Streamlined Catalytic Enantioselective Synthesis of α-Substituted β,γ-Unsaturated Ketones and Either of the Corresponding Tertiary Homoallylic Alcohol Diastereomers

Article abstract of DOI:10.1021/jacs.0c08732

A widely applicable, practical, and scalable strategy for efficient and enantioselective synthesis of β,γ-unsaturated ketones that contain an α-stereogenic center is disclosed. Accordingly, aryl, heteroaryl, alkynyl, alkenyl, allyl, or alkyl ketones that contain an α-stereogenic carbon with an alkyl, an aryl, a benzyloxy, or a siloxy moiety can be generated from readily available starting materials and by the use of commercially available chiral ligands in 52-96% yield and 93:7 to >99:1 enantiomeric ratio. To develop the new method, conditions were identified so that high enantioselectivity would be attained and the resulting α-substituted NH-ketimines, wherein there is strong CN → B(pin) coordination, would not epimerize before conversion to the derived ketone by hydrolysis. It is demonstrated that the ketone products can be converted to an assortment of homoallylic tertiary alcohols in 70-96% yield and 92:8 to >98:2 dr - in either diastereomeric form - by reactions with alkyl-, aryl-, heteroaryl-, allyl-, vinyl-, alkynyl-, or propargyl-metal reagents. The utility of the approach is highlighted through transformations that furnish other desirable derivatives and a concise synthesis route affording more than a gram of a major fragment of anti-HIV agents rubriflordilactones A and B and a specific stereoisomeric analogue.

Full text of DOI:10.1021/jacs.0c08732

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Article
Streamlined Catalytic Enantioselective Synthesis of α‑Substituted
β,γ-Unsaturated Ketones and Either of the Corresponding Tertiary
Homoallylic Alcohol Diastereomers
Juan del Pozo,§ Shaochen Zhang,§ Filippo Romiti,§ Shibo Xu, Ryan P. Conger, and Amir H. Hoveyda*
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ABSTRACT: A widely applicable, practical, and scalable strategy
for efficient and enantioselective synthesis of β,γ-unsaturated
ketones that contain an α-stereogenic center is disclosed.
Accordingly, aryl, heteroaryl, alkynyl, alkenyl, allyl, or alkyl ketones
that contain an α-stereogenic carbon with an alkyl, an aryl, a
benzyloxy, or a siloxy moiety can be generated from readily
available starting materials and by the use of commercially available
chiral ligands in 52−96% yield and 93:7 to >99:1 enantiomeric
ratio. To develop the new method, conditions were identified so
that high enantioselectivity would be attained and the resulting α-
substituted NH-ketimines, wherein there is strong CN →
B(pin) coordination, would not epimerize before conversion to the derived ketone by hydrolysis. It is demonstrated that the ketone
products can be converted to an assortment of homoallylic tertiary alcohols in 70−96% yield and 92:8 to >98:2 drin either
diastereomeric formby reactions with alkyl-, aryl-, heteroaryl-, allyl-, vinyl-, alkynyl-, or propargyl-metal reagents. The utility of the
approach is highlighted through transformations that furnish other desirable derivatives and a concise synthesis route affording more
than a gram of a major fragment of anti-HIV agents rubriflordilactones A and B and a specific stereoisomeric analogue.
that contain a methyl and an allyl group.7 A catalytic
1. INTRODUCTION
enantioselective strategy is available for preparation of ketones
Scores of catalytic methods have been and continue to be
masked as n-alkyl-substituted silylenol ethers, but the sole
developed for enantioselective synthesis of organic com-
option for a C-based substituent at the allylic stereogenic
pounds, but, typically, no more than a narrow range of
center is a 1,3-diester.8
products can be accessed, circumventing applicability to
Equally important, it is difficult to convertwith high
preparation of complex molecules. Two notable instances
diastereoselectivitythe aforementioned α-substituted ketone
relate to enantioselective synthesis of acyclic ketones
products to their derived tertiary alcohols, which are also
containing an α-stereogenic carbon center, a recurring unit
commonly occurring in bioactive compounds (e.g., rubri-
in bioactive molecules. Examples of natural products with one
flordilactones A and B,9−11 Scheme 1). Methods for catalytic
or more ketones adjacent to a stereogenic carbon include
enantioselective addition of allyl nucleophiles to ketones are
antibacterial jatrophenone1 and cebulactam A12 (Scheme 1).
