Facile access to cis-2,6-disubstituted tetrahydropyrans by palladium-catalyzed decarboxylative allylation: Total syntheses of (±)-Centrolobine and (+)-decytospolides A and B

Article abstract of DOI:10.1002/chem.201303328

Cis-2,6-Tetrahydropyran is an important structural skeleton of bioactive natural products. A facile synthesis of cis-2,6-disubstituted-3,6-dihydropyrans as cis-2,6-tetrahydropyran precursors has been achieved in high regioand stereoselectivity with high yields. This reaction involves a palladium-catalyzed decarboxylative allylation of various 3,4-dihydro-2H-pyran substrates. Extending this reaction to 1,2-unsaturated carbohydrates allowed the achievement of challenging b-C-glycosylation. Based on this methodology, the total syntheses of (±)-centrolobine and (+)-decytospolides A and B were achieved in concise steps and overall high yields.

Full text of DOI:10.1002/chem.201303328

DOI: 10.1002/chem.201303328
Communication
&
Organic Synthesis
Facile Access to cis-2,6-Disubstituted Tetrahydropyrans by
Palladium-Catalyzed Decarboxylative Allylation: Total Syntheses
of (Æ)-Centrolobine and (+)-Decytospolides A and B
Jing Zeng, Yu Jia Tan, Jimei Ma, Min Li Leow, Davin Tirtorahardjo, and Xue-Wei Liu*[a]
Abstract: cis-2,6-Tetrahydropyran is an important structur-
al skeleton of bioactive natural products. A facile synthesis
of cis-2,6-disubstituted-3,6-dihydropyrans as cis-2,6-tetra-
hydropyran precursors has been achieved in high regio-
and stereoselectivity with high yields. This reaction in-
volves a palladium-catalyzed decarboxylative allylation of
various 3,4-dihydro-2H-pyran substrates. Extending this re-
action to 1,2-unsaturated carbohydrates allowed the ach-
ievement of challenging b-C-glycosylation. Based on this
methodology, the total syntheses of (Æ)-centrolobine and
(+)-decytospolides A and B were achieved in concise
steps and overall high yields.
Pyran rings are important skeletons in a myriad of biologically
active compounds. In particular, cis-2,6-disubstituted tetrahy-
dropyrans are present in a large number of natural products
that exhibit interesting biological properties, such as aspergili-
de A, decytospolides A and B, diospongin A, centrolobine,
cryptopyranmoscatone B,
exiguolide,
and
neopeltolide
Figure 1. Examples of naturally occurring cis-2,6-disubstituted tetrahydro-
(Figure 1). Over the years, great efforts have been made to
achieve the efficient stereoselective synthesis of cis-2,6-disub-
stituted tetrahydropyrans.[1] Of particular importance are Prins
cyclizations,[2] intramolecular oxa-cyclizations,[3] oxa-Diels–Alder
reactions,[4] and Japp–Maitland reactions.[5] Despite these sig-
nificant achievements, the development of practical, simple,
and concise strategies towards the synthesis of cis-2,6-disubsti-
tuted tetrahydrapyrans with high stereo- and regioselectivity
remains imperative.
pyrans.
Recent advancements have demonstrated the efficiency of
palladium-catalyzed coupling reactions, particularly Heck reac-
tions and Tsuji–Trost reactions with alkenes. The olefin group
in cyclic enol ethers also allowed the extension of Heck reac-
tions on these substrates to the preparation of substituted di-
hydrofurans and dihydropyrans (Scheme 1a).[6] However, the
Tsuji–Trost-type reaction on cyclic enol ethers is less extensive-
ly investigated, because it has long been recognized that the
Scheme 1. Palladium-catalyzed preparation of substituted dihydropyrans.
[a] J. Zeng, Y. J. Tan, Dr. J. Ma, M. L. Leow, D. Tirtorahardjo, Prof. Dr. X.-W. Liu
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371
E-mail: xuewei@ntu.edu.sg
formation of Pd p-allyl species in electron-rich enol ethers is te-
dious and difficult (Scheme 1b).[7] To overcome this problem,
more active systems or additional activators were considered
indispensable.[8]
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303328.
Chem. Eur. J. 2014, 20, 405 – 409
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Communication
In recent years, however, decarboxylative allylation (DcA) has
become a powerful tool for CÀC bond formation and has
drawn considerable attention due to its high efficiency, mild
reaction conditions, and green features with CO2 as the only
byproduct released.[9] Tunge,[10] Trost,[11] and Stoltz,[12] for in-
stance, have reported a series of catalytic decarboxylative
allylation or benzylation reactions.[13] Given the allylic feature
of enol ethers (3,4-dihydro-2H-pyran, 1), we envisaged that the
use of acetyl acetate as a leaving group could first activate the
pyranose system to promote the palladium-induced p-allyla-
tion and further decarboxylative coupling would facilitate the
CÀC bond formation (Scheme 1c).
