Strain-Driven Dyotropic Rearrangement: A Unified Ring-Expansion Approach to α-Methylene-γ-butyrolactones

Article abstract of DOI:10.1002/anie.202013169

An unprecedented strain-driven dyotropic rearrangement of α-methylene-β-lactones has been realized, which enables the efficient access of a wide range of α-methylene-γ-butyrolactones displaying remarkable structural diversity. Several appealing features of the reaction, including excellent efficiency, high stereospecificity, predictable chemoselectivity and broad substrate scope, render it a powerful tool for the synthesis of MBL-containing molecules of either natural or synthetic origin. Both experimental and computational evidences suggest that the new variant of dyotropic rearrangements proceed in a dualistic pattern: while an asynchronous concerted mechanism most likely accounts for the reactions featuring hydrogen migration, a stepwise process involving a phenonium ion intermediate is favored in the cases of aryl migration. The great synthetic potential of the title reaction is exemplified by its application to the efficient construction of several natural products and relevant scaffolds.

Full text of DOI:10.1002/anie.202013169

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Strain-Driven Dyotropic Rearrangement: A Unified Ring-
Expansion Approach to α-Methylene-γ-butyrolactones
Authors: Yefeng Tang, Xiaoqiang Lei, Yuanhe Li, Yang Lai, Shengkun
Hu, Chen Qi, and Gelin Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202013169
Link to VoR: https://doi.org/10.1002/anie.202013169

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
Strain-Driven Dyotropic Rearrangement: A Unified Ring-Expansion
Approach to α-Methylene-γ-butyrolactones
Xiaoqiang Lei, Yuanhe Li, Yang Lai, Shengkun Hu, Chen Qi, Gelin Wang,*and Yefeng Tang*
Abstract: An unprecedented strain-driven dyotropic rearrangement
of α-methylene-β-lactones has been realized, which enables the
efficient access of a wide range of α-methylene-γ-butyrolactones
displaying remarkable structural diversity. Several appealing features
of the reaction, including excellent efficiency, high stereospecificity,
predictable chemoselectivity and broad substrate scope, render it a
powerful tool for the synthesis of MBL-containing molecules of either
natural or synthetic origin. Both experimental and computational
evidences suggest that the new variant of dyotropic rearrangements
proceed in a dualistic pattern: while an asynchronous concerted
mechanism most likely accounts for the reactions featuring hydrogen
migration, a stepwise process involving a phenonium ion intermediate
is favored in the cases of aryl migration. The great synthetic potential
of the title reaction is exemplified by its application to the efficient
construction of several natural products and relevant scaffolds.
Introduction
Figure 1. Representative bioactive MBL-containing compounds.
-Methylene-γ-butyrolactones (MBL) represents an extremely
appear versatile, they are not without limitation. Firstly, most of
important structural elements in bioactive natural products and
them only permit access to MBL with limited structural diversity,
pharmaceutics.[1] So far, more than 5000 MBL-containing natural
especially for the substituent patterns at C-4 and C-5 positions.
products have been identified,[1c] many of which display significant
Secondly, with a few exceptions, they are incapable of arranging
biological profiles and appealing pharmacological potential. For
these substituents in a regio- and stereo-chemically defined
examples, arglabin, a tricyclic sesquiterpene lactone, has been
manner. Thirdly, most of the known methods are built on
approved as a drug in Kazakhstan for the treatment of breast,
cyclization- and cycloaddition-type reactions, and rearrangement
colon, ovarian and lung cancers;[2] parthenolide, a small molecule
reactions have rarely been utilized for this purpose.
that can selectively kill cancer stem cells, is now being
investigated in clinical trials for the treatment of acute myelocytic
Defined by Reetz in the early 1970s,[8] dyotropic reactions
represent a unique class of pericyclic reactions that have attracted
leukemia and chronic lymphocytic leukemia (Figure 1).[3] Besides,
considerable interest from synthetic community.[9] Historically,
MBL has also been utilized as a key pharmacophore in myriad
various dyotropic reactions have been developed, among which
pharmaceutical agents[4] and chemical probes[5] of synthetic origin.
Lewis acid-promoted dyotropic rearrangement of β-lactones is
Interestingly, while MBL-containing compounds exhibit diverse
molecular architectures, they generally exert biological functions
particularly notable for its appealing synthetic potential. First
discovered by Mulzer and Brüntrup in 1979,[10] this type of
through a similar mode, in which the MBL unit reacts with
transformations has been investigated intermittently by the
biological target through Michael addition, and thus results in the
Black,[11] Reetz,[12] Cossío,[13] and Romo[14] groups over the past
disruption of certain biological processes within the cells.[6]
decades. A variety of β-lactones bearing different substitution
Owing to its great importance, tremendous effort has been
devoted to developing new methods for synthesis of MBL and
related scaffolds.[1,7] Although the existing synthetic toolkits
patterns have been proven to be amenable for this reaction. With
a few exceptions, most dyotropic rearrangements of β-lactones
proceeds through a concerted mechanism featuring a well-
defined transition state (TS, Figure 1a), in which the adjacent C4-
O1 and C5-R1 bonds disposed in an anti-coplanar alignment
[] X. Lei, S. Hu, C. Qi, Prof. Dr. G. Wang, Prof. Dr. Y. Tang
interchange their positions simultaneously, leading to the ring-
expansion products in a stereospecific manner. Despite a
seemingly attractive method to access multi-substituted γ-
School of Pharmaceutical Sciences, MOE Key Laboratory of
Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua
University, Beijing 100084, China
E-mail: yefengtang@tsinghua.edu.cn; dusps@tsinghua.edu.cn
butyrolactones,
the
synthetic
potential
of
dyotropic
Y. Li, Y. Lai
rearrangement of β-lactones has been largely underdeveloped,
particularly in the field of nature product synthesis.[9b] This, in part,
could be attributed to the difficulty in predicting and controlling the
reaction outcomes, which are usually determined by the mutual
interaction of the inherent steric and electronic factors associated
with the reactions.