available,12 but again, most instances involve a nonenolizable
Catalytic enantioselective protocols for synthesis of acyclic α-
ketone (e.g., aryl- or alkynyl-substituted; see the Supporting
substituted ketones have been reported, but several key
Information, SI, for extended bibliography);13,14 in one case
problems remain “still unconquered”, as characterized in a
reaction with an alkyl ketone led to low diastereomeric ratio
recent review article.3 The great majority of transformations
(dr),14b and in another selectivities were not at useful levels
deliver products where the carbonyl group and/or the
unless the α-substituent was sizable (e.g., a cyclohexyl
stereogenic center are aryl-substituted,4 a significant restriction
considering total synthesis of many bioactive molecules calls
for α-substituted aliphatic ketones (see Scheme 1). There are a
small number of strategies for enantioselective synthesis of α-
alkyl-substituted ketones, but these necessitate a priori
group).15 There are reactions that deliver homoallylic tertiary
alcohols bearing an E-alkenyl−B(pin) moiety but only if the
Received: August 13, 2020
generation of an enolate equivalent. There are also other
limitations. One method is confined to synthesis of
acylsilanes,5 another produces methyl ketones with an α-
quaternary stereogenic center attached to simple alkyl moieties
(Me and Et),6 and a third can be used to access only ketones
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We reasoned that if a wide range of enantiomerically
enriched β,γ-unsaturated, β-boryl ketones I (Scheme 2a) were
to become available, then the size of the β-B(pin) moiety could
be exploited toward stereoselective synthesis of every possible
tertiary alcohol isomer (II−V). We first considered accessing I
through a catalytic enantioselective multicomponent process
that might involve a monosubstituted allene, B2(pin)2, and an
aldehyde,13,18 followed by oxidation of the secondary alcohol.
We were however unable to isolate a β,γ-unsaturated ketone in
more than 30% yield (Scheme 2b). The major products were a
difficult-to-purify mixture of achiral α,β-unsaturated ketones
with a B(pin) and a B(OH)2 moiety, the latter of which,
containing a smaller boryl unit, is unsuitable for highly
diastereoselective additions (I → II−V, Scheme 2a). We
surmised that an activated form of a carboxylic acid derivative
might be used to prepare a β,γ-unsaturated ketone. In fact, a
catalytic enantioselective process involving acyl fluorides and
1,1-disubstituted allenes has been disclosed (Scheme 2b).19
Then again, substrates were aryl-substituted, and data
regarding processes involving monosubstituted allenes, which
would yield β,γ-unsaturated ketones prone to loss of
enantiomeric purity and/or alkene rearrangement, were not
included. In another recent disclosure, related transformations
were performed with anhydrides; as before, the method is
confined to 1,1-disubstituted allenes that must bear an aryl
moiety (Scheme 2b).20
Scheme 1. Bioactive Compounds Containing α-Substituted
Ketones or Tertiary Alcohol Derivatives
The state-of-the-art and the above considerations led us to
ponder the possibility of starting with nitriles, a readily
accessible set of compounds not used previously for
preparation of α-substituted ketones. We have demonstrated
that with an appropriate Cu-based catalyst reactions involving
a nitrile, a monosubstituted allene, B2(pin)2, and a silyl hydride
(PMHS) can be used to form a large assortment of β,γ-
unsaturated NH-ketimines (III, Scheme 3a), which are then
rapidly reduced in situ to afford the desired boryl-substituted
homoallylic amines (IV).21−23 The importance of the
envisioned strategy became clearer when we considered
possible enantioselective pathways for synthesis of the bicyclic
allylic carbon is quaternary (mostly methyl- and n-alkyl-
substituted).16 Another limitation is that the above trans-
formations generate one of the possible diastereomers,
undermining stereoisomeric analogues synthesis. Apropos, a
catalytic diastereodivergent and enantioselective approach for
preparation of tertiary homoallylic alcohols was recently
introduced; nonetheless, occasional low diastereoselectivities
aside, scope limitations were again an issue.17
Scheme 2. Initial Plan and Related Formerly Published Work
B
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Scheme 3. A Revised and More Flexible Strategy That Involves Nitriles as Substrates
segment and a diastereoisomeric analogue of rubriflordilac-
tones (2 and diast-2, Scheme 3b).24 We imagined a route that
could begin with commercially available alkyl nitrile 1, reaction
of which with a monosubstituted allene (i) and B2(pin)2 would
afford the corresponding β,γ-unsaturated NH-ketimine enan-
tioselectively. In situ hydrolysis would generate ii, a masked
and relatively stereochemically robust (less prone to loss of
enantiomeric purity) 1,3-diketone that bears differentiated
carbonyl groups. Ensuing diastereoselective addition to
generate tertiary alcohol iii, the alkenylboronate would be
oxidized to reveal the second ketone unit followed by lactone
generation. Formation of another tertiary alcohol (methyl
addition) would furnish iv, which would be converted to 2.
