Stereoselective Tandem Bis-Electrophile Couplings of Diborylmethane

Article abstract of DOI:10.1021/jacs.7b09309

A copper-catalyzed three-component linchpin coupling method for the stereoselective union of readily available epoxides and allyl electrophiles is disclosed. Transformations employ [B(pin)]₂-methane as a conjunctive reagent, resulting in the fo

Full text of DOI:10.1021/jacs.7b09309

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Stereoselective Tandem Bis-Electrophile Couplings of Diborylmethane.
Stephanie A Murray, Michael Z Liang, and Simon J. Meek
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09309 • Publication Date (Web): 21 Sep 2017
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Stereoselective Tandem Bis-Electrophile Couplings of Di-
borylmethane.
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Stephanie A. Murray, Michael Z. Liang, and Simon J. Meek*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290.
Supporting Information Placeholder
ABSTRACT: A copper-catalyzed three-component
linchpin coupling method for the stereoselective union
of readily available epoxides and allyl electrophiles is
disclosed. Transformations employ [B(pin)]2-methane
as a conjunctive reagent, resulting in the formation of
two C–C bonds at a single carbon center bearing a
C(sp3) organoboron functional group. Products are ob-
tained in 42–99% yield, and up to >20:1 dr. The utility
of the approach is highlighted by stereospecific trans-
formations entailing allylation, tandem cross coupling,
and application to the synthesis 1,3-polyol motifs.
Chemical processes that stereoselectively construct
multiple C–C bonds through single operations provide
efficient strategies for the synthesis of important, com-
plex bioactive molecules.1 In particular, substrate-
controlled diastereoselective tandem processes have en-
joyed significant attention as enabling strategies for rap-
id acyclic stereocontrol.2 Consequently, a number of
tandem reactions that construct two C–C bonds in a sin-
gle operation through a linchpin single-carbon center
Herein, we report a stereoselective one-pot three-
have been developed. Such examples include the dithi-
component Cu-catalyzed coupling strategy that employs
ane anion relay chemistry developed by Smith in which
[B(pin)]2-methane as a conjunctive reagent, which ena-
a dithiane unit (e.g., A) serves as a double carbanion
bles the couplings of epoxide and allyl electrophiles.
equivalent (Scheme 1a).3 In such transformations the
dithiane carbon does not turn into a new C(sp3) stereo-
The general reaction design that affords 1,3-hydroxy–
organoborons is illustrated in Scheme 1d. Ring-opening
center. This is in contrast to silyl glyoxylates utilized by
of readily available chiral epoxides with [B(pin)]2-
Johnson and co-workers in multicomponent electro-
C(H)Li (1) results in the formation of diastereomeric
phile/nucleophile couplings (Scheme 1a).4 Such rea-
cyclic boronates E and F. Through substrate-controlled
cyclic boronate formation or interconversion, subsequent
stereospecific deborylative transmetalation generates
gents represent dual cation/anion synthons, wherein the
acyl carbon becomes an C(sp3) stereocenter.
1,1-Diborylalkanes (e.g., D) also represent potential
versatile conjunctive reagents for stereoselective tandem
organocopper G, which can engage with an electro-
phile.7 Examples of stereocontrolled C–C bond forming
linchpin couplings due to their versatile nature (Scheme
reactions that proceed via the intermediacy of a chelated
1c). Not only can both boron units be functionalized by
boron-stabilized carbanion, include the coupling of zin-
deborylative processes,5 but due to the stabilizing effect
cated-hydrazones with alkenylboronates,8 and substrate-
of the two boron groups, the α-C–H bonds are rendered
controlled deborylative alkylations of tris-boronates.5b
relatively acidic (pKa ~31).6a-b In the presence of lithium
The overall transformation in Scheme 1d generates two
amide bases [B(pin)]2-C(H)Li (pin = pinacolato) can be
C–C bonds and a new tertiary stereogenic center con-
generated, which reacts with electrophiles.6
taining a versatile C(sp3)–B(pin) moiety.
