Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction

Article abstract of DOI:10.1038/s41586-018-0042-1

The unimolecular nucleophilic substitution (S_N1) mechanism features prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate enables the construction of highly congested carbon centres. However, the intrinsic instability and high reactivity of the carbocationic intermediates make it very difficult to control product distributions and stereoselectivity in reactions that proceed via S_N1 pathways. Here we report asymmetric catalysis of an S_N1-type reaction mechanism that results in the enantioselective construction of quaternary stereocentres from racemic precursors. The transformation relies on the synergistic action of a chiral hydrogen-bond-donor catalyst with a strong Lewis-acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and to achieve high levels of control over reaction enantioselectivity and product distribution. This work provides a foundation for the enantioconvergent synthesis of other fully substituted carbon stereocentres.

Full text of DOI:10.1038/s41586-018-0042-1

Article
https://doi.org/10.1038/s41586-018-0042-1
Quaternary stereocentres via an
enantioconvergent catalytic SN1 reaction
Alison e. Wendlandt1, Prithvi Vangal1 & eric N. Jacobsen1*
The unimolecular nucleophilic substitution (SN1) mechanism features prominently in every introductory organic
chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate
enables the construction of highly congested carbon centres. However, the intrinsic instability and high reactivity of
the carbocationic intermediates make it very difficult to control product distributions and stereoselectivity in reactions
that proceed via SN1 pathways. Here we report asymmetric catalysis of an SN1-type reaction mechanism that results
in the enantioselective construction of quaternary stereocentres from racemic precursors. The transformation relies
on the synergistic action of a chiral hydrogen-bond-donor catalyst with a strong Lewis-acid promoter to mediate the
formation of tertiary carbocationic intermediates at low temperature and to achieve high levels of control over reaction
enantioselectivity and product distribution. This work provides a foundation for the enantioconvergent synthesis of
other fully substituted carbon stereocentres.
Quaternary stereogenic centres are important structural motifs in the field of chemical synthesis, and several distinct catalytic, enanti-
natural products and biologically active compounds, conferring val- oselective approaches have been developed in response1–4. Notable
uable structural, conformational and metabolic properties. Their examples include cycloadditions5, α- and β-alkylation and aryla-
construction has long been recognized as an important challenge to tion of carbonyls6–8, 3,3′-additions9, SN2′ reactions10 and Heck-type
Fig. 1 | Approaches to the enantiocontrolled
construction of quaternary stereocentres.
a, Traditional methods for the synthesis of
quaternary-stereocentre-containing molecules use
stereochemically defined prochiral substrates.
b, The SN1 approach to the construction of quaternary
stereocentres described here. c, Enantioselective
allylation of propargyl acetates using chiral squaramide
catalysts and TMSOTf as a promoter. LG, leaving
group; Np, naphthyl; TMS, trimethylsilyl.
a
• Carbonyl α-functionalizations
• Alkene cross-couplings
• Conjugate additions
R
R1
R2
R
R1
R2
R3
R3
*
• 3,3′- and SN2′ additions
• Cycloadditions
Quaternary
stereocentres
Prochiral substrates
+
b
LG–
LG
Nuc
Nuc–
R1
R2
Catalyst
R1
R2
R3
R1
R2
R3
R3
–LG–
*
(
)
Fully substituted
stereocentres
Racemic substrates
Tertiary carbocation intermediate
Chiral HBD catalyst
N
H
N
H
R1
R1
+
Nuc
Nuc–M
–LG–M
Minimization of
undesired elimination
by-products
R3
R3
R1
R2
R3
R2
R2
LG–
Me
–LG–H
TMS
*
c
(6.0 equiv.)
AcO
Me
Catalyst (10 mol%)
TMSOTf (1.0 equiv.)
+
Ar
Ar
Ar
Et2O (0.1 M), –78 °C, 18 h
TMS
TMS
TMS
3a
Entry
4a
(
)-2a, Ar = 1-Np
CF3
O
O
Catalyst
3a:4a
e.e. 3a (%)
t-Bu
1a: R = H
Me
1b: R = Me
None
1a
1
2
3
4
5
1:1
40:1
0
91
1
N
R
N
R
N
Ph
CF3
O
CF3
Ph
1b
3.4:1
2.9:1
3.3:1
1c
20
–3
Me t-Bu
X
1c: X = S
1d: X = O
1d
Ph
N
N
H
N
H
CF3
Ph
O
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. *e-mail: jacobsen@chemistry.harvard.edu
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reSeArcH Article
TMS
Fig. 2 | Asymmetric allylation of
propargyl acetates. a, Substrate
scope. Reactions were run on
a 0.6-mmol scale with 0.1 equiv.
