Acyclic Stereocontrol in the Additions of Nucleophilic Alkenes to α-Chiral N-Sulfonyl Imines

Article abstract of DOI:10.1002/chem.201902790

Diastereoselective Lewis acid-mediated additions of nucleophilic alkenes to N-sulfonyl imines are reported. The canonical polar Felkin–Anh model describing additions to carbonyls does not adequately describe analogous additions to N-sulfonyl imines. Herei

Full text of DOI:10.1002/chem.201902790

A Journal of
Accepted Article
Title: Acyclic Stereocontrol in the Additions of Nucleophilic Alkenes to
α-Chiral N-Sulfonyl Imines
Authors: Lucas C Moore, Anna Lo, Jason S Fell, Matthew R Duong,
Jose A Moreno, Barry E Rich, Martin Bravo, James C
Fettinger, Lucas W Souza, Marilyn M Olmstead, Kendall N
Houk, and Jared Thomas Shaw
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To be cited as: Chem. Eur. J. 10.1002/chem.201902790
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Acyclic Stereocontrol in the Additions of Nucleophilic Alkenes to
α-Chiral N-Sulfonyl Imines
Lucas C. Moore, Anna Lo, Jason S. Fell, Matthew R. Duong, Jose A. Moreno, Barry E. Rich, Martin
Bravo, James C. Fettinger, Lucas W. Souza, Marilyn M. Olmstead, Kendall N. Houk,* and Jared T.
Shaw*
Abstract: Diastereoselective Lewis acid-mediated additions of
nucleophilic alkenes to N-sulfonyl imines are reported. The canonical
chiral aldehyde additions:
‡
Polar Felkin-Anh model describing additions to carbonyls does not
[M]
Felkin-Anh
control
adequately describe analogous additions to N-sulfonyl imines. Herein,
O
R
H
OH
Nu
we describe development of conditions to produce both syn and anti
products with high diastereoselectivity and good yields.
R
X
anti products
A
Nu
X
H
stereoelectronic model consistent with experimental outcomes is also
proposed.
O
[M]
R
Nu
+
‡
H
[M]
X
OH
Nu
O
H
X
Electrophilic imines are versatile substrates for the
construction of nitrogen-bearing stereogenic centers. N-sulfonyl
imines are of particular use, and have been used as electrophiles
in natural product[1,2] and pharmaceutical target[3,4] syntheses.
Acyclic stereocontrol in the additions of nucleophiles to chiral
aldehydes and ketones has been extensively studied. Useful
levels of predictability have emerged as the Cram chelation,[5,6]
polar Felkin-Anh,[7,8] and Cornforth-Evans[9,10] models of carbonyl
addition. Similar control has so far been absent for analogous
imines.
R
syn products
R
Cram chelate
control
Nu
H
X
previous chiral N-sulfonyl imine additions:
X = NR2 Reetz '91, '94
SO2R
SO2R
Nu
N
HN
X = Cl
Walsh '12, '13,
Marek '15
R
R
Nu
+
H
X = OR,
NHR
Shaw '17
X
X
syn products
this work:
Research into additions to alpha-chiral imines has been
limited to a few notable cases (Figure 1). Chelate-controlled syn-
additions to N-alkyl and N-aryl aldehyde-derived imines are well
known. Anti-additions are only consistent achievable with
auxiliary control[11,12] or β-chelate effects.[13,14] While the polar
Felkin-Anh model is often used to rationalize these anti-selective
results, a few examples of syn-selective additions using similar
substrates demonstrate that the model is sometimes ineffective in
predicting chiral imine addition outcomes.[15–17] Diastereoselective
additions to N-sulfonyl imines are limited to six reports. Reetz has
demonstrated anti-selective additions of Grignard reagents[18] and
cyanide[19] to α-amino N-tosyl imines. Walsh has reported
remarkable syn selectivity in the addition of organozinc
Ts
R3
HN
up to >95:5 dr (syn)
with ZnBr2
M = TMS
R
R
Y
Ts
N
OR1
R3
R1
+
M
H
Ts
R3
Y
HN
OR2
up to >95:5 dr (anti)
with BF3•OEt2
M = BF3K
Y
OR1
Figure 1. Imine acyclic stereocontrol summary.