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.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 2. Original ideal and rationalization.
to undergo various ring-opening reactions. Indeed, alkyl C-O
bond cleavage was documented as a side reaction in the previous
dyotropic rearrangement of β-lactones.[10b,18] We anticipated that
such tendency might be further enhanced in the current case
because of the increased RSE and the involvement of a stabilized
allylic carbocation intermediate. One the other hand, as a densely
functionalized small ring system, α-methylene-β-lactone could
also engage in other transformations such as acyl C-O
cleavage,[19] Michael addition,[20] and decarboxylation reaction.[21]
In this context, it would be challenging to achieve the expected
dyotropic rearrangement without the interference of underlying
side reactions. Beside reactivity issue, the selectivity of the
reaction also appeared uncertain. Taking -methylene-β-lactone
6 as example, it could undergo dyotropic rearrangement through
either C-C or C-H bond migration. A simple analysis of the
conformations of transition states TS-3a and TS-3b suggested
that the former showed less steric effect, and thus the pathway
leading to the 5/7-trans bicyclic compound 7 (path a) might be
favored if only considering the steric factor. However, distinct from
3,4-cis-disubstituted β-lactone, α-methylene-β-lactone possesses
more conformational flexibility, and thus steric factor may not play
a determining role in the current case. This hypothesis is
supported by our calculation study, which shows that the energy
differences between the conformations of TS-3a and TS-3b are
trivial (for details, see SI), indicating that both of them might be
adopted in practice. Since the orbital for C-H bond generally has
a higher energy than that of C-C bond, and a stronger orbital
overlap between the  (C5-H) and C4-O1) could be conceived
for TS-3b. Therefore, it is likely that C-H migration would take
place preferentially in practice, resulting in the 5/6-spiro bicyclic
compound 8 as a major product (path b).
Scheme 1. Historical development of dyotropic rearrangement of -lactones.
We have shown keen interest in dyotropic rearrangement of β-
lactones over the past several years, motivated by the objective
to unveil its underlying potential in natural product synthesis. In
2012, we reported a unique dyotropic rearrangement using 3,4-
cis-disubstituted β-lactones as substrates.[15] In this work, the
prearrangement of C-3 and C-4 substituents in a cis-configuration
is crucial for securing high chemo- and stereoselectivity. Since in
this scenario, a well-defined transition state (TS-1) with C5-H
directed towards R3 substitute should be adopted to minimize the
underlying syn-pentane interaction (Figure 1b). As a result, only
the C5-R1 bond that displays an anti-coplanar alignment with the
C4-O1 bond could engage in migration, leading to the
corresponding 3,4,5-trisubstituted butyrolactones in a highly
chemoselective and stereospecific manner. Hinging on this
reaction, we completed the collective syntheses of a series of
sesquiterpene lactones, namely, xanthanolides.[15,16] Of note,
while this reaction is ideally suitable for the synthesis of
xanthanolides bearing three contiguous stereogenic centers at
the C3-C5 positions (e.g. 3), extra functionality interconversion
(Me → =CH2) has to be implemented to access some other
congeners featuring a MBL moiety, such as xanthatin (5).
Apparently, from a synthetic perspective, the more redox- and
step-economy approach to access xanthatin-like natural products
should hinge on the dyotropic rearrangement outlined in Figure 2,
which entails -methylene-β-lactone 6 as substrate. However, we
noticed that this variant of dyotropic rearrangement had never
been explored before, which indicated it might be much more
challenging than expectation. It is likely that a small structural
change at the C-3 position of -lactone may notably change its
reactivity and selectivity in dyotropic reaction. On one hand, α-
methylene-β-lactone displays a higher ring-strain energy (RSE)
than those conventional β-lactones,[17] and thus it is more easily
Keeping the above rationalization in mind, we initiated a
program to explore the new variant of dyotropic rearrangement.
Rewardingly, we finally succeeded in the development of a
mechanistically interesting and practically useful dyotropic
rearrangement of α-methylene-β-lactones, which holds a great
promise to serve as an enabling tool in organic synthesis and
biomedical research.
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
Results and Discussion
(entry 13). Finally, it was found that the combination of
MgBr2•Et2O/Et2O could also serve as an alternative choice of
optimal conditions, which delivered 8 as the sole product in an
acceptable yield (63%) (entry 14).
Condition Optimization. In a line with our previous work,[15] the
designed dyotropic rearrangement of α-methylene-β-lactone 6[19]
was first conducted in toluene with Et2AlCl as promoter. The
starting material was quickly consumed, resulting in only one
isolated product in 34% yield, which was determined to be 6/5-
spiro bicyclic MBL 8 (entry 1, Table 1). Careful analysis of the 1H
NMR spectrum of 8 indicated that it was contaminated with a trace
amount of 5/7-trans-fused bicyclic MBL 7 (8:7 > 20:1).[22] The
preliminary outcome, albeit failed to afford the originally proposed
5/7-bicyclic MBL relevant to our natural target, proved that -
methylene-β-lactones could serve as suitable substrate for
dyotropic rearrangement. Encouraged by this discovery, we
continued to conduct a systematic condition optimization, with the
aim to develop the new variant of dyotropic reaction into an
enabling tools for the synthesis of MBL-containing compounds.
