Anion relay via intramolecular proton transfer to generate 3,3-Bis(silyl) allyloxy lithium: A useful scaffold for syn -addition to aldehydes and ketones

Article abstract of DOI:10.1021/ol4036402

A [1,5]-anion relay has been achieved in 3,3-bis(silyl) benzyl enol ether. Deprotonation at the sterically more accessible benzyl position triggers an intramolecular proton transfer to generate the thermodynamically more stable 3,3-bis(silyl) allyloxy lithium. This endo-oriented allyl anion is stable at -78 C and undergoes diastereoselective syn-addition at the γ-position with aldehydes and ketones to give monobenzyl-substituted 1,2-diols.

Full text of DOI:10.1021/ol4036402

Letter
pubs.acs.org/OrgLett
[1,5]-Anion Relay via Intramolecular Proton Transfer To Generate 3,3-
Bis(silyl) Allyloxy Lithium: A Useful Scaffold for Syn-Addition to
Aldehydes and Ketones
Xinglong Lin,† Xincui Ye,† Xianwei Sun,† Yuebao Zhang,† Lu Gao,† and Zhenlei Song*,†,‡
†Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy,
‡State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
S
* Supporting Information
ABSTRACT: A [1,5]-anion relay has been achieved in 3,3-
bis(silyl) benzyl enol ether. Deprotonation at the sterically
more accessible benzyl position triggers an intramolecular
proton transfer to generate the thermodynamically more stable
3,3-bis(silyl) allyloxy lithium. This endo-oriented allyl anion is stable at −78 °C and undergoes diastereoselective syn-addition at
the γ-position with aldehydes and ketones to give monobenzyl-substituted 1,2-diols.
eprotonation is one of the most general methods for
benzyl rather than an allyl group (Scheme 1, bottom). The
1
Dcreating carbanions. Nevertheless, deprotonation can be deprotonation at the sterically more accessible benzyl position
triggers intramolecular proton transfer to generate the
thermodynamically more stable 3,3-bis(silyl) allyl anion 2.
This endo-oriented allyl anion is stable at −78 °C and
undergoes diastereoselective syn-addition at the γ-position
with aldehydes and ketones to give monobenzyl-substituted
1,2-diol 3.
challenging when the proton to be removed lies inside a
sterically hindered microenvironment. Solutions to this
problem usually involve either an intermolecular approach
using extremely strong bases, such as the t-BuLi/TMEDA
complex2 or Schlosser’s base,3 or a semi-intramolecular
approach of directed metalation4 at a tethered alkoxy or
amide group (Scheme 1, top).
The reaction was first examined in THF and 3.0 equiv of
HMPA at −78 °C using n-BuLi as the base. While addition with
p-methoxybenzaldehyde gave the desired monobenzyl-substi-
tuted 1,2-diol 3a with a syn/anti ratio of 90:10, the yield was
only 26% (Table 1, entry 1). To our delight, switching n-BuLi
to more basic t-BuLi gave a much higher yield of 87% with a dr
of ≥95:5 (entry 2). Increasing the loading of HMPA to 10.0
equiv, or using DMI or DMPU as an additive, decreased both
yield and diastereoselectivity (entries 3−5). No reaction
occurred in the presence of TMEDA, even though it has
been widely used to form a strong complex with a lithium
cation and thereby enhance the basicity of the carbanion (entry
6).9 This additive is ineffective most likely because it fails to
promote the formation of a solvent-separated ion pair,10 which
is crucial for the initially formed benzyl anion to undergo
intramolecular proton transfer and generate allyl anion 2. Et2O
appeared be less effective as solvent than THF, dramatically
lowering the yield (entry 7). Increasing the temperature from
−78 °C, where 2 is stable, to −55 °C led to rapid [1,2]-Wittig
rearrangement11 to give alcohol 4 in 87% yield (entry 8).
To gain further mechanistic insights into this process, we
performed deuterium labeling experiments (Scheme 2).
Quenching allyl anion 2 with D2O allowed complete deuterium
substitution at the γ-position, affording Z-enol ether 1-D in
82% yield. Two conclusions can be drawn from this result.
First, the α-position, despite being more sterically hindered
Scheme 1. Deprotonation under Sterically Hindered
Circumstances (top); [1,5]-Anion Relay via Intramolecular
Proton Transfer (bottom)
We recently launched a series of investigations on structurally
novel geminal bis(silanes).5 In our initial attempts to generate
the corresponding geminal bis(silyl) carbanion, we failed to
achieve deprotonation by either intermolecular or semi-
intramolecular approaches. Therefore we designed and carried
out a [1,5]-anion relay6 in 3,3-bis(silyl) allyl enol ethers
involving intramolecular proton transfer.7 However, the
resulting allyl anion was unstable due to subsequent rapid
[2,3]-Wittig rearrangement.8 As a way around this problem, we
describe here a [1,5]-anion relay in enol ether 1 tethered with a
Received: December 17, 2013
Published: February 5, 2014
© 2014 American Chemical Society
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Letter
Table 1. Screening of Reaction Conditions
Table 2. Scope of Aldehydes
b
c
entry
base
solv
addit. (equiv)
t, °C
yield
dr
1
2
n-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
THF
THF
THF
THF
THF
THF
Et2O
THF
HMPA (3.0)
HMPA (3.0)
HMPA (10.0)
DMI (3.0)
−78
−78
−78
−78
−78
−78
−78
−55
26%
87%
52%
62%
65%
−
90:10
≥95:5
93:7
80:20
83:17
−
a
3
4
5
6
7
8
DMPU (3.0)
TMEDA (3.0)
HMPA (3.0)
HMPA (3.0)
23%
87:13
d
87%
−
a