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aReactions performed under N2 atm. bConversion to 3; values deter-
mined by analysis of 400 or 600 MHz 1H NMR spectra of unpurified
mixtures with dmf as internal standard.
We initiated our studies with the coupling of (R)-
styrene oxide (2) and allyl halide (Table 1). A key ob-
jective of the first phase centered on the ability to effi-
ciently form two C–C bonds to [B(pin)]2-methane in a
single operation. When (R)-styrene oxide (2) is treated
with [B(pin)]2-C(H)Li 1 (1.5 equiv) in tetrahydrofuran
(0 °C to 22 °C, 15 min), and the resulting mixture sub-
jected to 15 mol % CuCl and allyl chloride at 22 °C,
52% conversion to 1,3-hydroxyboronate 3 is observed in
24 h (with a diastereomeric ratio, dr, of 3:1 anti/syn)
b
aReactions performed under N2 atm. Yield represents isolated yield of
purified material and is an average of two experiments. cEpoxide opening:
22 °C for 24 h. dIsolated yield of diol after H2O2/NaOH oxidation. eEpox-
ide opening: 45 °C for 24 h.
is furnished in 60% yield but 2:1 dr. Lastly, sterically
congested limonene oxide provides 16 in 42% isolated
yield as a single stereoisomer.
Increasing substitution on the 1,1-diboron was found
to be tolerated in the epoxide-opening step, however, the
corresponding cyclic borate failed to undergo transmeta-
lation to Cu, and allylic substitution. For example, reac-
tion of 17 with 1-dodecene oxide efficiently generates
ketone aldol product 18 in 80% yield after oxidation
(Equation 1).
,
(Table 1, entry 1).9 10 Reactions run at 45 °C and 60 °C,
proceeded with similar efficiency but in 2:1 dr (entries
2–3). Lower dr and diminished reactivity is furnished
with phosphonate-, and acetate-derived allyl electro-
philes (entries 4–5). With allyl bromide the tandem re-
action afforded 3 in 77% conversion and 8:1 dr (entry
6). Varying the copper salt resulted in either diminshed
conversion and/or selectivity (entries 7–9). Lastly, reac-
tions in the presence of phosphine ligands proceed with
similar efficiency but lower dr (entries 10–11).
A wide array of terminal and internal epoxides partici-
pate in the three-component coupling reaction. To facili-
tate isolation of the C(sp3) organoborons, the 1,3-
hydroxyborons were protected as the TBS ethers. As
illustrated in Scheme 2, aryl-substituted 1,3-
hydroxyboronates (4–8) are generated in 45–70% yield
and in high dr (8:1 to >20:1 dr anti/syn). Reactions with
terminal epoxides bearing sterically less demanding al-
kyl substituents furnished 9–12 efficiently (61–80%
yield) albeit in up to 3:1 dr. With cyclohexene oxide,
tandem C–C bond formation results in the stereoselec-
tive synthesis of 13 in 74% isolated yield bearing three
stereogenic centers in >20:1 dr. Notably, trans-epoxides
failed to undergo efficient ring-opening by 2; for exam-
ple, trans-β-methylstyrene oxide results in <20% con-
version to a complex mixture of regioisomers and dia-
stereomers. Geminal disubstituted epoxides react with
varying efficiency, as the reaction to form 14 proceeds in
58% yield and 5:1 dr, whereas, β-pinene oxide derived
15
Follow up studies illustrated in Scheme 3, demonstrate
that a variety of substituted allyl electrophiles as well as
dienyl bromides perform efficiently under standard con-
ditions (15 mol % CuCl, 1.0 equiv 2, 1.5 equiv 1), estab-
lishing two new C–C bonds and a sterocenter in good
diastereoselectivity. Several features of these studies are
notable: (1) Substituents at the 2-carbon of the allyl unit
result in formation of the anti-product (e.g., 20, 22, and
