Silver-Assisted, Iridium-Catalyzed Allylation of Bis[(pinacolato)boryl]methane Allows the Synthesis of Enantioenriched Homoallylic Organoboronic Esters

Article abstract of DOI:10.1021/acscatal.6b00719

Described here is an enantioselective approach of making chiral, β-substituted homoallylic organoboronic esters. In the presence of LiO^tBu and a catalytic amount of silver salt, commercial bis[(pinacolato)boryl]methane participated in the iridi

Full text of DOI:10.1021/acscatal.6b00719

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Letter
Silver-Assisted, Iridium-Catalyzed Allylation of Bis[(pinacolato)boryl]methane
Allows the Synthesis of En-antioenriched Homoallylic Organoboronic Esters.
Miao Zhan, Ren-Zhe Li, Ze-Dong Mou, Chao-Guo Cao, jie liu, Yuanwei Chen, and Dawen Niu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00719 • Publication Date (Web): 22 Apr 2016
Downloaded from http://pubs.acs.org on April 23, 2016
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Silver-Assisted, Iridium-Catalyzed Allylation of
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Bis[(pinacolato)boryl]methane Allows the Synthesis of Enan-
tioenriched Homoallylic Organoboronic Esters.
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Miao Zhan‡, RenꢀZhe Li‡, ZeꢀDong Mou‡, ChaoꢀGuo Cao‡, Jie Liu*, YuanꢀWei Chen*, Dawen Niu*
Department of Emergency, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
ABSTRACT: Described here is an enantioselective approach of making chiral, βꢀsubstituted homoallylic organoboronic esters. In
the presence of LiOtBu and a catalytic amount of silver salt, commercial bis[(pinacolato)boryl]methane participated in the iridium
catalyzed asymmetric allylation reactions, delivered a 'CH2B(pin)' group, and yielded the title compounds from allylic carbonates.
The synthetic utility of the prepared chiral organoboronates was demonstrated by their conversion into other important classes of
compounds.
KEYWORDS: Boronic Esters, Bis[(pinacolato)boryl]methane, Iridium, Silver, Enantioselective Allylation, Catalysis.
Organoboronic acid derivatives [RB(OR’)2] are a significant
class of compounds in chemistry.1 With chemical stability and
synthetic versatility,2 RB(OR’)2 are deemed as attractive inꢀ
termediates for constructing complex natural products or diꢀ
versified chemical libraries. In addition, some of these comꢀ
pounds possess important biological activities3 and are used as
anticancer agents.4 As a result, general and selective methods
of making RB(OR’)2 are desirable and have been actively purꢀ
sued by the synthetic community. Over the last few decades,
tremendous efforts have been devoted to the development of
catalytic, asymmetric methods for their preparation, with subꢀ
stantial progress achieved. Many of the reported methods are
based on asymmetric hydroboration, 5 diboration, 6 or boroꢀ
functionalization7 of unsaturated organic compounds or nucleꢀ
ophilic substitution of boryl anions.8 These methods produce
chiral organoꢀboronic esters by addition of one or more boryl
[B(OR)2] groups.9,10
addition, the Meek group has established a copperꢀbased
deborylative addition of 1,1ꢀbisborylethane 7 to aldehydes 8,
Lately, a novel approach capitalizing on the facile monoꢀ
,
deborylation11 12 of 1,1ꢀbisborylalkanes has emerged, and proꢀ
vided unique accesses to complex organoboron compounds by
introducing an αꢀboroalkyl group (1 to 3, Scheme 1a). It is
believed that the deborylation process of 1,1ꢀbisborylated alꢀ
kane 1 is facilitated by the stabilizing effect of the threeꢀ
coordinate boron atom adjacent to the resulting anionic center
(cf. 2’).11h, 13 Therefore, this reaction stops at the monoꢀ
deborylation stage, and one boronic ester group is retained in
the product. Within this regime, some enantioselective reacꢀ
tions have been reported. For example, the Morken group has
developed palladiumꢀcatalyzed enantioselective deborylative
arylation12a and
alkenylation12b reactions of 1,1ꢀ
bisborylalkanes, giving highly valuable chiral benzyl and allyl
boronic esters (4+5 to 6, Scheme 1b). The Hall group later
reported an investigation of the effects of different ligands on
the palladiumꢀcatalyzed deborylative arylation reaction.12c In
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Scheme 1. a) Deborylation of 1,1-bisborylalkanes in the
synthesis of chiral organoboronates. b) and c) Prior work
that inspired this study. d) Deborylative allylation of 1,1-
bisborylated methane (This work).
