A broadly applicable NHC-Cu-catalyzed approach for efficient, site-, and enantioselective coupling of readily accessible (pinacolato)alkenylboron compounds to allylic phosphates and applications to natural product synthesis

Article abstract of DOI:10.1021/ja4126565

A set of protocols for catalytic enantioselective allylic substitution (EAS) reactions that allow for additions of alkenyl units to readily accessible allylic electrophiles is disclosed. Transformations afford 1,4-dienes that contain a tertiary carbon stereogenic site and are promoted by 1.0-5.0 mol % of a copper complex of an N-heterocyclic carbene (NHC). Aryl- as well as alkyl-substituted electrophiles bearing a di- or trisubstituted alkene may be employed. Reactions can involve a variety of robust alkenyl-(pinacolatoboron) [alkenyl-B(pin)] compounds that can be either purchased or prepared by various efficient, site-, and/or stereoselective catalytic reactions, such as cross-metathesis or proto-boryl additions to terminal alkynes. Vinyl-, E-, or Z-disubstituted alkenyl-, 1,1-disubstituted alkenyl-, acyclic, or heterocyclic trisubstituted alkenyl groups may be added in up to >98% yield, >98:2 S_N2′:S_N2, and 99:1 enantiomeric ratio (er). NHC-Cu-catalyzed EAS with alkenyl-B(pin) reagents containing a conjugated carboxylic ester or aldehyde group proceed to provide the desired 1,4-diene products in good yield and with high enantioselectivity despite the presence of a sensitive stereogenic tertiary carbon center that could be considered prone to epimerization. In most instances, the alternative approach of utilizing an alkenylmetal reagent (e.g., an Al-based species) represents an incompatible option. The utility of the approach is illustrated through applications to enantioselective synthesis of natural products such as santolina alcohol, semburin, nyasol, heliespirone A, and heliannuol E.

Full text of DOI:10.1021/ja4126565

Article
pubs.acs.org/JACS
A Broadly Applicable NHC−Cu-Catalyzed Approach for Efficient,
Site‑, and Enantioselective Coupling of Readily Accessible
(Pinacolato)alkenylboron Compounds to Allylic Phosphates
and Applications to Natural Product Synthesis
Fang Gao, James L. Carr, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: A set of protocols for catalytic enantioselective
allylic substitution (EAS) reactions that allow for additions
of alkenyl units to readily accessible allylic electrophiles is
disclosed. Transformations afford 1,4-dienes that contain a
tertiary carbon stereogenic site and are promoted by 1.0−5.0
mol % of a copper complex of an N-heterocyclic carbene
(NHC). Aryl- as well as alkyl-substituted electrophiles bearing
a di- or trisubstituted alkene may be employed. Reactions can
involve a variety of robust alkenyl−(pinacolatoboron)
[alkenyl−B(pin)] compounds that can be either purchased or prepared by various efficient, site-, and/or stereoselective
catalytic reactions, such as cross-metathesis or proto-boryl additions to terminal alkynes. Vinyl-, E-, or Z-disubstituted alkenyl-,
1,1-disubstituted alkenyl-, acyclic, or heterocyclic trisubstituted alkenyl groups may be added in up to >98% yield, >98:2
SN2′:SN2, and 99:1 enantiomeric ratio (er). NHC−Cu-catalyzed EAS with alkenyl−B(pin) reagents containing a conjugated
carboxylic ester or aldehyde group proceed to provide the desired 1,4-diene products in good yield and with high
enantioselectivity despite the presence of a sensitive stereogenic tertiary carbon center that could be considered prone to
epimerization. In most instances, the alternative approach of utilizing an alkenylmetal reagent (e.g., an Al-based species)
represents an incompatible option. The utility of the approach is illustrated through applications to enantioselective synthesis of
natural products such as santolina alcohol, semburin, nyasol, heliespirone A, and heliannuol E.
with diisobutylaluminum hydride (dibal−H),5 a number of
INTRODUCTION
■
shortcomings accompany their use.
Coupling reactions with organoboron compounds are among
One issue is the sensitivity of the metal−hydride reagent as
the most strategically significant processes in chemical
well as the resulting alkenylmetal complex to air and moisture.
synthesis.1 Robust (pinacolato)boron [B(pin)] derivatives are
The relatively high reactivity of the latter species with
utilized frequently, and alkenylboron species represent one of
commonly used functional units, such as a carbonyl unit
the more attractive substrate classes;2 the resulting olefin-
(unless it is conjugated with the reacting π system4b−d), also
containing products, particularly if generated stereoselectively,
detracts from the approach. Moreover, direct preparation of
can be functionalized in a number of ways. Site- and
several types of alkenylaluminum reagents would be challenging
enantioselective catalytic protocols involving alkenyl−B(pin)
reagents therefore carry substantial value, and their development
constitutes a compelling research objective.
