A new strategy for efficient synthesis of medium and large ring lactones without high dilution or slow addition

Article abstract of DOI:10.1021/ja400883q

We have developed an efficient method for medium and large ring lactone synthesis by a conceptually different ring-expansion strategy. The design of an unprecedented ring conjunction mode of oxetene, combined with the appropriate choice of a Lewis acid promoter and an additive, constitutes the key components of the new process. Enabled by this new approach, the reaction does not require high dilution or slow addition.

Full text of DOI:10.1021/ja400883q

Communication
pubs.acs.org/JACS
A New Strategy for Efficient Synthesis of Medium and Large Ring
Lactones without High Dilution or Slow Addition
Wanxiang Zhao,†,‡ Zigang Li,*,‡ and Jianwei Sun*,†
†Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
China
‡Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen 518055, China
S
* Supporting Information
Cyclobutenes and heterocyclobutenes are versatile species in
ABSTRACT: We have developed an efficient method for
medium and large ring lactone synthesis by a conceptually
different ring-expansion strategy. The design of an
unprecedented ring conjunction mode of oxetene,
combined with the appropriate choice of a Lewis acid
promoter and an additive, constitutes the key components
of the new process. Enabled by this new approach, the
reaction does not require high dilution or slow addition.
organic synthesis. Their aptitude to undergo electrocyclic ring-
opening to form (hetero)butadienes has led to the development
of numerous useful processes (eq 1).7 Among them, oxetenes
edium and large ring lactones are widespread subunits in
Mbiologically active natural products and therapeutic
agents.1 The development of efficient strategies for their
assembly has been a longstanding topic in organic synthesis.
Although significant progress has been achieved in the past few
decades, there remains a great need for new strategies. In
particular, the efficient synthesis of medium ring lactones
remains challenging due to unfavorable entropic and/or
enthalpic factors in the ring-closing approaches, such as
lactonization and ring-closing metathesis.1−5 Current strategies
to tune these largely inherent unfavorable kinetic and
thermodynamic parameters are limited. For example, high
dilution and/or slow addition have been constantly employed
to minimize the competitive undesired dimerization process, but
the effects are somewhat limited and unpredictable in terms of
substrate generality and yield enhancement, let alone the
consequent limitations in large-scale synthesis. Moreover, the
majority of these processes are intramolecular, because an
intermolecular approach would invoke additional complications
to this already challenging task.
Recently, we have reported an 8-membered lactone synthesis
enabled by the design of a class of new (1,6)-amphoteric
molecules.6 However, the process suffers from moderate
efficiency and a limited scope. The use of an alkyl linker in
place of the aryl linker between the oxetane and aldehyde
moieties in the amphoteric molecules results in no desired
lactone formation. The requirement of an aryl linker can be
explained by the relief of the decreased product transannular
interaction and the unfavorable entropy change as a result of the
restricted substrate flexibility. In continuation of our efforts, here
we describe a new intermolecular process for medium and large
ring lactone synthesis with significantly improved efficiency and
expanded scope by a conceptually different ring expansion
strategy that obviates high dilution or slow addition.
have received significant attention presumably because of their
easy conversion to synthetically versatile α,β-unsaturated
carbonyl compounds (e.g., alkyne-carbonyl metathesis).8−11
Fusion of an oxetene unit with another ring provides access to
various cyclic unsaturated carbonyl compounds. However, to the
best of our knowledge, currently known oxetene-containing ring
fusion topologies are limited to three types, i.e., fusion at the
neighboring or diagonal carbon atoms, none of which lead to ring
expansion (eqs 2−4).9−11 We envisioned that the fusion of a ring
unit only at the C(sp3) and oxygen atoms could result in
simultaneous ring expansion while oxetene ring-opening (eq 5).
However, the design and realization of such ring expansion
reactions are unprecedented.
We anticipated that the high reactivity of the oxetenium
species in eq 5 would overcome the conventional unfavorable
kinetic and/or thermodynamic factors typically impeding
medium and large ring formation by ring-closing approach.