Various Lewis acids were evaluated first, which revealed that they
exerted a profound influence on the reaction outcomes. Among
the aluminum-based Lewis acids (Et2AlCl, EtAlCl2 and AlCl3)
(entries 1-3), EtAlCl2 and AlCl3 afforded notably improved yields
(70% and 50%) than Et2AlCl, suggesting that an increase of Lewis
acidity is beneficial to reaction efficiency. However, in both cases
the chemoselectivity decreased. Indeed, we could even detect a
trace amount of 5/7-cis-bicyclic product (7′) in these cases. To
obtain an ideal balance between the efficiency and selectivity, we
further evaluated several other Lewis acids including TiCl4,
Substrate Scope. Having the optimal conditions in hand, we
turned to evaluate the substrate scope. Initially, the structural
variants at C-5 position were explored extensively. Based on the
substituent patterns, all of the examined α-methylene-β-lactones
were classified into five groups (Figure 3). For type I substrates
that bear two alkyls and one hydrogen on the C-5 position, all
reactions underwent C-H migration exclusively, delivering 5,5-
dialkyl-substituted BML (9-24) in satisfactory yields. Several 5/6-
spiro bicyclic MBL (9-11) were prepared by this method with high
diastereoselectivity, among which 10 was unambiguously
confirmed by the X-ray crystallographic study.[23] For -
methylene-β-lactones bearing two different alkyls (R1≠R2), a pair
of diastereoisomeric precursors (ca. 1:1 ratio) were used directly,
as they eventually resulted in identical products (14-21) after
migration. Two natural product-derived BML 23 and 24 were also
prepared through this reaction, suggesting that it can serve as an
enabling tool for late-stage modification of natural products.
For α-methylene-β-lactones carrying one aryl, one alkyl and
one hydrogen at C-5 position, the substrates were divided into two
categories: type II with C5-C(aryl) and C4-O1 bonds aligned in an
anti-configuration and type III with the opposite syn-configuration.
Gratifyingly, both types of substrates proved to be amenable for
dyotropic reaction by delivering the corresponding products (25-
70) in excellent yields. Several features of these reactions
deserve further discussion. Firstly, in all examined reactions, aryl
migration took place exclusively, giving rise to 4-aryl-5-alkyl-MBL
as the sole regioisomer. This result suggests that aryl has a
greater migratory priority than both hydrogen and alkyl. Secondly,
all of the reactions proceeded in a stereospecific manner, with
4,5-anti- and 4,5-syn-α-methylene-β-lactones leading to 4,5-
trans- (25-47) and 4,5-cis-substitued BML (48-70), respectively.
This finding shows that the stereochemistry of substrates could
perfectly transfer to products via stereospecific dyotropic
rearrangements, which renders the reaction predictable and
controllable. Thirdly, diverse functionalities (e.g. alkene, alkyne,
halides, oxygen- and sulfur ether) were tolerated in the reactions,
which paves the way for further derivatization upon needed.
Not surprisingly, for 5,5-diaryl-α-methylene-β-lactones (type IV),
aryl migration also took place exclusively, resulting in 4,5-diaryl-
substituted MBL. However, the chemoselectivity and
stereochemical outcomes turned out to be more complicated than
the aforementioned cases, largely depending on the interplay of
inherent electronic and steric factors. For example, for α-
methylene-β-lactones bearing two identical aryls (Ar1 = Ar2), 4,5-
trans-diaryl-substituted MBL (71-75) were obtained as the single
diastereoisomers. That means although the two aryls have same
electronic property, one of the diastereotopic groups (Ar1) is
easier to migrate than the other (Ar2) due to the favorable steric
effect associated with its corresponding transition state, in which
Ar2 was arranged far away from the β-lactone ring. The situation
becomes even intricate when two aryls are different (Ar1 ≠ Ar2),
since these substrates were only accessed as a pair of
inseparable diastereoisomers (1:1 ratio), both of which could
undergo dyotropic reactions. Generally, when the two aryls exhibit
little electronic bias (e.g. Ph vs 4-F-C6H4), both diastereomeric
precursors underwent dyotropic reactions through the sterically
.
.
.
MgBr2 Et2O, and BF3 Et2O (entries 4-6). Among them, MgBr2 Et2O
gave the best selectivity by affording 8 as a single product in an
acceptable yield. Next, a variety of solvents were explored with
EtAlCl2 as promoter (entries 7-12), among which the best yield
(71%) and selectivity (20:1) was obtained with Et2O. Furthermore,
increasing the reaction concentration could notably shorten the
reaction time without compromise of efficiency and selectivity
Table 1 Condition optimization of dyotropic rearrangement of
α-methylene-β-lactone[a]
Entry Lewis acid Solvent
c (mol.L-1) Time
Yield (%)[b]
(8:7)[c]
1
Et2AlCl
EtAlCl2
AlCl3
Toluene
Toluene
Toluene
Toluene
0.025
0.025
0.025
0.025
0.025
0.025
0.025
15 min
34 (>20:1)
2
1 min
3 min
1 min
10 min
36 h
70 (19:1)d
50 (5:1)d
62 (>20:1)
51
3
4
TiCl4
.
5
MgBr2 Et2O Toluene
.
6
BF3 Et2O
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
Toluene
CH2Cl2
14 (>20:1)
7
1 min
1 min
1 min
1 min
1 min
90 min
20 min
5 min
69 (9:1)
8
Mesitylene 0.025
64 (>20:1)d
60 (9:1)d
68 (>20:1)d
64 (>20:1)d
71 (>20:1)
74 (>20:1)
63
9
Benzene
C6F6
0.025
0.025
0.025
0.025
0.05
10
11
12
13
14
p-xylene
Et2O
EtAlCl2
Et2O
.
MgBr2 Et2O Et2O
0.05
aReaction conditions: 6 (0.20 mmol), 1.1 equiv Lewis acid. bIsolated yield.
cDetermined by 1H NMR. dWith a trace amount of 7′ detected.