1a, 1.0 equiv. TMSOTf and 6.0
equiv. allyltrimethylsilane
(6.0 equiv.)
a
1a (10 mol%)
TMSOTf (1.0 equiv.)
AcO
Me
Me
+
Ar
Ar
Ar
Et2O (0.1 M), –78 °C, 24 h
TMS
TMS
TMS
Me
2a–4n
3a–4n
4a–4n
in 0.1 M Et2O at −78 °C for 24 h.
aReaction time was 4 h. bReaction
time was 14 d. cNMR yield.
Substituent effects
Me
Me
Me
b, c, Hammett plot of the σ+ values
of the substituents in 2a–2d versus
the enantiomeric ratios (log(e.r.))
obtained in the formation of 3a–3d
TMS
TMS
TMS
TMS
Br
3a
3b
3c
3d
F
Me
82%b, 91% e.e.
30:1 (3d:4d)
91%a, 94% e.e.
40:1 (3b:4b)
95%, 91% e.e.
40:1 (3a:4a)
91%, 93% e.e.
40:1 (3c:4c)
(b) (ρ+
=−0.43) and versus the
relative reaction rates (log(νX/νH))
determined for each substrate
(c) (ρ+ =−5.48). d, Linear free-
energy plot of the calculated
Polarizability of aromatic ring
Me
Me
Me
polarizability of the aromatic
rings in 2a and 2e–2 g versus the
enantiomeric ratios (log(e.r.))
obtained in the formation of 3a and
3e–3g (R2 =0.97). a.u., arbitrary
units. e, The absolute configuration
of (−)-3b was determined by
X-ray crystallography (structure
shown), following derivatization
to triazole 5b; the configuration
of all other products was assigned
by analogy. Conditions: (a) tetra-
n-butylammonium fluoride (2.0
equiv.), THF, room temperature;
(b) 4-nitrobenzylbromide (1.1
equiv.), NaN3 (1.1 equiv.), CuSO4
(0.1 equiv.), sodium ascorbate (0.2
equiv.), tBuOH/H2O (1:2), 50 °C;
(c) HCl (3 M in Et2O).
TMS
TMS
TMS
3e
3f
3g
95%, 98% e.e.
85:1 (3e:4e)
74%, 86% e.e.
70:1 (3f:4f)
71%c, 60% e.e.
3.3:1 (3g:4g)
Steric effects
Me
Me
Me
Me
Et
Me
TMS
TMS
TMS
3j
3h
3i
3k
TMS
Me
40%c, 66% e.e.
6.9:1 (3h:4h)
58%c, 67% e.e.
3.2:1 (3i:4i)
78%c, 82% e.e.
5.0:1 (3j:4j)
64%c, 94% e.e.
2.3:1 (3k:4k)
Heterocyclic substrates
Me
Me
Me
S
O
TMS
TMS
TMS
S
3l
3m
3n
95%, 92% e.e.
>100:1 (3l:4l)
88%, 94% e.e.
>100:1 (3m:4m)
85%, 93% e.e.
>100:1 (3n:4n)
b
c
d
2.0
1.5
1.0
0.5
0
U
+ = –0.43
+ = –5.48
2
2
1
R
2 = 0.97
1-Nap
U
9-Phen
4-Me
4-F
H
4-Me
4-Br
4-F
1
0
H
0
2-Nap
4-Br
–1
–2
–1
–2
Ph
–0.4 –0.2
0
0.2 0.4
–0.4 –0.2
0
0.2 0.4
0
5
10 15 20 25 30 35 40
Polarizability (a.u.)