But our plan presented several challenges. The first
originated from the fact CN → B coordination enhances
ketimine electrophilicity, rendering it more susceptible to loss
of enantioselectivity than otherwise expected.21,25 A major
concern was not only if it would be possible to avoid
enantioselectivity erosion, but also whether enamine for-
mation, or isomerization to the (probably lower energy) α,β-
unsaturated isomer could be avoided. For conversion of the
same ketimines to the corresponding amines, rapid in situ
reduction of the NH-ketimine (see Scheme 3a) circumvented
such complications in the case of one set of stereoisomers, and
reduction at −78 °C was required for the other. Here, the
ketimine would have to remain intact for the duration of the
transformation, and without the need for low temperature
conditions, because hydrolysis would likely have to be
performed at room or near-ambient temperatures. We were
concerned that nitriles and/or allenes with an electron-
withdrawing substituent would be especially prone to these
types of side reactions. The same question extended to
ketimine hydrolysis and whether conditions could be found
that would be sufficiently mild so that the initial
enantioselectivity could be preserved.
Yet another issue was whether C = O → B coordination in ii
would be strong enough to allow for generation of one
diastereomer by allyl addition to a conformationally rigid
intermediate (ii → iii, Scheme 3b). If internal coordination
were to prove substantial, then we would have two options for
preparing diast-iii. One would entail, similar to the
aforementioned homoallylic amine syntheses (Scheme 3a),21
disruption of CO → B coordination with a stronger Lewis
acid (vs internal boron, to interact with the carbonyl
oxygen).21 Alternatively, we could begin with allyl nitrile 3
(also commercially available). Subsequent alkyl addition would
deliver diast-iii via vii; this would be followed by generation of
diast-iv and then diast-2, which is the fragment corresponding
C
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a
Scheme 4. Enantiomerically Enriched Ketones Bearing an α-Substituted C-Based Tertiary Stereogenic Center
a
Reactions were performed under N2 atm. Conversion (nitrile disappearance; > 98% in all cases) was determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields correspond to purified products ( 5%). Enantioselectivities were determined by HPLC analysis ( 1%).
b22 °C, 20 min. c2.2 mol % ligand (ent-phos-1 for 4k), 2.0 mol % CuMes, 1.2 equiv nitrile, 8 h. dFor 16 h, − 25 °C. eFor 36 h, − 40 °C. See the SI
for details.
to 5-epi-rubriflordilactone. The stability of 3 under the reaction
conditions would be key, as the corresponding allyl aldehyde is
more prone to alkene isomerization. If we were to find that
CO → B coordination is indeed weak, then we would
transform ketones ii and vii to tertiary alcohols iii and diast-iii
by sterically controlled diastereoselective addition of the
appropriate alkyl and allyl moieties via v and vi, respectively
(Scheme 3b). Regardless of the strategy used, the ability to
reverse the functional units within the substrate and the
nucleophilic agent would be critical, made possible by the
ready availability of nitriles. This all hinged on whether
additions to ketones would be highly diastereoselective.
of which can be purchased (Scheme 4a). The hydrolysis
conditions are mild (NH4Cl, typically for 10 min at 22 °C),
likely because, as already noted, of internal ketimine activation
by the neighboring Lewis acidic boron atom (see the SI for
screening studies).26
2.2. Range of α-Substituted Ketone Products. Aryl and
heteroaryl nitriles were converted to α-substituted β,γ-
unsaturated ketones in 71% to >98% yield and 95:5 to
>99:1 enantiomeric ratio (er; Scheme 4b). Transformations
with sterically hindered (2a), electron-deficient (2a-c), or
electron-rich (2d) nitriles were efficient and enantioselective.
Heteroaryl nitriles were equally suitable substrates (2e-h). An
aryl boronate (2b), an aryl bromide (2c), and an unprotected
amine (2d) were tolerated. Reactions with allenes that contain
a carboxylic ester (2a and 2d), a carbamate (2b), a methyl
(2c), or an aryl moiety (2i) were similarly effective.
Transformations of α,β-unsaturated nitriles afforded prod-
ucts in 66−91% yield and 99:1 er (Scheme 4c) without
competitive boryl conjugate addition, irrespective of the
alkene’s substitution pattern or stereochemistry. The case of
triene 3c demonstrates that allenes with an allylic substituent
are suitable substrates, and that Cu−B addition to an allene
occurs chemoselectively in the presence of a β-substituted aryl
olefin, which has been shown to undergo reaction readily with
a Cu−B(pin) complex (see also 4e, Scheme 4d).27
2. RESULTS AND DISCUSSION
2.1. Optimal Conditions for Synthesis of α-Substi-
tuted Ketones. After extensive screening, we identified
conditions for efficient enantioselective conversion of a nitrile,
an allene, and B2(pin)2 to the corresponding β,γ-unsaturated
ketone in high yield and enantioselectivity (Scheme 4). As
anticipated, reaction temperature (22 or −40 °C), the choice
of alcohol (MeOH), and the conditions for NH-ketimine
hydrolysis (time and the type of aqueous solution used) were
crucial factors (see below for analysis). The chiral catalyst was
generated in situ from a bisphosphine ligand (e.g., phos-1) and
a copper salt (e.g., CuMes (Mes, 2,4,6-trimethylphenyl)), both
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Additions to alkyl nitriles (Scheme 4d), which, as noted
above, are particularly important to synthesis of bioactive
compounds, were efficient and exceedingly enantioselective.