reagents[20,21] to α-chloro N-sulfonyl imines, and
a single
occurrence[21] of an anti addition using alkynyllithium. Marek
expanded Walsh’s additions of organozincs to α-chloro N-tosyl
imines to produce more stereochemically complex addition
products through acyclic stereocontrol.[22]
Preliminary studies began with an exploration of additions
of alkene nucleophiles to lactate-derived N-tosyl imine 1a (Table
1). AllylTMS 3a reacted with modest syn selectivity even in the
presence of BF3•OEt2 (entry 2). This result was in stark contrast
to similar additions to aldehydes, which give mostly anti products
under the same conditions (entry 1).[24] Syn-selective additions to
α-chiral imines using BF3•OEt2 are isolated to two reports, neither
of which propose a mechanistic rationale or overcome this
unexpected selectivity.[25,26] To further understand and reverse
this selectivity, we manipulated nucleophile strength, reaction
temperature, and Lewis acid mediator. Substitution of a stronger
nucleophile (allylSnBu3, entry 4) furnished product with nearly the
same selectivity. An attempt to use TMSOTf as an anti selective
mediator failed (entry 5). We later found that catalytic TfOH was
sufficient to provide the same diastereomeric outcome in a
comparatively fast reaction (entry 7) and that a nonnucleophilic
base eliminated reactivity (entry 6). It is likely that partial TMSOTf
hydrolysis produced the necessary catalytic TfOH. B3LYP
calculations show that an N-sulfonyl imine chelates a proton much
With these few examples as a backdrop, there has been no
systematic study of a-alkoxy imines that would provide similar
insight to their extensively-studied carbonyl counterparts. Our
interest in these additions was sparked during an investigation
into the Brønsted base-mediated formation of δ-lactams from α-
chiral N-sulfonyl imines and anhydride enolates.[23] We had
difficulty rationalizing the syn, or Cram-predicted, major products
as little had been reported on analogous additions using soft
nucleophiles in the absence of chelatable metals. We set out to
develop conditions that would enable complete stereocontrol in
the formation of a new stereogenic center from α-chiral N-sulfonyl
imines and soft nucleophiles alongside a stereoelectronic model
that is consistent with our reaction outcomes and provides
predictive power.
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Table 1. Unexpected selectivity in nucleophilic additions to N-sulfonyl imines.
Relative configuration established by X-ray crystallography (see SI).
Solvent- and Lewis acid screens aided in optimization of anti
selectivity. Although we found that catalytic amounts of BF3•OEt2
did not furnish full conversion, slightly over a full equivalent did.
With optimal conditions (1.1 equivalents) in hand, we conducted
a solvent screen (Table 2) and found that CHCl3 facilitated
somewhat higher anti selectivity compared to CH2Cl2. Finally, we
reduced the temperature of the reaction, and we found –20 °C
optimal for good levels of conversion and anti selectivity.
reagents
temp.
CH2Cl2
Ts
Ts
R
Y
HN
R
HN
R
[M]
H3C
H3C
H C
+
3
+
H
OBn
OBn
OBn
1a, Y = NTs
2, Y = O
3
4 (syn)
5 (anti)
Table 2. Anti-selective condition optimizations.
entry
Y
[M]
TMS
R
reagents
temp
syn:anti
1
O
H
H
H
H
H
H
H
H
H
H
H
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
TMSOTf
-78 °C
40:60
70:30
56:44
76:24
85:15
n.r.
BF3•OEt2
temp.
Ts
Ts
Ts
2
NTs TMS
NTs TMS
-78 °C to r.t.
23 °C
N
HN
HN
solvent
3
TMS
+
+
H3C
H3C
H3C
H
4
NTs SnBu3
NTs SnBu3
NTs SnBu3
NTs SnBu3
NTs TMS
NTs TMS
NTs TMS
NTs TMS
NTs TMS
NTs TMS
NTs TMS
NTs TMS
-78 °C to r.t.
-78 °C to r.t.
