Solution structures of lithium amino alkoxides used in highly enantioselective 1,2-additions

Article abstract of DOI:10.1021/ja412210d

Lithium ephedrates and norcarane-derived lithium amino alkoxides used to effect highly enantioselective 1,2-additions on large scales have been characterized in toluene and tetrahydrofuran. The method of continuous variations in conjunction with ⁶

Full text of DOI:10.1021/ja412210d

Article
pubs.acs.org/JACS
Solution Structures of Lithium Amino Alkoxides Used in Highly
Enantioselective 1,2-Additions
Angela M. Bruneau, Lara Liou, and David B. Collum*
Department of Chemistry and Chemical Biology Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, United States
*
S Supporting Information
ABSTRACT: Lithium ephedrates and norcarane-derived
lithium amino alkoxides used to effect highly enantioselective
1
,2-additions on large scales have been characterized in toluene
and tetrahydrofuran. The method of continuous variations in
conjunction with Li NMR spectroscopy reveals that the
6
lithium amino alkoxides are tetrameric. In each case, low-
6
temperature Li NMR spectra show stereoisomerically pure
homoaggregates displaying resonances consistent with an S4-
symmetric cubic core rather than the alternative D2d core. These assignments are supported by density functional theory
computations and conform to X-ray crystal structures. Slow aggregate exchanges are discussed in the context of amino alkoxides
as chiral auxiliaries.
INTRODUCTION
to quinazolinone 4 with an extraordinary 99.5% enantiose-
lectivity (eq 2). In this case, however, optimal selectivity was
obtained using a 3:1 mixture of norcarane-derived amino
alkoxide 3a and 1.
■
5
The idea of exploiting organolithium mixed aggregates to
control organolithium reactivity and selectivity lurked for
1
several decades, but it moved to center stage in the early 1980s
2
A Cornell−Merck collaboration traced the high enantiose-
largely owing to contributions of Seebach and co-workers. In a
lectivity in eq 1 to the reaction of substrate with 2:2
dramatic application of aggregate-based stereocontrol, the
process group at Merck has shown that 2 equiv each of lithium
cyclopropylacetylide 1 and lithium ephedrate 2b effect the 1,2-
6
(
ROLi) (R′Li) mixed tetramer 5. A subsequent Cornell−
2
2
DuPont collaboration attributed the enantioselectivity in eq 2
to the external attack of acetylide on 3:1 (ROLi) (substrate)
1
mixed tetramer 6. In both reactions, aging the reaction near
ambient temperature before addition at low temperature was
key to attaining high selectivity.
3
addition in eq 1 in 98% enantioselectivity. Synthesis of more
3
7
During these structural and mechanistic studies, the solution
structures of the amino alkoxide homoaggregates proved
elusive. The problem emanated from the difficulties associated
with characterizing O-lithiated species in solution, wherein high
symmetry and lack of O−Li coupling preclude direct NMR
8
spectroscopic analysis. Arnett and co-workers have previously
reported a crystal structure of the pseudoephedrate stereo-
than 50 000 kg of reverse transcriptase inhibitor efavirenz
(
Sustiva, Stocrin) using this protocol quashed any doubt abou4t
isomer of 2a displaying an S -symmetric tetrameric core, but
4
the practicality of stoichiometric amino alkoxide auxiliaries.
Subsequently, DuPont Pharmaceuticals prepared more than
2
000 kg of a second-generation reverse transcriptase inhibitor
Received: December 12, 2013
Published: January 28, 2014
using a seemingly analogous 1,2-addition of lithium acetylide 1
©
2014 American Chemical Society
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Article
their efforts to determine the solution structure were less
conclusive.
the chelates about the cubic tetramer frameworks of 7a,b and
9
8a,b (eq 3).
Considerable inroads have now been made toward character-
8
,10−12
izing the structures of O-lithiated species in solution.