24) in high selectivity 7:1 to >20:1 dr. (2) 3-Substituted
allyl bromides afford the desired alkyl-B(pin) products
with good regiocontrol but with diminution in dr (e.g.,
19, 21, and 23). (3) Vinyl halides (24) but not esters
(25) are tolerated under the reaction conditions. (4) Re-
action with (E)-5-bromopenta-1,3-diene affords SN2
substitution product 27 (45% yield, 7:1 dr). (5) Notably,
reaction with racemic 3-bromocyclohex-1-ene furnishes
26 with good diastereocontrol for the anti-1,3-hydroxy-
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2.5 mol % [Pd(ꢀ-Br)(Pt-Bu3)2]2 and benzaldehyde re-
1
sults in situ isomerization and diastereoselective allyl
addition to furnish homoallylic alcohol 30 in 69%
yield.13 In addition, the three-component coupling proto-
col can also be extended to include sequential stereo-
retentive cross coupling of the crude 1,3-hydroxy-B(pin)
products (Scheme 5b).14 For example, treatment of
crude 3 with 5 mol % Pd(dba)2, 5 mol % RuPhos, and an
arylbromide in KOH(aq) at 70 °C for 12 h delivers 32 and
33 in 40% and 54% isolated yield, respectively, and
>10:1 dr. Furthermore, the utility of the diborylmethane
linchpin coupling protocol is highlighted in the concise
approach to 1,3-polyol motifs through an iterative se-
quence (Scheme 5c).15 Beginning with styrene oxide 2
(5 mmol scale) under standard conditions with 2-
methylallylbromide, anti-1,3-diol 28 (1.03 g) is isolated
in 99% yield and 7:1 dr.16 Subsequent hydroxyl-directed
epoxidation (5 mol % V(O)(acac)2, t-BuOOH) of the
terminal alkene,17 and ketal formation furnishes 34 in
55% yield and 25:3.5:1 dr (2 steps). Subjecting 34 to
standard coupling conditions in Scheme 2 with al-
lylbromide delivers diol 35 in 75% yield and 4.5:1 dr
(equivalent to a ketone allylation). The sequential four-
step sequence enables the rapid stereoselective assembly
of four C–C bonds and three strereocenters (41% overall
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a–bSee Scheme 2. c3:1 SN2:SN2’.
B(pin), however, the additional stereocenter is formed
in 1:1 dr. The data above suggest that higher diastere-
oselectivity is associated with bromide electrophiles that
can react via an SN2’ pathway.
Consistent with the proposed pathway in Scheme 1c,
we set out to identify the cyclic boronates E and F, and
provide support for a model to explain the reaction dia-
stereoselectivity. As shown in Scheme 4a(i), monitoring
the ring-opening of 2 (1 equiv) with 1 (1.5 equiv) by 1H
NMR in d8-THF at 22 °C results in 73% conversion to
diastereomers I and II in 56:44 dr. Each stereoisomer
could be assigned through the absence of (e.g., I) or
presence of (e.g., II) an nOe diaxial interaction between
the carbinol methine (Ha and Hb) and the [(pin)B]2C–H
methane. 1H NMR of the mixture of I and II at 60 °C,
or after heating at 60 °C for 14 h, does not result in any
changes in the diastereoisomer ratio. Treatment of the
solution of I and II with 15 mol % CuCl and allyl bro-
mide (Scheme 4a(ii)), results in consumption of both
diastereoisomers at similar rates, and after 1 h ~20% I
still remains. Further time points (Scheme 4b) demon-
strate the dr of 28 (8:1) is independent of the time. This
data indicates that although the cyclic boronates are
formed in low dr, they both react at similar rates, and
thus the high anti-selectivity must arise from the kinetic
selectivity of Cu-alkyl species III and IV generated via
transmetalation. However, it is not known whether III
and IV are formed in high dr or if III and IV intercon-
vert rapidly (Curtin-Hammett) prior to C–C bond for-
mation.
from 2).
