Copper-Hydride-Catalyzed Enantioselective Processes with Allenyl Boronates. Mechanistic Nuances, Scope, and Utility in Target-Oriented Synthesis

Article abstract of DOI:10.1021/jacs.9b05465

Synthesis of complex bioactive molecules is substantially facilitated by transformations that efficiently and stereoselectively generate polyfunctional compounds. Designing such processes is hardly straightforward, however, especially when the desired route runs counter to the inherently favored reactivity profiles. Furthermore, in addition to being efficient and stereoselective, it is crucial that the products generated can be easily and stereodivergently modified. Here, we introduce a catalytic process that delivers versatile and otherwise difficult-to-access organoboron entities by combining an allenylboronate, a hydride, and an allylic phosphate. Two unique selectivity problems had to be solved: avoiding rapid side reaction of a Cu-H complex with an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly utilized boron-copper exchange. The utility of the approach is demonstrated by applications to concise preparation of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and enantioselective synthesis and structure confirmation of netamine C, a member of a family of anti-tumor and anti-malarial natural products. Completion of the latter routes required the following noteworthy developments: (1) a two-step all-catalytic sequence for conversion of a terminal alkene to a monosubstituted alkyne; (2) a catalytic S_N2′- and enantioselective allylic substitution method involving a mild alkylzinc halide reagent; and (3) a diastereoselective [3+2]-cycloaddition to assemble the polycyclic structure of a guanidyl polycyclic natural product.

Full text of DOI:10.1021/jacs.9b05465

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Copper−Hydride-Catalyzed Enantioselective Processes with Allenyl
Boronates. Mechanistic Nuances, Scope, and Utility in Target-
Oriented Synthesis
Yu Sun,§ Yuebiao Zhou,§ Ying Shi,§ Juan del Pozo,§ Sebastian Torker,‡ and Amir H. Hoveyda*,§,‡
§Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
‡Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, 67000 Strasbourg, France
S
* Supporting Information
ABSTRACT: Synthesis of complex bioactive molecules is substantially facilitated by transformations that efficiently and
stereoselectively generate polyfunctional compounds. Designing such processes is hardly straightforward, however, especially
when the desired route runs counter to the inherently favored reactivity profiles. Furthermore, in addition to being efficient and
stereoselective, it is crucial that the products generated can be easily and stereodivergently modified. Here, we introduce a
catalytic process that delivers versatile and otherwise difficult-to-access organoboron entities by combining an allenylboronate, a
hydride, and an allylic phosphate. Two unique selectivity problems had to be solved: avoiding rapid side reaction of a Cu−H
complex with an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly utilized
boron−copper exchange. The utility of the approach is demonstrated by applications to concise preparation of the linear
fragment of pumiliotoxin B (myotonic, cardiotonic) and enantioselective synthesis and structure confirmation of netamine C, a
member of a family of anti-tumor and anti-malarial natural products. Completion of the latter routes required the following
noteworthy developments: (1) a two-step all-catalytic sequence for conversion of a terminal alkene to a monosubstituted
alkyne; (2) a catalytic SN2′- and enantioselective allylic substitution method involving a mild alkylzinc halide reagent; and (3) a
diastereoselective [3+2]-cycloaddition to assemble the polycyclic structure of a guanidyl polycyclic natural product.
H-catalyzed reactions is that the products afforded by the
former strategy bear a versatile C−B bond (vs a hydrocarbon).
The stereochemically defined alkenyl−B(pin) moiety in ii
(Scheme 1a) has indeed been found to be pivotal to synthesis
of complex bioactive molecules.3c
A less developed strategy entails the reaction of a chiral Cu−
H catalyst and an unsaturated organoboron substrate. There
are only two known examples of this type, both involving an
alkenylboronate (see iv via iii, Scheme 1a). In one, vinyl−
B(pin) is merged with a monosubstituted allylic electrophile
(R = H; enantioselective),5 and in the other it is combined
with a disubstituted allylic electrophile (R = aryl, alkyl;
diastereo- and enantioselective).6 Apart from the need for high
1. INTRODUCTION
Catalytic processes that can deliver organic molecules in an
efficient, diastereo- and enantioselective manner are central to
advances in biology and medicine. It is also crucial that the
products contain functional groups that are ubiquitous in
bioactive targets and can be easily converted to a wide range of
derivatives. Myriad substructures and stereoisomers related to
medicinally relevant entities then become accessible without
the need for costly revision of synthesis routes.
At the heart of the present studies are catalytic reactions that
begin with the addition of a copper−boryl complex to an
unsaturated hydrocarbon, generating an intermediate that then
reacts in situ with an electrophile.1 Transformations involving
allenes2 are particularly noteworthy (Scheme 1a).3 A related
set of reactions are promoted by a Cu−H complex.4
A
Received: May 21, 2019
distinction between Cu−B(pin)- (pin = pinacolato) and Cu−
© XXXX American Chemical Society
A
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Scheme 1. Background and Goals of the Study
SN2′ selectivity and enantioselectivity, successful implementa-
tion hinges on two chemoselectivity requirements being
satisfied: (1) The Cu−alkoxide complex must react preferen-
tially with the silyl hydride to produce a Cu−H species (vs an
alkenyl−B(pin)7 moiety to give a Cu−alkenyl species. (2) The
Cu−H complex must add to the alkenylboronate substrate and
not the allylic phosphate as, otherwise, unsaturated hydro-
carbon byproducts would be formed.