6
Using a combination of Li NMR spectroscopy, the method of
8
,12,13
continuous variations (MCV),
and density functional
theory computations, we show herein that amino alkoxides 2a,b
and 3a,b form exclusively unsolvated homotetramers 7a,b and
Despite the THF dependence on the rate of chelate
1
1,12,14
12,15
6
8
a,b.
Several intraaggregate exchanges
are shown to
exchange, we conclude that THF is coordinated only
transiently based on a simple and powerful diagnostic probe
15
be remarkably slow. In conjunction with Li− N double-
labeling studies, the application of MCV is extended to
distinguish lithium hexamethyldisilazide-lithium amino alkoxide
12
as follows. Pyridine strongly coordinates lithium nuclei and
6
shifts Li resonances markedly (0.5 to >1.0 ppm) downfield
16
dimers 11 and the corresponding ladders 12 a structural
12c,20
even in neat THF solutions.
Amino alkoxides 2a,b and
ambiguity arising from opaque O−Li linkages that has dogged
3
a,b showed no measurable change in chemical shift in
12b,17
us for many years.
solutions of 1.2 M pyridine/toluene compared with that in
THF/toluene or toluene solutions, demonstrating that the
chelates occupy all available coordination sites.
The assignment of 7a is consistent with a crystal structure by
9
Arnett and co-workers. The assignment of 7b was
corroborated by an X-ray crystal structure of 5a showing the
S4-symmetric cubic tetramer core (Figure 1; Supporting
Information).
Figure 1. ORTEP of 5a as fully chelated tetramer bearing an S4-
symmetric cubic core.
Heteroaggregation and MCV. Assignment of 2a,b and
a,b as tetramers 7a,b and 8a,b relied critically on MCV.
8,12,13
3
In this experiment, the high symmetries of the lithium alkoxides
are disrupted by forming ensembles of homo- and hetero-
RESULTS
■
2
1,22
Homoaggregation. Lithium alkoxides 2a,b and 3a,b were
generated in toluene by treating the corresponding alcohols
aggregates (eq 4).
The number and symmetries of the
3
e,18
heteroaggregates and the dependence of the distribution on the
6
with 1.0 equiv of labeled lithium hexamethyldisilazide ([ Li]-
mole fraction (XA or X ) attest to the structures of the
B
1
9
LiHMDS). To facilitate the narrative, we note at the outset
that the data support cubic tetramers 7a,b and 8a,b bearing S4-
symmetric cores.
homoaggregates, A and B . In most previous applications of
n
n
MCV, cubic tetramers appear as a series of five homo- and
heteroaggregates with the characteristic resonance counts
6
8,12
Low-temperature Li NMR spectroscopy of all four alkoxides
illustrated in Chart 1.
reveals two resonances (1:1) that coalesce above −20 °C to
afford a single sharp resonance above 0 °C consistent with a
single aggregate containing two magnetically inequivalent
lithium nuclei. Note that cubic tetramers 7a,b and 8a,b
would show such a pair, whereas tetramers 9a,b and 10a,b with
A + B ⇒ A + An−1B1 + An−2B + ...Bn
(4)
n
n
n
2
Characterization of the alkoxides as tetramers using MCV is
illustrated with 2a and 2b emblematically. Mixtures of 2a and
2b in a 1:1 ratio in toluene or THF give intractable NMR
spectra at low temperature. The complexity inherent to
ensembles is exacerbated by the stereochemistry of chelation
(discussed in detail below). On warming, however, the
overlapping resonances coalesce to afford a sharp five-peak
ensemble at +60 °C consistent with a tetramer ensembleA4,
6
D -symmetric cores would each display a single Li resonance.
2d
The coalescence temperature in toluene (approximately −20
°
C for all four alkoxides) is higher than that in neat THF
(Tcoalesc ≈ −35 °C), suggesting that THF assists the exchange.
We attribute these behaviors to a degenerate rearrangement of
2
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Article
Chart 1
quality of the fit confirm the tetramer assignment. In
conjunction with the symmetry of the homoaggregates at low
temperature and solvent-independent chemical shift, MCV
completes the assignment of alkoxides 2a and 2b as solvent-free
tetramers 7a and 7b.