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 3 Dyotropic rearrangements of α-methylene-β-lactones bearing different substituents at the C5 position. aOtherwise noted, the reactions were conducted
with a standard protocol: α-methylene-β-lactones (0.20 mmol, 0.05M), EtAlCl2 (1.1 equiv.) in Et2O (4.0 mL) at RT for 20 min. b Isolated yield. c 50 min. d 90 min. e
.
MgBr2 Et2O, RT, 20 min. f 120 min. g 60 min. h 40 min. i gram-scale synthesis. j 30 min. k10 min.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
favorable transition states as mentioned above, thus resulting in
a mixture of 4,5-trans-MBL 76a and 76b through Ph- and 4-F-
C6H4 migration, respectively. Of note, 76a/76b could not be
separated by chromatographic method, and their identities were
determined by analogy to the well-established compounds.[24] In
contrast, for substrates having two electronically biased aryls (e.g.
Ph vs 4-MeO-C6H4), 4,5-trans- (77a) and 4,5-cis products (77b)
were isolated in 55% and 36%yields, respectively. Obviously, due
to its strong electronic donating nature, 4-MeO-C6H4 migrates
preferentially for both diastereomeric precursors, even though the
reaction leading to 77b would adopt a sterically unfavorable
transition state. Lastly, α-methylene-β-lactones bearing an all-
carbon quaternary carbon at C-5 position (type V) also proved be
suitable substrates. As expected, aryl migration occurred for the
substrates bearing one aryl and two alkyls (e.g. 78-81);
comparably, alkyl migration took place in the absence of aryl at
C-5 position (e.g. 82).
with the C4-O1 bond located at a tertiary carbon, the reaction may
proceed, at least in part, through a stepwise mechanism involving
an allylic tertiary carbocation intermediate. Thus, hydrogen
migration takes place preferentially due to the engagement of a
more stable diphenyl-substituted carbocation species.[25] On the
other hand, even a concerted mechanism is possible in this case,
aryl migration would be inhibited to some extent, owing to the
increasing steric hindrance between the migrating group and the
C4 substituents. Finally, we found that introducing an aryl onto the
C-4 position further increased the tendency of underlying E1-
elimination pathway. Indeed, the reaction of S87 only led to the
desired product (78) in a moderate yield, together with substantial
amounts of elimination product (not shown).
Figure 5 Dyotropic rearrangements of α-alkylidene-β-lactones
Besides-methylene-γ-butyrolactones, we envisioned that the
dyotropic reaction developed by us could also be applied to the
synthesis of α-alkylidene-γ-butyrolactones, another important
structural motif found in natural products and drugs.[1c] As the
proof-of-concept cases, α-alkylidene-β-lactones S88-S90, readily
prepared from the corresponding α-methylene-β-lactones through
cross metathesis reaction,[19] were evaluated under the optimal
conditions. Gratifyingly, all of them underwent dyotropic reactions
smoothly, giving rise to α-alkylidene-γ-butyrolactones 88-90 in
high yields and selectivity (Figure 5).
Figure 4 Scope of α-methylene-β-lactones bearing different substituents at C4
position. aOtherwise noted, the reaction was conducted with α-methylene-β-
lactones (0.20 mmol, 0.05M), EtAlCl2 (1.1 equiv.) in Et2O (4.0 mL) at RT for 20
.
min. b Isolated yield. c MgBr2 Et2O, RT, 1 h.
Computational Study and Mechanistic Rationalization. Having
fully explored the substrate scope of the dyotropic rearrangements
of α-methylene-β-lactones, we then conducted a computational
study to gain deep insight into the mechanisms of some
representative reactions. Stationary points on the potential energy
surface were located at PBE0-D3/def-TZVP level.[26] More
accurate single point energies were calculated with double-hybrid
functional at PWPB95-D3/def2-QZVPP level.[27] The solvent effect
in Et2O was evaluated with the SMD method.[28] All energies
mentioned below are solvated Gibbs free energies. First, we
studied the type I substrates using 6 as a model compound.
Transition states (TSs) for both stepwise and concerted
mechanisms are located (Figure 6a and Figure S1). For H-
migration process towards product 8, a concerted pathway
through TS1 is the favored mechanism with an activation Gibbs
free energy of 86.4 kJ/mol. The geometry of TS1 indicates that C-
O breaking precedes C-H migration (Figure 6b). An intrinsic
reaction coordinate (IRC) calculation starts from TS1 also
confirmed that the concerted process is highly asynchronous
(Figure 6b). Judging from the bond lengths, this rearrangement
Having explored the structural variants at C-5 positions, we
sought to expand the reaction to some more challenging
substrates (Figure 4). First, α-methylene-β-lactones bearing a
quaternary carbon at C-4 position were evaluated. Theoretically,
this type of substrates readily undergoes ring-cleavage through
E1-type elimination.[10b] To our delight, the dyotropic
rearrangements of this kind of substrates could be achieved under
the judiciously selected conditions. For example, both substrates
S84 and S85 underwent dyotropic reactions smoothly in the
presence of EtAlCl2; comparably, the reaction of S83 had to be
conducted with MgBr2•Et2O as promoter. Notably, both 84 and 85
share considerable similarity to the core skeletons of various
natural products (e.g. eriolangin and helenalin), which paves the
way to their application in natural product synthesis. Another
interesting case was the reaction of 4-methyl-5,5-diphenyl-α-
methylene-β-lactone (S86), wherein both aryl- (86a) and
hydrogen-migration (86b) products were obtained. Obviously, the
introduction of a methyl group on the C4 position partially inverts
the migratory sequence of aryl and hydrogen, presumably as a
result of the interplay of electronic and steric effect. On one hand,
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
(a)
(b)
TS1
7-[Al]
6-[Al]
Figure 6 (a) Energy profile for the dyotropic reactions of 6 (bond lengths in pm). [Al] = AlEtCl2. (b) Solvated electronic energies and selected bond lengths along the
IRC of TS1, showing three asynchronous stages of the concerted dyotropic process. Bond lengths labelled in TS1 structure are in pm.
