Propargylic cation-induced intermolecular electrophilic addition-semipinacol rearrangement

Article abstract of DOI:10.1039/c3cc49650c

A novel propargylic electrophile-induced tandem intermolecular addition-semipinacol rearrangement was developed efficiently under mild conditions. Various allylic silylether substrates as well as Co-complexed propargylic species were applicable to this pr

Full text of DOI:10.1039/c3cc49650c

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Yong-Qiang Tu et al.
Propargylic cation-induced intermolecular electrophilic
addition–semipinacol rearrangement

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Propargylic cation-induced intermolecular
electrophilic addition–semipinacol
rearrangement†
Cite this: Chem. Commun., 2014,
50, 5691
Received 20th December 2013,
Accepted 15th January 2014
Hui Shao, Xiao-Ming Zhang, Shao-Hua Wang, Fu-Min Zhang,
Yong-Qiang Tu* and Chao Yang
DOI: 10.1039/c3cc49650c
www.rsc.org/chemcomm
A novel propargylic electrophile-induced tandem intermolecular extended this method to accomplish the synthesis of lepadi-
addition–semipinacol rearrangement was developed efficiently formines.3c Recently, our group has also reported that an
under mild conditions. Various allylic silylether substrates as activated aldehyde carbonyl group of ethyl glyoxalate ester could
well as Co-complexed propargylic species were applicable to this trigger a reaction with dihydropyran-type allylic silylethers under
protocol and gave a series of synthetically useful b-propargyl catalysis by Cu(II), providing various tricyclic systems in high
spirocyclic ketones in moderate to good yields. Its synthetic applica- efficiency.3e In spite of these pioneering works mentioned above,
tion was also demonstrated by an efficient construction of the key the carbon electrophiles used in these intermolecular reactions are
tricyclic moiety of daphlongamine E.
only confined to oxonium ions derived from acetal or aldehyde
(Scheme 1a). Therefore, exploring multi-functionalizable electro-
As one of the most powerful methods for C–C bond formation and philes and further developing synthetically more versatile inter-
reorganization, the electrophilic addition–semipinacol rearrange- molecular carbon-electrophile-initiated semipinacol rearrangements
ment of allylic alcohol has been extensively utilized in organic are still in high demand for organic synthesis.
synthesis.1 Accordingly, lots of electrophiles have been explored
The challenge for developing this kind of intermolecular
for achieving different synthetic goals via this rearrangement, but reaction lies in not only finding suitable conditions to generate
most of them belong to non-carbon species,1b–d such as protons, a carbenium ion electrophile active enough to take part in an
halogens and some other heteroatom-containing species. In fact,
carbon electrophile-initiated rearrangements could generate more
complex and diverse carbon skeletons of the resulting molecules
if the electrophilic addition step could be realized, and thus
would play a much more important role in the synthesis of
complex architectures. However, it was not until 1969 that an
intramolecular acetal-participating semipinacol rearrangement
(also known as the Prins-pinacol reaction) was explored.2a,b
Later this reaction was further extended and used as a key step
in a number of synthetic approaches.1a,2 In contrast, inter-
molecular carbon electrophile-initiated rearrangements have
been largely underexplored in comparison with intramolecular
versions, despite them being more powerful and versatile than
the latter, in view of the complexity and diversity of carbon frame-
works generated.3 In 2007, Cha’s group reported a hemiacetal-
initiated intermolecular reaction,3a which was well used in the total
synthesis of cyathin A3 and B2.3b Later in 2010, Aube’s group further
´
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China.
E-mail: tuyq@lzu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 973585 (3j),
Scheme 1 Design of the carbon electrophile-initiated semipinacol
973583 (3n) and 973584 (6a). For ESI and crystallographic data in CIF or other
rearrangement.
electronic format see DOI: 10.1039/c3cc49650c
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 5691--5694 | 5691