OBn
1a
OBn
OBn
5
3a
9a (syn)
9b (anti)
6
TMSOTf + 6 -78 °C to r.t.
7
cat. TfOH
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
-78 °C
-78 °C
-20 °C
0 °C
85:15
80:20
68:32
63:37
58:42
37:63
27:73
20:80
18:82
8
syn:anti
entry
equiv BF3•OEt2 solvent
temp
23 °C
23 °C
23 °C
23 °C
-20 °C
9
1
2
3
4
5
1.1
1.1
1.1
1.1
1.1
CH2Cl2
toluene
Et2O
56:44
38:62
65:35
39:61
30:70
10
11
12
13
14
15
25 °C
-20 °C
0 °C
CH3 BF3•OEt2
CH3 BF3•OEt2
CH3 BF3•OEt2
CH3 BF3•OEt2
CHCl3
CHCl3
25 °C
40 °C
We anticipated that reactions mediated by chelatable
metals would be strongly syn selective. To that end, we screened
a range of chelatable metal halides and triflates (Table 3). While
several metal triflates enabled poor to modest anti selectivity,
many chelatable Lewis acids provided good levels of syn
selectivity. Our screen revealed that ZnBr2 afforded a high level
of chelation control consistent with Walsh’s work with α-chloro N-
sulfonyl imines.[20] Our calculations predict a highly organized zinc
chelate structure that is consistent with the high degree of syn
selectivity in analogous additions to both aldehydes and Walsh’s
α-chloro-N-tosyl imines (Figure 3).
t-Bu
N
6
t-Bu
more strongly than the analogous aldehyde, favoring the syn
addition (Figure 2).This result is consistent with a proposed
proton-chelating intermediate in Mann’s three-component
reaction of aldehydes, allyltrimethylsilane, and benzyl
carbamate.[27]
A
temperature screen demonstrated an
unexpected selectivity inversion. With BF3•OEt2, allylTMS added
to imine 1a at –78 °C with high syn selectivity. Increasing the
reaction temperature eroded this selectivity. Substitution of a
higher-reactivity nucleophile (methallylTMS, 1b) instead
produced anti products at low temperature, and we observed
better anti selectivity at higher temperatures. A similar effect has
been reported in chiral N-silyl imines and was attributed to
entropic factors.[28] We suspected that this temperature- and
reactivity-dependent selectivity change could be due to a change
in the dominant reaction mechanism.
Table 3. Chelatable Lewis acid screen.
Lewis acid
temp.
CH2Cl2
Ts
Ts
Ts
H
HN
HN
N
H3C
H3C
TMS
+
+
H3C
OBn
OBn
OBn
1a
3a
9a (syn)
9b (anti)
entry Lewis acid temperature
syn:anti
O
+
0
1
2
3
4
5
6
7
8
9
AlCl3
80:20
77:23
62:38
95:05
31:69
81:19
41:59
48:52
36:64
O
N
S
-78
0
AlCl3
H
CH3
=
O
Sc(OTf)3
ZnBr2
ΔGBinding = –129.9 kcal/mol
Ph
H
-78
0 to rt
-78
0 to rt
-78
0
H3C
Mg(OTf)2
FeCl3
7
Ln(OTf)3
La(OTf)2
Cu(OTf)2
+
H
O
=
O
ΔGBinding = –118.6 kcal/mol
Ph
H
H3C
8
ΔΔGBinding = –11.3 kcal/mol
Figure 2. Proton binding energy differential between imine 7 and aldehyde 8.
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imines,[30] as well as diastereoselective additions to chiral
aldehydes,[31,32] we substituted allylBF3K for allylTMS. Under
standard conditions, with 18-crown-6 added for solubility,
allylBF3K provided anti allyl adducts in good yield and excellent
diastereoselectivity compared to allylTMS (Table 5). With ZnBr2,
allylBF3K and imine 1a did not provide anti selectivity. We surmise
that liberated BF3 outcompetes the sparingly soluble ZnBr2 in the
reaction mixture to favor anti products later in the course of the
reaction, and so we did not attempt additions with the remaining
imines.