(a)
(b)
Figure 7 (a) Solvated activation Gibbs free energy for concerted reaction pathways of iPr- and tBu-substituted substrates. (b) SOMO isosurfaces (value = 0.07 a.u.)
generated by biorthogonalization for the fragments and the isosurfaces (value = 0.015 a.u.) for the overlap between two orbitals (defined by the product of those
orbitals
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
reaction can be divided into three asynchronous stages: (1)
C4-O1 breaking takes place; (2) C5-H breaking and C4-H
formation happen synchronously; (3) C5-O1 bond formation
occurs only after the above processes are finished. On the
contrary, stepwise pathways were found favorable for the
alkyl-migration processes. For the formation of 5/7-cis-fused
byproduct 7′, the optimal pathway goes through a Cl-assisted
mechanism (TS4, IM2, TS5), where TS5 is the rate-
determining state, giving a barrier of 109.6 kJ/mol, 23.2 kJ/mol
higher than that of H migration. As for 5/7-trans-fused
byproduct 7, a stepwise pathway via TS2, IM1, TS3 is located.
The migration/lactone formation transition state TS3 is the
rate-determine state, with a barrier of 108.2 kJ/mol, which is
21.8 kJ/mol higher than that of H-migration. We also located
several other pathways leading to product 8, 7 and 7′, which is
discussed in the Supporting Information.
(a)
To investigate the reason behind the preference of H
migration over alkyl migration, we compared the reaction
selectivity of iPr- (S12) and tBu-substituted (S82) substrates
(Figure 7a). The difference of activation Gibbs free energy
(ΔΔG‡) between H-migration (TS6) and Me-migration (TS7
and TS8) is about 15 kJ/mol, making H migration the favorable
pathway. To semiquantitatively decouple these two effects, we
could use TS9 as a reference. The difference of orbital
interaction between the migration group and the rest of the
molecule could be estimated by comparing TS6 and TS9,
which accounts for about 6.5 kJ/mol. For the difference in the
stabilization of the partial carbocation, we could compare
TS7/TS8 with TS9, which accounts for ca. 8.5 kJ/mol
difference. These comparison shows that carbocation
stabilization and orbital interaction have a similar level of
contribution to the tendency of H-migration over alkyl-migration.
To illustrate the orbital overlap in the transition state structures,
wavefunction analysis was performed.[29] In Figure 7b, the
transition states were fragmented into the migrating H or alkyl
groups and the rest of the molecule. SOMOs generated by
biorthogonalization for both fragments and the overlap is
shown. It shows better orbital interaction for H migration than
that of Me migration.
For substrates that have aryl substitution at C-5 position, we
need to understand the preference of aryl migration over H or
alkyl migration. Dyotropic rearrangement of the substrate S25
was chosen as a model reaction, wherein Ph-, H-, and Me-
migration pathways are located (Figure 8a). For Ph migration,
two pathways were found to have almost the same activation
Gibbs free energy of 83.6 kJ/mol, between which one is
concerted (through TS10), and the other has a shallow
phenonium ion intermediate (IM3). In the concerted pathway,
a flat area can be seen on the IRC path after the transition state
(Figure 8b, c.a. 5-25 a.u.), which also corresponds to a similar
structure that C5-Ar exists intermediary state between bonding
and non-bonding scenario. These observations indicate that
the delocalization of such carbocation strongly stabilizes the
transition-state-like structure, thus lowering the overall
activation Gibbs free energy. On the contrary, the pathways for
H migration and Me migration have an activation Gibbs free
energy of 100.1 kJ/mol (TS15) and 121.0 kJ/mol (TS13, IM4,
TS14), respectively. Interestingly, the optimal pathway for Me-
migration involves a shallow minimum IM4 with the C-H bond
stabilizing the generated partial carbocation.
(b)
TS10
S25-[Al]
25-[Al]
Figure 8 (a) Energy profile for the dyotropic reactions of aryl-substituted
substrate. (b) Energy and selected bond lengths for concerted Ph migration
along the IRC of TS10.
Synthetic Application. Several striking features of the
newly developed dyotropic reaction, including excellent
efficiency, broad substrate scope and high stereospecificity,
render it an appealing tool for accessing MBL-containing
natural products and pharmaceutical agents.
We first applied the present dyotropic rearrangement to the
preparation of enantiomerically enriched MBL. As shown in
Figure 9a, the enantiopure α-methylene-β-lactone S91 (for its
preparation, see SI) underwent dyotropic reaction smoothly,
giving rise to the chiral 5,5-disubstituted MBL 91 with high
efficiency (75%). A slight erosion of ee value (99%→85% ee)
was observed, indicating that both asynchronous concerted
and stepwise mechanisms coexisted in the reaction. This
result was in good agreement with our calculation study.
Next, several natural product-relevant scaffolds were prepared
based on the newly developed chemistry (Figure 9b). For
example, the 6/5-fused bicyclic MBL 92a/92b (trans:cis =
3.2:1), a key structural element in various natural products
such as santamarine,[30] was obtained from cyclopentyl
substituted α-methylene-β-lactone S92 in 54% yield, together
with small amounts of 5/5 bicyclic spiro product 92c (17%).