Studies of norcarane-derived alkoxides 3a and 3b afforded
results fully analogous to those of 2a and 2b in every respect,
supporting unsolvated cubic tetramers 8a and 8b. Relatively
minor quantitative differences include slightly faster chelate
exchanges and slightly slower intraaggregate Li−Li site
exchanges.
A B , A B , A B , and B with each stoichiometry appearing
3
1
2
2
1
3
4
as a single resonance (Figure 2). The apparent intraaggregate
The stereochemical preference for S rather than D cubic
4
2d
cores was examined using density functional theory computa-
tions at the B3LYP level of theory with the 6-31G(d) Pople
24
basis set. Free energies were calculated from an MP2-derived
single-point energy [6-31G(d) basis set] and a B3LYP-derived
thermal correction [6-31G(d)] at 195 K and 1 atm. The 21
kcal/mol preference for the S form in 7b (eq 5) is fully
4
6
Figure 2. Li NMR spectrum of a 1:1 mixture of lithium ephedrates 2a
and 2b in toluene recorded at +60 °C. The labels indicate the relative
A B stoichiometries. The asterisk denotes an unknown impurity.
m
n
8
,12,15,20a
Li−Li exchange
is well-precedented and has been
useful in characterizing O-lithiated species, but it is usually
significantly more facile. The exchange shows minor accel-
eration by THF relative to toluene. The aggregates were
monitored in the high temperature limit with varying
proportions of 2a and 2b and fixed total alkoxide concentration.
The relative integrations of the five distinct aggregates are
consistent with the experimental data. Although we often use
computations only qualitatively, this difference is very large for
25
isodesmic stereoisomers. Computations of a sterically less
23
congested variant in which the phenyl and methyl moieties
along the backbone of ephedrate 2a were omitted show a
plotted versus measured mole fractions (X or X ) of the two
A
B
components in Figure 3. The curves result from a parametric fit
8
,12
reduced but still sizable 7 kcal/mol preference for the S
eq 6).
4
core
as described previously.
The number of aggregates and
(
Lithium Alkoxide−LiHMDS Mixed Aggregates. During
the studies described above, we detected lithium alkoxide−
LiHMDS mixed aggregates that formed quantitatively with 1.0
22
equiv of excess LiHMDS. For example, lithium ephedrate 2a
6
15
6
with a 1.0 equiv excess of [ Li, N]LiHMDS displays two Li
doublets in a 1:1 ratio (JLi−N = 1.0 Hz) and a single resonance
appearing as a quintet in the 15N NMR spectrum (Figure 4).
The data are consistent with the basic mixed dimer subunits
1
1a,b or the corresponding ladder 12a. Once again, the
spectroscopically opaque Li−O linkages posed a problem, and
MCV offered the solution.
Figure 3. Job plot showing the relative integrations of tetrameric
2
3
homo- and heteroaggregates versus measured mole fractions of 2a
6
6
(
X ) for 0.10 M mixtures of lithium ephedrates [ Li]2a (A) and [ Li]
A
2
b (B) in toluene at +60 °C.
2
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Journal of the American Chemical Society
Article
Figure 4. 6Li NMR spectrum recorded on a 1:1 mixture of
6
15
[
Li, N]LiHMDS (0.10 M) and lithium amino alkoxides 2a (0.10
M total concentration) in toluene cosolvent at −30 °C.
Mixtures of lithium ephedrates 2a and 2b in toluene at
Figure 6. Job plot showing the relative integrations of mixed ladders
varying proportions but constant lithium alkoxide titer in the
6
12a (A ), 12b (B ), and 12c (AB) versus measured mole fractions of
2 2
presence of 1.0 equiv of excess LiHMDS afford Li spectra
2
b−LiHMDS (X ) in mixtures containing 0.10 total amino alkoxide
B
showing the two original resonance pairs along with additional
resonances consistent with mixed ladder 12c (Figure 5). The
and 0.10 M LiHMDS at −30 °C.
