Enantioselective and collective syntheses of xanthanolides involving a controllable dyotropic rearrangement of cis-β-lactones

Article abstract of DOI:10.1002/anie.201202643

Let's swap: A scalable, atom-economic, enantio-, and diastereoselective synthetic route to trisubstituted γ-butyrolactones based on a Wagner-Meerwein-type dyotropic rearrangement of cis-β-lactones is described (see scheme). This methodology was applied in efficient and protecting-group-free formal syntheses and total syntheses of various xanthanolide natural products. Copyright

Full text of DOI:10.1002/anie.201202643

Angewandte
Chemie
DOI: 10.1002/anie.201202643
Natural Product Synthesis
Enantioselective and Collective Syntheses of Xanthanolides Involving
a Controllable Dyotropic Rearrangement of cis-b-Lactones**
Weiwu Ren, Yichao Bian, Ziyang Zhang, Hai Shang, Pengtao Zhang, Yuejie Chen, Zhen Yang,*
Tuoping Luo,* and Yefeng Tang*
Dedicated to Professor Manfred T. Reetz
Chemo-, regio-, and stereoselective rearrangements, espe-
cially those that lead to skeletal reorganization, are widely
appreciated as powerful transformations in organic synthe-
sis.[1] A typical example is the Wagner–Meerwein-type
dyotropic rearrangement of b-lactones,[2–5] a rearrangement,
which involves concurrent migration of two vicinal s bonds
À
À
(one C O bond and one C C bond) to generate the ring-
enlarged product, that is, g-butyrolactones. Mechanistically,
most of the documented dyotropic rearrangements of
À
b-lactones are concerted and the migrating C C bond and
[2]
À
C O bond are antiperiplanar in the transition state.
Surprisingly, the synthetic utility of this intriguing trans-
formation has been largely overlooked, despite it being
a useful method for constructing g-butyrolactones, which are
ubiquitous motifs in biologically active compounds.[6] The low
usage of this transformation may be attributed to unpredict-
able product distributions, which are sensitive to reaction
parameters, such as the identity of substrates and Lewis acids.
To explore the full potential of dyotropic reactions
involving b-lactones, we aimed at developing synthetic
routes to the xanthanolides (Scheme 1A, 1–7), a large
group of natural products that were isolated primarily from
the genus Xanthium.[7] The xanthanolidesꢀ wide range of
biological activities, which include antitumor, antimicrobial,
anti-inflammatory, and allelopathic activities,[8] have
Scheme 1. A) Naturally occurring xanthanolides and the key synthetic
intermediate 8. B) Wagner–Meerwein-type dyotropic rearrangement of
cis-b-lactones.
prompted total synthesis studies involving a number of
strategies, although most of them suffer from long linear
sequences (> 15 steps) and low overall yields (less than
10%).[9] Of particular interest to us is the recently demon-
strated trypanocidal activity (IC50 = 10 mm against blood
stream forms of Trypanosoma brucei brucei) of xanthatin
(1).[10] A de novo synthetic approach that enables efficient
exploration of the structure-activity relationships of these
natural products, coupled with a genome-wide RNA-inter-
ference library screen platform in T. brucei,[11] would provide
valuable cues as to the mode of action of these natural
products and thus hopefully contribute to combating human
African trypanosomiasis, which is a deadly yet therapeutically
neglected disease.[12]
With regard to a synthetic strategy, we envisioned that the
highly substituted g-butyrolactone 8,[9b,h] if made in a concise
and scalable manner, would allow straightforward access to
xanthanolides wherein the g-butyrolactone is either cis- or
trans-fused to the seven-membered carbocycle. Notably, in
the first report on the Wagner–Meerwein-type dyotropic
rearrangement, Mulzer and Brꢁntrup demonstrated the
quantitative conversion of cis-b-lactone 9a into g-butyrolac-
tone 10a, which possesses the same stereochemistry of 8
(Scheme 1B).[3a] The presence of conformations containing
high-energy syn-pentane interactions in the substrate restricts
the substrate to a conformation wherein the subsequent
[*] Dr. W. Ren, Y. Bian, Z. Zhang, Dr. H. Shang, P. Zhang, Y. Chen,
Prof. Dr. Y. Tang
The Comprehensive AIDS Research Center
Department of Pharmacology & Pharmaceutical Sciences
School of Medicine, Tsinghua University
Beijing 100084 (China)
E-mail: yefengtang@tsinghua.edu.cn
Prof. Dr. Z. Yang
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education and Beijing National Laboratory for
Molecular Science (BNLMS), College of Chemistry
Peking University
Beijing 100871 (China)
Dr. T. Luo
H3 Biomedicine Inc., 300 Technology Square
Cambridge, MA 02139 (USA)
[**] We acknowledge the financial support from the National Science of
Foundation of China (20832003), China’s 985 project (411307141),
and New Teachers’ Fund for Doctor Stations, Ministry of Education
(20110002120011) to Y.T. T.L. is grateful to Prof. Stuart L. Schreiber
(Harvard University) for the inspiring education.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202643.