O
O
Br
Br
S
Zn
N
CH3
=
O
Ph
H
H3C
truncated 1a–ZnBr2 chelate ΔGBinding = –32.5 kcal/mol
Figure 3. Calculated zinc chelate structure.
In an effort to maximize anti selectivity, we synthesized α-
silyloxy imine 1d. Additions with nucleophiles 3b-d provided anti
products in moderate yield and excellent diastereoselectivity.
Initial attempts to form syn products from imine 1d and alkenes
3a and 3b resulted in poor selectivity, and so we did not attempt
additions with the remaining nucleophiles.
Our preliminary studies formed the basis of a more
expansive study of N-sulfonyl imines and soft nucleophiles (Table
4). Alpha-alkoxy imines 1a, 1b, and 1c reacted with alkenes 3a,
3b, and 3c in the presence of ZnBr2 to afford highly syn-selective
products in moderate to good yield. Anti-selective products were
similarly available when using BF3•OEt2, but selectivity when
forming allyl adducts (9b, 12b, and 15b) was low despite use of
optimal solvent and temperature. An attempt to use allylSnBu3 as
an alternate allylating agent did not result in an appreciable
increase in selectivity compared to 3a, so we explored less
commonly-used allyl nucleophiles. Inspired by Batey’s additions
of allyltrifluoroborates to achiral aldehydes[29] and N-sulfonyl
The stereochemical outcome of these reactions was
established by X-ray crystallography and NMR spectroscopy. The
relative configurations of products 9a, 11a, 13b, 14a, 16a, and
17a were established by X-ray crystallography.
The
stereochemistry for the remaining products were assigned by J-
value or chemical correlation to those determined by X-ray crysta-
Table 4. Reaction scope.
Ts
Ts
Ts
Lewis acid, solvent
nucleophiles 3a–3d
N
HN
HN
R1
R1
R1
+
H
Nu
Nu
temperature
OR2
OR2
OR2
:
syn
anti
1a–1d
conditions
nucleophile
ZnBr2, CH2Cl2, –78 °C
CH3
BF3•OEt2, CHCl3, –20 °C
OTMS
CH3
OTMS
TMS
TMS
BF3K
3d
TMS
Ph
3c
Ph
3c
3a
3b
3b
Ts
N
Ts
Ts
Ts
Ts
Ts
Ts
NH
NH CH3
NH
O
NH
NH CH3
NH
O
H3C
H3C
BnO
H3C
H3C
H3C
BnO
H3C
H3C
H
Ph
Ph
BnO
1a
BnO
10a, 63%
94:06 d.r.
BnO
11a, 91%
>95:05 d.r.
BnO
10b, 70%
10:90 d.r.
BnO
9a, 73%
95:05 d.r.
9b, 86%
11:89 d.r.
11b, 72%
<05:95 d.r.
Ts
Ts
Ts
Ts
Ts
Ts
Ts
H
NH
NH CH3
NH
O
NH
NH CH3
NH
O
N
Ph
Ph
Ph
H3CO
Ph
Ph
Ph
Ph
Ph
Ph
H3CO
12a, 77%
95:05 d.r.
H3CO
13a, 74%
>95:05 d.r.
H3CO
12b, 90%
<05:95 d.r.
H3CO
13b, 78%
15:85 d.r.
H3CO
14b, 61%
05:95 d.r.
H3CO
1b
14a, 50%
>95:05 d.r.
Ts
Ts
Ts
Ts
Ts
Ts
Ts
H
NH
NH CH3
NH
O
NH
NH CH3
NH
O
N
Bn
Bn
BnO
Bn
Bn
Bn
Bn
Bn
Ph
Ph
BnO
BnO
BnO
BnO
BnO
17b, 64%
10:90 d.r.
BnO
1c
15a, 74%
93:07 d.r.
16a, 62%
>95:05 d.r.
17a, 49%
>95:05 d.r.
15b, 78%
08:92 d.r.
16b, 64%
10:90 d.r.
Ts
Ts
Ts
Ts
Ts
Ts
Ts
H
NH
NH CH3
NH
O
NH
NH CH3
NH
O
N
H3C
H3C
H3C
H3C
H3C
H3C
H3C
Ph
Ph
OTBDPS
OTBDPS
19a
73:27 d.r.