V+
V+
e
Me
N
(a),(b),(c)
N
HCl
(–)-3b
N
Me
NO2
5b HCl
cross-couplings11. Each of these methods relies on enantiofacial addi- very substantial challenges to be overcome. The requisite catalytic sys-
tion across a prochiral substrate (Fig. 1a) and therefore requires the tem must (a) generate a reactive tertiary carbocationic intermediate,
preparation of stereochemically well-defined starting materials (such as (b) minimize undesired elimination and rearrangement pathways, and
trisubstituted olefins) and subsequent enantioselective bond formation. (c) exert enantiocontrol in additions of a carbon-centred nucleophile
We envisioned that stepwise nucleophilic substitution reactions that to a high-energy cationic intermediate. As a result, despite the prac-
proceed through prochiral carbocationic intermediates could provide tical appeal of an enantioconvergent approach to the construction of
a useful and complementary strategy for the enantioselective synthe- quaternary stereocentres, only isolated examples have been reported
sis of compounds with quaternary stereocentres. Unlike the synthetic so far9,13,14
.
approaches noted above, quaternary-stereocentre construction via
Over the past decade, chiral, dual hydrogen-bond-donor (HBD)
an SN1-like pathway might be stereoablative12 and could therefore catalysts have been developed that promote enantioselective nucleo-
use readily accessed racemic compounds as substrates (Fig. 1b). philic substitution and addition reactions via ion-pair intermediates.
Although realization of this strategy would lift the requirement for These catalysts promote ion-pair formation via direct anion abstrac-
stereocontrol in the synthesis of the substrate, doing so requires several tion15 or by substrate protonation with a co-catalytic Brønsted acid16.
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Article reSeArcH
a
Standard conditions
Same excess
Different excess
productive, enantioselective reaction pathways from such high-energy
intermediates.
3.0
2.5
2.0
1.5
1.0
0.5
0
Reaction development
After an extensive evaluation of potential tertiary electrophile–
carbon-centred nucleophile coupling partners, the reaction of propargyl
acetate 2a with allyltrimethylsilane was identified as a useful model
system with which to test this proposal (Fig. 1c). In the absence of an
HBD catalyst, the Lewis-acid-promoted reaction affords a 1:1 mix-
ture of the desired product 3a and the elimination product 4a (Fig. 1c,
entry 1). When readily accessed squaramide 1a (10mol%) was added
to the reaction, however, 3a was obtained in high yield (40:1 3a:4a;
Fig. 1c, entry 2) and enantioselectivity (91% enantiomeric excess, e.e.).
Product ratio and enantioselectivity were strongly dependent on the
nature of the HBD moiety: the related N,N-dimethylated squaramide
(1b), thiourea (1c) and urea (1d) catalysts afforded 3a in low yield and
enantiomeric excess (Fig. 1c, entries 3–5). No reaction was observed
with squaramide, thiourea or urea HBD catalysts in the absence of
TMSOTf.
0
0.05
0.10
0.15
[2b] (M)
1a
b
+TMS–OTf
+
Me
Ar
O
O
TMS
We then evaluated a series of tertiary propargyl acetates to probe
the reaction scope and to generate preliminary information about
the mechanism of the enantioselective substitution reaction (Fig. 2a).
Substrates with electron-donating (such as 2b and 2c) and electron-
withdrawing (2d) substituents underwent allylation with high
enantioselectivity (>90% e.e.) and product selectivity (>30:1 3:4). A
linear correlation with a small negative slope (ρ+ =−0.43, Fig. 2b) was
observed between the Hammett substituent σ+ constants and log(e.r.)
for substrates 2a–2d (e.r., enantiomeric ratio). By contrast, a linear cor-
relation with a large negative slope (ρ+ =−5.48, Fig. 2c) was obtained
from the corresponding plot of the σ+ constants versus log(νX/νH) for
the same substrates (where νX/νH is the reaction rate of substrate that
contains substituent X relative to that of the analogous unsubstituted
substrate). The observation of a linear free-energy dependence (ρ+)
of this magnitude provides direct evidence of positive charge accu-
mulation in the rate-determining transition state, consistent with an
SN1-type ionization mechanism21.