Notably, different from the substrate 6, C-C bond migration
took place predominantly in this case, likely attributed to that
cyclopentane has a higher ring-strain energy (RSE) than
cyclohexane,[31] and thus it is easier to undergo ring expansion
through alkyl migration. Besides, the 6/7/5 tricyclic MBL 93
was also prepared from the corresponding precursor (S93)
through dyotropic rearrangement involving aryl migration.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
Lastly, a formal synthesis of sacidumlignan D[35] was
completed based on a H-migration dyotropic reaction. As
shown, 5,5-diaryl-4-methyl substituted α-methylene-β-lactone
S96, upon treatment with MgBr2•Et2O in Et2O, underwent
dyotropic rearrangement smoothly, providing the 5,5-diaryl-4-
methyl substituted MBL 96 as a major product. Of note, a small
amount of aryl-migration product (structure not shown) was
also detected in this case. Since compound 96 has been
reported as
a key synthetic intermediate en route to
sacidumlignan D,[36] the present work provides a formal
synthesis of this natural target.
Conclusion
In summary, an unprecedented dyotropic rearrangement of
α-methylene-β-lactones has been developed, the key
essences of which include: (1) α-methylene-β-lactone, a highly
strained small ring system notorious for its fragile nature, has
been successfully introduced to dyotropic rearrangements for
the first time; (2) a unique reaction system (EtAlCl2-Et2O) has
been identified, which warrants the new variant of dyotropic
reactions proceed with high efficiency and chemoselectivity;
(3) a broad range of α-methylene-γ-lactones displaying
remarkable structural diversity have been accessed in a finely
controllable manner, which could not be readily achieved by
the conventional methods; (4) distinct from the previously
reported dyotropic reactions, the present one most likely
proceeds through an asynchronous concerted or a stepwise
mechanism. Taking together, this work not only enriches the
repertoire of dyotropic rearrangements, but also offers a
powerful tool for the synthesis of MBL-containing compounds.
We anticipate that it will find widespread application in organic
synthesis and medicinal chemistry. Particularly, many of the
obtained BML-containing compounds in this work are closely
relevant to bioactive natural products and pharmaceutical
agents, which hold a great promise to serve as leads or
chemical tools in biomedical research. Actually, we have found
that a number of the products obtained in this study displayed
significant cytotoxicity against a panel of cancer cells, with IC50
ranging from 1-10 M (for details, see SI). We are now working
on the identification of their biological targets. Meanwhile, we
are also striving to apply the present methodology to the total
synthesis of complex natural products, and related work will be
communicated in due course.
Figure 9 Synthetic application. (a) Synthesis of enantioenriched MBL. (b)
Synthesis of natural product-relevant MBL.
Sharing considerable structural similarity with the well-known
tricyclic sesquiterpenoids such as arglabin, 93 could serve as
a natural product mimic in biomedical research.
3-Hydroxyl-α-methylene-γ-butyrolactone features the core
skeleton of a unique family of natural products as represented
by licunolide A.[32] We envisioned that this class of natural
products could be accessed through dyotropic rearrangement
involving C-O migration. To test this idea, the chiral α-
methylene-β-lactone 94 (for its preparation, see SI) was
examined under the standard conditions. It turned out that the
dyotropic reaction did work. However, the resulting O-migration
product (94a) was unstable and readily advanced to 2(5H)-
furanone derivative 94b through a Cl--initiated SN2′ substitution
reaction. Carefully controlling the reaction time allowed for the
isolation of 94a and 94b in 20% and 32% yields, respectively.
In parallel, α-alkylidene-β-butyrolactone S95 was also
explored. To our disappointment, this substrate failed to deliver
the expected dyotropic rearrangement product. Instead, ent-
Acknowledgements
We acknowledge the financial supports from National Natural
Science Foundation of China (21772109, 21971140), Major
National Science and Technology Program of China for
Innovative
Drug
(2018ZX0971100-005-007,
2017ZX09101002-001-001), and Foshan-Tsinghua Innovation
Special Fund (FTISF).
Keywords: dyotropic rearrangement • -lactone • γ-
butyrolactone • ring expansion • natural product
licunolide
A
(95b)[33] was obtained as major product,
[1]
For selected review, see: a) H. M. R. Hoffmann, J. Rabe, Angew.
Chem. Int. Ed. 1985, 24, 94-110; Angew. Chem. 1985, 97, 96-112; b)
R. R. A. Kitson, A. Millemaggi, R. J. K. Taylor, Angew. Chem. Int. Ed.
2009, 48, 9426-9451; Angew. Chem. 2009, 121, 9590-9615; c) A.
Albrecht, Ł. Albrecht, T. Janecki, Eur. J. Org. Chem. 2011, 15, 2747-
apparently through the deprotection of TBS group followed by
intramolecular transesterification reaction.[13,34] Of note, the
absolute stereochemistry of 95b is identical to another natural
product 3-epi-litsenolide D2.[32]
8
This article is protected by copyright. All rights reserved.

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
2766; d) A. Janecka, A. Wyrębska, K. Gach, J. Fichna, T. Janecki,
Drug Discovery Today. 2012, 17, 561-572.
25, 479-483; j) T. H. Black, D. C. Smith, S. A. Eisenbeis, K. A.
Peterson, M. S. Harmon, Chem. Commun. 2001, 8, 753-754.
[12] M. T. Reetz, A. Schmitz, X. Holdgrün, Tetrahedron Lett. 1989, 30,
5421- 5424.
[2]
[3]
S. H. Lone, K. A. Bhat, M. A. Khuroo, Chemico-Biological Interactions.
2015, 240, 180-198.
a) R. R. A. Freund, P. Gobrecht, D. Fischer, H-D. Arndt, Nat. Prod.
Rep. 2020, 37, 541-565; b) K. Koprowska, M. Czyz, Postepy Hig.
Med. Dosw. 2010, 64, 110-114.
[13] I. Arrastia, B. Lecea, F. P. Cossío, Tetrahedron Lett. 1996, 37, 245-
248.
[14] a) V. C. Purohit, A. S. Matla, D. Romo, J. Am. Chem. Soc. 2008, 130,
10478-10479; b) R. L. Davis, C. A. Leverett, D. Romo, D. J. Tantillo,
J. Org. Chem. 2011, 76, 7167-7174; c) C. Zhao, T. A. Mitchell, R.
Vallakati, L. M. Pérez, D. Romo, J. Am. Chem. Soc. 2012, 134, 3084-
3094.
