Concise syntheses of (+)-austrodoral and (+)-austrodoric acid Based on H2O2 mediated oxidative ring contraction

Article abstract of DOI:10.1016/j.tetlet.2019.150973

Asymmetric synthesis of the marine nor-sesquiterpenoid (+)-austrodoric acid and (+)-austrodoral in seven and nine steps respectively from Wieland-Miescher ketone was described herein. The synthesis featured an oxidative ring contraction of α-formyl cyclic ketone mediated by H₂O₂ to forge the hydrindane scaffold together with the contiguous quaternary carbon centers simultaneously.

Full text of DOI:10.1016/j.tetlet.2019.150973

Journal Pre-Proof
Concise Syntheses of (+)-austrodoral and (+)-austrodoric acid Based on H2O2
Mediated Oxidative Ring Contraction
Hongbo Wei, Hongli Zhang, Shoule Han, Shan Mu, Ke Huang, Guzhou Chen,
Weiqing Xie
PII:
S0040-4039(19)30724-5
DOI:
https://doi.org/10.1016/j.tetlet.2019.150973
TETL 150973
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 June 2019
21 July 2019
23 July 2019
Please cite this article as: Wei, H., Zhang, H., Han, S., Mu, S., Huang, K., Chen, G., Xie, W., Concise Syntheses of
(+)-austrodoral and (+)-austrodoric acid Based on H2O2 Mediated Oxidative Ring Contraction, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.150973
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Graphical Abstract
Concise Syntheses of (+)-austrodoral and (+)-
austrodoric acid Based on H2O2 Mediated
Oxidative Ring Contraction
Leave this area blank for abstract info.
Hongbo Wei, Hongli Zhang, Shoule Han, Shan Mu, Ke Huang , Guzhou Chen, Weiqing Xie 
O
O
CO2H
CHO
H2O2
H
stereospecific
H
H
H
austrodoric acid
austrodoral