Aco
Me
TMS
R*
Ar
N
H
N
H
Ar
TMS
OTf–
Rate-
limiting
TMSOAc
1a TMSOTf
O
O
O
O
R*
Ar
N
H
N
H
R*
Ar
N
H
N
H
Me
+
OTf–
TMS
OTf–
Ar
Me
Ar
+
TMS
Enantiodetermining
–TfO–H
TMS
Despite the very subtle dependence of enantiomeric excess on the
electronic properties of the substrate substituents noted above, reaction
enantioselectivity was strongly responsive to changes in the expanse
and position of the aryl moiety of the substrate. A linear correlation
was observed between polarizability values calculated for the aryl sub-
stituent22 and log(e.r.) of products 3a and 3e–3g (Fig. 2d), indicating
that stabilizing aromatic interactions are likely to serve as a contri-
buting factor in enantiodifferentiation23. Evidence for the existence
of such stabilizing interactions could be gleaned from computational
analysis of the putative complex between catalyst 1a and substrate 2a
(Supplementary Fig. 9). Steric congestion near the reaction site also
correlates with enantioselectivity. Thus, the o-tolyl-substituted deriva-
tive 2j underwent an allylation reaction to afford a product with higher
enantiomeric excess (82%) than obtained using the p- or m-substituted
analogues 2h and 2i (66%–67%). Similarly, the ethyl-substituted
product 3k was obtained in higher enantiomeric excess (94%) than the
methyl-substituted product 3b (91%).
Ar
TMS
TMS
Fig. 3 | Kinetic data and catalytic cycle. a, Reaction-progress
kinetic analysis of the reaction of 2b with allyltrimethylsilane
([2b], concentration of 2b). Standard conditions:
[allyltrimethylsilane]0 =0.25 M, [2b]0 =0.10 M; ‘same excess’ conditions:
[allyltrimethylsilane]0 =0.195 M, [2b]0 =0.047 M; ‘different excess’
conditions: [allyltrimethylsilane]0 =0.315 M, [2b]0 =0.08 M; [X]0,
initial concentration of X. b, Proposed catalytic mechanism for the
enantioselective allylation of propargyl acetates.
Asymmetric induction is typically achieved from the resultant ion
pair as a consequence of specific attractive non-covalent interactions
between the corresponding cationic intermediate and the chiral HBD
catalyst17–19. Reported examples have been limited to heteroatom-
stabilized cations, owing to the challenges in generating the requisite
ion pair and suppressing elimination and rearrangement pathways. The
ability of HBD catalysts to control enantioselective nucleophile addition
into non-heteroatom-stabilized carbocations has, to our knowledge,
not been demonstrated.
It was discovered recently that chiral squaramide catalysts could
be used in conjunction with Lewis acids such as trimethylsilyl
trifluoromethanesulfonate (TMSOTf) to promote enantioselective
reactions20. This dual-catalyst system was shown to promote the for-
mation of oxocarbenium ions from dialkyl acetals—substrates that
are unreactive under previously developed HBD-promoted reaction
manifolds—while still engaging in attractive non-covalent interactions
to achieve enantioinduction. We envisioned that the strong ionizing
ability of this dual-catalyst system could provide access to carbocationic
intermediates that lack heteroatom stabilization, thus allowing us
to examine whether small-molecule HBDs can be used to promote
Substrates containing electron-rich heterocycles also under-
went highly enantioselective substitution. Representative S- and
O-heterocyclic substrates underwent reaction with allyltrimethylsilane
to afford quaternary products (3l–3n) in high yield and enantiomeric
excess and with no detectable elimination by-products. Following deri-
vatization, the absolute stereochemistry of product 3b was determined
by using X-ray crystallography (Fig. 2e).
Mechanistic studies
We undertook a mechanistic study of the reaction between a repre-
sentative tertiary propargyl acetate substrate and allyltrimethylsilane
promoted by squaramide 1a and TMSOTf to obtain insights into the
underlying catalytic mechanism. The disappearance of 2b could be
monitored over the entire course of the reaction using in situ infrared
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reSeArcH Article
Fig. 4 | Mechanistic studies to
probe the post-rate-limiting
steps of the allylation reaction.
a, Crossover experiment
a
AcO
Me
Me
TMS
TMS
TMS
(6.0 equiv.)
to establish the irreversible
formation of the alkene by-
product (illustrated here for 4a).
b, Partial reaction with scalemic
2f, demonstrating that allylation
proceeds via a stereoablative
mechanism rather than by a
dynamic kinetic-Resolution
process. c, Predicted and
2f (1.0 equiv.)