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rearrangement involves the migration of only one of the
diastereotopic methyl groups (TS-1).[13] However, when we
attempted the same rearrangement using cis-b-lactone 9b as
the starting material, only 9b was recovered (Scheme 1B),
thus indicating the crucial role of the phenyl group in 9a in
facilitating the rearrangement under the reaction conditions.
This result necessitated further investigation of the dyotropic
rearrangement of a-methyl-cis-b-lactones before it could be
used for the preparation of biologically active natural
products such as the xanthanolides. Herein we describe our
efforts in identifying reaction conditions for expanding the
substrate scope of this stereospecific rearrangement; this
methodology provided a foundation for the collective total
syntheses[14] of the naturally occurring xanthanolides (1–7) as
well as their unnatural analogues.
Toward evaluating the aforementioned transformation
using a model compound that is relevant to the total synthesis
of the xanthanolides, we commenced our studies by synthesiz-
ing enantioenriched b-lactone 9c by employing two organo-
catalytic reactions, one of which was developed by the
research group of MacMillan and the other by the research
group of Nelson (see the Supporting Information for
details).[15,16] Satisfyingly, the X-ray crystallographic analysis
g-butyrolactone 10c was obtained in 67% yield by using
a stoichiometric amount of TiCl4, although the product was
contaminated by an inseparable unidentified byproduct
(Table 1, entry 2). Ultimately, we found that when 9c was
treated with EtAlCl2 for 5 minutes at room temperature in
either CH2Cl2 or toluene 10c was obtained as the predom-
inant product (Table 1, entries 3 and 4). Surprisingly, the
reaction was complete within a short period of time and
reducing the reaction time to 2 minutes led to 10c being
isolated in 85% yield (Table 1, entry 5). Several other
aluminum Lewis acids were examined: whereas Et2AlCl
was as effective in mediating the reaction as EtAlCl2 (Table 1,
entry 6), a sluggish reaction was observed when Et3Al was
used. Specifically, when 9c was treated with Et3Al for 3 hours,
10c was isolated in 42% yield and the substrate 9c was
recovered in 48% yield (Table 1, entry 7). In sharp contrast,
the use of AlCl3 led to complete decomposition of 9c (Table 1,
entry 8), thus indicating that the nature of the organoalumi-
num Lewis acid is crucial for the rearrangement. When the
reaction temperature was reduced to À408C, the rate of the
reaction was lower and hence a reaction time of 4 hours was
required to achieve full conversion of 9c (Table 1, entry 9).