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self-rearrangement might take place prior to the formation of
the Co-complexed propargylic cation under promotion by Lewis
acids, we altered our experimental sequence.9 Thus, the mixture
of AlCl3 and 2a in DCM was first stirred at 0 1C for 1.5 hours, then
a solution of 1a in DCM was added at ꢁ78 1C. To our delight, this
operation improved the yield to 43% (entry 2). Then, more Lewis
acids were screened to further optimize this reaction. In the
presence of In(OTf)3 or SnBr4, only the undesired ketone 4 was
obtained (entries 3 and 4). Other Lewis acids, such as EtAlCl2,
BF3ꢀEt2O, and TiCl4, were effective, but also could not completely
avoid the formation of 4 (entries 5–7). Fortunately, a good overall
yield of 71% was achieved when SnCl4 was used, and only trace
amounts of 4 were obtained (entry 8). Furthermore, solvent effects
were also observed in this tandem process. When toluene was
used, the reaction yield decreased dramatically to 42% (entry 9).
While the use of some other solvents containing O- or N-atoms
(such as acetone, acetonitrile, THF, or DME) afforded much
poorer results, leading to only 4 or no reaction.
Under the specified optimized conditions (Table 1, entry 8,
for a detailed description see also ref. 9) we then probed the scope
of the substrate in this transformation (Table 2). First, a range of
active dihydropyran-type allylic silylethers 1a–1f was subjected to
the standard reaction conditions. Among them, 1b–1d with aryl
or alkyl substituents on the cyclobutane moiety went smoothly
through the rearrangement initiated by the unsubstituted
Co-complexed propargyl electrophile, giving the corresponding
spirocyclic ketones 3b–3d in moderate to good yields (65–75%).
A larger-sized cyclopentanol silylether 1e was also effective for
this rearrangement, albeit in a slightly lower yield (57%). This
protocol could be further extended to the secondary alcohol
silylether 1f, but the yield of 3f formed was much lower (31%),
which might be due to the partial decomposition of Co-complexed
3f in the acidic environment. Next, various substituted
Fig. 1 Natural products containing various spirocyclic units.
intermolecular addition to the allylic alcohol or its silylether, but it
also requires that the substrate survives self-rearrangement under
these conditions. In this regard and in consideration of the multi-
reactivity and broad synthesis of the propargylic electrophiles
generated from Nicholas Co-complexed propargylic species,4,5 we
envisioned that this in situ generated cation would be a sufficiently
active electrophile6 to promote such an intermolecular reaction
(Scheme 1b). Herein, we wish to present our preliminary research
results on this tandem propargylation–semipinacol reaction, which
has provided a series of a-quaternary b-propargyl spirocyclic
ketones and established a short route to the formation of the
5/6/7-tricyclic core of daphlongamine E.
As spirocyclic units possessing oxa-, aza- and all-carbon-
quaternary centers are present in numerous bioactive natural
products, for example capillosanane, vallesamidine and daphlong-
amine (Fig. 1), the allylic silylether substrates with the corres-
ponding dihydropyran,3e,7a dihydropyrrole7b and cycloalkenone7c,d
motifs, which can be readily prepared from commercially
available materials in short steps, were used to examine our
predicted tandem reaction for constructing these units. Firstly,
the dihydropyran-type allylic silylether 1a and the Ac-protected
Co-complexed propargylic species 2a were used as model
substrates to screen the reaction conditions (Table 1). Initially,
several Lewis acids (BF3ꢀEt2O, In(OTf)3, EtAlCl2 and AlCl3) were
tested in dichloromethane (DCM). Unfortunately, the reactions
always resulted in a single undesired self-rearrangement
product 4 in high yield, except when using AlCl3 (entry 1)8 in
which the desired product 3a could be produced in low total yield
of 32% after subsequent demetalation of the Co-complexed-
product with Fe(NO3)3ꢀ9H2O. Considering that the competing
Table 2 Reaction results of dihydropyran-type allylic silylethers 1a–1l
with Co-complexed propargyl electrophiles
Table 1 Optimization of Co-complexed propargyl electrophile initiated
semipinacol rearrangementa
Lewis
acid
Time
(min)
Yield of
Yield of
Entry
Solvent
3ab (%)
4b (%)
1c
2c
3c
4
5
6
AlCl3
AlCl3
In(OTf)3
SnBr4
EtAlCl2
BF3ꢀEt2O
TiCl4