Effective substrates included those bearing an n-alkyl
substituent (4a-f, 76−89% yield, 98:2 to >99:1 er), which
may contain a halide (4a), an alkene (4b), a terminal alkyne
(4c), a carboxylic ester (4d), an azide (4e), or a triazole
moiety (4f). Acetonitrile was transformed to β,γ-unsaturated
ketones 4g-i (70−90% yield and 96:4−99:1 er). Ketone 4d,
precursor to diast-2 (see Scheme 3), was prepared on
multigram scale with just 1.0 mol % of the catalyst present.
β,γ-Unsaturated ketones 4j and 4k were synthesized by the use
of phos-1 and ent-phos-1, respectively, along with commer-
cially available monofluoroacetonitrile and an enantiomerically
pure allene bearing a Boc-protected amino acid residue.
(Reactions of CF2HCN and CF3CN were not investigated, as
these gaseous compounds are significantly more toxic and
difficult to use.) The transformation with sterically congested
tert-butylnitrile delivered 4l in 87% yield and >99:1 er. β,γ-
Unsaturated ketones containing a second allylic moiety (4m),
a propargylic group (4n), or a β-ketoester (4o) were formed
with similar ease and enantiomeric purity. Preparation of
ketones 4p,q, in which the carbonyl group is flanked by two α-
stereogenic centers, illustrate that additions to enantiomercally
pure nitriles can be under catalyst control (98:2 diastereomeric
ratio (dr), >99:1 er).
Oxygen-substituted allenes, accessible in a single step from
readily available compounds, are another noteworthy substrate
set. Thus, α-siloxy or α-benzyloxy β,γ-unsaturated ketones
were synthesized efficiently and in high enantioselectivity (6a-f,
Scheme 6). There are a limited number of protocols for
Scheme 6. Enantiomerically Enriched Ketones Bearing an
a
α-Substituted O-Based Tertiary Stereogenic Center
a
Reactions were performed under N2 atm. Conversion (nitrile
disappearance; > 98% in all cases) was determined by analysis of
1H NMR spectra of unpurified product mixtures ( 2%). Yields
correspond to purified products ( 5%). Enantioselectivities were
determined by HPLC analysis ( 1%). See the SI for details.
1,1-Disubstituted allenes were converted to α,α-disubsti-
tuted β,γ-unsaturated ketones (Scheme 5). Thus, aryl- (5a),
Scheme 5. Enantiomerically Enriched Ketones Bearing an
α-Quaternary Carbon Stereogenic Center
preparation of related compounds,3 including one that is
,
a
diastereodivergent (see the SI for a detailed bibliography).28
Persisting scope issues and the difficulties associated with
product modification notwithstanding, such transformations
represent a different bond disconnection (i.e., enolate trapping,
aldol additions, or hydroxy-amine additions).
2.3. Other Key Points Regarding α-Substituted
Ketone Synthesis.
(1) Enantioselectivities are time-dependent, with epimeriza-
tion occurring largely at the ketimine stage (see the SI
for data). As noted, this is likely because the internal
ketimine−boryl coordination increases Cα proton acid-
ity. Alkene isomerization occurs as well with extended
reaction times.
(2) Most transformations can be performed and quenched
at ambient temperature under mild conditions with little
or no loss in enantiomeric purity. In certain cases, it was
preferable for reactions to be carried out at −40 °C.
These were instances when either the NH-ketimine
could displace a leaving group intramolecularly (e.g., 4a,
Scheme 4d), or lowering of er was more of an issue
because the product had an aryl-substituted ketone and
stereogenic center (e.g., 2i, Scheme 4b), or the nitrile
contained a Lewis basic or more strongly electron-
deficient moiety (e.g., 2g, Scheme 4).
(3) Reactions were faster when MeOH was used, delivering
products in higher er compared to when a larger alcohol
was utilized (see the SI for the relevant data). The
increased rate with the smaller alcohol likely results from
more efficient protonolysis of the bisphosphine−Cu−
ketimine complex, leading to faster catalyst regeneration;
there was only ∼10% conversion with t-BuOH.
Diminished enantioselectivity with i-PrOH is probably
a
Reactions were performed under N2 atm. Conversion (nitrile
1
disappearance; >98% in all cases) was determined by analysis of H
NMR spectra of unpurified product mixtures ( 2%). Yields
correspond to purified products ( 5%). Enantioselectivities were
determined by HPLC analysis ( 1%). See the SI for details.
heteroaryl- (5b,c), alkyl- (5d,e), and alkynyl-substituted (5f)
products were obtained in 52−94% yield and 93:7 to >99:1 er.