The proposed Cu−H-catalyzed allylic substitutions8 would
proceed via Cu−allyl-linear-E (Scheme 1b), which, after
isomerizing to the lower energy Cu−allyl-linear-Z,9 undergoes
an SN2′-selective allylic substitution to deliver alkenyl−
B(pin)-linear-1. There is a key difference between this
sequence and the formerly reported multicomponent reactions
that involve non-boryl-substituted allenes (Scheme 1a).
Conversion of the C−B bond in alkenyl−B(pin)-linear-1 to
B
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a
Scheme 2. Various Selectivity Challenges and Relevant Investigations
a
See the Supporting Information for details.
a C−C bond constituted a linear chain growth. In contrast, the
same sequence via ii (Scheme 1a) allows for, predominantly if
not exclusively, the formation of a methyl-bearing trisub-
stituted alkene, which, while valuable, is limited in applicability.
Chemo- and stereoselective functionalization at the termini
can lead to complex stereochemical arrays, not only diastereo-
and enantioselectively, but also diastereodivergently. For
instance, after alkenyl−B(pin)-linear-1 is transformed to
allylic phosphate-2 by chemoselective cross-metathesis
(Scheme 1b), a second catalyst-controlled allylic substitution
might deliver alkenyl−B(pin)-linear-2 and alkenyl−B(pin)-
linear-2′ in either diastereomeric form, depending on the Cu
complex enantiomer utilized. It is worth noting that catalytic
approaches for diastereo- and enantioselective synthesis of
vicinal carbon-substituted stereogenic centers, especially in a
stereodivergent manner, are scarce.10
A Lewis acidic boryl unit within the product, while
synthetically desirable, poses a new challenge: C−C bond
forming transformations must involve organometallic reagents
that, although sufficiently reactive, are not excessively
nucleophilic. Conversion of the alkenyl−B(pin) moiety to
yet another allylic phosphate would be followed by a third
catalyst-controlled allylic substitution, this time yielding 1,7-
diene-1 or 1,7-diene-1 (C6-diast) or 1,7-diene-1′ or 1,7-
diene-1′ (C6-diast). By performing the initial process with the
alternative catalyst enantiomer (i.e., formation of ent-1,7-
diene-1 or ent-1,7-diene-1 (C6-diast)), the remaining four
possible stereoisomers may be selectively synthesized by the
same sequence. Each allylic substitution would have to proceed
with high efficiency and exceptional regio- and stereochemical
control.
The proposed strategy has the necessary attributes for multi-
step synthesis applications and preparation of several isomers.
Diastereoselective catalytic cross-coupling of the alkenyl
boronate moiety in 3a (Scheme 1b) with an appropriate
partner, followed by conversion of the alkene terminus to an
alkyne moiety, would generate enyne 4, a compound
previously converted to pumiliotoxin B, a naturally occurring
anti-malarial, cardiotonic agent,11 after just four additional
steps.12 Transformation with the same allylic phosphate (2a)
but involving monosubstituted allenyl−B(pin) 1b could deliver
5a, two-directional modification of which by additional allylic
substitutions might furnish 6 and 7. The resulting cyclohexenyl
compound may be used for the first enantioselective total
synthesis of natural product netamine C,13 a member of a
family of potent anti-tumor and anti-malarial compounds14
(Scheme 1b). Because the stereochemistry at C8 has been the
subject of some debate,15 and since the approach could allow
access to either isomeric form (i.e., it is diastereodivergent), it
would be possible to establish the stereochemical identity of
the natural product rigorously.
Several points regarding a related study16 (Scheme 1c),
published during the final stages of this work, merit note. (1)
Although the reported yields and enantioselectivities are often
C
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a
Scheme 3. Ligand Screening for Reactions with 1,1-Disubstituted Allenyl Boronate 1a
a
All reactions were performed under N2 atmosphere. Conversion (>98% in all cases), SN2′, and Z:E selectivity were determined by analysis of 1H
NMR spectra of the unpurified mixtures ( 2%). Yields correspond to isolated and purified products and represent an average of at least three runs
( 5%). Enantioselectivities were determined by HPLC analysis ( 1%). See the Supporting Information for details. Abbreviations: redn, reduction;
NA, not applicable.
high, the approach has shortcomings that make it unsuitable to
target-oriented synthesis. A key limitation is that the allenyl
substrates as well as the allylic phosphate must each contain an
aryl substituent; otherwise, reactions are inefficient and/or
non-stereoselective (low E:Z ratios and/or enantioselectivity).
(2) Products are much less amenable to two-directional
modification, because they either contain two disubstituted
alkenes (one of which must be an aryl olefin), or one di-, or
one trisubstituted aryl alkene. (3) While a terminal alkene in a
1,5-diene product was converted (by cross-metathesis) to the
corresponding alkenyl−B(pin) derivative, such products are
distinct from alkenyl−B(pin)-linear-1 in three aspects, all
central to the utility of the strategy (see Scheme 1b): a
remaining disubstituted aryl olefin (vs a terminal alkene), a
stereogenic center that is allylic (vs homoallylic) to the
alkenyl−boronate unit, and the lack of a pathway to generate a
stereodefined trisubstituted alkene (e.g., G = Me in alkenyl−
B(pin)-linear-1).
not as substrates for Cu−X addition [e.g., X = H or B(pin)].