DISCUSSION
■
Synthetically important lithium amino alkoxides pose an
interesting challenge for structural organolithium chemists.
Arnett and co-workers have shown that crystalline pseudoephe-
drate stereoisomer of 2a is a cubic tetramer analogous to 9a,
but their efforts to determine the solution structure were less
6
conclusive. Messy Li NMR spectra cast doubt on the
colligative measurements, which are notoriously sensitive to
8
impurities. We previously studied amino alkoxides 2a and 3a
6
,7
using NMR spectroscopy and gleaned no useful information.
6
The current paper describes how a combination of Li NMR
spectroscopy and MCV allowed us to characterize 2a,b and
3
a,b as stereochemically pure cubic tetramers 7a,b and 8a,b.
Computational studies suggest that the S -symmetric cubic core
4
is inherently more stable than the D core, a preference that is
2d
amplified by the substituents along the chelate backbone (eqs 4
and 5). During these studies, we made a number of
observations and achieved some tactical developments in
MCV that call for further elaboration.
6
6
Figure 5. Li NMR spectra recorded on mixtures of [ Li]LiHMDS
0.10 M) and lithium amino alkoxides 2a and 2b (0.10 M total
(
In the low temperature limit, all four homoaggregates display
two distinct resonances that, with warming, coalesce into a
single resonance owing to facile degenerate isomerizations of
the chelates (eq 3). Although this observation proved critical to
complete the structural assignments, it foreshadowed severe
technical problems with the use of MCV. In typical applications
of MCV to characterize tetramer ensembles (eq 4), we would
observe three heteroaggregates of stoichiometries3:1, 2:2,
and 1:3displaying resonance counts and integrations
6
concentration) in toluene cosolvent at −30 °C: (a) 0.10 M [ Li]2b;
6
6
6
(
0
0
b) 0.080 M [ Li]2b and 0.020 M [ Li]2a; (c) 0.050 M [ Li]2b and
6
6
6
.050 M [ Li]2a; (d) 0.020 M [ Li]2b and 0.080 M [ Li]2a; and (e)
6
.10 M [ Li]2a.
downfield ensemble is not well resolved, yet the upfield
resonances clearly show 12a and 12b along with two
resonances (1:1) attributed to mixed ladder 12c. We suspect
that the well-resolved upfield resonances correspond to those
bearing the dialkylamino chelates. Maintaining the total
concentration of excess LiHMDS at 0.10 M and the total
alkoxide titer at 0.10 M while varying proportions (mole
fractions) of the two alkoxides afforded a mole fraction-
dependent distribution consistent with ladders 12a, 12b, and
12
reflecting the symmetries (Chart 1). The amino alkoxides,
by contrast, show a markedly increased resonance count arising
from stereochemical complexity (Chart 2). The homoaggre-
gates each show two rather than the usual one resonance. The
3:1 and 1:3 heterotetramers exist as two distinct diastereomers
each displaying eight resonances total. There are potentially four
diastereomeric 2:2 heterotetramerstwo C -symmetric dia-
2
1
2c. The resulting Job plot is illustrated in Figure 6. The
stereomers displaying two resonances each and two C -
1
resonance counts and quality of the fit confirm the 1:1
association of two mixed dimeric subunits and the overall
ladder motif.
symmetric diastereomers containing four discrete lithium
resonances each. Thus, the tetramer ensemble in the slow
exchange limit would include 32 resonances in total. It is not
2
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Chart 2
2
7,28
shocking, therefore, that ensembles generated from 2a/2b or
dynamic) than we ever suspected.
The effects of aging
3
a/3b pairings are intractable in the low temperature limit.