JOURNAL PRE-PROOF
1
Tetrahedron Letters
journal homepage: www.elsevier.com
Concise Syntheses of (+)-austrodoral and (+)-austrodoric acid Based on H2O2
Mediated Oxidative Ring Contraction
Hongbo Weia,1, Hongli Zhang, b,1 Shoule Hanc,1, Shan Muc,1, Ke Huang c, Guzhou Chena, Weiqing Xiea,d,
a Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling
712100, Shaanxi, China,
b State Key Laboratory of Stress Biology for Arid Areas, Northwest A&F University, Yangling, Shaanxi, China,
c The College of Plant Protection, Northwest A&F University
d Key Laboratory of Botanical Pesticide R&D in Shaanxi Province, Yangling, Shaanxi 712100, China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +86-29-8709-2662; fax: +86-29-8709-2662; e-mail: xiewq@nwafu.edu.cn
1 Those authors contributed equally to this work.
Article history:
Received
Asymmetric synthesis of the marine nor-sesquiterpenoid (+)-austrodoric acid and (+)-
austrodoral in seven and nine steps respectively from Wieland-Miescher ketone was described
Received in revised form
Accepted
Available online
herein. The synthesis featured an oxidative ring contraction of α-formyl cyclic ketone mediated
by H2O2 to forge the hydrindane scaffold together with the contiguous quaternary carbon centers
simultaneously.
Keywords:
sesquiterpene
2009 Elsevier Ltd. All rights reserved.
sustrodorane
asymmetric synthesis
oxidative ring contraction
The sesquiterpenoids are an important class of natural
products with diverse structural types, which exhibit a wide
variety of biological properties,1 including significant cytotoxic,2
anticancer,3 insect antifeedant4 and potent anti-HIV activity.5
Austrodoral (1) and austrodoric acid (2) are two nor-
sesquiterpenoid recently isolated from the skin of the marine
dorid Austrodoris kerguelenensis collected in Antarctica by
Gavagnin and co-workers (Figure 1).6 These two compounds
Figure 1. Structure of austrodorane and possible biosynthetic pathway
synthesis of austrodoric acid (2) from (+)-sclareolide,
establishing the absolute configuration of austrodorane.7a The
pivotal ring contraction of the epoxide intermediate for the
stereospecific construction of the quaternary carbon centers was
realized by treatment with tris(4-bromophenyl)aminium
hexachloroantimonate in 45% yield, which was greatly improved
by using FSO3H as promoter on a truncated epoxide in the
following paper.7b However, the synthesis was plagued by poor
diastereoselectivity (3:1) for the construction of key epoxide
intermediate. Soon after that, Alvarez-Manzaneda and coworkers
described a concise synthesis of austrodorane from (-)-sclareol
via a Pinacol rearrangement of a triol intermediate in the
presence of BF3·Et2O.8 Following this work, Akita described a
TFA promoted semi-Pinacol rearrangement of an unprotected
epoxide intermediate for the asymmetric synthesis of
austrodorane.9 Another BF3·Et2O-catalyzed highly regioselective
Pinacol-type rearrangement of 1,2-diol for the synthesis of (+)-
austrodoral (1) and (+)-austrodoric acid (2) using (+)-sclareolide
as starting material was reported by Wu in 2017.10 Recently,
Fañañas and Rodríguez reported a BF3·Et2O-catalyzed epoxide
rearrangement to deliver racemic austrodoral with complete
diastereoselectivity, which highlighted a cationic cyclization of
dienyne to forge the decalin scaffold.11 It should be pointed out
that all above-mentioned strategies exploited a Pinacol-type
rearrangement as key step to construct the contiguous quaternary
carbon centers of the austrodorane, while no other strategy of has
ever been attempted.
possess
a
rearranged perhydroindane moiety named
‘austrodorane’ and contiguous quaternary all-carbon centers,
which may be biogenetically derived from drimane-type
framework via ring contraction. Additionally, austrodoral (1) was
proposed to be a stress-metabolite generated by mollusk and
austrodoric acid (2) was a work-up product presumably by air
oxidation. However, the exact biological role of austrodoral (1)
has not been fully elucidated.
Austrodorane has received considerable attention from
chemical community owing to the intriguing structural features
and its potential role for chemical defending against predator.
Notable is the chiral contiguous quaternary all-carbon centers,
which constitutes a formidable challenge in natural products
synthesis because of the severe steric repulsion between the
substituents. In 2004, Gavagnin reported the first enantioselective
CHO
CO2H
ring
contraction
ox.
H
H
H
2
austrodoric acid ( )
1
austrodoral ( )
drimane