For these transformations, the catalyst derived from
commercially available (R)-(−)-DTBM-segphos afforded
superior results in most cases (vs phos-1; see the SI for
further analysis). It is worth noting that, compared to the
aforementioned approach involving acyl fluorides and
anhydrides,19,20 a broader range of products can be accessed.
E
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nucleophile, having to rely solely on steric factors (vs CO →
B(pin) coordination and its disruption).
due to slower protonolysis of the copper−ketimine
intermediate (i.e., less facile C = N−CuLn + ROH → C
= NH + ROCuLn), and, as already mentioned, the
longer reaction time allows for more extensive
enantioselectivity erosion prior to ketimine hydrolysis.
Because C−C bond formation is slower for products
containing a quaternary carbon (Scheme 5), proto-
nolysis of the copper−allyl intermediate becomes more
competitive (see the SI for further analysis). Use of a
bulkier ligand and/or proton source (epimerization no
longer an issue) thus proved to be advantageous, and the
transformations with 1,1-disubstituted allenes were
higher yielding with i-PrOH and/or DTBM-segphos
(see the SI for additional data).
Addition of MeLi to phenyl ketone 2k (−78 °C, thf)
afforded R,R-7a in 91:9 dr, and with MeMgBr, the reaction was
inefficient and minimally diastereoselective (17% conv, 68:32
dr). We reasoned that in a process largely controlled by steric
factors, a more sizable nucleophile should be more
diastereoselective, and thus investigated additions of organo-
cerium compounds.33,34 This led us to find that by combining
MeLi or MeMgCl and CeCl3·2LiCl,34 a salt that facilitates Li
or Mg/Ce ligand exchange,35 R,R-7a can be isolated in 77%
yield and 97:3 dr (Scheme 8). Under the same conditions, we
obtained doubly homoallylic tertiary alcohol 7b in 93:7 dr.
Synthesis of tert-butyl-substituted alcohol 7c and monopro-
tected 1,2-diol 7d did not require a Ce-based reagent,
presumably because t-BuLi is sufficiently large and the
benzyloxy unit can accommodate a chelate structure to ensure
high diastereoselectivity.36 As the neighboring hydroxy group
engenders partial hydrolysis of the pinacolato moiety, products
were isolated, after NaIO4/NH4OAc workup, as robust and
easily isolable boronic acids (see the SI for details). Analytical
data indicate that there is no adventitious loss of enantiomeric
purity during nucleophilic addition (e.g., 97:3 and 98:2 er for
7b and 7d, namely, the identical enantiomeric purity recorded
for the corresponding α-substituted ketone precursors; see the
SI for additional details).
Additions of aryllithium and heteroaryllithium compounds
were equally efficient and diastereoselective (Scheme 9).
Products S,R-7a, complementary to the aforementioned R,R-
7a (Scheme 9), doubly homoallylic alcohol S,R-8a, and
pyridyl-, and thienyl-substituted 8b and 8c were isolated in
63−81% yield and 92:8 to >98:2 dr. Diastereoselective
formation of aryl,aryl-substituted tertiary alcohols S,R-8d and
R,R-8d, preparation of which by alternative strategies would be
challenging, underscores the versatility of the approach. As
before, analysis of the enantiomeric purity of the tertiary
alcohols indicated that there was no epimerization occurring
during nucleophilic addition (see S,R-8d and R,R-8d, Scheme
9).
(4) Reactions are easy to perform. The chiral ligands are
purchasable; phos-1 belongs to a family of ligands used
on industrial scale.29,30 The majority of the nitriles are
commercially available and others can be synthesized in
one to two steps (see the SI for details). Many
stereochemically defined alkenyl nitriles (Scheme 4c)
can be prepared stereoselectively by catalytic cross-
metathesis.31 Most allenes can be obtained in one to two
steps (see the SI for details). Methylallene is a feedstock
compound used as fuel additive. A small excess of an
allene and B2(pin)2 suffices.
2.4. Diastereoselective Conversion to Tertiary Ho-
moallylic Alcohols. Owing to variations in reactivity and size
between nucleophiles and difficult-to-predict impact of
enthalpic and/or entropic factors,32 we surmised that different
sets of conditions and optimal reagents would be needed to
transform the above β,γ-unsaturated ketone products to
various corresponding tertiary homoallylic alcohols.