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS
1d
18a
54:46 d.r.
20a
n.d.
18b, 72%
<05:95 d.r.
19b, 71%
<05:95 d.r.
20b, 47%
<05:95 d.r.
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Ts
H
Table 5. Increase of anti selectivity with allylBF3K compared to allylTMS.
N
BF3
(2 equiv)
+
H3C
OBn
BF3•OEt2
CHCl3
–20 °C
Ts
H
Ts
Ts
N
HN
HN
ΔG (+25 °C) = 0.0
ΔG (–20 °C) = 0.0
ΔG (–78 °C) = 0.0
R1
R1
R1
+
M
+
OR2
1a-d
OR2
OR2
3a or 3d
syn
anti
F
F
F3B
Ts
Ts
H
F3B
Ts
B
N
syn:anti (3a) yield (3a) syn:anti (3d)
N
yield (3d)
entry imine product
N
O
H3C
H3C
Ph
1
2
3
4
1a
1b
1c
1d
9
30:70
26:74
49:51
31:69
60%
30%
46%
53%
11:89
< 05:95
08:92
86%
90%
78%
72%
H
Ph
H
+
12
15
18
O
Ph
H3C
BF3
+
O
F3B
BF4
21
22
23
< 05:95
ΔG (+25 °C) = –5.4
ΔG (–20 °C) = –6.7
ΔG (–78 °C) = –9.6
ΔG (+25 °C) = –2.3
ΔG (–20 °C) = –3.6
ΔG (–78 °C) = –6.7
ΔG (+25 °C) = –0.8
ΔG (–20 °C) = –4.2
ΔG (–78 °C) = –9.7
-llography. Syn allyl adduct 9a was synthesized in 97% ee from
(–)-L-ethyl lactate (99% ee), confirming minimal erosion of
enantiomeric purity through imine formation and nucleophilic
addition (see supplemental information for complete details).
Figure 4. Energy and distribution of intermediates. Energy in kcal/mol relative
to unbound imine.
Our exploration of scope revealed general guidelines for
these additions. ZnBr2 can reliably be employed to form syn
products using allylsilane and silyl enol ether nucleophiles.
Synthetically useful anti-selectivity is possible, but greater care
must be taken. Trace water in the reaction mixture may react with
the Lewis acid to produce a Brønsted acid, which can be chelated
and erode anti selectivity (see Table 1, entry 7). Additionally, more
nucleophilic alkenes[33] appear to react with higher selectivity;
trifluoroborates are preferable to trimethylsilanes, and more
substitution or electron richness also increases selectivity.
Silyloxy substitution also increases anti selectivity, possibly by the
inactivation of the proton-chelated syn-selective pathway.
We have calculated the free energy barriers from separated
reactants and have included standard state solvation
corrections.[43] See the Supporting Information for full
computational methods.
We first examined the absolute free energies of the three
proposed reactive intermediates. At ambient temperature we
predict that the most common species is the BF2 chelate
intermediate 21, and as the temperature shifts to cryogenic
conditions, both the double BF3 (23) and BF2 chelate (21)
intermediates are equally present. Given relatively low
thermodynamic constraints at –20 and –78 °C, we explored the
kinetic barriers from intermediates 21 and 23 and the syn or anti
products that result. Using B3LYP, we calculated six transition
structures (TS) that correspond to anti and syn additions to these
three intermediates. Our earlier observation of temperature- and
reactivity-dependent selectivity inversion (Table 1) prompted us
to explore the effect of temperature on these calculated transition
states.
With an expanded reaction scope, we sought to determine
the origins of the unexpected selectivity in BF3-mediated reactions.