This is less of an issue with alkenyl−B(pin) compounds
(Scheme 1a) because with an allenyl boronate the
intermediacy of a six-membered ring transition state (Scheme
2a) is not only feasible, it is probably favored (vs direct
exchange at the more congested C−B bond), rendering B/Cu
exchange more facile. Control experiments support this
contention. We find that 1a and 1b as well as vinyl−B(pin)
are fully converted to their organocopper derivative in the
presence of an NHC−Cu−alkoxide (NHC = N-heterocyclic
carbene) complex in just 10 min (at 22 °C). However, when
an equal mixture of 1a or 1b and vinyl−B(pin) are subjected to
the same conditions, only the allenyl boronates react and there
is no Cu−vinyl species formed.18 These findings indicated that
conditions that ensure efficient Cu−H addition to an allene as
opposed to B/Cu exchange would be needed (e.g., larger
amounts of copper hydride and/or sizable metal alkoxide; see
below).
Another complication is the regioselectivity of Cu−H
addition to an allenyl boronate. As with the reactions involving
an alkenyl boronate (see Scheme 1a), a boryl substituent’s
ability to stabilize electron density at the carbon of an incipient
Cu−C bond favors the more hindered branched Cu−allyl
derivative (Cu−allyl-branched), Scheme 2a); DFT studies
support this possibility.18 Nevertheless, unlike the previous
2. RESULTS AND DISCUSSION
2.1. Mechanistic Challenge. The proposed approach
poses several unique reactivity/selectivity issues. One relates to
the possibility of B/Cu exchange (Scheme 2a). As far as we
know, allenyl−B(pin) compounds have been utilized only as
precursors to Cu−allenyl or Cu−propargyl intermediates17 but
D
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a
Scheme 4. Scope of Catalytic Processes with 1,1-Disubstituted Allenyl Boronate 1a
a
All reactions were performed under N2 atmosphere. Conversion (>98% in all cases), SN2′, and Z:E selectivity were determined by analysis of 1H
NMR spectra of the unpurified mixtures ( 2%). Yields correspond to isolated and purified products and represent an average of at least three runs
( 5%). Enantioselectivities were determined by HPLC analysis ( 1%). Reaction mixtures typically contain 10−20% of side products from allylic
b
phosphate reduction. With 2.0 equiv 1a. See the Supporting Information for details.
cases, Cu−allyl-branched might either react directly with an
allylic phosphate to afford allylic boronate byproducts,
depending on whether the SN2 or SN2′ mode of addition
dominates, or might partially be converted to Cu−allyl-linear-
Z and/or Cu−allyl-linear-E, which would result in product
mixtures. For the desired alkenyl−B(pin)-linear to be formed,
isomerization of Cu−allyl-branched to Cu−allyl-linear-Z
must be faster than its reaction with an allylic phosphate.
The kinetic preference for the more congested Cu−allyl-
branched can also render Cu−H addition to an allylic
phosphate more competitive.
presence of polymethylhydrosiloxane (PMHS; at 22 °C;
Scheme 2b). In the case of disubstituted allenyl boronate 1a,
for which the branched Cu−allyl isomer was not detected,
there was 80% conversion to Cu−allyl-1a-linear-Z after just 10
min. When monosubstituted 1b was used, on the other hand,
not only was Cu−allyl-1b-branched generated as the sole
product (85% conversion, 10 min), it was sufficiently stable for
us to obtain an X-ray structure (Scheme 2b). The trans-
formation involving 1a probably proceeds via Cu−allyl-1a-
branched, and the increased steric pressure in the latter causes
it to collapse readily to Cu−allyl-1a-linear-Z. Whether the
higher stability of Cu−allyl-1b-branched would lead to
In search of further insight, we probed the reaction of
NHC−Cu-1 with equivalent amounts of 1a or 1b in the
E
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a
Scheme 5. Application to Diastereo- and Enantioselective Synthesis of the Linear Fragment of Pumiliotoxin B
a
All reactions were performed under N2 atmosphere. Conversion (>98% in all cases), SN2′, and Z:E selectivity were determined by analysis of 1H
NMR spectra of the unpurified mixtures ( 2%). Yields correspond to isolated and purified products and represent an average of at least three runs
( 5%). Enantioselectivities were determined by HPLC analysis ( 1%). See the Supporting Information for details.
inefficient transformations with disubstituted allenyl−B(pin)
1b remained to be determined.
with 3b in 64% yield, >98:2 SN2′:SN2 ratio, and 99:1 er. These
findings show that the substitution pattern within the NHC’s
aryl moiety is critical to whether Cu−H addition to 1a can
effectively compete with its undesired reaction with the allylic
phosphate (see Scheme 7 and related discussion below for
further analysis). The amount of LiOt-Bu was central to
minimizing competitive B/Cu exchange. For example, with 2.5
equiv metal alkoxide (vs 1.2 equiv), propargyl-1 was formed
predominantly (14:86 3b:propargyl-1); this is likely due to
faster B/Cu exchange when a tert-butoxyl borate derivative of
allenyl boronate 1a is involved.17b,18
Catalysts derived from phos-1−phos-3, previously used in
other Cu−H-catalyzed processes,4,22 were ineffective. There
was rampant byproduct formation due to breakdown in
chemoselectivity with up to ∼60% Cu−H addition to the
allylic phosphate, and the undesired linear product was the
predominant isomer (i.e., 91% to >98% SN2).