The first issue was whether there is significant internal C
O → B coordination within the ketone products. Spectroscopic
studies and X-ray structures of β,γ-unsaturated ketones 2j and
5g (Scheme 7) revealed thatunlike NH-ketimines21the
boron atoms are tricoordinate. That is, as noted before (see
Scheme 3), to access either diastereomer with high selectivity,
we would need to manipulate the identity of the nitrile and the
We then examined additions of different allylmetal
compounds to α-substituted β,γ-unsaturated ketones. This
included Ce-, Cu-, and Ti-based reagents generated in situ
from reaction of an allylmagnesium chloride or allylzinc
bromide (see the SI for details). Reaction with a blend of
allylmagnesium chloride and CeCl3 in thf resulted in
conversion of 2k to R,R-8a [for S,R-8a, see Scheme 9] in
80% yield and 91:9 dr after 10 min at room temperature. A
more generally effective protocol entailed the use of a mixture
of allylmagnesium chloride and manganese pivalate37 [pre-
pared from inexpensive Mn(OAc)2]. After 1 h at −78 °C,
doubly homoallylic tertiary alcohols R,R-8a and 9a-c were
isolated in 70−89% yield and 92:8 to >98:2 dr (Scheme 10).
These selectivity trends may be attributed to varying sizes of
the anionic ligand, a hypothesis supported by the observation
that when MnCl2 and MnBr2 were used, diastereoselectivities
were lower (e.g., R,R-8a in 85:15 and 86:14 dr, respectively).
α-p-Methoxybenzyl-substituted ketone 9d (Scheme 10) was
obtained in 76% yield and 97:3 dr when allylmagnesium
bromide was used (no Mn salt), likely due to chelation control.
Similar to diastereoselective alkyl and aryl additions, we did
not observe any loss of enantiomeric purity in a diaster-
eoselective allyl addition processes (see 9c-d, Scheme 10).
Scheme 7. X-ray Structures Show No Carbonyl to Oxygen
Coordination
a
a
See the SI for details.
F
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a
Scheme 8. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of an Alkyl Group
a
Reactions were performed under N2 atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields correspond to purified products ( 5%). Enantioselectivities were determined by HPLC analysis ( 1%).
See the SI for details.
The combination of vinylmagnesium bromide or an
alkynyllithium compound and CeCl3·2LiCl was used to
synthesize tertiary allylic and propargylic alcohols 10 and 11
(Scheme 11; in 88% and 85% yield and 96:4 and 97:3 dr,
respectively). We confirmed that alkynyl additions proceed
without any competitive epimerization of the α-substituted
ketone substrate (see 11). Homopropargylic tertiary alcohol
12a was prepared by treatment of ketone 2l with an organozinc
halide, formed in situ from the commercially available
bromide. Conversion of ester-substituted ketone 4d to
butyrolactone 12b was performed on multigram scale (78%
yield, >98:2 dr).
2.5. Functionalization of α-Substituted Ketones and
Tertiary Homoallylic Alcohols. Ketones and tertiary alcohol
products prepared through the strategies detailed above can be
efficiently, chemoselectively, and/or diastereoselectively modi-
fied to generate other desirable entities (Scheme 12; see the SI
for more examples). For instance, α-substituted ketone 4d was
transformed in two steps to trisubstituted alkenyl boronate 13
in 70% overall yield and 92:8 dr. Again, we did not detect any
loss of enantiomeric purity (13 in 97:3 er; see the SI for
details). Spirocyclic butyrolactones are recurring motifs in
naturally occurring bioactive compounds (e.g., anti-inflamma-
tory curcumalactones38,39). A different type of lactone was
prepared by catalytic conversion40 of S,R-8d to α,β-
unsaturated butyrolactone 14 in 71% yield (98:2 er, no loss
of enantiomeric purity), providing access to another building
block regularly found within bioactive compounds (e.g.,
antimalarial arteannuin41). Syntheses of homoallylic alcohols
15a,b, isolated in 93% and 91% yield after NHC−Cu-catalyzed
C−B to C−H transformation, are equally important
derivatives. Regarding 15a, the necessary alkyl-substituted
ketones cannot be easily prepared by alternative methods (e.g.,
catalytic multicomponent CuH-catalyzed approaches)14b,15
and enantioselective synthesis of 15b would be most
challenging through addition to a virtually symmetric ketone.