(e.g., Z-disubstituted or vinylboron compounds), and it would
not be a given that the stereochemical identity of the
organometallic reagent would be retained in the course of the
ensuing EAS. We have previously reported a sequence
involving silyl-substituted alkenylaluminum compounds
(Scheme 1B), accessed via a silyl-alkyne and its site-selective
hydroalumination.6 The catalytic EAS reactions proved to be
high yielding, and the expected 1,4-dienes were formed in up to
>98% SN2′ selectivity and >99:1 enantiomeric ratio (er);
nonetheless, silylated alkynes had to be prepared initially, and
the desired Z alkenes were revealed after protodesilylation.
It would be more efficient if Z-alkenylboron reagents were to be
One recent line of study in these laboratories has led to the
design of enantioselective processes with different types of
B-containing starting materials. Cu-catalyzed enantioselective
allylic substitution (EAS) processes3,4 involving alkenyl−B(pin)
compounds have been of interest, because they form C−C
bonds while delivering alkenyl groups of varying substitution
patterns that might contain sensitive functionality (e.g., a carbonyl
group). The significance of such attributes becomes evident
through comparison with the alternative catalytic transformations
that entail alkenylaluminum species (Scheme 1A and B). Although
the latter nucleophile set can be prepared through reaction of a
terminal alkyne (uncatalyzed or promoted by a Ni-based complex)
Received: December 12, 2013
© XXXX American Chemical Society
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Scheme 1. State-of-the-Art in Catalytic EAS Reactions Involving Alkenyl Nucleophiles
employed, especially if accessed through a catalytic stereo-
selective process; the need for transitory incorporation of a silyl
unit would thus be obviated. What is more, reactions of silyl-
substituted alkenylaluminum species and sterically demanding
electrophiles are inefficient,7 a limitation more likely to be
resolved with nonsilylated nucleophilic components. Addition
of an unsubstituted alkene can be more easily accomplished by
means of a vinyl−B(pin) reagent; as far as we are aware,
catalytic EAS reactions involving a vinyl group have not been
previously disclosed.
A significant recent advance by Carreira illustrates that a
variety of secondary allylic alcohols react with alkenyl(trifluoro)
boron potassium salts to generate EAS products in the presence
of a chiral phosphoramidite−Ir complex (Scheme 1C).8
Transformations are efficient and proceed in 75:25 to >98:2
branched:linear (SN2′:SN2) ratios and up to >99:1 er. A
distinguishing feature of the approach is that unsaturated
alcohols serve as starting materials (vs a more activated
derivative). Certain deficiencies remain to be addressed
however. Substrates are limited to aryl-substituted allylic
B
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Scheme 2. NHC−Cu-Catalyzed EAS with Alkenyl−B(pin) Reagents Developed in This Study and Related Applications
heterocyclic unit. In all cases, except one, organoboron reagents
can be used as purchased. Disubstituted (E or Z), trisubstituted
(linear or cyclic) variants, as well as vinyl−B(pin) species serve
as effective reagents. To the best of our knowledge, there are no
existing descriptions of catalytic EAS processes with hetero-
cyclic alkenylboron or vinyl−B(pin) compounds. In some
instances, alkenyl−B(pin) reagents are prepared by catalytic
site- or stereoselective processes, such as Z-selective cross-
metathesis (CM) with commercially available vinyl−B(pin) or
α-selective protoboryl additions to terminal alkynes. Catalysts
are derived from sulfonate-containing chiral imidazolinium salts
synthesized in four steps12 and are converted to N-heterocyclic
carbene (NHC) copper complexes through deprotonation and
reaction with commercially available CuCl. Utility is illustrated
through approaches to enantioselective syntheses of several
natural products (cf., Scheme 2).
alcohols with a terminal olefin, affording 1,4-dienes bearing a
monosubstituted alkene. The need for 2 equiv of hydrogen
fluoride detracts from the practicality of the approach. The
protocol requires the use of fluoroboryl compounds, which are
typically accessed via alkenyl−B(pin) compounds. The
alkenyl−BF3K species employed did not contain a carbonyl-
based moiety; EAS with vinylboron entities or alkenylboron
reagents that carry a trisubstituted heterocyclic unit were not
reported. A notable 2011 disclosure by Hayashi and Shintani
focused on NHC−Cu-catalyzed EAS processes with arylbor-
onic acid neopentyl glycol esters; this study included an
example of the addition of cyclohexenyl-derived species, which
furnished the desired product in 84% yield and complete site
selectivity (>99:1 SN2′:SN2) and in 86.5:13.5 er.9
Herein, we put forth a broadly applicable method for
catalytic EAS reactions of easily accessible di- or trisubstituted
allylic phosphates and alkenyl−B(pin) reagents, resulting in the
formation of tertiary C−C bonds (Scheme 2); only the
carboxylic ester and acetal-containing alkenylboron reagents
have previously been employed in EAS reactions that furnish
quaternary carbon centers.10 Products are obtained in 52% to
>98% yield, 93:7 to >98:2 SN2′:SN2 selectivity, and 83:17−99:1
er. A key attribute of the approach is that, in many cases,
products are obtained in high enantiomeric purity despite
containing a sensitive stereogenic center (cf., highlighted acidic
protons in Scheme 2); such a challenge was not germane to the
previously investigated transformations leading to quaternary
carbon stereogenic centers,10 nor did it pose a complication in
those performed with allenyl−B(pin) species.11 An assortment
of alkenylboron compounds can be used, including those
containing a carbonyl, an acetal, or an O- or N-substituted
RESULTS AND DISCUSSION
■
1. Catalyst Screening. We began by examining the ability
of a selection of chiral NHC−Cu complexes to promote the
EAS involving allylic phosphate 1a and commercially available
n-alkyl-substituted alkenyl−B(pin) 213 to afford diene 3
(Table 1). The transformation carried out in the presence of
C2-symmetric 4 and with C1-symmetric species derived from
imidazolinium salt 5 proceeded to 38% and 76% conversion,
respectively, generating the desired product with low site and
enantioselectivity (entries 1,2, Table 1). Similarly low efficiency
was observed with phenyl glycinol-derived 614 (entry 3); while
site selectivity improved substantially, underlining the crucial
ability of cuprate complexes (vs monodentate NHC−Cu) in
delivering SN2′ mode of addition, inferior er values persisted.