2.3. Scope with Disubstituted Allenyl Boronate 1a.
Transformations between 1,2-disubstituted allylic phosphates
and 1,1-disubstituted allenyl−B(pin) 1a (Scheme 4a) afforded
1,5-dienes with an electron-rich or an electron-poor aryl group
(3c−e), a congested o-substituted aryl moiety (3f,g), or a
heteroaryl fragment (3h,i). These products were isolated in
53−71% yield, >98% SN2′ and Z selectivity, and 98:2−99:1 er.
Alkyl-substituted (3j; see Scheme 5 for another example) as
well as cyclic allylic phosphates were effective substrates (3k,l).
Reactions with geraniol-derived allylic phosphate (Scheme
4b) proceeded to >98% conversion within two h at room
temperature, affording 8a in 74% yield, 95:5 SN2′:SN2
selectivity, >98:2 Z:E selectivity, and 95:5 er. As represented
by 8b−g, products bearing an aryl-, heteroaryl-, or alkyl-
substituted stereogenic center and a Z-trisubstituted alkenyl−
B(pin) moiety were obtained with similar efficiency and
stereoselectivity. The latter data have an additional notable
dimension because the corresponding Cu−B(pin)-catalyzed
multicomponent processes (Scheme 1a), while efficient, afford
only the linear product (SN2 addition). This difference in
2.2. Feasibility and Identifying an Effective Catalyst.
As the model reaction, we selected 1,1-disubstituted
allenylboronate 1a (prepared in two steps19) and allylic
phosphate 2b (Scheme 3); PMHS was the hydride source.
We began with disubstituted allene 1a, as we surmised that
transformations might be less complicated due to relatively
rapid formation of Cu−allyl-1a-linear-Z (vs the more
persisting Cu−allyl-1b-branched). Based on the initial
mechanistic studies (Scheme 2b), we reasoned that excess
PMHS and the sizable LiOt-Bu would favor conversion of the
in situ generated Cu−Ot-Bu complex to the corresponding
Cu−H species (vs B/Cu exchange, yielding Cu−propargyl),
minimizing B/Cu exchange and thus reduction byproduct
formation (dotted box, Scheme 3). Still, in view of the steric
requirement for the addition of the same complex to the
disubstituted allene, we remained concerned that Cu−H
addition to 2b would be competitive.
With the imid(O)-1-derived complex, optimal for Cu−
B(pin)-catalyzed allylic substitutions with allenes3c (see
Scheme 1a), there was significant reduction (44%; see dotted
box, Scheme 3) and enantioselectivity was low (23:77
enantiomeric ratio (er)). But at least the process was SN2′-
selective (88:12 3b:3b′) and 3b was obtained in 27% yield
(>98:2 Z:E). We then examined several catalysts derived from
sulfonate-containing NHC ligands, wherein a metal salt bridge
involving the pendant Lewis basic group within the chiral
ligand and the phosphate moiety can engender high SN2′
selectivity.20 The process with imid(S)-1a was more regio-
selective (>98:2 SN2′:SN2), furnishing 3b in 81:19 er. All the
same, as suspected, competitive Cu−H addition to the allylic
phosphate persisted (45% reduction). Then, to our surprise,
the reaction involving imid(S)-1b, a member of a class of
chiral NHC ligands originally designed and developed in these
laboratories,21 afforded no more than 14% byproduct
formation (removable by silica gel chromatography) along
F
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a
Scheme 6. Scope of Catalytic Processes with 1,1-Disubstituted Allenyl Boronate
a
All reactions were performed under N2 atmosphere. Conversion (>98% in all cases), SN2′, and Z:E selectivity were determined by analysis of 1H
NMR spectra of the unpurified mixtures ( 2%). Yields correspond to isolated and purified products and represent an average of at least three runs
( 5%). Enantioselectivities were determined by HPLC analysis ( 1%). Reaction mixtures typically contain 5% of side products from allylic
b
c
phosphate reduction. (R)-imid(S)-1b was used. For 6 h at 4 °C. See the Supporting Information for details.
regioselectivity, compared to the highly SN2′-selective
reactions with 1,2-disubstituted allylic phosphates, may be
attributed to the steric pressure inflicted by the sizable B(pin)
moiety and a substituent at the incipient quaternary carbon
center. Cu−H-catalyzed transformations with an allenyl−
B(pin) substrate are faster probably because the bulky
boronate is more distal from the site of C−C bond formation.
2.4. Formal Synthesis of Pumiliotoxin B. The utility of
the approach hinges on whether the Z-trisubstituted alkenyl−
B(pin) and the monosubstituted alkene moiety within the
products can be functionalized chemo- and stereoselectively.