Analysis of the enantiomeric purity of 15b indicated that there
was no loss in er during the pathway starting from the
corresponding α-substituted ketone (98:2 er). The p-
methoxybenzyl group in 6f was removed to give α-hydroxy
ketone 16 in 85% yield (Scheme 12) with a slight loss of
enantiomeric purity (98:2 vs 95.5:4.5 er). Compounds such as
16 have been used for enantioselective preparation of rare
sugars and the corresponding bioactive molecules.42
2.6. Application to Synthesis of Rubriflordilactones A
and B Fragment 2. The functional groups in an α-substituted
β,γ-unsaturated ketone may be modified chemoselectively, as
underscored by enantio- and diastereoselective synthesis of a
fragment of rubriflordilactones A and B (2; Scheme 13). The
same moieties can be found in other anti-HIV compounds,
such as members of the schisandraceae family of natural
triterpenoids.43
By using 2.0 mol % of the Cu complex derived from ent-
phos-1, we synthesized multigram quantities of ketone S-4m in
83% yield and 96:4 er. The reaction was performed with air-
stable Cu(PPh3)3F·2EtOH44 (vs CuMes) and without rigorous
exclusion of air and moisture. Diastereoselective addition of an
organocerium species, generated in situ by treatment of
commercially available chloride 17 and lithium 4,4-di-tert-
butylbiphenylide (LiDBB; to generate the alkyl−Li reagent)
and CeCl3, was followed by alkenyl boronate oxidation,
furnishing 18 in 99% yield and 96:4 dr, again without any
diminution in enantiomeric purity (96:4 er). The tertiary
alcohol was accordingly generated and the second ketone
moiety was unmasked by a single-vessel operation. One-step
acetal removal/cyclization and oxidation45 delivered lactone 19
(∼3.1 g). Chemoselective methyl addition to the ketone (vs
cyclic ester) by treatment of 19 with CeCl3 (22 °C) and then
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Scheme 9. Diastereoselective Synthesis of Tertiary
Homoallylic Alcohols Through Addition of an Aryl Moiety
Scheme 10. Diastereoselective Synthesis of Tertiary
Homoallylic Alcohols Through Addition of an Allyl Group
a
a
a
Reactions were performed under N2 atm. Conversion (nitrile
disappearance; > 98% in all cases) was determined by analysis of
1H NMR spectra of unpurified product mixtures ( 2%). Yields
correspond to purified products ( 5%). Enantioselectivities were
determined by HPLC analysis ( 1%). See the SI for details.
several methyl anion equivalents to lactone 12b (see Scheme
8), but were unable to isolate 23 in more than 20−30% yield.
Spectroscopic analysis indicated competitive addition to the
lactone carbonyl group. Identifying an alternative route was
not challenging because of the variety of nitriles that can be
easily accessed and the different nucleophilic compounds that
may be used to convert a β-boryl ketone to the desired tertiary
alcohol.
a
Reactions were performed under N2 atm. Conversion (nitrile
disappearance; > 98% in all cases) was determined by analysis of
1H NMR spectra of unpurified product mixtures ( 2%). Yields
correspond to purified products ( 5%). Enantioselectivities were
determined by HPLC analysis ( 1%). See the SI for details.
MeMgCl (−78 °C),46 delivered tertiary alcohol 20 (85% yield;
∼4.0 g). The corresponding α,β-unsaturated lactone was
subsequently prepared,47 leading to concomitant intramolec-
ular conjugate addition to generate bicyclic lactone 21 (55%
yield; 68% yield, based on recovered 20). Simultaneous
removal of the silyl groups and oxidation of the primary
alcohol afforded 2 (89% yield, 2 steps). Thus, the 11-step route
afforded the desired fragment in 22% overall yield (10 steps
and 27% overall yield if the alcohol precursor to the allene is
purchased vs 16% overall yield and 16 steps previously24). We
were able to synthesize ketone S-4m and tertiary alcohol 18 on
multigram scale easily, efficiently, and in high er and dr,
respectively (Scheme 13), allowing us to secure 1.06 g of 2.
The X-ray structure of 2 confirmed its assigned stereochemical
identity.
2.7. Synthesis of a Stereochemical Analogue of
Rubriflordilactones A and B Fragment. To synthesize
the fragment corresponding to 5-epi-rubriflordilactone (diast-
2), we began with 12c, a compound that carries the requisite
alkynyl moiety. This is unlike the route leading to 2 (Scheme
13) where an alkene-to-alkyne approach strategy was adopted.
The difference in strategy arises because for the earlier
sequence the necessary propargylic substrate, unlike most
other nitriles, was not sufficiently stable for us to obtain
reproducible results. We first investigated the addition of
We chose to retain the alkenyl boronate in 12c and use it to
generate 1,1-disubstituted alkene by catalytic cross-coupling
(Scheme 14).48 Regioselective synthesis of the tertiary alcohol
23 was accomplished by the use of a Co-based complex49
(61% overall yield for three steps from 4d, >98:2 dr).
However, attempts to prepare the derived α,β-unsaturated
lactone, under the conditions used to generate 21, were
ineffective (mixture of byproducts). We attributed this to
adventitious influence of the lithium alkoxide, likely formed
under the basic conditions. To address this problem, we
prepared the corresponding tertiary silyl ether prior to α,β-
unsaturated lactone formation.50 The desired bicylic lactone
was obtained cleanly by addition of a fluoride salt, unmasking
the tertiary and primary alcohols (one-pot operation).
Oxidation of the primary alcohol furnished diast-2 in 76%
yield (three steps from 23) and >98:2 dr (Scheme 14). The
nine-step route (seven steps, longest linear sequence) afforded
the desired product in 32% overall yield (including synthesis of
the allene in two steps and 78% yield). In comparison, the
same fragment has been formerly prepared in eight steps (six
steps, longest linear sequence) and 19% overall yield.51 Neither
of the reported strategies for diastereo- and enantioselective
synthesis of 2 or diast-2 are easily amenable to preparation of
the alternative diastereomer.