JOURNAL PRE-PROOF
2
Tetrahedron
O
O
CHO
for the critical oxidative ring contraction. To our delight,
treatment of 7 with aqueous H2O2 smoothly afforded (+)-
austrodoric acid (2) in 93% yield without detection of the C-C
bond cleavage product. Based on our previous hypothesis,
nucleophilic addition of H2O2 to α-formyl ketone followed by
cyclization delivered 1,2-dioxolone 8, which underwent a concert
alkyl migration/C-C bond and O-O bond cleavage to give the
desired product. Reduction of (+)-austrodoric acid (1) with
LiAlH4 and subsequent PCC-oxidation gave (+)-austrodoral in
30% yield for two steps. The optical rotations and the spectral
data of synthetic austrodoric acid (2) and austrodoral (1) were in
excellent agreement with those reported for natural product.
CO2H
oxidative
H
ring
constraction
H
H
H
2
austrodoric acid ( )
1
austrodoral ( )
3
O
O
O
H
5
Wieland-Miescher ketone ( )
4
Scheme 1. Retrosynthetic analysis of austrodorane
In conclusion, we described a concise synthesis of the marine
nor-sesquiterpene (+)-austrodoral (1) and (+)-austrodoric acid (2)
from Wieland-Miescher ketone. The key step featured an
oxidative ring contraction of cyclic α-formyl ketones facilitated
by aqueous H2O2 under mild conditions for the stereospecific
construction of the quaternary carbon centers in high efficiency.
In 2017, our group reported an oxidative ring contraction
reaction of cyclic α-formyl ketones promoted by H2O2.12 This
novel protocol was highly regioselective and enables
stereospecific construction of contiguous quaternary all-carbon
centers. To further showcase the synthetic potential of this novel
protocol, the asymmetric synthesis of austrodorane was thus
executed. As shown in Scheme 1, we surmised that austrodoral (1)
Acknowledgments
could be prepared from austrodoric acid (2) via
a
We gratefully acknowledge the financial support from the
Natural Science Foundation of China (201702166 to H.W. and
21722206 to W.X.) and the Scientific Startup Foundation for
Doctors of Northwest A&F University (No. Z109021702).
reduction/oxidation of the carboxylic acid moiety. Austrodoric
acid (2) would in turn arise from α-formyl ketone 3 via oxidative
ring contraction facilitated by the action of H2O2 to
stereospecifically forge the quaternary carbon centers. Bicyclic
ketone 3 could be diastereoselectively accessed via methylation
followed by hydroxymethylation/oxidation of ketone 4, which
was a known compound derived from Wieland-Miescher ketone
3.12
References and notes
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Gavagnin, M.; Carbone, M.; Cimino, G. Eur. J. Org. Chem. 2005, 1816-
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LDA, CH3I
4 steps
THF, rt
70%, 3:1 dr
O
H
H
6
5
4
KOH,CH2O (37%, aq.)
single diastereoisomer
88%
H
O
OH
O
O
O
Me
H

O
PCC, DCM
56%
H

H
8. (a) Alvarez-Manzaneda, E. J.; Chahboun, R.; Barranco, I.; Torres, E. C.;
Alvarez, E.; Alvarez-Manzaneda, R. Tetrahedron Lett. 2005, 46, 5321-
5324. (b) Alvarez-Manzaneda, E.; Chahboun, R.; Barranco, I.; Cabrera,
E.; Alvarez, E.; Lara, A.; Alvarez-Manzaneda, R.; Hmamouchic, M.; Es-
Samti, H. Tetrahedron 2007, 63, 11943-11951.
O
H
H
H
TS
7
3
H2O2, EtOAc
93%
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Hiroyuki. Chem. Pharm. Bull. 2012, 60, 562-570.
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O
O
HO
H
CO2H
1. LiAlH4, THF
CHO
OH
H
2. PCC, DCM
30% for two steps
HCOOH
H
H
1
austrodoral ( )
2
austrodoric acid ( )
8
Scheme 2. Total synthesis of austrodoric acid and austrodoral
As illustrated in Scheme 2, our synthesis commenced with the
preparation of bicyclic ketone 4 from Wieland-Miescher ketone 5
in four steps according to the literature procedure.13 α-
Methylation of ketone 4 mediated with LDA/MeI gave ketone 6
in 70% yield with 3:1 dr,14 which was inconsequential for the
next step. Fortunately, introduction of hydroxymethyl group was
successfully realized as a single diastereoisomer by treating
ketone 6 with formalin in basic medium (KOH/MeOH) at 60
oC.15 This may be rationalized by sever steric hindrance from the
axial methyl for the β attack in the transition state TS, which
favored the approach of electrophile from the α-face to give the
cis product 7.16 Oxidation of ketone 7 with PCC led to the
corresponding α-formyl cyclic ketone 3, which set to the stage
Supplementary Material
Supplementary data associated with this article can be found in the online
version, at http://dx.doi.org/ .

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3
Highlights
 Concise syntheses of (+)-Austrodoric acid and
(+)-Austrodoral was achieved
 Wieland-Miescher ketone was used as starting
material

H2O2-mediated oxidative ring contraction
forged the hydrindane scaffold

The contiguous quaternary carbon centers
were built up via rearrangement