To probe this matter, we chose to synthesize the linear
fragment of pumiliotoxin B (Scheme 5). We prepared 1.61 g of
1,5-diene 3a by using 2.2 mol% of the chiral ligand (S)-
imid(S)-1b (68% yield, 95:5 SN2′:SN2 selectivity, >98:2 Z:E
selectivity and 92:8 er). We then took advantage of a method
outlined by Aggarwal23 to effect a stereospecific cross-coupling
of the trisubstituted alkenyl−B(pin) moiety with enantiomeri-
cally pure propylene oxide. Acetonide formation led to 9 in
54% overall yield and 92:8 dr (i.e., C−C bond-forming step
proceeded with >99% diastereospecificity (ds)). The latter
sequence is not feasible with the products generated by the
G
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a
Scheme 7. Probing Polar Functional Group Compatibility
a
All reactions were performed under N2 atmosphere. Conversion (>98% in all cases), SN2′, Z:E selectivity, and the products derived from the probe
1
were determined by analysis of H NMR spectra of the unpurified mixtures ( 2%). Yields correspond to isolated and purified products and
represent an average of at least three runs ( 5%). Enantioselectivities were determined by HPLC analysis ( 1%). See the Supporting Information
for details.
recent Cu−H-catalyzed approach,16 further underlining the
importance of the alkenyl−B(pin) moiety in the products
generated by the present strategy.
selectivity and more byproduct formation and/or a sluggish
process (see Scheme 2b). Ligand screening indicated that Cu−
H addition to the allylic phosphate was again problematic.18
While adventitious B/Cu exchange with the less sterically
hindered monosubstituted 1b (vs 1a) could be addressed with
excess PMHS, the presence of a less hindered allene did less
than we hoped to counter competitive Cu−H addition to an
allylic phosphate. This was the case until we used the catalyst
derived from imid(S)-1b, the reaction with which generated
only 4% byproduct from Cu−H addition to the allylic
phosphate, far less than when imid(O)-1 or imid(S)-1a was
used (49% and 19%, respectively). The main side reaction was
B/Cu exchange, which led to 12% allenyl substitution.
Similar to the processes with 1a, excess LiOt-Bu gave more
allenyl side products (see Scheme 2a; e.g., >98% with 3.0 equiv
LiOt-Bu). As before, the reactions with phosphine ligands were
largely SN2-selective and generated up to 22% of the reduction
byproducts.
Alkyl- (5a−c), aryl- (5d−f), heteroaryl- (5g), and
carbocyclic-substituted (5h−j) 1,5-dienes were obtained in
56−83% yield and with exceptional regio-, diastereo-, and
enantioselectivity (Scheme 6a). The high diastereocontrol for
5i and 5j shows that either product isomer can be generated
when a chiral allylic phosphates with complete catalyst control.
Multicomponent reactions with a trisubstituted allylic
phosphate and monosubstituted allenyl−B(pin) were efficient
and stereoselective (12a−d, Scheme 6b). Still, additions to
alkenyl sites with a sterically demanding o-substituted aryl
group were efficient (e.g., o-bromo derivative of 12a: 10% yield
after oxidation to alcohol, >98:2 SN2:SN2′, 65:35 er). A
characteristic of the reactions in Scheme 6b is their lower
regioselectivity compared to when 1,1-disubstituted allene 1a is
involved (95:5 to >98:2 for 8a−g vs 80:20−90:10 SN2′:SN2 for
Conversion of the terminal alkene in 9 to alkyne 4 was more
complicated than expected. A two-step bromide formation/
elimination sequence24 led to modification at both olefinic
sites Oxidative cleavage of the less substituted alkene and
subjection of the resulting aldehyde to the Ohira−Bestmann
conditions,25 afforded the desired alkyne as equal mixture of
diastereomers, presumably due to epimerization.26 We there-
fore devised the following two-step/one-pot protocol. Z-
Selective cross-metathesis27 with 5.0 mol% Mo-1 and
commercially available 1,2-dibromoethene (∼2:1 Z:E mix-
ture), followed by the addition of LDA for 10 min (−78 → 0
°C) delivered 4 in 86% overall yield (Scheme 5).
Spectroscopic analysis indicated 94% conversion to 10, formed
as a 92:8 Z:E mixture. It is worth noting that Ru-based
complexes cannot be used to access halogen-substituted
alkenes,27 and that selective synthesis of Z-alkenyl halide is
key because elimination of the E isomer to the corresponding
alkyne is less facile.28
The seven-step sequence to 4 (32% overall yield, including
the two-step preparation of 1a) compares favorably with the
elegant pathway reported by Overman and co-workers in their
seminal studies (11 steps).12 The previously reported overall
yield is somewhat higher (39%). However, aside from the
significantly lower amounts of waste generated by the present
route the total reaction time is only 10 h, as opposed to 108 h
needed for the former sequence.
2.5. Reactions with Monosubstituted Allenyl Boro-
nate 1b. In the case of 1b, the less sterically hindered C−B
bond can lead to faster Cu−allene formation, and the greater
stability of Cu−allyl-branched-1b could mean lower regio-
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12a−d). Another distinguishing attribute is that SN2 addition
leads to chiral allylboronate side products (see 13, Scheme 6c
vs 3b’, Scheme 3). These findings suggest that the preference
for SN2′ selectivity arises from higher reactivityand not
greater stabilityof Cu−allyl-1b-linear (i.e., Curtin−Ham-
mett kinetics is operative). Reaction via I (Scheme 6c),
involving the more sterically demanding branched Cu−allyl
complex to form a tertiary C−C bond, thus becomes
competitive with reaction via II, leading to a more congested
quaternary carbon center site.