[4]
a) P. G. Baraldi, M. C. Nunez, M. A. Tabrizi, E. De Clercq, J. Balzarini,
J. Bermejo, F. Estévez, R. Romagnoli, J. Med. Chem. 2004, 47,
2877-2886; b) T. Janecki, E. Błaszczyk, K. Studzian, A. Janecka, U.
Krajewska, M. Różalski, J. Med. Chem. 2005, 48, 3516-3521; c) R.
Romagnoli, P. G. Baraldi, M. A. Tabrizi, J. Bermejo, F. Estévez, M.
Borgatti, R. Gambari, J. Med. Chem. 2005, 48, 7906-7910; d) Q.
Zhang, Y. Lu, Y. Ding, J. Zhai, Q. Ji, W. Ma, M. Yang, H. Fan, J.
Long, Z. Tong, Y. Shi, Y. Jia, B. Han, W. Zhang, C. Qiu, X. Ma, Q. Li,
Q. Shi, H. Zhang, D. Li, J. Zhang, J. Lin, L-Y. Li, Y. Gao, Y. Chen, J.
Med. Chem. 2012, 55, 8757-8769; e) S. Rana, E. C. Blowers,
C.Tebbe, J. I. Contreras, P. Radhakrishnan, S. Kizhake, T. Zhou, R.
N. Rajule, J. L. Arnst, A. R. Munkarah, R. Rattan, A. Natarajan, J.
Med. Chem. 2016, 59, 5121-5127.
[15] W. Ren, Y. Bian, Z. Zhang, H. Shang, P. Zhang, Y. Chen, Z. Yang,
T. Luo, Y. Tang, Angew. Chem. Int. Ed. 2012, 51, 6984-6988; Angew.
Chem. 2012, 124, 7090-7094.
[16] H. Shang, J. Liu, R. Bao, Y. Cao, K. Zhao, C. Xiao, B. Zhou, L. Hu,
Y. Tang, Angew. Chem. Int. Ed. 2014, 53, 14494-14498; Angew.
Chem. 2014, 126, 14722-14726.
[17] R. D. Bach, O. Dmitrenko, J. Am. Chem. Soc. 2006, 128, 4598-4611.
[18] a) T. H. Black, S. L. Maluleka, Tetrahedron Lett. 1989, 30, 531-534;
b) T. H. Black, S. A. Eisenbeis, T. S. McDermott, S. L. Maluleka,
Tetrahedron Lett. 1990, 46, 2307-2316.
[5]
a) M. H. Kunzmann, N. C. Bach, B. Bauer, S. A. Sieber, Chem. Sci.
2014, 5, 1158-1167; b) D. C. Davis, D. G. Hoch, L. Wu, D. Abegg, B.
S. Martin, Z-Y. Zhang, A. Adibekian, M. Dai, J. Am. Chem. Soc. 2018,
140, 17465-17473; c) C. A. Berdan, R. Ho, H. S. Lehtola, M.To, X.
Hu, T. R. Huffman, Y. Petri, C. R. Altobelli, S. G. Demeulenaere, J.
A. Olzmann, T. J. Maimone, D. K. Nomura, Cell Chem. Biol. 2019,
26, 1027-1035.
[19] C. A. Malapit, D. R. Caldwell, N. Sassu, S. Milbin, A. R. Howell, Org.
Lett. 2017, 19, 1966-1969.
[20] W. Adam, V. O. Nava-Salgado, J. Org. Chem. 1995, 60, 578-584.
[21] W. Adam, R. Albert, L. Haseann, V. O. N-Salgado, B. Nestler, E. M.
Peters, K. Peters, F. Prechtl, H. G. V. Schnering, J. Org. Chem. 1991,
56, 5782-5785.
[6]
[7]
R. Lagoutte, N. Winssinger, Chimia. 2017, 71, 703-711.
[22] M. G. Lloyd, M. D′Acunto, R. J. K. Taylor, W. P. Unsworth,
Tetrahedron 2015, 71, 7107-7123.
a) E. Lee, C. H. Yoon, Y-S.Sung, Y. K. Kim, M. Yun, S. Kim, J. Am.
Chem. Soc. 1997, 119, 8391-8932; b) M. G. Edwards, M. N.
Kenworthy, R. R. A. Kitson, M. S. Scott, R. J. K. Taylor, Angew. Chem.
Int. Ed. 2008, 47, 1935-1937; Angew. Chem. 2008, 120, 1961-1963;
c) M. G. Lloyd, M. D'Acunto, R. J. K.Taylor, W. P. Unsworth, Org.
Biomol. Chem. 2016, 14, 1641-1645; d) P. V. Ramachandran, G.
Garner, D. Pratihar, Org. Lett. 2007, 9, 4753-4756; e) X. Companyó,
A. Mazzanti, A. Moyano, A. Janecka, R. Rios, Chem. Commun. 2013,
49, 1184-1186; f) W. Chen, Q. Yang, T. Zhou, Q. Tian, G. Zhang,
Org. Lett. 2015, 17, 5236-5239; g) H. Zhang, Q. Yao, W. Cao, S. Ge,
J. Xu, X. Liu, X. Feng, Chem. Commun. 2018, 54, 12511-12514; h)
S-K. Kang, K-J. Kim, Y-T. Hong, Angew. Chem. Int. Ed. 2002, 41,
1584-1586; Angew. Chem. 2002, 114, 1654-1656; i) G. Yin, G. Liu,
Angew. Chem. Int. Ed. 2008, 47, 5542-5545; Angew. Chem. 2008,
120, 5522-5525; j) S.Takizawa, T. M-N. Nguyen, A. Grossmann, D.