Several reaction pathways and intermediates seemed possible
(Figure 4). Although we first considered the Felkin-Anh model with
a single BF3 bound to the imine nitrogen as the active intermediate,
we explored other possibilities. Given the optimal amount of BF3
was slightly over one equivalent, we hypothesized that one
equivalent of BF3 could bind to the imine nitrogen while any
excess BF3 could bind to the alkoxy oxygen, similarly to Reetz’s
proposed intermediate for BF3-mediated additions to β-chiral
A
computational exploration of reasonable reactive
intermediates and transition states revealed two competing
pathways (Figure 5). We found that TS’s arising from BF2 chelate
intermediate 21 favored syn additions at cryogenic temperatures
(–20 and –78 °C), while the doubly bound BF3 complex 23 favored
anti additions at all temperatures. TS’s that form from the single
BF3 intermediate 22 exclusively favor anti addition at all
temperatures. The lowest energy anti- and syn-TS originate from
intermediates 21 and 23 at all calculated temperatures, and TS’s
from intermediate 22 are generally higher in energy by up to 12
kcal mol–1 when compared to analogous TS from the other
intermediates. These results indicate that mono-BF3-coordinated
intermediate 22 has a minor role in the mechanism due to being
less favorable formation energy and leading to higher energy TS.
At cryogenic temperatures, syn-selective TS-1 from 21 is 2.6 kcal
mol–1 lower in energy than anti-selective TS-2 from 23. As the
temperature is increased to –20 °C, the free energy difference
between these two TS narrows to 0.6 kcal mol–1 in favor of syn
addition. At ambient temperatures, the anti-selective TS-2 from 23
is 3.2 kcal mol–1 lower in energy than the lowest energy syn-
selective TS which arises from 21.
aldehydes.[34] We also hypothesized
a
disproportionation
mechanism wherein a BF3 bound to an imine nitrogen could lose
-
a fluoride to another BF3, forming BF4 anion and chelated BF2.
While not seen in aldehydes due to their lower Lewis basicity
relative to imines, similar BF2 chelates have been observed and
isolated.[35,36] Furthermore, a similar process has been implicated
in the exceptional chelate-based selectivity observed in Evans’s
additions to aldehydes mediated by Al(CH3)2Cl.[37]
To investigate the mechanism and stereoselectivity we have
used the B3LYP[38,39] density functional, which has previously
been shown to give reasonably accurate free energies and
stereoselectivities for additions of this nature.[40,41] The 6-31G(d)
basis set was used for geometry optimizations, and for heavy
elements (Zn and Br) the LANL2DZ pseudopotential was
utilized.[42] The p-tolSO2 group has been truncated to a H3CSO2
group for computational fidelity. We have performed
a
conformational analysis of the initial imine reactants, BF3-bound
intermediates, and respective syn/anti transition structures, and
herein we report the lowest energy conformers for each species.
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‡
CH3
RO2S
N
O
H
F
B
F
F
F
Ts
Ts
B
H
HN
N
O
TMS
H3C
+
=
Ph
H
TMS
OBn
9a
H3C
ΔΔG‡ (–78 °C) = 2.6 (syn selective)
21
3a
TS-1
F3B
O
Ts
N
high-energy transition states
(unproductive)
TMS
H3C
+
H
Ph
22
3a
‡
TMS
Ts
F3B
Ts
HN
N
O
H
BF3
H3C
TMS
F3B
H3C
+
=
N
H
H
OBn
9b
CH3
O
Ph
RO2S
F3B
ΔΔG‡ (+25 °C) = 3.2 (anti selective)
23
3a
TS-2
entry
TS
ΔG‡ (–78 °C) ΔG‡ (–20 °C) ΔG‡ (+25 °C)
1
2
TS-1
TS-2
18.7
21.3
19.7
20.3
23.5
20.3
Figure 5. Computed reaction kinetics at cryogenic and ambient temperatures. p-tol truncated to CH3 to reduce calculation complexity. Energies in kcal mol-1
relative to separated imine 1a, 3a, and BF3. Methyl hydrogens on TMS hidden for clarity.