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Table 1. a) Condition optimization for iridium-catalyzed deborylative allylation of bis[(pinacolato)boryl]methane (10). b) A
hypothetical Ag/Cu assisted deborylative allylation pathway. c) H NMR spectrum of the crude reaction mixture obtained
from the entry 10 experiment.
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yielding 1,2ꢀhydroxyboronates 9 in good enantioꢀ and diaꢀ
make chiral homoallyl alcohol and amines. In this study, we
found addition of silver salts18 to be essential for the reaction
efficiency and selectivity. During the preparation of this manꢀ
uscript, the Cho group11f, Fu group11j, and Hoveyda group12e
have each reported a mechanistically distinct, copperꢀbased
approach to achieve the allylation of bis[(pinacolato)boryl]ꢀ
methane. By using the chiral NHC ligands developed by their
group, Hoveyda and coworkers accomplished the enantioseꢀ
lective variant of this reaction and applied it into an elegant
total synthesis of rhopaloic acid A. The copperꢀbased apꢀ
proaches developed in these groups require allylic phosphates
or halides as electrophiles, while our Ir/Ag catalyzed system
permits the use of the less reactive allylic carbonates 11.19
stereoselectivities12d (Scheme 1c).
Inspired by these seminal contributions, we contemplated
the possibility of uniting such a facile deborylation process of
1,1ꢀbisborylalkanes with the wellꢀestablished iridiumꢀ
catalyzed asymmetric allylative substitution (AAS) chemisꢀ
try14 as a strategy to prepare chiral, βꢀsubstituted homoallylic
organoboronic esters (10+11 to 12, Scheme 1d). Herein we
report our development of such a reaction. We established that
when in the presence of a suitable silver salt, the easily availaꢀ
ble bis[(pinacolato)boryl]methane15 (10) is an effective couꢀ
pling partner in the iridiumꢀcatalyzed AAS reaction, and deꢀ
livers a ‘CH2B(pin)’ group as a derivatizable oneꢀcarbon
unit.16 This reaction displayed significant substrate scope and a
variety of chiral βꢀsubstituted homoallylic organoboronates
could be prepared under mild conditions. Since boronic esters
could be readily converted to a hydroxyl or amine group,1,17
this method could also be viewed as an umpolung strategy to
We began our study by investigating the model reaction beꢀ
tween bisborylmethane 10 (1.5 equiv) and tertꢀbutyl cinnamyl
carbonate (13, 1.0 equiv), adopting the previously established
conditions of iridiumꢀcatalyzed AAS reactions,14 with LiOtBu
employed as the activator of 10 (Table 1, entry 1). Under these
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conditions, the desired product 17 was delivered in a promisꢀ
ing 32% yield and 93% ee. Also formed was a significant
Table 2. Substrate scope of iridium-catalyzed deborylative allylation of bisborylmethane.a
amount of allyl ether 16, indicating the nucleophilic attack of
LiOtBu to be a competitive process.20 Previous studies had
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shown that the identity of the metal counterions of the alkoxꢀ
ide bases exerts strong impact on the complexation processes
of these bases with bisboryl alkanes (cf. 1 to 2 or 2’ in Scheme
1a): the use of NaOtBu11h or KOtBu11g led to a more facile
formation of either αꢀboryl carbanion 2’ or boron ate complex
2 than the use of LiOtBu.12d Therefore, we screened the former
two bases, with the aim of raising the concentration of (the
presumably more nucleophilic) 2 or 2’, expecting to improve
the yield of 17. However, neither of these two bases gave betꢀ
ter results than did LiOtBu (entry 2 and 3). Instead, we noticed
the majority of 10 was decomposed under these conditions,
presumably via a protodeborylation process.11h,g We then proꢀ
posed to modulate the reactivity of 10 as a nucleophile by
addition of a copper or silver salt, since it had been reported
that 1,1ꢀbisboryl alkanes might undergo a deborylative
transmetallation process to form an alkyl copper12d,21 or alkyl
silver11g,22 species 18 in the presence of a metal alkoxide. We
surmised that species 18, if formed, might engage the allyl
iridium intermediate 19 more promptly (Table 1b), thereby
leading to a more rapid formation of the desired product. We
were aware that the presence of other transition metals might
compete with iridium metal for chiral ligands, nonetheless, we
tested the use of a variety of copper and silver salts in this
transformation (entry 4ꢀ9). While the use of CuBr gave mostly
the undesired linear product 15 (entry 4),11i we were glad to
find that the use of AgOTf significantly improved both the