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Table 1. Initial Screening of Different NHC−Cu
Scheme 3. NHC−Cu-Catalyzed EAS with Acetal-Containing
a
a
Complexes
Alkenyl−B(pin) Reagent 10
a
Reactions performed under N2 atm; conversion (allylic phosphate
consumption) and site selectivities ( 2%) were determined by analysis
of 400 MHz H NMR spectra of product mixtures prior to purifica-
b
c
b
d
1
entry imidazolinium salt conv (%)
yield (%)
SN2′:SN2
er
tion; yields ( 5%) are of products after purification; enantioselectiv-
ities ( 2%) were determined by HPLC analysis. See the Supporting
Information for experimental and analytical details.
1
2
3
4
5
6
7
4
38
76
38
91
72
98
97
31
59
30
90
70
93
97
67:33
79:21
>98:2
>98:2
98:2
45:55
74:26
78:22
41:59
34:66
87:13
92:8
5
6
7
subjection of 11 to a suspension of silica gel in Et2O, delivered
enal 12b in quantitative yield without detectable loss of
enantiomeric purity [93:7 er; >98% enantiospecificity (es)]
despite an acidic benzylic proton. Three more examples are
provided in Scheme 3. Two involve additions to a disubstituted
allylic phosphate, followed by hydrolysis to afford
α,β-unsaturated aldehydes 12a and 12c; the latter case entails
EAS with a sterically demanding substrate containing an
o-bromophenyl moiety. Also shown is a reaction with a
trisubstituted allylic phosphate, furnishing unsaturated ester 13,
with the acetal unit preserved, in 52% yield, >98:2 SN2′:SN2
selectivity, and 92:8 er. The discrepancy between the
conversion level and yield of the desired product in the last
case might be due to sensitivity of the acetal group to
adventitious hydrolysis upon purification.
3. Transformations with Carboxylic Ester-Containing
Alkenyl−B(pin) Reagent 14. The catalytic processes
involving the commercially available ethyl ester-substituted 14
present a more notable challenge in relation to retention of the
kinetically generated stereoisomeric purity (Scheme 4). Here,
the resulting stereogenic center must survive the basic
conditions needed for EAS reactions for 24 h (vs mild acidic
conditions needed for hydrolysis of the acetal-containing
products in Scheme 3).15 The most sensitive 1,4-diene
generated through the transformations illustrated in Scheme 4
relates to the EAS with m-trifluoromethylphenyl-substituted
allylic phosphate 1c; nonetheless, 15c was formed in 61%
yield,16 >98% SN2′ selectivity, and 96:4 er; undesired 1,3-diene
16 was obtained in 39% yield. Consistent with the aforementioned
complication, synthesis of 15a proceeded in an improved 95%
yield with 97% site selectivity and 92.5:7.5 er (Scheme 4).
Addition to the sterically demanding o-tolyl substrate leading
to 15d (95% yield, 96:4 SN2′:SN2, 92:8 er) illustrates that
8
9a
9b
98:2
98:2
a
b
Reactions performed under N2 atm. Conversion (allylic phosphate
consumption) and site selectivity ( 2%) were determined by analysis
of 400 MHz 1H NMR spectra of product mixtures prior to purification.
c
Yield of products ( 5%) after purification by silica gel chromatog-
raphy. Enantioselectivity ( 2%) determined by HPLC analysis. See
the Supporting Information for experimental and analytical details.
d
1,4-Diene 3 was formed with reasonable efficiency (91% conv)
and complete site selectivity (>98% SN2′) but only in 41:59 er
when imidazolinium salt 7 was utilized (entry 4). Particularly
noteworthy is that the copper complex derived from NHC−
sulfonate 8, which proved to be the most effective for EAS
with 2 and the corresponding trisubstituted allylic phosphate
leading to a quaternary carbon stereogenic center,10 promoted
a minimally enantioselective reaction (entry 5). Finally, we
established that bidentate copper complexes generated from
9a,b (entries 6,7), containing a 3,5-disubstituted NAr moiety,
deliver 3 efficiently and selectively; the complex derived from
9b afforded the desired product in 97% yield, 98:2 SN2′:SN2
selectivity, and 92:8 er (entry 7, Table 1). Reaction at lower
temperatures resulted in reduced efficiency and similar
selectivity. At this point, we turned to examining EAS
where the more synthetically versatile organoboron reagents
are used.