H
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Scheme 11. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of a Vinyl, an Alkynyl, or a
a
Propargyl Group
a
Reactions were performed under N2 atm. Conversion (nitrile disappearance; > 98% in all cases) was determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields correspond to purified products ( 5%). Enantioselectivities were determined by HPLC analysis ( 1%).
See the SI for details.
owing to internal coordination between the ketimine N and
the neighboring Lewis acidic B, would be able to retain its
enantiomeric purity for the duration of the transformation at
ambient or near-ambient temperatures. The presence of a
B(pin) moiety also had its advantages. The possibility of
generating useful derivatives (e.g., cross-coupling) aside, the
size of the boryl moiety made it possible for different
nucleophilic additions to the neighboring ketone to be
exceptionally diastereoselective.
The considerable scope of the approach is mostly because of
three factors: (1) countless nitriles can be purchased or
prepared easily, (2) various allenes are readily accessible, (3)
many useful C-based moieties can be added to the ketone
products in high yield and dr, and (4) key substrates, such as
allyl nitrile, are sufficiently robust to allow them to be used in
efficient and highly enantioselective transformations that
generate ketones and would be more difficult to prepare by
3. CONCLUSIONS
In brief, we offer practical and generally applicable solutions to
two longstanding problems in the synthesis of bioactive
compounds and their different analogues: streamlined methods
for enantioselective preparation of easily modifiable α-
substituted ketones and their diastereoselective conversion to
tertiary homoallylic alcohols, which may be accessed in either
diastereomeric form. Substrates, ligands, and the Cu salt are
commercially available or can be prepared easily. A large excess
of any of the starting materials partners or a glovebox is not
needed. The transformations are scalable.
One key challenge was finding a way to synthesize α-
substituted β,γ-unsaturated ketones that contain a B(pin)
moiety at Cβ in high enantioselectivity and avoiding
subsequent erosion of enantiomeric purity or isomerization.
This required identifying conditions under which the ketimine
intermediate, which is particularly prone to epimer formation
I
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a
Scheme 12. Representative Modifications of α-Substituted Ketones and Tertiary Homoallylic Alcohol Products
a
Reactions were performed under N2 atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields correspond to purified products ( 5%). Enantioselectivities were determined by HPLC analysis ( 1%).
See the SI for details.
a
Scheme 13. Enantio- and Diastereoselective Gram Scale Synthesis of a Fragment of Rubriflordilactones A and B
a
Reactions were performed under N2 atm. Conversion (nitrile disappearance; > 98% in all cases) was determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields correspond to isolated and purified products ( 5%). Enantioselectivities were determined by HPLC
analysis ( 1%). See the SI for details.
J
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Shaochen Zhang − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill, Massachusetts
02467, United States
Scheme 14. Enantio- and Diastereoselective Synthesis of a
Fragment of 5-epi-Rubriflordilactone A and B′′
a
Filippo Romiti − 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; orcid.org/0000-0003-1903-9901
Shibo Xu − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Ryan P. Conger − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c08732
Author Contributions
§These authors contributed equally to this work.
a
Reactions were performed under N2 atm. Conversion (nitrile
1
Notes
disappearance; >98% in all cases) was determined by analysis of H
The authors declare no competing financial interest.
NMR spectra of unpurified product mixtures ( 2%). Yields
correspond to isolated and purified products ( 5%). Enantioselectiv-
ities were determined by HPLC analysis ( 1%). See the SI for details.
ACKNOWLEDGMENTS
■
This research was supported by a grant from the National
Institutes of Health (GM-130395). S.Z. was supported as a
LaMattina Graduate Fellow in Chemical Synthesis. J.d.P. was
partially supported by a postdoctoral fellowship from Alfonso
Martin Escudero Foundation. We thank Dr. B. Li for assistance
in obtaining X-ray structures.
the use of an aldehyde, an ester, or an anhydride. By managing
the identity of the nitrile substituent and the organometallic
entity that serves as the nucleophile, a sizable assortment of
tertiary homoallylic alcohols can be prepared efficiently and in
high enantio- and diastereomeric purity in every possible
stereoisomeric form. The application to a fragment of
rubriflordilactones A and B and a stereoisomeric derivative
supports our claim.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c08732.
Experimental details for all reactions and analytic details
for all products (PDF)
NMR spectral details (PDF)
Crystallographic data (CIF)
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AUTHOR INFORMATION
Corresponding Author
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; orcid.org/0000-0002-1470-6456;
■
Email: amir.hoveyda@bc.edu, ahoveyda@unistra.fr
Authors
Juan del Pozo − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
K
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https://dx.doi.org/10.1021/jacs.0c08732
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX