Alternative Sm(II) Species-Mediated Cascade Coupling/Cyclization for the Synthesis of Oxobicyclo[3.1.0]hexane-1-ols

Article abstract of DOI:10.1021/acs.orglett.7b03613

The allylSmBr/HMPA/MsOH system has been found to be an efficient reagent for the "ester-alkene" coupling/cyclization cascade of readily available α-allyloxy esters. Oxobicyclo[3.1.0]hexane-1-ols were thus prepared in good to excellent yields and diastereo

Full text of DOI:10.1021/acs.orglett.7b03613

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Alternative Sm(II) Species-Mediated Cascade Coupling/Cyclization
for the Synthesis of Oxobicyclo[3.1.0]hexane-1-ols
Bingxin You,† Mengmeng Shen,† Guanqun Xie,†,‡ Hui Mao,† Xin Lv,† and Xiaoxia Wang*,†,‡
†Department of Chemistry, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, People’s Republic of
China
‡School of Environment and Civil Engineering, Dongguan University of Technology, Dongguan, 523808, People’s Republic of China
S
* Supporting Information
ABSTRACT: The allylSmBr/HMPA/MsOH system has been found to be an
efficient reagent for the “ester-alkene” coupling/cyclization cascade of readily
available α-allyloxy esters. Oxobicyclo[3.1.0]hexane-1-ols were thus prepared in
good to excellent yields and diastereoselectivities. Investigation on the
mechanism suggested the possible existence of a new Sm(II) species, namely,
CH3SO3SmBr, which resulted from the reaction between allylSmBr and MsOH
and may be the actual SET reagent.
Scheme 1. AllylSmBr/Additives-Promoted “Ester-alkene”
ivalent samarium regents, especially samarium diiodide
Coupling/Cyclization Reactions
D
(SmI2) have been widely employed in C−C bond-
forming reactions important in the synthesis of natural
products.1 The mechanism of these reactions continues to be
an important area of study, given the value of transformations
mediated by Sm(II)-based reagents.2 Among the reactions
promoted by SmI2, the coupling of a ketone or an aldehyde
with an alkene (the “carbonyl-alkene” coupling) has been well-
documented. In contrast, acid derivatives as the coupling
partner with alkenes mediated by divalent samarium reagent are
less known. Limited examples employed activated carboxylic
acid derivatives, such as acid chlorides,3 and the acyl-type
radical intermediate was involved. Unactivated esters and
amides were inert to SmI2 alone, and their reduction by the
reagent was reported to require the presence of either strong
acid or base additive, or amine/H2O.4 The “ester-alkene”
coupling mediated by SmI2 proved very challenging, since the
first step is highly endergonic.5 In recent years, the Procter
group6a−f and Szostak6g,h et al. have established that H2O or the
combination of H2O with other co-additives could greatly
enhance the reactivity of SmI2 and also achieve the intra-
molecular coupling of a lactone or an imide with unactivated
CC bond (even an aromatic ring) to construct fused-ring or
spirocyclic scaffolds. Coupling between unactivated esters and
CC bond was alternatively achieved by allylSmBr in the
presence of HMPA and other co-additives, such as HMPA/
H2O and HMPA/CuCl2·2H2O (Scheme 1, eqs 1 and 2).7
AllylSmBr has been used as a nucleophilic reagent8 and, only
in recent years, the reagent’s inclination to revert to the more
stable samarium(III) oxidation has drawn attention. The group
of Zhang reported the dual role of allylSmBr in the preparation
of 1,4-dienes and trienes starting from α-halo ketones and γ-
halo-α,β-unsaturated ketones.9a We unexpectedly found that
allylSmBr could promote reductive debenzotriazoylation.9b
Later on, the reactivity of the reagent to serve as the SET
reagent was found to be tunable by additives, such as HMPA,10a
H2O,10b MeOH,10b and (EtO)2P(O)H.10c The combination of
various additives may make allylSmBr a versatile SET reagent.
To further explore the use of allylSmBr in the preparation of
structurally diverse compounds, we envisioned that the readily
available α-allyloxy esters 1 may be useful substrates for the
preparation of oxobicyclo[3.1.0]hexane-1-ols 2, based on the
allylSmBr/additive mediated “ester-alkene” coupling cascade
(Scheme 1, eq 3).
It is noteworthy that, although 1 seemed to be reasonable
substrates for the preparation of 2 by Kulinkovich cyclo-
propanation strategy,11 the allylic ethers were unfortunately
found to be inapplicable to such a tranformation,12 because of
the efficient deprotection of allyl ethers into the corresponding
alcohols under the Kulinkovich cyclopropanation conditions.13
Received: November 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03613
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Letter
Therefore, the successful intramolecular “ester-alkene” coupling
in 1 would demonstrate the unique advantage of the allylSmBr-
based reagent.
As shown in Table 1, the reaction conditions were
investigated using substrate 1a as the model substrate. Initially,
the employment of SmI2/HMPA/MsOH was not effective.
When the reaction proceeded for 1 min, the starting materials
remained almost intact and only a trace amount of the desired
product could be detected. With the extension of time, the
starting material was consumed gradually. However, only a very
complicated mixture was obtained, which defied further analysis
(Table 1, entry 17).