Two general classes of intraaggregate exchanges would, in
(warming−cooling cycles) and catalytically active lithium salts
on aggregate equilibrations may profoundly influence stereo-
and regiochemical outcomes. Both chelate−chelate and Li−Li
site exchanges are observed at lower temperatures in THF than
in toluene, indicating a role of THF despite apparent lack of
solvation.
principle, simplify the spectra. Chelate−chelate exchange (eq 3)
without further deepseated adjustments within the cubic core
would reduce the complexity of Chart 2 to the simpler
distribution depicted in Chart 1 and lower the Li resonance
count from 32 to 8. Intraaggregate exchange of all Li
6
6
During the studies of homoaggregates we detected lithium
alkoxide−LiHMDS mixed aggregates in toluene. (LiHMDS
1
2,15
nuclei
within each aggregate would lead to further
29
symmetrization, causing the five-aggregate ensemble to appear
as five discrete Li singlets. In practice, warming the samples
does not form mixed aggregates in THF. ) The connectivities
6
6
15
obtained from Li− N double-labeling studies do not
appeared to elicit rapid chelate exchange, but we could not
readily observe all eight resonances at a single temperature
owing to differential exchange rates of the different aggregates.
Warming of the samples to 60−70 °C, however, elicited the
hoped-for rapid intraaggregate Li−Li site exchanges. We have
examined structures in the limit of rapid intraaggregate
distinguish cyclic dimer 11 from ladder 12, a distinction that
17
has eluded us previously. We used MCV to reveal that
mixtures of LiHMDS and alkoxides afford mixed ladders (12a−
c). The chirality of these mixed aggregates may also pique
curiosity among those interested in enantioselective reactions
of lithium amides.
1
2,20a
exchange before,
but the temperatures required for vicinal
amino alkoxides are remarkably high.
We previously noted the maxim “like aggregates with like.”
CONCLUSION
12
■
We have shown that cubic tetramers are a dominant form of
several lithium amino alkoxides. This study and others
Ensembles generated from lithium alkoxides and related O-
lithiated species of differing aggregation states resist hetero-
aggregation, affording no heteroaggregates whatsoever or an
ensemble of homo- and heteroaggregates that deviates
2
8
suggest that such tetramers composed of O-lithiated species are
very robust. It is not difficult to imagine, therefore, that
practitioners using lithium enolates to achieve stereocontrolled
carbon−carbon bond formation have been thwarted by
undetected aging and salt effects.
The importance of lithium amino alkoxides as auxiliaries in
organolithium chemistry has grown markedly in the absence of
any structural insights whatsoever.
studies of aggregates underlying the Merck chemistry (eq 1)
have played a direct role in the development of the protocols
subsequently used at DuPont (eq 2). In this context, we note
a curious observation that may prove important. Inserting
lithium salts into the cubic tetramers of 7a and 8a to form the
mixed tetramers 5 and 6 central to Merck’s and DuPont’s
enantioselective additions requires disruption of the chelate
12
significantly from statistical data. The most compelling
assignments stem from structurally related ROLi/R′OLi pairs.
At the outset, however, we thought that pairing structurally very
different alkoxides would be required to obtain sufficient
6
resolution in the Li NMR spectra. Nonetheless, the 2a/2b and
3
−5
3
a/3b pairs differing marginally at the dialkylamino appendages
Notably, structura6l
26
provide convincing results. More heterogeneous pairings of
lithium ephedrate and norcarane-derived lithium alkoxides2/
5
,7
3
pairsalso appeared to provide tetramer ensembles, but
rapid intraaggregate exchange demanded very high (>80 °C)
temperatures.
Mounting evidence suggests that cubic tetramers of enolates
and related O-lithiated species are far more robust (less
2
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Journal of the American Chemical Society
Article
orientations of the S core structure of homoaggregates 7a and
J. M. D.; Nguyen, D.; Luo, C.; Morgan, S. J.; Davis, W. P.; Confalone,
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Reider, P. J. J. Org. Chem. 1998, 63, 8536.
4
8a. We wonder: would mixed aggregates that allow three of the
four chelates in the S core to remain intact (eq 7) offer more
4
generalized control of the stereochemistry? Studies are, of
course, ongoing.
(
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■
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Reagents and Solvents. Toluene, THF, and pyridine were
distilled from blue solutions containing sodium benzophenone ketyl.