3f, 80% yield, 85% e.e.
Me
1a (10 mol%)
TMSOTf (1.0 equiv.)
+
+
Et2O (0.1 M),−78 °C, 18 h
TMS
3a
Not observed
TMS
TMS
4a (0.25 equiv.)
97%4a (recovered)
measured 12C/13C kinetic isotope
effects (KIEs) and equilibrium
isotope effects (EIEs). The
Me
AcO
Me
(S)-1a
b
Ar
Ar
+
+
1 h
TMS
TMS
experimentally determined
isotope effects (numbers) are
consistent with the predicted
mechanistic scenario (top row).
3f
2f
25% yield
72% recovered
70% e.e.
86% e.e.
AcO
Me
Me
(R)-1a
AcO
Me
Ar
Ar
1 h
TMS
TMS
3f
2f
TMS
29% yield
71% recovered
73% e.e.
–85% e.e.
(–)-2f: 81% e.e.
AcO
Me
Me
TMSOTf only
1 h
+
Ar
Ar
TMS
TMS
2f
<5% yield
83% recovered
75% e.e.
c
Predicted isotope effects
Measured isotope effects
0.999(5)
Enantioselectivity-determining nucleophile addition
No primary KIE
No primary KIE
Primary KIE
Me
TMS
1.027(6)
Me
Primary KIE
+
Slow
Fast
1.000
(assumed)
Me
Me
Ar
+
Ar
TMS
Ar
TMS
TMS
TMS
Enantioselectivity-determining elimination
Primary KIE
TMS
Small,
Small, inverse EIE
inverse EIE
Me
+
Slow
Fast
+
Ar
Me
Me
TMS
Ar
Ar
TMS
TMS
spectroscopy. Runs carried out at different initial concentrations of reacts directly with substrate 2. The non-zero y intercept is consist-
2b but with the same excess in concentration of allyltrimethyl silane ent with the competing background reaction that is observed in the
(a ‘same-excess’ experiment24) produce good graphical overlay in absence of 1a (see Supplementary Information). The observation that
the kinetic data (Fig. 3a), demonstrating that no catalyst decompo- optimal enantioselectivities are obtained under conditions where a
sition or product inhibition occurs over the course of the reactions. background, uncatalysed reaction is expected is intriguing, and the
The linearity of the plot further indicates that the reaction obeys a subject of continued study.
first-order rate dependence overall. Runs carried out with a different
Having established that the squaramide-TMSOTf-promoted forma-
excess in the initial concentration of allyltrimethyl silane relative to tion of the carbocationic intermediate is rate-limiting, we performed
2b also produce good overlay in the kinetic data (a ‘different-excess’ a series of experiments to interrogate the critical post-rate-limiting
experiment24), revealing that the reaction obeys a first-order rate steps. We determined that the formation of the elimination by-product
dependence on the concentration of 2b and has no rate dependence was irreversible on the basis of a crossover experiment in which
on the concentration of allyltrimethylsilane. These kinetic findings 1-naphthyl-substituted enyne (4a, 0.25 equiv.) was introduced to the
are consistent with a stepwise reaction mechanism whereby substrate reaction of 2-naphthyl-substituted acetate (2f) under otherwise stand-
C–O cleavage is turnover-limiting and nucleophile addition occurs in ard reaction conditions. This reaction afforded 2-naphthyl-substituted
a post-turnover-limiting step (Fig. 3b). Kinetic studies further revealed product 3f in 80% yield, and alkene 4a was recovered in 97% yield with
a sub-first-order dependence of the reaction rate on the concentration no trace of 1-naphthyl allylated product 3a detected (Fig. 4a).
of TMSOTf, and a first-order dependence of the reaction rate on the
To evaluate whether the reaction proceeds through an enantio-
concentration of 1a with a non-zero y intercept. The kinetic depend- selective or enantiospecific mechanism, the allylation was carried out
ence on the concentrations of 1a and TMSOTf is consistent with pre- by subjecting scalemic substrate (−)-2f (81% e.e.) to both enantiom-
equilibrium formation of a resting-state 1a·TMSOTf complex that ers of the squaramide catalyst 1a (Fig. 4b). After 1h of reaction time,
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Article reSeArcH
8. Murphy, J. J., Bastida, D., Paria, S., Fagnoni, M. & Melchiorre, P. Asymmetric
catalytic formation of quaternary carbons by iminium ion trapping of radicals.
