delgado, J. Am.
Chem. Soc. 116 (1994), 12133–12134.
diastereoselectivity was not observed in the aldol reaction, the
resulting diastereomeric mixture was chromatographically
separable, which provided access to both enantiomers of 1. The
key intramolecular reductive Heck-type cyclization was
successfully performed by treatment with a stoichiometric
amount of Ni(COD)2. In particular, the addition of Mg(OTf)2 was

4
Tetrahedron
Highlights：
Synthesis of both enantiomers of conosilane A was
achieved.
Conosilane A is an unprecedented sesquiterpene
isolated from Conocybe siliginea.
Its highly oxygenated tetracyclic ring system was
constructed stereoselectively.