Sustainable Asymmetric Organolithium Chemistry: Enantio- and Chemoselective Acylations through Recycling of Solvent, Sparteine, and Weinreb “Amine”

Article abstract of DOI:10.1002/cssc.201802815

The well-established Hoppe–Beak chemistry, which involves enantioselective generation of organolithium compounds in the presence of (?)-sparteine, was revisited and applied to unprecedented acylations with Weinreb amides to access highly enantioenriched α-oxyketones and cyclic α-aminoketones. Recycling of the sustainable solvent cyclopentyl methyl ether, sparteine, and the released Weinreb “amine” [HNMe(OMe)] was possible through a simple work-up procedure that enabled full recovery of these precious materials. The methodology features a robust scope and flexibility, thus allowing the enantioselective preparation of scaffolds amenable of further derivatization.

Full text of DOI:10.1002/cssc.201802815

Accepted Article
Title: Sustainable Asymmetric Organolithium Chemistry: Enantio-
and Chemoselective Acylations through Recycling of Solvent,
Sparteine and Weinreb “Amine”
Authors: Serena Monticelli, Wolfgang Holzer, Thierry Langer,
Alexander Roller, Berit Olofsson, and Vittorio Pace
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.201802815
Link to VoR: http://dx.doi.org/10.1002/cssc.201802815
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10.1002/cssc.201802815
ChemSusChem
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Sustainable Asymmetric Organolithium Chemistry: Enantio- and
Chemoselective Acylations through Recycling of Solvent,
Sparteine and Weinreb “Amine”
Serena Monticelli,[a] Wolfgang Holzer,[a] Thierry Langer,[a] Alexander Roller,[b] Berit Olofsson*[c] and
Vittorio Pace*[a]
Abstract: The well-established Hoppe-Beak chemistry, which
observed by Aggarwal in the course of the synthesis of ()-
involves enantioselective generation of organolithiums in the
presence of ()-sparteine, has been revisited and applied to
unprecedented acylations with Weinreb amides to access highly
enantioenriched α-oxyketones and cyclic α-aminoketones. Recycling
of the sustainable solvent cyclopentyl methyl ether, sparteine and the
released Weinreb “amine” [HNMe(OMe)] was possible through a
simple work-up procedure that enabled full recovery of these precious
materials. The methodology features a robust scope and flexibility,
thus allowing the enantioselective preparation of scaffolds amenable
of further derivatization.
stemaphylline in the presence of the (+)-sparteine surrogate.[18]
Surprisingly, the Hoppe-Beak approach did not find
application to synthesize ketones, thus underestimating its full
preparative potential.[19] This is quite astounding since
enantiomerically enriched α-substituted ketones constitute
privileged frameworks across the chemical sciences. Based on
our experience of chemoselective acylations of α-substituted
carbanions with Weinreb amides,[20] we devised an enantio- and
chemoselective methodology to reach a wide scope of α-
oxyketones and cyclic α-aminoketones in high yields, without the
need for column chromatography (Scheme 1c). Furthermore, a
practical method for the sustainable recovery of solvent,
sparteine and Weinreb amine was devised, and the recovered
materials were demonstrated to be equally efficient in
subsequent transformations.
Introduction
Construction of new carbon-carbon bonds with full control of
stereochemistry is highly demanded in organic synthesis.[1] The
conceptual simplicity of transferring an enantioenriched
nucleophile to a given electrophile emerged over the years as a
reliable technique to accomplish this goal.[2] In the beginning of
the 1990s, pioneering studies of Hoppe[3] and Beak[4] culminated
in the development of strategies for asymmetric generation of
highly nucleophilic organolithium species, which could be
delivered to
stereofidelity (Scheme 1a).[5] The combination of the Lupinus
mutabili alkaloid (
)-sparteine[6] and s-BuLi to provide a chiral
a
plethora of electrophiles with excellent

base for the deprotonation event, and the use of an apolar
solvent (e.g. diethyl ether) often ensured the preservation of the
stereochemical information contained in the nucleophile.[7]
Unfortunately, both factors pose severe limitations on the
sustainability of the processes.