The use of a catalytic amount of EtAlCl2 was also effective,
although a longer reaction time was required and 10c was
isolated in lower yield than the reaction wherein a stoichio-
metric amount of EtAlCl2 was used (Table 1, entry 10 versus
entry 5). To the best of our knowledge, there is no precedent
for the organoaluminum-promoted dyotropic rearrangement
of b-lactones.[18] Importantly, compound 10c was isolated as
a single diastereomer, the structure of which was determined
unambiguously by X-ray crystallography.[17]
The scope of the EtAlCl2-mediated Wagner–Meerwein-
type dyotropic rearrangement was investigated with respect
to various cis-b-lactones (Table 2). Enantiopure b-lactones
9d–9 f were converted into the corresponding trans-fused
[5.3.0] bicycles 10d–10 f in good yields (Table 2, entries 1–3);
notably, 10 f only differs from 8, the key intermediate toward
the xanthanolides, by the absence of a methyl group. The
rearrangement of 9g also proceeded smoothly to afford
tricycle 10g (Table 2, entry 4). Moreover, [4.3.0] bicyclic
compound 10h was obtained in 82% yield from b-lactone 9h,
suggesting that this protocol has the potential to construct
polycyclic systems other than [5.3.0] bicycles (Table 2,
entry 5).[19] The superiority of EtAlCl2 over MgBr2 in
promoting the current reaction of a-methyl-cis-b-lactones
was evident again in the successful conversion of 9b into 10b
in quantitative yield under the optimized conditions (Table 2,
entry 6 versus Scheme 1B). In the case of b-lactone 9i, the
phenyl group migrated in the transformation, thus furnishing
10i in 78% yield (Table 2, entry 7). Most interestingly, a pair
of diastereomers, cis-b-lactones 9j and 9k, underwent methyl
migration and 2-phenylethyl migration, respectively, to form
the corresponding trisubstituted g-butyrolactones 10j and
10k, respectively (Table 2, entries 8 and 9), thus demonstrat-
ing that this reaction is stereospecific. In addition to a-methyl
cis-b-lactones, a a-ethyl-cis-b-lactone, 9l, also underwent the
EtAlCl2-mediated rearrangement, thus affording 10l in 76%
yield (Table 2, entry 10).
À
of 9c confirmed the antiperiplanar relationship of the C5 C6
s bond and the C4 O s bond (see scheme in Table 1).[17] If the
À
conformation of the transition state structure of the dyotropic
reaction of 9c is similar to the solid-state conformation of 9c,
À
we anticipate that the migration of the C5 C6 s bond would
À
À
be more favored than that of the C5 C10 and C5 H s bonds,
thus affording g-butyrolactone 10c as the major product.
Encouraged by this rationalization, we screened various
Lewis acids that we thought could facilitate the rearrange-
ment; among these, the use of MgBr2 (Table 1, entry 1),
Zn(OTf)2, In(OTf)3, Yb(OTf)3, and TMSOTf failed to
promote the desired transformation and led to recovery of
the starting material or substantial decomposition. Pleasingly,
Table 1: Optimization of reaction conditions for the dyotropic rear-
rangement of 9c into 10c.[a]
Entry
Lewis acid
Solvent/T
t
Yield [%][b]
1
2
3
4
5
6
7
8
MgBr2
TiCl4
Et2O, RT
12 h
1 h
0[c]
67[d]
73
75
85
CH2Cl2, RT
CH2Cl2, RT
toluene, RT
toluene, RT
toluene, RT
toluene, RT
toluene, RT
toluene, À408C
toluene, RT
EtAlCl2
EtAlCl2
EtAlCl2
Et2AlCl
AlEt3
AlCl3
EtAlCl2
EtAlCl2
5 min
5 min
2 min
2 min
3 h
3 h
4 h
1.5 h
81
42[e]
0[c]
70
9
10[f]
67
[a] [9c]=0.025m (0.3 mmol), 1.1 equiv Lewis acid. [b] Yields after
column chromatography. [c] Substrate 9c decomposed. [d] Yield deter-
mined by NMR analysis using mesitylene as internal standard. [e] Sub-
strate 9c was recovered in 48% yield. [f] 0.2 equiv Lewis acid was used.
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Table 2: Scope of the EtAlCl2-mediated Wagner–Meerwein-type dyo-
tropic rearrangement of cis-b-lactones.[a]
Entry
1
b-lactones
Product
Yield [%][b]
83
2
3
88
77
4
71
Scheme 2. Synthesis of the key intermediate 8. Reagents and condi-
tions: a) NaHMDS (1.1 equiv), THF, À788C; then allyl bromide
(3.0 equiv), À408C; b) Grubbs 2nd generation cat. (10 mol%), ethylene,
toluene, 408C; c) LiBH4 (1.0 equiv), MeOH (1.0 equiv), THF, 08C;
d) (COCl)2 (2.0 equiv), DMSO (4.0 equiv), Et3N (8.0 equiv), CH2Cl2,
À788C to 08C; e) TMSQ (10 mol%), LiClO4 (3.0 equiv), DIPEA
(2.5 equiv), EtCOCl (2.0 equiv), Et2O/CH2Cl2 (1:2), À408C; f) EtAlCl2
(1.1 equiv), toluene, RT. DIPEA=diisopropylethylamine, DMSO=di-
methylsulfoxide, NaHMDS=sodium hexamethyldisilazide, TMS=tri-
methylsilyl.