The toluene contained approximately 1% tetraglyme to dissolve the
6
6
15
ketyl. [ Li]LiHMDS and [ Li, N]LiHMDS were prepared and
(
(
m) Milne, D.; Murphy, P. J. J. Chem. Soc., Chem. Commun. 1993, 884.
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1
9
recrystallized using modified literature protocols. Air- and
moisture-sensitive materials were manipulated under argon using
standard glovebox, vacuum line, Schlenk, and syringe techniques.
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̈
n, M.; Naef, R. Tetrahedron:
̈
̈
ller,
1
2c
NMR samples were prepared using protocols described previously.
̈
6
Li NMR spectra were typically recorded on a 500 or 600 MHz
spectrometer with the delay between scans set to >5 × T1 to ensure
accurate integrations. Chemical shifts are reported relative to a 0.30 M
̈
6
LiCl/MeOH standard at −80 °C.
ASSOCIATED CONTENT
Supporting Information
Spectra, additional Job plots, and authors for ref 24. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
*
S
3
1
(
7
375. (x) Gros, P.; Fort, Y.; Cauber
997, 3071.
5) (a) Parsons, R. L., Jr. Curr. Opin. Drug Discovery Dev. 2000, 3,
83. (b) Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; Stone, B. R. P.;
̀
e, P. J. Chem. Soc., Perkin Trans. 1
AUTHOR INFORMATION
Corresponding Author
dbc6@cornell.edu
■
Parsons, R. L.; Pesti, J. A.; Magnus, N. A.; Fortunak, J. M.; Confalone,
P. N.; Nugent, W. A. Org. Lett. 2000, 2, 3119.
Notes
(6) (a) Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski,
E. J. J.; Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120,
The authors declare no competing financial interest.
2
028. (b) Xu, F.; Reamer, R. A.; Tillyer, R.; Cummins, J. M.;
Grabowski, E. J. J.; Reider, P. J.; Collum, D. B.; Huffman, J. C. J. Am.
Chem. Soc. 2000, 122, 11212.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM077167) for
support and Merck and Bristol−Myers Squibb (formerly
DuPont) for a number of amino alcohols.
(7) Parsons, R. L., Jr.; Fortunak, J. M.; Dorow, R. L.; Harris, G. D.;
Kauffman, G. S.; Nugent, W. A.; Winemiller, M. D.; Briggs, T. F.;
Xiang, B.; Collum, D. B. J. Am. Chem. Soc. 2001, 123, 9135.
(
8) For extensive leading references to solution structural studies of
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■
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22) After surveying a subset of the community, we have chosen to
2
(
̈
(
refer to (LiX) and (LiX) (LiX′) (such that X and X′ contain the
n
m
n
same heteratom) as a “homoaggregate” and “heteroaggregate”,
respectively, and reserve the term “mixed aggregate” for (LiX) (LiY)n
m
(such that X and Y are different heteroatoms).
(
23) Measuring the mole fraction within only the ensemble of
interest rather than the overall mole fraction of lithium alkoxides
added to the samples eliminates the distorting effects of impurities.
(
24) Frisch, M. J.; et al. GaussianVersion 3.09, revision A.1; Gaussian,
Inc.: Wallingford, CT, 2009.
25) When the chemical bonds broken in the reactant are the same as
the type of bonds formed the reaction is isodesmic.
26) Although homo- and heterosolvated dimeric enolates
(
(
coordinated by N,N,N′,N′-tetraalkyldiamines fail resolve (unpub-
lished), the corresponding mixed diamine solvates of n-BuLi and
PhLi resolve well: (a) Hoffmann, D.; Collum, D. B. J. Am. Chem. Soc.
1
998, 120, 5810. (b) Rutherford, J. L.; Hoffmann, D.; Collum, D. B. J.
Am. Chem. Soc. 2002, 124, 264.
27) Casy, B. M.; Flowers, R. A. J. Am. Chem. Soc. 2011, 133, 11492.
(
2
891
dx.doi.org/10.1021/ja412210d | J. Am. Chem. Soc. 2014, 136, 2885−2891