Table 1. Ligand screening.[a,b]
We have achieved a stereoselective synthesis of cis-2,6-di-
substituted dihydropyrans by palladium-catalyzed decarboxyla-
tive allylation on readily available sugar scaffolds (glycals),
which allowed the achievement of challenging b-C-glycosyla-
tion.[14] The reaction is a formal intramolecular reaction on a gly-
cosyl acetylacetate scaffold in the presence of Pd(OAc)2 and
1,1’-bis(di-isopropylphosphino)ferrocene (DiPPF). Given the
high efficiency of this palladium-catalyzed decarboxylative cou-
pling reaction, we envisioned that this methodology could be
further applied to the common pyran system to provide a prac-
tical access to naturally occurring cis-2,6-tetrahydropyrans.
Herein, we further report the results of our efforts in extending
this reaction to the synthesis of cis-2,6-disubstituded-3,6-dihy-
dro-2H-dihydropyrans with high regio- and stereoselectivity.
Our investigation commenced with the decarboxylative cou-
pling reaction of (Æ)-3a[15] under the optimized reaction condi-
tions established previously (Pd(OAc)2: 5 mol%, DiPPF:
10 mol%, toluene, 608C; Table 1). After 3 h, the starting materi-
al was consumed and the desired product (Æ)-4a was ob-
tained in 92% yield. However, only a ratio of 7:1 cis to trans se-
lectivity was observed. Further screening of ligands revealed
that bulky ligands could increase the diastereoselectivity.
Among them, ligand B significantly enhanced the selectivity to
20:1, whereas ligand I afforded the cis product as a single
isomer in 91% yield. Other ligands, such as 1,2-bis(diphenyl-
phosphino)ethane (dppe) D and 1,5-bis(diphenylphosphino)-
pentane (dpppen), E gave poor selectivities, whereas xanphos
G and xphos H were observed to provide the desired product
with moderate selectivities, albeit in good yields. Interestingly,
ligand C could not promote this decarboxylative coupling
reaction.
[a] Reactions were carried out on a 0.2 mmol scale in the presence of
0.01 mmol of Pd(OAc)2 and 0.02 mmol of ligand in toluene (2 mL) at
608C. [b] Isolated yields, selectivity was determined by 1H NMR spec-
troscopy.
tion could be tolerated in this decarboxylative coupling reac-
tion and the reactions proceeded smoothly to provide the de-
sired products in good to excellent yields (6h–m).
The synthetic utility of this transformation was further dem-
onstrated by the total syntheses of selected natural products.
We have previously reported the formal total synthesis of as-
pergillide A from a sugar substrate by palladium-catalyzed de-
carboxylative C-glycosylation.[14] In this work, we focused on
the total syntheses of centrolobine 10 and decytospolides 19
and 20.
Centrolobine is a naturally occurring antibiotic, isolated from
the heartwood of Centrolobium robustum, tomentosum, and
the stem of Brosinium potabile.[16] Centrolobines have been
found to exhibit anti-inflammatory, antibacterial, and antileish-
manial properties.[17] The excellent bioactivities and relatively
simple chemical structure have drawn considerable interest to-
wards the total synthesis of centrolobine, both in the racemic
and optically pure forms.[18] Our synthesis started from the ra-
cemic cis-alcohol (Æ)-5. Esterification of 5 with b-keto acid 6
furnished b-keto ester 7, which was submitted to the decar-
boxylative coupling reaction conditions, and, as expected, cis-
2,6-disubstituted-3,6-dihydro-2H-dihydropyran 8 was obtained
in good yield. Further reduction of the carbonyl group of 8
with LiBH4 and triethylsilane produced compound 9 in 84%
yield. However, attempts to reduce the double bond by rou-
tine hydrogenation led to a low yield of the desired product
due to the unexpected ring opening of the tetrahydropyran.[19]
Fortunately, hydrogenation under acidic conditions both re-
The substrate scope was further examined as depicted in
Table 2. Gratifyingly, in all cases, good to excellent yields and
absolute cis selectivity were observed. A variety of functional
groups at the a-position of the ketone could also be tolerated
(4b–g). Interestingly, sterically hindered substituents, such as
isopropyl and tertiary butyl, gave slightly higher yields (6d,
6e) in comparison to the less hindered substituents (6b, 6c).