Thus, the aged allylSmBr/HMPA/MsOH system was found
to be a suitable reagent for the cascade cyclization/coupling
reaction of 1a. With the optimized conditions in hand, the
scope of the reaction was explored. The results are summarized
in Scheme 2.
Table 1. Optimization of the Coupling/Cyclization
a
Conditions
A variety of methyl or ethyl esters 1, with R or R1 being aryl,
allyl, or alkyl, all underwent the cascade ester-alkene radical
cyclization, smoothly affording the desired oxobicyclo[3.1.0]-
hexane-1-ols 2 in moderate to excellent yields and diaster-
eoselectivities. When the benzyl ester of mandelic acid 1a′ was
used as the substrate, a complicated mixture was resulted.
Reductive removal of the α-allyloxy did not occur to a
significant extent, except for the tert-butyl ester 1a″, which
afforded tert-butyl 2-phenylacetate in 50% yield. Slight
debromination during the formation of 2g was detected,
which was contaminated by 2a in 7% yield. It is noticeable that
products 2q−2t were sensitive to common silica chromatog-
raphy, and Et3N must be used to pretreat the silica column.
As for the stereoselectivity, more than 80% selectivity was
observed in most cases. To have deeper insight in the
diastereoselectivity, the single crystal of 2j14 (Figure 1) was
developed, and the X-ray diffraction analysis showed the
hydroxyl and the naphthyl assumed a cis-configuration as the
major diastereomer.
The mechanism of the reaction was further investigated. At
the beginning of the conditions optimization stage, MsOH was
attempted as a proton source. However, the role of MsOH may
be reconsidered, based on the observations that, when MsOH
was added to the allylSmBr/HMPA reagent, an overnight
stirring of the mixture was required to ensure better yields. It
may imply MsOH was not simply a proton source and a
different reducing species may be generated during the
overnight “aging” process. AllylSmBr/HMPA might react with
CH3SO3H gradually to generate a CH3SO3SmBr/HMPA
complex,15 which could be indispensable for the coupling/
cyclization reaction here. The assumption may be supported by
the control experiments.
(1) 1a was subjected to allylSmBr/HMPA and allylSmBr/
MsOH reagent, respectively. In the former case, the diallylation
product 3a was isolated as the major product, together with 2a
and other unidentified byproducts, while no reaction could be
observed between 1a and allylSmBr/MsOH (Table 1, entries 1
and 17; also see Scheme 3, eqs 1 and 2). The lack of
nucleophilicity in the latter case may imply the exclusion of the
nuleophilic allylSmBr species.
(2) Instead of addition of HMPA first in the standard
conditions, MsOH (2 equiv) was added prior to HMPA to the
allylSmBr in THF. The characteristic purple color of allylSmBr
faded immediately and a gray-blue suspension was obtained (it
was proposed as CH3SO3SmBr). When HMPA was then
added, the purple color regenerated immediately (the probable
generation of CH3SO3SmBr/HMPA complex).
b
entry
additive (equiv)
temp (°C)
reaction time
yield (%)
d
1
2
c
rt
rt
overnight
overnight
overnight
overnight
overnight
10 min
10 min
overnight
2 h
17
H2O (1.6)
40
e
3
CuCl2·2H2O (1.6)
MeOH (1.6)
tBuOH (1.6)
CH3COOH (1.6)
HCOOH (1.6)
CF3COOH (1.6)
TsOH·H2O (1.6)
CF3SO3H (1.6)
MsOH (1.6)
rt
8
4
rt
35
32
51
30
f
5
rt
6
rt
7
rt
8
rt
9
rt
45
45
57
58
39
52
50
70
trace
10
11
12
13
14
15
16
17
rt
10 min
1 min
rt
MsOH (2.0)
rt
1 min
MsOH (1.0)
rt
20 min
20 min
20 min
1 min
MsOH (2.0)
−20
−30
rt
MsOH (2.0)
g
MsOH (2.0)
h
MsOH (2.0)
rt
overnight
a
Reaction conditions: a mixture of Sm powder (4.67 equiv), THF (15
mL), and allylBr (3.0 equiv) was stirred under N2 at rt for 1 h. Then,
HMPA (12 equiv) was added via syringe (unless otherwise specified).
After additional stirring for 10 min, CH3SO3H was added. Stirring was
continued for another 10 min and 1a (1.0 mmol) in THF was added
via syringe (unless otherwise specified). Isolated yield. No other
additive was used besides HMPA. Together with 30% of the
diallylation products and other unidentified mixtures. Complicated
unidentified mixture. No reaction. The mixture of the allylSmBr/
HMPA/MsOH was stirred overnight before the introduction of 1a.
b
c
d
e
f
g
h
SmI2 was used instead of allylSmBr.
HMPA was attempted as the only additive and 17% yield of the
desired product 2a was obtained (Table 1, entry 1). The
addition of H2O as the co-additive afforded 40% yield (Table 1,
entry 2). Using CuCl2·2H2O7b afforded an even poorer yield
(Table 1, entry 3). However, the combination of MeOH or
tBuOH as the proton source was less effective (Table 1, entries
4 and 5). Organic acids were also examined as co-additives.