Nature 532, 218–222 (2016).
9. Zhang, P., Le, H., Kyne, R. E. & Morken, J. P. Enantioselective construction
of all-carbon quaternary centers by branch-selective Pd-catalyzed allyl–allyl
cross-coupling. J. Am. Chem. Soc. 133, 9716–9719 (2011).
10. Jung, B. & Hoveyda, A. H. Site- and enantioselective formation of
allene-bearing tertiary or quaternary carbon stereogenic centers through
NHC–Cu-catalyzed allylic substitution. J. Am. Chem. Soc. 134, 1490–1493
(2012).
11. Mei, T.-S., Patel, H. H. & Sigman, M. S. Enantioselective construction of remote
quaternary stereocentres. Nature 508, 340–344 (2014).
12. Bhat, V., Welin, E. R., Guo, X. & Stoltz, B. M. Advances in stereoconvergent
catalysis from 2005 to 2015: transition-metal-mediated stereoablative
reactions, dynamic kinetic Resolutions, and dynamic kinetic asymmetric
transformations. Chem. Rev. 117, 4528–4561 (2017).
13. Braun, M. & Kotter, W. Titanium(IV)-catalyzed dynamic kinetic asymmetric
transformation of alcohols, silyl ethers, and acetals under carbon allylation.
Angew. Chem. Int. Ed. 43, 514–517 (2004).
14. Zhao, W., Wang, Z., Chu, B. & Sun, J. Enantioselective formation of all-carbon
quaternary stereocenters from indoles and tertiary alcohols bearing a
directing group. Angew. Chem. Int. Ed. 54, 1910–1913 (2015).
15. Reisman, S. E., Doyle, A. G. & Jacobsen, E. N. Enantioselective thiourea-
catalyzed additions to oxocarbenium ions. J. Am. Chem. Soc. 130, 7198–7199
(2008).
16. Xu, H., Zuend, S. J., Woll, M. G., Tao, Y. & Jacobsen, E. N. Asymmetric cooperative
catalysis of strong Brønsted acid-promoted reactions using chiral ureas.
Science 327, 986–990 (2010).
17. Brak, K. & Jacobsen, E. N. Asymmetric ion-pairing catalysis. Angew. Chem. Int.
Ed. 52, 534–561 (2013).
18. Kennedy, C. R., Lin, S. & Jacobsen, E. N. The cation–π interaction in
small-molecule catalysis. Angew. Chem. Int. Ed. 55, 12596–12624
(2016).
19. Neel, A. J., Hilton, M. J., Sigman, M. S. & Toste, F. D. Exploiting
non-covalent π interactions for catalyst design. Nature 543, 637–646
(2017).
product 3f was obtained in 86% enantiomeric excess and 24% yield
using (S)-1a; in the presence of (R)-1a, product 3f was obtained in simi-
lar yield but with opposite enantioselectivity (−85% e.e.). In both cases,
the substrate 2f that was recovered was observed to have undergone
only a small degree of epimerization, comparable to that observed when
2f was treated with TMSOTf and in the absence of squaramide catalyst.
The results of these experiments are consistent with a stereoablative
mechanism, that is, an enantioselective process that proceeds through
an achiral carbocationic intermediate. By contrast, a dynamic kinetic-
Resolution pathway can be ruled out, whereby 2f undergoes rapid
racemization and one enantiomer preferentially undergoes stereo-
specific substitution.
We considered two limiting mechanistic possibilities with regard
to the enantiodetermining step: (a) irreversible nucleophile addition
followed by rapid silyl elimination (Fig. 4c, top), and (b) rapid and
reversible nucleophile addition, followed by enantiodetermining silyl
elimination (Fig. 4c, bottom). These two scenarios are predicted to pro-
duce different carbon isotope effects at the allyl fragment. The carbon
kinetic isotope effects (KIEs) were determined with natural-abundance
materials using an NMR methodology25 (Fig. 4c, see Supplementary
Information). A large primary KIE of 1.027 was observed at the posi-
tion of bond formation (internal allylic methylene), whereas no KIE
was observed at the terminal position. These results demonstrate
that the first C–C bond-forming step is irreversible and therefore
enantiodetermining.