Reaction conditions: 0.15 mmol of 1, 0.45 mmol of HMPA, and 0.45
mmol of t-BuLi (1.3 M in pentane) in 1.2 mL of THF, −78 °C, 1.5 h;
b
then 0.3 mmol of p-methoxybenzaldehyde, 10 min. Isolated yields
c
after purification by silica gel column chromatography. Ratios were
1
determined by H NMR spectroscopy. The syn-stereochemistry was
assigned based on NOE experiments with the acetonide of 12 in
d
Scheme 5. Isolated yield of 4.
Scheme 2. Deuterium Labeling Experiments
than the γ-position, has higher electron density. This may
reflect not only the effects of an anion-destabilizing OBn group
at the γ-position but also the dual stabilizing effect of two silyl
groups at the α-position, referred to as the α-effect of silicon.12
Second, allyl anion 2 adopts an endo-orientation, probably
promoted by coordination of an internal lithium ion by the
OBn group.13 Reaction of 1-D with p-methoxybenzaldehyde
under optimal conditions provided 3a-D in 85% yield with ca.
80% D-labeled at the benzylic position.14 This result proves
that formation of 2 proceeds predominantly by [1,5]-anion
relay through an intramolecular proton transfer, despite partial
intermolecular deprotonation occurring probably due to the
presence of excessive t-BuLi.
Next the scope of the approach was tested using various
aldehydes. Electron-rich phenyl or heterocyclic aldehydes
(Table 2, entries 1 and 4) reacted with higher diastereose-
lectivity than did phenyl or electron-deficient phenyl aldehydes
(entries 2 and 3). The steric effects on the syn/anti ratio were
also observed with alkyl aldehydes. While linear and β-
disubstituted aldehydes gave a moderate diastereoselectivity
of 67:33 (entries 5 and 6), α-di- and trisubstituted aldehydes
gave a dr of ≥95:5 (entries 7−10). Formation of 3j (entry 10)
showed selective addition of a substituent to the aldehyde
group but not to the ester group, suggesting that the γ-position
in 2 features a soft nucleophilicity. Reaction of 2 with α-
stereogenic aldehyde 5 gave a good dr of 84:8:8 with the syn/
syn isomer 3k as a predominant product (Scheme 3). The
stereochemistry was confirmed by X-ray analysis of 6,15 which
was formed by removing two silyl and benzyl groups from 3k,
followed by diesterification with 3,5-dinitrobenzoyl chloride.
This reaction also proved suitable for acyclic and cyclic
ketones (Table 3). No obvious deprotonation of acetone was
observed, which would have formed the corresponding lithium
a
Isolated yields after purification by silica gel column chromatography.
Ratios were determined using H NMR spectroscopy.
b
1
enolate. These results are consistent with the soft nucleophil-
icity and weak basicity of 2. Reaction with acetophenone gave a
syn/anti ratio of 63:37, lower than the dr of 91:9 obtained in the
reaction with benzylaldehyde.
To interpret the syn selectivity that we observed during the
addition, two “open” transition states 7a and 7b were proposed
in Scheme 4. We suggest that 7a is favored over 7b, which
suffers a gauche interaction between the bulky geminal
bis(triethylsilyl) group in endo-2 and the R group on the
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We then demonstrated the power of this approach by
achieving a sequential anion relay process, in which a negative
charge is transferred in different directions (Scheme 5). The
Scheme 3. Synthesis of 3k and X-ray Structure of 6
Scheme 5. Sequential Anion Relay To Synthesize 11 and 13
Table 3. Scope of Ketones
reaction of 2 with aldehyde 9 initially generated lithium
alkoxide 10 with a dr of 75:25. Then 10 underwent CuI-
promoted [1,4]-C to O-silyl migration in situ17 to create a new
phenyl anion within the electrophile structure. Subsequent
alkylation with methyl iodide or allylbromide afforded,
respectively, 11a and 11b in 56% and 50% yield. In contrast,
1,2-diol 12 underwent n-BuLi/CuCN-promoted [1,4]-silyl
migration to generate a new vinyl anion within the nucleophile
structure. Alkylation with allylchloride led to the formation of
13 in 60% yield.
In summary, we have described a [1,5]-anion relay in 3,3-
bis(silyl) benzyl enol ether. Deprotonation at the sterically
more accessible benzyl position triggers an intramolecular
proton transfer to generate the thermodynamically more stable
3,3-bis(silyl) allyloxy lithium. As a demonstration of the
approach, we used a sequential anion relay process to perform
a multicomponent reaction. Further applications of this method
are under development.
a
Isolated yields after purification by silica gel column chromatography.
The ratio was determined using H NMR spectroscopy.
b
1
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 4. Model-Based Analysis of Stereochemical
Outcome
Experimental procedures and spectra data for products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhenleisong@scu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC
(21172150, 21321061, 21290180), the NBRPC (973 Program,
2010CB833200), the NCET (12SCU-NCET-12-03), and
Sichuan University 985 project.
aldehyde. This preference for 7a would explain not only the
observed syn-selectivity but also our finding that bulkier R
groups give a higher dr (Table 2, entries 5−10). Combining the
preference for 7a with the classical Felkin−Ahn model 816
would explain the syn/syn selectivity observed during formation
of 3k.
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