The full potential of this versatile methodology is limited by the
scarce commercial availability of sparteine in both enantiomeric
forms,[8] and the inherent issues for its total synthesis
methodologies.[9] Additionally, the hazards of diethyl ether
(flammability, low boiling point, peroxide formation, etc.)[10] make
this tactic poorly attractive from a green chemistry perspective,
clearly violating the 3nd, 4th, 5th and 7th Anastas’ Principles.[11]
Notwithstanding, the sparteine-mediated methodology is quite
flexible and adaptable to conceptually different chemistries to
access highly versatile enantioenriched building blocks (Scheme
1a), e.g. Aggarwal’s homologated boronates,[12] O’Brien’s chiral
sulfoxides[13] and Baudoin’s arenes,[14] which can be further
elaborated e.g. in Aggarwal’s assembly line synthesis.[15]
During a recent study on the synthesis of thioamides from
isothiocyanates and organolithium reagents,[16] we noticed that
the combination of sparteine and the sustainable solvent
cyclopentyl methyl ether (CPME)[17] effectively achieved a high
level of stereocontrol (Scheme 1b). Additionally, this solvent
promoted fast lithiations of hindered benzoate esters, as
Scheme 1. General context of the work.
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Results and Discussion
Table 1. Optimization of the reaction.
Hoppe’s carbamate 1[5a] and the challenging Weinreb amide
2,
featuring a potentially exchangable bromine substituent, were
selected as the model substrates (Table 1). The use of 1.3 equiv
s-BuLi and 1.3 equiv (
)-sparteine resulted in a satisfactory
isolated yield and enantiomeric ratio (97:3) of ketone
3
after a
Entry
Solvent
1 / s-BuLi / Lithiation
Yield of er of
(-)-sparteine
(equiv)
time (min)
3 (%) [a]
3
lithiation time of 2 h (entry 1). Increased reagent amounts only
slightly improved the yield (entries 2-3), suggesting that the
reagent loading does not play a crucial role in the process. We
were delighted to find that reduced lithiation time increased the
1
CPME
CPME
CPME
CPME
CPME
CPME
CPME
THF
1 / 1.3 / 1.3
1.5 / 1.6 / 1.6
1.9 / 2.0 / 2.0
1.5 / 1.6 / 1.6
1.5 / 1.6 / 1.6
1.5 / 1.6 / 1.6
1 / 1.3 / 1.3
120
120
120
60
65
70
72
78
95
45[b]
81
55
30
21[b]
-
97:3
97:3
97:3
97:3
97:3
-
2
efficiency of the reaction, and an excellent 95% yield of
observed after only 30 min (entries 4-5). Shorter lithiation time
proved insufficient, and a mixture of ketones and different
3 was
3
3
4
unidentified byproducts were formed, presumably due to attack
of s-BuLi on the Weinreb amide (entry 6). The reaction proved
less efficient with 1.3 equiv reagents also when 30 min lithiation
time was used (entry 7).
5
30
6
15
7
30
97:3
60:40
80:20
-
Solvents were subsequently screened, and THF dramatically
induced racemization (entry 8), in agreement with previous
studies.[5a] This was true also for toluene (entry 9), whereas
lithiation in the commonly employed Et2O was very limited within
30 min (entry 10). Clearly, the chemical stability of the lithiated
carbamate is the main factor governing the transformation and
its prompt generation in CPME ensures the success of the
process. This solvent very efficiently preserves the
stereochemical information of the nucleophile during the
substitution event. CPME is a promising, apolar solvent[21] that is
highly stable under strongly basic conditions, features low
peroxide formation tendency, and narrow explosion range, thus
fulfilling the 3nd, 4th, 5th and 12th Green Chemistry Principles.[11]
Furthermore, the use of CPME was essential to avoid
chromatographic purifications.
8
1.5 / 1.6 / 1.6
1.5 / 1.6 / 1.6
1.5 / 1.6 / 1.6
1.5 / 1.6 / 1.6
1.5 / 1.6 / 1.6
1.5 / 1.6 / 1.6
30
9
Toluene
Et2O
30
10
11[c]
12[d]
13[e]
30
CPME
CPME
CPME
30
-
30
18
91
94:7
97:3
30
[a] Isolated yields. [b] Byproducts were observed. [c] The corresponding
[d]
ester was employed instead of 2. The corresponding acid chloride
was used instead of 2. [e] (-)-Sparteine recovered from the reaction in
entry 5 was employed.
With the optimized conditions in hand, the scope of the reaction
was investigated using a range of Weinreb amides (Scheme 2).
High chemoselectivity was uniformly observed, and aromatic (
10), heteroaromatic (11 12), conjugated (13 14) and aliphatic
15 17 ketones were formed in excellent yields and
3-
Weinreb amides proved to be crucial as acylating agents for
the reaction outcome,[22] as demonstrated by the lack of reactivity
of the corresponding ester (entry 11) and by the limited yield with
the corresponding acid chloride (entry 12).
-
,
(
-
)
enantiomeric ratios. Substitution across the aromatic moieties of
Weinreb amides was well tolerated, except in the case of ortho-
The sustainability elements of the process make this efficient
transformation highly attractive: a) recovering the precious (-)-
sparteine according to the Aggarwal procedure[15] proved easily
applicable to the presented methodology, and neither chemical
yield nor er were affected when it was reused in another reaction
(entry 13). b) Analogously, the N,O-dimethylhydroxylamine
fragment of the Weinreb amide, which is released at the end of
the sequence, can easily be recycled and reused for preparation
of additional Weinreb amides.[23] c) The substantial immiscibility
of CPME with water allowed avoidance of classical organic
solvents (e.g. EtOAc, Et2O) during the work-up and, more
fluoro analogue
6 which gave somewhat lower er. Sterically
congested amides, as well as α-substituted amides, could also
be employed (15-17). The protocol manifests genuine 1,2-
selectivity with unsaturated Weinreb amides (13, 14), which in
principle could suffer from conjugate addition (vide infra).
Gratifyingly, both enantiomers of a given ketone could be
prepared in comparable efficiency and enantiopurity by selecting
()- or (+)-sparteine, respectively. Recovered (average 80%)
sparteine, was employed in several entries to demonstrate the
efficiency of this process (footnote b – Scheme 2). Furthermore,
the protocol allowed to recover with comparable efficiency
CPME and N,O-dimethylhydroxylamine which could be
advantageously reused whenever necessary. Unambiguous
importantly, analytically pure ketone
3 was obtained after simple
recrystallization from the reaction medium. d) The CPME could
be recovered by a simple destillation.
proof of the absolute stereochemistry of
through X-ray crystallographic analysis.
3 was ascertained
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Cognizant of the stereochemical integrity of enantioenriched α-
oxy-α-methylbenzyllithium reagents,[24] we were pleased to find
that such trisubstituted carbanions were suitable for our
methodology (Scheme 3). Upon deprotonation of enantiopure α-
methyl carbamate 18 with s-BuLi in CPME, a series of α-
quaternary carbonyl compounds could be prepared in excellent
yields and ers starting from the R or S carbamates (sparteine
was not required for deprotonating these chiral starting
materials). The trapping with a formyl Weinreb amide provided
the corresponding α-oxyaldehyde 19, and aromatic (20
aliphatic 22 or propargylic 23 analogues yielded the
corresponding ketones.
, 21),
(
)
(
)
a
Scheme 3. Reactivity of α-oxy-α-methylbenzyllithiums with Weinreb amides.
Reaction performed using (S)-18. b Reaction performed using (R)-18. c Only one
diastereoisomer observed.
The corresponding ketone 23 was formed via a stereoinversion
sequence, presumably due to the energetically low LUMO of
propargylic systems. Reactions with α,β-unsaturated Weinreb
amides surprisingly resulted in selective 1,4-addition to yield
amides 24, 25 with full diastereo- and enantio-control, instead of
the commonly observed 1,2-addition.[25] As noticed in the case of
product 23, inversion of configuration occurred at the quaternary
lithiated center, while the configuration of the tertiary
stereocenter created during the reaction was determined by the
sterical hindrance of the carbamate.
We have recently reported the isolation of tetrahedral
intermediates formed upon the addition of racemic functionalized
organolithium reagents to Weinreb amides.[26] To our delight, the
reaction with an optically active organolithium reagent to form
product (R)-4 could be intervened by addition of TMS-imidazole
(ImTMS). Thus, the enantiomerically enriched tetrahedral
intermediate could, for the first time, be isolated as O-TMS
hemiaminals 27 and 28 (Scheme 4a). However, the high
chemical instability of this species did not allow an efficient
separation of the diastereomers (40:60 dr mixture) via flash
chromatography or preparative HPLC.
a
b
Scheme 2. Reaction scope. Reaction run with (+)-sparteine. Run with
recovered sparteine. See the SI for full details.
The stereochemical course of the transformation is mainly controlled
by the ability of the expelled leaving group to coordinate the lithium
cation, and/or by the LUMO involved.[24] Based on the assumption that
NMe(OMe) efficiently coordinates Li, in analogy to a general RO
group of an ester, it is possible to affirm that Weinreb amides preferred
suprafacial attack with retention of configuration. The absolute
configuration of the ketones has been assigned based on comparison
with literature data for compounds 19 and 20.
N-acylpyrroles[27] form highly stable carbinols upon reactions
with carbon nucleophiles according to studies by Evans[28] and
Brandänge[29]. Pleasingly, the reaction of the lithiated Hoppe’s
carbamate with N-acylpyrrole 29 resulted in isolable,
diastereopure tetrahedral intermediates 30
, 31 in excellent er
and dr (Scheme 4b). By running the reaction in the presence of
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either enantiomer of sparteine, four stereoisomers were formed
and easily separated through chromatography on silica gel.
Subsequent HPLC analysis of each of the stereoisomers
confirmed the enantiopurity of each single stereoisomer.
Scheme 5. Enantioselective synthesis of α-pyrrolydinyl ketones. a Reaction run
with (+)-sparteine. b Run with recovered sparteine. See the ESI for full details.
The synthetic potential of selected compounds is illustrated in
Scheme 6. The reduction of the enantiomerically pure α-
oxyketone (R)-
7 with L-selectride efficiently afforded the
Scheme 4. Isolation of hemiaminal-type optically active tetrahedral
intermediates. a Diasteromeric ratio determined by 1H-NMR analysis. b Reaction
run with (+)-sparteine.
monoprotected 1,2-diol 40 (Scheme 6a). Subsequent removal of
the carbamate moiety under O’Brien’s conditions[32] delivered the
challenging 1,2-diol (R,R)-41 as a single diastereoisomer with
excellent enantiopurity. The relative configuration was
determined to be syn by diagnostic NOESY experiments on the
corresponding acetonide.[33] Analogously, the reaction of
Hoppe’s carbamate with the chiral Weinreb amide 42 yielded a
diastereopure α-,α’-disubstituted ketone 43, which was directly
subjected to reduction with L-selectride. Alcohol 44 was obtained
as a single diastereoisomer in excellent yield with very high
enantiopurity (Scheme 6b).
To further expand the synthetic potential of the methodology, it
was applied to the synthesis of chiral α-pyrrolidynyl ketones,
which also constitute biologically active substances.[30]
Enantioselective lithiation of N-Boc pyrrolidine[31]
(32) in CPME
followed by treatment with a range of Weinreb amides delivered
the targeted scaffolds with excellent enantiocontrol (Scheme 5).