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selectivity profile of the reaction and the yield of the desired bonates bearing dioxolane (12n), furan (12o), indole (12p-n),
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product 17 (entry 5). Encouraged by these results, we screened
a series of other silver salts and found that all of them had
beneficiary effects on the reaction outcomes (entry 5ꢀ9), of
which Ag3PO4 gave the highest (91%) yield of 17 with an ee
of 93% (entry 9). Raising the reaction temperature to 50 °C led
to full conversion of cinnamyl carbonate 13 and slightly highꢀ
er yield of 17, with negligible effect on the stereoselectivity
(entry 10). A H NMR spectrum of the crude product mixture
of entry 10 experiment is depicted in Table 1c, showing the
overall cleanliness of this transformation, which in turn
thiophene (12s), and pyridine (12t) rings underwent this reacꢀ
tion smoothly, delivering the branched products in good yields
and selectivities. Xꢀray crystallographic analysis of 12q conꢀ
firmed its absolute configuration, which is the same as those
OH
OH
NHAc
Ref 22
Ph
Ph
1
Me
21
89% yield, 93% ee
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22
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NaBO3•4H2O
facilitated the isolation of these products. Conꢀ
trol experiment showed that iridium is essential for the reacꢀ
tion to proceed (entry 11).23
BPin
O
1) benzofuran, nBuLi
then, NBS
With the conditions using L1 optimized, we proceeded to
investigate the use of L2 and L3 in this reaction, since the
latter two ligands often show complementary substrate scope24
to L1 in iridiumꢀcatalyzed AAS reactions (see below). In the
presence of Ag3PO4, we found L2 performed well in the modꢀ
el reaction, giving the opposite enantiomer of 17 in decent
yield and enantioselectivity (entry 12). The use of Pꢀolefin
bidentate ligand L3 developed in the Carreira group called for
the branched allylic carbonate 14 as electrophile (entry 14ꢀ16).
Interestingly, nearly racemic mixture of products was formed
when a 1.5:1 ratio of 10 to 14 was used (entry 14). We specuꢀ
lated that under these conditions, each isomer of 14 underꢀ
went a stereoretentive allylation process,16 leading to the forꢀ
mation of 17 as a racemate. With this rationale, we performed
the reactions using excess (2.1 equiv) of 14, to find the desired
product 17 was obtained in excellent yield and enantioselectivꢀ
ity this time25 (entry 15 and 16). The ee of the unreacted 14 in
entry 15 experiment was determined to be 87%, suggestive of
a kinetic resolution process.26 Intriguingly, when either ligand
was used, a silver salt proved to be essential for the efficiency
and selectivity of the reaction (entry 12 vs. 13 and entry 16 vs.
17).
Ph
2) 9-BBN
then,
NaOH, H2O2
Ph
OH
17
93% ee
23
59% yield, 92% ee
nBuLi, MeONH2
then, Boc2O
R1
NHBoc
n
Ref 24
N
R2
Cbz
Ph
24
Ph
25
71% yield, 92% ee
9-BBN
then,
NaOH, H2O2
Bn
HO
Ph
Ref 25
N
OH
Ph
26
74% yield, 93% ee
27
Scheme 2. Elaboration of homoallyl boronates.
of the products generated from other typical nucleophiles (e.g.,
amines) in Irꢀcatalyzed AAS reaction.
With the above reaction conditions established, we explored
the scope and limitations of this transformation, as summaꢀ
rized in Table 2. First, we found the reaction efficiency is not
reduced when performed at gram scale, and more than 1 gram
of compound 17 was prepared in one batch with 93% ee. Beꢀ
sides, we noticed a variety of cinnamyl carbonate derivatives
could be converted to the corresponding chiral homoallyl
boronates in good to excellent isolated yields and with high
enantioselectivity (12a-t). For example, cinnamyl carbonates
containing electronꢀdonating methoxy (12a) or dimethylamino
group (12b) were effective reaction partners. Those with haloꢀ
genated aromatic rings (12c-e) were tolerated as well. When
substrates bearing orthoꢀsubstituents (12f-h) were used, ligand
L2 was required for good enantioselectivity.24a Cinnamyl carꢀ
bonates with strongly electronꢀwithdrawing substituents were
found to be much less reactive in this reaction.18 Nonetheless,
products with electronꢀdeficient aromatic rings (12i-l) could
be obtained from the corresponding branched allyl carbonates
(2.1 equiv) with L3 used as the chiral ligand. Additionally,
dienyl carbonates also participated in this reaction, and generꢀ
ated the branched product 12m in 80% yield, with >20:1 regiꢀ
oselectivity and 93% ee. Unfortunately, aliphatic allylic carꢀ
bonates reacted sluggishly under a variety of conditions we
examined, giving only low yield of the desired product (12u).