Satisfyingly, the use of CH3COOH afforded 2a in 51% yield
(Table 1, entry 6). The use of HCOOH, CF3SO3H, or TsOH·
H2O did not bring about any improvement (Table 1, entries 7,
9, and 10). CF3COOH seemed totally destructive, since the
characteristic purple color of Sm(II)-HMPA complex dis-
appeared upon its addition (Table 1, entry 8). MsOH afforded
slightly better yield (57%) than CH3COOH (51%). Increasing
the loading of the acid to 2 equiv led to a slightly higher yield of
2a, while decreasing the acid loading was unfavorable (Table 1,
entries 12 and 13). Attempts to conduct the reaction at lower
temperature did not afford better yields (Table 1, entries 14
and 15). However, when the mixture of allylSmBr/HMPA/
MsOH was stirred overnight before the introduction of 1a, a
70% yield of 2a was obtained (Table 1, entry 16). In contrast,
(3) To the above recipe (namely, allylSmBr/MsOH/HMPA,
where MsOH was added to the allylSmBr and the mixture was
stirred 10 min before HMPA was introduced and the resulting
mixture was stirred for 30 min more) was added 1a. In this
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DOI: 10.1021/acs.orglett.7b03613
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Scheme 2. Scope of the AllylSmBr/HMPA/MsOH Promoted
a b
,
Cascade Synthesis of Oxobicyclo[3.1.0]hexane-1-ols
Figure 1. X-ray crystal structure of 2j.
Scheme 3. Control Experiments of the Reactivity of
AllylSmBr/Additive(s)
Based on the above experiments, a possible mechanism was
proposed in Scheme 4. AllylSmBr I reacted with HMPA and
Scheme 4. Proposed Mechanism for the Formation of 2
a
Reaction conditions: a mixture of Sm powder (4.67 equiv), THF (15
mL) and allylBr (3.0 equiv) was stirred under N2 at rt for 1 h. Then
HMPA (12 equiv) was added via syringe. After additional stirring for
10 min, MsOH (2.0 equiv, 129 μL) was added to the mixture and
stirring at rt was continued overnight. Substrate 1a in 2 mL of THF
b
was introduced and the reaction was completed immediately. Isolated
MsOH slowly to produce a CH3SO3SmBr/HMPA complex
II.16 II may act as a more-powerful SET reagent than SmI2/
HMPA and was able to reduce the ester group to the ketyl III,
which would take a more stable transition state and undergo
the ketyl-alkene coupling to cyclize to IV. IV accepted a second
electron from II and was transformed to the carbanion V. The
subsequent intramolecular nucleophilic addition constructed
the oxobicyclo[3.1.0]hexane-1-ol skeleton VI and finally
afforded product 2 after workup.
In summary, several acids could be used as the additive to
allylSmBr to promote the reductive cyclization of α-allyloxy
esters. The selective electron transfer to the unactivated ester
carbonyl is impressive, and the oxobicyclo[3.1.0]hexane-1-ols
c
yield. Contaminated by 7% yield of 2a, which was generated by
reductive removal of bromo. d2t tended to deteriorate quickly and the
NMR of 2t was inevitably contaminated with minor impurities.
Change of the deuterated solvent from CDCl3 to DMSO-d6 did not
improve the spectra.
case, the desired 2a was produced in comparable yield (Scheme
3, eq 3) to that obtained from the optimized conditions (Table
1, entry 16).
Besides, the generation of propene during the aging process
has been detected by GC (comparison with authentic propene)
and GC-MS (see the Supporting Information).
C
DOI: 10.1021/acs.orglett.7b03613
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Organic Letters
Letter
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were prepared in moderate to good yields with good to
excellent diastereoselectivities. Initial probe on the mechanism
indicated the possible formation of a CH3SO3SmBr/HMPA
complex, which may act as an important Sm(II) species for
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03613.
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■
S
Detailed experimental procedures; spectral data of new
substrates and products (PDF)
Accession Codes
CCDC 1582390 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangxiaoxia@zjnu.edu.cn.
ORCID
Xiaoxia Wang: 0000-0001-5094-0269
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Natural Science Foundation of
Zhejiang Province (Nos. LY14B020001 and LY16B020003),
and National Natural Science Foundation of China (No.
21202152).
(10) (a) Yin, R.; Zhou, L.; Liu, H.; Mao, H.; Lu, X.; Wang, X. Chin. J.
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Chem. 2013, 31, 143. (b) Li, J. Y.; Niu, Q. S.; Li, S. C.; Sun, Y. H.;
Zhou, Q.; Lv, X.; Wang, X. X. Tetrahedron Lett. 2017, 58, 1250. (c) Li,
Y.; Hu, Y. Y.; Zhang, S. L. Chem. Commun. 2013, 49, 10635.
(11) For general reviews, see: (a) Kulinkovich, O. G.; de Meijere, A.
Chem. Rev. 2000, 100, 2789. (b) Sato, F.; Urabe, H.; Okamoto, S.
Chem. Rev. 2000, 100, 2835.
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