2. Transformations with Acetal-Substituted Alkenyl−
B(pin) Reagent 10. The NHC−Cu-catalyzed EAS involving
p-nitrophenyl-substituted allylic phosphate 1b and commer-
cially available alkenylboron species 10 proceeded to >98%
conv, affording 11 in 90% yield, 96% site selectivity, and 93:7 er
(Scheme 3). Hydrolysis of the acetal group, achieved by
D
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a
Scheme 4. NHC-Cu-Catalyzed EAS with Carboxylic Ester-Substituted Alkenyl−B(pin) Reagent 14
a
Reactions performed under N2 atm; conversion (allylic phosphate consumption) and site selectivities ( 2%) were determined by analysis of
400 MHz 1H NMR spectra of product mixtures prior to purification; yields ( 5%) are of products after purification; enantioselectivities ( 2%) were
determined by HPLC analysis. See the Supporting Information for experimental and analytical details.
NHC−Cu-catalyzed EAS can be performed with sterically
demanding electrophiles. Alkyl-substituted allylic phosphates are
suitable starting materials as well, underscored by the efficient and
highly selective formation of 17 (>98% conv, 95% SN2′, 92.5:7.5
er); subsequent treatment with MeLi delivered the tertiary
alcohol, and concomitant removal of the acyl group revealed an
irregular monoterpene derived from Artemisia annua L., from
which the potent antimalarial artemisinin was isolated.17
4. Transformations with Z-Alkenyl−B(pin) Com-
pounds. Our goal in this segment of our investigations was
2-fold. We wished to introduce a catalytic EAS protocol that
leads to incorporation of Z alkenes and is of broad scope.
Moreover, we aimed to establish a catalytic EAS protocol with
the more readily accessible (in many cases through a catalytic
stereoselective process) and robust alkenyl−B(pin) systems.8
What renders such a task challenging is the reduced Lewis
acidity of the boron center and the larger size of the pinacol
moiety, attributes that diminish the rate of transmetalation
leading to the NHC−Cu−alkenyl intermediate of the
catalytic cycle; such a complication is exacerbated by the
increased steric hindrance of a Z alkenyl−B(pin) reagent
(vs an E isomer).
was obtained in 76% yield, with >98% SN2′ selectivity, without
any isomerization to the E isomer (>98% Z) and in 95:5 er.
An assortment of allylic phosphates can be employed:
electrophilic alkenes attached to electron-deficient (cf., 19b),
electron-rich (cf., 19c), or sterically demanding (cf., 19d) aryl
groups were transformed to the desired products in 76−82%
yield, exceptional site selectivity (>98% SN2′), and 97:3−
98:2 er. Reactions with electrophilic components containing a
trisubstituted alkene, previously determined to be a relatively
challenging and more sparsely examined substrate class,18
whether it is a methyl group (20a−c) or a carboxylic ester
(21a−c), remained reasonably efficient (74−96% yield),
generating little or none of the achiral linear product isomer
(≤2% SN2).
4.2. Catalytic EAS with Z-Alkenyl−B(pin) Compounds
Generated by Catalytic Stereoselective Cross-Metathesis
(CM). The feasibility of efficient EAS reactions with Z-alkenyl−
B(pin) reagents allows for a two-stage catalytic process that
begins with a Z-selective CM. Regarding the first stage, CM
transformations promoted by Mo monopyrrolide aryloxide
catalysts involving commercially available vinyl−B(pin) (22)
were recently shown to proceed efficiently and with high Z
selectivity.19
4.1. Catalytic EAS with Z Alkenyl−B(pin) 18. We first
investigated transformations involving methyl-substituted re-
agent 18, a compound that can be purchased in the purely Z
form (<2% E; Scheme 5). We established that the Cu-catalyzed
process involving 1a and 18 proceeds to 90% conversion at
ambient temperature within 8 h (Scheme 5); Z-1,4-diene 19a
The transformation culminating in the formation of enal
26 demonstrates the effectiveness of the catalytic CM/EAS
sequence (Scheme 6). Z-Selective CM of commercially
available 22 and a readily accessible silyl ether in the presence
of 5.0 mol % Mo complex 23a, generated and used in situ,20
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a
Scheme 5. NHC−Cu-Catalyzed EAS with Z-Alkenyl−B(pin) Reagent 18
a
Reactions performed under N2 atm; reaction times are 8.0 h for 19a−d, and 24 h for the other cases. Conversion (allylic phosphate consumption)
and site selectivities ( 2%) were determined by analysis of 400 MHz 1H NMR spectra of product mixtures prior to purification; yields ( 5%) are of
products after purification; enantioselectivities ( 2%) were determined by HPLC analysis. See the Supporting Information for experimental and
analytical details.
afforded Z-alkenyl−B(pin) 24 in 70% yield and 96:4 Z:E
selectivity. The ensuing EAS with allylic phosphate 1d delivered
Z-1,4-diene 25 in 81% yield as its pure Z isomer21 with >98%
site selectivity and in 99:1 er. Unmasking of the allylic alcohol
and subsequent oxidation afforded enantiomerically enriched
26 in 78% overall yield with complete retention of diastereo-
and enantiomeric purity (>98% Z and 99:1 er). As
demonstrated through syntheses of 27a−c and 28, a variety
of 1,4-dienes can be accessed efficiently and with ≥95% SN2′
selectivity and 96:4−99:1 er, and as ≥93% Z isomers.