5
6
7
8
82
99
78
76
asymmetric [2+2] reaction with propionyl chloride to give cis-
b-lactone 14 as a single diastereomer in 55% yield over three
steps (2 g scale). The desired compound 8 was then obtained
by the EtAlCl2-mediated dyotropic rearrangement, although
the yield upon isolation fell from 75% to 67% when the
reaction was scaled up from 100 mg to 500 mg. The high
chemo-, regio- and stereoselectivity of this key transforma-
tion can be rationalized by considering the transition state
TS-2 (Scheme 2). The analytical data of 8 were identical to
those reported for the compound previously; in these
previous reports, 8 was converted to natural products
xanthatin (1) and 11a,13-dihydroxanthatin (4) in three steps
and two steps, respectively.[9b,h]
9
82
76
10
[a] Conditions: b-lactone (0.3 mmol, 0.025m), EtAlCl2 (1.1 equiv), tolu-
ene, RT, 2 min. Note: b-lactones and rearrangement products were
isolated in >19:1 diastereomeric ratio.
With a scalable method for the preparation of the critical
intermediate 8 established, we proceeded to make a variety of
xanthanolides wherein the g-butyrolactone moiety is cis fused
to the seven-membered carbocycle (Scheme 3). Ring-opening
of g-butyrolactone
8 with N,O-dimethylhydroxylamine
hydrochloride followed by redox manipulations and lactoni-
zation effected the inversion of the C8 stereogenic center,
thus affording bicycle 15 in 55% yield over three steps.
Notably, compound 15 was synthesized en route to (+)-8-epi-
xanthatin (2) by Shindo and co-workers.[9j] Hydroboration of
15 and subsequent oxidation gave sundiversifolide (3). Cross
metathesis of compound 15 and methyl vinyl ketone (MVK)
catalyzed by the second-generation Hoveyda–Grubbs catalyst
furnished 11a,13-dihydro-8-epi-xanthatin (5), which was fur-
After establishing this synthetic methodology, we then
moved toward the total syntheses of various xanthane-type
sesquiterpenoids involving intermediate
8
(Scheme 2).
Diastereoselective allylation of compound 11[20] afforded 12
(75% yield, 5 g scale), which was then subjected to ring-
closing enyne metathesis to give compound 13 (80% yield, 2 g
scale). Consecutive reduction and oxidation yielded the
aldehyde, which was then subjected to an organocatalytic
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ships, which can be extremely informative.[23] These inves-
tigations are underway and will be reported in due course.
Received: April 5, 2012
Published online: && &&, &&&&
Keywords: dyotropic rearrangement · lactones · rearrangement ·
.
total synthesis · xanthanolides
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Scheme 3. Syntheses of various xanthane sesquiterpenoids from 8.
Reagents and conditions: a) iPrMgCl (5.0 equiv), MeNH(OMe)·HCl
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THF, 08C; h) iPrMgCl (5.0 equiv), Et2NH·HCl (2.5 equiv), THF, 08C.
DMP=Dess–Martin periodinane, LDA=lithium diisopropylamine, 9-
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
Natural Product Synthesis
W. Ren, Y. Bian, Z. Zhang, H. Shang,
P. Zhang, Y. Chen, Z. Yang,* T. Luo,*
Y. Tang*
&&&& — &&&&
Enantioselective and Collective Syntheses
of Xanthanolides Involving a Controllable
Dyotropic Rearrangement of cis-b-
Lactones
Let’s swap: A scalable, atom-economic,
enantio-, and diastereoselective synthetic
route to trisubstituted g-butyrolactones
based on a Wagner–Meerwein-type dyo-
tropic rearrangement of cis-b-lactones is
described (see scheme). This method-
ology was applied in efficient and pro-
tecting-group-free formal syntheses and
total syntheses of various xanthanolide
natural products.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!