Enders, H. Sasai. Angew. Chem. Int. Ed. 2012, 51, 5423-5426;
Angew. Chem. 2012, 124, 5519-5522; k) T. P.Montgomery, A.
Hassan, B. Y. Park, M. J. Krische, J. Am. Chem. Soc. 2012, 134,
11100-11103.
[23] X-ray CCDC 2016289 (10), 2016266 (22), 2016272 (S67), 2016267
(67), 2016268 (71), 2016269 (76a/b), 2016270 (81) and 2016271
(93) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[24] P. V. Ramachandran, H. N. G. Nair, P. Gagare, Tetrahedron Lett.
2014, 55, 5722-5726.
[25] C. J. Collins, V. Molecular Rearrangements, J. Am. Chem. Soc.1955,
77, 5517-5523.
[26] a) C. Adamo, V. Barone, J. Chem. Phys. 1999, 110, 6158-6170; b)
A. Schäfer, C. Huber, R. Ahlrichs, J. Chem. Phys. 1994, 100, 5829-
5835.
[27] a) L. Goerigk, S. Grimme, J. Chem. Theory Comput. 2011, 7, 291-
309; b) F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7,
3297-3305.
[28] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009,
113, 6378-6396.
[8]
[9]
a) M. T. Reetz, Angew. Chem. Int. Ed. 1972, 11, 129-130; Angew.
Chem. 1972, 84, 161-162; b) M. T. Reetz, Angew. Chem. Int. Ed.
1972, 11, 130-131; Angew. Chem. 1972, 84, 163; c) M. T. Reetz,
Tetrahedron 1973, 29, 2189-2194.
[29] The α-HOMO orbitals after biorthogonalization were taken as the
SOMO orbital, after confirming that biorthogonalized α-HOMO orbital
and β-HOMO orbital has overlap integrals close to unity.
Biorthogonalization and the overlap between two cube data were
calculated using Multiwfn 3.7: T. Lu, F. Chen, J. Comput. Chem. 2012,
33, 580-592.
a) I. Fernꢀndez, F. P. Cossío, M. A. Sierra, Chem. Rev. 2009, 109,
6687-6711; b) C. L. Hugelshofer, T. Magauer, Nat. Prod. Rep. 2017,
34, 228-234.
[30] F. S. El-Feraly, Y.-M. Chan, J. Pharm. Sci. 1978, 67, 347-350.
[31] K. B. Wiberg, Angew. Chem. Int. Ed. 1986, 25, 312-322; Angew.
Chem. 1986, 98, 312-322.
[10] a) J. Mulzer, G. Brüntrup, Angew. Chem. Int. Ed. 1979, 18, 793-794;
Angew. Chem. 1979, 91, 840-841; b) J. Mulzer, A. Pointner, R.
Straßer, K. Hoyer, U. Nagel, Tetrahedron Lett. 1995, 36, 3679-3682;
c) J. Mulzer, K. Hoyer; A. Müller-Fahrnow, Angew. Chem. Int. Ed.
1997, 36, 1476-1478; Angew. Chem. 1997, 109, 1546-1548.
[32] N. Kutsumura, A. Kiriseko, K. Niwa, T. Saito, J. Org. Chem. 2018,
83, 11450-11457.
[33] H. Tanaka; Y. Takaya, J. Toyoda, T. Yasuda, M. Sato, J. Murata, H.
Murata, K. Kaburagi, O. Iida, K. Sugimura, E. Sakai, Phytochem. Lett.
2015, 11, 32−36.
[11] a) T. H. Black, W. J. DuBay III, Tetrahedron Lett. 1987, 28, 4787-
4788; b) T. H. Black, J. D. Fields, Syn. Commun. 1988, 18, 125-130;
c) T. H. Black, J. A. Hall, R. G. Sheu, J. Org. Chem. 1988, 53, 2371-
2374; d) T. H. Black, W. J. DuBay III, P. S. Tully, J. Org. Chem. 1988,
53, 5922-5927; e) T. H. Black, W. J. DuBay III, Tetrahedron 1988, 29,
1747-1750; f) T. H. Black, T. S. McDermott, S. A. Eisenbeis,
Tetrahedron Lett. 1990, 31, 6617-6620; g) T. H. Black, T. S.
McDermott, G. A. Brown, Tetrahedron Lett. 1991, 32, 6501-6502; h)
T. H. Black, J. Huang, Tetrahedron Lett. 1993, 34, 1411-1412; i) T. H.
Black, G. A. Brown, D. C. Smith, S. M. Martinie, Syn. Commun. 1995,
[34] R. Zemribo, M. S. Champ, D. Romo, Synlett 1996, 3, 278-280.
[35] L.-S. Gan, S.-P. Yang, C.-Q. Fan, J.-M. Yue, J. Nat. Prod. 2005, 68,
221-225.
[36] C. Xie, D. Bai, S.-H. Huang, X. Jia, R. Hong, Asian. J. Org. Chem.
2014, 3, 277-280.
9
This article is protected by copyright. All rights reserved.

10.1002/anie.202013169
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
An unprecedented dyotropic
rearrangement of α-methylene-β-
lactones has been realized, which
provides an enabling tool for the
synthesis of various structurally
diverse α-methylene-γ-
butyrolactones. Distinct from
conventional dyotropic
rearrangements, the present
reactions proceed through either an
asynchronous concerted or a
stepwise mechanism.
Xiaoqiang Lei, Yuanhe Li, Yang Lai,
Shengkun Hu, Chen Qi, Gelin Wang,*
and Yefeng Tang*
Page No. – Page No.
Strain-Driven Dyotropic
Rearrangement: A Unified Ring-
Expansion Approach to α-
Methylene-γ-butyrolactones
10
This article is protected by copyright. All rights reserved.