4.3. Catalytic EAS with Z-Alkenyl−B(pin) Compounds with
a Large Substituent; Applications to Enantioselective
Synthesis of Nyasol, Heliespirone A, and Heliannuol E.
When the Z-alkenylboron reagent carries a sizable group,
EAS processes proceed with lower site- and enantioselectivity
with imidazolinium salt 9b serving as the catalyst precursor.
One example (Scheme 7) is the transformation involving the
cyclohexyl-containing allylic phosphate 29a and phenyl-
substituted alkenylboron species 30 (obtained through Z-
selective CM);19 31 was obtained in 74:26 SN2′:SN2 and er.
To address the above issue, we returned to the stereo-
chemical model for catalytic EAS reactions (I, Scheme 7).
We considered the possibility that the large group of the
Z-alkenylcopper intermediate (G) might elevate the energy of
complex I due to steric interactions involving the tri-i-propylphenyl
moiety in 9b. Accordingly, modes of transformation involving
substrate−catalyst association through the alternative enantio-
topic face of the allylic phosphate could become competitive,
leading to lowering of er. Our analysis suggested that the
latter complex (cf., II), with the protruding group of the NAr
group at its ortho position, might be better able to
accommodate the sizable alkenyl substituent.22 We therefore
prepared chiral imidazolinium salt 9c and probed the ability of
the derived NHC−Cu complex in catalyzing the formation of
1,4-diene 31, which was accordingly obtained in quantita-
tive yield and significantly improved >98% SN2′ selectivity and
91:9 er.
To demonstrate utility, we carried out a concise, diastereo-
and enantioselective synthesis of nyasol (Scheme 8).23 The
requisite p-methoxyphenyl-substituted Z-alkenyl−B(pin) re-
agent 32 was prepared in 69% yield and 93% stereoselectivity
through Mo-catalyzed CM performed with 3.0 mol %
23b and 1.5 equiv of p-methoxystyrene. Subsequent NHC−
Cu-catalyzed EAS with 1e afforded 33 in 92% yield, with
complete site selectivity, as a single alkene isomer (>98% Z
after purification) and in 97:3 er. Nyasol was generated after
removal of the methoxy and tosyl groups in 79% overall yield.
In contrast to a route reported previously, also involving an
F
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Scheme 6. Combining Mo-Catalyzed Z-Selective
Cross-Metathesis and NHC−Cu-Catalyzed EAS
Scheme 7. EAS with Hindered Z-Alkenyl−B(pin) Reagents
a
a
and Alteration of the Catalyst Structure
a
Reactions performed under N2 atm; all alkenyl−B(pin) reagents were
obtained through Mo-catalyzed Z-selective cross-metathesis (CM).
Conversion (allylic phosphate consumption), site-, and Z/E
selectivities ( 2%) were determined by analysis of 400 MHz 1H
NMR spectra of product mixtures prior to purification; yields ( 5%)
are of products after purification; enantioselectivities ( 2%) were
determined by HPLC analysis. See the Supporting Information for
experimental and analytical details.
the presence of hydrogen fluoride was not necessary
(see Scheme 1C), and the Z-alkenyl−B(pin) compound
could be employed directly without the multistep procedures
needed for the formation of the corresponding trifluoroborate
salts.24
a
Reactions performed under N2 atm. Z:E ratios for EAS products are
the same as the alkenyl−B(pin) used, except noted otherwise.
Conversion (allylic phosphate consumption) and site selectivities
( 2%) were determined by analysis of 400 MHz H NMR spectra of
unpurified product mixtures; yields ( 5%) are of products after
purification; enantioselectivities ( 2%) were determined by HPLC
analysis. See the Supporting Information for experimental and
1
The possibility of a succinct route for enantioselective
synthesis of diol 38 (Scheme 9), used to prepare different
members of the heliannuol family of natural products25 as well
as the structurally related heliespirones,26 presented us with an
opportunity to explore further the scope of the catalytic
protocol with a more sterically demanding Z-alkenyl−B(pin)
(vs 30 and 32 in Schemes 7 and 8). We established that
reaction of 1d with allylic t-butyldimethylsilyl ether 3427
promoted by 5.0 mol % of the NHC−Cu complex derived from
9c furnishes 1,4-diene 35 in >98:2 SN2′:SN2 selectivity and
98:2 er (>98% Z). That is, the highly encumbered boron center
of alkenyl−B(pin) 34 readily participates in metal exchange
with the NHC−Cu−OMe intermediate. The resulting sizable
NHC−Cu−alkenyl complex undergoes reasonably efficient
b
analytical details. Conditions were the same as those used for 25,
except 1.0 equiv of Z-alkenyl−B(pin), 1.25 equiv of allylic phosphate,
c
and 1.25 equiv of NaOMe were used. The alkenyl−B(pin) reagent
used consisted of a 96:4 Z:E and >98% Z samples for 25 and 27c,
respectively (in each case, the pure Z isomer of the EAS product was
isolated after silica gel chromatography).