However, the extremely unstable nature of this species also
invokes a significant challenge for its formation. As shown in
Scheme 1, inspired by a disconnection (path a) orthogonal to the
oxetene ring-opening (path b), we hypothesized that the
oxetenium species C can be formed via [2+2] cycloaddition
Received: January 26, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja400883q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
With the established standard conditions, we examined the
reaction scope. A range of siloxy alkynes with different
substituents reacted smoothly with acetal 1a to afford the
corresponding 8-membered lactones with high efficiency and
stereoselectivity (only Z isomer, Table 2). Bulky substituents on
Scheme 1. Design of the Ring-Expansion Strategy
Table 2. Alkyne Scope
from a cyclic oxocarbenium (e.g., A) and an alkyne (e.g., B). We
reasoned that the use of electron-rich siloxy alkynes12 can
facilitate the formation of the highly reactive intermediate C.
Subsequent ring-opening and desilylation are expected to form
D, thereby representing a new lactone formation process.
Initially, we targeted the most challenging 8-membered
lactone formation, so we chose acetal 1a as the 6-membered
ring oxocarbenium precursor (Table 1). In the presence of a
Table 1. Condition Optimization
a
Isolated yield, Z/E > 20:1.
the alkynes did not affect the reaction efficiency (entries 4 and 5).
Arene- or alkene-conjugated alkynes were also suitable reaction
partners (entries 6 and 7). While it is highly desirable to form
lactone 3 without the α-substituent (R = H), the corresponding
terminal siloxy alkyne was not successfully prepared in pure form.
The reaction also exhibits an excellent acetal scope (Table 3).
Under our standard conditions, a range of 8-membered lactones
could be obtained efficiently from the corresponding acetals with
various substituents at different positions of the ring skeleton
(entries 1−10). Fusion with an arene did not result in lower
efficiency (entries 8 and 9). It is noteworthy that ketal 1n, which
bears a hindered reactive center, could smoothly afford the
tetrasubstituted alkene 3r as a single Z isomer (entry 10). The
mild conditions are compatible with a diverse set of functional
groups, such as silyl-protected alcohols, esters, azides, alkenes,
and alkynes. In addition, our protocol can also be applied to the
synthesis of lactones with other ring sizes (entries 11−17). For
example, starting from the 5-, 7-, 8-, and 16-memberd ring
acetals, the expected 7-, 9-, 10-, and 18-membered lactones were
all formed in good to excellent yields. The existing stereocenters
in acetal 1r were not affected (entry 14). While the 7- to 9-
membered unsaturated lactones were uniformly obtained as a
single Z-alkene, the 10-membered lactone 3x was obtained as a
1:1 mixture of Z/E isomers. However, only E isomer was
observed for the large ring lactone 3y. We believe that the
configuration is determined by torquoselectivity during the
oxetenium ring-opening, which can be affected by product ring
size.13 Unfortunately, highly oxygenated sugar-derived acetal 1w
is not reactive under our standard conditions (entry 18).
a
b
c
NMR yield with CH2Br2 as an internal standard. Isolated yield. The
d
e
mass balance is a complex mixture. The alkyne was recovered. 2,4,6-
Collidine (4a), pyridine (4b), 2,6-di-tert-butylpyridine (4c).
range of typical Lewis acids (entries 1−6), such as Sc(OTf)3,
TiCl4, AgNTf2, and Au(PPh3)NTf2, the reaction of 1a and siloxy
alkyne 2a in DCM (0.1 M) gave a mixture of unidentifiable
products with essentially no desired lactone formation. Further
survey revealed that Et2AlCl and BF3−OEt2 could promote the
desired process, albeit in low yields (16% and 42%). We next
evaluated the effect of the acetal leaving group (entries 9−11).
Bulky alkoxyl groups, such as OiPr and OtBu, significantly
reduced the reaction efficiency, but the acetate group could
slightly improve the yield (64%, entry 11). After considerable
efforts, we found that the addition of a substoichiometric amount
of 2,4,6-collidine (4a) improved the yield (entry 12). However,
the use of equimolar 4a completely shut down the reaction
(entry 13). Further tuning indicate that the use of 2 equiv of
BF3−OEt3 and 1 equiv of 2,4,6-collidine led to the highest
efficiency (91% yield, entry 14). Acetal 1d was equally efficient
(entry 15). Other additives, such as pyridine (4b) and 2,6-di-tert-
butylpyridine (4c), gave inferior results, indicating that the steric
bulk of the additive is crucial (vide infra). Notably, the Brønsted
acid HNTf2 could not promote the present ring expansion
reaction (entry 18).6
To further demonstrate the utility of our lactone formation
reaction, we carried out iterative ring expansions (Scheme 2).