The reaction of substrates possessing aromatic substituents at
the a-position of the ketone proceeded very well and afforded
the corresponding products in higher yields than that of ali-
phatic substituents (6 f, 6g). The R1 substituent on C6 of the
dihydropyran ring was also modified to further investigate the
functional-group tolerance of the reaction conditions. Both
electron-rich and deficient aromatic substituents at the R1 posi-
Chem. Eur. J. 2014, 20, 405 – 409
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Table 2. Substrate scope of the common pyran system.[a,b]
Scheme 3. Total syntheses of decytospolides A and B: a) TsCl (1.2 equiv), pyr-
idine, 08C–RT, 87%; b) BuMgBr (4 equiv), CuI (2.0 equiv), THF, 08C–RT, 65%;
c) propionyl acetic acid (1.5 equiv), N,N’-diisopropylcarbodiimide (DIC;
1.5 equiv), 4-dimethylaminopyridine (DMAP; 0.1 equiv), CH2Cl2, 08C–RT, 86%;
d) Pd(OAc)2 (0.05 equiv), DtBPF (0.1 equiv), toluene, 608C, 87%; e) Wilkin-
son’s catalyst (0.1 equiv), H2, toluene, 508C, 95%; f) DDQ (2.0 equiv), CH2Cl2/
H2O, 89%; g) Ac2O, pyridine, 91%. DtBPF=1,1’-bis(di-tert-butylphosphino)-
ferrocene.
[a] Reactions were carried out on a 0.2 mmol scale in the presence of
0.01 mmol of Pd(OAc)2 and 0.02 mmol of DtBPF in toluene (2 mL) at
608C; [b] Isolated yields.
Cytospora sp., an endophytic fungus from Ilex canariensis, by
Zhang and co-workers recently.[20] Our synthesis started from
the commercially available glucal 11 (Scheme 3). Transforma-
tion of the primary alcohol of 11 to a butyl group by two
steps afforded 13 in good yield. Coupling of 13 with propionyl
acetic acid generated g-keto ester 14 in 86% yield. Again, our
methodology of decarboxylative coupling worked well on sub-
strate 14, affording 2,6-cis-dihydropyran 15 in good yield.
However, the same problem as that in our synthesis of centro-
lobine was encountered when we attempted to
reduce of the double bond by conventional hydro-
genation. Even when substrate 15 was subjected to
the acidic hydrogenation conditions utilized in the
synthesis of centrolobine, a low yield was obtained.
Fortunately, the hydrogenation reaction performed
in the presence of Wilkinson’s catalyst proceeded
smoothly and the desired product 16 was obtained
in excellent yield. Finally, with the removal of the p-
methoxybenzyl (PMB) protecting group, the total
synthesis of decytospolide A 17 was achieved in six
steps with an overall yield of 35%. Decytospolide B
18 was obtained in 91% yield by the acetal protec-
tion of the free OH group of decytospolide A with
acetic anhydride in pyridine. The optical rotations
and spectral data of 17 and 18 are identical with
those reported.[20]
duced the double bond and removed the protecting group to
provide (Æ)-centrolobine 10 in 76% yield (Scheme 2). The
physical and spectroscopic data obtained for 10 are in full
agreement with the literature.[16]
To further examine the synthetic utility of this novel DcA
strategy, we next attempted the synthesis of (+)-decytospoli-
des A and B. (+)-Decytospolides A and B were isolated from
In conclusion, we have further extended our
Scheme 2. Total synthesis of centrolobine: a) DCC, DMAP, CH2Cl2, 6, 91%; b) Pd(OAc)2,
DtBPF, toluene, 94%; c) 1) LiBH4, Et2O; 2) TFA, Et3SiH, 84%; d) Pd/C, H2, EtOH/EtOAc, 2m
HCl, 76%.
methodology of palladium-catalyzed b-C-glycosyla-
tion by decarboxylative allylation to normal pyran
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systems, and cis-2,6-disubstituted tetrahydropyrans were gen-
erated in good to excellent yields with exclusive selectivity.
This methodology provided a new and facile mode of access
to naturally occurring cis-2,6-tetrahydropyrans. The efficiency
of this methodology was further demonstrated by the total
syntheses of (Æ)-centrolobine and decytospolides A and B in
concise steps and high yields, highlighting the possibility of ex-
tending this methodology to industrial applications.
Acknowledgements
We gratefully acknowledge the support by Nanyang Techno-
logical University (RG50/08) and support by an NMRC grant
(H1N1 R/001/2009) from the Ministry of Health, Singapore.
Keywords: centrolobine · decytospolides · stereoselectivity ·
tetrahydropyrans · total synthesis
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Received: August 25, 2013
Published online on November 27, 2013
Chem. Eur. J. 2014, 20, 405 – 409
www.chemeurj.org
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