NHC−Cu-catalyzed EAS,6 preparation and use of a silyl-
substituted alkenylaluminum reagent and subsequent desily-
lation was not needed. Additionally, unlike the recent route
to nyasol involving a phosphine−Ir-catalyzed EAS reaction,8
complete site selectivity was attained (vs 74:26 SN2′:SN2),
G
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a
Scheme 8. Application to Enantioselective Synthesis of Nyasol
a
See the Supporting Information for experimental and analytical details.
addition to generate 35; although 18% of the allylic phosphate
was recovered, the expected product was isolated in 79% yield
(82% conv). When performed on ca. 0.5 g scale, the reaction
proceeded to 79% conv, affording 35 in 71% yield (ca. 0.4 g)
and with identical levels of selectivity. Desilylation, oxidation,
and alkylation of the resulting ketone delivered tertiary alcohol
36 in 60% overall yield (no detectable change in stereoisomeric
purity). Attempts at the preparation of the Z-alkenyl−B(pin)
containing the tertiary alcohol or the derived silyl ether moiety
(obviating the above deprotection/oxidation/alkylation se-
quence) by hydroboration of the appropriate terminal alkyne27
proved unsuccessful. Site- (chemo-) and diastereoselective
epoxidation,28 in the presence of excess Ti(Oi-Pr)4 likely
needed due to steric hindrance at the hydroxyl directing group
or competitive coordination to Lewis basic OMe groups,29
afforded 37 in 92:8 diastereomeric ratio (dr), which was
isolated as a single diastereomer in 76% yield (15% epoxide
derived from the terminal alkene was also isolated after
chromatography). Reductive cleavage of the epoxide proceeded
with >98% site selectivity through a Ti-mediated procedure,30
furnishing 38 in 55% yield. The latter diol has been utilized in
the enantioselective synthesis of heliespirone A and C26 (only
the former shown in Scheme 9) and heliannuol E.25e
5. Catalytic EAS with Trisubstituted Alkenyl−B(pin)
Reagents. Another class of nucleophiles that have been used
less commonly in catalytic EAS reactions involves those that
contain a trisubstituted alkene.6,8,9 As far as we are aware, there
are no reported examples involving transformations with
heterocyclic alkenyl moieties.
5.1. Transformation with an Acyclic Trisubstituted
Alkenylboron Reagent To Prepare Santolina Alcohol. The
EAS shown in eq 1 delivers natural product santolina alcohol31
in 65% yield (some loss due to product volatility), complete
SN2′ selectivity, and 96:4 er. The catalytic process involves
alkyl-substituted substrate 39, which contains a hydroxyl-
substituted quaternary carbon center immediately next to the
reactive site. Although the transformation involves the sterically
demanding reagent 40 (commercially available), enantioselec-
tive addition proceeds readily. It is equally noteworthy that
protection of the tertiary alcohol, a measure adopted to curtail
the competitive and adventitious protonation of the inter-
mediate alkenyl−Cu complex, is not necessary here. Such an
advantage is likely the result of the inability of the sterically
encumbered hydroxyl unit to approach the NHC−Cu−alkene
species; however, use of 2.5 equiv of 40 is needed for achieving
complete conversion (vs 1.5−2.0 equiv), perhaps because the
above-mentioned complication does remain operative to a
limited extent.
5.2. Transformations with Heterocyclic Trisubstituted
Alkenylboron Reagents; Application to Enantioselective
Synthesis of Semburin. Various heterocyclic alkenyl−B(pin)
compounds can be either purchased or prepared by catalytic
protocols,32 including ring-closing metathesis procedures.33
The NHC−Cu-catalyzed EAS reactions in Scheme 10 involve
commercially available heterocyclic organoboron reagents,
affording products that contain unsaturated NBoc- or O-
containing unsaturated rings in 52−98% yield, 93% to >98%
site selectivity, and 91:9−98:2 er. A range of allylic phosphates
serve as competent reaction partners, and a (pinacolato)boron-
bearing trisubstituted cyclic allylic ether (e.g., 44−46,
Scheme 10) or enol ether (e.g., 47a,b, 48) readily undergoes
addition with high site- and enantioselectivity. Aryl-substituted
variants may contain a sterically demanding ortho group (e.g.,
42, 45, or 47b, Scheme 10), electron-withdrawing (e.g., 42, 44,
47a), or electron-donating units (e.g., 45). Transformations
with alkyl-substituted allylic phosphates (e.g., 43b, 46, 48),
those containing a trisubstituted olefin with a methyl (e.g.,
43a,b, 46), or a carboxylic ester group (e.g., 44, 47a,b, 48)
proceed efficiently and with high site- and enantioselectively.