Under the standard conditions, acetal 1v was successfully
expanded to form 7-membered lactone 3s in 93% yield. After
hydrogenation and reductive acylation, lactone 3s was easily
converted to acetal 5, which was subjected to a second ring
expansion with alkyne 2h to form 9-membered lactone 6. Thus,
our protocol is in principle capable of assembling medium and
large lactones of all sizes starting from a small ring acetal.
To probe the mechanism of the efficient ring expansion
process, we carried out several control experiments. We reasoned
B
dx.doi.org/10.1021/ja400883q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Synthesis of Medium and Large Ring Lactones
good yield under our standard conditions. In contrast, from
cyclic orthoester 11, we anticipated the formation of a lactone
product if the OMe could serve as the leaving group and thus the
ring-fused oxetenium G could be formed (eq 8). As expected, the
desired lactone 12 was obtained in 82% yield. Finally, subjecting
linear unsaturated ester 13 to our standard conditions did not
lead to the formation of lactone 3a (eq 9), which ruled out the
possible mechanism involving an initial acetal olefination
followed by lactonization.
On the basis of the above observations, we have proposed a
plausible mechanism (Scheme 3). The reaction begins with the
Scheme 3. Proposed Mechanism
BF3-promoted formation of oxocarbenium H from acetal 1. The
resulting trifluoro(methoxy)borate next activates the siloxy
alkyne to form ynolate J. The formation of TIPSF can be
observed. Subsequent [2+2] cycloaddition between the two
highly active species (H and J) forms oxetenium intermediate L,
presumably by a stepwise mechanism via ketene K. Finally,
electrocyclic ring-opening of L delivers the observed ring-
expansion product 3. While the exact role played by 2,4,6-
collidine is still not clear, we propose that it can reversibly form
the pyridinium I with the highly unstable oxocarbenium H. Thus,
adduct I can be considered a reservoir of H to prevent its
decomposition before reacting with ynolate J. We were able to
a
b
c
Isolated yield, Z/E > 20:1. Run at room temperature. Z/E = 1:1.
d
e
E/Z > 20:1. No desired lactone formation; 1w was recovered.
Scheme 2. Iterative Ring Expansions
1
observe a peak at δ ∼6.0 ppm by in situ HNMR, which is
characteristic for this type of pyridinium species.14 On the basis
of the report by Fujioka and Kita, pyridine can also form a similar
adduct, but this adduct is much less reactive than that from 2,4,6-
collidine.14 This result is consistent with our observation that the
use of pyridine as additive resulted in no desired lactone
formation (Table 1, entry 16). We believe that the superiority of
2,4,6-collidine is attributed to the excellent stabilization of the
that cyclic acetal 7 and acyclic mixed acetal 9 would give linear
ester products if the reactions proceed via the hypothesized
oxetenium intermediates E and F, respectively (eqs 6 and 7).
Indeed, the expected acyclic esters 8 and 10 were obtained in
C
dx.doi.org/10.1021/ja400883q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
131, 12109. Morales-Serna, J. A.; San
́
chez, E.; Velaz
́
quez, R.; Bernal, J.;
oxocarbenium intermediate while still maintaining sufficient
reactivity for the subsequent lactone formation process.
In summary, by a conceptually different strategy, we have
developed a highly efficient and general method for medium and
large ring lactone synthesis. The design of an unprecedented ring
conjunction mode of oxetene, combined with the appropriate
choice of a Lewis acid promoter and an additive, constitutes the
key components of the new process. Owing to this unusual ring
expansion strategy, our lactone formation reaction, overcoming
the unfavorable entropic and/or enthalpic factors typically
encountered by ring-closing approaches, does not require high
dilution or slow addition for high efficiency. The method also
represents one of the few intermolecular reactions for medium
and large lactone synthesis, thereby contributing to convergent
synthesis. Moreover, the mild reaction conditions are compatible
with a wide range of functional groups. An example of iterative
ring expansions was also provided to demonstrate the great utility
of our process. This efficient process, employing readily available
substrates and reagents, is anticipated to find applications in
organic synthesis.
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
sunjw@ust.hk; lizg@szpku.edu.cn
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by HKUST (DAG11SC01 to
J.S.), the National Natural Science Foundation of China
(21102024 to J.S. and 21102007 to Z.L.), and Shenzhen Science
and Technology Innovation Committee (SW201110060 and
SW201110018 to Z.L.).
(i) Escalante, L.; Gonzal
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