Conclusion
We have shown that the cooperative effect of chiral squaramides and
TMSOTf generates tertiary carbocations that lack heteroatom stabili-
zation from racemic precursors, controls enantioselectivity in additions
of a carbon-centred nucleophile, and attenuates undesired elimination
20. Banik, S. M., Levina, A., Hyde, A. M. & Jacobsen, E. N. Lewis acid enhancement
by hydrogen-bond donors for asymmetric catalysis. Science 358, 761–764
(2017).
21. Brown, H. C. & Okamoto, Y. Substituent constants for aromatic substitution.
J. Am. Chem. Soc. 79, 1913–1917 (1957).
pathways. The strategy outlined here may be generalizable to the con- 22. McKinney, J. D., Gottschalk, K. E. & Pedersen, L. The polarizability of planar
aromatic systems. An application to polychlorinated biphenyls (PCB’s), dioxins
struction of many types of highly congested stereogenic centre.
and polyaromatic hydrocarbons. J. Mol. Struct. (Theochem) 105, 427–438
(1983).
Data availability
23. Hunter, C. A. & Sanders, J. K. M. The nature of π–π interactions. J. Am. Chem.
Soc. 112, 5525–5534 (1990).
24. Blackmond, D. G. Reaction progress kinetic analysis: a powerful methodology
for mechanistic studies of complex catalytic reactions. Angew. Chem. Int. Ed. 44,
4302–4320 (2005).
25. Singleton, D. A. & Thomas, A. A. High-precision simultaneous determination of
multiple small kinetic isotope efects at natural abundance. J. Am. Chem. Soc.
117, 9357–9358 (1995).
The crystallographic data for compound 5b·HCl can be obtained free of charge
from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk)
under identifier CCDC 1822228. The raw data for the kinetics experiments are
available from the corresponding author on request. All other data that support
these findings are available within the paper or Supplementary Information.
Received: 8 November 2017;Accepted: 23 February 2018;
Published online 25April 2018.
Acknowledgements Financial support for this work was provided by the NIH
through GM043214 and a postdoctoral fellowship to A.E.W. We thank S. McCann
and C. Fry for assistance with NMR experiments, E. E. Kwan for discussions
regarding the KIE studies, and S.-L. Zheng for X-ray structure determination.
1. Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of
quaternary carbon stereocentres. Nature 516, 181–191 (2014).
2. Liu, Y., Han, S.-J., Liu, W.-B. & Stoltz, B. M. Catalytic enantioselective construction
of quaternary stereocenters: assembly of key building blocks for the synthesis
of biologically active molecules. Acc. Chem. Res. 48, 740–751 (2015).
3. Das, J. P. & Marek, I. Enantioselective synthesis of all-carbon quaternary
stereogenic centers in acyclic systems. Chem. Commun. 47, 4593–4623
(2011).
Reviewer information Nature thanks R. Gilmour and the other anonymous
reviewer(s) for their contribution to the peer review of this work.
Author contributions A.E.W. and E.N.J. conceived the work, A.E.W. and P.V.
conducted the experiments, E.N.J. directed the research, and A.E.W., P.V. and
E.N.J. wrote the manuscript.
4. Feng, J., Holmes, M. & Krische, M. J. Acyclic quaternary carbon stereocenters via
enantioselective transition metal catalysis. Chem. Rev. 117, 12564–12580
(2017).
5. Wilson, R. M., Jen, W. S. & MacMillan, D. W. C. Enantioselective
organocatalytic intramolecular Diels−Alder reactions. The asymmetric
synthesis of solanapyrone D. J. Am. Chem. Soc. 127, 11616–11617 (2005).
6. Krautwald, S., Sarlah, D., Schafroth, M. A. & Carreira, E. M. Enantio- and
diastereo-divergent dual catalysis: α-allylation of branched aldehydes. Science
340, 1065–1068 (2013).
Competing interests The authors declare no competing interests.
Additional information
Supplementary information is available for this paper at https://doi.
org/10.1038/s41586-018-0042-1.
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reprints.
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7. Behenna, D. C. & Stoltz, B. M. The enantioselective Tsuji allylation. J. Am. Chem.
Soc. 126, 15044–15045 (2004).
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