Processes involving unsaturated esters (Scheme 9) were carried
H
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a
Scheme 9. Application to Enantioselective Synthesis of Heliespirone A and Heliannuol E
a
Reactions performed under N2 atm; conversion (allylic phosphate consumption), site selectivities, and diastereoselectivities ( 2%) were
1
determined by analysis of 400 MHz H NMR spectra of product mixtures prior to purification; yields ( 5%) are of products after purification;
enantioselectivities ( 2%) were determined by HPLC analysis. See the Supporting Information for experimental and analytical details.
out with 2.5 mol % catalyst loading (vs 5.0 mol % for
other cases). Except for heterocyclic alkenyl−B(pin) 49 (cf.,
Scheme 11) where silica gel chromatography is required for
optimal results, the commercially available organoboron
reagents can be used as received in EAS reactions to generate
products with reasonable efficiency and similarly high site- and
enantioselectivity as would be observed with the materials that
have been purified.34
of the heterocyclic moiety to α,β-unsaturated lactone 51
proceeded in 78% yield. At this point, a diastereoselective
1,4-reduction of the cyclic enoate was required. Investigation of
different Cu complexes reported previously to be effective for
reductions involving polymethylhydrosiloxane as the hydride
source36 led to either inefficient and/or minimally selective
reactions.37 As an example, when the (achiral) NHC−Cu
complex reported to be effective for such transformations was
used,36b the desired saturated lactone was obtained in 81% yield
and 45:55 dr (in favor of the undesired isomer). We therefore
probed a number of chiral imidazolinium salts prepared pre-
viously in the context of catalytic enantioselective processes.38 We
determined that with the Cu complex derived from C1-symmetric
enantiomerically pure heterocyclic salt 52,39 lactone 53 can be
obtained in 92% yield and 78:22 dr. Removal of the silyl unit,
reduction of the ester group, and cyclization to the desired
bicyclic acetal delivered diastereomerically pure semburin in 65%
overall yield and 96:4 er after silica gel chromatography.
The diastereo- and enantioselective synthesis of semburin35
demonstrates utility. The route in Scheme 11 includes a key
NHC−Cu-catalyzed stereoselective conjugate reduction devel-
oped to complement the EAS process. Formation of
unsaturated pyran 50 from reaction of alkyl-substituted allylic
phosphate and organoboron reagent 49 is efficient (>98%
yield) and site-selective (97% SN2′); nevertheless, the desired
product is generated in moderate enantioselectivity (83:17 er);
examination of various Cu complexes and silyl ether derivatives
did not lead to identification of superior conditions. Oxidation
I
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Scheme 10. NHC−Cu-Catalyzed EAS with Heterocyclic
Scheme 11. Application to Diastereo- and Enantioselective
Synthesis of Semburin
a
a
Alkenyl−B(pin) Compounds
a
Reactions performed under N2 atm; conversion (allylic phosphate
consumption), site-, and diastereoselectivities ( 2%) were determined
by analysis of 400 MHz 1H NMR spectra of product mixtures prior to
purification; yields ( 5%) are of products after purification;
enantioselectivities ( 2%) were determined by HPLC analysis. See
the Supporting Information for experimental and analytical details.
ppts = pyridinium p-toluenesulfonate.
a
Scheme 12. Combining Site-Selective NHC−Cu-Catalyzed
Reactions performed under N2 atm; conversion (allylic phosphate
a
consumption) and site selectivities ( 2%) were determined by analysis
of 400 MHz 1H NMR spectra of product mixtures prior to
purification; yields ( 5%) are of products after purification;
enantioselectivities ( 2%) were determined by HPLC analysis. See
the Supporting Information for experimental and analytical details.
Alkyne Protoboration and EAS
b
Reaction performed at 60 °C under otherwise identical conditions as
c
shown for the formation of 42. Reaction performed at 60 °C with
2.5 mol % 9b (for 47a and 48) or 9c (for 47b) and 25 mol % CuCl
under otherwise identical conditions as shown for the formation
of 42.
6. Catalytic EAS with 1,1-Disubstituted Alkenyl−
B(pin) Reagents Derived from NHC−Cu-Catalyzed
Protoboration of Terminal Alkynes. In addition to catalytic
Z-selective CM reactions (cf., Schemes 6−8), another set of
processes that can be combined with catalytic EAS processes
is NHC−Cu-catalyzed site-selective protyl-boron additions
to terminal alkynes. For instance, 1,1-disubstituted alkenyl−
B(pin) compounds that can be accessed directly through
efficient and α-selective alkyne protoborations in the presence
of 1.0 mol % of a Cu complex derived from a commercially
available imidazolinium salt.40,41 Alkenyl-B(pin) 56, formed
through a transformation with NHC−Cu complex 55 in 91%
yield and >98:2 α:β selectivity, was used to prepare 1,4-diene
57a in 89% yield, >98% SN2′ selectivity, and 98:2 er (Scheme 12).
Similarly, allylsilane 57b was isolated in 93% yield, >98:2
SN2′:SN2 selectivity, and 97:3 er. Because the B-based reagents
are relatively unhindered, the Cu complex derived from 9b was
a
Reactions performed under N2 atm; conversion (allylic phosphate
consumption) and site selectivities ( 2%) were determined by analysis
of 400 MHz 1H NMR spectra of product mixtures prior to
purification; yields ( 5%) are of products after purifica-
tion; enantioselectivities ( 2%) were determined by HPLC analysis.
See the Supporting Information for experimental and analytical
details.
J
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Scheme 13. NHC−Cu-Catalyzed EAS with Vinyl−B(pin) as
CONCLUSIONS
■
a
Reagent
We have developed a generally applicable class of catalytic EAS
transformations involving the use of an assortment of readily
accessible and/or commercially available alkenyl−B(pin)
reagents that possess a number of noteworthy attributes:
(1) The NHC−Cu-catalyzed C−C bond-forming processes
have a reasonably general scope. Monosubstituted, E- and
Z-1,2-disubstituted, 1,1-disubstituted, as well as acyclic and
cyclic trisubstituted alkenyl−B(pin) compounds can be reacted
with aryl- or alkyl-containing allylic electrophiles efficiently to
afford the desired products in high branched:linear (SN2′:SN2)
and enantiomeric ratios. The scope of the approach and the
range of ways through which enantiomerically enriched EAS
products can be functionalized are underscored through
applications to enantioselective synthesis of several small
molecule natural products.
(2) Catalytic transformations require an abundant and
inexpensive metal salt and proceed readily with alkenyl−B(pin)
compounds, robust reagents that can be purchased or prepared
through catalytic processes. The strategy of combining Mo-
catalyzed Z-selective CM or Cu-catalyzed protoboration of
terminal alkynes and NHC−Cu-catalyzed EAS is notable.
(3) Alkenyl moieties bearing conjugated carbonyl units can
be added efficiently under conditions that are sufficiently mild
to allow the isolation of 1,4-dienes that contain a sensitive
stereogenic tertiary carbon center in 61−95% yield and
92:8−96:4 er.
Collectively, the NHC−Cu-catalyzed transformations de-
scribed above allow access to a considerable range of versatile
enantiomerically enriched 1,4-dienes, the synthesis of which
would have otherwise been less efficient and concise. Design
and development of catalytic methods for efficient EAS
processes involving other versatile classes of boron-based
reagents and their applications to synthesis of natural products
are in progress.
a
Reactions performed under N2 atm; conversion (allylic phosphate
consumption) and site selectivities ( 2%) were determined by ana-
lysis of 400 MHz 1H NMR spectra of product mixtures prior to
purification; yields ( 5%) are of products after purification;
enantioselectivities ( 2%) were determined by HPLC analysis. See
the Supporting Information for experimental and analytical details.
b
c
Reaction performed with 10 mol % 9b and 10 mol % CuCl. Reaction
performed with 3.0 equiv of 22.
used (cf., Schemes 7 and 8). It should be noted that alkenyl
reagents such as 56 (Scheme 12) cannot be synthesized
alternatively through hydrometalation reactions due to rapid
substrate decomposition.5 Elevated temperatures (60 °C) were
required for complete conversion to 57a, perhaps as a result
of diminution of reactivity as a result of intramolecular amide
chelation to the Cu center, which is absent in the case of 57b,
formation of which proceeds to >98% conversion at 22 °C. The
catalytic EAS leading to 57a was significantly more sluggish at
22 °C, while delivering identical enantioselectivity (e.g., 37%
conv after 24 h formed in 98:2 er).
7. Catalytic EAS with Vinyl−B(pin). Another noteworthy
class of EAS transformations involves the use of robust
and commercially available vinyl−B(pin). An assortment of
allylic phosphates, including those that contain a sterically
demanding, electron-withdrawing, or electron-donating aryl
group (59a−d, Scheme 13), undergo EAS in the presence of
2.5 mol % 9b and 25 mol % CuCl to afford the desired
products bearing an α,β-unsaturated ester in 68−85% yield,
complete SN2′ selectivity, and ≥98:2 er. Addition of a vinyl
group can be performed with an alkyl-substituted allylic
phosphate, delivering 61 in 66% yield, >98% site selectivity,
and 94:6 er. The use of excess CuCl in the reactions in Scheme
13 merits note. Initial screening indicated that in the presence
of 10 mol % 9b and 10 mol % CuCl, >98% conversion can be
achieved with er values similar to those shown; subsequent
investigations revealed that with 10−25 mol % of CuCl present,
the amount of the more valuable chiral imidazolinium salt can
be decreased. The precise reason for the need for excess CuCl
might be attributed to association of the Lewis acidic salt with
the carbonyl unit of the ester moiety to facilitate EAS.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details for all reactions and analytic details for all
enantiomerically enriched products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
amir.hoveyda@bc.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is dedicated to the fond memory of Professor Harry
H. Wasserman. Financial support was provided by the NIH
(GM-47480; GM-59426) and the NSF (CHE-1111074). F.G.
was a Bristol-Myers Squibb Graduate Fellow. We thank Dr. E.
S. Kiesewetter and E. C. Yu for valuable experimental assistance
and helpful discussions.
REFERENCES
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