We were also interested in incorporating pharmaceutically
relevant heterocycles into our products, and found allyl carꢀ
The roles played by silver salts in this transformation are not
yet clear. Hartwig and coworkers showed in a recent study that
the use of silver phosphate [e.g., AgOP(O)(OPh)2] dramaticalꢀ
ly enhanced the diastereoselectivitity of the Irꢀcatalyzed allylaꢀ
tion reaction of azlactones.18 Through careful mechanistic
study, they found the presence of phosphate counterion rather
than the silver metal was key for the augmented selectivity.
However, the following two observations led us to believe that
silver ion might be responsible for the enhanced efficiency and
selectivity in our reaction. First, various silver salts containing
different types of counterions (entry 5ꢀ9 in Table 1 and Figure
S1 in Supporting Information) worked efficiently in this
deborylative allylation reaction, suggesting the effect of counꢀ
terion not to be critical. Second, the use of AgCl, Ag2O or
AgBr gave much superior results than the use of CuCl, Cu2O,
or CuBr (see Figure S1 in Supporting Information for details).
The fact that AgCl or AgBr also significantly promoted the
reaction performance ruled out the possibility that silver salts
exerted their effects through abstracting chloride ions from the
iridium complex. Nonetheless, more detailed mechanistic
studies are required to delineate the specific roles of silver
additives in this reaction.
To further demonstrate the synthetic utility of this transforꢀ
mation, we converted the obtained homoallylic boronic esters
products into other important classes of compounds using esꢀ
tablished chemistry (Scheme 2). For example, compound 17
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Thomas R. Hoye (University of Minnesota) for assistance in the
preparation of this manuscript.
could be readily oxidized by NaBO3•4H2O to the homoallylic
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3
4
5
6
7
8
alcohol 21, which had been engaged in a diverse array of
chemical transformations to generate structurally complex
products, including amino alcohol derivative 22.27 Moreover,
the boronic ester group in 17 could be converted to aromatic
rings following the protocols developed in the Aggarwal
group, 28 giving, after a hydroborationꢀoxidation sequence,
alcohol 23 in 59% overall yield. Further, compound 17 unꢀ
derwent an efficient C–B to C–N conversion when treated
with LiNHOMe,17 and yielded homoallylamine 24 after Boc
protection in the same pot. Notably, compound 24 was a key
intermediate used in the preparation of bicyclic piperidines
like 25,29 and had been previously made in 4 steps29 from meꢀ
thyl cinnamyl carbonate (vs. 2 steps from tertꢀbutyl cinnamyl
carbonate in our sequence). Lastly, we subjected 17 to a direct
hydroboration–oxidation sequence to give diol 26, which has
been employed in the synthesis of chiral pyrolidines like 27.30
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In conclusion, we have developed an efficient iridiumꢀ
catalyzed asymmetric allylation strategy to prepare chiral
homoallyl boronic esters. This method utilizes readily availaꢀ
ble bis[(pinacolato)boryl]methane and allylic carbonates as
reactants, demonstrates broad substrate scope, and is amenable
for the preparation of various βꢀsubstituted, chiral homoallyl
boronic esters, including those with orthoꢀsubstitutions and
heterocycles. The utility of these products is highlighted by
their straightforward conversion to other useful synthetic inꢀ
termediates. Importantly, we have noticed in this study that the
addition of silver salt is essential for the efficiency and selecꢀ
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might prove useful in the development of other iridiumꢀ
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ongoing in this laboratory.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and compound characterization are proꢀ
vided (PDF)
AUTHOR INFORMATION
Corresponding Authors
* Eꢀmail: niudawen@scu.edu.cn; ywchen@scu.edu.cn;
liujie2011@scu.edu.cn.
Author Contributions
All authors have given approval to the final version of the manuꢀ
script. / ‡These authors performed the experiments and contributꢀ
ed equally. / D. N conceived the idea and wrote the manuscript
with feedback from M. Z., J. L., and Y. C.
ACKNOWLEDGMENT
This investigation was supported by the startꢀup grant from State
Key Laboratory of Biotherapy and Cancer Center, West China
Hospital, Sichuan University, and “1000 Talents Plan” Program
of Chinese central government. We thank LWL Development
LTD. for characterizing some of our products. We thank Professor
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