Felkin-Anh model, our findings that the monocoordinated imine-
BF3 adduct 22 is unreactive suggest that the model does not fully
These calculated transition state energies correlate well
with observed reaction outcomes in CH2Cl2. At low temperatures,
the reaction mainly proceeds through BF2 chelate intermediate 21
and results in syn selectivity. At higher temperatures, the reaction
proceeds through double BF3 intermediate 23 and results in anti
selectivity. To our surprise, the Felkin-Anh-like pathway arising
from intermediate 22 is unproductive in the reaction. In fact, the
transition states leading to major products appear to correlate to
those proposed in the Cornforth-Evans model, with the imine and
α-substituents arranged as to minimize the dipole of the
intermediate.[9,10] Guided by these computational results, we
describe the underlying reactivity of systems other than additions
to chiral carbonyl compounds. Other reactions that include
substrates with multiple strong Lewis basic sites may also form
similar BF2 chelates that could lead to unexpected reactivity.
Further investigation into the reactions of BF3 and its Lewis base
adducts are required.
In conclusion, we have demonstrated a practical method in
achieving acyclic stereocontrol in the addition of nucleophilic
alkenes to α-chiral N-sulfonyl imines. We developed
a
hypothesized that additional BF3•OEt2 would not have
a
mechanistic rationale for the diastereoselectivity that is
comparable to additions to analogous chiral carbonyl compounds.
While syn-selective reactions can be favored using Cram
chelation control, anti-selective reactions are not as
straightforward. Computational evidence revealed an unexpected
mode of reactivity compared to the commonly-understood
monocoordinating nature of BF3 as a Lewis acid. These
considerations were crucial in anti-selective reaction optimization.
Because the Polar Felkin-Anh model does not account for these
deviations in reactivity, care must be taken in in its application to
systems other than additions to chiral carbonyl compounds.
Furthermore, nucleophilic additions using BF3 as a Lewis acid
mediator that produce unexpected diastereoselectivity should be
reevaluated. Further applications of these methods to construct
highly stereochemically complex products are under development.
detrimental effect on the diastereoselectivity of the reaction, as
any potential BF2 chelate intermediate would be in equilibrium
with the doubly-bound BF3 intermediate. To that end, we
reattempted several somewhat low-yielding reactions with 2
equivalents of BF3•OEt2 and found that yields increased while
diastereoselectivity was unchanged.
The reactivity of doubly-BF3-bound imine 21 and BF2
chelate 23 hints at implications beyond the direct scope of this
investigation. The syn-selective nucleophilic additions to other
chiral imines using BF3•OEt2 at low temperature may have been
due to a chelated BF2 intermediate similar to 23.[25,26] Additionally,
although anti-selective additions to other chiral imines are
reported to be consistent with predictions made using the Polar
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10.1002/chem.201902790
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Conflict of Interest
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Acknowledgements
This work was supported by a grant from the National Science
Foundation (CHE-1414298 and CHE-1765409-0). L.C.M.
acknowledges support from UC Davis in the form of a Bradford
Borge Fellowship. J.S.F. acknowledges the computational
resources provided by UCLA Institute for Digital Research and
Education and the National Science Foundation through XSEDE
Science Gateways Program (TG-CHE040013N). J.M. thanks UC
Davis for providing a Provost’s Undergraduate Fellowship (PUF).
B.E.R. acknowledges support from the National Science
Foundation REU Program (CHE-1560479). K.N.H. acknowledges
support from the National Science Foundation (CHE-1764328).
We thank Austin Kelly (Franz group, UC Davis) for providing
assistance with HPLC traces. We thank the National Science
Foundation (Grant CHE-1531193) for the dual source X-ray
diffractometer.
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Keywords: ab initio calculations • allylation • diastereoselectivity
• Lewis acids • reaction mechanism
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Lucas C. Moore, Anna Lo, Jason S. Fell,
Matthew R. Duong, Jose A. Moreno,
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Olmstead, Kendall N. Houk,* and Jared
T. Shaw*
Ts
R3
HN
up to >95:5 dr (syn)
with ZnBr2, M = TMS
R
R
Y
Y
Ts
H
R3
N
OR1
HN
Lewis acid
M
R1
+
Y
Ts
R3
OR2
up to >95:5 dr (anti)
with BF3•OEt2, M = BF3K
Page No. – Page No.
OR1
Acyclic Stereocontrol in the
Additions of Nucleophilic Alkenes to
α-Chiral N-Sulfonyl Imines
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