The scope includes (hetero)aromatic (33
-35), unsaturated
(
36 37) and aliphatic (38 39) α-aminoketones. Remarkable
,
,
The propargylic ketone (R)-13 was used as platform for
asymmetric construction of the 1,2,3-triazole 45 through a 1,3-
dipolar cycloaddition in the presence of diethyl aluminumazide[34]
in CPME (Scheme 6c). Moreover, the same ketone underwent
chemoselectivity was observed in reactions with Weinreb
amides presenting additional electrophilic sites, leading to
products with cyano (34), cinnamoyl (36) and propargyl (37
)
substituents. Aliphatic Weinreb amides with an acidic α-proton
are also suitable substrates for the transformation, delivering
cyclic α-aminoketones 38 and 39. The latter compound was
obtained with perfect diastereoselectivity starting from an
optically active Weinreb amide, and the stereochemistry was
unambiguously assigned by X-ray analysis. Again, the opposite
enantiomers were prepared with equally excellent stereofidelity
by employment of (+)-sparteine.
an efficient chemoselective homologation with
a lithium
carbenoid to produce the α-oxyepoxydes 46 (1:1 dr) with
excellent enantiopurity (Scheme 6d).[35]
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compounds, thus avoiding purification by column chromoatography.
Selective manipulations of the synthesized
Experimental Section
General procedure for synthesis of compound 3
A solution of 3-phenylpropyl diisopropylcarbamate (1, 0.077 g, 0.294
mmol, 1.5 equiv) and ()-sparteine (0.073 g, 0.313 mmol, 1.6 equiv)
under argon in anhydrous CPME (2.0 mL) was cooled to -78 °C. A
solution of s-BuLi (1.4 M in cyclohexane/hexane 92:8, 0.022 mL,
0.313 mmol, 1.6 equiv) was added dropwise and the reaction mixture
was stirred for 30 min, then 3-bromo-N-methoxy-N-methylbenzamide
(2, 0.048 g, 0.196 mmol, 1.0 equiv) in CPME was added slowly. The
reaction mixture was quenched after 3 h with HCl (1N solution, 5 mL)
and stirred 1-2 min before the two phases were separated. The pure
compound was recrystallized from the same solvent. Compound 3
was obtained in 95% yield (0.087 g) as a white solid; mp 75-82 °C.
CPME (bp 106 °C) was redistilled and could be reused. The acidic
aqueous layer was basified with NaOH (20% aq.) and extracted with
CPME (5 mL). The organic layer was distilled to recover N,O-
dimethylhydroxylamine (bp 43 °C), CPME (bp 106 °C) and sparteine
(137-138 °C, 1.33 mbar). Recovery data for CPME, sparteine and
N,O-dimethylhydroxylamine are presented in Tables S1, S2 and S3
of the SI.
Scheme 6. Synthetic manipulations of enantiopure α-oxyketones.
Crystallography
Conclusions
CCDC 1871507 [(S)-3], 1871508 [(R)-3], 1871505 [(R,R)-24],
1571506 [(S,S)-24], 1871509 [(R,R)-39] contain the supplementary
crystallographic data for this paper. These data are provided free of
charge by the Cambridge Crystallographic Data Center (CCDC).
In conclusion, we have disclosed a conceptually novel flexible,
versatile and high-yielding acylation of enantiopure
organolithium reagents (Hoppe’s carbamates and N-Boc
pyrrolidine) en route to novel α-oxyketones and cyclic α-
aminoketones. The combination of Weinreb amides and CPME
as an environmentally benign reaction medium enables access
to the targeted compounds with excellent stereofidelities within
short reaction times. Both enantiomers of a given scaffold are
accessible by simply selecting the appropriate sparteine
enantiomer. Analogously, configurationally stable α-oxy-α-
methylbenzyllithiums, prepared without requirement of
sparteine, can be added to Weinreb amides for enantioselective
synthesis of α-quaternary ketones.
Acknowledgements
We thank the University of Vienna and Stockholm University for
generous support. S. Monticelli acknowledges the university of
Vienna for a Uni:docs doctoral fellowship. We thank F. Pisapia
and K. Dimov for experimental assistance.
Keywords: green solvent; asymmetric chemistry;
chemoselectivity; acylation; organolithiums.
Furthermore, several sustainable features of these novel
transformations have been developed to meet the drawbacks related
to the use of the necessary substrates and reagents. The precious
sparteine ligand was efficiently recycled (80% average) in a practical
fashion that also enabled recovery the Weinreb amine and the solvent.
The beneficial effect of CPME is further showcased by its excellent
ability as a recrystallization medium to obtain analytically pure
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