Scheme 8. Regarding Higher Efficiency with imid(S)-1b (vs
imid(S)-1a)
a
2.6. Functional Group Compatibility. To probe the
compatibility of the above methods to some of the more
commonly occurring functional units, the experiments
summarized in Scheme 7 were carried out. The catalytic
reaction proceeds without any complication in the presence of
a carboxylic ester or a carbamate (Scheme 7a,b). The presence
of an unprotected aniline did not have any inhibitory effect
(entry c). The same is not true with ketones, however; with
acetophenone present, while 5d was generated with slightly
lower efficiency but without any diminution in selectivity, the
ketone reacted completely to generate the derived secondary
alcohol (hydride addition; 75:25 er) and a mixture of
unidentifiable side products. Further studies showed com-
petitive reactivity with a ketone site is less problematic if the
carbonyl group is relatively hindered (entries e and f). The last
case (entry f) further underlines the fact that basic amines do
not adversely impact the rate of the multicomponent process.
2.7. Rationale for Unique Selectivity with imid(S)-1b.
The key mechanistic question at this point was: Why is the
copper complex derived from imid(S)-1b17b uncommonly
effective in promoting a multicomponent process? Control
experiments indicated that the Cu−H complexes derived from
imid(S)-1a and imid(S)-1b are similarly efficient in their
reaction with an allylic phosphate.18 This implies that what
makes the Cu−H complex derived from imid(S)-1b uniquely
effective is its ability to react more efficiently with an allenyl
boronate.
For better understanding, we carried out DFT calculations
(at the MN15/Def2-TZVPP//M06L/Def2-SVP level), which
indicated that the energy barrier for IIIgs → IIIts (Scheme 8) is
higher compared to IVgs → IVts (12.4 and 9.8 kcal/mol,
respectively). This may be due to several factors. (1) The
absence of an o-aryl substituent in the imid(S)-1b-derived
Cu−H complex allows the NAr ring to adopt a nearly coplanar
orientation with respect to the ligand heterocycle on the NHC
(C−N−C−C dihedral angle of 125.2° and 163.1° for IIIts and
IVts, respectively). Steric repulsion between the allene and the
N-aryl moiety is therefore minimized. (2) In the complex
derived from imid(S)-1b, the B(pin) and the protruding
isopropyl substituents seem to prefer being in a sterically
repulsive orientation (IVts). This may be attributed to
molecular recognition due to attractive dispersion forces
between the bulky isopropyl groups and the B(pin) moiety.29
The magnitude of Grimme’s D2 dispersion on the reaction
barriers (ωB97XD single-point calculations) indicate that the
corresponding attractive forces are approximately 5.0 kcal/mol
larger for conversion of IVgs to IVts (22.5 kcal/mol as opposed
to 17.5 kcal/mol for IIIgs → IIIts). Nevertheless, we are aware
that, recent support for such interactions28 aside, the precise
contribution by dispersion interactions in solution is subject to
debate.30
a
DFT calculations were carried out at the MN15/Def2-TZVPP//
b
M06-L/Def2-SVP level. Corresponds to Grimme D2 dispersion
obtained at the ωB97XD/Def2-TZVPP//M06-L/Def2-SVP level. See
the Supporting Information for details. Abbreviations: gs, ground
state; ts, transition state.
natural products, such as netamine C, are typically assembled
through modification of an amine, or by condensing a
guanidinyl substrate with an enone or an α-halocarbonyl
compound.31 Our plan was based on a completely different
strategy where an aliphatic aldehyde would be utilized, an
approach which, to the best of our knowledge, has not been
previously explored.
We prepared 1.73 g of 1,5-diene 5a by a multicomponent
process performed with 2.0 mol% catalyst loading (Scheme
9a). We formerly reported an alternative route for preparation
of 5a, entailing catalytic enantioselective allylic substitution
with a propargyl(pinacolato)boron reagent.20 The route, which
involves commercially 1b, furnished 5a directly in 73% yield,
and 93:7 er within 2 h. In the previously reported approach, 36
h was needed for a three-step sequence that gave the same
product in 41% overall yield and 91:9 er. Cross-metathesis of
5a and bis-phosphate 14a, derived from commercially available
2.8. Total synthesis of Netamine C. 2.8.1. Gram-Scale
Preparation of a Boryl-Substituted 1,5-Diene. Heterocyclic
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a
Scheme 9. Total Synthesis and Stereochemical Identity of Netamine C
a
All reactions were performed under N2 atmosphere. Conversion (>98% in all cases), SN2′, and Z:E selectivity were determined by analysis of 1H
NMR spectra of the unpurified mixtures ( 2%). Yields correspond to isolated and purified products and represent an average of at least three runs
( 5%). Enantioselectivities were determined by HPLC analysis ( 1%). See the Supporting Information for details.
diol 14b, delivered allylic phosphate E-15 in 69% yield and
95:5 E:Z ratio; this chemoselective reaction allowed us to use
the alkenyl−B(pin) moiety as masked allylic phosphate, to be
utilized later for a pair of allylic substitutions.
2.8.2. A Mild Catalytic Allylic Substitution Compatible
with a B(pin) Moiety. Achieving an efficient SN2′- and
diastereoselective allylic substitution to introduce an n-hexyl
moiety was next. The main issue here was that the Lewis acidic
boronate does not tolerate an alkyllithium, an alkylmagnesium
halide, a dialkylzinc compound, or a trialkylaluminum
reagentorganometallic species commonly used for such
transformations.32 We had to identify a process that would
involve a milder, but sufficiently nucleophilic, alkylmetal
reagent.
A search of the relevant literature led us to two approaches,
one entailing an in situ-generated alkylborane and a Z-allylic
chloride,33 and the other an alkylzinc halide and an aryl-
substituted secondary allylic carbonate.34 In the earlier study,
the only example of a reaction with a substrate containing an
allylic substituent proceeded with relatively low efficiency and
stereoselectivity. Adopting the latter approach would mean
generating a secondary allylic alcohol from the monosub-
stituted alkene, demanding manipulations that could probably
cause loss of enantioselectivity (i.e., via the aldehyde). We
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therefore set out to identify conditions for an efficient, regio-,
and stereoselective catalytic allylic substitution, involving a
primary E-allylic phosphate that contains an α-branched allylic
unit and a mild alkylmetal reagent.
eodivergency of the approach, by synthesis and spectroscopic
analysis of the originally proposed isomer (Scheme 9b).14
Subjection of E-15 to the aforementioned conditions, except
with (R)-imid(S)-1b, afforded the alternative diastereomer
(S,R)-16 in 76% yield and 92:8 dr (99% ds); comparison of
these data with those obtained when (S)-imid(S)-1b was used
(76:24 dr) indicated that the reaction involving E-15 and (R)-
imid(S)-1b represents the matched combination. The derived
alkenyl boronate was converted to (S,R,S)-7 as described
earlier (47% overall yield, 3 steps). The originally proposed
netamine C stereoisomer14 was obtained in 72% overall yield
(for 3 steps) and as a single diastereomer by treatment of the
latter aldehyde with hydrazine hydrate and concentrated HCl,
followed by catalytic hydrogenolysis and cyanogen bromide
(one-vessel protocol). When we instead used benzyl hydrazine
in the reaction with (S,R,S)-7, there was no detectable
conversion to the desired product, probably due to steric
repulsion caused by the n-hexyl substituent (oriented toward
the side chain). Spectroscopic analysis reconfirmed the
stereochemical assignment.
Exploratory studies revealed that an alkylzinc halide would
be suitable, and ligand screening showed that only the catalyst
derived from imid(S)-1b is effective, (primary allylic bromide
formed otherwise). Subjection of E-15 to n-hexylzinc bromide
(commercially available) and 5.0 mol% of the in situ-generated
NHC−Cu complex derived from (S)-imid(S)-1b afforded
(R,R)-17 in 70% yield and 76:24 dr (82% diastereospecificity,
ds). To improve efficiency and stereoselectivity, we examined
the same reaction except with Z-15 (Scheme 9a), prepared by
cross-metathesis between 5a and 14b with catechothiolate Ru-
2,35 followed by phosphate formation (53% overall yield,
>98:2 Z:E). We accordingly isolated (R,R)-16 in higher yield
(81%) and with improved stereoselectivity (89:11 dr, 96% ds).
Notably, the same isomer was generated predominantly,
regardless of E- or the Z-allylic phosphate being used.36 To
the best of our knowledge, the above processes are the first
cases of catalytic SN2′- and enantioselective allylic substitutions
with an alkylzinc halide reagent.32
3. CONCLUSIONS
The alkenyl−B(pin) terminus was converted to allylic
alcohol (R,R)-17 and then its corresponding phosphate
(R,R)-18 (77% overall yield, >98:2 E:Z). Another multi-
component allylic substitution with allenyl−B(pin) 1b and
catalyzed by the Cu−H complex derived from (S)-imid(S)-1b,
followed by oxidative workup, afforded γ-alkyl-substituted
aldehyde (R,R,S)-6 (65% yield, 96:4 dr). Ring-closing
metathesis gave cyclohexenyl intermediate (R,R,S)-7 in 93%
yield (Scheme 9a). We were thus able to address every issue
relating to absolute or relative stereochemical control by a
blend of three different allylic substitutions, all facilitated by
the Cu complex derived from imid(S)-1b.
The strategies introduced here represent an efficient, regio-
and enantioselective way of preparing versatile, multifunctional
organoboron compounds that can be used to prepare organic
molecules that possess important biological activities. High
efficiency was made possible by achieving high chemo-
selectivities, at times innately countering the desired sequence
of events. Multi-gram quantities of the requisite sulfonate-
containing imidazolinium salt imid(S)-1b can be accessed in
four steps and 54% overall yield by a revised procedure
developed as part of this study.18 Furthermore, 2.0 mol%
ligand loading suffices for reactions that are performed on gram
scale.
2.8.3. A Cycloaddition That Generates the Desired
Polycyclic Stereoisomer. To assemble the polycyclic core,
we first opted for an intramolecular [4+2] cycloaddition37
involving a 1,3-diazo-1,3-butadiene precursor (20, Scheme 9a).
N-Guanidinyl acetal (R,R,S)-19 was accessed by the use of a
procedure38 originally introduced for generating N-acyl-N,O-
acetals (73% yield). Treatment of (R,R,S)-19 with trifluoro-
acetic acid (110 °C, microwave, 1 h) and catalytic hydro-
genation, however, furnished the undesired diastereomer 21 in
88:12 exo:endo selectivity (58% yield). Examination of
molecular models pointed to considerable steric pressure in
the endo transition state 20a, favoring the exo alignment (i.e.,
favoring 20b → 21).
We can only go as far as our catalyst takes us, and for this set
of transformations several aspects of the NHC−Cu complex
derived from imid(S)-1b carried us a significant distance.
While other sulfonate bearing Cu complexes also afford
unusually high SN2′ selectivity (compared to other NHC− or
bisphosphine−Cu catalysts), a key distinction here is the subtle
but crucial influence of the substitution pattern at one of the
N-aryl moieties of the chiral ligand, allowing the rate of Cu−H
addition to an allene to be faster than its reaction with an
allylic phosphate.
The applications in multistep synthesis, aside from
confirming that the approach is indeed readily applicable to
preparation of relatively complex organic molecules, are
noteworthy for several reasons. In the case of the linear
fragment of pumiliotoxin B, the alkenyl−B(pin) group was first
used to effect a diastereoselective coupling with an
enantiomerically pure epoxide, and then the alkene terminus
was transformed to a monosubstituted alkyne by a catalytic Z-
selective cross-metathesis/elimination protocol. Sequences like
this have not been widely used and underscore the
considerable applicability of the poly-unsaturated organoboron
products obtained. Netamine C and its diastereomer were
synthesized by first converting the terminal alkene and then the
alkenyl−B(pin) unit, both to an appropriate allylic phosphate
in preparation for regio- and stereoselective allylic substitution.
The netamine C synthesis features three allylic substitutions,
all uniquely facilitated by the same NHC−Cu complex. One
allylic substitution provided access to 1,5-diene 5a by a highly
SN2′-selective and enantioselective Cu−H-catalyzed process,
To achieve endo selectivity, we turned to a [3+2]
cycloaddition strategy.39 We reasoned that, to attain the
proper orientation, the unfavorable exo pathway (22a) would
have to bear substantial strain. We prepared the necessary N-
benzyl hydrazone and heated it to 100 °C for 4 h, leading to
23, which was directly subjected to catalytic hydrogenolysis,
sodium methoxide, and cyanogen bromide,40 respectively. The
three-step/one-vessel protocol furnished the polycyclic prod-
uct corresponding to the revised netamine C structure in 88%
yield and >98:2 dr (Scheme 9a). The 10-step (eight-vessel)
synthesis route (14% overall yield) was thus completed.
2.8.4. Synthesis of the Originally Proposed Netamine C.
1
Comparison of the H and 13C NMR spectra of the above
product showed it to be identical to the natural product,
supporting Snider’s proposed structural revision.15 We sought
to confirm this assignment further, highlighting the diaster-
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functionalization of allenes via allyl copper intermediates. Chem. Sci.
2017, 8, 5240−5247.
another afforded (R,R)-16 after a mild, yet sufficiently
nucleophilic, alkylzinc bromide (formerly unknown), and a
third delivered (R,R,S)-6 through a Cu−H-catalyzed multi-
component transformation. The outcome of each C−C bond-
forming process is catalyst-controlled, constituting a flexible
and stereodivergent strategy for accessing every possible
stereoisomeric combination.
(4) (a) Tsai, E. Y.; Liu, R. Y.; Yang, Y.; Buchwald, S. L. A regio- and
enantioselective CuH-catalyzed ketone allylation of terminal allenes. J.
Am. Chem. Soc. 2018, 140, 2007−2011. (b) Miki, Y.; Hirano, K.;
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hydroamination of styrenes with polymethylhydrosiloxane and
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b05465.
■
S
(5) Han, J. T.; Jang, W. J.; Kim, N.; Yun, J. Asymmetric synthesis of
borylalkanes via copper-catalyzed enantioselective hydroallylation. J.
Am. Chem. Soc. 2016, 138, 15146−15149.
(6) Lee, J.; Torker, S.; Hoveyda, A. H. Versatile homoallylic
boronates by chemo-, SN2′-, diastereo-, and enantioselective catalytic
sequence of Cu−H addition to vinyl−B(pin)/allylic substitution.
Angew. Chem., Int. Ed. 2017, 56, 821−826.
(7) Gao, F.; Carr, J. L.; Hoveyda, A. H. A broadly applicable NHC−
Cu-catalyzed approach for efficient, site-, and enantioselective
coupling of readily available (pinacolato)alkenylboron compounds
to allylic phosphates and applications to natural product synthesis. J.
Am. Chem. Soc. 2014, 136, 2149−2161.
Experimental details for all reactions and analytic details
for all products (PDF)
X-ray crystallographic data for Cu−allyl-1b (CIF)
X-ray crystallographic data for 8d (CIF)
AUTHOR INFORMATION
Corresponding Author
*amir.hoveyda@bc.edu or ahoveyda@unistra.fr
■
́
́
(8) Basle, O.; Denicourt-Nowicki, A.; Crevisy, C.; Mauduit, M.
Copper-Catalyzed Asymmetric Synthesis;Alexakis, A., Krause, N.,
Woodward, S., Eds.; VCH-Wiley, 2014; pp 85−125.
ORCID
Amir H. Hoveyda: 0000-0002-1470-6456
Notes
The authors declare no competing financial interest.
(9) Semba, K.; Shinomiya, M.; Fujihara, T.; Terao, J.; Tsuji, Y.
Highly selective copper-catalyzed hydroboration of allenes and 1,3-
dienes. Chem. - Eur. J. 2013, 19, 7125−7132.
(10) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M.
Enantio- and diastereodivergent dual catalysis: α-allylation of
branched aldehydes. Science 2013, 340, 1065−1068.
ACKNOWLEDGMENTS
■
This research was supported by a grant from the National
Institutes of Health (GM-47480 and GM-130395). Y. Zhou
and Y. Shi were partially supported as LaMattina Graduate
Fellows Program in Chemical Synthesis. We thank B. Li for
assistance in obtaining X-ray structures.
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