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
90
90
90
45
10
10
10
10
90
32
43
None
None
23
37
58
71
42
23
40
70
42
66
37
25
Trace
Trace
7
8
SnCl4
SnCl4
9c
a
Unless otherwise specified the reaction operated in a general process.9
Isolated yield. Reaction performed at ꢁ78 1C to RT.
b
c
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Scheme 2 Reaction results of the cyclohexenone-type allylic silylethers
5a and 5b with Co-complexed propargyl electrophiles.
Fig. 2 X-ray crystal structures of 3j, 3n and 6a.13
this reaction.12 Consequently, separable spirocyclic diones 6a
and 6a0 were obtained in 65% overall yield with the diastereo-
selectivity 2.2 : 1. The configuration of the major diastereomer
6a was also unambiguously confirmed by single crystal X-ray
analysis (Fig. 2). To our delight, 5b could provide 6b as a single
diastereomer under the same conditions, indicating that a bulky
C4-substituent at the cyclohexenone ring could control well the
diastereoselectivity of this reaction (Scheme 2).
After realizing the tandem Nicholas–semipinacol reaction on
various types of allylic silylethers, we then focused our attention
on its synthetic applications. In connection with our research
interest in the total synthesis of daphlongamine E,7d,14,15 we
proposed that the propargyl group introduced in compound 6a
could be used to construct concisely the key and challenging all-
carbon 5/6/7-tricyclic motif 9 of this type of alkaloid. As shown in
Scheme 3, controlled hydrogenation of the triple bond of 6a with
Lindlar Pd afforded olefin 7 in 80% yield. Then, selective protec-
tion of the carbonyl group of the cyclohexenone moiety with
ethylene glycol16 generated compound 8. Introduction of another
allyl group to 8 with allylzinc bromide,17 followed by a direct ring-
close metathesis18 with Grubbs II catalyst 10, readily provided the
5/6/7-tricyclic structure 9 (65% yield in two steps).
Co-complexed proparyl electrophiles were examined under the same
conditions.9 Fortunately, different substitutions at C1 and C3 of the
Co-complexed propargyl electrophiles were well tolerated without
significantly affecting the reaction efficiency, affording the corre-
sponding products 3g–3l in moderate to good yields in most cases.
Additionally, the use of the 3,3-dimethyl-substituted Co-complexed
propargyl electrophile only resulted in the self-rearrangement
product, probably because the in situ formed cation underwent
proton-elimination before electrophilic addition.10 The trans-
relative configurations between propargyl and the migrating
carbon in the products 3a–3l were deduced by X-ray diffraction
of 3j as a representative (Fig. 2), which was consistent with the
stereoselectivity of a typical electrophilic addition–semipinacol
rearrangement.11
Subsequently, the dihydropyrrole-type allylic silylether 1g was exam-
ined and demonstrated to be well effective to several Co-complexed
propargylic electrophiles under standard conditions,9 producing 3m,
3n, and 3o in good yields (Table 3). The relative configuration of 3m–o
was deduced by X-ray diffraction of 3n (Fig. 2).
Having obtained the results above, we then attempted to further
extend the substrate scope to cyclohexenone-type allylic silylethers
5a and 5b. Frustratingly, when substrate 5a was subjected to the
above reaction conditions,9 only trace amounts of desired product
were observed. Considering that SnCl4 might be ineffective
for these types of substrates, we re-screened the Lewis acids
and found that EtAlCl2 was the best choice for promoting
In summary, we have successfully developed a Nicholas
propargyl electrophile-induced tandem intermolecular semipinacol
rearrangement, which is applicable to a wide range of allylic silylether
substrates as well as Nicholas species, yielding a series of b-propargyl
spirocyclic ketones in moderate to good yields. Its additional features
include: good efficiency, high diastereoselectivity, mild reaction con-
ditions, and easy handling. We believe this methodology must find
good utility in the synthesis of polycyclic natural products such as
daphlongamine E.
Table 3 Reaction results of dihydropyrrole-type allylic silylether 1g with
Co-complexed propargyl electrophiles
Scheme 3 Synthesis of the key 5/6/7-tricyclic unit of daphlongamine E.
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5694 | Chem. Commun., 2014, 50, 5691--5694
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