Scheme 4. Mechanistic Studiesa
a. 1H NMR Studies:
(pin)B
(pin)B
nOe
Ha
Hb
(pin)B
O
(pin)B
H
Li
Li
(pin)B
O
Ph
Ph
O
+
+
Ph
Li
d8-THF
22 °C, 1 h
H
I
II B(pin)
2
1
73% conv, 56:44 dr
(1 equiv)
(1 equiv)
(i) After 1 h at 22 °C:
(No change in dr at 60 °C
or after 14 h at 60 °C)
Ha
Hb
(ii) With 15 mol % CuCl, allylbromide, 60 °C, 1 h: Both are consumed (~20% remains)
H
H
(pin)B
O
(L)Cu
H
Ha Hb
(pin)B
(pin)B
(L)Cu
Ph
Ph
O
H
B(pin)
IV
III stereochemically relevant
intermediates
b. Reaction Time:
(pin)B
optimal
conditions
O
OH OH
2.5 h: 38% yield, 8:1 dr
3.5 h: 47% yield, 8:1 dr
24 h: 73% yield, 8:1 dr
+
Ph
(pin)B
Li
Ph
NaOH, H2O2
2
1
28
(1 equiv)
(1.5 equiv)
aSee SI for details.
The
1,3-hydroxy-homoallylboronates
accessible
To conclude, we have introduced a stereoselective
linchpin coupling method that utilizes [B(pin)]2-methane
as a C1 conjunctive reagent for the linking of epoxide
and allyl electrophiles. Reactions proceed efficiently,
delivering products with good levels of diastereoselec-
tivity that are amenable to accessing a range of useful
organic molecules. Further stereoselective reactions of
cyclic borates are in progress.
through the linchpin three-component coupling method
are amenable to a wide range of useful functionaliza-
tions (Scheme 5a).
homoallyl boronates 4 can be efficiently converted to the
corresponding 1,3-amino alcohol 31 in 85% yield,11
For example, TBS protected
a
key intermediate in the stereoselective synthesis of (+)-
allo-sedamine.12 Homoallyl-B(pin) 29 in the presence of
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aSee SI for details. b1H NMR yield (4:1 E-alkene isomers).
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and spectral
and analytical data for all products. This material is available free
of charge via the Internet at http://pubs.acs.org.
(6) (a) Matteson, D. S.; Moody, R. J. J. Am. Chem. Soc. 1977, 99,
AUTHOR INFORMATION
3196–3197. (b) Matteson, D. S.; Moody, R. J. Organometallics 1982,
1, 20–28. (c) Endo, K.; Hirokami, M.; Shibata, T. J. Org. Chem.
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Corresponding Author
sjmeek@unc.edu
Notes
(7) For examples of generation and trapping of diastereomeric
Authors declare no competing financial interests.
Cu(I)alkyl species, see: (a) Dieter, R. K.; Watson, R. T.; Goswami, R.
Org. Lett. 2004, 6, 253–256. (b) Dieter, R. K.; Oba, G.; Chandupatla,
K. R.; Topping, C. M.; Lu, K.; Watson, R. T. J. Org. Chem. 2004, 69,
3076–3086.
ACKNOWLEDGMENT
Financial support was provided by the National Institutes of
Health (R01GM116987, 3R01GM116987-01S1) and the Univer-
sity of North Carolina at Chapel Hill. AllyChem is acknowledged
for donations of B2(pin)2. We are grateful to Amber Charitos for
experimental assistance.
(
8
) Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem.
Soc. 2008, 130, 15688–15701.
) 15 mol % CuCl was found to afford slightly improved yields
(
9
vs. 10 mol %. This is likely due to reaction mixture turning hetero-
genous as the reaction proceeds.
(
10) SFC analysis of 3 compared to 1, indicates there is no loss of
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